Note: Descriptions are shown in the official language in which they were submitted.
DEI\/IANDES OU BREVETS VOL,UMINEUX
LA PRÉSENTE PARTIE DE CETTE DEMANDE OU CE BREVET
COMPREND PLUS D'UN TOME.
CECI EST LE TOME / DE
.
''~
NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des
::
brevets
:
~ S 5 ~1
::
. ~ ~ ~
. -:-~
JUMBO APPLICATIONS/PATENTS
.
.. , ~
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE `: :
THAN ONE VOLUME
THIS IS VOLUME OF Z--
'...'''
NOTE: For addltlonal volume~ plea~e contact the Canadian Patent Offlce . : :
. ~'','-.
105~99~
Tbis invention relates to penam derivatives and
preparation thereof.
The invention particularly relate~ to novel anti-
bacterial penam agents which are of value as animal feed
supplements, as therapeutic agents for the control of in-
fectious diseases caused by gram-positive and gram-negative
bacteria, and for the sterilization of ho~pital surfaces
and the like; and to novel intermediates for their produc-
tion. More specifically, the antibacterial compounds of
the instant inventlon are derivatives of 6-a ino-2,2-
dimethyl-penam, which also bear a S-tetrazolyl group or
certain l- or 2-substituted 5-tetrazolyl groups at the 3- `
position of the penam nucleus.
In spite of the large number of penam derivatives
which have been proposed for use as antibdcteridl agents,
there still exists a need for new agents.
,:
United States Patents 3,427,302 and 3,468,874 ~-
disclose penam~derivaeives which incorporate a tetrazolyl
group~as part of the~6-acylamino substituent; however, the
compounds of the lnstant 1nvention are unique in having a
tetraso1yl groUp bonded~direatly to the Qenam nua1eu~.
The vast ma~ority o~ penam compounds ai~cloi3ed in
,
th- prior are have~a carboxyllc acid group (or a s-lt
thereof~ attached~to the 3-posit10n. Ho~ ver, penam com-
25 ~pounds with other carboxy11a acld derivatives at the C-3
~.o~9~
locuq are also known. P~am~-carl~lic ac.~ e~t~r~ have be~n
disclosed, for example, by Kirchner et al., Journa.l oE
Organic Chemistry, 14, 3~8 (1949); Carpenter, Journ~1 of
the American Chemical Socie~y, 70, 29S4 (194S); Johnson,
S Journal of he .~merican Chemical Society, 75, 3636 ~1953);
Barnden et al., Journal of the Chemical Society (London),
3733 (1953) and Jansen and Russell, Journal cf the -
Chemical Society (I,ondon), 2127 (1965); and penam-3-carbox-
amides have been reported, for example, by Holysz and -
Stavely, Journal of the American Chemical Society, 72,
.:
4760 (1950) and Huang et al., Antimicrobial Agents and ``
_ _ .
Chemotherapy, 493 (1963). Peron et al., (Journal _f
Medicinal Chemistry, 7, 483 tl9643) prepared-several 6-
(substituted aminoj-2,2-dimethyl-penam-3-carboxylic acid ~ -
1~ azides, which were subsequently converted into the corre-
sponding 3-isocyanates and 3-~enzylcarbamates. Peron et
al., (loc. cit.~ also reported certain 3-(hydroxymethyl)-
penam derivatives. Dekydration of the simple amide of
benzylpenicillin yields the corresponding n trile
(Khoskhlov et al., Doklady Akad. Sci. Nauk S.S.S~R., 135,
875 tl960]). Generally, opinion in the art has been that
modification of the 3-position would be unlikely to give
improved results.
The invention provides a novel 6-amino or 6-sub-
stituted amino-2,2-dimethylpenam derivative having a 5-
tetrazolyl or substituted tetrazolyl group in the 3-posi-
tion of the penam structure.
Thus th~ invention ~rovides a met~od o~ prepa~ing
a pen~ derivative oL ~ormula.
-3- `
.
~os9g9z
RX--f ~C 3
LNI~ H3
RY
or the salts thereof,
wherein Rx is amino or substituted amino, which
substituted amino group is
R1-NH or (R )'-NH-
and Ry is a tetrazolyl group, which is
C ~ N C ~ ~
R
wherein R or R is hydrogen, trialkylsilyl having from
one to four carbon atoms in each of said alkyl groups,
alkanoy~loxymethyl~ having from three to eight carbon atoms,
l-(alkanoyloxy)ethyl having from four to nine carbon atoms, ~
phthalidyl or a tetrazolylpenam nitrogen protecting group .
removable from a specific aompound of said formula;
: R is an acyl group of an organic carboxylic
acid; and (R ) is an amino protecting group for a specific
compound of said formula;
wherein there is included in said method at
~least one of the step of
(a) acylatlng the amlno group in a compound of the
formula
CH3 ::
N~ R
~' ', .
` -: ' ', ' '
10S~99'~ ,
by reaction with an acid of the formula
R7 ~ CH ~ ~ OH
L 1 ~ n
wherein R is selected from the group consisting of
hydrogen, alkyl having from one to twelve carbon atoms,
alkenyl having from two to twelve carbon atoms, cycloalkyl -
having from three to seven carbon atoms, cycloalkenyl
having from five to eight carbon atoms, cycloheptatrienyl,
1,4-cyclohexadienyl, l-aminocycloalkyl having from four to .
seven carbon atoms, cyanomethyl, 5-methyl-3-phenyl-4- :
isoxazolyl, 5-methyl-3-(o-chlorophenyl)-4-isoxazolyl, 5-
methyl-3-~2,6-dichlorophenyl)-4-isaxazolyl, 5-methyl-3-(2- ;
chloro-6-fluorophenyl)-4-isoxazolyl, 2-alkoxy-1-naphthyl
having from one to four carbon atoms in said alkoxy,
phenyl, phenoxy, phenylthio, pyridylthio, benzyl,
lS sydnonyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl,
pyrimidinyl, tetrazolyl, triazolyl, imidazolyl, pyrazolyl,::
substituted phenyl, substituted phenoxy, substituted .
phenylthio, substituted pyridylthio, substituted benzyI,
subotituted thienyl, substituted fury}, substituted - ;
pyridyl, cubstituted tetrazolyl, substituted thiazolyl,
sub~tituted isothiazolyl, substituted pyrimidinyl, sub- -:
s-tltuted triazolyl, substltUted imidazolyl and substituted
pyrazolyl each substltUted moiety belng sUbstituted by up
: to two member9 9elected from the group consisting of
: 25 ~fluoro, chloro, bromo, hydroxy, hydroxymethyl, amino, N,N-
diaIkylamino having from one to four carbon atom~ in each
of said alkyl groups, alkyl having from one to four carbon
atoms., aminomethyl, alkoxy having from one to four carbon
4a-
,
1~5999'~
atoms, alkylthio having from one to our carbon atom~, 2-
aminoethoxy and N-alkylamino having from one to four
carbon atoms;
Q is selected from the group consisting of
hydrogen, alkyl having from one to six carbon atoms,
hydroxy, azido, carboxy, sulfo, carbamoyl, phenoxycarbonyl,
indanyloxycarbonyl, sulfoamino, aminomethyl, amino and
NH-(CO-CH2-NH)m-CO-Z;
wherein Z is selected from the group consisting
of alkyl having from one to six carbon atoms, phenyl, sub-
stituted phenyl, furyl, thienyl, pyridyl, pyrrolyl, amino,
N-alkylamino having from one to six carbon atoms, anilino,
substituted anilino, guanidino, acylamino havinq from two
to seven carbon atoms, benzamido, substituted benzamido,
thiop~enecarboxamido, furancarboxamido, pyridinecarbox-
amido, aminomethyl, guanidinomethyl, alkanecarboxamidino-
methyl having from three to eight carbon atoms, benzamidino- :
methyl, (substituted benzamidino)methyl, thiophenecarbox-
amidinomethyl, furancarboxamidinomethyl, pyridinecarbox-
amidinomethyl, pyrrolecarboxamidinomethyl and 2-benz-. ~.:
imidazolecarboxami~inome~hyl, each substituted moiety
being substituted by up to two members selected from the
group consisting of fluor~, chloro, bromo, iodo, alkyl
having from one to four carbon atoms, alkoxy having from
5 one to four carbon atoms, sulfamyl, carbamoyl and cyano7
and n is 0 or 1, or an acid halide, a mixed
anhydride or an active ester thereof, in the case where
the acid itself is employed the reaction being carried out
in the presence of a known coupling agent and when n is 1
0 and Q is -NH-(CO-CH2-NH)m-CO-Z; opti~nally effecting the
-4b-
lOSg~9'~
conversion in two stages, first effecting the above
acylation with an acid of the above formula wherein n is 1
and Q is NH2 or the acid halide, mixed anhydride or
activated ester thereof and subsequently effecting a
further acylation with an acid of the formula Z-CO-(NH-
CH2-CO) -OH or an acid halide, mixed anhydride or activated
ester thereof, in the case where the acid itself is
employed, the reaction being carried out in the presence .
of a known coupling agent or by reaction with an appro-
priate isocyanate, isothiocyanate or imidate; or .
(b) converting the COOH group in a compound of the
formula
(R )'NH
S~y~CH3
H3
~ OOH
into the group R by .
(a) converting a -COOH group at 3-position of a
precursor into a group Ry by (i) first forming an amide
group of formula -C(=O)-NH(R )' by coupling the COOH with
an amine of the formula NH2CH2CH2-Y or NH2(R6)' or by
reaction with an isocyanate of the formula O=C=N-C(=O)-
O-R or O=C=N-S(02)-0-R wherein Y is selected from the
group consisting of cyano, alkoxycarbonyl having from two
to seven carbon atoms, phenoxycarbonyl, alkylsul~onyl
havlng from one to six carbon atomq, phenylsulfonyl and
-So2-NRl5Rl6 are each selected from the group consisting
:~ 25 of hydrogen, alkyl havlng from one to four carbon atoms,
~ benzyl and phenyl;
: R 4 is selected from the group consisting of
.: '
,
lOS~99;~
alkyl having Erom one to six carbon atoms, benzyl, phenyl
and phenyl substituted by up to two moietie~ selected
from the group conisting of nitro, fluoro, chloro, bron;o,
alkyl having from one to four carbon atoms and alkoxy
having from one to four carbon atoms;
and (R )' is selected from the group consisting
of ~ R4 . -
17
-CH R20
Rl g ILII
wherein R and R are each selected from the group con-
sisting of hydrogen, hydroxy, nitro, fluoro, chloro,
bromo, iodo, alkyl having from one to six carbon atoms,
alkoxy having from one to six carbon atoms, alkanoyloxy
having from two to seven carbon atoms, formyloxy, alkoxy-
methoxy having from two to seven carbon atoms, phenyl and .
benzyloxy;
R18 is selected from the group consisting of
hydrogen, alkyl having from one to four carbon atoms and
phenyl;
Rl9 and R are selected from the group censist-
ing of hydrogen and methyl; :~
and X is selected from the group consisting of
oxygen and sulfur; ~ii) converting the -C(=0)-NH-(R2)'
group into a group of the formula -C(Cl)-N-(R2)' by
reaction with thionyl chloride, phosphorus pentachloride
or phosgene in the presence of at least one mole of a --.
tertiary amine and (iii) converting the -C(Cl)-N-(R )'
g9;~'
group into a tetrazolyl group by reaction with an azide.
The invention will be particularLy illustrated in
relation to certain preferred compounds where Rn is an
acylated amino group and these compounds are those of
formulae
Rl-NH S CH3 - --~
~C/i~
N N . -
1R2/ I
R -NH / S ~ ~ CH3
~ ~ CH3
\C~
N N
\ R3 II
-4e-
~U5~99;~
and the salts thereo~;
wherein Rl is an acyl moiety of an organlc carb-
oxyllc acid;
R2 i9 selected ~rom the group consisting of hydro-
gen, trialkylsllyl having from one to four carbon atoms in
each of said alkyl groups, alkanoyloxymethyl having from ~ -
three to eight carbon atoms, 1-(alkanoyloxy)ethyl having -
from four to nine carbon atoms, phthalidyl and a tetrazolyl- -
penam nltrogen protecting group, the nature of which is to
be deflned hereinafter,
and R3 is selected from the group consisting
hydrogen, trialkylsilyl having from one to four carbon atoms
in each o~ the said alkyl groups and alkanoyloxymethyl having
from three to eight carbon atoms, l-(alkanoyloxy)ethyl having
from ~our to nlne carbon atoms and phthalidyl.
Other structures on the amino group are avallable. -~
In chooslng the appropriate substitute amino structure,
structures whlch are found to be of use in other forms o~
penicillln would appear to be also actlve with the tetrazolyl
~ubstituent at the 3-position. Thus, although the present
lnvention partlcularly illustrated by the acyl substituent,
other substituents can be used as wlll be illustrated later. ~`~
As intermediates there are partlcularly valuable
the stru¢tures ln whlch Rn i9 amino or amino substituted ;~-~
wlth an amino protectlng group as hereina~ter de~lned and ~ `
alternatlvely or ln addltlon R2 or R3 i9 trialkylsilyl havlng
~rom 1 to 4 carbon atoms ln each alkyl group or R2 ls a tetr- ;-;-
- azolyl penam nltrogen protectlng group.
Partlcularly deslrable penam compounds o~ the
present lnventlon, by virtuè of their hlgh activity against `-
; " . , , . . : ~
' '' ~": ', -
"
105~9;~
a wide range o~ pathogenic bacteria, are those compound~ of
Formulae I and II, wherein R2 and R3 are each hydrogen and
Rl i9 a mono- or di-substituted acetyl group, such as, for
example, 2-arylacetyl, 2-amino-2-arylacetyl and 2-(substi-
tuted amino)-2-arylacetyl.
Particularly indicated as intermediates are those
of formulae: :
R5-NH S CH3
~ y C 3 :
C~
N N .
R~ ... III
R5-NH S CH
~ ~ 3
O N ~ ~ :
C~
N N~ R3 --I
and the salts thereof;
wherein R5 is selected from the group consisting :
. ..
of hydrogen, trialkylsilyl having from one to four carbon
atoms in each of the said alkyl groups and an amino protec~
ting group, the nature of which ls to be defined later; ~.
and R2 and R3 are as previously defined ~ .
The compounds of Formulae III and IV, whereln R2, - .
R3 and R5 are each selected from the group consisting of :"
hydrogen and trlalkylsilyl having from one to four carbon
atoms in each of said alkyl groups are especially valuable
for the preparation of the novel penam compounds of Formulae ` :
I and II. .
-6~
,,, ~,, ',
: .:
,.,
._, .,., .. . , .. . , , .,. , .. . . . . . .. ,.. .. .. , . . ... , ., . . . ~ . .
lOS~t~9~
The term "amino protecting group" encompa~ses
those groups which protect the amino group on the 6-posltlon
of the penam ring system durlng synthesis of the ba~lc ~truc-
ture, and partlcularly during the synthesis of the tetrazole
rlng; and it is a necessary requirement of such groups that
they can be removed easily before or after acylation of the
nitrogen atom to which they are attached. In the specific - ~
embodiment of the invention the term is intended to contem- -
plate all protecting groups known, or obvious, to one with
ordinary skill in the art, which will (a) permit synthesis
of the ~compounds of Formula III, wherein R5 is protected
amino and R2 is a tetrazolylpenam nitrogen protecting group;
and (b) can be removed from a compound of Formula III, `^~ `
wherein R2 is selected ~rom the group consisting of hydrogen
and a tetrazolylpenam nitrogen protecting group, using con- ~
dltions wherein the penam ring system remains substantially -
intact. Thus, when R5 is an amino protecting group, it can
represent any group which will effectively protect the 6- ` -; -~
amino moiety of 6-amino-penicillanic acid, during the process -
to be described in detail later in this specificatlon for
the conversion o~ 6-(protected amino) penicillanic acid into
the said compounds o~ Formula III, and is removable under
condltions which do not destroy the penam ring system. There
are situations, however, wherein a group can be regarded as
an amino prote¢ting group, when it (a) oan be attaohed to the i
amino group at the o-6 position of the tetrazolylpenam ring
system; (b) will then permit aoylatlon of the C-6 amino group; ` -
and (c) can then be removed from the nltrogen atom to which
P it is attached. Specific examples of amino protecting groups
of each type are triphenylmethyl and trialkylsilyl, respec- ` --
: ~ ''`''''." --`' ;''
', ,'. '- '.,'- '
,, ~:.,''`,'.. -.:
:
... , . , ,, ,, ~ ,, , I ~
l()S~99'~
tively. However, all such groups of both types are to be
considered with the scope of this invention. The exact
chemical structure of the amino protecting group i9 no'
critical to the invention, since its importance resides in
its ability to perform in the above-described manner. Iden-
tification and selection of individual groups which can be
used will be readily accomplished by one skilled in the art,
and the nature of the group chosen does not affect the
novelty of the antibacterial agents of this invention in
any way. Additional examples of groups which can be used
as amino protecting groups for the purposes of this inven-
tion are enumerated hereinafter.
In like manner, the term "tetrazolylpenam nitrogen
protecting group" is intended in the most general sense to
cover those groups which protect the tetrazole ring during
or after formation thereof, and can encompass a group such
as traialkylsilyl or triphenylmethyl which can be attached to
the tetrazole ring during for example acylation of the amino
substituent at the 6-position. In the specific and preferred
embodiment of the invention, however, this term is intended
to connote all groups known, or obvious, to one skilled in
the art, which can ke used (a) to permit the synthesis of
the compounds of Formula III, wherein R is an aminoprotect-
ing group and R is the said tetrazolylpenam nitrogen pro-
tecting group, by the process starting with 6-~protected
amino~penicillanic acid described hereinafter7 and ~b) can
be removed from a~compound of Formula I, wherein Rl is an
acyl group and R is the said tetrazolylpenam nitrogen pro-
tecting group, or from a compound of Formula III, wherein R
is selected from the group consisting of hydrogen and a~n~amino
~ .
-8-
.. --,
1(~5~9g'~
protecting group, and R2 19 the said tetrazolylpenam nitro-
gen protecting group, using a method wherein the penam ring
system remains substantially lntact. The tetrazolylpenam
nitrogen protecting group is required in order to protect
the nitrogen atom which ultimately becomes N-l of the tetr-
azole ring ln the said compounds o~ Formulae I and III,
during the conversion of a 6-(protected`amino)penicillanic
acid into a comp~und of Formula III. It is likewise the
ability of the tetrazolylpenam protecting group to per~orm
a specific function, to be discussed in more detail herein- ;
, . . .
after, rather than its precise chemical structure, which is --
. -
important, and the novelty of the antibacterial agents of the `~invention does not depend upon the structure of the protec-
ting group. Selection and identification of appropriate pro- -
tecting groups can be made readily and easily by one skilled -
in the art, and examples of several applicable groups are ~ -
given hereinafter.
~he invention also includes the production of penam -
derivatives wherein a carboxyl group at the 3-position is
converted into the tetrazolyl ring. Where the structure of
the substituted amino group permits such conversion could ` -
. .
directly prepare an active compound but in the most usual ;~ -~
instance, particularly for acyl structures, the conversion
from the carboxyl ring to the tetrazolyl ring will be effect- :
:: ..: - - .
ed prior to atta¢hing an aotive group to the nltrogen on the -
6-posltlon. ~hus, for lnstance, a tetrazolyl group oan be ~ ~
~ormed then a ~ree amino group at the 6-posltion whloh oan ~ -
.. . :.: :-: :
then be acylated. The partiaular cholce of sequence ls of ;
¢ourse dependent on the groups involved but would offer no
problem to one skilled ln the art from a knowledge of the
_g_ ",.,.'. ' .':
.' :',~`.::
, . - .. . ..
l~)S~5'9;~
stability of the groups in question and the proces6es to
be applied.
Thus, there is particularly provided a proces~
for the production of a compound of Formula I or II, whlch
comprises acylatin~ a compound of Formula III or IV, whereln
R5 is selected from the group consisting of hydrogen and
trialkylsilyl having from one to four carbon atoms in each
of said alkyl groups, and R2 and R3 are as previously de~
fined. ; -~
A particular process is for the intermediates of
Formula III, wherein R5 is a protected amino group and R2 ,;
. - . - . . .
is a tetrazolylpenam nitrogen protecting group, which com-
prises the novel sequence of: (a) converting a 6-(protected
amino)penicillanic acid into an amide of formula:
(R5)'-NH S ~ 3
0 ~ ~ ~ C-NH~
O ; -, .
(b) contacting the said amide w1th an imidoyl halide form- ~ -
ing agent, in the presence of a tertiary amine; and (c) con- -
tacting the so-produced imidoyl halide with a source of
azide ion; wherein (R5)' is an amino protecting group and
. .
1s a tetrazolylpenam nitrogen protecting group or a group
which is readlly convertlble to a tetrazolylpenam nitrogen
protecting group during or after the lnstant pro¢ess.
me novel lntermedlates so produoed are used to
prepare the penam compounds of Formulae I and II by methods
: . . .
to be dlscussed in detail hereinafter. ; :;
Alternatlve techniques for conversion of a carb-
oxy group to a tetrazolyl group are visualizable. ~
-10 ,,",~,,
,
: , ,
lQ5~99'~
From another polnt of view in the pre~erred embodi-
ments of the invention the invention may be regarded as lylng
in taklng the tetrazolyl derivative with an amino or protect-
ed amino group on the 6-position and converting to the acyl
group. Before or after acylation the tetrazolyl penam pro- ~ ~
tective group can be removed and correspondingly the alkanoyl- ~ - -
oxyalkyl group substituent for Rl or R2 can be attached before
or after acylation.
A further additional ob~ect of this invention is -~
to provide a method for the treatment and prevention of in~
fectious diseases caused by gram-positive and gram-negative
bacteria; for the topical control of bacteria on human
.. .i..:: ~ ~ .
tissue, hospital surfaces and the llke; and for the supple-
mentation of animal feeds; which comprises utilizing an
effective amount of compound of Formula I or II, or a salt
thereof, wherein Rl is an acyl group and R2 and R3 are each
selected from the group con8isting of hydrogen, alkanoyloxy~
.-. ^ ^ .. ... .
methyl havlng from three to eight carbon atoms, l-(alkanoyl- ; `
oxy)ethyl havlng from four to nine carbon atoms and phthalidyl.
For the s~ake of convenience the compounds of the ` -~
invention are identified as derivatives of "penam", whlch has
been deflned by Sheehan et al., in the J~ur~al o~ h~ Ame.ican ,`
Chemlcal Societyj~75, 3293 (1953), as referrlng to the struo-
... .. .
tUre: `
.i '~
~ 2 .
Although the term penam does not normally carry any stereo-
chemlcal lmpllcatlons, the stereochemlstry of the penam com-
, ~ , :
~ pounds of the inst:ant invention corresponds to that found ln
--11-- .. .
: ..-
"- ~ . ,':''
lOS~g9;~
the naturally-occurring penicillins. Using this terminology,
the well-known antibiotic penicillin G tbenzYlPenicillin) i~
designated as 6-(2-phenylacetamido)-2,2-dimethylpenam-~-carb-
oxylic acid.
Many of the compounds of this invention are also
5-substituted tetrazoles, and 5-substituted tetrazoles ean
exist in two isomeri~c forms, viz: R2 ~ -
As will be appreciated by one skilled in the art, when the
substituent R is hydrogen, the two forms eo-exist in a
dynamic, tautomerie, equilibrium mixture. However, in the
ease where R is a substituent other than hydrogen, the two
forms represent different ehemical entities, whieh do not , --
spontaneously interconvert.
The preferred antibaeterial agents of this inven-
tion are the compounds of Formulae I and II, and the salts
thereof, wherein R is an acyl moiety of an organic earb- -
oxylic aeid, and R and R are eaeh seleeted from the group
eonsisting of hydrogen, alkanoyloxymethyl having from three
to eight earbon atoms, l-(alkanoyloxy~ethyl having from four ~
to nine earbon atoms and phthalidyl. The possession of anti- ---
bae*erial properties by the said compounds of Formulae I and
II is not predieated upon the seleetion of the aeyl sub-
stituent R . Indeed, any aayl moiety of any carboxylic acid
ean serve as Rl, and all the eompounds of Formulae I and II,
wherein R and R are eaeh seleeted from the group consisting
o~ hydrogen, alkanoyloxymethyl having from three to eight
-12-
,
1055~9~Z :
carbon atoms, 1-(alkanoyloxy)ethyl having from four to nine
carbon atoms and phthalidyl, which bear an acyl group at R1,
have useful antibacterial properties. The carboxyllc acld
from whlch the acyl group i8 derived can be a mono- or poly-
carboxylic aci~. Included within the scope of "acyl" arethe acyl moieties of carboxylic acids which themselves can~
not be isolated, but which nonetheless exist in the form of ::q- :
their esters, amides acid chlorides, etc.
However, a particularly favorable configuration of
the acyl moiety is: -
H 0 ~. .
R7 C C~
. :: :
Q ... V : ~:.:: :-
_ _ n .
. ... ~ . : . - ..
wherein n is 0 or 1; .: .
R7 is selected from the group consisting of hydro- ;; :.. - -~
gen, alkyl having from one to twelve carbon atoms, alkenyl .. ~ .
having ~rom two to twelve carbon atoms, cycloalkyl having ~;- .
from three to seven carbon atoms, cycloalkenyl having from ;. ~
five to eight carbon atoms, cycloheptatrienyl, 1,4-cyclo- .:.-;- .
hexadienyl, l-amino-cycloalkyl having ~rom ~our to seven
carbon atoms, cyanomethyl, 5-methyl-3-phenyl-4-isoxazolyl,
5-methyl-3-(o-chlorophenyl)-4-isoxazolyl, 5-methyl-3-(2,6- .
dichlorophenyl~-4-isoxazolyl, 5-methyl-3-(2-chloro-6-rluoro- .
phenyl)-4-isoxazolyl, 2-alkoxy-1-naphthyl havin~ ~rom one to
~our carbon atOms in said alkoxy, phenyl, phenoxy, phenyl- ~ .
thio, pyridylthio, benzyl, sydnonyl, thienyl, ~uryl, pyrldyl, ~ -.
thiazolyl, isothiazolyl, pyrimidinyl, tetrazolyl, triazolyl,
:: imidazolyl, pyrazolyl, substituted phenyl, substituted :
phenoxy, substituted phenylthio, substituted pyridylthio, ~-
-13-
:. .'
'', '.'~`'''
........ . ...
lOS~9g;~ ,
substituted benzyl, substituted thienyl, sub~tituted furyl,
substituted pyridyl, substituted tetrazolyl, substituted :
thiazolyl, substituted isothiazolyl, substituted pyrimldinyl,
substituted triazolyl, substituted imidazolyl and substituted
pyrazolyl, each substituted moiety being substituted by up :
to two members selected from the group consisting of fluoro,
chloro, bromo, hydroxy, hydroxymethyl, amino, N,N-dialkyl-
amino having ~rom one to four carbon atoms in each of said ~ .
alkyl groups, alkyl having from one to four carbon atoms, . :~ -
aminomethyl, aminoethyl, alkoxy having from one to four -
carbon atoms, alkylthlo having from one to four carbon . ~ . -
atoms, 2-aminoethoxy and N-alkylamino having from one to four
carbon atoms,
and Q is selected from the group consisting of : . .
hydrogen, alkyl having from one to six carbon atoms, hydroxy, .
azido, carboxy, sulfo, carbamoyl, phenoxycarbonyl, indanyl- - -
~, .
oxycarbonyl, sulfoamino, aminomethyl, amino and ;;~
NH-(CO-CH2-NH)m-CO-Z; , ,., ~ .. ~.,,
wherein Z is selected from the group conslsting of
alkyl having from one to six carbon atoms, phenyl, substituted
phenyl, furyl, thienyl, pyridyl, pyrrolyl, amino, N-alkyl-
amino having from one to six carbon atoms, anilino, substi- ~ .
tuted anilino, guanidino, aoylamino having from two to seven
carbon atoms, benzamido, substituted benzamido, thiophene- `
oarboxamldo, ~uranoarboxamido, pyridineoarboxamid~, amino-
methyl, ~uanidinomethyl, alkaneoarboxamidinomethyl having .
from three to eight carbon atoms, benzamidlnomethyl, (sub- -
stituted benzamldino)methyl, thiopheneoarboxamldinomethyl,
~: ~uranoarboxamidinomethyl, pyridinecarboxamidinomethyl, -
pyrrolecarboxamldinomethyl and 2-benzlmldazolecarboxamldlno-
-14-
, ':. .:
.
105~9gZ : '
methyl, eaoh substituted moiety being suhstituted by up to
two members selected ~rom the group consisting of ~luoro,
chloro, bromo, iodo, alkyl havlng from one to ~our carbon
atoms, alkoxy having from one to ~our carbon atoms, sulfamyl,
carbamoyl and cyano;
and m is 0 or 1,
provided that when R7 is l-aminocycloalkyl, n is 0; ~
and provided that when R7 is selected from the group ;
consisting of phenoxy, phenylthio, pyridylthio, substituted -
phenoxy, substituted phenylthio and substituted pyridylthio - ~ -
and n is 1, Q is selected from the group consisting of hydro-
gen, alkyl having from one to six carbon atoms, carboxy,
sulfo, carbamoyl, phenoxycarbonyi, substituted phenoxycarbonyl,
indanyloxycarbonyl and aminomethyl.
Particularly useful antibacterial agents o~ the
instant invention are the compounds of Formulae I and II,
wherein R2 and R3 are each hydrogen and Rl is of Formula V, ~ -
wherein n is 1 and R7 is selected from the group consisting ~ `
.: .. ' :.
of phenyl, phenoxy, substituted phenyl and substituted phenoxy.
Especially valuable members of this series of
compounds are the compounds of Formulae I and II, wherein R2
and R3 are each hydrogen and R1 is of Formula V, wherein n
is 1, R7 is selected from the group consisting of phenyl,
phenoxy, substituted phenyl and substituted phenoxy and Q is
hydrogen.
Further especially valuable members of this series
are the compounds of Formulae I and II, wherein R and R3
are each hydrogen and Rl is of Formula V, wherein n is 1,
R7 is selected from the group consisting of phenyl and sub-
stituted phenyl and Q is amino.
-15-
.' ', .
,' .. . ' ~
' ~:
.'' `.' ~:~ -
1(~55'99~
Still further especially valuable members of this
ser-ies are the compounds of Formulae I and II, wherein R2
and R3 are each hydrogen and Rl is of Formula V, wherein n
is 1, R7 is selected from the group consisting of phenyl
and substituted phenyl and Q is NH-(C0-CH2-NH)m-C0-Z. The
preferred value for m is 0, and preferred values for Z are
benzamido, substituted benzamido, thiophenecarboxamido,
furancarboxamido, pyridinecarboxamido, aminomethyl, benz-
amidinomethyl, (substituted benzamidino)methyl, thiophene~
carboxamidinomethyl, pyridinecarboxamidinomethyl and 2-
benzimidazolecarboxamidinomethyl. ~.
In like manner, there is a second series of parti-
cularly useful antibacterial agents of this invention, which
is the compounds of Formulae I and II, wherein R2 and R3 are
each hydrogen and Rl is of Formula V, wherein n is 1 and R7
is selected from the group consisting of sydnonyl, thienyl,
furyl, pyridyl, thlazolyl, isothiazolyl, pyrimidinyl, tetra- -
zolyl, triazolyl, imidazolyl and pyrazolyl, each of which ~
can be substituted as indicated hereinbefore. Preferred -
heteroaryl groups are thienyl, furyl and isothiazolyl.
Within this second series of compounds of Formulae
I and II, especially valuable sub-series are those in which
Q is hydrogen, those in which Q is amino and those in which
Q is NH-(C0-CH2NH)m-C0-Z. The preferred value for m is 0,
and preferred values for Z are those listed above.
Compounds of the instant invention which are ex- ; i
tremely valuable are:
6-(2-phenylaoetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,
. :. .
6-(2-phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)-
penam,
~ -16- ;~
~' ~,'-''".
1Ct55~5~9'~
6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetra-
zolyl)penam,
6-(D-2-amino-2-[~-hydroxyphenyl]acetamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam, ~
6-(D-2-amino-2-~3-chloro-4-hydroxyphenyl]acetamido)-2,2- :.... - .
dimethyl-3-(5-tetrazolyl)penam, -
6-(D-2-amino-2-[2-thienyl~acetamido)-2,2-dimethyl-3-(5- - ~ -
tetrazolyl)penam, . ~ . - -
6-(D-2-amino-2-~3-thienyl]acetamido)-2,2-dimethyl-3-(5- : .
tetrazolyl)penam, ~
6-(D-2-[2-aminoacetamido]-2-phenylacetamido)-2,2-dlmeth- . ..~....
yl-3-(5-tetrazolyl)penam,
5-(D-2-[2-aminoacetamido}-2-[4-hydroxyphenyl~acetamido)- . -
2,2-dimethyl-3-(5-tetrazolyl)penam,
6-(D-2-[2-aminoacetamido]-2-[2-thienyl]acetamido)-2,2
dimethyl-3-(5-tetrazolyl)penam, .
6-(D-2-[2-aminoacetamido]-2-[3-thienyl]acetamldo)-2,2- ~ : .
dimethyl-3-(5-tetrazolyl)penam,
:~ 6-(2-[o-(aminomethyl)phenyl]acetamido)-2,2-dimethyl-3- : :i
(5-tetrazolyl)penam,
6-(D-2-[2-(4-pyridinecarboxamidino)acetamldo]-2-phenyl- .
acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, and . ~:
6-tD-2-[2-(3-[guanyl]ureido)acetamido]-2-~4-hydroxy- .
phenyl~acetamido)-2,2-dimethyl-3-(5-tetrazolyl) :. .: :
penam. . . `
: As will be recognized by one skilled in the art,
the aoyl group Rl oan contain one or more asymmetric centers, ~ ~
and asymmetrlo centers can exist in one or two forms, the
so-called D- and L-forms. Both forms of each asymmetric .-
oenter, and all oombinations o~ each of the ~orms, are to be . .:
: -17- :~
;:
'',
~OS~99'~
considered within the scope and purview of this inventlon.
SCHEME I
CH3
~2 ~/ `¦--CH3 :
o~J~C02H
(R5) '-NH~, CH3
0~ C~
/ III 2 ~N_ :
CH 'C ~I CH3 .
NH2 .,S / 3 (R5) '-NH S : ^
~ `I--CH3 ~--~ ~ rCH3
0~ J~C ~N'~N ~~N--~C~ ~N
2) ~N_N/ / HN--N
.
~c,~ N~ o ~ ~N
(R2) ~ N
~1 : / :,^-,-
R ~(~13
0~ C~ ~ . ......
: ~N~
,.
Rl is an acyl group.
(R2)' is a tetrazol~lpenam nitrogen protecting group. : . . ~-
(R5)' is an ~no protecting grioup. .-
~ : ^- ~. . :
:~ :
1 8 . : :
., .
~::: . .....
~:, . . -
lOS~99z
SCHE~'E II ;:
(R5) '-NH ICH3
-- H3 ;
~N_ \c,~N\
HN_N~
NH2 \~3 (R5 ) ' 3
_CH3 -N~S~
~N_ ~c~N~ ~N_~C~
HN_ 6 ~N
CH3 C 3
Rl-NH~S~ ~3
,~N\ o~NJ~C,~N~7
26 \N_N . .
, ~
Rl-NH S H3 : ~:
3 : .. . -~
1~26
1.; . . ,
R 18 an aoyl grou~. ~. .;
(R5)' ls an amino proteotlr~ ~oup. . .
R26 is a~noyloxymethyl, l-(a}kanoylo~r)eth~l or phthalld~
.
lOS5'9g~
When contemplating methods to be used ~or the
synthesis of the prererred antibacterial a~ents of thi~ ln-
vention of Formulae I and II, wherein Rl is an acyl group
and R and R3 are each hydrogen, they can be prepared start-
ing from the well-known intermediate 6-aminopenicillanic
acid (6-APA), and several of the ways in which this can be
accomplished are outlined diagrammatically in Scheme I.
Ways in which the antibacterial agents of ~ormulae I and II
wherein Rl is an acyl group and R2 and R3 are each selected
~rom the group consisting of alkanoyloxymethyl, l-~alkanoyl-
oxy)ethyl and phthalidyl, are prepared, are outlined in
Scheme II. However, in Scheme II, for the sake of simpllclty,
the substituent R26 has been shown only at N-l of the tetra-
zole ring. However, as explained hereinafter, alkylation of
a 5-monosubstituted tetrazole results in mixture of mono- ~-
alkylated produ¢ts, in which the newly-introduced group is
located at either N-l or N-2 of the tetrazole ring. ~
From a consideration of Scheme I, the manner in - -~ -
which the compounds of Formulae I and III, wherein R2 is a ~ `
tetrazolylpenam nitrogen protecting group, are useful as
intermediates for antibacterial agents of the invention will ~
be apparent. When consldering the nature of the sald tetra- ~ -
zolyIpenam nitrogen protecting group, the group must fulfill
two fun¢tions. ~irst, it must permit the synthesis o~ com-
pounds o~ Formula III, wherein R5 is an amino prote¢tln~
group and R2 19 the sald tetrazolylpenam nitrogen protecting
group. Second it must be removable ~rom a compound of ~ -
Formula I, wherein Rl is an acyl group and R is the tetra-
zolylpenam nitrogen protecting group; or from a compound of
Formula III, wherein R5 is hvdrogen and R2 is the tetrazolyl-
~ -20-
lV~9g;~
penam nitrogen protecting group; or from a compound o~ Formula
III, wherein R5 is an amino protecting group and R2 is the
tetrazolylpenam protecting group, in each case without de-
composing the penam ring system. As will be apparent from
the discussion which follows, not all the tetrazolylpenam
nitrogen protecting groups useful in this invention need be
removable from each of the said compounds of Formulae I and
III. In order to be useful in this invention, the tetra- -~
zolylpenam nitrogen protecting group needs to be removable
from at least one of the following three types of compounds:
(a) compounds of Formula I, wherein Rl is acyl and R2 is the
said tetrazolylpenam nitrogen protecting group; (b) compounds
of Formula III, wherein R5 is hyd~ogen and R is the tetra-
zolylpenam nitrogen protecting group; and (c) compounds of
Formula III, wherein R5 is an amino protecting group and R2 :
is the tetrazolylpenam nitrogen protecting group. The con- : ~
-. .:: :.
ditions which it will be necessary to use for removal of a
- . .. ~ - : - .-: .
given tetrazolylpenam nitrogen protecting group will be known ::
or obvious to one skilled in the art. Moreover, the reaction -
conditions which can be used without causing decompositlon ;`~
.:
of the penam ring system are also well-known, and obvious,
by reference to the prlor art on penam compounds. ~ ~
A specific group of tetrazolyl protective groups `
are -CH2CH2Y, -C(=o)-o-R14, So2-R14 or (R6)';
wherein Y is selected from the group conslstlng
of cyano, alkoxycarbonyl havin~ from two to seven carbon
atoms, phenoxyaarbonyl, alkylsulfonyl having from one to slx
carbon atoms, phenylsulfonyl and -So?-NRl5Rl6 are each
selected from the group group consisting of hydrogen, alkyl
having from one to four carbon atoms, benzyl and phenyl;
-21-
~ ':
'
1()~'.~!~9;~
R14 is selected from the group consisting of alkyl
having from one to six carbon atoms, benzyl, phenyl and
phenyl substituted by up to two moieties selected ~rom the
group consisting of nitro, ~luoro, chloro, bromo, alkyl
havlng from one to ~our carbon atoms and alkoxy havlng from
one to ~our carbon atoms,
and (R6)' is selected from the group consisting o~
R4
R18 ~ R17
-CH X ~ R20 . :
Rl9 ~ ~:-
wherein R4 and R17 are each selected from the group consist- . -
ing of hydrogen, hydroxy, nitro, fluoro, chloro, bromo, lodo, . .:
alkyl having from one to six carbon atoms, alkoxy having ~rom . ; - -~
one to six carbon atoms, alkanoyloxy having from two to seven
carbon atoms, formyloxy, alkoxymethoxy having from two to ~. -
se~en carbon atoms, phenyl and benzyloxy;
R18 is selected from the group consisting of hydro-
gen, alkyl having from one to four carbon atoms and phenyl;
Rl9 and R20 are selected from the group consisting :-:
of hydrogen and methyl;
and X i8 selected from the ~roup oonsisting of
oxygen and sulfur.
An example of a typical tetrazolylpenam nltrogen .
protecting group is . -
~ CH2 - CH
; ~ ~Y' ''.,','' :''` '
: : 25 wherein Y is an electron-withdrawing group, and Y' is either ~ -;
-22- .
'~'"'~',':
.: ~
.... .
lOS~'~9~
hydrogen or a ~urther electron-withdrawing group, whlch can
be the same as or di~ferent from Y. ~he function of the
electron-withdrawing group i9 to render a hydrogen atom,
on the carbon atoms to which Y and Y' are attached, suf~i-
ciently acidic that the group is removable in a retrograde
Michael reaction. Such a reaction is well-known in the art.
For example consult House, "Modern Synthetic Reactions",
W.A. Benjamin, Inc., New York/Amsterdam, 1965, page 207.
Typical electronwithdrawing groups are cyano, alkoxycarbonyl ~ :
having from two to seven carbon atoms, phenoxycarbonyl, .~-~
.. . :
alkylsulfonyl having from one to six carbon atoms, phenyl~
sulfonyl and So2-NR15R16, wherein R16 are each selected -~
from the group consisting of hydrogen, alkyl having from one
to four carbon atoms, phenyl and benzyl. A particularly : -
convenient configuration for this protecting group is that ~ : :
wherein Y' is hydrogen; and preferred values for Y are
alkoxycarbonyl having from two to seven carbon atoms and
phenylsulfonyl.
A further tetrazolylpenam nitrogen protecting
group which can be used is a grouping of formula -C(=o)-o-R14.
Such a grouping can be removed by mild hydrolysis, such as
mild alkaline hydrolysis, or by treatment with a nucleophile,
such as an amine, or a thiol or thiolate anion. Although a
wide variety of groups can serve as R14, particularly oon-
~5 venient values are alkyl having from one to 9iX carbon atoms,benæyl, phenyl and substituted phenyl, ~or example, phenyl
substituted by up to two moieties each selected from the group :~
consisting of nltro, fluoro, chloro, bromo, alkyl having from
one to four carbon atoms and alkoxy having from one to ~our
carbon atoms.
3 .-
. ~ :.
'' :'~' ~
lOS999Z
A still ~urther tetrazolylpenam nitrogen protec-
ting group whlch can be used is a grouping of formula
-So2-Rl4. Such a group is also removed by hydrolysis, or
by treatment with a nucleophilic agent, as indicated for
the group -(=o)-o-Rl4~ and convenient values for Rl4 are
also alkyl having from one to six carbon atoms, benzyl, ~ .
phenyl and substituted phenyl, for example, phenyl sub- ;; --
stituted by up to two moieties each selected from the group
consisting of nitro, fluoro, chloro, bromo, alkyl having ~
from one to four carbon atoms and alkoxy having from one to ~ --
four carbon atoms. : -
A yet further tetrazolylpenam nitrogen protecting : ;
group which can be used is .
W
-CH ~ ~ -
W ' . ~.
wherein W is phenyl, substituted phenyl, furyl, substituted
furyl, thienyl or substituted thienyl and W' is hydrogen, ~ ~ .
alkyl, phenyl, substituted phenyl, furyl, substituted furyl,
thienyl or substituted thienyl. When W is phenyl or sub- ..
stituted phenyl, and W' is hydrogen, alkyl, phenyl or sub- :
stituted phenyl, thls group can be removed by hydrogenolysis. ~
~his group can also be removed by solvolysis in trifluoro- : .
acetic acid, when the combined effect of W and W' is suf- - .
ficienb to offer the requisite degree of stability to the
incipient carbonium ion
~ ~ W'
Partlcularly convenient configurations for this protecting
group are
"' ':
' - ~
lOS999~, ;
R4
Rla ~ Rl7
and .
-CH ~ R20 -
R19 I .
wherein R4 and Rl7 are each selected from the group consis~
ting of hydrogen, hydroxy, nitro, fluoro, chloro, bromo, iodo,
., "
alkyl having from one to six c~arbon atoms, alkoxy having from :~
one to six carbon atoms, alkanoyloxy having from two to seven ~ -
carbon atoms, formyloxy, alkoxymethoxy having from two to
seven carbon atoma, phenyl and benzyloxy;
R18 is selected from the group consistlng of hydro- ~ :
gen, alkyl having from one to four carbon atoms and phenyl; :.
Rl9 and R20 are each selected from the group consis- ~ ~
tlng of hydrogen and methyl; .~ :
and X is selected from the group consistlng of oxy-
gen and sulfur.~
- As will be recognized by one skilled in the art,
other groups whloh will also stabili~e the carbonium lon ~ .
(W-CH-W')+ can replace those cited above for W and W'. . ~ -
Still another teerazolylpenam nitrogen protecting
group whioh can be used is phenacyl or substituted phenaoyl. ~ -
.
SUch a group is removed by reaotlon w:ith a nuoleophilio re- ~ .
: agent, such as thiophenoxide. ~ypioal phenacyl groups whioh
oan be used are those o~ formula~
a -c~ ~ ~ ~
~ : ~ -25~
~ : .
. .
~: . .. .
i(~5~99;~
wherein R21 is selected from the group consisting of hydro-
gen, nitro, fluoro, chloro, bromo and phenyl.
Several individual methods for the preparation of
the antibacterial agents of this invention are now to be
discussed and descrlbed in detail. For convenience, they
will be designated as Methods A, B, C, D, E and F.
Methods A, B and F relate to removal of penam
tetrazolyl protective groups, method C is acylation t~o form
R', method D relates to alkylation of the tetrazolyl ring,
method E is related to method C in providing modification of
the acylation reaction product to form other acyl derivatives.
It will be appreciated that to form a particular product
two or more of these methods can be employed. For instance ~ -
method A may be used to remove a protective group from an
intermediate followed by an acylation under method C with
or without modification by method E and then acylation by ~
method D. Clearly choice of a particular method or sequence ~ -
of steps is not determined by other than the known character- - :
istics of the compounds and chemical processes involved.
Method A is useful for the synthesis of compounds :-
of Formulae I and II, wherein Rl is an acyl group, and R2
. ., .., -:
and R3 are each hydrogen. The method comprises catalytlc ;~
hydrogenolysls of a compound of Formula I, wherein Rl is an `
acyl group and R is
~ R4 ~ ~
R18 ~ 17 ;~ -
R ~
.,... : .
: :..
wherein R4 and R17 are each selected from the group consist-
ing of hydrogen, hydroxy, nitro, fluoro, chloro, bromo, iodo,
-26-
. .
. ' ~ ' ' - . '
l(~S~9;~
alkyl having from one to 9iX carbon atoms, alkoxy havlng
from one to six carbon atoms, alkanoyloxy having from two
to five carbon atoms, ~ormylo~y, alkoxymethoxy having ~rom
two to seven carbon atoms, phenyl and benzyloxy.
The starting material can be prepared by acyla-
tion of an appropriate corresponding compound of Formula III
or salt thereof wherein R5 is selected from hydrogen and
trialkylsilyl of 1 to 4 carbon atoms in the alkyl groups
with R2 substituted as indlcated above. Acylation can be
as described subsequently under method C.
The reaction can be carried out by a variety of
procedures well known in the art for this type of trans-
formation, such as, for example, those discussed by Augustine
in "Catalytic Hydrogenation", Marcel Dekker, Inc., New York
1965, pp. 139-142. As will be appreciated by one skllled ,
in the art, however, conditions must be chosen which are ~-
compatible with the ~-lactam moiety of the moiety of the
penam nucleus. A particularly convenient procedure comprises
shaking or stirring a solution of the reactant in a reaction-
inert solvent, such as methanol, ethanol, ethyl acetate or - -
water, or mixtures of these solvents, in the presence of a
catalyst, such as 10% palladium-on-carbon, under an atmo
sphere of hydrogen. The catalyst is normally present in an
amount from about 10% to about 100 % by weight based on the
penam startlng mat~rial, and the hydrogen pressure can vary
~rom about one to about one hundred atmospheres. At or
around ambient temperature the reaction takes a few hours ~ -
to reach completion. ,
Method B is useful for preparing compounds of -
Formulae I and II, wherein Rl ls an acyl group, and R2 and
-27-
1()5S'~
R3 are each hydrogen. The method comprises treating a com-
pound of Formula I, wherein R1 i9 an acyl group, and R2 is
R4
-CH2 ~ ~17
wherein at least one of R4 and R17 is a hydroxy group at the
2- or the 4-position, with base. The starting mateiral can
be prepared by hydrogenolysis of the corresponding compound
wherein any hydroxy group at R4 or R17 is protected as its
benzyl ether. The procedures discussed under method A are -
conveniently used. Indeed one can go directly from method ~;~
. " ~
A to method B without separation or where a hydrogenolysis
is effected in the presence of a basic agent method B ~ay -~
occur concomitantly with hydrogenolysis. Under certain~ i
hydrogenolysis conditions formation of the penam compound
where R2 is a hydroxy benzyl group is immediately followed
by hydrogenelitic removal of the hydroxy benzyl group to ; ` -
produce the compound of Formula I or II wherein R2 and R -~
are each hydrogen. The reaction of Method 9 is carried out
by dissolving starting mnterial in an appropriate solvent,`- -
and then adding about one molar equivalent of a base, at
around ambient tempernture or slightly below. The reaction -
is usually complete within a few minutes. Appropriate 901v- ~ii ;~
ent9 for thi9 pro~ess are tho9e Which will 9erve to dlssolve ~ -
the starting materlal but are otherwise inert. Examples of
so1vents which find utility are esters, 9uch a9 ethyl acetate `
~and butyl acetate; lower-aliphatic ketones, such as acetone
nnd methyl ethyl ketone; chlorinated hydrocarbons, such as - ~
chloroform, methylene ohloride and 1,2-di¢hloroethane; and : -
` -28- ~ ;
: "' '~'' ' . ^' '
. -
1(~5~
lower-alkanols, such as methanol and ethanol; and tetrahydro-
furan. A wide variety of basic agents are operative in this
process, since it appears ~hat the primary purpose of the
basic agent is to remove the hydrogen from the phenolic
hydroxyl group of the hydroxybenzyl protecting group. Basic
agents which can be used include alkali metal salts of
alkanoic acids, such as sodium acetate and sodium 2-ethyl-
hexanoate; organic amines, such as tributylamine, triethyl-
amine, N,N-dimethylaniline, N-ethylpiperidine, pyridine and , ~ -
lC N-methylmorpholine; alkali metal hydroxides, such as sodium
hydroxide and potassium hydroxide; alkaline earth metal hydr-
oxides, such as barium hydroxide and calcium hydroxide; and
alkali and alkaline earth metal hydriaes, such as sodium
hydride, potassium hydride and calcium hydride. Although it
is usual to employ about one molar equivalent of base in this
. . ~ .
process, an excess of base can be used under certain circum- .
stances. In fact in those cases where there is another acidic
function in the starting material, it becomes necessary to
add two molar equivalents of the basic agent. It will be
appreciated by one skilled in the art, however, that con- `
ditions for this reaction must be chosen with due regard or ~;
the sensitivity o~ the ~-lactam moiety of the penam nucleus,
and the pre~enae in the reaction medium of an excess of a
basic agent which will adversely react with the said ~-
lactam is to be avoided. A particularly ¢onvenient method
o carrying out this process is to expose the starting mate-
rial to an aqueous solvent system, at a pH in the range from
about 7.5 to about 9.5
~ethod C is useful or the preparation of compounds
of Formulae I and II, wherein Rl is an acyl group and R2 and
-29- ;
.. . . .
. .
105~9'~ :
R3 are each selected from the group consisting of hydrogen,
alkanoyloxyme~hyl having from three to eight carbon atoms,
l-(alkanoyloxy)ethyl having from four to nine carbon atoms
and phthalidyl. Broadly, this method comprises acylation of
a compound of Formula III or IV, or a salt thereof, wherein
R2 iS selected from the group consisting of hydrogen,
alkanoyloxymethyl, l-(alkanoyloxy)ethyl and phthalidyl and
trialkylsilyl having fxom one to four carbon atoms in each
... . .
of said alkyl groups, followed, if necessary, by treatment
.: .: . . . :
with a protic solvent. The latter treatment is necessary ~ ;
when either R2, R3 or R5 is trialkylsilyl. The acylation
. . . - .: ; .
is carried out by contacting the said compound of Formula
III or IV, or a salt thereof, with an activated derivative ;
of the appropriate carboxylic acid, in an appropriate solv-
ent system.
.. , . . -
An activated derivative commonly used is an acid
halide, such as an acid chloride. In a typical acylation -
procedure, approximately one molar equivalent of an acid i~-
chloride is added to a solution of the said compound of
Formula III or IV, or a salt thereof, dissolved in a solvent
., . . .. . -
such as a chlorinated hydrocarbon, for example, chloroform -
or methylene chloride; an ether, or example, tetrahydro- ;
~ . . .. . -
furane or 1,2-dimethoxyethane; an ester, for example, ethyl ~ ~
... ..
acetate or butyl aaetate; a lower aliphatic ketone, for ex-
. ~ .. ..
ample, acetone or methyl ethyl ketone; ox a ~ertiary amlde, `~ ~ ;
for example, N,N-dimethylformamide or N-methylpyrrolidone;
at a temperature in the range from about -40C. to about - ;
30C., and preferably from about -10C. to about 10C., ~ -
... . . ... .
optionally in the presence of about one molar equivalent of
.: . . :. . .
an acid-binder, e.g., triethylamine, pyridine or sodium bi- ` ;
~ -30- `~ -
.,~: :- :, -
. . .
. .
~S~9'~
carbonate. The reaction is complete within a short period,
i.e., approximately one hour. When R2 and R3 are hydrogen,
it is convenient to employ a tertiary amine salt, for example,
the triethylamine salt, of the compound of Formula III ro IV.
An alternate procedure useful for the acylation of a compound
of Formula III or IV, wherein R2, R3 and R5 are each hydrogen,
with acid halides involves the use of an aqueous.solvent
system. In this procedure, which approximates the Schotten~
Baumann procedure, the.acid halid.is.added to.a solution of
the starting material.in water, or.a mixture of water and
another inert solvent, at, or slightly below, ambient ~emp~
erature, with the pH of the solvent being maintained within ;~
...... . .
the range from about 6.0 to about 9.0 before, during, and .: ~
after the addition. ` . ~:
Another activated derivative of the carboxylic :
acid with finds used in Method C..is a mixed anhydride. In
... .
this case, a.carboxylate salt of the appropriate carboxylic . : .
acid is.treated with.about.one.molar equivalent of a lower- :~-
alkyl.chloroformate.in a.reaction-inert, aprotic organic .~
solvent, at a temperature in the range from about -20C. to ..
about 20C. and preerably at about 0C. Appropriate salts
for this process.are.alkali.metal.salts.,.such as sodium and .
potassium.salts.,:and.tertiary amine..salts,.such as triethyI-
amine., tributylamine., N-ethylpiperidine., N,N-dime~hylaniline,
N-methylmorphaline.and.pyridine.salts; and.appropriate solv-
ents are.r.for example.chloroform, methylene ahloride~ aceto~
.. . . .
; nitrile~.tetrahydrofuran, dioxane and.. N,N-dimethylformamide. ::
~he~mixed.carboxylic-carbonic.anhydride.. thus.formed is / .
. usually.used.in..situ..to.aaylate the.said compound of Formulae
III or IV. This is normally carried out by mixing solutions
~ -31- :.:
1(~5~
of the preformed mixed anhydride and the compound of Formulae
III or IV. When R and R3 are hydrogen, it is particularly
convenient to employ.a tertiary.amine salt, for example the
triethylamine.salt., of.the compound of.Formula III or IV.
S The acylation is.normally conducted.at a temperature in the . .
range from about.-30C. to.about 20C.,.and.preferably at `~
about.-10C., and it.usually takes a few hours to reach com~
pletion. In most instances the mixed anhydride and the com~
pound of Formulae III or IV are contacted substantially in a
1:1 molar ratio.
Another variation of Method C, comprises conversion
of the carboxylic acid to an active ester, followed by treat- .~h .. ;~ :
metn with a compound of Formula III or IV or a salt thereof. ;
Active esters which can be used in this regard are, for ex- ~ :
ample, phenyl esters, such as ~-nitrophenyl and 2,4,5-tri~
chlorophenyl esters, thio esters, such as thiol phenyl and -~
thiol methyl esters; and N-hydroxy esters, such as N-hydxoxy~
succinimide and N-hydroxyphthalimide esters. The esters are :~
prepared by methods well established in the art, and the . . ... ..
acylation is conveniently conducted by dissolving the active : ~ ~
ester and the said compound of Formula III or IV, or a salt ; .`... .
thereof, in a dipolar aprotic solvent such as N,N-dimethyl~
formamide, N,N-dimethylacetamide or N-methylpyrrolidone. The .. :
solution is stored at about ambient temperature for several ;~
hours, for example overnight, and then the produot i8 lsolat- . ;-.:
ed by standard methods. In many cases the active ester used
in this process can be replaced by the corresponding acid
azide. ~. `. -
A still further variation of Method C which is use~ .``
ful for the acylation of compounds of Formulae III and IV .: ~.
-32~
' ".: :.
l(~S~9'~
comprises contacting the said compound of Formulae III or IV
with a carboxylic acid in the presence of certain agents in
the art or forming peptide bonds. Such agents include carbo-
diimides, for example, dicyclohexylcar~odiimide and l-ethyl-3- .
(3-dimethylaminopropyl)carbodiimide, alkoxyacetylenes, for ~ .
example methoxyacetylene and ethoxyacetylene, and N--ethoxy- .
carbonyl-2-ethoxy-1,2-dihydroquinoline. The reaction is ~
carried out in an appropriate solvent, i.e., one which will : ~-
serve to dissolve the reactants, and does not adversely
interact with.the starting materials or the product, for ::
example acetonitrile, N,N-dimethylformamide and N-methyl- .'
pyrrolidone. ~:
Implicit in the above description of Method C,
is the observation.that.in.a process for the acylation of a : -
1~ compound.o Formula.III or IV, hydrogen substituents located - .
at R2, R3 or R5 can successfully be replaced by trialkyl-
silyl substituents.. Said trialkylsilyl.substituents.are then
removedt and.replaced..by.hydrogen, at.the end.of the acyla-
tion, simply by.brief~exposure of the product to a protic `
solvent system, such as water or.a.loweralkanol, for example,
methanol or ethanol...By.virtue.of.the ready.availability of
.the.starting materials.,.the trimethylsilyl group.is a pre-
ferred member. It can be introduced into the starting penam ... `
o Formula III or IV by methods well known in the art, such
as, for example, using trimethylchlorosllane or N-trimethyl- ; :
silylacetamide, as discussed by Birkofer a~d Ritter in
Angewandte Chemie (International Edition in English), 4, ~.
~ 417-418 and 426 (1965). Conditions must be chosen, however,
: which are compatible with the -lactam group of the penam
nualeus. Also, operative in Method C are the silylated
` -33-
~)SS~9'~
derivatives formed by interaction of the said compounds of
Formulae III and IV with dichlorodi(lower-alkyl)silanes. The
silylation step is carried out by methods known in the art
(for example, German Patent No. 1,933,187). After the acyla-
tion reaction, the silyl group is removed by treatment with
a protic solvent, such as water or a lower-alkanol, for ex- . :
ample, methanol or ethanol. ' -~
Additionally, if desired, the tetrazole ring of a . .
compound of Formula III or IV, wherein R2, R3 and R5 are
each hydrogen, can be protected by.various other groups,
prior to acylation by Method C. The protecting group is .- :
then removed, after acy~ation, to liberate the desired anti- :.- ~ . -
bacterial agent of Formula I or II, wherein.Rl is acyl and -.. ~
~ _ . ; .. .- - .
R~ and Rs are each hydrogen. A.wide variety of protecting ` : :.
groups.can be used for.this purpose, such as,.for example, .
triphenylmethyl., substituted..triphenylmethyl, alkoxymethyl,
benzyloxymethyl, substituted benzyloxymethyl and cyanomethyl. .
A particularly convenient group, however, is the triphenyl~
~. .. ..
... . methyl group. . ~ .
It will be appreciated by one.skilled in the art
that not.all.the..variations discussed under Method C are
equally effective or.convenient in..all.cases,.for the acyla-
tion of.a compound of Formula III.or IV. The relative
effectiveness of a particular variation.will differ according
25 .to a.number... of.factors, such as,.for example, the precise . :
structure.of the said compound of.. Formula III or I~, the -
.availability.of.starting.. materials.,.. the.scale of the reac- ~. .... -
.tion.and.,.in.particular,.the structure and reactivity of the .
. .
acyl group being introduced. In practice, one skilled in the ~ :
30. art.will select the most appropriate variation in each case, . :
~ -34- :.
~ ,.... . ...
~)S!~'39'~ :
having full regard or the relevant factors. Moreover, in
some instanaes certain further precautions and modiications
become necessary or desirable, especially in.the cases wherein
Rl has the Formula V and n is 1. For example, in the case
wherein Rl is of Formula V, wherein.n is l.and Q is phenoxy- ,
carbonyl, substituted phenoxycarbonyl or indanyloxycarbonyl, .
use can be made of the acylation technique taught in United .~- -
States Patent No. 3,679,801. Further, in the preparation of
the compounds of Formulae I.and II, wherein Rl is of Formula . ~ :
10 . V, wherein n. i5. 1, Q.is.carboxy.. and.R7.is selected rom the :.
group consisting of.phenyl, substituted.phenyl, heterocyclyl :
and.substituted heterocyclyl, the.. mono-acid chloride of the . .
2-substituted malonic.acid.precursor.is an effective and
.useful.acylating agent.in.Method.. C. .. Preparation and use of -~
.. ..
the..said mono-acid..chlorides...is.taught.in.Belgian Patent No.
788,928. In the case wherein Rl is of the Formula V, wherein
n is 1 and Q is or contains a basic, primary or.secondary, : ; : ;
.amino group, it is necessary to protect.the.amino group in
the starting carboxylic acid, prior to.activation of the ~
carboxy group of the said acid. After the amino group has ~-: ..
been protected, the carboxy group is activated, the acyla-
tion is carried.out.by.one of.the.methods described under
Method C, and then the antibacterial.penam compound of
Formula.I or.II is obtained by removal of the.protecting
group. A wide ~ariety of.protecting groups known in the art
for protecting amino groups during peptide synthesis can be
. used for this purpose.. Groups which have been.found to be - -
. . . particularly suitable are the benzyloxycarbonyl group use of ~:.
which is.taught by Doyle, et al.,.in.. the.. Journal of the : : -
... 30. .Chemical.Society~.(London~, 1440 (19621, and the enamines ..
''~ ' .:'
~os~9;~ ~:
formed by interaction o ~he ~tarting amino-aaid with a ~-
dicarbonyl compound, as taught by Dane and Dockner in the
Angewandte Chemie (Internakional Edition in English) 3, 439
(1964), and in Chemische ~erichte der Deutschen Chemischen
Gesellschaft, 98, 789 (1965). For the use of other protect-
ing groups, consult Greenstein and Winitz, "Chemistry of the
Amino Acids", John Wiley & Sons, Inc., New York/London, 1961, .... . :
- pp.882-922. In certain instances where n is 1 and Q is or .`. .~.. :
contains a basic amino group, a particularly valuable acyl~
ation procedure comprises use of the acid chloride hydro- .. ..
chloride of the precursor acid The acid chloride hydro- : :.;.... ; :chlorides are prepared, and the acylation is conducted, by .~. :. -.
the methods described.for the-preparation of 2-amino-2- .~ .~
phenylacetyl chloride hydrochloride and the subsequent acyl- ~ ' A'''' ,"''
ation of 6-aminopenicillanic acid, respectively, ~United ~ -
States Patent No. 3,140,282). ~.-.;. ;
Method D is useful for the preparation of compounds `~
of Formulae I and II, wherein Rl is an acyl group and R and
R3 are each alkanoyloxymethyl, l-(alkanoyloxy)ethyl or ; .~
phthalidyl. This.Method.comprises alkylation of the corre- . :
sponding compound of Formula I or II,.wherein Rl i8 an acyl ~ .;.
,., q ..
group and R~ and R~ are each hydrogen, with an alkanoyloxy- .. .
methyl, l-(alkanoyloxy)ethyl or phthalidyl.halide. In thls
. context,.the:term "ha}ide'' is intended to.contemplate-iodide, . .:
25 . bromidel.and ahloride. The reaction is conveniently aarried
out by dissolving a tetrazolate.salt of the said compound of
Formula I or II, wherein R2 and R3 are each hydrogen, in a
. ,. ,.: ..
suitable, polar, organic solvent, such-as N,N-dimethylform- . ..
amide, and then adding about one molar equivalent of the ~
.:
alkanoyloxymethyl halide. Salts of the starting material ; . ..
: -36- ... .
. ' ' '~ .:
~()SS~19;~
which are commonly used are alkali metal salts, such as
sodium and potassium salts, and tertiary amine salts, such
as triethylamine, N-ethylpiperidine, N,N-dimethylaniline
and N-methylmorpholine salts. ~he reaction is usually run
S at about ambient temperature, and the length of time needed
to reaah.completion varies according to a variety of factors,
such as.the concentration of.the.reactants.and the.reactivity
of the reagen~s. Thus.,.when.considering the halo.compound, : ~ -
the iodide.reacts faster than.the.bromide,.which in turn re~
.10 acts faster than the chloriae. In fact, it.is customary, ::
. . : '
.when.utilizing.a chloro.compound., to add~up.to one.molar
equivalent of an alkali metal iodide.... ...This.has.the effect - -
of.. speeding up.the.. reaction.,.and.it.. is postulated.that this . .
technique.brings about.a..halogen..exchange.,.thereby generating ...
in situ some o the more reactive iodo-compound. With
full.regard for the foregoing factors, reaction times of ~ . .
several hours, e.g., overnight, are quite commonly used.
As discussed.earlier, for any given substituent Rl, the com~
pounds of Formulae I.. and.II, wherein R2 and.R3 are each - : ::
hydrogen, co-exist in.an equilibrium.mixture, and it is found
that the.crude product obtained from..alkylation of this
mixture also comprises.. a mixture... The.mixture consists of .
mono-alkylated products,.in.which the.newly-introduced -. .
alkanoyloxymethyl group. i9 located at.. either the N-l or N-2 .
position of the~tetrazole moiety. The.ratio.of product~
varies..according to a variety of.factors, such as the struc- .:
ture of.the..penam, the.structure...o.the alk~lating agent,
:~ and.. the conditions~under.:.which the reaction is run. In some
instances..one isomer may.be produced almost.exclusively.
Although.this.misture..of.products~..can..be separated by con~
'. :-.'-'': :.
':' ` -
- . ~. - . . . .. .. . .
~OS9'39'~
ventional means, for example by chromatography, hoth isomer~
have antibacterial properties, and the mixture of isomers :
can be used for the further synthetic transformations to be
described hereinater, if desired. . :
The alkanoyloxyalkyl halides are either known com- :
pounds, or they are prepared by known procedures (Ulich and . ~
Adams, Journal of the American Chemical Society, 43, 662 .: ~ ....
/I9217; Daehne.et..al., Journal of Medicinal Chemistry, 13,
607 /19707). .
Method E is valuable for the.preparation of compounds
of Formulae I and II, wherein R2 and R3 are each selected ..
from the group consisting of hydrogen1 alkanoyloxymethyl, :. :-
1-~alkanoyloxy)ethyl and phthalidyl, and Rl is of Formula V,
wherein R7 is as previously defined, n is 1 and Q is selected .~ .
from the group.consisting of carboxy, sulfoamino, carbamoyl, .;. ;
amino and NH-(C0-CH2-NH)m-C0-Z. This Method comprises carry~
ing out further transformations on.certain of.the compounds - ~: :
of Formulae I and II which are prepared by ~ethod C. ~ .:
~ Thus, the compounds of Formulae I and II, wherein
n is 1 and Q is carboxy, can be obtained from the correspond- ~
ing compound.. of Formula I.or II, wherein Q is phenoxycarbonyl, .. - .
substituted phenoxycarbonyl.or indanyloxycarbonyl, by mild .
hydrolysis of the phenoxycarbonyl,.substituted phenoxycarbonyl : . .
or indanyloxycarbonyl group to liberate a.carboxy group. The . :
reaction is carried out by exposing the starting.material to
a mildly-alkaline aqueous solvent system.until hydrolysis is
substantially complete, for example,.according to the procedure
of United States Patent No. 3,679,801. .;-
~he compounds wherein:n is.l and Q is sulfoamino, .. . .
can be obtained from the corresponding compound of Formula I ;..-: .
-38-
~.''' '.'
' ~
': ;.: '
or II, wherein Q is amino, via direct sulfonation. The
sulfonation can conveniently be carried our using the methods
described in United States Patent No. 3,381,001.
The compounds wherein n is 1 and Q is carbamoyl, -~
can be obtained from the corresponding compound wherein Q
is phenoxycarbonyl or preferably, phenoxycarbonyl substituted
by one or more electron-withdrawing groups, by treatment
with ammonia. Particularly convenient suhstituted phenoxy-
carbonyl groups are nitro- and dinitro-~iubstituted phenoxy- -
carbonyl groups, and the reaction is carried out u~ing well-
known methods (Consult Johnson, Journal of the American
Chemical Society, 75, 3636, /19537).
The compounds wherein n is 1 and Q is NH-(CO-CH2-
NH)m-CO-Z, wherein m is 0 and Z is selected from the group --
consisting of alkyl having from one to six carbon atoms,
phenyl, substituted phenyl, furyl, thienyl, pyridyl and
pyrrolyl, are prepared from the corresponding compound of
Formula I or II, wherein Q is amino by reaction with an
activatedi derivative of the appropriate carboxylic acid. -
.: . .
The techniques for activation of a carboxylic acid, and for
acylation, discussed above under Method C can ~e used in
the instant process. In many instances, use of the acid
chloride of the carboxylic acid is a particularly convenient
technique~
The compounds wherein n i9 1 and Q is NH-(CO~CH2-
NH~m-CO-Z, wherein m is 0 and Z is aminomethyl, are prepared
from the corresponding compound of Formula I or II, wherein
Q is amino, via coupling with glycine. The coupling procedure ~ ;
comprises the steps of: (1) protecting the amino function of i ~-
the glycine; (2) activating the carboxyl group of the N-pro-
39
`: :
~(~5~
tec~ed glycine; (3) reacting the ~o-produced intermediate
with the said compound of Formula I or II, or a salt thereof;
and (4) removing the N-protecting group. Convenient tech-
niques for achieving these steps are taught in Belgian Patent
S No. 681,660.
The compounds wherein n is 1 and Q is NH-(CO-CH2-
NH)m-CO-Z, wherein m is 0 and Z is anilino or substituted
anilino, are prepared from the corresponding compound of
~ormula I or II, wherein Q is amino, by reaction with phenyl
isocyanate or a substituted phenyl isocyanate. The reaction
is carried out by contacting substantially equimolar pro-
portions of the isocyanate and the penam compound, or a salt
t~ereof (e.g., the triethylamine salt), in a reaction-inert
organic solvent ~e.g., N,N-dimethylformamide) at about
ambient temperature. The reaction requires a few hours
~e.gA, about three hours), and the product can be isolated
..... .
simply by evaporation of the solvent. ~
.- .:
The compounds wherein n is 1 and Q is NH-(CO-CH2-
N~m-CO-Z, wherein m is 0 and Z is guanidino, are prepared
from the corresponding compound of Formula I or II, wherein ;
Q is amîno, via reaction with a guanylcarbamoylating agent. :-
The guanylcarbamoylating agents obtained by treatment of - ~
4-guanylsemicar~azide either with a source of nitrous acid, - -
or with certain oxidizing agents, are particularly valuable
in this proaess. Preparation and use of these carbamoylating
agents are described in United States Patents Nos. 3,579,501
,
and 3,579,514. ~he term "amidino" is an accepted synonym for ~:
guanyl.
The compounds wherein n is 1 and Q is N~-(CO-CH2-
NH~m~CO-Z, wherein m is 0 and Z is guanidinomethyl, are pre-
_40_
.
105~
pared from the corresponding compound of ~ormula I or II,
wherein Q is amino via reaction with the acid chloride
__
hydrochloride of guanidinoacetic acid~ The reaction is
normally carried out by treating a solution of the start-
ing penam compound, or a salt thereof~ in a polar, organicsolvent such as N,N-dimethylformamide or N,N-dimethylacet-
amide, at about 0C., with guanidinoacetyl chloride hydro-
chloride. The reaction commonly takes around two hours to
reach completion. A salt of the starting material is used
in those cases wherein R2 or R3 is hydrogen, and appropriate ~ -
salts are, for example, alkali metal salts and tertiary amine
salts. In order to achieve a good yield of product, it is
usually necessary to utilize at least one molar equivalent,
and preferably up to about four molar equivalents, of the --
acylating agent.
The compounds wherein, n is 1 and Q is NH-(CO-CH
NH)m-CO-Z, wherein m is 0 and Z is selected from the group
consisting of acylamino, benzamido, substituted benzamido,
thiophenecarboxamido, furancarboxamido and pyridinecarbox-
amido, are prepared from the corresponding compound of ;- ~
Formula I or II, wherein Q is amino, by reaction with the ~ -
appropriate acylisocyanate. The acylisocyanates are prepared
and the reaction is carried out, according to the procedures
described in United States Patent No. 3,479,339. `
~he compounds wherein n i9 1 and Q is NH (CO-CH~
NH)m-CO-Z, wherein m is 1 and Z is selected from the group
consisting of alkyl having from one to six carbon atoms,
phenyl, substituted phenyl, furyl, thienyl, pyridyl, pyrrolyl,
aminomethyl, anilino, substituted anilino, guanidino, guan-
idinomethyl, acylamino, benzamido, substituted benzamido,
~ -41-
105~3~9Z
thiophenecarboxamido, furancarboxamido and pyridinecarbox-
amido, are prepared in a manner analogous to that described
for the corresponding compounds wherein m i9 0, except that
the corresponding compound of Formula I or II, wherein Q iB
NH-CO-CH2-NH~ replaces the compound wherein Q is amino.
The compounds wherein n is 1 and Q is NH-(CO-CH2-
NH)m-CO-Z, wherein m is 0 and Z is selected from the group
consisting of alkanecarboxamidinomethyl having from three
to eight car~on atoms, benzamidinomethyl, (substituted benz-
amidinomethyl), thiophenecarboxamidinomethyl, furancarbox-
amidinomethyl, pyridinecarboxamidinomethyl, pyrrolecarbox-
amidinomethyl and 2-benzimidazolcarboxamidinomethyl are pre-
pared from the corresponding compound of Formula I or II,
wherein Q is NH-CO-CH2-NH2 by a reaction with the appropriate -
lS imidate ester (e.g. r ethyl benzimidate). The reaction is
normally carried out by contacting substantially equimolar -;
quantities of the imidate ester and the penam compound, or - --
a salt thereof (e.g., the triethylamine salt), in a reaction-
inert organic solvent (e.g., chloroform, N,N-dimethylform-
amide or N,N-dimethylacetamide) at about ambient temperature. ~-
The reaction ùsually takes several hours (e.g., about six
hours), and the product is isolated. The imidate esters
used in the instant process are either known compounds or
they are prepared by known methods. For example, they can-~
be prepared by the acid-catalyzed addition of an alkanol to
the appropria~e nitrile (the Pinner reaction), by reaction
of the corresponding carboxamide with the trialkyloxonium
fluoborate (e.g., triethyloxonium fluoborate), or in some
cases, by the base-catalyzed addition of an alkanol to a
nitrile. The base-catalyzed reaction is particularly con-
-42-
'::
1()S~3~9~
venient when the cyano moiety is bonded to an electron-
withdrawing group (~.g., 4-cyanopyridine). Consult Shriner
and Neumann, Chemical Reviews, 35, 354-358 ~1944); Meerwein,
Organic Syntheses, Collective Volume V, 1080-1082 ~1973);
Schaefer and Peters, Journal of Organic Chemistry, 26, 412
(1961); Belgian Patent No. 803,094 and references cited.
Method F is valuable for the preparation of com-
pounds of Formulae I and II, wherein Rl is an acyl group and
R2 and R3 are each hydrogen. The Method comprises hydrolysis ;
o~ the corresponding compound of Formula I, wherein Rl is an
acyl group and R2 is a group of Formula -C(=o)-o-Rl4 or
~o2-Rl4 wherein R14 is selected from the group consisting of ~ -
alkyl having from one to six carbon atoms, benzyl, phenyl ~ ~
and phenyl substituted by up to two moieties selected from ~ -
the group consisting of nitro, fluoro, chloro, bromo, alkyl
ha~ng from one to foux carbon atoms and alkoxy having from
one to ~our carbon atoms~ The hydrolysis is normally carried
out by contacting the starting material with an aqueous or
partially aqueous solvent system, at a temperature normally
in the range from about -5C. to about 30C~, and preferably
from about 10C~ to 25C~, at a pH in the range from about
7~5 to 9.5, and usually at about 8~5, until hydrolysis is
substantially complete. The reactign usually takes about 1
hour to reach completion. It is usual, although not essential,
to uae a co-solvent in this process. Co-solvents which ~an
be used are those which are miscible with water, and will `
serve to dissolve the starting penam compound~ Typical
examp}es of co-solvents which can be used are acetone; lower ~ `
alkanols, such as methanol and ethanol; ethylene glycol; mono- `--
and di~lower-alkyl) ethers of ethylene glycol, such as
'.:' ~'.. : .:
'.. ~
l.OS~g9;~
2-methoxyethanol and 1,2-dimethoxyethane; tetrahydrofuran; dioxane
and acetonitrile. The product is isolated by methods well-known
in the art.
The starting penam compounds of Formulae III and IV,
wherein R2, ~3 and R5 are each hydrogen, u~ed in Method C, can be ~.
obtained from the appropriate compound of Formula III, or an acid - : -
addition salt thereof, wherein RS is hydrogen and R2 iB selected - ~-
from the group consisting of
~ (R4)'
C ~ (R17)-
and .
_ ~ ~ 20
. .
wherein (R4)' and (Rl7j~ are each selected from the group con~isting
of hydrogen, hydroxy, fluoro, chloro, bromo, iodo, alkyl having
from one to six carbon atoms, alkoxy having from one to six carbon
atoms, alkanoyloxy having from two to seven carbon atoms, formyl~
,
oxy, alkoxymethoxy having 2 to 7 carbon atoms phenyl and benzyl- ~ - :
oxy; R18 is selected from the group consisting of hydrogen, alkyl
having from one to four carbon atoms and phenyl; Rl9 and R20 are
each selected from the group consisting of hydrogen and methyl;
and X i~ selected from the group consisting of oxygen and ~ulfur;
prov~dod that when R18 i8 hydrogen, at lea~t one of (R4)' and
~R17)' 1~ ~elected from the group consi~ting of 2- and 4-hydroxy,
2- and 4-alkoxy having from one to 9iX carbon atoms, 2- and 4-
alkanoyloxy, having from two to seven carbon atoms, 2- and 4-formyl-
oxy, 2- and 4-alkoxymethoxy having from two to ~even carbon atoms,
,
and 2- and 4-benzyloxy, by treatment with trifluoroacetlc
-44- ~.
:
1(~5~
acid. Although this is not essential, it is usually pre-
ferable to add to the reaction an alkoxybenzene, such a~
anisole, phenetole or veratrole. The reaction is conven-
iently carried out by dissolving the starting material in a
small volume of trifluoroacetic acid, containing anisole,
:
maintaining the solution at a temperature in the range from
about 20C. to about 70C., and preferably at about 30-40C~
for an appropriate time period, and then precipitating the
product by the addition of a non-solvent. The product can
. ~ . .
then be recovered by filtration.
Alternatively, particularly when operating on a ;;~
small scale, it is sometimes convenient to arrest the reac-
tion by rapid evaporation of the trifluoroacetic acid, at
or around am~ient temperature, in vacuo. The amount of
trifluoroacetic acid used in this process is not critical,
provided that enough is present to efficiently dissolve the --
starting material, and from about ten molar equivalents to
a~out one hundred molar equivalents based on the penam com-
pound is commonly used~ About one molar equivalent of anisole
is normally used, but larger amounts, even as large as ten
molar equivalents~ may be added, if desired. A starting
material which operates particularly efficiently in this
process is a sulfonate salt, for example, the methanesulfon~
ate or ~-toluenesulfonate salt, o the said compound o~
Formula III, The time course of the instant reaction varies
according to a variety of factors, such as the reaction
temperature, the structure of the starting material, the
concentration of the solution. However, a convenient mode `~ -
of operation involves monitoring pilot reactions using
nuclear magnetic resonance spectroscopy, 90 that the time --
~ ~45~ ~ ~
~ - .
': ~' ''.
,. :" ~:
1059~gZ :,, '
period whiah leads to the optimum conversion to product for
a given set of reaction conditions can be determined. When
working at about 35C., reaction times in the range from
about O.l to about 1.5 hours are commonly employed.
The starting penam compounds of Formula III and IV,
.. .. , :,
wherein R2, R3 and RS are each hydrogen, used in Method C,
can also be obtained by hydrogenolysis of the appropriate -~
compound of Formula III, or an acid-addit-on salt thereof,
wherein R5 is hydrogen and R2 is selected from the group ~-
consisting of
-CH ~ 17
wherein R4 and Rl7 are selected from the group consisting
of hydrogen, hydroxy, nitro, fluoro, chloro, bromo, iodo,
alkyl having from one to six carbon atoms, alkoxy having
from one to six carbon atoms, alkanoyloxy having from two
to seven carbon atoms t phenyl and benzyloxy. The same tech-
ni~ues and conditions discussed earlier under Method A are
useful in the instant process. ,
A still further method for obtaining the starting
materials of formula III and IV, wherein R2, R3 and R5 are
each hydrogen comprises removal of the triphenylmethyl pro-
tecting group from a compound o Formula III, wherein R5 is
triphenylmethyl and R2 is hydrogen. ~he triphenylmethyl
protecting group is removed by treatment of the said compound
of Formula III with acid, and a wide variety of acidic re~
agents and conditions known in the art for removal of the
triphenylmethyl group are operable fn this process. For ex~
ample, it is possible to use a sulfonic acid, such as methane --
-46~
lt~S~19'~,
sulfonic acid, benzenesulfonic acid or ~-toluenesulfonia acidl
an anhydrous hydrohalic acid, such as hydrogen chloride or
hydrogen bromide; or an alkanoic acid, such as hydrogen
chloride or hydrogen bromide; or an alkanoic acid, such as
acetic acid, propionic acid, chloroacetic acid, trifluoro-
acetic acid and the like. The reaction is normally carried
out by dissolving the starting material in an appropriate -~
solvent and adding about two molar equivalents of the acid
reagent, at or about ambient temperature~ Reaction is com-
plete within about one hour, and the product is present in
the reaction medium in the form of the acid-addition salt
.~ . -
corresponding to the acid reagent used. A solvent should ~ -
be chosen which will dissolve the starting penam, and ex-
amples of solvents which find use are: ethers, such as di-
ethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxy-
ethane; chlorinated hydrocarbons, such as chloroform, methyl- -
ene chloride and 1,2-dichloroethane; lower aliphatic ketones, ~ - -
such as acetone, methyl ethyl ketone and methyl isobutyl
: :
ketone; esters, such as ethyl acetate and butyl acetate; ~ --
hydrocarbons, such as hexane, cyclohexane and benzene; and
lower alkanols, such as methanol, ethanol and butanol. -~
Although it is common to use about two molar equivalents of
.- :.
acid in this process, only one molar equivalent is necessary
when either the reaction is carried out in the presence of
: .
one molar equivalent of water, or the aaid i9 introduced as
a monohydrate. However, as will be realized by one skilled ;
~ - .
in the art, the product from this reaction should not be ex- ` -
posed to an excess of acid for prolonged periods, since in
this case there is a danger of destroying the ~-lactam sys-
tem. A particularly convenient mode of operation for this ~
~ -47- -
'~ " ' '.-
,' :.'.: '
~.,, ~ ' , ,
`:
lt~S~
process, is to choose an acid~solvent system such that the
starting material is soluble, but the acid-addition salt
generated during the reaction precipitates as it ls formed.
It can then be recovered by filtration at the end of the re-
action. When using the combination of p-toluenesulfonic
acid in acetone, the ~-toluenesulfonate salt of the product
often precipitates.
In like manner, the starting materials of Formula
III, wherein R5 is hydrogen and R2 is selected from the
group consisting of -Ct=O)-Rl~, -So2-R14 and (R6)', wherein
R14 is selected from the group consisting of alkyl having
~rom one to six carbon atoms, benzyl, phenyl and phenyl sub-
stituted by up ~o two moieties selected from the group con-
sisting of nitro, fluoror chloro, bromo, alkyl having from ,~ -~
one to four carbon atoms and alkoxy having from one to four
carbon atoms; and (R6)' is selected from the group consisting ~ -
o~ ~ :
-CN ~ 4 ' :
and
-CN ~ R20
wherein R4 and R17 are each selected rom the group con~
sisting of hydrogen, hydroxy, nitro, fluoro, chloro, bromo,
iodo, alkyl having from one to six carbon atoms, alkoxy ~,
having from one to six carbon atoms, alkanoyloxy having from
two to seven carbon atoms, formyloxy, alkoxymethoxy having
from two to seven carbon atoms, phenyl and benzyloxy, R18 is ~--
~4~~
.. . .
1(~5~9'~
selected from the group consisting of hydrogen, alkyl having
from one to four carbon atoms and phenyl; R19 and R20 are
each selected from the group consisting of hydrogen and
methyl, and X is selected from the group consisting of oxy-
gen and sulfur, are prepared from the corresponding compound
wherein R5 is triphenylmethyl. The triphenylmethyl group is
removed by treatment with acid, exactly as described herein-
before.
The starting materials of Formula III, wherein R5
is triphenylmethyl and R2 is hydrogen are prepared by a retro-
grade Michael reaction, on a corresponding compound wherein
R2 is -CH2CH2Y, wherein Y is selected from the group consist-
ing of cyano, alkoxycarbonyl having from two to seven carbon ; -
.~. . . .
atoms, phenoxycarbonyl, alkylsulfonyl having from one to four
carbon atoms, phenylsulfonyl and So2-NR15R16, wherein R15 and
R16 are each selected from the group consisting of hydrogen,
alkyl having from one to four carbon atoms, phenyl and benzyl.
The retrograde Michael reaction comprises treating the said --
compound with about one equivalent of base, using conditions ~ ;
known in the art for retrograde Michael reactions, but which
are compatible with the penam ring system. Typically, the
said compound of Formula IV is treated with about one equival- ; ;
ent of a relatively non-nucleophilic base, in a non-hydroxylic ~'
solvent, at a temperature in the range from about 0C. to ~
about 25 C., for a period of from about ten minute~ to about ~`
two hours. (Consult further Journal of the Chemical Society
~Londo ~, Part B, 5867 ~97 ~).
Preparation of those starting materials for Method :: -
C which are compounds of Formulae III and IV, wherein R5 is -
hydrogen, R and R are each selected from the group consist~
~ -49- -
',~'~ ' ''~. ''.' ' .
: ::
~)S~9'~
ing of alkanoyloxymethyl having rom three to eight carbon
atoms, l-(alkanoyloxy)ethyl having from four to nine aarbon
atoms and phthalidyl, is achieved by alkylation of a tetr-
azolate salt, such as the triethylamine salt of the corre-
sponding compound of Formula III or IV, wherein R2 and R3are hydrogen, using the appropriate alkanoyloxyalkyl or
phthalidyl halide. The procedure of Method D is used in
this process, except that it is common to utilize at least ~ -
two molar equivalents, and preferably about three molar
equivalents, of the alkylating agent.
The ultimate starting materials for production
of the antibacterial compounds of this invention are the
novel penam compounds of Formula III, wherein R5 is an amino
protecting group for example triphenylmethyl and R2 is a
tetrazolyl penam protective group for example oen selected
from the group consisting of -CH2CH2Y, -C(=o)-o-Rl4 and -; :
(R6)l, wherein Y, Rl4 and (R6)' are as previously defined.
The compounds can be prepared by a novel three step series
of reactions, which forms an important embodiment of this
invention, and which is now to be described and discussed in
detail.
The said novel penam derivatives of Formula III
can be prepared starting from the well-known intermediate,
6-triphenylmethylaminopenicillanic acid, via certain trans-
formations of the C-3 carboxyl function. Preparation of
6-triphenylmethylaminopeniaillanic acid i9 taught by Sheehan
and Henery-Logan in the Journal of the American Chemical
Society, 81, 5838 (1959).
In Step l, 6-(triphenylmethylamino)penicillanic
0 acid is converted into an amide of Formula VI
-50-
.
~)s~
CH3
(C6H5) 3-C-NH~/S~H3
~ N ¦ :
-~-NH-G
O .~.VI
wherein G is selected from the group consisting of : . -
-C(=o)=o-Rl4, -So2-Rl4, CH2CH2Y and R6; wherein R 4 is as
previously defined and R6 is selected from the group con- : :
., . :. ,
sisting of
R4)~
-~C~18~7)~
and
:
--CH ~X ~ R2 0 - .. .. ~;, .,
Rl9 ~ ~ c
wherein R 8, Rl9, R20, X and Y are as previously defined,
and (R41~ and (R4)" and (Rl7)" are each selected from the . .. - -:
. :- , .
group consisting 0f hydrogen, hydroxy, nitro, fluoro, chloro,
bromo, iodo, alkyl having from one to six carbon atoms,
alkoxy ha~ing from~one to six carbon atoms, phenyl and . i
~enzyloxy~
r ::.::: .- `.
In the case~wherein G is -CH2CH2Y or R~ the amide
o~ Formula VI is prepared by activation of the 3-carboxy . ....... .~.`
,. `:: . ` .
group of 6-~triphenylmethylamino)penicillani¢ acid, e.g~, : ` ;~
by mLxed anhydride ~ormation, followed by reaation with an :
20~ amine of Formula NH2CH2CH2Y or R6-NH2. Thus, formation of `~
the~mixed anhydride involves suspending or dissolving an ~.. ` ..
appropriate carbQxylate~salt of the 6-triphenylmethylamino- 5.'. ,'.'~ " '.'` ', '
penicillanic aaid in a reaction-inert organic solvent, and .. - -
:, : . . : . .
~()s'3~g~
then adding to this susp~nsion or solution a reagent selected
from pivaloyl chloride and lower-alkyl chloroformates. Appro-
priate salts are, ~or example, alkali metal salts, such as
sodium or potassium salts, and amine salts, such as triethyl-
ammonium, pyridinium, N-ethylpiperidinium or N,N-dimethyl-
anilinium salts. Appropriate solvents are those which serve
to dissolve at least one of the reactants, and the mixed an-
hydride product, and do not adversely interact with the re-
actants or product. Examples of such solvents are chlorinated
hydrocarbons, such as chloroform, methylene chloride; aromatic
hydrocarbons, such as benzene, toluene and xylene; and ethers,
such as diethyl ether, tetrahydrofuran and 1~2-dimethoxy~
ethane. ~he reaction is usually carried out at a temperature
in the xange from about -50C. to about 30C., and preferably
at about 0C. At about 0C., the reaction commonly requires
about one hour. The triphenylmethylaminopenicillanic acid
~alt and the pivaloyl chloxide or lower-alkyl chloroformate ~
axe normally present in roughly equimolar proportions, - -
although in some instances a small excess of the acid chloride -
component is used. The product can be isolated simply by - -
filtering off the insoluble materials, and then evaporating
... . .
the solvent in vacuo to give the crude product. The latter
can be used directly, or purified further by methods known ; ~-
in the art. If desired, however, the mixed anhydride product
need not be isolated~ It can be used in situ for reaction
with the amine of Formula NH2CH2CH2Y or R6-NH2. Reaction of ~ -
the mixed anhydride with the amine of formula R6-NH2 or ;; -
NH2CH2CH2Y is usually carried out simply by contacting the
reactants in an inert solvent, for about 0.5 to about 2.0 `~
hours, at a temperature in the range from about -30C. to
-52-
.
1()5~
about 30C. and preerably at around 0C. The same solvent~
identified above for mixed anhydride formation are u~eul for
the instant reaction, and the reagents are usually used in
approximately equimolar proportions. As will be realized by
one skilled in the art, the product should not be exposed
to an excess of the starting amine, since this runs the risk -~
of causing extensive decomposition of the penam ~-lactam.
In the cases wherein this reaction is conducted in a water~
immiscible solvent, the product is usually isolated by wash-
ing the reaction mixture with water and then concentrating
the organic solvent to dryness in vacuo, to give the crude
product, The latter product can be used immediately for
Step 2, or, if desired, it can be purified further by well-
known methods. However, it is sometimes convenient simply
to wash the reaction mixture with water, and then use the so- ~ - --`
produced solution of amide directly in Step 2. In the cases
:~ :, . . .
wherein the reaction is conducted in a water-miscible solv~
i: .: -: . .
ent, the product is usually isolated by first removing the ---
. ~ ., .- . ~: ~
water-miscible solvent by evaporation in vacuo, replacing it -
by a water~immiscible solvent, and then proceeding as de~
: '-.':. ::. .
scribed above, ~^; - -
,...,..-.: :.-
When the amine R6-NH2 is of formula:
~R4)"
R18~ ` ~ ;. ``
wherein either ~R4~" or tR17)" i9 a hydroxy group, it is
convenient to protect the phenolic hydroxy group of the
hydroxybenzylamide produced, before proceeding to Step 2. -
A wide variety of protecting groups known in the art for
protecting hydroxy groups are operative for this purpose.
,, ,; '
' . "' ':
..' :.
. - .
~(~s~L~g~
For example, the hydroxy group can be proteated as an alkoxy-
methyl or tetrahydropyranyl ether, or it can be silylated.
The types of silyl derivatives, and the methods of prepara-
tion, referred to hereinbefore under "Method C" are useful
in the instant process. Also, the hydroxy group can be con-
verted to an alkanoyloxy group, by reaction with an alkanoyl
halide, e.g., an alkanoyl chloride; or to a formyloxy group,
by reaction with formic acetic anhydride. Techniques for ~
the acylation of phenolic hydroxyl groups are discussed by ~ -
Sandler and Karo in "Organic Functional Group Preparations", ;~
Academic Press, New York & London, 1968, p 250. Conditions
compatible with the penam ring system must be chosen, how-
ever. This, of course, then provides intermediates ~rhich
are precursors of compounds of Formula III, wherein R5 is
triphenylmethyl and R2 is
R4 ~ :
-CH ~ R17
wherein either R4 or R17 are alkanoyloxy, formyloxy or alkoxy-
methoxy.
In the case wherein G is -C(=o)-o-Rl4 or So2-Rl4~
the amide of Formula VI is prepared by reaction of 6-~triphenyl- -
methylamino)penicillanic acid with the appropriate isocyanate rl
of Formula R14-o-C('oj-N=C~o or Rl4-So2-N~c=o~ ~he reaction
i~ usually carried out by contaating substantially e~uimolar
quantities of the reactants, in a reaction inert organic solv-
ent, at a temperature in the range from about 0C to about
30C., for a period of from about one hour to about twenty
hours. The product can be isolated simply by removal of the
solvent in vacuo or the solution of the amide of Formula VI
'~ ,; ' ~.
'
1~5~992
can be used ln situ for Step 2. The iisocyanates of formula
Rl4-o-(c=o)-N=c=o are prepared by reaction o a carbamate of
formula R14-o-C(=o)-NH2 with oxalyl chloride, and the iso-
cyanates of for~ula Rl4-So2-N=c=o are prepared by reaction
S of a sulfonamide of formula Rl4-So2-NH2 with oxalyl chloride~
(See J. Hetero. Chem., 6, 261 tl969). ~ -
In Step 2 of the said novel three-step series of
reactions, the product from Step 1, or a simple transforma-
tion product thereof in which any phenolic hydroxy groups
have been converted into an alkanoyloxy, formyloxy or alkoxy- -~
methoxy group, as discussed above, is converted into an ~ ;
imidoyl chloride of formula: -
.. . .. .
CH3 - - - -- -
S . - .,
(C6H5)3-C-NH ~ \ - CH3
o C=N-G' ;
.- .
Cl
wherein G' is selected from the group consisting of -CH2CH2-Y,
-C(=o)-o-R14, -So2R14 and (R6~', wherein Y, R14 and (R6)' are
.. ~ .:.: ..: :
as previously defined. For imidoyl chloride formation, a ;
convenient method comprises dissolving the said amide in a
- ... ...
reaction-inert organic solvent and then ~reating the solution
with phosgene and a tertiary amine. About one mo}ar equival-
ent of phosgene is usually used, but amounts up to about twoor three molar equivalents are sometimes employed~ The
tertiary amine is pre~erably present in an amount equal to or
greater than the amount of phosgene. The reaction is carried
out at a temperature in the range from about -20C. to about
30C., and preferably at about 25C~, and it usually requires
a few hours to reach completion. It is sometimes advantageous,
,~
-55-
.: . "
.' ' ' ''-' ~
.:
' ,.:
~t~s~99~
from a standpoint of has~ening complete conversion to imino
chloride, to add fur~her quantities of tertiary amine and
phosgene as the reaction proceeds~ A variety of tertiary
amines can be used in this process, for example trimethyl-
amine, triethylamine, N,N-dimethylaniline, N-methylmorpholine
and pyriding, and the like, and typical solvents which can
be used are chlorinated hydrocarbons, such as chloroform,
methylene chloride and 1,2-dichloroethane, and ethers such
as tetrahydrofuran and 1,2-dimethoxyethane. If desired, the
imidoyl chloride can be isolated by evaporation of the
filtered reaction mixture, but in many instances it is con-
venient to use the imlno chloride in situ. `
Several other reagents, for example r thionylchloride or a phosphorus halide such as phosphorus penta-
chloride are operative in the imidoyl chloride forming re~
action, Moreover, if desired, use can be made of the corre- ~ `
sponding imidoyl bromide~
In Step 3 of the said novel three-step series of
reactions, the above imidoyl chloride is converted into a
tetrazolylpenam compound of formula
CH3
(C6HS~3-c-NH ; ~ H3
N ~ ~ N
N _ N~
G~'
wherein G' is as previously deined, ~his transformation
comprises treating the said imidoyl chloride with a source
of azide ion and a convenient way o carrying out this trans-
: .
formation involves dissolving the imidoyl halide in anappropriate solvent, and then adding about one molar equiv-
-56- -~
:. :' :
.'"'' ~ '
l(JS~9;~
alent, or sometimes a small excess, of the azide ion source.
The reac~ion mixture is then stored at or about ambient
temperatures for several hours, for example, overnight, until
conversion into ~etrazole is substantially complete. A wide -
S variety of azide ion sources are operative in this process, ~-~
and excamples of those which are particularly valuable are
- .. . - .-
trialkylsilyl azides having from one to four carbon atoms ~-
.. . .
in each of said alkyl groups, such as trimethylsilyl azide - -
..; .: - . . -
and triethylsilyl azide; metal salts of hydrazoic acid, such
as potassium azide and sodium azide, tributylammonium azide, :: ;
N,N-dimethylanilinium azide, N-methylmorpholinium azide and ~ -
.: :, --
pyridinium azide; tetramethylguanidinium azide. Appropriate
.... .
solvents are those which will serve to dissolve both the ~ -
imidoyl halide and the azide ion source, but do not adversely ~ -
react with either the reactants or the products of the pro~
cess. In the cases where the azide ion source is a trialkyl~
:: . - -1: , .
5ilyl azide or a trisubstituted ammonium azide, chlorinated ~-~
hydrocarbon solvents, such as chloroform, methylene chloride `
and 1,2-dichloroethane, are commonly used. However, dipolar
aprotic solvents such as N-methy}pyrrolidine, can also be
used; and in the cases where a metal salt of hydrazoic acid
, ",.
constitutes the azide ion source, these dipolar aprotic solv-
ents become the solvent-type of choice. As regards ease of
operation, and availability of reagents, the use of trimethyl-
25 8ilyl azide in chloroorm is partiaularly convenient. Asindicated earlier, the reaction takes several hours to reach
dompletion. ~owever, the conversion to tetrazole can often ~;
. , ~ ,
~ ~ be hastened by adding further quantities of azide ion during : -
, .
;~ the course of the reaction. Product isolation is achieved - :
- 30 using~standard methods~ ~hen a low boiling chlorinated hydro- -~
~ -57-
i .:: . .. ..
. ::
. ,. ,.''.: . -.'., .
.:: - ., .:
; , ~ : -
g;~
carbon is the solvent, the reaction solution is washed with
dilute alkali and then the organic solvent is evaporated of~.
When a dipolar aprotia solvent is the solvent, the reaction
mixture is usually first diluted with a large excess of
dilute alkali, and then, after appropriate adjustment of the
pH, the product is isolated by solvent extraction.
As indicated hereinbefore, synthesis of the anti-
bacterial agents of this invention involves the use of two
kinds of protecting groups, and these groups have been
identified in terms of their ability to function in a parti-
cular fashion.
The tetrazolylpenam nitrogen protecting group has
been identified in terms of its ability to fulfill two func-
tions. The first of these, its capacity to be removed under
certain specified conditions, has already been discussed.
The second of these is its ability to permit the synthesis
of a compound of Formula III, wherein R5 is an amino protec- ~
ting group and R2 is the said tetrazolylpenam nitrogen pro- -
tecting group.
From the foregoing discussion it will be apparent
that the tetrazolylpenam nitrogen protecting group must be
a group which will permit operation of the above-described -
three-step series of reactions. That is, it must be of such ~
, . . .
a nature that the amide of Formula VI can be prepared, that `
the amide can be converted to an imidoyl halide, and that
the imidoyl halide can be converted to the saie l protected
5-tetra201ylpenam compound of Formula IV, substantially as ~-
described, `~
In like manner, the amino protecting group must
fulfill two functions~ The first of these is that, after
-58~
', ' . .
: : -
~)5S~9;~
attachment ~o the 6-amino function of 6-aminopenicillanic ~.
acicl, it must permit operation o~ the above-described three- .
step series of reactions. That is, it must protect the penam
ring system during formation o the amide of Formula VI,
during conversion into an imidoyl halide, and during con- : .
version into the l-protected 5-tetrazolylpenam compounds ~:
of Formula III. ~he second function of an amino protecting : -` : :
group for use in this invention, is that it must be removable . -
under conditions which do not decompose the penam ring system
~... ,. ,., .. :.. ,,... -,
from either: (a) a compound of Formula III, wherein R5 is
the said amino protecting group and R2 is a tetrazolylpenam ~ ~ .
nitrogen protecting group; (b) a compound of Formula III,
wherein R5 is the said amino protecting group and R2 is hydro~
gen; or (c) a compound of Formula III wherein R5 is selected .~ : .
from the group consisting of alkanoyloxymethyl, l-(alkanoyl- .-. . .
oxy)ethyl and phthalidyl. :
Selec~ion of appropriate amino protecting groups : ~.
will ~e achieved readily and easily by one skilled in the :.
art. In particular all such groups known in the art for :
peptide synthesis are operative. However, particularly con- : .
venient protecting groups are triphenylmethyl, substituted .: ::
triphenylmethyl and ~ -trihaloethoxycarbonyl, such as
~ tribromoethoxycarbonyl and ~ trichloroethoxy- ~ :
carbonyl. Examples of substituted triphenylmethyl groups
which are espeaially ~aluable are those of ~ormula~
.;
~ ' ' , . .:
... . ..
.., ... ~,.,, .-..
.: . - ::
.. . . .
; ' .'':
,, ~...:, .
. , : .: : , .
-59~
: .
,.;.. . .
::: :
,:' ~::
. . ~:~ ,.. : .
~. .. ..
R22
R2~ C
R24
wherein R22, R23, and R24 are eaah selected from the group
consisting of hydrogen, fluoro, chloro, bromo, alkyl having
from one to four carbon atoms, alkoxy having from one to
four carbon atoms and phenyl. Because of its readily avail~
ability, the triphenylmethyl group is especially valuable. ~
The amines of formulae NH2CH2CH2Y and NH2-R6, used - -
in Step 2 above, are either known compounds or they are pre- ~ -
.. .. .
pared by known methods from commercially-available starting ~ -
-.
materials. For example, amines of formula - :
:: ;:.:: . .
tR4)" :
NH2 CH ~ -
R18 ~ (R17)1. . .VII
can conveniently be prepared from the corresponding alde~
hyde or ketone o ormula
O-C .. _.~( > ~,`''': ,
R18 ~ ~R17)n ~-
15 ; via~conver~ion to the oxime followeù by reduction, or, in `:
cases where the ~R4)" and/or ~R14)" groups would be unaffec- ~ -
ted, by the reductive;alkylation of ammonia. (Consult
H~arrLson and ~arrison, "Compendium of Organic Synthetic
~ ~, ., .: . .
~ 60- ~
: . : . ~.. ::
.
~()59~
Methods", Wiley-Interscience, 1971, pages 233-235 and 25~-261).
A further sub-class of novel 3-(S-tetrazolyl)penam
compounds which are valuable antibacterial agents, and which
fall within the scope and purview of the instant invention
are those compounds of formulae:
- CH- C ~ ~`
C ~ ~ ~ N
N
R ~ ... VIII
R8 ~/0
CH
C ~ ~ ~
0 ~ N ~ -.
C N : : -
N ~ Rll ~ ~
.~ ,;..''.' :..
, . . : . .
wherein R8 is se}ected from the group consisting of phenyl,
.. . . .
1,4-cyclohexadienyl, 3-sydnonyl, thienyl, furyl, pyridyl, . ; :.
thiazolyl, isothiazolyl, tetrazolyl, triazo}yl, imidazolyl, . :
pyrazolyl, substituted phenyl, substituted thienyl, substi- :
tuted furyl, ~ubstituted pyridyl, substituted thiazolyl,
substituted isothiazolyl, substituted triazolyl, substituted ..:
imidazolyl and substituted pyrazolyl, each substituted moiety . .
.
being substituted by up to two members selected from the :~
: . ,.
group consisting of fluoro, chloro, bromo, hydroxy, alkyl
having from one to six carbon atoms, alkoxy having from one ` :
-61-
, . ..
to six carbon atoms and alkylthio having from one to six
carbon atoms; R9 and RlO are each selected from the group
consisting of hydrogen, methyl and ethyl; and Rll is selèat-
ed from the group consisting of hydrogen, alkanoyloxymethyl
having from three to eight carbon atoms, l-(alkanoyloxy)-
ethyl having from four to nine carbon atoms and phthalidyl.
The compounds of Formula VIII and IX are prepared from the
corresponding compound of Formula I or II, wherein Rl is of
Formula V wherein n is 1, Q is amino and R7 is as defined
above for R8 and R2 and R3 are as defined above for R11, by
condensation of the said compound of Formula I or II with
the appropriate aldehyde or ketone of Formula R9-CO-Rl0.
The condensation reaction is usually carried out by contact-
ing the starting penam compound with a large excess of the -
aldehyde or ketone in the presence of at least one molar ~-
equivalent of a tertiary amine, at or slightly below room
temperature. A sufficient amount of the aldehyde or ketone
is normally used so that a further solvent is not necessary. `
However, a further diluent which does not adversely react
with either the starting materials or the product can be -~
used if desired~ Examples of tertiary amines which are -;~
operative in the process are triethylamine, tributylamine,
pyridine, N,N-dimethylaniline, N-methylmorpholine and
quinoline. Although at least one equivalent of tertiary -
amine is required, it is common to use a fairly large excess,
up to about ten molar equivalents. ~he instant process
normally requires a reaction time of several hour~, for ex-
ample overnight. In those cases wherein the product is out
of solution at the end of the reaction it is filtered off.
Alternatively, when the product is in solution at the end of
~ -62- ;~
~s~g~
the reaation, it is recovered by evaporation of the solvent
in vacuo.
A still further sub-ala3s of novel 3-(5-tetrazolyl)-
penam compounds which are valuable antibacterial agents,
and which fall within the scope and purview of this invention, . .
are those compounds of Formulae~
Rl ~ S CH3 :
N y CH3
C ~ - N
N
R~ ... X ~ -
N_C~=N ~ ~ 3
N
N N ~
Rll ... XI : .
: ~ wherein R12 and R13 are each alkyl having fram one to six
carbon atoms, or, when taken together with the nitrogen to . -.
wh~ch they are attached, they represent a member selected ;
from the group consisting of pyrrolidino, morpholino, piper- ::
idlno and a~acycloheptan-l-yl7 and Rll is as defined above,
The compounds of Formula X and XI, are prepared from the ~ :
appropriate oorresponding compound of Formula III or IV,
wherein R2 and R3 ar- ao defined above for Rll and R5 is .
hydrogen, by introducing the formamidine moiety, using the
methods taught by Lund and Tybring ( ature, New Biology, ~ :
236, 135 /197 ~
A characteristic feature of the compounds of
.
' :
: . . ', '
Formulae I, II, III, IV, VIII, IX, X and XI, ~rherein R2, R3
and Rll are hydrogen, is their ability to form salts. By
virtue of the acidic nature of a 5-monosubstituted tetrazole,
the said compounds have the ability to form salts with basic
agents, and these salts, referred to generically as
"tetrazolate" salts in this specification, are to be con- -
sidered within the scope of this invention. The salts can .
be prepared by standard techniques, such as contacting the ::
acidic and basic components, usually in a 1:1 molar ratio, ~ :
in an aqueous, non-aqueous or partially aqueous medium, as - -
appropriate. They are then recovered by filtration, by
precipitation with a non-solvent followed by filtration, by
evaporation of the solvent, or, in the case o~ aqueous solu- - .
tions, by lyophilization, as appropriate~ Basic agents :- .
which are suitably employed in salt formation belong to - ~
both the organic and inorganic types, and they include .; ;
ammonia, organic amines, alkali metal hydroxides, carbonates,
~icarbonates, hydrides and alkoxides, as well as alkaline
earth metal hydroxides, carbonates, hydrides and alkoxides. . -
~epresentative examples of such bases are primary amines, ~ .
such as n-propylamine, n-butylamine, aniline, cyclohexyl-
amine, benzylamine, ~-toluidine and octylamine; secondary . .
amines, such as diethylamine, N-methylaniline, morpholine, :
pyrrolidine and pipexidine; tertiary amines, such as triethyl-
amlne, N,N-dimethylaniline, N-ethylpiperidine, N-methyl-
morpholine and 1,5-diazabicyclo/4,3.07non-5-ene; ~ydroxides,
such as sodium hydroxide, potassium hydroxide, ammonium
hydroxide and barium hydroxide; alkoxides, such as sodium
ethoxide and potassium ethoxide; hydrides, such as calcium
hydride and sodium hydride; carbonates, such as potassium : ~-
-64- . ~ ~ :
~059~9'~
carbonate and sodium carbonate; and bicarbonates, such as
sodium bicarbonate and potassium bicarbonate.
Further, the compounds of Formulae' ~and II,
wherein Rl contains one or more acidic functions (e.g.,
carboxy, sulf~ etc.), have the ability to form other salts
(e.g., salts of the carboxylate and sulfonate tupe). ~hese -
salts, which can be prepared in exactly the same manner and
using the same basic agents, as described above for the -
tetrazolate salts, are also within the purview of this in- ~ -
vention. Clearly, certain of the compounds of Formulae I ~ -
and II can form both mono- and poly-salts. When considering - -
: :.: . . ,.- .
poly-salts, the various cationic moieties can be the same or ~ -
different.
The compounds of Formulae I, II, III and IV which
contain a basic group, have the ability to form acid-addi-
tion salts. Said acid-addition salts are also to be con-
sidered as being within the scope of this invention. Ex-
:~, . .. .
amples of acid-addition salts which are particularly valuable
are: hydrochloride, hydrobromide, phosphate, perahlorate,
citrate, tartrate, pamoate, glutarate, benzoate, sulfate,
lactate, and arylsulfonate salts. `~
When therapeutic use in mammals is being contem-
plated for a salt of a compound of the instant invention, it
is of course essential to use a pharmaceutically-acceptable
2S salt. However, other salts are useful for a variety of other
purposes; such as, for example, isolating and purifying in-
dividual compounds, changing the solubility characteristics
of an individual compound, and for interconverting pharma-
ceutically-acceptable salts with their non-salt counterparts.
.... ~ ..
The antibacterial penam compounds of the instant ~ -
-65- ` ~ ~
`',` ' '' ' -
. :
~05~t3~Z
invention show activity against a wide variety of gram-
positive and gram-negative bacteria. Th~ in vitro activi,ty '
can be demonstrated by the oonventional two-fold serial dilu-
tion technique in Brain-Heart Infusion broth (Difco). The
broth is inoculated with the bacterial culture, and with ,
the test antibiotic, and then it is incubated overnight. ,On the next day, the test is read visually. The minimum -''
inhibitory concentration (MIC) is the lowest concentration ' -
of antibiotic which prevents'turbidity, i~e. r which prevents ,-
growth of the microorganism. In vitro activities of several -
o~ the penam compounds of the invention are presented later
in this specification.
The in vitro activity of the antibacterial compounds ~ '
of the instant invention makes them particularly suitable
for topical application, for example, in the form of creams
and ointments, and for the sterilization of sickroom and -~
hospital surfaces, equipment, and the like. ,, `'
The antibacterial penam compounds of the instant ~ ,-
invention are also active in vivo. In determining such
activity, the test antibiotic is administered to infected ,~
mice, using a multiple dosing regimen. The severity of the '
infection varies from about one to about ten times that ' -
needed to kill 100% of the mice under the conditions of the ' ~
test. At the end of the test, the activity of a compound i9
assessed by counting the number of survivors among the treated ~ ~
an1mals. Both the subcutaneous ~SC) and the oral (PO) dosage , ' '~ -
routes are used. Results are given in Table I for two of - -
the compounds of the invention. The ability of the compounds '
.:: , -
to protect mice against systemic infections caused by a lethal -
intraperitoneal inoculum of Staphylococcus aureus or of '-
~'' ',: '
,;: . ~,.
~ os5~{~g~ .
Escheriahia c _ is presented.
TABLE I
DOSAGE PER CENT PROTECTION
COMPOUND (mg./kg.) DOSAG~ S~ aureus E. coli :
56-(D-2-amino-2-
/3-thienyl7-acet-
amido)-2,2-di- . ~
methyl-3-(5-tetr- :
azolyl)-penam 50 SC 40 20 :
. .
" 25 SC 60 20 ~-
" 12 SC 50
" 6 SC 50 ::
.. 200 PO
6-tD-2-amino-2- ~:
/p-hydroxyphenyl7- :.
acetamido)-2,2-~i- . . ~
methyl-3-(5-tetr- ~ :
azolyl)-penam 50 SC 80 100 :
" 25 SC 70 80 : :
" 12 SC 50 ..
" 6 SC 50
" 200 PO 100 :
The in vivo activity of the antibacterial compounds of this
invention makes them suitable for the control of bacterial
in~ections in mammals, including man, by both the oral and -
parenteral modes of administration. The compound~ will find
wide use in the control of infections caused by susceptible ~ -.
gram-positive and gram~negative bacteria in human sub~ect~.
When cons~dering therapeutic use of a compound of :
this invention, or a salt thereof, in a mammal, particularly ~ -
man, the compound can be administered alone, or it can be ;~-.
mixed with other antibiotic substances and/or pharmaceutic- . `
ally-acceptable carriers or diluents, Said carrier or
diluent is chosen on the basis of the intended mode of ad-
~ ,
~05~
ministration. For example, when considering the oral mode
of administration, an antibaaterial penam compound o this
invention can be used in the form of tablets, aapsules,
lozenges, troches, powders, syrups, elixirs, aqueous solu-
S tions and suspensions, and the like, in accordance withstandard pharmaceutical practice, The proportional ratio
of active ingredient to carrier will naturally depend on
the chemical nature, solubility and stability of the active
ingredient, as well as the dosage contemplated. In the case
of tablets for oral use, carriers which are commonly used ~ -
include lactose, sodium citrate and salts of phosphoric acid.
Various disintegrants such as starch, and lubricating agents,
such as magnesium stearate, sodium lauryl sulfate and talc,
are commonly used in tablets. For oral administration in
capsule form, useful diluents are lactose and high molecular
weight polyethylene glycols. When aqueous suspensions are ; ~ ;
required for oral use, the active ingredient is combined
with emulsi~ying and suspending agents, If desired, certain
s~eetening and~or flavoring agents can be added, For paren~
teral administration, which includes intramuscular, intra-
. .. .. .
peritoneal, subcutaneous and intravenous use, sterile solu~
tions of the active ingredient are usually prepared, and the `~
pH of the solutions are suitably adjusted and buffered. For
intravenous use, the total concentration of solutes should
be controlled to render the preparation isotonic.
As indiaated earlier, the antibacterial penam com~
pounds of this invention are of use in human sub~ects and
the daily dosages to be used will not differ significantly
r`~
~ from other, clinically-used, penam antibiotics. The pre- :
::: - . . - -
scribing physician will ultimately determine the appropriate -
.,:
-68- - ~
~ .; . ' ... .:
....: - .
:'-. ', .-. ~ '-
:. - . -
' ;, ~: ':. :' .
:. , : .-
~QS~yl9;~
dose for a given human sub;ect, and this can be expeated to
vary according to the age, weight, and response of the in-
dividual patient, as well as the nature and the severity
of the patient's symptoms. The compounds of this invention
will normally be used orally at dosages in the range from
about 10 to about 200 mg. per kilogram of body weight per
day, and parenterially at dosages from about 5 to about -
100 mg. per kilogram of body weight per day. These figures ~ -
are illustrative only, however, and in some cases it may be
necessary to use dosages outside these limits.
Certain of the compounds of this invention have
the ability to form solvates (e.g., hydrates), and all such
hydrates are to be considered within the scope and purview
of the invention. , -
The following examples are provided solely for
the purpose of further illustration. Infrared (IR) spectra~ ~ -
are measured as potassium bromide discs (KBr discs) or as
Nujol mulls, and diagnostic absorption bands are reported in ~-
wave numbers (cm~l). Nuclear magnetia resonance spectra ~ -
~MRl are measured at 60 MHz for solutions in deuterochloro-
form tCDC13), perdeutero dimethyl sulfoxide (DMSO-d6) or '
deuterium oxide ~D20), and peak positions are expressed in
~. :
parts per million ~(ppm) downfield from tetramethylsilane or ~
sodium 2,2-dimethyl-2-silapentane-5-sulfonate. The follow- -
ing abbreviations for peak shapes are used: 9, ~inglet;
d, doublet; t, tripleti q, ~uartet~ m, multiplet.
.
-69-
., ~ '
~(~5~
EXAMPLE I
6-(Triphenylmethylamino)-2,2-dimekhyl-3-(1-~-methoxybenzy ~-
_etra~ol-5-yl)penam
6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-~-meth-
oxybenzyl7carbamoyl)penam -- To a stirred slurry of 216 g.
of 6-aminopenicillanic acid in 1,500 ml. of anhydrous chloro-
form is added 278 ml. of triethylamine, and the mixture is
then stirred at ambient temperature until a clear solution
is obtained. This requires about 15 minutes. The solution
is cooled to about 0 C., and then 306 g. of triphenylmethyl
chloride is added. The stirring is con~inued at about 0C.
for 30 minutes, and then at ambient temperature for a further
24 hours. The mixture is cooled to about 0C. again, and
14 ml. of triethylamine, followed by 95 ml. of ethyl chloro-
formate, is added. During this process the temperature
rises to about 15C., and a precipitate forms. To facilitate
stirring a further 200 ml. of chloroform is added. The
stirring is continued for 30 minutes. Then, at about 0C.,
50 ml. of 4-methoxybenzylamine (available from the Aldrich
Chemical Company, Inc.) is injected into the reaction medium,
below the surface of the solvent. At 10 minute intervals,
three further ali~uots of 4-methoxybenzylamine (35 ml., 25
ml. and 21 ml.) are injected in the reaction in similar l
fashion. The total volume of 4-methoxybenzylamine added is
131 ml. ~he ¢ooling bath is then removed, and the reaction
is stirred for a further 1 hour. ~he ahloroform solution is
washed successively with five 2,000 ml. portions of water and ~
one 2,000 ml. portion of saturated brine. The chloroform is ~ - --
finally dried using anhydrous sodium sulfate. ;~
Examination of the reaction mixture at this point
-70-
': ''.',' - ' '; '
',~', . ' - '
~05~
by NMR spectroscopy, reveals that the conversion into amide
i8 approximately 85% complete. Accordingly, the chloroorm
solution i9 cooled in an ice-bath and 21 ml. of triethyl-
amine, followed in about 5 minutes by 14.2 ml. of ethyl chloro-
formate, is added. After a further 15 minutes, 9.8 ml. of
4-methoxybenzylamine is added, and then in another 5 minutes
a further 9.8 ml. of 4-methoxybenzylamine is added. The
reaction is concentrated in vacuo giving 6-(triphenylmethyl-
amino)-2,2-dimethyl-3-(N-~4-methoxybenzyl7carbamoyl)penam,
as an amorphous solid.
6-~Triphenylmethylamino)-2,2-dimethyl-3-(chloro-
/N-(4-methoxybenzyl)imino7penam -- The amide described above
is dissolved in 480 ml. of pyridine, and then the solution
is cooled to about -5C. To this solution is added dropwise,
:: . -
with stirring during 10 minutes, 108 ml. of thionyl chloride.
me reaction mixture is then allowed to warm slowly to ambient ;
temperature for a further 21 hours. All the volatile com-
ponents are removed in vacuo leaving the crude imino chloride
as an amorphous solid. The NMR spectrum (in CHCl3) of this
product shows absorption bands at 4.70 ppm tsinglet~ C-3
hydrogen), 4.65 ppm (singlet, benzyl hydrogens), 4.30-4.60 ppm
(multiplet, C-5 and C-6 hydrogens), 3.75 ppm (singlet, methoxy
hydrogens), 1.57 ppm (singlet, C-2 methyl hydrogens) and 1.38
ppm (singlet, C-2 methyl hydrogens).
6-~Triphenylmethylamino)-2,2-dimethyl-3-(l-~-meth-
oxybenzyl7tetrazol-S-yl)penam -- The imino chloride described :
above is re-dissolvea in 500 ml. of chloroform and then the
solution is cooled to about -5C. in an ice-salt bath. To
the solution is then added, with stirring, 160 ml. of tri-
methylsilyl azide tavailable from the Aldrich Chemical Com- ~-71- ~ --
.
ll)S~
pany, Inc.). After being allowed to warm to ambient temper-
ature, the reaction mixture is stirred for a further 22 hours.
It is then cooled to about 0C. and 2,000 ml. of 1.5N sodium
hydroxide solution is added, followed by sufficient additional
1.5N sodium hydroxide to bring the pH of the aqueous to 6Ø
The aqueous phase is separated off, and the chloroform phase
i5 washed successively with five 2,000 ml. portions of water
and one 500 ml. portion of saturated brine. The chloroform -
is then dried by filtration through anhydrous sodium sulfate, -
~nd finally concentrated to dryness. The residue is tri-
turated with 1,000 ml. of ether, and then filtered off. This ;
affords 150 g. of crude product, m.p. 174-178C. The crude --
product is purified by re-dissolving it in chloroform and
filtering the solution through chromatographic grade silica
gel. The chloroform is removed by evaporation in vacuo, and
the residue is again triturated with ether. This affords
128 g. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4- -
methoxybenzyl]tetrazol-5-yl)penam as a light tan solid,
m.p, 193-195C. The infrared spectrum (KBr disc) of the pro~
duct shows an absorption band at 1790 cm 1 (~-lactam carbonyl). --
The NMR spectrum (in CDC13) shows absorption bands at 7.25 ppm ;
tmultiplet, aromatic hydrogens), 5~50 ppm (broad singlet, -
~enzyl hydrogens), 5.05 ppm (singlet, C-3 hydrogen), 4.40 ~`
ppm ~broad singlet, C-5 and C-6 hydrogens), 3.80 ppm (singlet, --
methoxy hydrogens), 1.45 ppm (singlet, C-2 methyl hydrogens) ; ~ ;
and 0.70 ppm (singlet, C-2 methyl hydrogens).
EXAMPLE II ~-
The following compounds are prepared by repeating
the procedure of Example I, except that where necessary the ~ - -
triphenylmethyl chloride is replaced by an equimolar amount
-72- -~;
' ,''.. ;''.', '
, .' ~' ,. .
, . '` ,~
of the Appropriately-substituted triphen~lmethyl chloride,
and where necessary the 4-methoxybenzylamine i~ replaaed by
an equimolar amount of the requisite amine.
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-benzyltetr-
azol-5-yl)penam,
6-~triphenylmethylamino)-2,2-dimethyl-3-(1-[2-methoxy-
benzyl]tetrazol-5-yl)penam, .-
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-14-isopro~
poxybenzyl]tetrazol-5-yl)penam, -
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[3-chloro- ' ~ -
benzyl~tetrazol-5-yl)penam, .
6-(triphenylmethylamino)-2,2-dimethyl-2-(1-13-methyl-
benzyl]tetrazol-5-yl)penam,
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-~3-chloro~
4-methoxybenzyl]tetrazol-5-yl)penam, : . -
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[1-phenyl-
ethyl]tetrazol-5-yl)penam, :
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetr- -
azol-5-yl)penam, : -
6-(diphenyl-4-fluorophenylmethylamino)-2,2-dimethyl-3- . ~ -
(1-[4-nitrobenzyl]tetrazol-5-yl)penam,
6-(diphenyl-3-tolylmethylamino)-2,2-dimethyl-3-(1-14-
ethoxybenzyl]tetrazol-S-yl)penam,
6-(diphenyl-2-methoxyphenylmethylamino)-2,2-dimethyl-3- :
~1-14-phenylbenzyl]tetrazol-5-yl)penam,
6-~diphenyl-4-chlorophenylmethylamino)-2,2-dimethyl-3- ~ ; .
.. .
~l-ldiphenylmethyl]tetrazol-5-yl)penam, -.
6-~diphenyl-4-bromophenylmethylamino-2,2-dimethyl-3- :~:
1-[2-thienylmethyl]tetrazol-5-yl)penam, ~.
~ 30 6-~di[4-methoxyphenyl]phenylmethylamino)-2,2-dimethyl- ~ ~-
: 73 ~ -
~ ~`: ' ' ' , '
~ : .
, ' , '
1()5g~
3~ benzyltetrazol-5-yl)penam,
6-(di[3-chlorophenyl]phenylmethylamino)-2,2-dimethyl-3-
(1-[4-methoxybenzyl]tetrazol-5-yl)penam,
6-(di[2-tolyl]phenylmethylamino)-2,2-dimethyl-3-(1-
~2,4-dimethoxybenzyl~tetrazol-5-yl)penam,
6-(~4-chlorophenyl][4-methoxyphenyllphenylmethylamino)-
2,2-dimethyl-3-(1-[4-methoxyphenyl)ethyl]tetrazol-5-yl)penam,
6-(di[4-fluorophenyl][biphenylyl]methylamino)-2,2-di-
methyl-3-(1-[1-(4-chlorophenyl)butyl]tetrazol-5-yl)penam,
6-(tri[4-tolyl]methylamino)-2,2-dimethyl-3-(1-[(4- -- --~
methoxyphenyl)phenylmethyl]tetrazol-5-yl)penam,
6-(tri~3-ethoxyphenyl]methylamino)-2,2-dimethyl-3-(1- -~
[4-ethylbenzyl]tetrazol-5-yl)penam,
6-(diphenyl-[3-bromophenyl]methylamino)-2,2-dimethyl-
3-(1-[3-furylmethyl]tetrazol-5-yl)penam, and ~
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[5-methyl- --
furfuryl]tetrazol-S-yl)penam, -
respectively. ~; ;
EXAMPLE III
6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[4-benzYloxy-
benzyl]tetrazol-5-yl)penam -
6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-4-benzyl- -
oxybenzyl]carbamoyl)penam -- To a stirred solution of 20.0 g. -
of 6-triphenylmethylamino-penicillanic acid (Sheehan and -~
Henery-Logan, Journal of the American Chemical Society, 81, -
5836 ll9S9]) in 140 ml. of acetone, at 0-5C., is added
6.08 ml. of triethylamine followed by 5.78 ml. of isobutyl .
chloroformate. After a further 10 minutes, the mixture i8
filtered directly into a stirred solution of 9.28 g. of
4-benzyloxybenzylamine in 1,000 ml. of water and 300 ml. of -
-74-
.' . '~ -.
,,:
s~t~g~
acetone at ambient temperature. The mixture so obtained is
stirred for 4 minutes, and then an additional 500 ml. of
water is added. Stirring is continued for a further 7
minutes, and then the reaction mixture is extracted with
ether. The ether is dried using anhydrous magnesium sulfate,
and then evaporated to dryness in vacuo. The crude product
so obtained is redissolved in 200 ml. of ether, which is
then added dropwise over 10 minutes to 2,500 ml. of hexane. ~-
The solid which precipitates is filtered off, giving 21.5
g. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-benzyl-
oxybenzyl]carbamoyl)penam.
6-(Triphenylmethylamino)-2,2-dimethyl-3-(chloro-
[N-(4-benzyloxybenzyl)imino]methyl)penam -- To a stirred
solution of 2.0 g. of the above-described amide in 10 ml. ~ ---of dry chloroform, at 0-5C., is added 0.99 ml. of pyridine, -
followed by 5.42 ml. of a 2.26 M solution of phosgene in
chloroform. The reaction mixture is then stirred at ambient
temperature overnight. At this point, it is evaporated to
dryness in vacuo, yielding a viscous gum, which is extracted -~
with 100 ml. of ether. The ether is filtered, and evapora-
tion of the filtrate affords the imino chloride as a yellow
foam.
6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[4-
benzyloxybenzyl]tetrazol-5-yl)penam -- The above described
imino chloride is redissolved in 8 ml. of dry N,N-dimethyl-
formamide. To th1s solution is added 249 mg. of potasslum
azide, and the turbid solution is stirred at ambient tempera- -
ture for 2.25 hours. The solvent is evaporated at ambient
temperature, under high vacuum leaving a brown gum. This
residue is partitioned between 60 ml. of water and 150 ml.
-75-
:
:
5~Z
of ether. The ether phase is separated off, wa~hed with
saturated brine, dried using anhydrous sodium sulate, and
finally evaporated to dryness in vacuo. The residue is
980 mg. of 6-(triphenylmethylamino)-2,2-dimethyl-3~ [4-
benzyloxybenzyl]tetrazol-5-yl)penam. Its NMR spectrum (in
CDC13) shows absorption bands at 7.30 ppm (multiplet,
aromatic hydrogens), 5.45 ppm (quartet, benzyl hydrogens),
5.05 ppm (singlet, C-3 hydrogen), 5.00 ppm (singlet, benzyl
hydrogens), 4.40 ppm (multiplet, C-5 and C-6 hydrogens), ~ ~
1.40 ppm (singlet, C-2 hydrogen) and 0.70 ppm (singlet, C-2 - -
hydrogen). ~ ~
EXAMPLE IV - ~-
The procedure of Example III, is repeated, except - -
that the 4-benzyloxybenzylamine used therein is replaced by ~
an equimolar amount of the appropriate amine, to produce -; -- - -
: .: . - . . .
the following congeners:
6-(triphenylmethylamino)-2,2-dimethyl-3-(l-[4-methoxy- ;
benzyl]tetrazol-5-yl)penam,~;
::
6-(triphenylmethylamino)-2,2-dimethyl-3-(l-14-n-hexyl- `
20 oxybenzyl]tetrazol-5-yl)penam, ;
6-(triphenylmethylamino)-2,2-dimethyl-3-(l-~4-fluoro-
..... ~
benzyl]tetrazol-5-yl)penam, ;
6-(triphenylmethylamino)-2,2-dimethyl-3-(l-14-isopropyl-
benzyl]tetrazol-5-yl)penam,
6-(triphenylmethylamino)-2,2-dimethyl-3-(l-13,4-di-
methoxybenzyl]tetrazol-5-yl)penam,
6-(triphenylmethylamino)-2,2-dimethyl-3-(l-[3,5-di- `~
chlorobenzyl~tetrazol-5-yl)penam,
6-(triphenylmethylamino)-2,2-dimethyl-3-(l-13-chloro-
4-ethoxybenzyl]tetrazol-5-yl)penam,
~'':`'''' ~ '''
: . .. : :
.:,
~os~9~
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-~1-(4-
chlorophenyl)ethyl]tetrazol-5-yl)penam,
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-~1-phenyl-
propyl]tetrazol-5-yl)penam,
6-(triphenylmethylamino)-~,2-dim~thyl-3-(1-[1-(4-tolyl)-
butyl]tetrazol-5-yl)penam,
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[phenyl(4-
tolyl)methyl]tetrazol-5-yl)penam, --
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryl- :
tetrazol-5-yl~pena~ and
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[(5-methyl-2-
thienyl)methyl]tetrazol-S-yl)penam,
respectively.
EXAMPLE V
6-(TriphenylmethYlamino)-2~2-dimethyl-3-(1-[4-methoxyben
tetrazol-5-yl)Penam -
(A) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-14-methoxy~
benzyl]carbamoyl)penam
To a stirred slurry of 86.4 g. (0.8 mole) of 6-amino-
penicillanic acid in 600 ml. of anhydrous chloroform is added .
11.2 ml. (0.4 mole) of triethylamine, and the mixture is ~-
stirred at ambient temperature until a clear solution is ob-
tained (ca. 15 minutes). To this solution is then added,
portionwise over about 25 minutes, 134.9 g. (0.44 mole) of
90% pure triphenylmethyl chloride, at ambient temperature.
Stirring is continued for a further 64 hours, and then 5.6 ml.
of triethylamine is added. The solution is cooled to 0-5C.
and then an ice-cold solution of 38 ml. (0.4 mole) of ethyl -
chloroformate in 80 ml. of chloroform is added dropwise during
30 minutes with the reaction temperature being maintained ~
_77_ "'., ~'' ' : ' :
... ~ .
~()5~
between 4 and 9C. After a further 15 minutes of ~tirring
52~4 ml. (0.4 mole) of 4-methoxybenzylamine is injected into
the reaction medium, below the surface of the ~olvent, at
4 to 9C., and over a period of 30 minutes. Stirring i~ con-
tinued for a further 30 minutes at 3 to 6C., for 20 minutes
while the reaction medium warms to 20C. The reaction mix- -
ture is then washed with water, followed by brine. Finally, -~
it is dried using magnesium sulfate to give a chloroform ^ -
solution of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4- ` -
methylbenzyl]carbamoyl)penam. -~
(B) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-p-methoxy-
benzyl]tetrazol-5-yl)penam
To a chloroform solution containing 69.4 g. (0.120 ~
' . .; :' . .:: . ' :
mole) of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-~4-
methoxybenzyl]carbamoyl)penam, and having a volume of 133.3
ml., prepared by the method described in (A) above, is added
a further 132.7 ml. of chloroform, followed by 29.1 ml.
(0.360 mole) of pyridine. This solution is cooled to 10C.
and then 26.22 g. (0.126 mole) of phosphorus pentachloride
is added during 15 minutes, with stirring. Stirrine is con-
tinued at ca. 10C. for 10 minutes, and then at ambient `;
temperature for a further 1.5 hours, giving a solution of
the imino chloride. To a one-sixth aliquot of this imino
chloride solution is added 4.85 ml. (0.060 mole) of pyridine,
followed by 2.42 ml. (0.060 mole) of methano} at ca. 25C.,
with stirring. After a further 15 minutes of stirring 2.03 g.
~0.038 mole) of ammonium chloride, followed by 2.59 g.
(0.039 mole) of 95% pure sodium azide, is added. The reac- :
tion mixture is then stirred at ambient temperature for a `
further 4 hours. At this point, 400 ml. of water and 200 ml.
"',' . '
.'; . ' '"' '
'., ''.'``''' ~,' '-
~()s~9g~ :
of chloroform are added, and then the layer~ are separated.
The organic phase is washed with water, dried using magnesium
sulfate, and then concen~rated to a small volume in vacuo.
This final chloroform solution is added dropwise with stir-
ring to a large volume of diisopropylether, and, after 30
minutes, the precipitate which has formed is filtered off.
This affords 6.1 g. of 6-(triphenylmethylamino)-2,2-dimethyl- -
3-(1-14-methoxybenzyl]tetrazol-5-yl)penam. The infrared -~
spectrum of the product (KBr disc) shows an absorption band ~
at 1790 cm 1 (~-lactam); and the NMR spectrum (in CDC13) ~-
shows absorptions at 7.25 ppm (multiplet, aromatic hydrogen~
5.40 ppm (broad singlet, benzyl hydrogens), 5.05 ppm (singlet,
C-3 hydrogen), 4.50-4.30 ppm (multiplet, C-5 and C-6 hydro-
gens), 3.70 ppm (singlet, methoxy hydrogens), 3.50-3.10 ppm
(broad peak, NH), 1.50 ppm (singlet, C-2 methyl hydrogens)
and 0.75 ppm (singlet, C-2 methyl hydroyens).
EXAMPLE VI
.
When the procedure of Example V is repeated, and
the 4-methoxybenzylamine used therein is replaced by an
equimolar amount of the appropriate amine, the following com-
pounds are obtained:
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-ethoxy-
benzyl]tetrazol-5-yl)penam, -
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-13-chloro-
4-methoxy~tetrazol-5-yl)penam,
6-~triphenylmethylamino)-2,2-dimethyl-3-(1-11-phenyl-
ethyl]tetrazol-5-yl)penam, ~
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-1diphenyl- ~ ~ -
methyl]tetrazol-5-yl)penam, and
. . . -. . - .
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryl- - ~ -
_79-
.... . .
' ~ '
l()S~9~
tetrazol-5-yl)penam, respectively.
EXAMPLE VII
6-(Triphenylmethylamino)-2,2-dimethyl-3-(l-furu3Yltetra
5-yl)penam
(A) 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-furfuryl-
carbamoyl)penam
To a stirred slurry of 216 g. (1 mole) of 6-amino~-
penicillanic acid in 1500 ml. of chloroform, is added, at ` -
25-30C., 278 ml. (2 mole) of triethylamine. To the solu-
tion thus obtained is added, portionwise during 25 minutes,
306 g. (1.1 mole) of triphenylmethyl chloride, at 25-30C. ~
Stirring is then continued for 44 hours at ambient tempera- ;
ture. i -
A 522 ml. portion (0.25 mole) of the above 6-(tri- ~ -
phenylmethylamino)penicillanic acid solution is cooled to
4C., and then 3.5 ml. of triethylamine is added. With
vigorous stirring is then added 23.75 ml. of ethyl chloro- ~ ~ -
formate at 5-10C. Stirring is continued for a further 30 ~ -
minutes at ca. 6C. at the end of the addition, and then
8.43 ml. of furfurylamine is injected into the reaction
medium below the surface of the solvent. At 10 minute inter- :
vals, three further portions of furfurylamine (5.90 ml.,
4.22 ml. and 3.54 ml.) are then injected into the reaction - ~ :
medium in similar fashion. The total volume of furfurylamine
added i9 22.09 ml. ~0.25 mole), and the temperature i9 main-
tained at ca. 6C. throughout the addition of the amine.
When the addition of the amine is complete, the cooling bath
is removed and the reaction medium is stirred at ca. 25C.
.....~ - - .. , . :
for 45 minutes. It is then washed successively with three
portions of water, and one portion of brine. Finally, it is
-80-
~",''':
'~
;~ " " ,
1~S~5~9~
dried using anhydrous magnesium sulfate. Thi~ affords 610
ml. of a chloroform solution of 6-ttriphenylmethylamino)-
2,~-dimethyl-3-(N-furfurylcarbamoyl)penam. The NMR spectrum
of this solution showed absorptions at 7.3 ppm ~17H, m), 6.2
ppm (lH, m), 4.35 ppm (3H, m), 4.0S ppm t2H, s), 1.6 ppm (3H,
s) and 1.35 (3H, s).
(B) 6-(triphenylmethylamino)-2,~-dimethyl-3-(1-furfuryl- ~ -
tetrazol-5-yl)penam
To a stirred solution o 3.05 g. (5.7 mmole) of
6-triphenylmethylamino)-2,2-dimethyl-3-(N-furfurylcarbamoyl), -
penam, in 8 ml. of chloroform, at 0C., is added 1.35 ml.
(17 mmole) of pyridine, followed by 2.64 ml. of a 4.33 M solu-
tion of phosgene in chloroform. Stirring is then continued
for 1 hour at 25C. The chloroform, and excess phosgene and
pyridine, are then removed by evaporation in vacuo, and the - -
residue is redissolved in 5 ml. of chloroform. The solution
is cooled to 0C., and then 2.25 g. (14.4 mmole) of tetra- -~
methylguanidinium azide is added in several small portions.
Stirring is continued for 15 minutes at ambient temperature
and then 20 ml. of chloroform, followed ny 30 ml. of water,
are added and the pH is adjusted to 6.5. The chloroform
layer is separated off, washed with water, followed by brine,
. ~ .
and then dried (MgSO4). Removal of the solvent by evapora-
tion in vacuo leaves 3.37 g. of a dark red foam. The foam
is redissolved in a small volume of chloroform and absorbed `~ -
onto a column of chromatographic silica gel. Elution of the
column with chloroform, followed by evaporation of the
appropriate fractions in vacuo, affords 6-(triphenylmethyl- ;
amino~-2,2-dimethyl-3-~1-furfuryltetrazo}-5-yl)penam. The
;~ 30 NMR spectrum of the product ~CDC13) shows absorptions at
-81-
'' "'', '' ~ .
' ., ' ,. .
:... : -
-: -
, .
~)S~9;~
7.40 ppm (m, 16 H), 6.40 ppm ~m, 2H), 5.50 ppm ~, 2H),
S.20 ppm (9, lH), 4.90 ppm (m, 2H), 1.60 ppm (g, 3H), and
0.80 ppm (s, 3H).
EXAMPLE VI~I :
The procedure of Example VII i~ repeated, except
that where necessary the triphenylmethyl chloride used
therein is replaced by an equimolar amount of the appro-
priately-substituted triphenylmethyl chloride, and where
necessary the furfuryl amine is replaced by the requisite . .
amine, to produce the following congener~
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-benzyltetr- -
azol-5-yl)penam, . : --
6-~triphenylmethylamino~-2,2-dimethyl-3-~ 4-methoxy-
benzyl]tetrazol-5-yl)penam, -.
6-~tripheny}methylamino)-2,2-dimethyl-3-~1-15-methyl- ~ :
furfuryl~tetrazol-5-yl)penam, ;.
6-~diphenyl-3-chlorophenylmethylamino)-2,2-dimethyl-3- .~
4-iodobenzyl]tetrazol-5-yl)penam, . ~
6-~diphenyl-2-fluorophenylmethylamino)-2,2-dimethyl-3- : .
~1-14-tolylmethylltetrazo1-5-yl)penam, : :-
6-~diphenyl-2-methoxyphenylmethylamino)-2,2-dimethyl-3- . ~ :
~l-t4-biphenylylmethyl]tetrazol-5-yl)penam,
6-~diphenyl-~4-tolylmethylamino)-2,2-dimethyl-3-~1-11- `.
~4-benzyloxybenzyl]tetrazol-5-yl)penam,
:25 6-~diphenyl-4-chlorophenylmethylamino)-2,2-dimethyl-3- :
(1-13,4-diethoxybenzyl]tetrazol-5-yl)penam, `;
6-(diphenyl-4-i~opropylphenylmethylamlno)-2,2-dimethyl- `~
3-(1-12-methoxyben~yl]tetrazol-5-yl)penam, ` ~ .
6-(diphenyl-4-n-butylphenylmethylamino)-2,2-dimethyl-3- ~ :
(1~4-isopentylbensyl]tetrazol-5-yl)penam,
-82-
, '
~ ~ .
:1()5'3~9;~
6-~diphenyl-3-isopropoxyphenylmethylamino)-2,2-dimethyl-
3-(1-~3-chloro-4-ethoxybenzyl]tetrazol-5-yl)penam,
6-(diphenyl-3-n-butoxyphenylmethylamino)-2,2-dimethyl-3-
(1-13-n-pentyloxy-4-benzyloxybenzyl]tetrazol-5-yl)penam,
6-(di~3-methoxyphenyl]phenylmethylamino)-2,2-dimethyl-
3-(1-[1-phenylethyl]tetrazol-5-yl)penam,
6-(di[2-tolyl]phenylmethylamino)-2,2-dimethyl-3-(1-
[1-(4-methoxyphenyl)ethyl]tetrazol-5-yl)penam,
6-(tri[4-tolyl]methylamino)-2,2-dimethyl-3-(1-[1-phenyl-
pentyl]tetrazol-5-yl)penam,
6-(tri[3-methoxyphenyl]methylamino)-2,2-dimethyl-3-(1- ;
[4-n-hexylbenzyl]tetrazol-5-yl)penam and
6-(tri[4-biphenylyl]methylamino)-2,2-dimethyl-3-(1-[4- ~ -
methoxybenzyl]tetrazol-5-yl)penam, respectively.
ExAMæLE IX --
6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-14-hydroxybenz~l]= -`
tetrazol-5-yl)penam
(A) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-[4-hydroxy- ~ ~
benzyl]carbamoyl)penam ` ~ -
To a stirred slurry of 43.2 g. (0.20 mole) of
6-aminopenicillanic acid in 300 ml. of chloroform is added
55.6 ml. (0.40 mole) of triethylamine, followed by 61.2 g. ;~ -
(0.22 mole) of triphenylmethyl ahloride, at ambient tempera- -
ture. Stirring i9 then continued for a further 48 hours at
ambient temperature.
A 120 ml. portion (containing 0.060 mole of tri-
ethylammonium 6-~triphenylmethylamino]penicillanate) of the
above chloroform solution is withdrawn. It i9 diluted with
a further 40 ml. of chloroform, and then 1.67 ml. (0.012 mole)
30 of triethylamine is added. ~The mixture is cooled to ca. 4C., ;~
. ~ - ~: .
10$~99;~
in an ice-bathr and then 6.84 ml. of ethyl chloroformate i~
added all at once, with stirring. Stirring i9 continued for
30 minutes with ice-bath cooling, and then 7.5 g. (0.060
mole) of 4-hydroxybenzylamine i8 added. Stirring is contin-
S ued for 10 minutes with ice-bath cooling, and then for a
further 1 hour without cooling. At this point, the chloro- ~ ;
form solution is washed with water, followed by brine, and
then dried using anhydrous sodium sulfate. Removal of the -
solvent by evaporation in vacuo affords the crude amide.
The crude amide is re-dissolved in 50 ml. of chloroform and :
absorbed on a column of chromatographic grade silica gel.
The eolumn is eluted with chloroform, taking 400 ml. frac-
tions. Fractions 9 to 15 are combined and concentrated to
an oil, which solidifies on trituration with methylene
ehloride. After further trituration with ether; there is
obtained 12.63 g. of 6-(triphenylmethylamino)-2,2-dimethyl-
3-(N-[4-hydroxybenzyl]carbamoyl)penam, m.p. 166-168C. `
. ~ -
(dec.). The infrared spectrum of the product (CHC13 solu-
tion) shows absorptions at 1785 em 1 (f3-laetam) and 1675 em~
(amide I). The NMR speetrum of the product (CDC13) shows
absorptions at 7.60-6.40 ppm (multiplet, 20H, aromatic hydro-
gens and amide hydrogen), 4.70-4.10 ppm (multiplet, 5H,
C-5 and C-6 hydrogens, benzyl methylene hydrogens and C-3
~ hydrogen), 2.98 ppm (doublet, lH, amine nitrogen), 1.64 ppm
(singlet, 3H, C-2 methy}hydrogens) and 1.31 ppm (singlet, 3H,
C-2 methyl hydrogens).
(~) 6-(~riphenyImethylamino)-2,2-dimethyl-3-(1-~4-hydroxy-
benzyl]tetrazol-S-yl)penam
To a stirred solution of 1.-69 g. (3 mmole) of
6-~triphenylmethylamino)-2,2-dimethyl-3-(N-t4-hydroxybenzyl]- ~
-84- -
~'
l()S9~9;~
carbamoyl)penam ~prepared as de~cribed in A) in 9 ml. of
chloroform is added 1 ml. (12 mmole) of pyridine. The solu-
tion is cooled to ca. 4C. in an ice-bath and 0.80 ml. of
chlorotrimethylsilane is added. The solution i8 stirred for
40 minutes at ambient temperature, and then it is again
cooled to ca. 4C. Phosgene (1.5 ml. of a 4.3M solution in
chloroform (6.45 mmole) is added and the cooling bath is
removed. Stirring is continued for a further 1.5 hours,
and then all the volatile components are removed by evapora-
tion in vacuo.
The oily residue is redissolved in 6 ml. of chloro-
form and the solution is cooled to ca. 4C. in an ice-bath. ~ -
To the stirred solution is added 0.95 g. (6 mmole) of tetra-
methylguanidinium azide, and then stirring is continued for
a further 1 hour at ambient temperature. At this point, -
25 ml. of water is added, followed by sufficient lN sodium -
hydroxide to bring the pH of the aqueous phase to 10. The
chloroform layer is separated off, washed with water, dried -
using sodium sulfate and evaporated to dryness in vacuo. The --
oily residue ~2.3 g.) is dissolved in a small volume of -
chloroform and absorbed on a column of 30 g. of chromato-
graphic silica gel. The column is eluted with chloroform,
taking 50 ml. fractions. Fractions 13 to 19 are aombined
and concentrated in vacuo to give 0.71 g. of 6-(triphenyl-
methylamino)-2,2-dimethyl-3-(1-~4-hydroxybenzyl]tetrazol-5-
yl)penam. The infrared spectrum of the produ¢t (in CHC13~
shows an absorption at 1780 cm~l (~-lactam). The NMR spectrum
(CDC13) shows absorptions at 7.80-6.67 ppm (multiplet, 20H,
aromatic hydrogens and phenolic hydrogen), 5.66-5.10 ppm
(quartet, 2H, benzyl methylene hydrogens), 5.02 ppm (singlet, - -
-85-
.: . ~, .. . :
.:
.,, ~,, . :
' ~' .:' ' ",
: :. .
.' ~' :.` .:
! ',', , ., ~, . , .. . , . , . ..... , . ~, . .. . .
~05~9'~
lH, C-3 hydrohen), 4.60-4.20 ppm (multiplet, 2H, C-5 and C-6
hydrogen), 3.10 ppm (doublet, lH, amine hydrogen), 1.44 ppm
(singlet, 3H, C-2 methyl hydrogens) and 0.71 ppm (singlet, 3H
C-2 methyl hydrogens).
EXAMPLE X
The procedure of Example IX is repeated, except
. .
that where necessary the triphenylmethyl chloride is replaced
by the appropriately-substituted triphenylmethyl chloride, and
where necessary the 4-hydroxybenzyl amine is replaced by the -
requisite hydroxybenzylamine, to produce the following con~
... , . .. ..- .- .
geners~
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-12-hydroxy-
benzyl]tetrazol-5-yl)penam,
..
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-13-hydroxy- `
benzyl]tetrazol-5-yl)penam,
6-(diphenyl-[3-methoxyphenyl]methylamino)-2,2-dimethyl-
3-(1-[4-hydroxybenzyl]tetrazol-5-yl)penam, ~ ;
6-(di[4-chlorophenyl]phenylmethylamino)-2,2-dimethyl-3- `
(1-[4-hydroxybenzyl]tetrazol-5-yl)penam, and ~-
6-(tri[4-tolylimethylamino)-2,2-dimethyl-3-(1-[4-hydr-
oxybenzyl]tetrazol-5-yl)penam, respectively. `~
EXAMPLE XI
6-(~riPhenylmethylamino)-2,2-dimethyl-3-(1-[4-acetoxybenzyl]-
tetrazol-5-yl)~penam
To a stirred solution of 1.69 g. (3 mmole) of
6-(trlphenylmethylamino)-2,2-dimethyl-3-(N-~4-hydroxybenzyl]-
carbamoyl)penam in 9 ml. of chloroform i9 added 1 ml. (12
mmole) of pyridine. The solution is cooled to ca. 4C. in
an ice-bath and 235 mg. of acetyl chloride is added slowly.
~he solution is stirred for 2 hours at ambient temperature,
-86- '~
:.. . :
1(~5,'3'3~'~
and than it is again cooled to ca. 4C. Phosgene (1.5 ml. o~
a 4.3M solution in chloroform ~6.45 mmole]) is added and the
cooling bath is removed. Stirring is continued for a urther
1.5 hours, and then all the volatile components are removed
by evaporation in vacuo. The residue is redissolved in 6 ml.
of chloroform and the solution is cooled to ca. 4C. in an
..: .. . :
ice-bath. To the stirred solution is added 0.95 g. (6 mmole) ~ - -
of tetramethylguanidinium azide, and then stirring is con-
tinued for a further 1 hour at ambient temperature. At this
point, 25 ml. of water is added, followed by sufficient lN
- .
sodium hydroxide to bring the pH of the aqueous phase to 10. ~ ~
.
The chloroform layer is separated off, washed with water,
dried using sodium sulfate, and evaporated to dryness ln
vacuo. This affords crude 6-(triphenylmethylamino)-2,2-di-
methyl-3-(1-[4-acetoxybenzyl]tetrazol-5-yl)penam, which is
purified further by chromatography.
EXAMPLE XII
Starting with the appropriate 6-(triphenylmethyl-
amino)-2,2-dimethyl-3-(N-[hydroxybenzyl]carbamoyl)penam or
6-(substituted triphenylmethylamino)-2,2-dimethyl-3-(N-
[hydroxybenzyl]carbamoyl)penam, and where necessary replacing
the acetyl chloride by the requisite acid chloride, and follow-
ing the procedure of Example XI, the following compounds are
prepared:
6-~triphenylmethylamino)-2,2-dimethyl-3-(1-12-acetoxy-
benzyl]tetrazol-S-yl)penam,
. .
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-iso-
butyryloxybenzyl]tetrazol-5-yl)penam, ~ -
6-(diphenyl-[4-methoxyphenyllmethylamino)-2,a-dimethyl- ~ - -
3-(1-[4-heptanoy}oxybenzyl]tetrazol-S-yl~penam,
-87-
: ~
. . ..
....
' .:
lOS~9'~
: .
6-(diphenyl-12-fluorophenyl]methylamino)-2,2-dimethyl-
3-(1-[3-propionyloxybenzyl]tetrazol-S-yl)penam,
6-(di[3-methoxyphenyl]phenylmethylamino)-2,2-dimethyl-
3-(1-12-acetoxybenzyl]tetrazjl-5-yl)penam, and
6-(trit4-tolyl]methylamino)-2,2-dimethyl-3-(1-E2-acet- .
~, .
oxybenzyl]tetrazol-5-yl)penam, respectively.
The starting penam compounds used in this Example
are prepared according to the procedure of Example IX, ~ -
Part A, by utilizing triphenylmethyl chloride, or the appro-
priately substituted triphenylmethyl chloride, and the .
appropriate hydroxybenzylamine. :
EXAMPLE XIII : -
Starting with the appropriate 6-(triphenylmethyl-
amino)-2,2-dimethyl-3-(N-~hydroxybenzyl]carbamoyl)penam or
6-(substituted triphenylemthylamino)-2,2-dimethyl-3-(N-
hydroxybenzyl]carbamoyl)penam, and replacing the acetyl :
chloride by formic-acetic anhydride, and following the pro-
cedure of Example XI, the following compounds are obtained:
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-formyl-
oxybenzyl]tetrazol-S-yl)penam, :
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[2-formyl-
oxybenzyl]tetrazol-5-yl)penam,
6-(diphenyl-[2-ethoxyphenyl]methylamino)-2,2-dimethyl- ;:
3-(1-t4-formyloxybenzyl]tetrazol-5-yl)penam,
6-(dil4-chlorophenyl]pheny1me~hylamino)-2,2-dimethyl-3-
(1-13-formuloxybenzylltetrazol-5-yl)penam and
6-ltri[3-tolyl]methylamino)-2,2-dimethyl-3-11-[4-form-
yloxybenzyl~tetrazol-5-yl)penam, respectively. .` .
~: The starting penam compounds used in this Example ~` :
; l30 are prepared by the procedure of Example IX, Part A, by
-88- :
.: .
:, ~
l(~S95~9'~
ut:Llizing triphenylmethyl chloride, or th~ approprlately
substituted triphenylmethyl chloride, and the appropriate
hydroxybenzylamine.
EXAMPLE XIV
By following the procedure of Example XI, but
starting with the appropriate 6-(triphenylmethylamino)-2,2-
dimethyl-3-~jN-~hydroxybenzyl]carbamoyl)penam or 6-(sub-
stituted triphenylmethylamino)-2,2-dimethyl-3-(N-lhydroxy-
benzyl]carbamoyl)penam, and replacing the acetyl chloride ; ~
by the requisite alkoxyalkyl chloride, the following com- -
pounds are prepared~
6-(triphenylmethylamino)-2,2-dimethyl-3-(1-~4-methoxy- `
methoxybenzyl]tetrazol-S-yl)penam, ~ :
6-~triphenylmethylamino)-2,2-dimethyl-3-(1-[2-ethoxy-
lS methoxybenzyl]tetrazol-S-yl)penam, :
6-(diphenyl-[3-tolylJmethylamino)-2,2-dimethyl-3-(1-
[4-n-butoxymethoxybenzylltetrazol-S-yl)penam, and ~`
6-(tri[3-chlorophenyl]methylamino)-2~2-dimethyl-3-(l- ~: -
[4-n-hexyloxymethoxybenzyl]tetrazol-S-yl)penam, .` ;
~ " , , ,: ,
: 20 respectively.
: :.. :. .
: The starting penam compounds used in this Example are
prepared by the procedure of Example IX, Part A, by utiliz- ~`
: ing triphenylmethyl chloride, or the appropriately-substitut~
ed triphenylmethyl chloride, and the appropriate hydroxy- ; :
~: 25 benzylaminc. : :.
EXAMPLE XV ~ ~.
6-(~r1phenvlmethylamino)-2~2-dimethyl-3-(1-[5-methYlfurfur~l]-
tetrazol-5-Yl)Penam ;
The title compound is prepared according to the pro- ~ -
30 ~ ccdure of Examplc VII, but using S-methylfurfurylamine in ~ :
. : -89- . ~
~ ~ `',.'``:;: ~" ,',
. ' ~
'';: :' '`,
l(~S9~2
place of urfurylamine. The NMR spectrum ~CDC13) of the pro-
duct show~ absorptions at 7.36 ppm (m, lSH), 6.33 ppm (m, 1~),
5.93 ppm (m, lH), 5.50 ppm (s, 2H), 5.20 ppm (s, lH), 4.50 ppm
(m, 2H), 3.23 ppm (d, lH~, 2.26 ppm (s, 3H), 1.63 ppm (s, 3H)
and 0.90 ppm (m, 3H).
EXAMPLE XVI
6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[2,4-dimethoxy- -
benzyl]tetrazol-5-yl)penam
The title compound is prepared in 46% overall
yield from 6-(triphenylmethylamino)penicillanic, by replacing
the furfurylamine of Example VII by 2,4-dimethoxybenzylamine.
The crude product is purified by recrystallization from a
mixture of methylene chloride and methanol. The NMR spectrum
of the product (CDC13) shows absorptions at 7.40 ppm (m, 16H),
6.45 ppm (m, 2H), 5.40 ppm (s, 2H), 4.50 ppm (m, 2H), 3.75
ppm (s, 3H), 3.70 ppm (s, 3H), 1.55 ppm (s, 3H) and 0.90
(s, 3H).
EXAMPLE XVII -
6-Amino-2,2-dimethyl-3-~ 4-methoxybenzyl]tetrazo1-5-yl)-
penam ~-toluenesulfonate ~ ;
To a stirred slurry of 143 g. of 6-(triphenyl-
methylamino)-2,2-dimethyl-3-(1-~4-methoxybenzyl]tetrazol-5-
yl)penam in 1,000 ml. of dry acetone is added 45.0 g. of
~-toluenesulfonic acid monohydrate, at ambient temperature.
~he solids slowly dissolve, giving a clear solution. After
about lS minutes, the product starts to precipitate. Stir- -
ring is continued for a further 45 minutes after the product
starts to appear, and then a first crop of product is filter-
ed off and washed with chloroform. The acetone is evaporat-
ed to dryness, and the solid residue is slurried for 45 ~ ~
.~: '90 ' . -:
'. ' '
105999'~
minutes in 300 ml. of chloroform. This af~ords a second
crop of product. The two crops are combined, slurried for
1 hour in 1,000 ml. of chloroform, filtered off, and dried
ln vacuo giving 123 g. of 6-amino-2,2-dimethyl-3-(1 [4-
methoxybenzyl]tetrazol-5-yl)penam ~-toluenesulfonate, m.p.
174-175.5C. The infrared spectrum (KBr disc) of the pro-
duct shows an absorption band at 1795 cm 1 $he NMR spec-
trum (in DMSO-d6) shows absorption bands at 7.20 ppm (multi-
plet, aromatic hydrogens), 5.80 ppm (multiplet, benzyl
hydrogens, C-5 hydrogen and C-3 hydrogens), 5.20 ppm (doub- ;
let, C-6 hydrogen), 3.75 ppm (singlet, methoxy hydrogens), - ^ -
2.35 ppm (singlet, sulfonate methyl hydrogens), 1.70 ppm
(singlet, C-2 methyl hydrogens) and 0.85 ppm (singlet, C-2
: : .-: :. -
methyl hydrogens). ;~
. ..: .: :
EXAMPLE XVIII ~-
By reacting the appropriate 6-(triphenylmethyl~
amino)-2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penam
or 6-(substituted triphenylmethylamino)-2,2-dimethyl-3-
(l-substituted tetrazol-5-yl)penam, chosen from those in
Examples II, III, IV, and VI to XVI, with ~-toluenesulfonic
acid, according to the procedure of Example XVII, the follow-
ing compounds are obtained as their ~-toluenesulfonate salts:
6-amino-2,2-dimethyl-3-(1-benzyltetrazol-5-yl)penam, -
6-amino-2,2-dimethyl-3-(1-[2-methoxybenzyl]tetrazol~
5-yl)penam,
6-amino-2,2-dimethyl-3-~1-[4-isopropoxybenzyl~tetrazol- ~ -
. :.: - .
5-yl)penam,
. -. .:: - .. .
6-amino-2,2-dimethyl-3-(1-[3-chlorobenzyl]tetrazol-5-
:: .: , :-: -
yl)penam, :
6-amino-2,2-dimethyl-3-~1-13-chloro-4-methoxybenzyl]-
.. . .. . ..
- 9 1 - , ;. , :: -
:: .,-- :.
. .'- '~ ': '
:. . . .- .: -
~ - ., .~, .
5'3~
tetrazol-5-yl)penam,
6-amino-2,2-dimethyl-3-(1-[1-phenylethyl]tetrazol-5-
yl)penam,
6-amino-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam,
6-amino-2,2-dimethyl-3-~1-[4-nitrobenzyl]tetrazol-S-
yl)penam,
6-amino-2,2-dimethyl-3-(1-[4-ethoxybenzyl]tetrazol-5-
yl)penam, . :
6-amino-2,2-dimethyl-3-(1-[4-phenylbenzyl]tetrazol-5-
yl)penam,
6-amino-2,2-dimethyl-3-(1-[diphenylmethyl]tetrazol-5-
yl)penam,
6-amino-2,2-dimethyl-3-(1-[2-thienylmethyl]tetrazol- ~
5-yl)penam, ~ ~:
6-amino-2,2-dimethyl-3-(1-[2,4-dimethoxybenzyl]tetr- ~. -
... . . .
azol-5-yl)penam,
6-amino-2,2-dimethyl-3-(1-[1-(4-methoxyphenyl)ethyl]- . :~
tetrazol-5-yl)penam, ~:
6-amino-2,2-dimethyl-3-(1-[1-(4-chlorophenyl)butyl]-
tetrazol-5-yl)penam,
6-amino-2,2-dimethyl-3-(1-[(4-methoxyphenyl)phenyl- '
methyl]tetrazol-5-yl)penam, ~:
6-amino-2,2-dimethyl-3-(1-[3-furylmethyl]tetrazol-5-y})- `~
penam,
6-am~no-2,2-dimethyl-3-(1-[4-_-hexyloxybenzyl]tetrazol- .
S-yl)penam,
6-amino-2,2-dimethyl-3-(1-[4-fluorobenzyl]tetrazol-5-
yl)penam,
6-amino-2,2-dimethyl-3-(1-[3,4-dimethoxybenzyl]tetrazol- : -.
5-yl)penam, . ;
-92~
~. :
lOS~9'~
6-amino-2,2-dimethyl-3-~l-[4-isopropylbenzyl]tetrazol-
5-yl)penam,
6-amino-2,2-dimethyl-3-(l-1(5-methyl-2-thienyl)methyl]-
tetrazol-S-yl)penam,
6-amino-2,2-dimethyl-3-tl-[5-methylfurfuryl]tetrazol~
S-yl)penam,
6-amino-2,2-dimethyl-3-(1-[4-iodobenzyl]tetrazol-5-yl)~
- ,: -- ,
penam, - -- --
6-amino-2,2-dimethyl-3-(l-[4-biphenylylmethyl]tetrazol- :. -
5-yl)penam, `- -:
6-amino-2,2-dimethyl-3-(l-14-n-hexylbenzyl]tetrazol-5- . :~
,- : - . .
yl)penam, -.i -
6-amino-2,2-dimethyl-3-(l-[4-hydroxybenzyl]tetrazol-5-
yl)penam, :~
.- .
6-amino-2,2-dimethyl-3-(l-[2-hydroxybenzyl]tetrazol-5
yl)penam, -- .
6-amino-2,2-dimethyl-3-(l-[2-acetoxybenzyl]tetrazol-5-
yl)penam,
,. ~ . ~ .: . .
6-amino-2,2-dimethyl-3-(l-14-aoetoxybenzylltetrazol-5- ::;:
yl)penam, ~ : :
6-amino-2,2-dimethyl-3-(l-[4-isobutyryloxybenzyl]tetr- . .
azole-5-yl)penam,
.. -: . :. -
6-amino-2,2-dimethyl-3-(l-[4-formyloxybenzyl]tetrazol- `. -- .`
~ . ,., .- . .
5-yl)penam, and . : .. ~ .
: 6-amino-2,2-dimethyl-3-tl-12-ethoxymethoxybenzyl]tetr- :: -
, . : --
azol-5-yl~penam, respectively.
. ::..-
EXAMPLE XIX
6-Amino-2,2-dimethvl-3-(l-[4-benzyloxvbenzYl]tetrazol-5-yl)- -. - :
penam
. :..: . -,
~ 30 A solution consisting of 558 mg. of 6-(triphenyl-
. . , ~ ,:
:; . ~
. . ~ '
.
l(JSS~3'~
methylamino)-2,2-dimethyl-3-(1-~4-benzyloxybenzyl~tetrazol-
5-yl)penam, 156 mg. of ~-toluenesulfonic acid monohydrate
and 1 ml. of acetone is stored at ambient temperature for
2.5 hours. It is then added with stirring to 50 ml. of
ether. After stirring for a further 10 minutes, the solid
which has precipitated is filtered off. This affords 394
mg. of the p-toluenesulfonate of the product. A 304 mg. - -aliquot of this ~-toluenesulfonate salt is dissolved in
10 ml. of methylene chloride, and to the solution is added
69.7 ~1. of triethylamine. After 3 minutes, 5 ml. of water
are added and the mixture is stirred vigorously. The
organic phase is then separated off, diluted with ether,
dried using anhydrous magnesium sulfate, and evaporated to ~
dryness in vacuo. The residue is 189 mg. (69% yield) of --
2-amino-2,2-dimethyl-3-(1-~4-benzyloxybenzyl]tetrazol-5-
yl)penam. ~he NMR spectrum (in CDC13) of the product shows
absorption bands at 7.40 ppm (singlet, phenyl hydrogens),
7.15 ppm (quartet, phenylene hydrogens), 5.55 ppm (broad
singlet, C-5 and benzyl hydrogens), 5.20 ppm (singlet, C-3
hydrogens), 5.10 ppm (singlet, benzyl hydrogens), 4.60 ppm
(doublet, C-6 hydrogen), 1.50 ppm (singlet, C-2 methyl
hydrogens) and 0.90 ppm (singlet, C-2 hydrogens).
EXAMPLE XX -~
6-Amino-2,2-dimethyl-3-(l-furfurYltetrazol-s-yl)penam .~,
:
To a stirred solution of 0.422 g. ~0.75 mmole) of
6-~triphenylmethylamino)-2,2-dimethyl-3-~1-furfuryltetrazol- -
5-yl)penam in 1 ml. of acetone at ambient temperature, is `
added 0.142 g. ~0.75 mmole) of ~-toluenesulfonic acid mono-
hydrate. Stirring is continued for 30 minutes, and then the
solvent is removed by evaporation in vacuo. This affords
~94~
'
,i ~ ~`
. .,. . . :. . . . . . .. . . . . . . ` .
~()5~92
the title compound as its ~-toluenesulfonate salt. IR
(Nujol mull): 1780 cm 1 (3-lactam). NMR (DMSO-d6): 7.20
ppm (~, 4H), 6.40 ppm (m, 2H), 5.90 ppm (s, 2H), S.60 ppm
(m, 2H), 5.00 ppm (d, lH), 2.20 ppm (s, 3H), 1.60 ppm ~s,
3H), 0.80 ppm (s, 3H).
EXAMPLE XXI
6-Amino-2,2-dimethyl-3-(1-[5-methylfurfuryl]tetrazol-5-y
. . ,
penam
To a stirred solution of 1.827 g. of 6-(triphenyl~
methylamino)-2,2-dimethyl-3-(1-[5-methylfurfuryl]tetrazol- ~-
5-yl)penam in 3 ml. of acetone is added a solution of 0.59 `~
g. of ~-toluenesulfonic acid monohydrate in 2 ml. of acetone.
The mixture is stirred at ambient temperature for 30 minutes, ~and then the precipitate which has formed is filtered off. ;
This affords 0.87 g. (54% yield) of the title compound as ~ -
its ~-toluenesulfonate salt. The NMR spectrum of the pro- -
duct (CDC13) shows absorptions at 7.28 ppm (q, 4H), 6.50 ppm ~-
(d, lH), 6.01 ppm (s, lH), 5.86 ppm (s, 2H), 5.71 ppm (s, ~ :-
. -~ ' .. .. .
lH), 5.68 ppm (d, lH), 5.09 ppm (d, lH), 2.00 ppm (2s, 6H), - -
.-
1.66 ppm (s, 3H) and 0.88 ppm (s, 3H). ;
. . . . ..
EXAMPLE XXII ; -
. ,..,, : ~ .,,
6-Amino-2,2-dimethyl-3-(1-~2,4-dimethoxybenzyl]tetrazol-5-
yl)penam
To a stirred solution of 2.0 g. of 6-(triphenyl-
methylamino)-2,2-dimethyl-3-(1-t2,4-dimethoxybenzyl]tetr-
azol-5-yl)penam in 40 ml. of methylene chloride, i8 added
a solution of 0~600 g. of ~-toluenesulfonic acid mono-
hydrate in 4 ml. of acetone. The resulting clear solution
is stirred at ambient temperature for 18 hours, and then
.~- ... .
the solvent is removed by evaporation ln vacuo. The
-95- ~-
' :.
J~
residue is triturated with ether, to give 1.76 g. (99%
yield) of a white solid, which is the title compound as
its ~-toluenesulfonate salt. ~he NMR speatrum (DMSO-d6)
shows absorptions at 7.65 ppm (m, 5H), 6.90 ppm (m, 2H),
5.95 ppm (m, 3H), 5.40 ppm (d, lH), 3.95 ppm (s, 3H), 2.45
ppm (s, 3H), 1.95 ppm (s, 3H) and 1.15 ppm (s, 3H).
EXAMPLE XXIII
6-Amino-2,2-dimeth~l-3-(5-tetrazolyl)penam
A stirred solution of 32.0 g. of 6-amino-2,2-
dimethyl-3-(1-~4-methoxybenzyl]tetrazol-S-yl)penam ~-tolu-
enesulfonate, and 24 ml. of anisole, in 96 ml. of tri-
fluoroacetic acid is maintained at 40 + 1C. for 35 minutes.
The trifluoroacetic acid is then removed rapidly by vacuum
distillation. A 120 ml. portion of ether is added to the ~-
residue, which produces a white flocculent suspension. The
suspension and solvent is cooled to about 0C., and to it
is then added, portionwise, 80 ml. of 2N sodium hydroxide,
.
giving two clear phases. The pH of the aqueous phase at - ~
this point is about 2.7. The layers are separated, and the ~ -
ether phase is discarded. The pH of the aqueous phase is
raised to 4.1 with 2N sodium hydroxide. This aqueous phase -
, . . . .
is then washed with 100 ml. of ether and filtered. It is
combined with the corresponding aqueous phases from four
other identical experiments, and the total aqueous solution
is lyophilized to give arude 6-amino-2,2-dimethyl-3-(5-
tetrazolyl)penam. ~hls crude product is slurried in a small
amount of water and filtered off. It is then re-suspended
in water and brought into solution by raising the pH to 7.4 ~ ~ -
by the addition of sodium hydroxide solution. ~he clear ` -
solution is extracted with ether and the extracts are dis-
-96~
, ~
:
:. ~: . .
105~
carded. 'rhe pH of the aqueous phase i9 ad~usted to 4.1
using dilute hydrochloric acid, and the product which
precipitates is filtered off. The infrared spectrum of the
product shows an absorption at 1795 cm~l. Its NMR spectrum
(in DMSO-d6) ~hows absorptions at 5.65 ppm (doublet C-5 ,-
hydrogen), 5.20 ppm (singlet, C-3 hydrogen), 4.70 ppm
(doublet, C-6 hydrogen), 1.65 ppm (singlet, C-2 methyl
hydrogens) and 1.10 ppm (singlet, C-2 methyl hydrogens).
EXAMPLE XXIV -
Reaction of the ~-toluenesulfonate salt of a
6-amino-2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penam, ~ -~
selected from~
6-amino-2,2-dimethyl-3-(1-[2-methoxybenzyl]tetrazol~
5-yl)penam, - `
6-amino-2,2-dimethyl-3-(1-14-isopropoxybenzyl]tetrazol- ~
5-yl)penam, ~- -
::: .. : :
6-amino-2,2-dimethyl-3-(1-13-chloro-4-methoxybenzyl]- ~ ;
tetrazol-5-yl)penam,
6-amino-2,2-dimethyl-3-(1-~1-phenylethyl]tetrazol-5-
yl)penam,
6-amino-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam,
6-amino-2,2-dimethyl-3-(1-[4-ethoxybenzyl]tetrazol-5-
yl)penam,
6-amino-2,2-dimethyl-3-(1-~4-phenylbenzyl]tetrazol-5- ~
yl)penam, -
6-amino-2,2-dimethyl-3~ diphenylmethyl]tetrazol-S-
yl)penam,
6-amino-2,2-dimethyl-3-(1-~2-thienylmethyl]tetrazol-5- ~ i
yl)penam, ~-
6-amino-2,2-dimethyl-3-(1-11-(4-methoxyphenyl)ethyl]-
-97- ~ ~-
.,: , . . ...
..
"~ ' ' '.' ' .. ' ' ' .
` ': ~ ' -' '
~(~S~9'~
tet:razol-S-yl)penam,
6-amino-2,2-dimethyl-3~ (4-methoxyphenyl)phenyl-
methyl~tetrazol-5-yl)penam,
6-amino-2,2-dimethyl-3-(1-[3-furylmethyl]tetrazol-5- :
yl)penam,
6-amino-2,2-dimethyl-3-(1-~4-n-hexyloxybenzyl]tetrazol- -
5-yl)penam,
6-amino-2,2-dimethyl-3-(1-~3,4-dimethoxybenzyl]tetr-
azol-5-yl)penam, ~ -
6-amino-2,2-dimethyl-3-(1-~5-methyl-2-thienyl]tetrazol-
5-yl)penam, .-
6-amino-2,2-dimethyl-3-(1-~5-methylfurfuryl]tetrazol- ~ ;-
5-yl)penam,
-: :
6-amino-2,2-dimethyl-3-(1-[4-biphenylylmethyl]tetrazol-
5-yl)penam,
6-amino-2,2-dimethyl-3-(1-[2,4-dimethoxybenzyl]tetrazol-
5-yl)penam,
6-amino-2,2-dimethyl-3-(1-14-hydroxybenzyl]tetrazol-5- . ~ :
yl)penam, -
6-amino-2,2-dimethyl-3-(1-[2-hydroxybenzyl]tetrazol-5-
yl)penam,
6-amino-2,2-dimethyl-3-(1[2-acetoxybenzyl]tetrazol-5-
yl)penam,
6-amino-2,2-dimethyl-3-(1-[4-acetoxybenzyl]tetrazol- :~
5-yl)penam,
6-amino-2,2-dimethyl-3-(1-[4-isobutyryloxybenzyl]-
tetrazol-5-yl)penam, :. .
:6-amino-2,2-dimethyl-3-~ 4-formyloxybenzyl]tetrazol-
~: ~ 5-yl)penam and ~ .
:: 30 6-amino-2,2-dimethyl-3-(1-[2-ethoxymethoxybenzyl]tetr-
-98- ``
'
"~
: ." ' , ~ :
~'"
~os999~ ~
azol-5-yl)penam,
with trifluoroacetic acid and anisole, according to the
procedure of Example XXIII, produces 6-amino-2,2-dimethyl-
3-~5-tetrazolyl)penam in each case.
EXAMPLE XXV
6-tTriphenylmethylamino)-2~2-dimethyl-3-(5--etrazolyl)penam
To a stirred solution of 1.69 g. (3 mmole) of ~
6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-hydroxybenzyl]- ; ~-
carbamoyl)penam prepared as described in Example IX) in ~ ~
9 ml. of chloroform is added 1 ml. (12 mmole) of pyridine. -~ -
The solution is cooled to ca. 4C. in an ice-bath and -
0.80 ml. of chlorotrimethylsilane is added. The solution
is stirred for 40 minutes at ambient temperature, and then -
it is again cooled to ca. 4C. Phosgene (1.5 ml. of a
4.3M solution in chloroform 6.45 mmole) is added and the `
, ,-. :,~
cooling bath is removed. Stirring is continued for a
further 1.5 hours, and then all the volatile components
are removed by evaporation in vacuo. The oily residue is
redissolved in 6 ml. of chloroform and the solution is
cooled to ca. 4C. in an ice-bath. To the stirred soIution ~ :
is added 0.95 g. (6 mmole) of tetramethylguanidinium azide, ~ "
and then stirring is continued for a further 1 hour at
ambient temperature. At this point, 25 ml. of water is
added, followed by sufficient lN sodium hydroxide to bring
the pH of the aqueous phase to 10. The chloroform layer
is removed, washed with water, dried using sodium sulfate, `;
and evaporated to dryness in vacuo. This affords crude
6-(triphenylmethylamino)-2,2-dimethyl-3~ 4-trimethylsilyl-;
oxybenzyl]tetrazol-5-yl)penam, which-is purified ~y chroma-
,:::
tography on silica gel using chloroform aæ eluant.
'' ',.'`', '., ~,',,'-. .' '.
'' ~ ``''' ;' ,'."
1()5~3~
To a stlrred solution of 200 my. o the purified
trimethylsilyloxybenzyl derivative, in 4 ml. of tetrahydro-
furan, is added 0.3 ml. of l.ON sodium hydroxide. ~he solu-
tion is stirred at ambient temperature for 50 minutes, and
then the pH is adjusted to 5.7 using 5~ hydrochloric acid.
The solvent is removed by evaporation in vacuo to yield
crude 6-(triphenylmethylamino)-2,2-dimethyl-3-(S-tetrazolyl)-
penam.
EXAMPLE XXVI - -
When the procedure of Example XXV is repeated,
but using as starting material 6-(triphenylmethylamino)-
2,2-dimethyl-3-(N-[2-hydroxybenzyl]carbamoyl)penam, there :
is produced 6-(triphenylmethylamino)-2,2-dimethyl-3-(5- -
tetrazolyl)penam.
The 6-(triphenylmethylamino)-2,2-dimethyl-3-lN-
[2-hydroxybenzyl]carbamoyl)penam is prepared according to
the procedure of Example IX, Part A, but using 2-hydroxy-
benzylamine in place of 4-hydroxybenzylamine.
EXAMPLE XXVII -
Starting with the appropriate 6-(substituted
triphenylmethylamino)-2,2-dimethyl-3-(N-[4-hydroxybenzyl]-
càrbamoyl)penam, and following the procedure of Example
XXV, there is obtained the following congeners:
6-(diphenyl-[3-methoxyphenyl]methylamino)-2,2-dimethyl- -~
3-(5-tetrazol-5-yl)penam, `~
6-~diphenyl-[2-fluorophenyl]methylamino)-2,2-dimethyl~
3-~5-tetrazol-5-yl)penam, ~
6-~di[4-chlorophenyl]phenylmethylamino)-2,2-dimethyl- ~- -
3-~5-tetrazol-5-yl)penam, and : -
6-~tri[4-tolyl]methylamino)-2,2-dimethyl-3-(5-tetr- ~
-100-
" ' " `~
" '~ :: .'
~()S~35~9Z
azolyl)penam, respectively.
The starting materials used in this Example are
prepared by the method of Example IX, ~art A, but u~ing the
appropriately-subs~ituted triphenylmethyl chloride.
EXAMPLE XXVIII
6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]-
carbamoyl)penam ;
(A) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-ethoxycarbon- -
yl-carbamoyl)penam ~-
To a stirred solution of 4.58 g. (10 mmole)
6-(triphenylmethylamino)penicillanic acid and 1.45 ml. (10
mmole) of triethylamine, in 75 ml. of acetonitrile, is added -
1.15 g. (10 mmole) of ethoxycarbonyl isocyanate dissolved
in 5 ml. of acetonitrile. The resulting solution is stirred ; -
at ca.25C. for 16 hours, and then the solvent is removed
by evaporation ln vacuo. ~he residue is redissolved in
chloroform and the chloroform solution is washed successively
w!ith water, sodium bicarbonate solution and sodium chloride
solution. The chloroform solution is then dried using an-
hydrous magensium sulfate, and evaporated ln vacuo. Theresidue is again redissolved in chloroform, and the chloro-
form solution is washed with dilute hydrochloric acid, ;
dried using magnesium sulfate, and again evaporated in vacuo.
This affords the crude product, which is purified by chroma-
tography using silica gel as the adsorbent and eluting the
column with chloroform containing 4% by volume of ethanol.
The final yield of 6-(triphenylmethylamino)-2,2-dimethyl-3
: . - :
(N-lethoxycarbonylcarbamoyl)penam is 2.54 g. (48% yield). ~ `
' '. :'..'';
-101-
'
.
lOS~g9'~
(B) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxy-
carbonyl]tetrazol--5-yl)penam -
To a stirred solution of 529 mg. (1 mmole) of
6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[ethoxycarbonyl]
carbamoyl)penam and 240 mg. (3 mmole) of pyridine, in 25
ml. of methylene chloride, is added 208 mg. (1 mmole) of
phosphorus pentachloride, at 0C. The reaction mixture
is stirred at 0C. for 0.5 hour and then at ca. 25C. for --
2 hours. The solvents and the excess pyri~ine are then
removed by evaporation in vacuo, and the residue is re-
dissolved in lS ml. of chloroform. The latter chloroform
solution is cooled to 0C., and 0.47 g. (3 mmole) of tetra-
methylguanidinium azide is added in several small portions
with stirring. Stirring is continued for 2 hours at
ambient temperature, and then to the reaction mixture is
added a further lS ml. of chloroform followed by 30 ml.
of water. The pH is adjusted to 6.S, and then the chloro- - -
form layer is removed. The chloroform solution is washed -
with water followed by brine, and then it is dried using
anhydrous sodium sulfate. Removal of the solvent by evapora- ~
tion in vacuo affords crude 6-~triphenylmethylamino)-2,2- - -
dimethyl-3~ ethoxycarbonyl]tetrazol-5-yl)penam. ~he ~ ~
crude product is purified further by chromatography using ~ --
silica gel.
EXAMP~E XXIX -
Starting with 6-~triphenylmethylamino)peni~illanic
acid, or the appropriately-substituted 6-(triphenylmethyl- -
i amino)peniaillanic acid, and the requisite isocyanate of
formula R14O-C(=o)-N=C=o, and following the procedure of
3 Example XXVIII, the following compounds are prepared:
'. ~ -102-
~ 'l ' :, ', ',
lOS9~g~ '
R22 :~
R23
S ~ ~ ~
4 1 . :
O=C :-
oRl 4
R2 2 R2 3 R2 4 Rl 4 . . . : ,
H H H CH3
H H H CH3CH2CH2
H H H (CH3~2CHCH2 ;~ . :
H H CH3(CH2)4CH2
H H H C6H5CH2 .
H H `
H H H 2 FC6H4 ~ .
10 H H H 3-BrC6H4
H H H C6H5 .: ....... .
H .H H 4-(CH3[CH2]2CH2)c6H4 .
H H H 3-CH3c6H4 .
H . H H 4-(tcH3]2cHo)c6H4
H H H 2,4-C12C6H3 .
H H H 3~4-~cH3cH2o)2c6H3
H H H 3~5-~cH3)2c6H3 ~`
H . H H 4-Cl-3-CH3C6H
3-CH3 H H 4-~CH3CH2cH2O)-2-o2Nc6H3
4-CH3CH2CH2 H H 4-~CH31cH2]2cH2O)c6H4
4-Br H H CH3CH2 ~. -
-103- ~
~(~s'~
R22 R23 R24 R14
2-F H H C6H5CH2
3 C6H5 H H C6H5
3-CH3CH20 H H 4-02NC6H4
4-C1 4-Cl H 2,4-(02N)2C6H3 -~
4-CH3 3-CH30 3-CH30 CH3CH2 ~ .
4-CH3 4-CH3 4-CH3 C6H5
EXAMPLE XXX
Starting with 6-(triphenylmethylamino)penicillanic -
acid, or the appropriately-substituted 6-(triphenylmethyl-
amino)penicillanic acid, and the requisite isocyanate of :
formula R14-So2-N=C=o, and following the procedure of
Example XXVIII, the following compounds are prepared~
R22 ' .' ~.
~23
.''..`: '" '' '~' - ~ ' '
C N
SO2 ~'
R22 R23 R24 R14
H H H CH3
H H H CH3CH2 ..
H H H (CH3)2CHCH2
H H H C6H5CH2
H v H H C6H5
H H H 4-02NC6H4
, '-; `.
' .... ' ` '
lOSg99'~
R22 R23 R24 R14
H H H 3-FC6H4
H H H 2-ClC6H4
H H H 4-~rC6H4
H H H 2-(CH3CH2)C6H4
H H H 3-(CH3CH2CH2CH2)c6H4
H H H 4-CH30c6H4
H H H 3-([CH3]2CHcH20)c6H4 ~ -
H H H 2,4-C12C6H3
H H H 3-CH3-4-CH30
H H H 2'4-(02N)2C6H3
H H H 2-CH30-5-02NC6H3 ;
2-CH3 H H CH3
3-CH3CH2 H H 6H5CH2
3-Cl H H 2 6 4 ~ -
4-CH30 H H C6H5 -
4-C6H5 H H CH3CH2
3-C1 3-Cl H 4-ClC6H
3-CH30 3-CH30 3-CH30 2,4-(02N)2C6H3 -
2 0 EXAMPLE XXXI
6-(~riPhenylmethylamino)-2,2-dimethYl-3-~5-tetrazolyl)Penam
To a stirred mixture of 2 ml. of tetrahydrofuran -
and 4 ml. of water is added 150 mg. of 6-(triphenylmethyl-
amino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]-tetrazol-5-yl)-
penam. ~he pH of the mixture i9 adju~ted to 9.5, and
stirring i9 continued at that pH for a further 30 minutes,
at ambient temperature. ~he bulk of the tetrahydrofuran
is removed by evaporation in vacuo, and the residue is
portioned between water and ethyl acetate at pH 9. ~he
ethyl acetate is removed and discarded. Fresh ethyl ~, -
-105- ~' ' :`.
' . . ,.'
:,,~. ' `
..
~5999'~
acetate ~8 added and the pH i8 ad~u~ted to 2Ø The othyl
acetate layer is removed, washed with water, dried u~lng
anhydrous ~odium ~ulfate, and evaporated ln vacuo to glvo
the crude title compound.
S EXAMPLE XXXII
Reaction Of any of the 6-(triphenylmethylamino)- :~:
2,2-dimethyl-3-(}-substituted tetrazol-5-yl~penam or ~:~
6-(substituted triphenylmethylamino)-2,2-dimethyl-3-(1-
substituted tetrazol-5-yl)penam compound~, listed in
Examples XXIX and XXX, with water at p~ 9.5, accordlng to
the procedure of Example XXXI, re~ult~ in removal of the
C(=o)-o-Rl4 or So2-Rl4 group and it~ replacement by hydro-
gen. In this way, the following compound~ are obta~ned~
22 - :-
R23 ~ R
~ '':'"'~',':',
~3 o~ 1~",~
HN N
R24 . : , ' , :
:
lS R22 R23 R24 ;
_ . . .. .
H H H
3-CH3 H H
4-CH3CH2CH2 H H .
4-~r H ~ .
20 2-F H H -~
3-C6H5 H H
: 3-CH3CH2O H H .
.~ , . .
4-C1 4-Cl
-106- -~
', .~ ' .: ' .
,;',' :.`"
., ~
1059~9Z
R22 R23 R24
4-CH3 3~CH30 3-CH30
4-CH3 4-CH3 4-CH3
2-CH3 H H
3-CH3CH2 H H
3-Cl H H
4-CH30 H H ~-
4-C6H5 H H
3-C1 3-Cl H -
:~. . - ---.::. ~.
3-CH30 3-CH30 3-CH30 -
EXAMPLE XXXI I I . ~ .
6-Amino-2,2-dimethYl-3-(5-tetrazolyl)penam
To a stirred solution of 2.0 g. of 6-(triphenyl-
methylamino)-2,2-dimethyl-3-(S-tetrazolyl~penam in 35 ml. of -
15- acetone, is added 788 mg. of ~-toluenesulfonic acid mono-
hydrate, at ambient temperature. Stirring is continued for
45 minutes and then the solvent is removed by evaporation -
in vacuo. To the residue is added 30 ml. of water and 30
ml. of ether, and the pH is adjusted to 7Ø The ether
layer is separated and discharged. The pH of the aqueous
phase i9 adjusted to 4.1, and then the aqueous phase i9
concentrated to small volume. The solid whiah has precip-
itated is removed by filtration and dried. This affords `~
the title compound.
: . ~
2 5 ~ EXAMPLE XXXIV
When each of the 6-~substituted triphenylmethyl-
amino)-2,2-dimethyl-3-tS-tetrazolyl)penam compounds de~crib- ;~
ed in Example XXXII i9 reacted with ~-toluenesulfonic acid,
according to the procedure of Example XXXIIIj the product in
each case is 6-amino-2,2-dimethyl-3-~5-tetrazolyl~penam.
-107- ';
' ~',~'' ''
, , :
105999,'~
EXAMPLE XXXV
6-Amino-2,2-dimethyl-3-(1-[ethoxYcarbonyl]tetrazol-5 yl)-
~enam
To a stirred solution of 554 mg. of 6-(triphenyl-
methylamino)-2,2-dimethyl-3-(1-tethoxycarbonyl]tetrazol-5- `~
yl)penam in 2 ml. of acetone is added a solution of 190 mg. ~ -
of p-toluenesulfonic acid of 1 ml. of acetone. Stirring
is continued for a further 3 hours, and then the acetone is
removed by evaporation in vacuo. The residue is slurried - - -
in ether, filtered and dried, to give the title compound as -
its p-toluenesulfonate salt.
The above ~-toluenesulfonate salt is added to a
mixture of lS ml. of water and 15 ml. of chloroform. The
- pH of the aqueous phase is adjusted to 7.0, and the chloro-
form layer is removed. The chloroform is dried using sodium ``
sulfate, and then it is evaporated in vacuo to give the
title compound as it9 free base.
EXAMPLE XXXVI -
Reaction of the appropriate 6-(triphenylmethyl- ~ ~
amino)-2,2-dimethyl-3-(1-substituted tetrazol-S-yl)penam ~ ; -
or 6-(substituted triphenylmethylamino)-2,2-dimethyl-3 (1- ~; `
substituted tetrazol-S-yl)penam, chosen from those in
Examples XXIX and XXX, with ~-toluenesulfonic aoid, accord-
ing to the procedure of Example XXXV, provides the follow-
ing compounds as their ~-toluenesulfonate salt~
-108-
~ " . ..
;~ q,~
-`',' . ''~. :.. . ,,:
:.'.,.- :
~osgg9z :: ~
R2
CO2CH3
C2~CH2CH2cH3 ~: ~
CO2(CH2CH~CH3]2)
C2cH2c6H5 ~.
CO2 (4-C6H4N02
C2 (2-C6H4F) , ~ . .
CO2(3-C6H4Br) :
CO2C6H5 :
CO2(4-C6H4CH2CH2CH2cH3) ~.
C2 (3-C6H4CH3) ' ' ' '
Co2(4-c6H4ocH~cH3]2)
co2(2~4-c6H3cl2)
Co2(3~4-c6H3[ocH2cH3]2)
CO2(3'5-C6H3[CH3]2)
C2(C6H3-4-C1-3-CH3)
CO2(C6H3-4-[OCH2cH2cH3]-2-No2)
C2 (4-c6H4ocH2cH2cH2cH3)
CO (2 4 C H ENO2] )
SO2aH3
,
2CH2CH3 ' ' ' ' '
SO2~CH2CH[CH3]2) ~ :
SO2CH2C6H5 ~ .
2C6H5 ~ ;~
So2~4-c6H4No2)
SO2(3-C6H4F) ~ :
S2(`2 C6H4Cl) .. :
' ' S2 (4-C6H4Br) , ', ~
.. . . ..
- ~' S2(2-C6H4CH2CH3)
~ 30 So2(3-
, .
1 0 9~ " ' ' " ~
~; ~ ' ~ ' ' ': '
~ossss~
R2
-
S2 ~4-C6H40cH3)
So2(3-c6H4ocH2c~cH3~2)
So2~2~4-c6H3cl2)
S02~C6H3 3 C~3 4 oCH3)
So2~2~4-c6H3~No2]2)
S02(C6H3-2-0cH3 2 N2
EXAMPLE XXXVII
6-(TriPhenYlmethYlamino)-2,2-dimethYl-3-~ 2-methoxYcarbon- ~ - -
ylethvl]tetrazole-5-Yl)Penam -
~A) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-~2-methoxy-
carbonylethyl]carbamoyl)penam
To a stirred solution of 35 g. of 6-(triphenyl-
methylamino)penicillanic acid in 250 ml. of dry, ethanol- -
.
free chloroform, is added 11.7 ml. of triethylamine at ~ ~
0-3C. The solution thus obtained is then added dropwise, -~ ;
with stirring, at 0-6C., to a second solution, prepared
from 7.3 ml. of ethyl chloroformate in 155 ml. of dry,
. ,-- ,. ~-. -, -.
ethanol-free chloroform. Stirring is continued for a ~ -
further lO minutes. This affords a chloroform solution of ~ -
the mixed anhydride of 6-(triphenylmethylamino)penlcillanic
a¢id.
In a separate flask, a ~olution of ~-alanine methyl
ester is prepared by adding 11.7 ml. of triethylamine to a -~-
. . .. .
slurry of 10.73 g. of ~-alanlne methyl oster hydrochloride ; -;
and 2 g. of anhydrous sodium sulfa~e ln 115 ml. of dry,
.
ethanol-free ahloroform, a~ ca. 10C. 8tirring is continued
for a further lO minutes.
: ,.: . - .
The latter amino-ester solution is then added drop-
wise, with stirring at 3-6C., to the above-described mixed i
: : -' ':
: ~ :,.. ' ': '
1(~5~9g;~ ~
anhydride solution. After the end of the addition, stirring
is continued for a further 2 hours.
At this point, the reaction solution i9 washed
successively with three portions of water and one portion
of brine. The solution i5 then dried using anhydrous sodium
sulfate, and evaporated in vacuo to give 40.1 g. of crude
6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[2-methoxycarbonyl-
ethyl]carbamoyl)penam as a glassy solid, m.p. 60-70C. The ~-
crude product is purified by extracting it into refluxing
ether, treating the filtered solution with activated carbon,
and then re-precipitating the produat by the addition of
petroleum ether.
(B) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[2-methoxy-
carbonylethyl]tetrazol-5-yl)penam ~
To a stirred solution of 2 g. of the amide describ- -
ed under (A) above, in 5 ml. of dry, ethanol-free chloroform, ~
is added, at ca. 0C., 1.36 ml. of pyridine, followed by a ~ - -
solution of 620 mg. of phosgene in 4 ml. of dry, ethanol- ~ ~
. . .
free chloroform. The solution is stirred for 2.5 hours, at ~ ~ ~
. ~ .
ambient temperature, and then the solvent is removed by '
evaporation in vacuo. The residue is re-dissolved in 9 ml.
of dry, ethanol-free chloroform, and 580 mg. of tetramethyl-
guanidinium azide is added. The reaction mixture is stirred ~ -
for 45 minutes, at which point a further 200 mg. of tetra-
methylguanidinium azide is added. The reaction mixture is
then stirred 18 hours to complete the conversion to tetra201e.
To the reaction solution is then added saturated sodium bi-
carbonate solution, in sufficient quantity that the pH of
the aqueous phase is 7.6. The chloroform layer is removed, -
washed with water at pH 5, washed with water at pH 7, dried
-111- ::.
~05g'~9;~
using anhydrous sodium sulfate, and finally evaporated in
vacuo. This affords 2.19 g. o crude product, which is re-
crystallized from methanol giving 1.11 g. (48% yield) of
product with m.p. 100-105C. The NMR spectrum (CDC13) shows
absorptions at 7.40 ppm (m, 15H), 5.15 ppm (s, lH), 3.80
(m, 4H), 3.70 ppm ~s, 3H), 3.10 ppm (s, 3H) and 1.17 ppm
(s, 3H), and further indicates that the product contains
methanol of solvation. ~ -
EXAMPLE XXXVIII
. .
The procedure of Example XXXVII is repeated,
except that where necessary the 6-(triphenylmethylamino)-
penicillanic acid is replaced by the appropriately-sub-
stituted 6-(triphenylmethylamino)penicillanic acid, and
where necessary the ~-alanine methyl ester is replaced by ;~
the appropriate amine to produce the following compounds:
R22 ~
C NH S CH3 -;;----
CH3 -
~/ ~ ~ , - N
R24 ~ C\ /N
Y CH2CH2 .
R2 2 R2 3 R2 4 y
:: .
H H H C~=O)OCH2CH3 -
H H H C~O)OCH~CH3)2
H H H C~=O)OCH2~CH2)4CH3 ; ;
H H H C~=O)OC6H5 `-
H H H S02CH3
-112
,`'. .'',' ' ':
: . .
.: .~ .: - ., .
~055~9'~
R22 R23 R24 y
-
H H H S02CH2(CH2)2cH3
H H H S02NHC6H5
H H H S02N(C6H5)2
H ~ H S02N(CH3)c6HS
H H H S020CH3
H H H S020CH2CH3
H H H S020CH2CH(CH3)2
H H H S2C6H5
H H H S2NH2
H H H So2NHcH3 ~-
H H H S02N(CH2cH2cH3)2 ::
H H H S2NHCH2C6H5 ~:
H H H CN ,
2-F H H C(=O)OCH3
3-CH30 H H S02CH2CH3
3-C6H5 H H so2Nn(cH2lcH2]2cH3) .~
3-C1 3-Cl H C(=O)OCH3 ::
4-CH3 4-CH3 4-CH3 C(=O)OCH2CH3
EXAMPLE XXXIX
6-(TriPhenYlmethYlamino)-2,2-dimethY1-3-(1-~2-methoxycarbon
Ylethvl]tetrazol- S-Y1 ) Penam
To a stirred solution of 8 g. of 6-(triphenyl-
methylamino)-2,2-dimethyl-3-(N-~2-methoxycarbonylethyl]carb-
amoyl)penam (prepared as described in Example XXX~II, Part A)
in 20 ml. of dry, ethanol-free chloroform, is added 5.4 ml.
of pyridine. To this solution i9 then added a solution of
2.7 g. of phosgene in 16 ml. of dry, ethanol-free chloro-
form, at ca. 0C. The reaction mixture is stirred at
~: 30 ambient temperature for 1.5 hours, and then the ~olvent is ~.-. -
113- ~.:
. .
~ .: -
iOS'3~9;~
removed by evaporation ln vacuo. The viscou~ resldue i9
re-dissolved in 36 ml. of dry chloroform, the solution i~
cooled to ca. 0C., and 2.6 ml. of trimethylsilyl azide i8
added. ~he reaction mixture i9 stirred at ambient tempera-
ture for 17 hours. At this point 1.26 g. of solid sodiumbicarbonate is added to the chloroform solution, followed
by sufficient aqueous saturated sodium bicarbonate to give
a pH of 7.6. The chloroform is separated, washed with ~ ~
water, washed with brine, dried using anhydrous sodium ~ ~-
sulfate, treated with 200 mg. of activated carbon, and ~ ~
finally evaporated in vacuo. The residue iq triturated ~ ~ -
with cyclohexane, and then recrystallized from methanol,
giving 3.85 g. (46% yield) of the title compound, m.p.
94-98~C. After further recrystallization of the product `
from methanol, the melting point is raised to 104-106C.
The NMR spectrum (CDC13) shows absorptions at 7.40 ppm `-i
(m, 15H), 5.15 ppm (s, lH), 3.80 ppm (m, 4H), 3.70 ppm
(s, 3H), 3.1Q ppm (t, 2H), 1.70 ppm (s, 3H) and 1.17 ppm `-
- : -
(s, 3H), and further indicates that the product contains ;
ca. 3% of methanol of solvation.
EXAMPLE XL
, .. :::: ~ -
6-(~riPhenvlmethYlamino)-2,2-dimethY1-3-(5-tetrazolyl)- ;`-~-
m
. - . ..: .
To a stirred solution of 600 mg. of 6-(triphenyl-
methylamino)-2,2-dimethyl-3-(1-~2-methoxycarbonylethyl]-
.. . .
tetrazol-5-yl)penam ~containing ca. 4.5~ of methanol) in
1 ml. of chloroform, is added a solution of 375.2 mg. of
: . .. :
diazabicyclo~4.3.0]non-5-ene in 0.5 ml. of chloroform. ~ `
; . . .: .
Stirring i8 continued for a further 3 hours, and then the ~-
:: :- ,-, ....
solution i~ diluted with a further 2 ml. of chloroform.
-114-
'' ' ` '
~S~39'~
The latter solution is washed qulckly with 5 ml. of 2N
hydrochloric acid, and then a further 5 ml. of 2N hydro-
chloric are added. The resulting mixture ii3 cooled to ca.
0C., and the solid which precipitates is filtered off,
giving 323 mg. (71% yield) of the title compound. The NMR
spectrum (DMS0-d6) of the product shows absorptions at
7.40 ppm (m, 15H), 5.30 ppm (s, lH), 4.60 ppm (m, 2H),
1.58 ppm (s, 3H) and 0.78 ppm (s, 3H). ~
EXAMPLE XLI -
Reaction of any of the 6-(triphenylmethylamino)- ~
2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penam or -
6-(substituted triphenylmethylamino)-2,2-dimethyl-3-(1-
substituted tetrazol-5-yl)penam compounds, listed in
Example XXXVIII, with diazabicyclo[4.3.0]non-5-ene, accord- ~ -
ing to the procedure of Example XL, results in removal
of the 2-substituted ethyl substituent from the tetrazole
ring, and its replacement by hydrogen. In this way, the
following compounds are obtained:
R22
R23
~ ?
R2~ HN
' .~ '
~ :,
-115-
~os~9~
R22 R23 R24
H H H
2-F H H
3-CH30 H H
3-C6H5 H H
3-C1 3-Cl H
4-CH3 4-CH3 4 CH3
The above 6-(substituted triphenylmethylamino)-
2,2-dimethyl-3-(S-tetrazolyl)penam compounds are converted
into 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam by reaction , '4 .
. ' I :. , ' - .
with ~-toluenesulfonic acid, according to the procedure of
Example XXXIII.
EXAMPLE XLII
6-(3-[o-Chlorophenyl]-5-methyl-4-isoxazolecarboxamido)-2~2-
dimethYl-3-(S-tetrazolYl)Penam ;
: . - ,
A stirred slurry of 240 mg. of 6-amino-2,2-di-
. .,, , - .
methyl-3-(5-tetrazolyl)penam in 10 ml. of water is cooled - - -` --
to 0C., and then the pH is adjusted to 7.1 using lN sodium ; : ~
hydroxide. The resultant solution is diluted with 10 ml. ;~ -
of acetone, and then a solution of 281 mg. of 3-(o-chloro-
phenyl)-5-methylisoxazole-4-carbonyl chloride (Doyle, et al.,
Journal of the Chemical Society [London] 5838 ~1963]) in . -
- , .
10 ml. of dry acetone is added portionwise during 3-4 -
minutes. During the addition the pH of the solution is
maintained in the range from 5.5 to 6.5 by adding O.lN
90dium hydroxide. At the end of the addition the reaction
is stirred an additional 15 minutes at around QC. At thi~
.
point, the acetone is removed by evaporation under reduced
pre3sure at around 15C., the resultant aqueous phase is
filtered and the p~ is lowered to 2 with dilute hydrochloric ~ -
.,
-116- . ~
. ,~ , "';
~OS~t~
acid. The product is extracted into chloroform. ~he
extract is dried using anhydrous sodium sulfate, and then
it is evaporated ln vacuo to give the crude product as a
gum. The gum is re-dissolved in 3 ml. of tetrahydrofuran,
and then the solution is added to lS ml. of water at 10C. -;
The pH of the solution is raised to 7.0 by the addition
of O.lN sodium hydroxide, the solution is filtered, and
then it is lyophilized. This affords 430 mg. of the
sodium salt of 6-(3-[o-chlorophenyl]-5-methyl-4-isoxazole- '
carboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as an
amorphous solid. The infrared spectrum (KBr disc) of the
product shows absorption bands at 1770 cm~l (~-lactam
carbonyl), 1650 cm~l (amide I band) and 1520 cm~l (amide
II band). The NMR spectrum (in CDC13) shows absorption -
lS bands at 7.40 ppm (multiplet, aromatic hydrogens), 5.90 and
5.60 (2 doublets, C-5 and C-6 hydrogens), 5.15 ppm (singlet,
C-3 hydrogen), 2.80 ppm (singlet, isoxazole methyl hydro-
gens), 1.50 ppm (singlet, C-2 methyl hydrogens) and 1.05
ppm (singlet, C-2 methyl hydrogens).
EXAMPLE XLIII ~
When the procedurè of Example XLII is repeated, ~ -
and the 3-(o-chlorophenyl)-5-methylisoxazole-4-carbonyl
chloride used therein is replaced by 3-phenyl-5-methylis-
oxazole-4-carbonyl chloride, 3-(2,6-dichlorophenyl)-5-methyl-
isoxazole-4-carbonyl chloride and 3-~2-chloro-6-fluoro-
phenyl)-S-methylisoxazole-4-carbonyl chloride, respectively,
there i9 produced:
6-(3-phenyl-5-methyl-4-isoxazolecarboxamido)-2,2-di-
methyl-3-(5-tetrazolyl)penam; -
6-(3-[2,6-dichlorophenyl]-5-methyl-4-isoxazolecarbox- -
-117- ;
' ~
'~' ~ ~..'`
:,, '', "~ ' ' :
amido)-2,2-dimethyl-3-(5-tetrazolyl)penam, and
6-~3-[2-chloro-6-fluorophenyl]-5-methyl-4-isoxazole-
carboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,
respectively.
The starting acid chlorides used in this experi- '
ment are prepared by the action of thionyl chloride on ~
the corresponding acids, which in turn are prepared by the - ~-
published methods (Long, et al., Journal of the Chemical ~ -
Society [London], 5838 11963); United States Patent No.
~0 2,996,501). -
EXAMPLE XLIV -
: ... , ,....... :.
6-(2-Azido-2-Phenvlacetamido)-2,2-dimethYl-3-(5-tetrazolyl)-
~enam ;
A solution of 1.61 grams (9.1 mmole) of 2-azido- :~
lS 2-phenylacetic acid [Forster and Mueller, J. Chem. Soc., -
97, 138 (1910)] and 5 ml. of thionyl chloride is heated ~
under reflux for hour. The reaction solution is evaporated --
under reduced pressure to furnish a residue of 2-azido-2- :: -
phenylacetyl chloride which is dissolved in 10 ml. of di- i~
chloromethane and is added over 5 minutes to a stirred ice- ~ `
bath cooled solution of 2.4 grams (10 mmole) of 6-amino-2,2- `- `
dimethyl-3-(5-tetrazolyl)penam, 2.02 grams (20 mmole) of
triethylamine and 50 ml. of dichloromethane. After 30
minutes the reaction solution is allowed to warm to room
. .
2S temperature. After a further 3 hours, the more volatile
aomponents of the solutian are evaporated under reduced
pressure and the residue is taken up in 50 ml. of water.
The aqueous solution is washed twice with 25 ml. portions
of ethyl acetate, and it is then adjusted to pH 2.5 by the
careful addition of 6N hydrochloric acid. The resulting
-118-
:::. .. ..
: ., ,' - ,:' ''.
',', '..''
:' ' '.
1~).5~9;~
cloudy mixture i~ extracted twice with 30 ml. portions of
ethyl acetate. After being dried using anhydrous sodium
sulfate, the combined extracts are filtered and the solvent
is evaporated in vacuo. The residue is dissolved in 10 ml.
of dichloromethane; 1.0 ml. of triethylamine is added, and
the resulting solution is poured into 350 ml. of rapidly
stirred diethyl ether. The solid which precipitates is -
filtered off giving 1.62 g. (38% yield) of the title com-
pound as its triethylamine salt. IR (KBr disc): 1792 cm 1
~-lactam) and 1693 cm 1 (amide I). NMR (in D2O/NaHCO3):
7.40 ppm (s, SH, aromatic hydrogens), 5.60 and 5.80 ppm
(m and m, 2H, C-S and C-6 hydrogens), 5.30 ppm (m, 2H, C-3 ~ ~ -
hydrogen and side-chain methine hydrogen), 3.20 (q, 6H,
NCH2CH3), 1.60 ppm (s, 3H, C-2 methyl hydrogens), 1.30 ppm
(t, 9H, NCH2CH3), 1.10 ppm (s, 3H, C-2 methyl hydrogens).
EXAMPLE XLV
6-(2-Cyanoacetamido)-2,2-dimethYl-3-(5-tetrazolYl)penam
To a solution of 2.0 g. of 2-cyanoacetic acid
and 2.7 g. of N-hydroxysuccinimide, in S0 ml. of tetrahydro-
furan, is added 4.85 g. of dicyclohexylcarbodiimide. The
mixture is stirred at ambient temperature overnight, and
then the precipitate is filtered off and discarded. Evapora-
tion of the solvent then affords the N-hydroxysuccinimide
ester of cyanoacetic acid, which after recrystallization
from chloroform has m.p. 123-30C. and is suitable for use
as described below. ~A more highly purified sample has
m.p. 128-130C.)
To a stirred suspension of 177 mg. of 6-amino-2,2-
dimethyl-3-(5-tetrazo}yl)penam in 10 ml. of methylene ~ ~
chloride, under nitrogen, is added 157 mg. of triethylamine. ~-
-119- ~ ~
1()5~9~
Stirring is continued until a clear ~olution is obtained
(ca. 35 minutes~. To this solution ls then added 135 mg.
of the N-hydroxysuccinimide ester of cyanoacetic acid, all
in one portion. Afte~ stirring for a further 2.5 hours,
the reaction mixture is poured into 15 ml. of water and
the pH of the aqueous phase is adjusted to 8Ø The
methylene chloride layer is separated off and discarded.
~he aqueous phase is acidified to pH 2, and then extracted
with ethyl acetate. The ethyl acetate is dried using an- : --
. .
hydrous sodium sulfate, and then to it is added a solution ~:
o 110 mg. of sodium 2-ethylhexanoate in a small volume
.. . .
of ethyl acetate. The precipitate which forms is filtered ~-~
off, to give 138 mg. ~57% yield) of the sodium salt of
6-~2-cyanoacetamido)-2,2-dimethyl-3-~5-tetrazolyl)penam.
The infrared spectrum (KBr disc) of the product shows ;
absorption bands at 2260 cm~l (cyano), 1775 cm~~ lactam
carbonyl), 1680 cm~l (amide I band) and 1550 cm~l (amide
II band). The NMR spectrum (in D20) shows absorptions at
5.90 and 5.40 ppm ~2 doublets, C-5 and C-6 hydrogens),
5.30 ppm (singlet, C-3 hydrogen), 1.65 ppm (singlet, C-2
methyl hydrogens) and l.OQ ppm (singlet, C-2 methyl hydrogens).
EXAMPLE XLVI ;
6-(2-[1-Tetrazolyl]acetamido)-2,2-dimethyl-3-~5-tetrazolYl)-
penam
To a stirred solution of 90 mg. of tetrazol-l-
acetic acid and 71 mg. of triethylamine, in 5 ml. of chloro-
form, cooled to 0C., is added 85 mg. of pivalo~l chloride.
. :
Stirring is continued at 0C. for a further 30 minutes, -
and then the resultant solution is added to an ice-cold
solution prepared from 169 mg. of 6-amino-2,2-dimethyl-3- ` ~ -
-120- ~
: ,'~' ,' ,` . ` .
. ::: :::
:: .
"..' :' - .
105999~
(5-tetrazolyl)penam, 142 mg. of triethylamine and 5 ml. of
chloroform. This combined solution is stirred at about
0C. for 2.5 hours. It is then warmed to ambient temp-
erature and poured into 20 ml. of water. The pH of the
a~ueous phase is raised to 7.0, the layers are separated,
and the chloroform is discarded. The aqueous phase is
acidified to pH 2, and then it is extracted with ethyl
acetate. The ethyl acetate is dried, and then to it is -~
added a solution of 100 mg. of sodium 2-ethylhexanoate in
a small volume of ethyl acetate. The solid which pre-
cipitates is filtered off, giving 80 mg. (31% yield) of
the sodium salt of 6-(2-[1-tetrazolyl]acetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum of
the product (KBr disc) shows absorption bands at 1785 cm 1
(~-lactam carbonyl), 1695 cm 1 (amide I band) and 1575 cm 1
(amide II band). The NMR spectrum (in D20) shows absorp-
tion bands at 5.90-5.40 ppm (multiplet, C-5 and C-6
hydrogens), 5.25 ppm (broad singlet, tetrazole hydrogen),
5.20 ppm (singlet, C-3 hydrogen), 1.70 ppm (singlet, C-2
methyl hydrogens) and l.OO ppm (singlet, C-2 methyl
hydrogens).
The tetrazole-l-acetic acid used in this Example
is obtained by the method described in United States
patent no. 3,468,874.
-121-
: . .
.' ~
~OS~5~9;~
EXAMPLE XLVII
Using the procedure of Example XLVI, and replacing
the tetrazole-l-acetic acid by the appropriate acid, the
following compounds are prepared as their sodium salts.
6-(2-~2-tetrazolyl]acetamido)-2,2-dimethyl-3(5- :
tetrazolyl)penam, . ~.:
6-(D-2-hydroxy-2-phenylacetamido)-2,2-dimethyl-3-
(5-~etrazolyl)penam,
6-(D-2-hydroxy-2-~p-hydroxyphenyl]acetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam,
6-(D-2-hydroxy-2-[p-hydroxyphenyl~acetamido)--2,2-
dimethyl-3-(5-tetrazolyl)penam,
6-(~-2-hydroxy-2-[2-furyl]acetamido)-2,2-dimethyl- :
3-(5-tetrazolyl)penam,
6-(D-2-hydroxy-2-[2-thienyl]acetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam, .
6-(2-.[2-(hydroxymethyl)phenyllacetamido)-2,2- :
dimethyl-3-(5-tetrazolyl)penam and ~ .
6-(2-[4-(hydroxymethyl)phenyl]acetamido)-2,2- -:-
dimethyl-3-(5-tetrazol-5-yl)penam, :-
respectively.
The tetrazole-2-acetic acid is prepared by the
method described in United States patent No. 3,468!874. . :
D-2-Hydroxy-2-phenylacetic acid is commercially available.
. .: . . .
25 D-2-Hydroxy-2-(p-hydroxyphenyl)acetic acid, D-2-hydroxy-
2-(mj-chlorophenyl)acetic acid, D-2-hydroxy-2-(2-furyl)-
acetic acid and D-2-hydroxy-2(2-thienyl)acetic acid are -~
each prepared from the corresponding aldehyde, using the : .
method of Corson et al., Organic Synthesis, Collective : .
30 Volume I, p. 336. -~:
,~ ..
,~:
-122-
:~'
10599~ ,
EXAMPLE XLVIII
6-(2-Phenoxyacet_mi )-2~2-dimethyl-3-(5-tetrazolyl)penam
A stirred slurry of 480 mg. of 6-amino-2,2-
dimethyl-3-(5-tetrazolyl)penam in 10 ml. of water is
cooled to OC., and then the pH is adjusted to 8.0 using '
lN sodium hydroxide. To this solution is then added 0.25
ml. of phenoxyacetyl chloride, in portions, with the pH of
the solution being maintained between 7 and 8 during the
addition, u~ing O.lN sodium hydroxide. The solution is
stirred a further 30 minutes at oC. at pH 8. It is then
extracted with chloroform, and the extracts are discarded.
The aqueous phase is acidified to pH 2 with dilute hydro-
chloric acid, and then it is further extracted with chloro--
form. The latter extracts are dried using calcium sulfate
and then evaporated in vacuo to give the crude product as
a gummy solid. This is purified by dissolving it in 20 ml.
of chloroform, and adding the resultant solution dropwise
to 250 ml. of hexane. The precipitate which forms is fil-
:tered off, giving 385 mg. of 6-(2-phenoxyacetamido)-2,2-
dimethyl-3-t5-tetraZolYl)Penam as~a white amorphous solid.
The infrared spectrum (KBr disc) of the product shows
absorption bands at 1785 cm (~-lactam carbonyl), 1670 cm 1
(amide I band) and 1540 cm (amide II band). The NMR
spectrum (in DMS0-d6) showg absorption bands at 7.50-6.70
ppm (multiplet, aromati~ hydrogen8), 5.70` ppm ~multiplet,
C-5 and C-6 hydro~ens), 5.35 ppm (singlet, C-3 hydrogen),
4.60 ppm (singlet, methylene hydrogens), 1.60 ppm
(singlet, C-2 methyl hydrogens), and 1.05 ppm (singlet,
C-2 methyl hydrogens).
- ~ ' ~ ' , ~ ,'' '
-123-
... ~ .
lOSg99'~
EXAMPLE XLIX
The procedure o Example XLVIII i~ repeated,
using the appropriate acid chloride, to provide the
following compounds
Rl-N ~ 3
¦ 3 ~:-
~N
HN__N
:, .
- .
~ 124-
--
.
lOS999Z
~,
r.
~m o~¢ ~m _lo
~ ~~ ~`~`~I
_ _-- O ~
_ O O~ O1~ o_I o
Q . . ~ . u~ . u~ .
_
~ ~ _ m--
~: ~C O
S~ ~ ~ . r~
__ ~ ~ _ ~ O-- ~ ~~
~ o o o O u~
u~ o o~ t . I~
. . ;~ a ~ ~ u~ . .
æ ~ ~ . ~ ~ . _ ~ . _ . S,
_ ~ _ ~ ~ _ X _ _
~ 0 ~
___ ___ O---- o--P:
00000~~700I`OU~
~1 01`~1 ~_I ~
~ ~ e
CD O U~ In '' '
I` I` I` r~ -: .
~, ~, _I ~, . -
OD 00 U~ O O
~ I o1~ a~ o o
H U~--
:::
~r co o
~: _I _1 ~1 _I . .
.,1 ~ _ I I I ,
11)
O~ O ~r o
:~ 2~
.
o
~ ~ N 3
125-
:
. .
:
.. . .. .,, , ,., ,., . ,,,, "~,,~ . ... ..
1059g92
EXAMPLE L
6-Acetamido-2,2-dimethyl-3-(5-tetraZolyl)penam
The procedure of Example XLVIII i8 repeated,
except that the phenoxyacetyl chloride used therein i9
replaced by acetic anhydride. This affords a 48% yield of
the title compound. IR (KBr disc): 1780 cm (~-lactam),
--1 .,
1645 cm (amide I). NMR (in DMO-d6): 5.65 ppm (m, 2H), -
5.25 ppm (s, lH), 1.95 ppm (s, 3H), 1.70 ppm (s, 3H), and - -
1.10 ppm (s, 3H).
.' ' '.
,
: ~ ~
~ -126-
.
. .
~ .
1~)55~95~'~
EXAMPLE LI
Reaction of 6-amm~-2,2-dimethyl-3-(5-tetrazolyl)
penam with the appropriate acid chloride, according to the
procedure of Example XLVIII, provides the following
compounds:
6-(2-lcyclopent-2-enyl]acetamido)-2,2-dimethyl-3- :
(5-tetrazolyl)penam,
6-(2-[cyclohex-2-enyl]acetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam,
6-(2-[cyclohept-1-enyl]acetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam,
6-(2-[cyclooct-1-enyl]acetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam and,
6-(2-[cyclohept-2,4,6-trienyl]acetamido)-2,2- :
dimethyl-3-(5-tetrazolyl)penam, - `
respectively.
'~
"..:
,.
-127-
'.'
~)s999~
EXAMPLE LII
The procedure of Example XLVIII is repeated,
except that the phenoxyacetyl chloride used therein is
replaced by an equimolar amount of the appropriate acid
chloride, to produce the following congeners:
6-propionamido-2,2-dimethyl-3-(5-tetrazolyl)penam,
6-octanamido-2,2-dimethyl-3-(5-tetrazolyl)penam, :
6-acrylamido-2,2-dimethyl-3-(5-tetrazolyl)penam,
6-(3-methylacrylamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam,
6-(3,3-dimethylacrylamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam,
6-(2-cyclopentylacetamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam,
6-(2-cyclohexylacetamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam,
6-(2-cycloheptylacetamido)2,2-dimethyl-3-(5-
tetrazolyl)penam,
6-(2-[cyclohex-3-enyllacetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam,
6-(2-lcyclohex-1-enyl]acetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam,
6-(o-methoxybenzamido)-2,2- dimethyl-3-(5-tetra-
zolyl)penam,
6-(2,6-dimethoxybenzamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam,
6-(2,6-diethoxybenzamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam,
6-(2,6-dipropoxybenzamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam,
6-(2,6-dibutoxybenzamido)-2,2-dimethyl-3-t5-
: tetrazolyl)penam,
6-(2-methoxy-1-naphthamido)~ 2,2-dimethyl-3_(5_
tetrazolyl)penam,
6-(2-ethoxy-1-naphthamido)-2,2-dimethyl-3-(5- :~
tetrazolyl)penam,
6-(2-n-butoxy-1-naphthamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam, ~ -
-128- .
, .. .
105999'~
6-(4-isothiazolecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)-
penam,
6-(2-imidazolecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)-
penam,
6-(2-azido-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl~
penam,
6-(3-phenylpropionamido)-2,2-dimethyl-3-(5-tetrazolyl)- :
penam,
6-(2-[phenylthio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)-
penam,
6-(2-[3-sydnonyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)-
penam,
6-(2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl). : .
penam,
6-(2-[2-furyl~acetamido)-2,2-dimethyl-3-(5-tetrazolyl)-
penam,
6-(2-13-methyl-2-thienyl]acetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam,
6-(2-ll-pyrazolyl]acetamido)-2l2-dimethyl-3-(5-tetrazolyl)~
penam,
6-(2-[1,2,4-triazol 1-yl]acetamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam,
6-(2-[2,4-dimethylthiazol-5-yl]acetamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam,
6-(2-[N-methylpyrrol-2-yl]acetamido)-2,2-dimethyl-3- ...
(5-tetrazolyl)penam,
6-(2-[1-pyrrolyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)_
penam,
6-(2-[~-chlorophenyl]acetamido)-2,2-dimethyl-3-(5-tetra- : :.
zolyl)penam,
6-(2-[m-methoxyphenyl]acetamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam, and
6-(2-[~-tolyl~acetamido)-2,2-dimethyl-3-(5-tetrazolyl).
penam,
respectively. -~.
.`'.
:.
-129- . ~
.. -
~()s~g~
~ he acid chlorides used in this Example are pre-
pared from the corresponding acids, using methods well
known in the art (Buehler and Pearson, "Survey of Orgar.ic
Syntheses," Wiley-Interscience, 1970, pp. 859-867).
2-(Cycloheptyl) acetic acid and 2-(cyclohex-1-enyl)acetic acid
are prepared from their corresponding nitriles (which are
items of commerce) by hydrolysis, using methods discussed
by Buehler and Pearson (loc. cit., pp. 752-753).
2-(cyclohex-3-enyl)lacetic acid is prepared by the method of
Boehme, Journal of Organic Chemistry, 26, 2107 (1961).
The 2,6-dialkoxybenzoic acids are prepared according to
Doylej et al., Journal of the Chemical Society (London),
1453 (1962), and the 2-alkoxy-1-naphthoic acids according
to British ~atent No. 880,400. 2-(3-Sydnonyl)acetic acid
is prepared by the method of Stewart, Chemistr~ and
IndustrY tLondon)~ 1411 (1961). The 2-(3-thienyl)acetic
acid, 2-(2-furyl)acetic acid, 2-(3-methyl-2-thienyl)acetic
acid, 2-(1-pyrazolyl)-acetic acid, 2-(1,2,4-triazol-1-yl)
acetic acid, 2-(2,4-dimethylthiazol-5-yl)acetic acid, 2-
(N-methylpyrrolyl)acetic acid and 2-(1-pyrrolyl~acetic
acid are prepared by methods disclosed in Belgian Patent
No. 618,663. All the other acids are items of commerce.
-130-
105999;~
EXAMPLE LIII
6-(3-[Carbamoyl]acrylamido)-2,2-dimethyl-3-(5-
To a stirred mixture of 1.15 g. (10 m mole) of
maleamic acid and 1.40 ml. of triethylamine in 40 ml. of
dry tetrahydrofuran, at OC., is added 1.57 ml. (12 m mole)
of -ïsobut~l chloroformate followed by three drops of N-
~ethylmorpholine. Stirring is continued for a further 30
minutes at OC. To this mixed anhydride is then added a
~olution prepared by adding 2.40 g. (10 m mole) of 6-amino-
2,2-dlmet~yl-3-(5-tetrazolyl)penam to a mixture of 15 ml.
o4 water and 15 ml. of tetrahydrofuran and adjusting the
pH to 7.5. The resulting mixture is then stirred for a
further 1 hour at OC. At this point, the tetrahydrofuran
is removed by evaporatlon in vacuo, and the residue is
diluted with more water. The pH is adjusted to 8.0 with
6 N sodium hydroxide, and then the mixture is extracted
with ethyl acetate. The extracts are discarded. The pH
~ the residual aqueous phase is adjusted to 2.0 with 4 N
2a hydrochl~ric acid and then the product is extracted into
ethyl acetate. The organic layer is dried and concentrated
in vacuo to- give 6-(3-~carbamoyl]-acrylamido)-2,2-dimethyl- ~`
3-(5-tetrazoIyl)penam (1.03 g., 33% yield). The infrared
spectrum (KBr disc) of the product shows absorption bands -
at 1818 cm (~-lactam) and 1692 cm . The NMR spectrum
(DMSO-d6) shows band~ at 7.00 and 6.25 (quartet, 2H, J - 12
Hz, ~le~inic hydrogens), 5.80-5,48 ppm (multiplet, 2H, C-5
and C-6 hydrogens), 5.26 ppm (singlet, lH, C-3 hydrogen), ;
1.65 ppm (singlet, 3H, C-2 methyl hydrogens) and 1.06 ppm
(singlet, 3H, C-2 methyl hydrogens).
-131- ~ `
,..,:
.~ -
105999~ :
E~AMPLE LIV
6-Formamido-2l2-dimethyl-3-(S-tetrazolyl)penam
To a stirred solution of 480 mg. of 6-amino-2,2-
dimethyl-3-(5-tetrazolyl)penam and 0.56 ml. of triethyl-
amine in 5 ml. of methylene chloride, at OC., is added 0.3ml. of formic acetic anhydride. Stirring is continued for
a further 45 minutes, at OC., and then the solvent is
removed by evaporation _ vacuo. The residue is par-
titioned between water and ethyl acetate, and then the
ethyl acetate is separated off and dried. Evaporation of
the ethyl acetate in vacuo affords 0.216 g. of 6-formamido-
2,2-dimethyl-3-(5-tetrazolyIjpenam as a foam. The NMR
spectrum (CDC13) shows absorptions at 8.20 ppm (singlet,
lH, formamido hydrogen), 5.80 ppm (multiplet, 2H C-5 and
C-6 hydrogen), 5.30 ppm (singlet, lH, C-3 hydrogen), 1.70
ppm (singlet, 3H, C-2 methyl hydrogens) and 1.10 ppm
(singlet, 3H, C-2 methyl hydrogens). The infrared spectrum - -
of the sodium salt (KBr disc) shows absorptions at I760
cm and 1660 cm
~ ~ ' ' '' '''
~ ~ .
-132-
~ .
~05999'~
EXAMPLE LV
6-~2-Bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam
To a stirred suspension of 3.0 g (0.0125 mol~) o
6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 15 ml o~
water is added 1.74 g (0.0125 mole) of bromoacetic acid
dissolved in 5 ml of water. The pH of the mixture is
adjusted to 6.0 using 20% sodium hydroxide solution. The
resulting clear solution is cooled to OC, and then 2.4 g
(0.0125 mole) of 1-ethyl-3-(3-dimethylaminopropyl) car-
bodiimide hydrochloride is added. The solution is stirred
at OC. for a further 2.5 hr, during which time the pH is
maintained between 6 and 7 by the addition of 6N hydro-
chloric acid. At this point, the pH is adjusted to 7.0 -
and the reaction mixture is extracted with ethyl acetate.
15 The extract is discarded. The pH of the reaction mixture -
is then lowered to 2.0 (6N hydrochloric acid), and the
product is extracted into ethyl acetate. The ethyl acetate
is washed with water, dried, and evaporated to give 3.2 g
(72% yi~eld) of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5~
tetra~olyl)penam as a white `~oam. The infrared spectrum
(KBr disc) of the product shows absorption bands at 1795
cm 1 (~-lactam), 1670 cm (amide I) and 1530 cm 1 (amide
II). The NMR spectrum (CDC13) shows absorption bands at
10.6-9.6 ppm (broad singlet, tetrazole hydrogen), 8.8 ppm
(doublet, amide hydrogen), 5.8-5.4 ppm (multiplet, C-5 and
C-6 hydrogen9), 5.35 ppm (singlet, C-3 hydrogen), 4.0 ppm
(singlet, methylene hydrogen), 1.90 ppm (singlet, C-2
methyl hydrcgens) and 1.15 ppm (singlet, C-2 methyl hydr~gens).
The above product is dissolved in 15 ml of water --
containing 1 equivalent of sodium bicarbonate. The re-
.- .
-133-
.. .
105999'~
sulting solution is then lyophilized leaving the sodium
~alt of the title compound (3.4 g, 72% yield).
~XAMPLE LVI
6-(2-[4-Pyridylthio]acetamido)-2,2-dimethyl-3-(5-tetra-
zo y penam
To a stirred suspension of 1.0 g (0.0028 mole)
of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam
in 25 ml of methylene chloride is added 0.28 g (0.0028
mole) of triethylamine. The mixture is stirred at ambient
temperature until a clear solution is obtained, and then
0.39 g of 4-mercaptopyridine is added. Stirring is con-
tinued for a further 4 hours at ambient temperature, and
then the solid which has precipitated is filtered off. It
is washed with methylene chloride, followed by ether, to
give 0.68 g (78~ yield) of 6(2-[4-pyridylthio]acetamido)-
2,2-dimethyl-3-(5-tetrazolyl)penam, m.p. 120C. (dec.).
The infrared spectrum of the product (KBr disc) shows
absorption bands at 1790 cm (~-lactam), 1670 cm (amide
II). The NMR spectrum (DMSO-d6) shows absorption bands at
9.0-7.0 ppm (multiplet, pyridine hydrogens), 5.9-5.5 ppm
(multiplet, C-5 and C-6 hydroge~), 4.0 ppm (singlet,
methylene hydrogens), 1.7 ppm (singlet, C-2 methyl
hydrogens) and 1.1 (singlet, C-2 methyl hydrogens).
; -134-
' .
105999~
EXAMPLE LVII
6-(2-~ Diethylamidinothio]acetamido)-2~2-dimeth ~ 3-
( -tetr~zolyl)penam
To a stirred solution of 1.40 g (0.039 mole) of
6-(2-bromoacetamido)-2,2-dimethyl-3~(5-tetrazolyl)penam in
25 ml of methylene chloride is added 0.54 ml (0.039 mole)
of triethylamine, followed by 0.52 g (0.039 mole) of N,N- -
diethylthiourea. Stirring is continued for a further 45
minutes, and then the solvent is decanted from the oil
10 which has separated. The oil is triturated with ether, -
giving a white solid, which is filtered off. The yield is
1.28 g (76% of theory) of 6-(2-[N,N- diethylamidinothio]-
acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The in- ~-
frared spectrum (KBr disc) of the product shows absorption
bands at 1780 cm (,B-lactam) and 1670 cm (amide I).
The NMR spectrum (DMSO-d6) shows absorption bands at 5.65
ppm (multiplet, C-5 and C-6 hydrogens), 5.15 ppm (singlet,
C-3 hyrogen), 4.10 ppm (singlet, methylene hydrogens),
3.45 ppm (quartet, ethyl hydrogens), 1.60 ppm (singlet, C-2
methyl hydrogens), 1.10 ppm (triplet, ethyl hydrogensl and
1.00 ppm (singlet, C-2 methyl hydrogens).
';''-' ,"
-' ' '" '.
''':
-135- ~ -
,, .
~os9g9~
EXAMPLE LVIII
5-(2,6-Dimethoxybenzamido)-2,2-dimethyl-3-(5-tetrazolyl)--
penam
. _
To a stirred solution of 1.2 g. (5 mmole) of 6-
amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 1.01 g. (10
mmole) of triethylamine and 50 ml. of methylene chloride,
is added 1.0 g. (5 mmole) of 2,6-dimethoxybenzoyl chloride
(Norris and Ware, J. Amer. Chem. Soc.,61, 1418 [1936], at --
ca. 0C. Stirring is then continued for three hours at - -
ambient temperature. To the reaction mixture is added 50
ml. of water, and the pH of the aqueous phase is adjusted
to 8Ø The organic phase is separated off and discarded.
The pH of the residual aqueous phase is lowered to 2.5,
and the precipitate which forms is filtered off. This
affords 1.2 g. (59% yield) of the title compound, m.p.
215C. (dec). IR (KBr disc): 1808, 1643 and 1605 cm
NMR (in D2O/HCO3): 7.50 ppm (t, lH), 6.90 ppm (d, 2H), ~ -
5.90 and 6.0 ppm (q, 2H), 5.40 ppm (s, lH), 4.00 ppm
(s, 6H), 1.80 ppm (s, 3H) and 1.20 ppm (s, 3H).
-136-
lOS~g'~
EXAMPLE LIX
6-(2-Ethoxy-l-naphthamido)-2,2-dimethyl-3-(S-tetrazolyl)_
penam
Following the procedure of Example LVIII, the
title compound is prepared from 2.84 g. (0.012 mol) of 6-
amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 1.39 (0.006
mol) of 2-ethoxy-1-naphthoyl chloride and is isolated as ~-
the sodium salt by standard procedures: yield 1.5 (54%); -
IR (KBr); 1780 1715, 1667 cm ; NMR (D2O) 8.0-6.8 ppm
(m, 6H), 5.85 (s, lH), 5.40 (s, lH), 5.25 (s, lH), 3 90
(q, 2H), 1.45 (s, 3H), 1.25 (t, 3H) 1.00 (s, 3H).
-137- `
lOSggg'~
EXAMPLE LX
6-(L-2-Amino-2-phen acetamido)-2,2-dimethyl-3-(5-tetra-
A stirred suspension of 200 mg. of 6-amino-2,2-
dimethyl-3-(5-tetrazolyl)penam in 5 ml. of water is cooled
to 0-5C. in an ice-bath. The pH is then adjusted to 7.0
using dilute sodium hydroxide solution. At this point,
274 mg. of D-2-amino-2-phenylacetyl chloride hydrochloride
(HardCaStle et al., Journal of Organic Chemistry, 31, 897
1(1966]) is added portionwise during 15 minutes at 0-5C.,
and with the pH maintained between 6 and 7 by the addition
of dilute sodium hydroxide. At the end of the addition,
the reaction mixture is stirred for a further 15 minutes
and then filtered. The pH of the mother liquors is
ad~usted to 4.4 with dilute hydrochloric acid, and then
the solution is stored overnight in the refrigerator. The
solution is then filtered, and the mother liquors are
placed on a column of 25 g. of Sephadex LH-20 (Pharmacia
Fine Chemicals, ~nc.) made up in water. The column is
eluted with water, taking fractions, and the composition
of the fractions is assayed by thin-layer chromatography.
The fractions containing the pure product are combined,
and evaporated under high vacuum to a volume of approx-
imately 1 ml. After this 301ution has been set aside for a
short period, the produat crystallizes out. It is filtered
off, washed briefly with water and dried. The yield is 55
mg. of pure 6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam, m.p. 192-196C. The infrared spec-
trum (KBr disc) shows absorptions at 1770 cm (~-lactam
carbonyl), 1680 cm (amide I band) and 1520 cm 1 (amide II
band).
-138-`
`, '
~', .
lOS999Z
EXAMPLE LXI
When the procedure of Example ~X is repeated,
and the D-2-amino-2-phenylacetyl chloride hydrochloride
used there is replaced by an equivalent amount of the
appropriate acid chloride hydrochloride, the following
compounds are produced.
6-(DL 2-amino-2-phenylacetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam,
6-(DL-3-amino-2-phenylpropionamido)-2j2-dimethyl~ .
3 ~ tetrazolyl)penam~
6-(2-[2-pyrid~l]acetamido)-2,2-dimethyl-3-(5- . . -
-tetrazolyl)penam, .. -
~-(2-~3-pyridyl]ace~amido)-2,2-dimethyl-3-(5- . .
te~razolyl)penam,
- . ,.
6-(2-[4-pyria~l]acetamido)2,2-dimethyl-3-(5- ; .
tetrazolyl.)penam,
6-(2-[4-pyridylthio]acetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam,
6-(2-[p-aminophe~yl]acetamido)-2~2-dimethyl-3~
(5-tetrazolyl)penam, :
6~ amino.cyclobutanecarboxamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam,
6-(l-aminocyclopentanecarboxamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam,
25 . . 6-(l-aminocyclohexanecarboxamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam,
6-(l-aminooycloheptanecarboxamido)-2,2-dimethyI- .
3-(5-tetrazoly}~penam,
6-(2 1m-(N-methylamino)phenyl]àcetamidoj-2,2-
dimethyl-3-(5-tetrazolyl.)penam and
6-(2-[p-1N~n-b~tylamino)phenyl]acetamido)-2,2- .:.
dimethyl-~-(5-tetrazolyl)penam,
resp-ectively. :
.DL-2-Amino-2-phenylacetic acid, 2-pyridylacetic
35. .acid, 4-pyridylacetic acid and p-aminophenylacet~ic acid
. are it.ems:of commerce. D~-3-amino-2-phenyl-propionic acid
is prepared by the me~hod of Testa et al., Annalen der
-13g- ~
.
. ' '
.~ . ,
.
1~)5~
Chemie, 614, 167 (1958, and (4-pyridylthio)acetic acid is
prepared by the method described in Netherlands Patent No.
6,912,855. The l-aminocycloalkanecarboxylic acids are
prepared by the method of Alburn et al., Antimicrobial
Agents and Chemotherapy, 586 (1967). The amino-acids are
converted into their acid chloride hydrochlorides by
sequential treatment with hydrogen chloride gas and
phosphorus pentachloride (Hardcastle et al., Journal of
Organic Chemistry, 31 987 [1966].
-140-
~os~9~
EXAMPLE LXII
Acylation of 6-amino-2,2-dimethyl-3-(S-tetra-
zolyl)penam with the acid chloride hydrochloride of 2-(N-
methylamino)-2-phenylacetic acid, 2-(N-ethylamino)-2-
phenylacetic acid, 2-(N-isobutylamino)-2-phenylacetic
acid, 2-(N-n-hexylamino)-2-phenylacetic acid, 2-(N-methyl- -
amino)-2-(2-thienyl)acetic acid and 2-(N-methylamino)-2-
(p-chlorophenyl)acetic acid, respectively, according to -: .:
the procedure of Example LX, produces the following con- .~ .
geners:
6-(2-[N-methylamino]-2-phenylacetamido)-2,2- :
dimethyl-3-(5-tetrazolyl)penam, :.
6-(2-[N-ethylamino]-2-phenylacetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam,
lS 6-(2-[N-isobutylamino]-2-phenylacetamido)-2,2- . - .
dimethyl-3-(5-tetrazolyl)penam,
6-(2-1~-n-hexylamino]-2-phenylacetamido)-2,2-.
dimethyl-3-(5-tetrazolyl)penam, -
6-(2-[N-methylamino]-2-[2-thienyl]acetamido)-2,- -
2-dimethyl-3-(5-tetrazolyl)penam and /~
6-(2-[N-methylamino]-2-[~-chlorophenyl]acet_ :.
amido)-2,2-dimethyl-3-(5-tetrazolyl)penam, :
respectively.
2-(N-Methylamino-2-phenylacetic acid is prepared
by the method of Araga et al. (Nippon Kagaku Zasshi, 86, :.
111 tl9651; Chemical Abstracts, 62 16365 [l9651). The
other amin~-acids are prepared in analogous fashion, using
the appropriate aldehyde and amine. Acid chloride hydro-
chlorides are prepared by the method of Hardcastle et al.
.
30` ~Journal of Organio Chemistry, 31, 897 [1966]).
''; . ':
:: -141-
,. ~
. . ~ '
.
l~Sg~
EXAMPLE LXIII
6-(~~2-Amino-2-phenyladetamido)-2~2-d1methyl-3-(5-tetra-
zoly penam y roc ori e
A slurry of 50 mg. of 6-(D-2-amino-2-phenyl-
acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 2 ml. of
de-ionized water is stirred for 5 minutes at ambient temp-
erature. The pH is then adjusted to 2.45 using dilute
hydrochloric acid, and the solution thus o~tai~ed is `
immediately lyophilized. This affords 52 mg. of 6-(D-2-
amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl~
penam hydrochloride as a fluffy white solid.
-142-
~05999~
EXAMPLE LXIV
-
6~ 2-Amino-2-phenylacetamido)-2,2-dimethyl-3-(S-tetra-
zolyl)penam
To a stirred solution of 23.8 ml. of ethyl
chloroformate in 600 ml. of acetone, is added 25 ml. of a
3~ solution of N-methylmorpholine in acetone. The re-
sulting solution is cooled to -40C., and then 75.2 g. of
sodium N-(2-methoxycarbonyl-1-methylvinyl)-D-2-amino-2-
- phenylacetate is added. The temperature is adjusted to
-20C. and stirring is continued for 28 minutes. The
solution is re-cooled to -40C., and an ice-cold solution,
prepared by suspending 60.0 g. of 6-amino-2,2-dimethyl-3-
(5-tetrazolyl)penam in 250 ml. of water and then adjusting
the pH to 7.0, is added. The resulting solution is stirred
for 30 minutes without further cooling, and then the
acetone is removed by evaporation in vacuo. To the
aqueous residue is added an equal volume of tetrahydro-
furan, and then, at 5C. the pH is adjusted to 1.5 with
dilute hydrochloric acid. The mixture is held at this
temperature and pH for 30 minutes, and then the tetra-
hydrofuran is removed by evaporation in vacuo. The aqueous -
residue is extracted with ethyl acetate, followed by
ether, and the extracts are discarded. The pH of the -~
remaining aqueous phase is raised to 5.4, and the product
begins to crystallize out. After 1 hour it i9 filtered
off and dried. The crude yield is 68.8 g. ~ :
The product is suspended in water at 25C., and
the pH is lowered to 1.5. After stirring for a short
period, the insoluble materials are filtered off, and the
filtrate is extracted with ether. The aqueous solution is
then cooled to 5C., and the pH is ad~usted to 5.2. The
-143-
.. .. . . . . . . . . .. . . . . . .
105999'~
solid which precipitates i9 filtered off, giving 62.7 g.
(58.7%. yield) of 6-(D-2-amino-2-phenylace~do) 2,2-
dimethyl-3-(5-tetrazolyl)penam trihydrate, m.p. 201-202C.,
[a]D + 228.2 (1% in CH30H). IR (KBr disc): 1780 cm 1 (~_
lactam). NMR (in DMSO-d6/D2O): 7.60 ppm (s,5H)/ 5.70 ppm
(d, lH), 5.55 ppm (d, lH), 5.~iO pp~ (s~ I) 7 5.15 pp~
(d, lH), 1.50 ppm (s, 3H) 0.90 ppm (s, 3H).
Analysis - Calcd. for C16H19O2N7S- 3H2O (per-
cent): C, 44.95; H, 5.89; N, 22.94; S, 7.50. Found
(percent: C, 45.01; H, 5.84; N, 22.81; S, 7.34.
The sodium N-(2-methoxycarbonyl-1-methylvinyl)-
D-2-amino-2-phenylacetate is prepared from methyl
acetoacetate and D-2-amino-2-phenylacetic acid by the pro-
cedure used by Long et al. (J. chem Soc., London, Part C,
1920 [1971]) for the corresponding _-hydroxy compound.
,
~osg99'~ :
EXAMPLE LXV
The procedure of Example LXIV is repeated, except that the [
sodium N-(2~me ~ xycarbonyl-1-methylvi~yl)-2-amino-2-phenylacetats is
replaced by the appropriate ~-amino acid, protected as its
acetoacetic ester enamine derivative. This affords the
following compounds. In some instances, the products are
purified by Sephadex chromatography of their sodium salts. .
O , . , -
R - CH-C-NH ~ 3
~2 ~ ~ C~
' ' '
~' .
:-:
'.''".
-'. ~
~ ~ .
-145-
.:
' ' '
~\
~. 10'~
-
- ` ~
~9 - ~
`O ` ~ `~D O ~ o o ~
~-1 0 ~ U~ ~1 ou~-- In--
`I` ~ ~ ~a OO~J~D ~o
~ IC ~--~ ~ O ~n
_ ~ ~ ~ o ~ ~ a
--_ er--_-- _ _ ~ _ I . --_ _ _ _
~ :~ ~ ~ U) $ ~ 1 O ~
O _ _ ~ _ ~ _ ~ $ O --$--
U~ ~ ' O 5 U~ $ u)-- ~ O
` ~ ` ~ ~ ; o D
~ a
~i --~------5 ---- ~ _ --_-- O $-- $
I--sc ------I--$ --$--I-- IP I~$ ~P~ ~~~
u~ ~ ~7 i~ ~ O~ O ~ In _I o~ r ~ o
u~ o u~ IY7 ` Ot~ ~ ou~ o ~ O
- ~n - - - ~q~a . .. . ~ a
tD ~ O U~ O .'
co co c~ o ..
~D ~ U~ ~D 1`
~ O . ~ O u~ O u~ ~ ~ o
H u~--
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:~--
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,1 nJ
~ ~ c~ al ~ 1 al a~ 1 al
~rl o
~O ~a. ~ Z~; o ~ o o
:~ ~ 5 æl,~
-146-
~ ~J `~1~
~; '~ O
.1 .
- lOS999;~ .
~ , ,, . ,
1~ Ir^
. ~o o~ , . :
~ - .:
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`l ~ 6' ~ E3 ' . .:
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0 ~ 6 ' :;
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`D ~ ~ O ~ o ^ i . ''.-:
. 00 ~ 0 ~ 6 Cq 6 uî 0 ~ !
O~ U)O ~ . .. -'.
I ~ 0~ .,'~''''','''', -.
. l ~ O , O u~ 'O ` ~' ' ' ~
: ~ ~ 1 ' ' ' ' ' "'' ':
I ~ ~I) IEi 0 ~ ô ô u~ ::' :
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: ` ' ~ ,~
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,..... . ' . . -i47-
~os~99~
~1 ~ ` 0
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~m m ~ o ~m ~m . u~
~ ~ ~I O
~ a
~ --_~1 ------ _-- -- -
~ m r~ m o p~
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_ ~D ~ ` ~ ~In ~ ~ ~ o
I m~
P U) ~ o~1 ~1
_, ~ O ~ ~ O
~ O
f3 __~ __,~ ~ . __ __ _ .
~ rr~ m o ~ m ~
t) ~u~o u~ ~ ~_ ~1_ ~a,l ~__
~ ~ C -- o -- --:r: O
P ~ ` ~` O ~ ~ 10 ` ~ ~1 ` N ~ ~I
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Z; ` 0
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m o ~: ~ m ,I mco P: mo
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__I_~_~_____p_,~
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U~ oO _ o ~ _ ~ ~ ~ ~ ~ C
r~ ~ o ~ ~1 ~1 1` ~1-- 1`--o o ~1 -
q~
co ao co~ ~ o ~
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~: a3 b ', æ ~ b b ~ ~ ~
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14 8-
S~gg~
The starting enamines are obtained by con-
densation of the appropriate glycine with methyl aceto-
acetate, according to the procedure of Long, et al
(Journal of the Chemical Society [London], Part C, 1920
[1971]). Those ~-amino acids which are described in the
literature are prepared by the published procedures. The
new ~-amino acids are prepared from the corresponding
aldehydes vla a Strecker synthesis, techniques for which ~`
are discussed by Greenstein and Winitz in "Chemistry of -
the Amino Acids," John Wiley and Sons, Inc., New Yorkt-
London, 1961, pp. 698-700, and references cited therein.
The Strecker synthesis produces DL amino acids, which are
resolved into their optical isomers by conventional means
(consult Greenstein and Winitz, loc. cit., pp. 715-755;
Nishimura, et al.-, Nippon Kagaku Zasshi, 82, 1688 [1961]
[Ghemical Abstracts, 58, 11464 (1963)]): and Belgian
patent No. 795,874). See also British patent No.
1,221,227.
5-(3-Pyridyl)hydantoin is prepared by the method
of Henze and Knowlesj J. Org. Chem., 19, 1127 (1954), and
it is hydrolyzed to 2-amino-2-(3-pyridyl)-acetic acid by
the method described by Davis et al. (Archives Biochem
and BioPhys., 87, 88 [1960]) for the corresponding 4-
isomer.
-149-
... ,~.
. ~ .
1()5~3'~
EX~MPLE LXVI
__
Starting with the appropriate 2-substituted
sodium N-(2-methoxycarbonyl-1-methylvinyl)-2-aminoacetPte,
and following the procedure of Example LXIV, the following
compounds are prepared: .
6-(D-2-amino-2-~-fluorophenyl]acetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam,
6-(L-2-amino 2-[ -fluorophenyl]acetamido)-2,2
dimethyl-3-(5-te.~razolyl)penam,
6-(D-2-amin~-2-Eo-chlorophenyl]acetamido)-2,2-
dimethyl-3-~5-tetrazolyl)penam,
6-(L-2-amino-2-[o-chlorophenyllacetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam,
6-(D-2-amino-2-[m-bromophenyl]acetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam,
6-(L-2-amino-2-[m-bromophenyl]acetamido)-2,2- :-
dimethyl-3-(5-tetrazolyl)penam, . .
6-(D-2-amino-2-[m-chlorophenyl]acetamido)-2,2- -
dim~thyl-3-(5-tetrazolyl)penam, .
6-(L-2-amino-2-[m-chlorophenyl]acetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam,
6-(D-2-amino-2-lp-chlorophenyl]acetamido)-2l2
dimethyl-3-(5-tetrazolyl)penam,
6-(L-2-amino-2-[p-chlorophenylJacetamido)-2,2- . .
dimethyl-3-(5-tetrazolyl)penam,
6-(DL-2-amino-2-[2,4-dichlorophenyl]aoetamido)-
2,2-dimethyl-3-(5-tetrazolyl)penam,
6-(DL-2-amino-2-[3,4-dichlorophenyl]acetamido)- ~-
. 2,2-dimethyl-~-(5-tetrazolyl)penam,
6-(D-2-amino-2-[~o-fluorophenyl]acetamido)-2,2- - ;
- dimethyl-3-(5-tetrazolyl)penam, . ~.. - .
6-(DL-2-amino-2-[o-fluorophenyl]acet~mido)-2,2- ; `:
dimethyl-3-(5-tetrazolyllpenam, : :~
.
'. :' ".
, ~
.:
. -150- :
.
. .
:~.-1 , ' .
~059~
6-(D-2-amino-2-~m-fluorophenyllacetamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam,
6-(L-2-amino-2-[m-fluorophenyl]acetamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam,
6-(D-2-amino-2-[~-bromophenyl]acetamido)-2,2-dimethyl-
3-(~-tetrazolyl)penam,
6-(L-2-amino-2-[m-hydroxyphenyl]acetamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam,
6-(DL-2-amino-2-[~-hydroxyphenyl]acetamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam,
6-(D-2-amino-2-[m-tolyllacetamido)-2,2-dimethyl-3-~5-
tetrazolyl)penam,
6-(L-2-amino-2-[m-tolyl]acetamido)-2,2-dimethyl-3-(S-
~tetrazolyl)penam,
6-DL-2-amlno-2-[~-isopropylphenyl]acetamido)-2,2-dimethyl-
3-~-tetrazolyl)penam,
6- (D- 2-amino-2-[~-amylphenyl]acetamido)-2,2-dimethyl-
3-(~-tetrazolyl)penam,
6- (DL-2-amino-2-[o-methoxyphenyl]acetamido)-2,2-dimethyl-
3-(~~tetrazolyl)penam,
6-(DL 2-amino-2-[~-isopropoxyphenyl]acetamido)-2,2- .
- dimethyl-3-(5-tetrazolyl)penam,
6-(D-2-amino-2-[m-butoxyphenyl]acetamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam,
6-(~L-2-amino-2-[m-butoxyphenyl]acetamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam,
6-(DL-2-amino-2-[~-amyloxyphenyl]acetamido)-2,2-dimèth~l-
3-(~~tetrazolyl)penam,
~-(D-2-amino-2-[~-amyloxyphenyl]acetamido)-2,2-dimethyl-
`~-(5-tetrazolyl)penam,
6-(DL-2-amino-2-[3,4-dimethoxyphenyl]acetamido)-2,2-
dim~hyl-3-(5-tetrazolyl)penam,
6-(DL-2-amino-2-~3,S-dimethoxyphenyl~aaetamido)-2,2-
dimethyl-3-~5-tetrazolyl)penam,
- 35 6-~DL-2-amino-2-[p-methylthiophenyl]aaetamido)-2,2-
. . dim~hyl-3-~5-tetrazolyl)penam,
.
-151-
~ ~l
:
l(~S~
; . . ,
i 6-(DL-2-amino-2-[p-isopropylthiophenyllacetamido)-
2,2-dimcthyl-3-(S-tetra~iolyl)penam,
c 6-~-2-amino-2-[1,4-cyclohexadienyl]acetamido)-2,2-
. dimethyl-3-(5-tetrazolyl)penam,
6(L-2-amino-2-[1,4-cyclohexadienyl]acetamido)-2,2-
. dimethyl-3-(5-te~razolyl)penam, -- .. :
. 6-(DL-2-amino-2-cyclopropylacetamido)-2,2-dimethyl-
. 3-(5-tetrazolyl)penam, - ~-
,~. . 6-(DL-2-amino-2-cyclopentylacetamido)-2,2-dimethyl- -.
- 10 3-(5-tetrazolyl)penam, .
6-(D-2-amino-2-cyclohexylacetamido)-2,2-dimethyl-3- ~.
. (5-tetrazolyl)penam, ..
. 6-(DL-2-amino-2-cycloheptylacetamido)-2,2-dimethyl-
; .3-(5-tetrazolyl)penam,
6-(D-2-aminopropiona~ido)-2,2-dimethyl-3-(S-tetra-
. zolyl)penam,
: 6-(D-2-aminobutyramido)-2,2-dimethyl-3-(5-tetra- ; ::
zolyl)penam, . : ~.
6-~2-amino~aleramido)-2,2-dimethyl-3-(5-tetrazolyl)-
penam, .
6-(DL-2-amino-2-allylacetamido)-2,2-dimethyl-3-(5-.:~
tetrazolyl)penam, .~
. 6-(DL-2-amino-2-(2-butenyl)acetamido)-2,2-dimethyl- .: : . -
. (5-tetrazolyl)penam
6- ~ 2-amino-2-[3-thienyl]acetamido-2,2-dimethyl-3- . --. : -
(5-tetrazolyl)penam, ; :.. :
6 ~-2-amino~2-[2-thienyl]acetamido)-2,Z-dimethyl- . ..
. 3-(5-tetrazolyl)penam, ' .
6-~-2-amlno-2-[3-furyl]acetamido)-2,2-dimethyl-3- : .: -
(5-tetra701yl)penam,
6- ~-2-amino-3-[5-ethyl-2-thienyl]acetamido)-2`,2- ~-
dimethyl-3-(5-tetrazolyl~penam~ . .. ~
6- ~-2-amino-2-E3-hydroxymethyl)phenyl]acetamido)-2,- ~ -. .
2-dimethyl-3-(S-tetrazolyl)penam - :
6-~-2-amino-2-[4-thydrox~methyl)phenyl]acetamido)-2,- . - :
2-dimethyl-3-t5-tetrazolyl)penam .. -. ~:.
6-~DL-2-amino-2-[4-isothiazolyl~acetamido)-2,2-dimethyl- :
3-(5-tetrazolyl)?enam :.
. ' , .
:~; .-152-
. ~ . `:'' '`. ,~ ' .
~ ' ' ` ~ -: -' '
9~
respectively.
The starting 2-substituted sodium N-(2-methoxy
carbonyl-l-methylvinyl)-2-amino-acetates are obtained by
condensation of the appropriate 2-substituted glycines
with methyl acetoacetate, according to the procedure of
Long, et al. (Journal of the Chemical Societ~ [London],
Part C, 1920 [1971]). Those 2-substituted glycines which
are described in the literature are prepared by the
published procedures. The new 2-substituted glycines are
prepared from the corresponding aldehydes via a Strecker
synthesis, techniques for which are discussed by Greenstein
and Winitz in "Chemistry of the Amino Acids," John Wiley
and Sons, Inc., New York/London, 1961, pp. 698-700, and
- references cited therein. The Strecker synthesis produces
DL amino acids, which are resolved into their optical
isomers by conventional means (consult Greenstein and
Winitz, loc. cit., pp. 715-755; Nishimura, et al.,
Nippon Kagaku Zasshi, 82, 1688 ~1961~ ~Chemical Abstracts,
58, 11464 (1963)])
-153-
,
,
, .
1~.)5~3~
EXAMPLE LXV I I
6-(D-2-Amino-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-
3-(5-tetrazol ~) enam
__ Y P
To a stirred s~lution of 0.19 ml. of ethyl
chloroformate in 15 ml. of dry acetone, cooled to OC., is
added 1 drop of N-methylmorpholine, followed by 576 mg. of
sodium N-(2-methoxycarbonyl-1-methylvinyl)-D-2-amino-2-(4-
hydroxyphenyl)acetate (Long et al., Journal of the Chemical
Society [London], Part C, 1920 [1971]). The mixture is
stirred for a further 30 minutes, and then it is cooled to
about -35C. To it is then added an ice-cold solution of
the sodium salt of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)-
penam, prepared by adding 10% sodium hydroxide to a
suspension of 436 mg. of 6-amino-2,2-dimethyl-3-(5-tetra-
zolyl)penam in S ml. of water (to give a pH of 7.8),followed by dilution with 25 ml. of acetone. The cooling
bath is removed, and the reac~ion mixture is stirred for
a further 30 minutes. At this point, the acetone is
removed by evaporation under reduced pressure, and then ~-
20 ml. of methyl isobutyl ketone is added to the aqueous
residue. The two-phase system is cooled to 10C.,
acidified to pH = 0.9 with dilute hydrochloric acid, and
then it is stirred at 10C. for 1 hour. The methyl iso-
butyl ketone is removed and discarded. The pH of the
aqueous phase is raised to 6.6, and then it is ~tored in
the refrigerator for 3 hours. The precipitate whlch forms
is filtered off, giving 320 mg. of 6-(p-2-amino-2-[4-
hydroxyphenyl]acetamido-2,2-dimethyl-3-t5-tetra;~olyl~ -~
penam. The infrared spectrum (KBr disc) o the product
shows absorptions at 1775 cm (~-lactam carbonyl) and
1680 cm (amide I band). The NMR spectrum (in DMSO-d6/D2O)
. . .
. ' ' . ~ . ' ' .
' ' , . `' '.
.
~05gg9'~
shows absorptions at 7.35 and 6.85 ppm ~2 doublets,
aromatic hydrogens), 5.60 ppm (quartet, C-S and C-6
hydrogens), 5.10 ppm (multiplet, benzyl hydrogen and C-3
hydrogen), 1.45 ppm (singlet, C-2 methyl hydrogen~) and
0.95 ppm (singlet, C-2 methyl hydrogens).
-155-
,
~05999'~,
EX~MPLE LXVIII
6-(D-2-Amino-2-[3-thienyl~acetamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam
The procedure of Example LXVII is repeated,
except that the sodium N-(2-methoxy-carbonyl-1-methyl-
vinyl)-D-2-amino-2-(4-hydroxyphenyl)acetate used therein
is replaced by an equimolar amount of N-(2-methoxy-
carbonyl-l-methyl-vinyl)-D-2-amino-2-(3-thienyl)acetate.
There is obtained a 38% yield of 6-(D-2-amino-2-~3-thienyl]-
acetamido)-2,2-dimethyl-3-(5-tetrazolyl) penam. The
infrared spectrum of the product (KBr disc) shows
absorptions at 1770 cm 1 (~-lactam carbonyl), 1680 cm 1 ;~
(amide I band) and 1505 cm (amide II band). The NMR
spectrum (in DMSO-D6/D2O) shows absorptions at 7.60-7.05
ppm (multiplet, aromatic), 5.70-5.35 (multiplet, C-5 and - -
C-6 hydrogens), 5.30 and 5.10 ppm (2 singlets, mathine
hydrogen and C-3 hydrogen), 1.50 ppm (singlet C-2 methyl
.hydrogens) and 0.95 ppm (singlet, C-2 methyl hydrogens). ~- -
; The sodium N-(2-methoxycarbonyl-1-methylvinyl)-
D-2-amino-2-(3-thienyl)acetate used in this Example is
prepared from D-2-(3-thienyl)glycine and methyl aceto- ` -~
acetate using the method described by Long, et al.
(Journal of the Chemical Society [London], Part C, 1920
[1971]) for the condensation of D-2-(4-hydroxyphenyl)-
25 glycine with methyl acetoacetate. The D-2-(3-thienyl) -
glycine is prepared from thiophene-3-aldehyde by a Strecker
reaction, followed by resolution of the DL-2-(3-thienyl) -
glycine so produced into its optical antipodes (Nishimura
et al., Nippon Kagaku Zasshi, 82 1688 [1961]) (Chemical
Abstracts, 58, 11464 [1963]).
'.
-156-
.
lOS999'~
EXAMPLE LXIX
6~ 2-~mino-2-[4-aminophenyl]acetamido)-2,2-dimethyl-3-
(5-tetrazolvl)nenam
.~
A mixture of 23.9 g. of D-2-amino-2-(4-amino-
phenyl)acetic acid dihydrochloride (United States patent
No. 3,634,405), 45.4 ml. of triethylamine and 90 ml. of
methanol is stirred at 25C. for lO minutes, and then it
is heated under reflux for 30 minutes. It is cooled to
25C. again, and 31.5 ml. of methyl acetoacetate is added.
This new reaction mixture is stirred at ambient temperature
for 20 minutes, and then it is heated under reflux for 40
mlnutes. The cooled reaction mixture is then poured, with
stirring into 3,000 ml. of ether. The solid which pre-
cipitates is filtered off and discarded. Removal of the
solvent by evaporation in vacuo leaves 42.3 g. (93% yield)
of the required triethylammonium N,N'-bis (2-methoxy-
carbonyl-l-methylvinyl)-D-2-amino-2-(4-aminophenyl)acetate.
To l9.0 g. of the above bis-enamine in 200 ml.
of tetrahydrofuran i9 added with vigorous stirring 8 drops
of N-methylmorpholine, followed by 5.38 ml. of isobutyl
chloroformate, at 0-5C. Stirring is continued for l hour
at 0-5C. at the end of the addition. A solution is then
prepared by suspending 9.85 g. of 6-amino-2,2-dimethyl-3-
(5-tetrazolyl)penam in 80 ml, if water, cooling to 0-5C.,
~5 adding 6N sodium hydroxide to give a pH of 7.5, and finally
diluting with 200 ml. of tetrahydrofuran. This latter
solution is then added to the above mixed anhydride
solution at ca. -40C. The resulting mixture is stirred
at 0-5C. for l hour. ~he pH is then lowered to 2.0 and
the stirring is continued for a further 30 minutes at
0-5C. At this point, the bulk of the tetrahydrofuran is
-157-
~(~5~3~39'~
removed by evaporation in vacuo, and then the residual
aqueous phase is washed twice with ethyl acetate. The
aqueous phase is then cooled to 5C., adjusted to pH 6.0,
filtered, and lyophilized. This affords the title compound
in a crude state. It is purified by chromatography on
Sephadex LH-20. The final yield is 591 mg. (3.7%). IR
(KBr disc): 1770 cm . NMR (DMSO-d6~: 7.18 and 6.60 ppm
(q, J=8Hz, 4H), 5.61 and 5.50 ppm (q, J=4Hz, 2H), 5.03 ppm
(s, lH), 4.91 ppm (s, lH), 1.51 ppm (s, 3H) and 0.95 ppm
(s, 3H).
-158-
1~)5~5~9'~
EXAMPLE LXX
6-(D-2-Amino-2-[3-amln~phenyl]acetamido)-2,2-dimethyl-3-(5-
tetrazolvl)~enam
To a stirred solution of 5.0 g. of D-2-amino-2-
(3-nitrophenyl)acetic acid in 26 ml. of l.ON sodium
hydroxide, at 5C., is added 4.4 g. of benzyl chloro-
formate. Stirring is continued for 1 hour with the pH
being maintained between 9 and 11. The reaction mixture
is washed with ethyl acetate, and then the pH is lowered
to 2Ø The aqueous residue is then extracted with ethyl
acetate. The extract is dried using anhydrous sodium
sl~lfate, and then it is evaporated in vacuo to give 5.3 g.
of N-(benzyloxycarbonyl)-D-2-amino-2-(3-nitrophenyl)acetic
acid, [~I D =-108 (C=l, CH30H).
To a stirred suspension of 5.0 g. (15 mmole) of
the above benzyloxy carbonyl derivative, and 3.6 g. of 6-
amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 70 ml. of
water is added sufficient 20% sodium hydroxide to adjust
to pH to 6Ø The resulting solution is cooled to 5C,
20 and to this is added a solution of 2.8 g. (15 mmole) of -~
l-ethyl-3,3'dimethylaminopropylcarbodiimide hydrochloride
in 10 ml of water. The pH of the solution is maintained
between 6.0-6.2 for 2 hours. The reaction is then warmed
to room temperature and the pH adjusted to 7Ø The
solution is washed with 50 ml. of ethyl acetate and the pH
is then readjusted to 2.0 (6N hydrochloric acid). ~he
solution`is extracted with 300 ml.ethyl acetate, and the
ethyl acetate layer dried and evaporated, to yield 3.5
grams of 6-(2-lN-benzyloxycarbonylamino]-2-phenyl-
acetamido) 2,2-dimethyl-3-(5-tetrazolyl)penam.
.
-159
;', .,
~ . ~ ~
'lOS~g9'~
A suspension of 3.4 g. of the above penam com-
pound in 60 ml. o water is adjusted to pH 7.0 using l.ON
sodium hydroxide. To the resultant solution is added J.4
g. of 10% palladium-on-carbon, and the mixture is shaksn
for 2 hours under an atmosphere of hydrogen at 50 psi.
The reaction mixture is then filtered, acidified to pH
2.0, and extracted with ethyl acetate. The extracts are
discarded, and the pH of the aqueous phase is adjusted to -
5 5 The solution is then lyophilized. The residue is -~
10 stirred with 30 ml. of N,N-dimethylformamide for 20 -
minutes, and then the insoluble material is removed by
filtration and discarded. The filtrate is added drop-wise ~-
to 800 ml. of hexane. The resulting precipitate~is
collected by filtration to give 0.78 g. of 6-~D-2-amino-2-
[3-aminophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)
penam. IR (KBr disc): 1775 and 1650 cm . NMR (DMSO-
d6/D2O): 6.7-7.4 ppm (m, 4H), 6.4-6.8 ppm (m, 2H), 5.10
ppm (s, lH), 5.00 ppm (s, lH) 1.50 ppm (s, 3H) 0.90 ppm
(s, 3H). [~]D =196 (C=.l lN HCl).
-160-
1~5g99'~
EXAMPLE LXXI
6-(2-[4-Aminomethylphenyl]acetamido)-2,2-dimethyl-3-(5-
5-tetrazolvl)~enam
Sodium 4-[(1-methoxycarbonyl-2-propenyl)amino-
methyl]phenylacetate is prepared from 4-aminomethylphenyl-
acetic acid [~augg and Horrom, J. Am. Chem. Soc., 80,
4317 (1958)] and methyl acetoacetate by the method
described by Dane and Dockner [Chem. Ber., 98, 789
(1965)]. A suspension of this salt (2.15 g, 7.5 mmole),
7 drops of N-methylmorpholine and 100 ml. of tetra-
hydrofuran is stirred at -20C; ethyl chloroformate (0.81
g. 7.5 mmole) is added and the mixture is stirred for 60
minutes. 6-Amino-2,2-dimethyl-3-(5-tetrazolyl)penam (1.80
g., 7.5 mmoles) is suspended in a 50:50 mixture of tetra- --
hydrofuran and water (40 ml), and the pH is adjusted to
7.5 with lN sodium hydroxide solution whereby a homo-
geneous solution is obtained. This is added to the above
suspension, in one portion, the new mixture is stirred at
-20C. for 1 hour and then it is allowed to warm to room
temperature over 1 hour. Most of the tetrahydrofuran is
removed in vacuo, the resultant aqueous solution is cooled
in an ice bath, and the pH is adjusted to 1.5 with 3N
hydrochloric acid. After 30 minutes the pH is adjusted
to 2.5, and the solution is extracted with ethyl acetate.
The aqueous phase is adjusted to pH 6.0 and freeze-dried.
The resultant lyophylate is combined with that from
another preparation (5 mmoles) and chromatographed on
Sephadex LH-20 (150 g~ eluting with water. Like fractions
(tlc analysis) are combined and freeze-dried, yielding the
title compound as a colorless amorphous solid (570 mg.,
-161-
~(~55~
11% yield), m.p. 190-200C. IR(KBr): 1770, 1650 and 1515
cm . NMR (DMSO-d6-D2O): 7.4 ppm (s, 4H) 5.65 ppm (d,
J=4Hz, lEI), 5.45 ppm (d, J=4Hz, lH) S 2 ppm (5, lH), 4.1
ppm (s, 2H), 3.6 ppm (s, 2H), 1.6 ppm (s, 3H) and 1.0 ppm
(s, 3H).
When the above procedure is repeated, and the 4-
aminomethylphenylacetic acid is replaced by an equimolar ~
amount of 3-(2-aminoethyl)phenylacetic acid,- 4-(2-amino- ~ -
ethyl)phenylacetic acid, 5-(2-aminoethyl)-1-tetrazolyl- -
acetic acid and 5-(2-aminoethyl)-2-tetrazolylacetic acid,
respectively, there is obtained: -
6-(2-[3-(2-aminoethyl)phenyl]acetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam,
6-(2-[4-(2-aminoethyl)phenyl]acetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam,
6-(2-[5-(2-aminoethyl)-1-tetrazolyl]acetamido)-
2,2-dimethyl-3-(5-tetrazolyl)penam and
6-(2-[5-(2-aminoethyl)-2-tetrazolyl]acetamido)-
2,2-dimethyl-3-(5-tetrazolyl)penam,
respectively.
-162- ~-
~(~s~
EXAMPLE LXXII
6-[2-[o-(Aminomethyl)phenyl]acetamido)-2,2-dimethyl-3-(5-
tetrazolvl)penam
,
To a stirred mixture of 2.25 g. of sodium N-(l-
methyl-2-methoxy-carbonylvinyl)-2-(o-[aminomethyllphenyl)-
acetate and 2 drops of N-methylmorpholine in 20 ml. of
tetrahydrofuran, at -10C., is added 0.856 g. of ethyl
chloroformate. Stirring is continued for a further 15 -
minutes at ca. -5C., and then the mixture is cooled to --
-30C. To this mixture is then added a solution prepared
by adding 1.68 g. of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)-
penam to 20 ml. of 1:3 water-tetrahydrofuran and adjusting -`
the pH to 7Ø After the addition, the cooling bath is
removed, and the reaction mixture is allowed to warm to
ambient temperature. The tetrahydrofuran is removed by
evaporation in vacuo, and 15 ml. of tetrahydrofuran are
added to the aqueous residue. The pH is adjusted to 1.5,
and then the mixture is stirred at this pH for 30 minutes.
The pH is thenraised to 3.0 and the tetrahydrofuran is
removed by evaporation in vacuo. The aqueous residue is
washed with ethyl acetate, and then the aqueous solution
is concentrated to small volume. The solid which pre-
cipitates is filtered off giving 0.52 g. of 6-(2-lo-(amino-
methyl)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)
penam. The infrared spectrum of the product (KBr disc)
shows absorptions at 1780 cm 1 (~-lactam) and 1645 cm 1.
The NMR spectrum (DMSO-d6/D2O) shows absorptions at 7.45
ppm (singlet, 4H), 5.60 ppm (quartet, 2H), 5.10 ppm
(singlet, lH), 4.10 ppm (singlet, 2H), 3.80 ppm (singlet,
2H), 1.65 ppm (singlet, 3H), and 0.95 ppm (singlet, 3H).
The starting sodium N-(l-methyl-2-methoxy-
-163-
~.05g~9;~
carbonylvi.nyl)-2-(o-[aminomethyl]phenyl)acetate is pre-
pared from 2-(o-[aminomethyl]phenyl)acetic acid (United
States patent No. 3,766,175) and methyl acetoacetate using
the method of Long et al. (Journal of the Chemical
~ [London], Part C, 1920 [1971) for the condensation ~;
of D-2-(p-hydroxyphenyl)glycine with methyl acetoacetate.
-164-
-
~)S99~
EXAMPLE LXXIII
6-(2-[2-(Aminomethyl)phenylthio]acetamido)-2,2-dimethyl-
3 (5-tetrazolyl)penam
The title compound is prepared in 14% yield, as
a colorless amorphous solid, by acylation of 6-amino-2,2-
dimethyl-3-(5-tetrazolyl)penam with 2-(2-[aminomethyl]- -
phenylthio)acetic acid (United States patent No.
3,766,176), using the method of Example LXXII. IR (KBr
disc): 1780 and 1655 cm . NMR (DMSO-d6/D2O): 7.50 ppm
(m, 4H), 5.70 ppm (d, lH), 5.43 ppm (d, lH), 5.19 ppm
(s, lH), 4.35 ppm (s, 2H), 3.94 ppm (s, 2H), 1.60 ppm
(~, 3H), and 1.00 ppm (s, 3H).
~ -165-
lOS9g9'~ .
EXAMPLE IXXI
6~ Aminocyclohexanecarboxamido)-2,2-dimethyl-3-(5-tetra-
zolyl)penam
The pH of a stirred suspension of 720 mg. (3.0
mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in
50 ml. of water, at OC, is adjusted to 7 using 1.0 N
sodium hydroxide. When all the solid has dissolved, the
pH is lowered to 6.0 (1.0 N hydrochloric acid), and then -
750 mg. (3.4 mmole) of 2,4-oxazaspiro[4.5]decane-1,3-dione
(Alburn, et al~, Antimicrobial Agents and Chemotherapy,
586 [1~967]) is added. The reaction mixture is stirred at
ca. 0C., and at pH 6, for 1 hour. It is then filtered.
The pH is adjusted to 4.2, and the reaction is lyophilized.
The residue is dissolved in 5 ml. of methyiene chloride
containing 606 mg of triethylamine. This new solution is
added dropwise with stirring to 100 ml of ether, and the
solid which precipitates is filtered off. This affords -
1.3 g (93% yield) of a 2:1 complex of the title compound
and triethylamine. IR (KBr disc): 1786, 1680 and 1640 -
cm . NMR (in D2O): 5.90 ppm (d, lH), 5.40 ppm (d, lH), - -
5.30 ppm (s, lH), 3.10 ppm (q, 3H), 1.90-1.50 ppm (m, lOH),
1.60 ppm (s, 3H), 1.20 ppm (t, 4.5H), 1.00 ppm (s, 3H).
-166-
lOSg99'~
EXAMPLE LXXV
6-(D-2-Amino-2-[1,4-c~clohexadienyl]acetamido)-2,2-
dimethyl-3-(5-tetrazol~l)penam
Following the procedureused to prepare 6-(1-
aminocyclohexanecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)-
penam (Example LXXIV), the title compound is prepared from
0.5 g (2.8 mmole) of D-4-(1,4-cyclohexadienyl)-1,3-
oxazolidin-2,5-dione and 6-amino-2,2-dimethyl-3-(S-tetra-
zolyl)penam; the product is isolated as a 1:2 complex with
triethylamine: yield 520 mg (36%); IR (KBr) 1779, 1678
cm . NMR (in D2O): 6.10 ppm (s, lH), 5.80 (s, 2H), 5.90
ppm (d, lH), 5.60 ppm (d, 2H), 5.40 ppm (s, lH), 4.50 ppm
(s, lH), 3.30 ppm (q, 12H), 2.80 ppm (broad s, 4H), 1.70
ppm (s, 3H), 1.40 ppm (5, 18H), 1.20 ppm (s, 3H).
D-4-(1,4-cyclohexadienyl)-1,3-oxazolidin-2,5-
dione is prepared from 2.0 g (13.1 mmole) D-2-(1,4-
cyclohexadienyl)glycine (Dolfini et al., J. Med. Chem. 14,
117 [1971]) and phosgene by the method described by
Alburn, et al. (Antimicrohial Agents and Chemotherapy,
586 [1967]): yield 1.2 g (51%).
-167-
io5'~3g~3~
EXAMPLE I.XXVI
6-(D,L-3~Amino-2-phenylpropionamido)-2,2-dimethyl-3-
~5-tetrazol~1)penam
,A _ _ . _
Sodium D,I.-3-([1-methoxycarbonyl-2-propenyl]-
amino)-2-phenylpropionate is prepared from DL-3-amino-2-
phenylpropionic acid [Testa, Fava and Fontanella, Annalen,
614, 167 (1958)] and methyl acetoacetate by the method
described by Dane and Dockner [Chem. Ber., 98, 789 (1965)].
A suspension of 1.43 grams (5 mmole) of this salt, one
drop of N-methylmorpholine, 5 ml. of tetrahydrofuran and
30 ml. of dichloromethane is stirred at OC.; 0.6 grams
(~ mmole) of 2,2-dimethylpropionyl chloride is then added,
and the mixture is stirred for 30 minutes. A solution of
1.2 grams (5 mmole) of 6-amino-2,2-dimethyl-3-(5-tetra-
zolyl~penam, 1.01 grams (10 mmole) of triethylamine, and -
30 ml, of dichloromethane is added to the suspension, and
the new mixture is cooled and stirred for two hours. The
volatile components are evaporated under reduced pressure,
and the residue is dissolved in 60 ml. of water. This
mixture is stirred and cooled in an ice bath while it is
adjusted to pH 2.7 by the addition of lN hydrochloric acid.
After an hour some gummy material is filtered, and the
filtrate is cooled and is adjusted to pH 4.5 by the
addition of 2N sodium hydroxide. After stirring the new
mixture for 30 minutes another small amount of solid matter
is filtered, and the filtrate is lyophilized. The
lyophilate is slurried in 50 ml. of dichloromethane and
this mixture is filtered. The insoluble portion is dis-
solved in 100 ml. of dichIoromethane and 4 ml. of tri-
ethylamine; a small amount of insoluble matter is filtered,and the filtrate is evaporated. The residue from the
-168-
~OS'3~g~
filtrate is tri.turated under ether to furnish the title
compound as an amorphous 1:3 complex with trlethylamine:
yield 600 mg. (17~). IR (KBr disc): 1792, 1681 and 1618
cm . NMR (in D2O): 7.50 ppm (s, 5H), 5.80 ppm (d, lH),
5.60 ppm (d, lH), 5.30 ppm (s, lH), 4.20-3.50 ppm (m, 3H),
3.30 ppm (q, 18H), 1.50 ppm (s, 3H), 1.30 ppm (t, 27H),
1.00 ppm (s, 3H).
-169- ::
~05~9'~
EXAMPLE I.XXVII
6-(2-[2-(2-Aminoethoxy)pheny]]acetamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam
_
The title compound is prepared in 64% yield from
2-(2-[2-amino-ethoxy]phenyl)acetic acid (United States
patent No. 3,759,905) and 6-amino-2,2-dimethyl-3-(S-tetra-
zolyl)penam, by a procedure analogous to that of Example
LXXVI, IR (KBr disc): 1780 cm (~-lactam) and 1667 cm
(amide I). NMR (in D2O): 7.1 ppm (m, 4H), 5.7 ppm (d, lH),
5.5 ppm (d, lH), 5.2 ppm (s, lH), 3.7-3.3 ppm (m, 4H), 3.1
ppm (q, 12H), 1.6 ppm (s, 3H), 1.2 ppm (t, 18H), 1.0 ppm
(~, 3H). The product is a 1:2 complex of the title com-
pound and triethylamine.
-170-
~os~
EXAMPLE LXXVIII
.
6-(2--[3-(2-Aminoethoxy)phenyl]acetamido)-2,2-dimethyl-3-
( etra201yl)penam
The title compound is prepared in a manner
analogous to that used to make its isomer 6-(2-[2-(2-amino-
ethoxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam
(Example LXXVII), and consists of a 1:1 molar ratio of the
tetrazole product to triethylamine. The starting material,
2-[3-(2-aminoethoxyphenyl]acetic acid, is obtained by the
procedure described in U.S. patent 3,579,905. On a 3.5
mmol scale the yield is 600 mg. (33%): IR (KBr) 1780 and
1660 cm ; NMR (D2O-NaHCO3) 7.4-6.7 ppm (m, 3H), 5.70
(d, lH), 5.40 (d, lH), 5.25 (s, lH), 4.35-4.00 (m, 2H),
3.70-3.35 (m, 4H), 3.15 (q, 6H), 1.50 (s, 3H), 1.25
(t, 9H), 0.95 (s, 3H).
-171-
105~99'~
EXAMPLE LXXIX
6-(2-[4-(2-Aminoethoxy)phenyl]acetamido)-2,2-dimethyl-3-
(5-tetrazoly])Penam
The title compound is prepared in a manner
analogous to that used to make its isomer 6-(2-[2-(2-
aminoethoxy)phenyl]acetamido)-2,2-dimethyl-3-(5-tetra-
zolyl)penam (Example LXXVII), and consists of a 3:1 molar
ratio of the tetrazole product to triethylamine. The
starting material, 2-[4-(2-aminoethoxy)phenyl]acetic acid
is obtained by the procedure described in U.S. patent
3,759,905. On a 5.0 mmol scale the yield is 1.35 g. (60%):
IR (KBr) 1785 and 1667 cm ; NMR (D2O) 7.10 ppm (q, 4H),
5O75 (d, lH), 5.40 (d, H)-, 5.30 ~s, lH) 4.40-4.05 (m, 2H),
3.7-3.4 (m, 4H), 3.20 (q, 2H), 1.60 (s, 3H), 1.35 (t, 3H),
15 1.05 (s, 3H).
-172-
~ .
l()S~g9'~
EXAMPLE LXXX
6-(2-~4-(2-Azidoethoxy)phenyl]acetamido)-2,2-dimethyl-3-
(5-tetrazolvl)~enam
A stirred mixture of 1.2 g.(5 mmol) of 6-amino-
2,2-dimethyl-3-(5-tetrazolyl)penam, 1.1 (5 mmol) of 4-(2-
azidoethoxy)phenylacetic acid [U.S. patent 3,759,905], and
20 ml of water is adjusted to pH 7 by the careful addition
of 6_ sodium hydroxide. After a clear solution is
obtained, the pH is adjusted to 6 by the careful addition
of 6N hydrochloric acid. With ice bath cooling and con-
tinuous stirring, the solution is treated with 0.96 g.
(5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride, The reaction solution is stirred, cooled
and maintained at pH 6 for 90 minutes. The solution is
then adjusted to pH 6.9 and is washed twice with 20-ml.
- portions of ethyl acetate. The aqueous solution is then
adjusted to pH 2.0, and the product is extracted into
ethyl acetate. The extract is then stirred with 20 ml. of
water and the mixture is then adjusted to pH 6.8. The
aqueous phase is separated, and is then Iyophilized to
furnish the title compound as its sodium salt: yield 1.31
g(56~); IR (KBr) 2105, 1770 and 1660 cm 1; NMR (D2O)
7.4-6.8 ppm (m, 4H), 5.80 (d, lH), 5.55 (d, lH), 5.40
(s, lH), 4.3-4.0 (m, 2H)~ 3.9-3.4 (m, 4H), 1.55 (s, 3H), -~ -
1.00 (s, 3H).
'~.'.:
-.;' :.
, ' . ~ ':
~ -173- ~ ~
'.:..; :'
i . , - , . .
' . : '.: '-
1(15!~99'~
EXAMPLE LXXXI
6-(L-2-Amino-3-[~-hydroxyphenyl]propionamido)-2,2-dimethyl-
3-(5-tetrazol 1) enam
Y .P
The title compound is prepared from 1.5 g. of
sodium N-(l-methoxycarbonyl-2-propenyl)-L~2-amino-3-(p-
hydroxyphenyl)propionate and 1.2 g. of 6-amino-2,2-
dimethyl-3-(5-tetrazolyl)penam, by a procedure analogous
to that of Example LXXVI. The crude product is purified
by chromatography using 25 g. of LH 20 grade dextran gel
as the column packing, and eluting with water. The final
yield is 90 mg. of the title compound as its sodium salt.
IR (KBr disc): 1780, 1688 and 1-620 cm . NMR (in D2O):
6~9 ppm (q, 4H), 5.7 ppm (d, lH), 5.4 ppm (d, lH), 5.2 ppm
(s, lH), 3.1-2.7 ppm (m, 3H), 1.4 ppm (s, 3H), and 1.0 ppm
(s, 3H).
'
~ -174-
. :
10~9;~
EXAMPLE LXXXII
6-(2-[Benzamido]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)
~enam
,
To a stirred solution of 0.80 g. (2.7 mmole) of
6-(2-aminoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam
and 0.453 g. (5.4 mmole) of sodium bicarbonate in 21 ml.
of water and 15 ml. of acetone at 0-5C. is added 0.32 ml.
(2.8 mmole) of benzoyl chloride. Stirring i6 continued
for a further 20 minutes at ca. OC., and then the acetone
is removed in vacuo. The aqueous residue is extracted
with ethyl acetate and the extracts are discarded. The pH
Oc the aqueous phase is adjusted to 2.0, and the product
is extracted into ethyl acetate. The solvent is dried
(Na2SO4) and then concentrated in vacuo to give 150 mg.
(37% yield) of the title compound, m.p. 85-93C. IR (KBr
disc): 1785 cm (~-lactam) and 1695 cm 1 (amide I). NMR
(in D2O): 7.90 ppm (m, 2H), 7.50 ppm (m, 3H), 5.82 ppm
(s, lH), 5.58 ppm (s, lH), 5.19 ppm (s, lH), 4.25 ppm
(m, 2H), 1.67 ppm (s, 3H), 1.67 ppm (s, lH).
' '
-175-
1()5~99~
EXAMPLE LXXX I I I
6-(2-[2-Bromoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-
t5-tetrazolyl)penam
To a stirred slurry of 4.27 g. (10 mmole) of 6-
(2-amino-2~phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)
penam in 25 ml. of water, at OC., is added 1.39 g. -
(10 mmole) of bromoacetic acid in 6 ml. of water. The pH
is adjusted to 6.0, and then 1.9 g. (10 mmole) of l-ethyl- ~ - `--
3-(dimethylaminopropyl)-carbodimide hydrochloride in 9 ml. ~ ;
10 of water is added. The mixture is stirred for 3 hours at --~
pH 6. At this point, the FH is raised to 7.0, and the
reactlon mixture is washed with ethyl acetat~. Th pH is ;-
then lowered to 2.0, and the product is extracted into -
ethyl acetate. The dried extracts are concentrated to -;
dryness in vacuo to give 2.0 g. (40~ yield) of the title
compound, m.p. 128-135C. IR (KBr disc): 1800 cm - -
(~-lactam) and 1653 cm (amide I). NMR (in DMS0-d6/D20): ;
7~43 ppm (s, 5H), 5.73 ppm (s, lH), 5.63 ppm (m, 2H), 5.23
ppm (s, lH), 4.02 ppm (s, 2H), 1.60 ppm (s, 3H), 1.00 ppm
(s, 3H)
- -176-
l()S~99'~
EXAMPLE LXXXIV
6-(2 [2-(4-Pyridylthio)acetamido]-2-phenylacetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam
. _
To a stirred solution of 644 mg. of 6-(2-[2-
bromoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam in 15 ml. of N,N-dimethylformamide is
added 45 mg. of 4-mercaptopyridine followed by 0.19 ml.
of triethylamine. Stirring is continued for 3 hours at
2soc,and then the reaction solution is added dropwise into
200 ml. of vigorously stirred chloroform. The precipitate
is removed by filtration, and the filtrate is added drop-
wi~e with stirring to 400 ml. of hexane. This causes the
product to precipitate. After being slurried with --
methylene chloride, it weighs 228 mg. (33% yield), m.p.
182-198C. (dec.). IR (KBr disc): 1780 cm (~-lactam)
and 1667 cm (amide I). NMR (DMSO-d6/D2O): 8.33 ppm
(d, 4H), 7.33 (s, 5H), 5.60 ppm (m, 3H), 5.15 ppm (s, lH), -~
3.68 ppm (s, 2H), 1.47 ppm (s, 3H), 1.00 ppm (s, 3H).
-177-
l~sl3g9~
EXAMPLE LXXXV
6-(2-[2-(~ -Imidazolin-2-ylthio)acetamido]-2-phenyl-
acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam
The title compound i9 obtained in 734 yield by ~;
replacing the 4-mercaptopyridine of Example LXXXIV with
ethylene thiourea. The product has m.p. 166-175C.
(dec.). IR ~KBr disc): 1785 cm (~-lactam), 1667 cm
(amide I). NMR (in D2O): 7.37 ppm (s, 5H), 5.65 ppm
( ), 5.53 ppm (m, 2H), 5.23 ppm (s, lH), 3.62 ppm
(s, 2H), 3.50 ppm (m, 4H), 1.42 ppm (s, 3H), 0.87 ppm
(s, 3H).
: .
'~
` ~ -178-
j
l~)S9~g;~
EXAMPLE LXXXVI
.A
6-(~-2-[2-chloroacetamido]-2-phenylacetamido~2,2-dimethyl-
3-(5-tetrazolyl)penam
To a stirred solution of 2.02 g. of 6-(D-2-
amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazol-5-yl)
penam and 1.5 ml. of triethylamine, in 25 ml. of dichloro-
methane, is added, dropwise, 0.48 ml. of chloroacetyl
chloride, at OC. Stirring is continued for a further 2 ---
hours at OC., and then the solvent is removed by
evaporation in vacuo. The residue is stirred with chloro- :
form and recovered by filtration. This afords 1.16 g
(48~ yield) of the title compound, m.p. 142-146C. IR
(KBr disc): 1780 and 1650 cm . NMR(DMSO-d6/D2O): 7.47
ppm (m, 5H), 5.77 ppm (s, lH), 5.67 ppm (m, ZH), 5.25 ppm
(s, lH), 4.25 ppm (s, 2H), 1.63 ppm (s, 3H) and 1.02 ppm
(s, 3H).
-179-
:
~ `
10~95~9~
EXAMPLE LXXXVII
6-(D-2-[2-Chloroace~do] -2-[2-furyl]acetamido)-2,2-
dimethyl 3-(5-tetrazol~l)penam _ __ _ _
To a solution of 10 drops of N-methylmorpholine
in 40 ml. of acetone, cooled to -50C., is added 0.30 ml.
of ethyl chloroformate (3.2 mmole). After stirring 5
minutes at -50C., a solution of 0.696 g. (3.2 mmole) of
N-chloroacetyl-2-[2-furyl]glycine [ap=-170 ethanol] and
0.44 ml. of triethylamine (3.2 mmol), in 10 ml. of acetone, -
is added. The resulting solution is stirred 10 minutes at
-50C. and then a solùtion prepared by suspending 0.72 g.
(3 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam
in a mixture of 12 ml. of water and 8 ml. of acetone and
adjusting the pH to 7.0, is added in one portion. The
cooling bath is removed, and the solution is allowed to
warm to room temperature over a 45 minute period with
stirring. The acetone is removed using a rotary evaporator
and an equal volume of ethyl acetate is added to the
aqueous layer. The pH is adjusted to 2.0, and the ethyl -
acetate layer is separated. The aqueous layer is extracted
with ethyl acetate (2 x 50 ml.) and the combined organic
layers are washed with water, brine, and dried (Na2S04).
Concentration in vacuo gives an oily solid,- which is washed
with dichloromethane and dried to give 590 mg. (45~i yield)
of the title compound a8 a white 801id, mp 149-151C. IR
(K~r disc): 1785 and 1667 cm 1 NMR (DMS0-d6): 7.57 ppm
(m, lH), 6.35 ppm (m, 2H), 5.77 ppm (d, lH), 5.60 ppm
tm, 2H), 5.17 ppm (s, lH), 4.13 ppm (m, 2H), 1.60 ppm
tu, 3H), and 1.03 ppm (s, 3H).
.
.
-180-
9'~
EXAMPLE LXXXVIII
6-(D-2-[N,N'-dimethylamidinothio)acetamido]-2-phenylacet-
~b)-2,2-dimethyl-3-(5-tetrazolyl)penam
To a stirred solution of 300 mg. of sodium azide
in 30 ml. of acetone, is added a solution of 900 mg. of
6-(D-2-[2-chloroacetyl]-2-phenylacetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam and 0.3 ml. of triethylamine in 20 ml.
of acetone. A solution of 208 mg. of N,N'-dimethylthiourea
in 10 ml. of acetone is added, and then the resulting
reaction mixture is heated at 55C. or 8 hours. At this
point, the mixture is cooled to 25C. and the precipitate
is removed by filtration to give 390 mg. (37% yield) of the
title compound, m.p. 240-250C. IR (KBr disc): 1775 and
1667 cm . NMR (DMSO-d6/D2O~: 7.4 ppm (m, 5H), 5.8 ppm
(s, lH), 5.68 ppm (m, 2H-), 5.16 ppm (s, lH), 4.2 ppm -
(s, 2H), 2 97 ppm (s, 6H), 1.50 ppm (s, 3H), and 0.90 ppm
(s, 3H).
-181-
. .
1()5~g9~
EXAMPLE LXXXIX
Using the procedure of Example LXXXVIII, but
replacing the N,N'-dimethylthiourea with the appropriate
reagent, the following compounds are prepared.
~
H~ 3 ~ 5 ~ 33
~l
~-- O'~ ~ ~ ~
2 H
l25 ~ :
,-''.
. .
-182-
.
10~
co a~
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u~
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_ ~ ~ mm -I _ m
X~
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rd ~ ~ ~ ~ U~
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O _ . ~ ~ O ~ O
U~
~,~ m^ ~_ _ ~
^ ~ mm _l _ O ~ ~ o
m
m
m m
-- ~ o o ~ ~ ~ ~ ~ ~ ~ ~n
~ O ~ U~
In ~ O
~ m :c _~ ~ . . ~ .
_ ~ mm m~o __~ mo
m
m
~ m ~
u~ ~ ~ --m m ~o m --m ~ m
O -- ' ` ~D In O t` O ~ ~O _ ~ I~ ~ ~ ~
~ _ ",,",, ", ~ "~ _ _ .-- ,n ~ ~
--e r~
Q ` ~ `--` ``--I ~ a~ `U~ OD
Q $er o mt`~ $ P~ ~ m ~ o `~ m-
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. ~ .
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~ N ~ ~ N
N r~ ~a
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-183- .
... .
~05S~99~
EXAMPLE XC
6- (D-2- [3- (2- [Guanylthio~acetyl)ureido]-2-phenylacetamido)-
2,2-dimethyl-3-(5-tetrazol-5-~l)penam
To a stirred solution of 225 mg. o sodium iodide
in 7.5 ml. of acetone is added, with stirring, at 25C.,
865 mg. of 6-(D-2-[3-(2-chloroacetyl)ureido~-2-phenyl-
acetamido)- 2, 2 -dimethyl-3-(5-tetrazo}yl)penam, followed by - -
114 mg~ of thiourea. Stirring is continued for 24 hours,
and then the precipitate which has formed is removed by ~
filtration. This affords 720 mg. (92% yield) of the title ~ -
compoùnd, mp 193-211C. (dec.). IR(KBr disc): 1780 and
1650 cm 1
-184'
1055~9;~
EXAMPLE XCI
6~ 2-[3-(2-[N,N'-- diethylguanylthiolacetyl)ureido]-2-
phenyl acetamidor-2,2-dimethyl-3-(5-tetrazolyl)penam
The title compound is prepared in 31.5% yield by
repeating the procedure of Example XC, but using N,_'-
diethylthiourea in place of thiourea. IR(KBr disc): 1780
and 1670 cm
. ' ~'.
.- , ' .
-185-
-..~.
lOS~99Z
EXAMPLE XCII
6-(D-2-Methanesulfonamido-2-phenylacetamido)-2,2-dimeth~l-
3-(~-tetrazolvl)Denam
.. .. _ - ,
The pH of a stirred solution of 1.42 g. of
6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetra-
zolyl)penam in 6 ml. of water and 6 ml. of tetrahydrofuran
is adjusted to 7.8 (6N sodium hydroxide). To this solution
is then added 570 mg. of methanesulfonyl chloride, and
stirring is continued for 1 hour with 6N sodium hydroxide
being added as necessary to maintain the pH at 7.2. At
this point, the tetrahydrofuran is removed by evaporation
in vacuo, and the aqueous residue is washed with ethyl
acetate. The pH is then lowered to 2.0, and the product ~ ~
i5 extracted into ethyl acetateO The ethyl acetate is ~ -
15 washed successively with 6N hydrochloric acid and water, --
- ; and then dried using anhydrous sodium sulfate. Evaporation
of the solvent in vacuo gives the crude product. This
crude product is dissolved in the minimum amount of ethyl -
acetate, and then the solution is added dropwise with
stirring to 200 ml. of hexane. The solid which pre-
cipitates is filtered off, giving 675 mg. (45%) of the
title compound, m.p. 117-48C. IR(Nujol mull~: 1785 cm
(~-lactam). NMR (in DMSO-d6): 9.45-9.15 ppm (m, lH), 8.05
ppm (d, lH), 7.60-7.10 ppm (m, 5H), 5.60-5.15 ppm (m, 4H),
2.75 ppm ~9, 3H), 1,60 ppm ~9, 3H), and 1.00 ppm ~9, 3H).
.
"
., .
.~
-186-
~os~9g~
EXAMPLE XCIII
Reaction of either 6-(~-2-amino-2-phenylacet_
amido)-2,2-dimethyl-3-(5-tetrazolyl)penam or 6-(D-2-[2-
aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam with the appropriate sulfonyl chloride,according to the procedure of Example XCII provides the
following congeners: -
~ ''''.
H-CO-N ~ ~ ~ H3
\ ,~N
H ___N
~- -187-
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-189- - -
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EXAMPLE XCIV
6~ 2-[propanesulfonamido]-2- r p-hydroxyphenyl]acetamido)
_ 2,2-dimethyl-3-(5-tetrazolv~ enam
.. . .
The title compound is prepared in 38% yield from 6-
(D-2-amino-2-[~-hydroxyphenyl]acetamido)-2j2-dimethyl~3-(5-tetrazolyl)-
penam and propanesulfonyl chloride, using the procedure of Example
XCII. The product has m~p~ 115-157C. (dec.)~ IR (Nuiol mull)
("Nujol" is a trademark): 1780 cm~l (~ lactam). NMR (in DMSO-d6):
9.20-8.90 ppm (m, lH), 7.90 ppm (d, lH), 7.30 ppm ~d, 2H), 6.70 ppm
(d, 2H), 5.70-5.00 ppm (m, 4H), 2.80 ppm (t, 2H), 1.90-1.30 ppm (m, SH),
1.10-0.65 ppm (m, 6H).
~"~
: `',"',,':
.' ,'. '' ' ,
.:
~'~ ' '' '' '
:: :. .
': . ~ ' '
'' ~''' ." '' ''''
: -. ...
~ ~ -190-
'
~'"~'' ~:'
, '
.~ :' .' -
lOS999'~
EXAMPLE XCV
6-(D-2-lBenzenesulfonamido]-2-[p-hydroxyphenyl]acetamido)-
2,2-~imethyl-3-(5-tetrazolyl)penam
The title compound is prepared in 53~ yield from
6-(D-2-amino-2-[p-i~,ydroxyphenyl]acetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam an~ benzenesulfonyl chloride, using the
procedure of Example XCV. T~e product has m.p. 152-165C.
(dec.). IR (Nujol mull): 1780 ~ -lactam). NMR
(in DMSO-d6): 9.10 ppm (d, lH), 3.50 ~pm (d, lH), 7.90-
7.40 ppm (m, 5H), 7.10 ppm (d, 2H), 6.55 p~m (d, 2H), 5.60-
5.10 ppm (m, 4H), 1.55 ppm (s, 3H), 1.00 ppm (s, 3H).
.-~'' '
';
-191- '.
.
. ~ .
,... . . _ ' ' ' .. 1 .' ' ' ' ', ~ : ` ' , . ' '
~os~g~
EXAMPLE XCVI
6-(2-D-[2-Benzamidoacetamido]-2-phenylacetamido)-2,2-
dimeth l-3-(S-tetrazolvl)~enam
Y . .. ..
To a stirred solution of 1.29 g of 6-(2-D-[2-
aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(S-tetra-
zolyl)penam and 1.3 ml. of triethylamine in 15 ml. of
dimethylformamide, is added 0.4 ml. of benzoyl chloride.
Stirring is continued for a further 30 minutes, and then
the reaction mixture is filtered. The filtrate is added
dropwise to 300 ml. of ether, which causes a gummy solid
to precipitate. The ether is removed by decantation, and
the solid is partitioned between ethyl acetate and water.
The pH ~f the aqueous phase is adjusted to 2.0 (dilute
hydrochloric acid), and the ethyl acetate layer is
removed and combined with a further ethyl acetate extract
of the acidified aqueous phase. The combined extracts are
washed with water, foIlowed by brine, and then dried using
anhydrous sodium sulfate. Evaporation of the soIvent in
vacuo gives a gum, which is redissolved in 30 ml. of ethyl
acetate, and then the solution is added dropwise to 200 ml.
of hexane. The white solid which precipitates is filtered
off, giving 0.85 g. of the title compound, m.p. 150C.
(dec.). IR (KBr disc): 1780 cm 1 (~-lactam). NMR
(DMSO-d6): 9.40-9.20 ppm (m, lH), 8.90-8.40 ppm (m, 2H),
8.00-7.10 ppm ( , 12H), 5.90-5.40 ppm (m, 3H), 5.25 ppm
(s, lH), 4.00 ppm (d, 2H), 1.60 ppm (s, 3H) and 1.00 ppm
( 9, 3H).
.
'. :
. .
-192- -
. .- , ~
. ....................................................................... .
1()5S~99'~
EXAMPLE XCVII
.
Following the procedure of Example XCVI, and
replacing the benzoyl chloride used therein by the
appropriate acid chloride, the following congeners are
S produced: ~
G~ .~ ~.
~H-CO-N ~ ` ~ `
NH ~ ~N~
CH2 H~ 1 .
1H
~o ~ ',
.-.~.
..
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,
,:,; ' ~ `'
.~
.
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~05S~g9;~
EXAMPLE XCVIII
Using the procedure of Example XCVI, the following
compounds are prepared by the acylation of 6-amino-2,2-dimethyl-
3-(5-tetrazolyl)penam, 6-(D-2-amino-2-phenylacetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam or 6-(D-2-[3-aminopropionamido]-
2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam with -
the appropriate acid chloride. ~
H3 . -:
Rl_NH ~ ~ ~CH3 :
HN-N ~: :
'.
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:, ,:'.'
":'','''''.
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-195-
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- 10S~99~
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N-- N-- t~ _ u~ l o
O o o I t~
~::C O ~ $ u~
~ ~ m_ ~
Z ~ O
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m :r: m
~ e ~ ~ e~
~C O :~ O O
_I ~ ~ u ~ ~ P: o _ I ~ --
o ~ o ~ ~ o ~ ~ o ~ oo o ~ ~r o o--~o o ~ I` ` . - ,
~ e
OD _I--0 ,I R _I CD ~
,. :''' :-
~
~ I O o o u~ ~n o o
H ~ OD ooco oo o~
,
. .
~d
_ _I ~:n ~ ~ I` ~r ~ :
. dP ~r~ d' W U~
"-- ., .
~I rl O~'~I ''" '
e ~ ~
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N I N IO 1: ~
U O `' .:
O Q~
rl U I
u ~ lao I o oo o u I o
~ 1~ h ~ ~1~~ ~ 'a--I
_ ~1 10 -1 0 111~ 1 '1 ~1
- 1 N ~ ~ O
_I ~ C N ~ ~ ~U ~: ~1 ~ ~ U
P; J~ 1 1 o I o I-~
1 ~ ~~ Ei U
N l l l ~:
o ~ ~1 ~ o ~ a~
1 ~ o a~ ~ o a) ~1 o o ~ o ~I I ; -
I I e I h U I 'a U I ~ U I h I ~
-197
~()55~9'~
EXAMPLB XCIX
Reaction of the approprlate 6-(2-substituted-2-
aminoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam or ~-
(2-substituted -2-[2-aminoacetamido]acetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam with the requisite acid
chloride, according to the procedure of Example XCVI,
affords the following congeners:
R7 - ------CH------ --CONN~ CH3
~ 12~
_ l=o
I m
R7 m z
isopropyl O methyl
isopropyl O phenyl
isopropyl O p-chlorophenyl
isopropyl o 2-thienyl
phenyl O propyl
phenyl O isobutyl
phenyl O n-hexyl
phenyl O m-tolyl
phen~l O ~-methoxyphenyl
~-hydroxyphenyl O p-bromophenyl
~:: 20 p-hydroxyphenyl O 2-furyl
m-methoxyphenyl O 4-pyridyl
o-tolyl -\O p-fluorophenyl
m-bromophenyl ~O 3,4-dichlorophenyl
: ' ~
'
1()5~9;~
R7 m Z
_
2-thienyl o ~-n-hexyloxyphenyl
3-thienyl o phenyl
2-furyl 0 3-thienyl
5 ~-(hydroxymethyl)phenyl 0 2-furyl
phenyl 1 n-butyl
phenyl 1 2-pyridyl
phenyl 1 m-bromophenyl .
~-hydroxyphenyl 1 2-thienyl
10 p-hydroxyphenyl 1 methyl .
.
~ ','-.', ','',.
105999;~
EXAMPL~ C
6-~2-[3-Phenylureido]-2-[p-hydroxyphenyl]acetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam
To a stirred solution o~ 0.78 g. (0.002 mole) of
6-(2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam in 40 ml. of 1:1 acetone-water, the
pH of which has been adjusted to 6.0 by the addition of
sodium bicarbonate solution, is added 0.238 g. (0.002 mole)
of phenyl isocyanate, at ambient temperature. Stirring is
continued at ambient temperature for a further 30 minutes,
and then 50 ml. of ethyl acetate is added. The pH of the
a~ueous phase is lowered to 1.5 with 1 N hydrochloric
acid, and then the organic layer is removed, dried and
evaporated to dryness in va~uo. The residue is re-
dissolved in a small volume of ethanol, to which 0.2 ml.
of triethylamine is then added. The resulting solution is
added dropwise to 200 ml. of ether, with vigorous stirring,
and then the solid which precipita*es is filtered off.
This affords 0.8 g. (66% yield~ of 6-(2-E3-phenylureido]-
2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetra-
zolyl)penam as its triethylamine salt, m.p. 165-170C.
(dec.). The infrared spectrum of the product (KBr disc)
shows absorptions at 1790 cm 1 (~-lactam) and 1670 cm 1
tamide I). The NMR spectr~m (DMSO-d6/D2O) shows absorp-
tions at 7.60-6~70 ppm (multiplet, 9H, aromatic hydro-
gens), 5.80-5.50 ppm (multiplet, 3H, C-5 and C-6 hydrogens,
and side-chain methine hydro-gen), 5.05 ppm (singlet, lH,
C-3 hydrogen), 3.Q5 ppm (quartet, 6H, N-CH2CH3), 1.55 ppm
(singlet, 3H, C-2 methyl hydrogen), 1.10 ppm (triplet, 9H,
N-CH2CH3) and 0.95 ppm (singlet, 3H, C-2 methyl hydrogens).
The MIC of the title compound against Strep.
~ ':
., ' '~ .
'
105999'~
pyoqenes is <0 .1 ug . /ml
EXAMPLE CI
.
Using the procedure of Example C and
reacting either 6-(2-amino-2-phenylacetamido)-2,2-di- :.
methyl-3-(5-tetrazolyl)penam or 6-(2-amino-2-[~-hydroxy-
phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam with --
the appropriate isocyanate, the following compounds are
prepared. The compounds are isolated as their triethyl-
amine salts. :
R --CH-CONH ~S~C:H3
a~rCH3
\ ~N~ . . : .
N _~ -
H
- . :.
; ~ ' ' :
:
: -201-
.
lOS~5~9~
Q, _
. . , , o
u~ a) ~ o o o o u~ o o
~ .
U o ~ V V V V o V V
H :~ ~ ~D H
~- ~ .
_ ` ~
~ ~ o ~ n è ~
.~ x m U _ ~ :~ . o m
O ~ ~ ~D O ~ ~ ~ ~ ~D Ul ~ ~ O 1` 0 ~O O ~r ~D O
u~ ~ O ~oo O O ~ O ~ U~ O
01~ O ~C 10OD O Ci~ CO O ~ --1 0 ~ N O~ 11~ _ ~-1 a~ 1` ~\
~ O . ~ m ~
Ul ~
~: ~ o . _ ~a~ o m o ~ ~ ~O
a _--u~ D N ------t~
_ m 5: o _ m :~ m ~ m o ~ m o $ m
3 ~ ~ ~ P ~ ,P.
s~ __ ~ ~ ___ _ ____ _ . _ . _ _, __ ----_ .
~ "~ o__ o,~ o ~ o ,~ ~ ~ $ o u~o m ~u m
o ~ ~ m U~ N O ~ ~ ~ ~ ~ CO _1 n ~ N CO r-- ~ 1` ~
u~ I I tn ~ I --m I -- I m --m--m I --m I --m
u~ ~ o ~ I o ~ o ~ ~ o ~ u~
m ~ m ~ m P~
ul O In o ~ ~ u~ o u~
s~ _~ o _I o ~ n ~ o o
a~
u~ o u~ o u~ o u~ o ul ul o o o o
_ r~ .~ OD O~ OD O ~` O U~ t~ n a~
h ~
S ~ ~ u) o u~ o u~ o u~ o In In U~ U~ Ul O
~ ~ U~ U~ o o
_ Ir~ 1~) Ir) In N 1`
Q~ C~ CD 0~ N O N Ll~ 0 :
. O ~
~, _ ,'
m m
Z ~ Z
o Z ~ ~ :
~ ~ Z m
o m~ z m~
m~D
m ~ z
m p~ .
W ~D
~; ~ o
--202-
~'-.
105999Z
EXAMPLE CII
6-(D-2-[2-Aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-
3-(~-tetrazolyl)penam
To 0.418 g. of sodium N-(2-ethoxycarbonyl-l-
methylvinyl)-2-aminoacetate in lO ml. of tetrahydrofuran
is added 2 drops of N-methylmorpholine and 0.19 ml. of
ethyl chloroformate with stirring. St ~ ing is continued
further 30 minutes at -10C. and then the solution is
cooled to -30C. To this solution is then added o.708 g.
of 6-(D-2-amino-2-phenylacetamido~-2,2-dimethyl-3-(5-tetra-
zolyl)penam dissolved in lO ml. of l~l tetrahydrofuran-
water and adjusted to pH 8.7. Stirring is then continued
for a further 30 minutes without cooling. At this point, --
the pH is adjusted to 1.5, and the reaction mixture is
stirred at OC. for 30 minutes. The tetrahydrofuran is
removed by evaporation ln vacuo; and then the aqueous
residue is washed with ether, washed with ethyl acetate, ;
adjusted to pH 6.4 and lyophilized to give a white solid.
The solid is stirred for 20 minutes in 20 ml. of N,N-di- --- `
20 methylformamide, and the solid which does not dissolve is
filtered off and discarded. The filtrate is added dropwise
to 200 ml. of chloroform, and the solid which precipitates
i8 filtered off and dried giving 0.3 g. (36.6~i yield) of
the title compound, m.p. 211-230C. (dec.). IR (KBr disc):
1770 cm (~-lactam). NMR (in DMSO-d6): 9.50-9.15 ppm
(d, 2H), 7.40 ppm (s, 5H)/ 6.80-5.30 ppm (m, 9H), 5.00 ppm
(s, lH), 3.65 ppm (s, 2H)~, 1.50 ppm (s, 3H), 0.90 ppm
(s, 3H).
-203-
lOS9g9'~
EXAMPLE CIII
-
6-[2-[2-Aminoacetamido]-2-[p-hydroxyphenyl]acetamido)-
2 2-dimeth 1-3-(5-tetrazolv~)penam
Y . .~ _ _
The title compound is prepared in 45% yield from
6-(2-amino-2-p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam and sodium _-(2-ethoxycarbonyl-1-
methylvinyl)-2-aminoacetate, using the procedure of
Example CII. The product has m.p. 173-188C. (dec.). IR
(KBr disc): 1785 cm (~-lactam). NMR (DMSO-d6): 7.55-
7.10 ppm (m, 2H), 7.00-6.00 ppm (m, 2H), 5.75-5.40 ppm -~
(m, 3H), 5.10 ppm (s, lH), 3.65 ppm (m, 2H), 1.55 ppm
(s, 3H), 0.95 ppm (s, 3H).
-204-
.. :
.. . . . . . .. .. ... .. ... .. . . . .. ~ . .
105999~
EXAMPLE CIV
Reaction of the appropriate. 6-(2-amino-2-sub-
stituted acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam or
6-(2-[2-aminoacetamido]-2-substituted acetamido)-2,2-di-
methyl-3-(5-tetrazolyl)penam, with sodium N-(2-ethoxy-
carbonyl-l-methylvinyl)-2-aminoacetate, according to the
procedure of Example CII, provides the following compounds:
R7 - IU - CO~ ~ C 3 ~:
H m H ` .
CO
l~2
NH2 .- ' ~.
R7 m
methyl o
isopropyl O
allyl O
cyclohexyl O
3-cyclohexenyl O
1,4-cyclohexadienyl o
benzyl 0
~. ,,
~-chlorophenyl 0
p-hydroxybenzyl O
m-bromophenyl O
. p-fluorophenyl O
o-chlorophenyl O
3,4-dichlorophenyl O
-205-
lOS999Z
R7 m
3-chloro-4-hydroxyphenyl 0
p-methoxyphenyl O
m-butoxyphenyl O
p-(hydroxymethyl)phenyl O
3,4-dimethoxyphenyl 0
m-tolyl a
2-thienyl 0
3-thienyl o
2-furyl 0
3-furyl o
3-pyridyl o
5-ethyl-2-thienyl 0
methyl 1
phenyl
~-hydroxyphenyl 1
~-chlorophenyl
'.: -
~: , .: ,.
~ ~ :
: ~ ,.
. .
-206- ~
~: .
lOS99g'~
EXAMPLE CV
6-(D-2-[3-Aminopropionamido]-2-phenylacetamido)2,2-di-
methyl-3-(5-tetrazolyl)penam
To a stirred solution of 0.95 ml. of ethyl
chloroformate and 2 drops of N-methylmorpholine, in 30 ml.
of tetrahydrofuran, is added 2.39 g. of N-~2~h~
carbonyl-l-methylvinyl)-3-aminopropionic acid, at -10C.
Stirring is continued for 30 minutes, and then the
reaction mixture is cooled to -30C. To it is then added
a solution prepared by ~uspending 3.8 g. of 6-(D-2-amino-
2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam tri-
hydrate in 15 ml. of water and 15 ml. of tetrahydrofuran
and adjusting the pH to 7.8. After the addition, the
cooling bath is removed and stirring is continued fer a
15 ~ further 30 minutes. The temperature of the reaction mix-
ture is then adjusted to 0C., the pH is adjusted 1.5, and
stirring is continued for 30 minutes. At this point, the
tetrahydrofuran is removed by evaporation in vacuo, the
aqueous residue is extracted with ethyl acetate, and then
the pH of the aqueous residue is adjusted to 6Ø
Lyophilization of the aqueous residue then affords the
crude product. It is purified by stirring with 400 ml. of
dimethylformamide, filtering, and added the filtrate
slowly to 500 ml. of chloroform. The purified product is
filtered off. The yield is 3.30 g, mp 190C. (dec.). IR
(KBr disc)s 1765 cm 1. NMR (DMS0-d6)s 9.4-8.8 ppm
(m, 2H), 8.0-7.1 ppm (m, lOH), 5,9-5.3 ppm (m, 3H), 5.0
ppm (8, lH), 3.3-2.5 ppm (m, 4H), 1.55 ppm (8, 3H), and ~-
0.9 ppm (8, 3H~.
-207-
~()5~5~9'~
EXAMPLE CVI
6-(D-2-[2-(~enzamidino)acetamido]-2-phenylacetamido)-2,2-
dimeth 1-3-(5-tetrazolvl)~enam
Y ~ .
A mixture of 1.72 g. of 6-(D-2-[2-amino-
S acetamido]-2-phenylacetamido-2,2-dimethyl-3-(5-tetrazolyl)-
penam, 0.66 g. of ethyl benzimidate and 20 ml. of N,N-
dimethylformamide is stirred for 1 hour at 25C. The
filtered reaction mixtu~e is then added dropwise with
stirring to a large excess of chloroform, and the solid
which precipitates is filtered off. This affords 0.93 g.
(43% yield) of the title compound, m.p. 198C. (dec.).
IR (KBr disc): 1770 cm 1 (~-lactam). NMR (DMSO-d6):
9.35-9.00 ppm (m, 2H), 8.00-7.15 (m, 12H), 5.95 ppm
(d, 2H), 5.55 - 5.30 ppm (m, 2H), 5.00 ppm (s, lH),
4.35 ppm (s, 2H), 1.50 ppm (s, 3H), and 0.90 ppm (s, 3H).
-208-
.. ... . . .. .. .. .. . . .. . . ... .. .. ... - . . .. . : . . . . . - - -
l()S~99'~
EXAMPLE CVII
Following the procedure of Example CVI, and
reacting 6-(D-2-~2-aminoacetamido]-2-phenylacetamido)-2,2-
dlmethyl-3-t5-tetrazolyl)penam with the approprlate
imldate ester, the followlng compound~ are prepared: -
C~-CO~ S C~
NH ~ y CH3
clo o ~C~`7
H N
-209-
~,`` ~ . .
lOS95'9;~
.
v $ ~ $
~ ~ _ ~ $ P
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O --$
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E~ ~ O X ~ I P:~ _ o ~ $ $ ' I
Q ~ o ~ 7 $
m ~ ~ $ ~ $ $ _$
~5 ~ _ N _ ~ CO t~J ` 15) --_ ~ o O a'~
~ ~ D ~ U~ p~ $ U~ O ~ _ ~ $ t~
l -- ~ ~ r$ ~ ~ o ~ ~-- ~--
o $ mu~ o OD ~
~n I~ ~ a7 o ~ _ $ _ ~ --t~ ~ a~ In -
~ o $ r~ $ _~ In~ . . . .
~i ~ m U)~ m $ ~3 $ _~ I m ~
_ ---- -- ~ o ~1 ~ D $ `` M ~ ~ $ ~1
~ I U) ~ --O -- Ul ` ` ~ ~ _
:1 1--0 1~ '1-- I $ ---- 1`-- '1:) Il~ ~ Il') 1.') U')-- ~ _ $ $ 5~ $
I o --~ --m
a~ o ~ r o 1~ . u~
_ O- co _ tO ~ n e
r~ ~ ~ r~ ~Ul r~
U~~ ~ ~ o -- ~ m ~ ` _ _ $ ~ ~ ` oco o . o
r $~ r _$ ~I m~
m~ $ ~ $-- mer $ $ ` $ $ ~ $~ x It~
m $ e ~ In e $ f3 ~ $ ~ $
m ~ m o~ n U x-- ~
o ~ ~ o ~ I~ o _ o~ a~ er _ ~ ~ _ ~r _ o ~1 ~ ~ u) o~ u~ o
o ~ -m - $ '$ m - - - -
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O l o u~ o u~ u~ o o o ~ ul u~ o
o cn
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~ a ~ ~ ~ o ~ ~ rl a ~ o
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~ i 3 ~ ~ ~ ~ u~
-210-
lOS~g9
~D
. ~ o
U~
--o o
~1 ` u~ bq N --J ~ 0
,c~ m ~ D O_ _,
~ ~ O--
e ~ .
~u e ~
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l ~ ~ u) R lo ~ ~
O U) ~ U~ O ~ ~: -- ,~ CD -- ` ,4 ` -- ` -- -
_ "~ * o
~ m
~ m ~ $ ~
_~ m ~ ~ ~ m ~ m
m a~U) m
P ~ m --
~ ~ e ~
.~ m m ~ m ~
~, e ~ m U ~ ", P~ `_ m m~ m~ m m
r m ~ m ~ m ~ ~
e m --~ --, --~, ,4 _ _ ,~, _ ~, _ _
~ ~-- co ,l ~ ~ o u~ o u~ o u~ a) o ~ ~ o u~ o ~ ~"
~ ~ ..
--
~ ~H
U I u~ O 1~ 0 1~ ~ _I O t`
O O
~ N N
~ . l l l l
~l ~rl ~,) N Ir) ~ I~ ~a~ .
P- ~I CO 0~ O0~ .
. ~.'
~_~
. .
3 3 ~ ~ a
r~ ~ ~U ~ ~ .,1 .
~ e ~ a) pO
t~ ~ i N a~ O _l O ~ 1 0 0 e o
"~ I o ~1o
x ~ g ~O ~ o ~lJ
N:~ N ~ N,~ N O n~ .,.
o 3
~ ~ ' ~ N ~ N O ~ ~~ ~ ~ ~ ~ ~ N ,~
::
-211- -
;--, -
~OS999Z
EXAMPLE CVIII
Reaction of the appropriate compound of Formula
I or II, wherein R and R3 are each hydrogen and Rl 18 of
Formula V, wherein n is l and Q is amino, with the
requisite ethyl imidate, according to the proçedure of
Example CVI, preduces the following compounds
l CH3
R -NH ~ S ~ CH3
C ~ N ~.
H :
-212- ~ .
~ : ''",'.".:
: ..
lOSg99'~
p~
`
~ ~ m
t~
.~ ~D` ~D ` O
o_ ~
$ ~Itq--I ~ ~1 ~ 1~ ~ ~ -
lO ~D~ ~ O r7 oO
O~9 `CO ` f'~ ` I~ _ I` $--
Cl~ bq
11') ` O
I~ O t~
_ O _ ~
~ ~ m
I` ~ o ~ ~1 o
~nO ~Q' tn ~ ~ ~ -- ' ~ '
~r o o,~
O
~_ . __ ~ _ _ . _ Ul _ _ . _ ~
_, $ ~ P~ ~ U') $ $ N 5~
~ ~ ~ --m ~
U~ ~, ~, O ~, ~~ I o _l O
o ~r ~ o o~ ~ o _ o
o O O O ,.
CO CD ~ 00
a~ 3
~_I
~ u I u~ In o o o u
H ~ ~ r~
` O
~ * _ O~) CO ~ OD ',
.,1 ~ o~1 ~1 ~1 _I
~ l l l l
_I ~rl OO 0 00 10 C~
a) o o -- ~` ,, t` ,~
~ P-- ~1 ~1 ~1 ~1 ~1
':
': .
1 0 ~ ~1 U ~ O O
~ "
~; ~ ~~ U ~rl ~ O ~a ~ ~ ~ ~ .
~ e o ~ ,, ,, ,~, O
I O ~ 0 ~ ~ O ~ 0 ~ ~1 0 ~
U~ o ~ ~ ~ o
~r ~ ~ ~ ~ ~ ~ ~ ~P
1 o ~
N ~
~-213- :
10~999'~
E%AMPLE CIX
Using the procedure of Example CVI, and reacting
6-~D-2-~3-aminopropionamidol-2-phenylacetamido)-2,2-di-
methyl-3-(5-tetra~olyl)penam with the appropriate ethyl
imidate, the following compounds are prepared~
CH3
_NH ~ S \ ~ CH3
-I l .-
~ N . ~ ~\ //N
HN-N . . ~
. ~.
~.
' '';''.
,'' '
'.
; '' .-
.
, .
-214-
.
.~ ' ''`"'.
~ ' ' "' .
~os999~
~ ~m ~ ~ O
I" ~ I ~ . . ~ _
O
E ~~ ~ N el
O-- ~ ~ x m
. 0~ ~ o ~ ~-- ^ ~ ~
~r ~m ~ O ~ m . . co~
~ O_ ~ x m
u~ m ~
~r o ~ u~ I ~ o u~
~- o . . ~ m
~ CO N r--
~ o u~
m
~ -- m _ . _ .
e ~ m
- m~ --U ~ m ~
m ~ -- ~ U u m
I u~ Ul 1~~1-- --U~ N N ~ ~D 1` ~1 ~0
_ ~ ') N--
. ~ w ~ O U~ e~ ~ -- ~ N _ U~
_ N _ U'l 11~ _ 117 N ~
~ m ~ N m ~,~o
~ t`~ ~ ~ co o _ N
_ ~ In m ~ m . ~ q o
m ~ -- _ m ~ a ~ m
~ m m ~ --N
m ~ + ~ 0 O
~ m ~ m m ~ N E~ -- -
-- --u~ _ a O
"~ o ~ o ~ ~ ~
. . _ --W. U~ . 00 o ~ _ -- -- . . _ ~ _I _ _
,l ~ m O~ U o ~ m I P: P;
~r o ' o I~ ~; Il') ~o ~ o _~ N CO ~ ~ It)
~ ~ ~ O _ N ' O ` E3 a ~ ~ o
__ ~m a-- co_ ~ m e ~
5~ + ~ m--~----
~W ~D m
~~ I c~ ~ O ~ o--I ~ ~ I o ~ m --
0~ O ~ U~ ' ~I t.q O U~ O _I ~ ' N ~ I O
o ~ co 3 ~ w er ~ ~ o ~ 1`
_
,1
l U~ o U~ U~ o o
H U I` I~ I` t~ r-- I~
al _ ~) N CD ~ t`l O
~_
~
R O ~ ~I R ~ R 8 ~ R
I O ~1 ~ 0 O) ~rl I S-l ~rl ~rl I
R ~ ~ 1 U 'a N ,
~-1 o 11~
rl ~1 1
1 0 ~
~1 ~ l O ~1 1 0 ~1 Il~ O -I
P~ ~ e ~ e N
o ~ e ~ J~
e ~ e ~ o ~ h ~u ~ ~ u
.1 1 , e ~ I a ~
~) N ~ O _I ~ ~ ~1 ~ O ~1
_-~ ~ --O ~1 --'
I ;a _ I o I e ~ e I e e I ~ e
N X O ~ I O ~ a O N O ~ U N O a~
b~ dl, ~ blg~a bl ~ bl~ al~
--215--
11 ~05999Z . I
I _~ N S
l ~ O
~ I ~ A~ ~o , : ,~ , ' ;'~
. ~ ~ , '.`':',''' '"' ''-' ''""
. Uo)~ oEi '
': p~ o ~~
: ' ,' ' , .
~: ~ l Rl B uI ~ B C
~ ' , ' . '' ' ~ '`''`
~: : -216- ` .: .
: . ...
. . ,'~ .',.',".. '
10S~9'~ '
EXAMPLE CX
Reaction of the appropriate 6-(2-substituted-2-
aminoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam or
6-(2-substituted-2-~2-aminoacetamido]acetamido)-2,2-di-
methyl-3-(5-tetrazoly)penam with the appropriate imidate
ester, according to the procedure of Example CVI produces
the following congeners:
R7_~H-coN~H3
~ ~ 2 ]
IH m
CO
R7 m Z
methyl 0 acetamidinomethyl i-
methyl 0 benzamidinomethyl ~ .
methyl 0 p-chlorobenzamidinomethyl ;
isopropyl 0 m-bromobenzamidinomethyl
isopropyl 0 p-methoxybenzamidinomethyl
isopropyl o 3,5-dichlorobenzamidinomethyl
isopropyl 0 2-furancarboxamidinomethyl
isopropyl 0 4-pyridinecarboxamidinomethyl
phenyl 0 m-methoxybenzamidinomethyl
phenyl 0 ~-fluorobenzamidinomethyl
phenyl 0 p-methylbenzamidinomethyl
phenyl 0 m-methylthiobenzamidinomethyl
~-hydroxyphenyl 0 2-benzimidazolecarboxamidino-
methyl . .
~-hydroxyphenyl 0 benzamidinomethyl
~-(hydroxymethyl)phenyl Q benzamidinomethyl
~ -217-
l(~S~
_ R m Z
2-thienyl O 4-pyridinecarboxamidinomethyl
2-thienyl O 2-thiophenecarboxamldinomethyl
3-thienyl O benzamidinomethyl
2-furyl O 3,5-dichlorobenzamidinomethyl
3-chloro-4-hydroxy- O 4-pyridinecarboxamidinomethyl
phenyl
p-methoxyphenyI O benzamidinomethyl :~
m-tolyl O 3-pyr1dinecarboxamidinomethyl ~ --
10 phenyl O propanecarboxamidinomethyl -- -.
phenyl O butanecarboxamidinomethyl ~-
~-hydroxyphenyl O hexanecarboxamidinomethyl
m-butoxyphenyl O benzamidinomethyl -
methyl 1 acetamidinomethyl -
15 methyl 1 benzamidinomethyl ~
isopropyl 1 4-pyridinecarboxamidinomethyl :~.
phenyl 1 b1~tanecarboxamidinomethyl
phenyl 1 3,5-dichlorobenzamidinomethyl
phenyl 1 2-thiophenecarboxamidinomethyl
20 ~-hydroxyphenyl 1 benzamidinomethyl
p-chlorophenyl 1 4-pyridinecarboxamidinomethyl
-218-
~05~9'~
EXAMPLE CXI
6-(D-2-[2-(4-Pyridinecarboxamidino)acetamidol-2-
(p-~ydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)-
p~nam . .~
The title compound is prepared in 80% yield from
6-(D-2-[2-aminoacetamido]-2-[p-hydroxyphenyl]acetamido)-2,_
2-dimethyl-3-(5-tetrazolyl)penam and ethyl 4-pyridine-
carboximidate, using the procedure of Example CVI. The
product has m.p. 195C. (dec.). IR (KBr disc): 1775 cm
NMR (DMSO-d6): 9.3-8.8 ppm (m, 4H), 8.8-7.0 ppm (m, 4H),
7.75 ppm (d, 2H), 7.25 ppm (d, 2H), 6.75 ppm (d, 2H),
5.85-5.45 ppm (m, 3H), 5.05 ppm (s, lH), 4.35 ppm (s, 2H),
1.55 ppm (s, 3H), 0.95 ppm (s, 3H),
-219--
, ~ .
'
~05S`9~
EXAMPLE CXII
6-(D-2-[2-(3-Ethylureido)acetamido]-2-phenylacetamido)-2,~
2-d~methvl-3-(5-tetrazolvl)~enam
~ ~ ~ _
A mixture of 1.29 g. o 6-(D-2-[2-aminoacetamido]-
2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,
0.23 g. of ethyl isocyanate and 15 ml. of N,N-dimethyl-
formamide is stirred at room temperature for 45 minutes.
The filtered reaction mixture is then added dropwise with -
stirring to 300 ml. of ether, and the precipitate which --
forms is filtered off. The solid is partitioned between
water and ethyl acetate, and the pH 1s adjusted to 8Ø
The ethyl acetate is removed and discarded. The pH of the
aqueous phase is adjusted to 2.0, and the product is
extracted into ethyl acetate. The washed (water) and
dried (Na2SO4) ethyl acetate is concentrated to small
volume and the product crystallizes out. It is filtered
off. The yield of the title compound is 0.74 g. (49~),
m.p. 162C. (dec.). IR (KBr disc): 1785 cm (~-lactam).
NMR (DMSO-d6/CDC13): 9.3-9.1 ppm (s, lH), 8.3 ppm (d, lH),
7.65-7.2 ppm (m, SH), 6.3-5.5 ppm (m, SH), 5.2 ppm (s, lH),
3.8 ppm (d, 2H), 3.3-2,9 ppm (m, 2H), 1.65 ppm (s, 3H),
1.2-0.9 ppm (m, 6N).
'"- ".
.
-220-
105~99~
EXAMPLE CXIII
Reaction of 6-(D-2-~2-aminoacetamido]-2-phenyl-
acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam with the
appropriate isocyanate, according to the procedure of
Example CXII, provides the following compounds.
~ ~-.
1~ ,
CH-CONH ~ ~ CH3
hH ~ CH3
~H2 ,N_ N
NH H
lo
. ',
Melting Infrared
Yield Point* Spectrum NMR Spectrum
Z (%) ~C.) (~m 1) (DMSO-~6: ppm)
10 anilino38 158 1780 9.3-9.0(m, lH),
8.7-8.4(m, 2H), -
7.7-6.9(m, 10H),
6.6-6.3(m, lH),
5.9-5.45(m, 3H),
5.2 (s, lH), 3.95
(d, 2H), 1.65
(s, 3H), 1.05
(s, 3H).
methyl 33 154 1785 9.25-9.05 (m, lH),
20 amino 8.15 (d, lH), 7.6-
7.15 (m, 5H), 6.3-
5 . 2 (m, 5H), 5.15
(9~ lH~, 3,8(d,
2H), 2,65 (d, 3H),
1.6(s, 3H), 1.05 -
; (s, 3H).
:: '
~: * . .
With decomp~sition
, "
.
.
-221- -
~os999~
EXAMPLE CXIV
6-(D-2-[2-Phenoxyacetamidol-2-[4-hydroxyphenyl]acetamido)-
2,~-dimethvl-3-(5-tetrazol-5-vl)~enam
To a stirred mixture of 1.0 g. of 6-(D-2-amino-
2-~4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazol-
5-yl)penam, and 0.91 ml. of triethylamine, in 20 ml. of
methylene chloride, iB added 3 ml. of N,N-dimethyl-
formamide. This solution i9 then aooled to OC., and a
solution of 0.375 g. of phenoxyacetyl chloride in 10 ml.
;10 of methylene chloride is added dropwise. The mixture is
stirred for 30 minutes after the end of the addition, and
then the solvent is removed by evaporation in vacuo. The
resLdue is dissolved in water. The a~ueous solution is
extracted with ethyl acetate and then acidified to pH 2.4.
The aqueous phase i8 again extracted with ethyl acetate,
and the latter extract- is dried using anhydrous sodium
sulfate. Removal of the solvent by evaporation in vacuo
leave~ 0.91 g. of crude~ product. The crude product is
purified by chromatography using Sephadex LH-20 as
adsorbant, and eluting with water. The yield of purified
product is 0.33 g. (30~), mp 180-}92C. (dec.). IR (KBR
disc): 1786, 1667, 1613 and 1515 cm 1. NMR (CDC13/DMSO-d6):
9.13 ppm (d, J=7Hz, lH), 8.58 ppm (d, J=8Hz, lH), 7.00-7.60
ppm (m, 9H), 5.90 ppm (d, J=8Hz, lH), 5.60 ppm (m, 2H),
z5 5.03 ppm (9, lH), 4.65 ppm (s, 2H), 1.57 ppm (s, 3H) and
0.97 ppm (9, 3H~.
-222-
lOS~g9'~
EXAMPLE CXV
6-(D-2-Phthalimido-2-phenylacetamido)-2,2-dimethyl-3-
(5-~etrazolyl)penam
To a stirred solution of 1.07 g. of 6-(D-2-
amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam
and 1.03 ml. of triethylamine, in 20 ml. of methylene
chloride, is added, at 0C., a soluti~n of phthalic
anhydride in 10 ml. of methylene chloride. The mixture is
stirred at ambient temperature for 1.5 hours, and then the
solvent is removed by evaporation in vacuo. The residue
i9 dissolved in water at pH 7.8, and the water is washed
with ethyl acetate. The pH of the aqueous phase is then
lowered to 2.0 and the product is extracted into ethyl
acetate. The latter ethyl acetate ls washed with water,
dried uslng anhydrou~ sodium sulfate, and evaporated in
vacuo. This affords 1.2 g. (92% yield) of the title com-
pound, mp 185-197C.(dec.). IR (KBr disc): 1795, 1724
and 1639 cm 1. NMR (CDC13/DMS0-d6): 8.67 ppm (m, 3H),
8.25 ppm (d, J=8Hz, lH), 7.50 ppm (m, 9H), 5.98 ppm
Zo (d, J=8Hz, lH), 5.65 ppm (m, 2H), 5.28 ppm (s, lH), 1.67
ppm (s, 33~, and 1.10 ppm ~s, 3`3).
.
' :-
.
.:
-223- ~
..
' .
l~S~g9'~
EXAMPLE CXVI
6-(D-2-[3-Phenylthioureido]-2-phenylacetamide)-2,2-
dim~thvl-3-(5-tetrazol)~enam
_
To a stirred solution of 910 mg. of 6-(D-2-
amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl~-
penam, and 0.61 ml. of triethylamine, in 20 ml. of
methylene chloride, is added 0.27 ml. of phenyl isothio-
cyanate. Stirring is continued for 2 hours at ambient -
temperature, and then the solvent is removed by evaporation
in vacuo. The residue is dissolved in water at pH 7.8,
and the water is washed with ethyl acetate. The pH of the
aqueous phase is then lowered to 2.0 and the product is
extracted into ethyl acetate. The latter ethyl acetate is
washed with water, dried using anhydrous sodium sulfate,
and evaporated in vacuo. This affords 707 mg. (644 yield)
of the title compound mp 150-167C. (dec.). IR (KBr disc):
1786, 1681 and 1515 cm . NMR (CDC13/DMSO-d6): 9.17 ppm
(s, lH), 8.27 ppm (m, lH), 7.97 ppm (d, J=7H~i, lH), 7.4
ppm (m, lOH), 6.3 ppm (d, J=7HZ, lH), 5.63 ppm (m, 2H),
5.27 ppm (s, lH), 1.6 ppm (s, 3H) and 1.1 ppm (s, 3H).
-224-
,1 ' .
10~999'~
EXAMPLE CXVII
6-(D-2-[3-Guanylureido]-2-phenylacetamido)-2,2-dimethyl-3-
t5-tetrazolvl)~enam
To a ~tirred solution of 0.5 g. of guanylsemi-
carbazide dihydrochloride (United States patent No.
3,579,514) in 5 ml. of water, is added dropwise, 0.184 g.
of sodium nitrite in 2 ml. of water, at ca. OC. The
resulting solution is stirred for 10 minutes at ca. 0C.
A second solution is then prepared from 1.14 g. of 6-(D-
2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)-
penam, 20 ml. of water, 6 ml. of dioxane and sufficient
triethylamine to bring the pH to 8Ø The pH of the second
solution is then lowered to 7.5, and the first solution is ~-
added dropwise at ca. OC. The xesulting reaction mixture -~
is stirred for 45 minutes. To it is th~n added a solution
prepared from 0.95 g. of sodium nitrite, 0.25 g. of
guanylsemicarbazide dihydrochloride and 3 ml. of water.
Stirring is continued for a further 45 minutes, and then
the reaction mixture is lyophilized.- The residue is
extracted with chloroform. The insoluble material is then
suspended in 20 ml. of water, the pH of which is then
adjusted to 5Ø The solid is filtered off and dried, to
give 0.87 g. (71% yield) of the title compound, m.p. ~ -
192-194C. (dec.). IR (KBr disc): 1785 cm 1 (~-lactam).
NMR ~in DMSO-d6): 7.55 ppm (m, 5H), 5.85-5.55 ppm ~m, 3H),
S.10 Ppm ~s, lH), 1.55 ppm ~s, 3H), 0.95 ppm ~9, 3H).
In lika manner, starting from 6-(D-2-amino-2-14-
hydroxyphenyllacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,
there is prepared a 94~i yield of 6-(D-2-[3-guanylureido]-2-
14-hydroxyphenyllacetamido)-2,2-dimethyl-3-~5-tetrazolyl)-
penam, m.p. 186-199C. IR (KBr disc): 1783, 1695 and 1667
-225-
lO~ggg~
cm 1 NMR (DMSO-d6/D20): 0.95 (s, 3H), 1.55 ~s, 3H), 5.1
(s, lH), 5.4-5.8 (m, 3H), 6.8 (d, 2H), 7.35 (d, 2H).
EXAMPLE CXVIII
Following the procedure of Example CXVII, and
reacting the appropriate 6-(2-amino-2-substituted-
acetamido)-2,2-dimethyI-3-(5-tetrazolyl)penam with
diazotized guanylsemicarbazide, the following compounds
are prepared. -
R7--CH-CONE ~3
~0 ~ ~ N ~
NH f 11
~ - . .
NH2-~=NH
R7
methyl
isopropyl
cyclopentyl
3-cyclohexenyl
1,4-cyclohexadienyl
m-hydroxyphenyl
p-chlorophenyl
o-fluorophenyl
3,4-dichlorophenyl
~-methoxyphenyl .
p-tolyl
3,4-dimethoxyphenyl
2-thienyl
3-thienyl
2-furyl
3-pyridyl
3-chloxo-4-hydroxyphenyl
-226-
- '
105~5~9',~
BXAMPLE CXIX
6-(D-2-Ureido-2-phenylacetamido)-2,2-dimethyl-3-(S-tetra-
zolyl)-penam
__ _ _
A mixture of 0.5 g. of 2-(D-2-amino-2-phenyl-
acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and 94 mg.
of potassium cyanate in 10 ml. of water is heated rapidly
to 80C., and then cooled rapidly to 25C. The reaction
mixture is stirred at ambient temperature for 18 hours,
and then filtered. The filtrate is acidified to pH 2.0,
and the solid which precipitates is filtered off. It is
dissolved in a small volume of ethanol, to which 0.067 ml.
of triethylamine is added, and then this solution is
poured into 100 ml. of ether. The solid which precipitates
is filtered off, giving 0.23 g. (38% yield) of the title
compound as its triethylamine saltr m.p. 138-150C. (dec.).
IR (KBr disc): 1785 cm (~-lactam) and 1670 cm
(amide I). NMR (in DMSO-d6/D2O): 7.45 ppm (m, 5H), 5.80-
5.40 ppm (m, 3H), 5.10 ppm (s, lH), 3.10 ppm (q, 6H), 1.60
ppm (s, 3H), 1.20 ppm (t, 9H), 0.95 ppm (s, 3H).
-227-
i()S~9~'~
EX~NPLE CXX
6-(D-2-Sulfamoyl-2-phenylacetamido)-2,2-dimethyl-3-(5-
tetrazolvl)Penam
A suspen~ion of 1.5 g. of 2-sulfamoyl-2-phenyl-
acetic acid in 15 ml. of thionyl chloride is heated underreflux for 30 minutes, and then the thionyl chloride is
removed by evaporation ln vacuo. To the residue is added - --
50 ml. of benzene and the mixture is evaporated to dryness
in vacuo again. The residue is then dissolved in 30 ml.
of acetone, and added dropwise, with stirring, at OC., to
a solution of 0.84 g. of 6-amino-2,2-dimethyl-3-(5-tetra-
zolyl)penam in 25 ml. of water and 3.5 ml. of lN sodium
hydroxide. During the addition, and for 30 minutes after-
wards, the pH is maintained at 6.0-6.2. At this point,
the reaction mixture is adjusted to pH 2.0, and the product
is extracted into ethyl acetate. The ethyl acetate is
dried using anhydrous sodium sulfate, and then it is
evaporated to dryness in vacuo. The residue is dissolved
in methylene chloride containing 4.9 ml. of triethylamine.
The solvent is again evaporated to dryness in vacuo,
giving 1.1 g. (58% yield) of the title compound as its
triethylamine salt, m.p. 129-139C. (dec.). IR (KBr disc):
1770 cm (~-lactam). NMR (DMSO-d6/D2O): 7.60 ppm (m, 5H),
5.90-5.40 ppm (m, 3H), 5.05 ppm (9, lH), 1.55 ppm (s, 3H),
0.95 ppm ~s, 3H).
Preparation of 2-sulfamoyl-2-phenylacetic acid
i9 described in Briti~h patent No. 1,067,965.
-228-
10~9~
EXAMPLE CXXI
_ _
6-(D-2- E 2-Guanylacetamido]-2-phenylacetamido)-2,2-
dimethyl-3-(5-tetrazolyl)Penam
. ~ . . . ~ ,
To a stirred solution of 405 mg. of p-nitrophenol
in 10 ml. of N,N-dimethylformamide is added 620 mg. of
dicyclohexylcarbodiimide followed by 410 mg. of 2-
guanylacetic acid hydrochloride. Stirring is continued for
4 hours, and then to this solution is added a solution of
948 mg. of 6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam triethylamine salt in 10 ml. of N,N-
dimethylformamide. Stirring is continued overnight, and
then the filtered reaction mixture is poured into 300 ml.
of ether. A gummy precipitate forms, and the excess
solvent is removed by decantation. The gummy material is
then slurried in 300 ml. of methylene chloride containing
1 ml. of triethylamine. This affordsl after filtration,
0.4 g. (44~ yield) of the title compound, m.p. 1i2-176C.
(dec.). IR (KBr disc): 1780 cm 1 (~-lactam). NMR (in DMSO-
d6/D2O): 7.45 ppm (m, 5H), 5.85 ppm (d, lH), 5.55 ppm
(m, 2H), 5.05 ppm (s, lH), 2.70 ppm (m, 4H), 1.55 ppm
(s, 3H), 0.95 ppm (s, 3H).
The 2-guanylacetic acid hydrochloride used in
this Example is prepared from ethyl 2-cyanoacetate in a
manner analogous to that described for the preparation of
25 3-guanylpropionic acid hydrochloride. -
-229-
'."
~.
l()S~99;~
EXAMPLE CXXI I
6-(D-2-[~-Guanidinobenzamido]-phenylacetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam
A mixture of 2.15 g. of p-guanidinobenzoic acid
hydrochloride and 75 ml. of thionyl chloride is heated
under reflux for 18 hours. It is then cooled to 25C , and
concentrated to dryness in vacuo. The residue is washed
thoroughly with ethylene dichloride. This affords 1.7 g.
of p-guanidinobenzoyl chloride hydrochloride.
To a stirred solution of 0.854 g. of 6-(D-2-
amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam
trihydrate and 0.54 ml. of triethylamine in 10 ml. of N,N-
dimethylformamide is added, at oC., 0.468 g. of p-guani-
dinobenzoyl chloride hydrochloride. Stirring is continued
for 30 minutes, and then a further 0.14 ml. of triethyl-
amine and 0.124 g. of p-guanidinobenzoyl chloride hydro-
chloride is added. After being stirred for a further 30
minutes, the reaction mixture is filtered and the filtrate
is added dropwise to 300 ml. of ether. The solid which
precipitates is filtered off, and washed thoroughly with
methylene chloride containing triethylamine. This affords
0.8 g. (75% yield) of the title compound, m.p. 196-200C.
IR (KBr disc): 1770 cm (~-lactam). NMR (in DMSO-d6/D2O):
8.25-7.20 ppm (m, 9H), 6.00 ppm (d, lH), 5.50 ppm (m, 2H),
5.05 ppm (s, lH), 1.50 ppm ~s, 3H), 0.95 ppm (s, 3H).
The preparation of ~-guanldinobenzoic acid i8 ::
described in Rec. Trav. Chim. Pay-Bas, 72, 643 (1952).
. .
-2 3~-
105~99;~
EXAMPLE CXXIlI
-
Reaction of 6-(D-2-amino-2-phenylacetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam or 6-(D-2-amino-2-14-
hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)-
penam with the appropriate acid chloride hydrochloride,according to the procedure of Example CXXII, provides the
following congeners. Acid chloride hydrochlorides are
prepared from the corresponding acids by the method of
Hardcastle et al., Journal of Organic Chemistry, 31, 897
tl966).
l CH3
R -NH ~ ~ CH3
H
. -231- `;
'
,: ','
, :
9~
~a~ o ~ _o o ~ ~~_ o ~ In U) -- ~ U~ O
o u~ o r~
O ~ O
O ~ o _ ~ _ , _ _ , ~ ~ Ir~ _ ~r
~ u ~ u _ m o ~ ~o ~ o _~ _ I P: ~ .
a In ~
~ , ~ O P
u ~ u~ e~ 0
m
l ~ o ~ ~ o ~ ~ ~ ~
O ~ ~ o u~ ~ ~ ~ _ In ~ ~ ~ ~ _ co
U~ ~ O o m . u~
~: ~ ~ -- ~ o ~ U~--
a ~ In ~,, ,,. ~ u~ ,,,. .,
u) ~ ~ ~ ~ $ -~ ~ ~: ~ m U~
O 0~ ~I X ~ ~1 0 ~ Ul _I ~ I 1:~ ~1 (~ I
Q ~ N
---- ~ ~D ~ $
~: ~ ~ F
~ ~ O CO ~_ _ U~
S~ p~ 0 $ E3 --- ~^ ~^
O ~ O
a) ~ o rn ~ m
~1 u~ ~ o ~ o u~
o o ~ o _I ~ o u~ o
I~ ~ -- o ~ o ~ ~ o
~ ~ : -
~ ~--
o ul O In ~ Inu~ t~ ~ I~ ~o ~1 u~
C) I OD OD 00 O~ u~ ~ u~ X co
I` I` I` t` t`' ~I~ U~ t~ U~ t~ U~
H U~ ~
h~ . U~ t~ O ~D00 U~
~c I~ I~ O CO O t~ I_ I~
~ ~ .
~1 ~1 C,) ~ O DO O u~ CO U~ In
a~ o O tD r~ o u~ u~ u~ u~
_I _ I~ I~ ~ In a~ o
~1
O '~ ~1 ~1 0 ~1
~:1 1 0 ~ ~ ~ I ~ O
~ e
C~ ~ U ~ U
~ ~ I o ~I o
U o ~
~d N ~1 I PltJ~ N _
~ u ~1 u I _ la 8 ~ ~, ~ , a) , a~ , ~
a er o ~ ~ zla~~ o ~ o ~ ~ ~ u
~,, ._ ~ ~ ~,, ~ U
o
~ ~u~ 0 al~ ~I h 1l~
O ~ O . , . ~
-23 2- -
I' ~ , . ., ~ ,"
) ou~ ou~ o~
., I ~ P. 00~ 0~D~ 0~ 0 ~ ,`:'' -.'"':
I . ,~
I ~ . . i'"'~
; ~ , j & â ~ L
¦ ' L L ~ L~ I L
i~
213-
., ' ~ " '"''`'''' ' .
lO~gg,~
The acid chloride hydrochlorides used in thi~
Example are prepared from the corresponding acids, using
thionyl chloride. 2-(Guanylureido)acetic acid is prepared
by the method of Frankel and Sheradsky, J. Chem. Soc.
(London), C, 2698 (1967); 2-(p-guanidinophenyl)acetic acid
is prepared by the method of Leanza et al., Nature, 207,
1395 (1965); and 3-guanylpropionic acid is prepared by the
method of McElvain and Schroeder, J. Amer. Chem. Soc., 71,
40 (1949).`
-234- :
-.
105~g9'~ .
EXAMPLE CXXIV
Following the procedure o Example CXXIII and
reacting the appropriate 6-(2-amino-2-substituted-acet-
amido)-2,2-dimethyl-3-(5-tetrazolyl)penam with 2-guanidino-
acetyl chloride hydrochloride, the following compoundsare prepared: .
R7 - f~ CONH CH3 ::
- NH2- = NH . : H
R7 :
methyl
isopropyl
- allyl :
cyclohexyl -
3-cyclohexenyl . . :-
1,-4-cyclohexadienyl ~ -
15 . ~-hydroxyphenyl
~-chlorophenyl -
m-methoxyphenyl
o-fluorophenyl --
. 3,4-dichlorophenyl -~
~-tolyl . . ~:
3-chloro-4-hydroxyphenyl
2-thienyl -;
... .
3-thienyl
2-furyl
3-pyridyl
5-tetrazolyl .-
5-ethyl-2-thienyl
. -235-
,
1()~5~99'~
EXAMPLF' CXXV
6-(D-2-[3-(2-Furoyl)ureido]-2-phenylacetamido)-2,2-
dimethvl-3-(5-tetrazolvl)~enam
To a stirred suspension of 5.0 g. of 6-(D-2-
amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam
in 50 ml. of methylene~chloride is added 2.72 g. of tri-
ethylamine. After 10 minutes, the solution is dried
(Na2SO4), and then it is concentrated to dryness ln vacuo
giving the triethylamine salt of 6-(D-2-amino-2-phenyl-
acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam.
To 948 mg. of the above triethylamine salt, in
10 ml. of methylene chloride, at 0C., is added 274 mg. of
2-furoyl isocyanate dissolved in a small volume of
methylene chloride. After 10 minutes, the solvent is
removed in vacuo. The residue partitioned between ethyl
acetate and water, and the pH is adjusted to 7.7. The
ethyl acetate is removed and discarded. The pH of the
remaining aqueous phase is adjusted to 2.5 and the product
is extracted into ethyl acetate. The ethyl acetate is
washed with water, followed by brine, and then it is
evaporated to dryness in vacuo. The residue is dissolved
in methylene chloride containing 145 mg. of triethylamine -
and again the solution is evaporated to dryness in vacuo. ;
This affords 930 mg. (76% yield) of the title comp~und or -~;
its triethylamine 9alt, mp. 90-115C. (dec.). IR ~XBr
disc): 1778 am~l ~-lactam). NMR (in CDC13): 8.2-7.2
(m), 6.5 (m), 6.0-5.4 (m), 1.7 (s), 1.1 (s).
.
-236-
lOS~9'~
EXAMPLE CXXVI
Uqing the procedure of Example CXXV, and
reacting either 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam
or 6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam with the appropriate acyl isocyanate,acyl isothiocyanate or sulfonyl isocyanate, the following
compounds are prepared
CH3
RlNH ~ H3 :
- ~ \ ~N ~ -~
H
'
- ',
''-'. :',
'",.-''-
' ` '
' ,. ~.'. -
.....
.. : ~.
:':
.:
. . :.
-237-
. ~ . ' ~ .
lOS999'~
~ ~D O Ln r~
U~
g _ ~ ~ o o m _ ~o
, ~ n e ^
~ ~ ~ In
~1 ~ O
$ ~ ~ 1 0
P _-- m ~
P 0 ~ m
. ~ e ^ -
.~ ~ ~ e-- ` t` -- -- m ~ o
~ ~ ~ . O
e
~ ~ m ~ m
_ ~ ,_ m ~ e m
3 oo a~ N _ ` `- ` ~ e
m ~q ~ m
_~ ~1 o~ ~ ~ m
P ~ ^ e,~ e- e e I ~ e,~
m ~ e ~ m
~r ~ ~ er co ~ o ~ ~D ~ ~ ~ O-- I` ~ ~ ~ I~ I` ~
.. .. . ~q .. . ~ - m . m m
O ut U~ ~ O U~ O O O ut U~ O O O U~ O
CO O~ co x x ~ o . -
0 1 In ln o o o ~ o o o o ul U~ o o o u~ o o o o o ;,
CO et' 0~ co o ~ ~ a~ ~ o
~1 ~ ~ ~ ,,~ ~ .
P~ 1 10 ~ I I O --I O -1 0
~ ~ ~ a ~ a ~ O ~ 0 ~
I ~ o
o ~ o ~
U ~ 1 ~ 1 o ~ ~I
P ~ a ,~ R a R ~ a a
~ ~ N ~ I p,.~ I J~ I
~ I I a ~ o ~ ~ I I I R U I ~1 1 1
O :~ U ~ U U ~ ~ ~
(~ o .4 --o --~ o P. ~ o ~ o .a ~ o
* * # OJ# ~ * # # Qj* # `# #
~ ~ -238- `
'':
;
,, .
~ .
.
lOS~99Z
u~ ~ o
~r :d
` ~ `
_ In_ I I
tn muq
", ~ m
~ ~ ~ m m --
_U~
u~
O
U~ o
-- m o o --~ .
_P ~ o ~ ~ ~ ~ ~,g , ,
~ O ~r
o -, ,.
~ '~ ` ~
O ~ o ~
I rl ". ,,
~ ~ , " ~
3 ~_ 5~ _I __ I I u) ` ` oq
_ ~ ~ 7 o CD -- ~ ' `' "'
~ u~ n O o _l ~
u~ a~ ~--O ~ ,I t~ ~ _ ~ ~_ ~1 ,,
~ I "
~ ~ o o 5~ m o
X _ _ co_I _I ~ ~ ~ ~o . - ~, ^:
m
~ m 5~ e . ~ e ~ F?,--
_ ~ ,e, _
~ I` O CO ~r ~
o ~ o Oq ~
o .. -
In U~ Inn o o u~ U :
~3 e o~
~ O I o u~~ o o o o o E~
~ v ,e a~ ~ 00
H ~n--~
'~1 ' .'
Q~--co o _I ~ o a~
-~
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~ ~o ~o
~ o ~ o l ~ ~ `
~ ~ u ~
2 I N I ~ 0 al O ~ O ,L;
~:1 o :1 ~t~ 1::~ a~ ~,q o ~ .
S1 ~ O I I ~ I U~ U~ ~ ~ "
~1 ~ O --~ O --~ O ~ ~ ~ U ~1 U ~ , . .
U
I I I ~ I h ~ `J I 0,~ S
I t~ N
~ ` ` '. ~
.
:..
, :
105~99~
EXAMPLE CXXVII
Using the procedure of Example CXXV, and
reacting 6-(2-amino-2-substituted-acetamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam or 6-(2-[2-amino-acetamido]-2-sub-
stituted-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam
with the appropriate acyl isocyanate, provides the
following compounds.
R - CH CONH f 3
NH ~ CH3
CO 0~ ~C~ ~ ;;' '~
~H2 + ~ ` ~' .
~ 1H (CH3CH2) 3NH ,: . ~
1o
7 ~ :
R Z m
10 methyl 2-furancarboxamido O
methyl benzamido O
isopropyl acetamido O
isopropyl 2-furancarboxamido
phenyl p-chlorobenzamido O
15 phenyl m-bromobenzamido O
phenyl o-fluorobenzamido O
phenyl 3, 4-dichlorobenzamido O
phenyl p-methoxybenzamido O
phenyl m-n-butoxybenzamido O
20 phenyl ~ 3,4-dimethoxybenzamido O
phenyl p-isopropylbenzamido O
:~ ~-hydroxyphenyl 2-furancarboxamido O
p-hydroxyphenyl benzamido O :
p-chlorophenyl propionamido o
` -240-
.' '
' ` :
~()s~9~
R7 Z m
_
m-methoxyphenyl 3,4-dichlorobenzamido O
~-tolyl 2-thiophenecarboxamido O
3,5-dichlorophenyl 3-thiophenecarbo~id~ 0
3-chloro-4-hydroxy- 2-furancarboxamido O
phenyl
3-chloro-4-hydroxy- benzamido O
phenyl
2-thienyl 2-furancarboxamido O
10 2-thienyl benzamido O
3-thienyl p-chlorobenzamido O
3-thienyl n-butyramido O
2-furyl 3-furancarboxamido O
3-furyl p-iodobenzamido O
15 3-pyridyl . benzamido o
1,4-cyclohexadienyl 2-furancarboxamido O
methyl benzamido
phenyl 2-furancarboxamido l
~-hydroxyphenyl 3,5-dichlorobenzamido
20 3-chloro-4-hydroxy- benzamido 1
phenyl
2-thienyl 2-furancarboxamido
3-thienyl benzamido
25 3-chloro-4-hydroxy- acetamido Q
phenyl
p-chlorophenyl propionamido O
2-thienyl n-butyramido O
3-furyl
30 isopropyl n-hexanoyl O
phenyl isobutyramido O
phenyl acetamido 1
~-hydroxyphenyl propionamido
-241-
:-
:
105~9~'~
EXAMPLE CXXVIII
6-(D 2-[4-Aminobenzamido]-2-phenylacetamido)-2,2-dimethyl-
3-(5-tetrazolYl)~enam
_ . .,
A solution is prepared by suspending 1.05 g. of
6-(D-2-[4-nitrobenzamido]-2-phenylacetamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam in 50 ml. of water, and adjusting
the pH to 7.3 using sodium bicarbonate solution. To this
solution is then added 1.0 g. of 10% palladium on carbon,
and the mixture is shaken under an atmosphere of hydrogen,
at a pressure of ca. 40 psi, until hydrogen uptake ceases.
The spent catalyst is removed by filtration, and the
aqueous solution is lyophilized. This affords 0.91 g. of
crude product. A portion of the crude product is purified
further by column chromatography using Sephadex LH-20 and
eluting with water. The purified product has mp 260-272C.
IR(KBR disc): 1770 and 1626 cm . NMR (D2O): 7.6-7.0
ppm (m, 7H), 6.5 ppm (d, J-9Hz, 2H), 5.6-5.4 ppm (m, 3H),
5.2 ppm (s, lH), 1.4 ppm (s, 3H), and 0.88 ppm (s, 3H).
-242- -~
:
; .
lOS~9'~
EXAMPLE CXXIX
6-(D-2-[2-(4-Aminophenyl)acetamido]-2-phenylacetamido~-2,-
2-d~methyl-3-(5-tetrazolyl)penam _ _
The title compound is prepared in 23% yield by
hydrogenation of 6-(D-2-[2-(4-nitrophenyl)acetamido]-2-
phenylacetamido) -2~ 2-dimethyl-3-(5-tetrazolyl)penam, using
the procedure of Example CXXVIII. The product has mp
260-270Co (dec.). IR(KBr disc): 1770~ 1653 and 1515 --
cm . NMR (2) 7.6-6.8 ppm (m), 5.6 ppm (m), 5.2 ppm
(s), 3.4 ppm (sl, 1.3 (s) and 0.8 ~s).
':
.
` -243-
105999'~
EXAMPLE CXXX
6-(~-2-Hydroxy-2-phenylacetamido)-2,2-dimethyl-3-(5-tetra-
zo y penam
A mlxture of 0.152 g of L-mandelic acid, 0.115 g
of ~-hydroxysuccinimide and 0.206 g of N,N-dicyclohexy-
carbodiimide in 10 ml of tetrahydrofuran in a 25 ml flask,
is stirred at ambient temperature overnight. In a
separate flask, 0.216 g of 6-amino-2,2-dimethyl-3-t5-tetra-
zolyl)penam and 0.23 ml of triethylamine in 10 ml of
chloroform and 10 ml of methylene chloride is stirred
overnight. The mixture in the first flask is then fil-
tered, and the filtrate is added slowly to the second
flask. The resultant mixture is stirred for 4 hours at
ambient temperature. The solvents are then removed by
evaporation in vacuo, and the residue is partitioned
between ethyl acetate and water. The pH is adjusted to
4.7 (lN sodium hydroxide), and then the organic phase is
withdrawn and discarded, The pH of the aqueous phase is
then reduced to 2.0 (5% hydrochloric acid), and the product
is extracted with ethyl acetate. The solvent is washed
with dilute hydrochloric acid followed by brine, dried ~-
using anhydrous sodium sulfate, and then it is added drop-
wise with stirring to 400 ml of hexane. The precipitate -
which forms is filtered off, giving 170 mg of 6-(L-2-
hydroxy-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)
penam. NMR (in DMSO-d6): 8.16 ppm (broad singlet, lH, Oa),
7.47-7.04 ppm (multiplet, 6H, aromatic protons and NH).
5.73-5.50 ppm (multiplet, 2H, C-5 and C-6 hydrogens), 5.31
and 5.07 ppm (2 singlet, 2H, C-3 hydrogen and side-chaln
methine hydrogen), 1.67 and 1.10 ppm (2 singlets, 6H, C-2
methyl hydrogens).
-244-
105~99'~
EXAMPLE CXXXI
6-~D-2-Hydroxy-2-phenylacetamido)-2,2-dimethyl-3-t5-tetra-
zolyl)penam
The procedure of Example CXXX is repeated, except
that the L-mandelic acid used therein is replaced by an
equivalent amount of D-mandelic acid. This affords a 77%
yield of the title compound. NMR (in DMSO-d6): 8.40-8.20
ppm (broad doublet, lH, NH), 7.48-7.18 ppm (multiplet, 6H, -
aromatic hydrogens and OH), 5.31 and 5.07 ppm (2 singlets,
2H, C-3 hydrogen and side-chain methine hydrogen), 1.65
and 1.07 ppm (2 singlets, 6H, C-2 methyl hydrogens).
-245-
:: .
.
10~9,~
EXAMPLE CXXXII
6-(2-Carboxy-2-phenylacetamido)-2,2 dimethyl-3-(5-tetra-
zolyl)penam
To a stirred solution of 150 mg of 6-amino-2,2
dimethyl-3-(5--tetrazolyl)penam in 5 ml of water is added
dropwise dilute sodium hydroxide to give a pH of 6.1. To
this solution is then added 150 mg of phenylmalonic acid,
followed by 120 mg of 1-ethyl-3-(3-dimethylaminoprop-1-yl)
carbodiimide. The solution is stirred for a further 3.5
hours, during which time the pH is maintained in the range
from 6.1 to 6.3 by the dropwise addition of dilute hydro-
chloric acid. At this point, the pH is raised to 7.3 by
the addition of saturated sodium bicarbonate ~olution, and
the reaction mixture i~ extracted with ethyl acetate. The
extract is discarded. The aqueous phase is then acidified
to pH 2 using dilute hydrochloric acid, and it is again
extracted with ethyl acetate (two 30-ml portions). The
latter extract is dried, and concentrated to a volume of
about 25 ml. To this solution i8 then added a solution of
20 180 mg of sodium 2-ethylhexanoate in 1.25 ml of ethyl
acetate. The precipitate which forms is filtered off to
give 176 mg of the disodium salt of 6-(2-carboxy-2-phenyl-
acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The in-
frared spectrum of the product (XBr disc) shows absorptions
25 at 1765 om 1 (3-lactam carbonyl), 1670 cm 1 (amide I band)
and 1600 cm 1 (carboxylate carbonyl). The NMR spectrum
(in D2O) shows absorptions at 7.40 ppm (broad singlet,
aromatic hydrogens), 5,70 ppm (doublet, C-5 hydrogèn), 5.50
ppm (doublet, C-6 hydrogen), 5.25 ppm (2 singlets, C-3
30 hydrogen), 1.50 ppm ~2 singlets, C-2 m~thyl hydrogens) and
0.95 ppm ~2 singlets, C-2 methyl hydrogens).
-246-
. ~.
1055~5~9~
EXAMPLE CXXXI I I
-
Following the procedure of Example CXXXII, and
replacing the phenylmalonic acid used therein by an
equimolar amount of the appropriate 2-substituted malonic
acid, there is produced
6-(2-carboxy-2-[2-furyl]acetamido)-2,2-dimethyl-
3-(5-tetrazolyl)penam,
6-(2-carboxyvaleramido)-2,2-dimethyl-3-(5-tetra-
zolyl)penam,
6-(2-carboxy-2-[p-chlorophenyl]acetamido-2,2-
dimethyl-3-(5-tetrazolyl)penam,
6-(2-carboxy-2-[~-tolyl]acetamido-2,2-dimethyl-
3-(5-tetrazolyl)penam, -.
6-(2-carboxy-2-11,4-cyclohexadienyl]acetamido-2,~
2-dimethyl-3-(5-tetrazolyl)penam, . ~
6-(2-carboxy-2-cyclohexylacetamido)2,2~dimethyl- : .
- 3-(5-tetrazolyl)penam and
6-(2-carboxy-3-phenylpropionamido)2,2-dimethyl-
3-(5-tetrazolyl)penam, ~ .
respectively.
~ ` ' ' `
~... ,
~ .
lOS999'~
EXAMPLE CXXXIV
6-(2-Carboxy-2-[2-thienyl]acetamido)-2,2-dimethyl-3-(5-
tetrazolvl)~enam
To a stirred suspension of 370 mg (0.002 mole)
of 2-(2-thienyl)malonic acid (Netherlands Patent No.
6805524) in 4 ml. of water is added 480 mg. (0.002 mole) of
6-amino-2,2-dimethyl-3-(5-tetrazolyl~penam, and then the
pH is adjusted to 6.5 using 20% sodium hydroxide. The
resulting clear solution is cooled to 0C, and 384 mg.
(0~002 mole) of 1-ethyl-3-(3-dimethylaminopropyl)carbo-
diimide hydrochloride is added. The solution is stirred
for 3.5 hours at 0C, wîth the pH maintalned between 6 and
7 using lN hydrochloric acid. At this point, the pH of
the solution is then lowered to 2.0 and the mixture is
extracted with ethyl acetate. The extracts are combined, ~ -
dried and then concentrated to ca. 15 ml. To this solution
is added a solution of 665 mg (0.040 mole) of sodium 2-
ethylhexanoate in 2.6 ml. and then the solid which pre-
cipitates is filtered off, and dried, to give 462 mg.
(51% yield) of 6-(2-carboxy)-2-[2-thienyl]acetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam as its disodium salt. The
infrared spectrum of the product (KBr disc) shows
absorption bands at 1780 cm 1 (~-lactam), 1670 cm 1 (amide
I), 1615 cm (carboxylate) and 1560 cm 1 (amide II). The
NMR speCtrUm (in D2O) shoWs absorptions at 7.50-7.1 ppm
~multiplet, thienyl hydrogens), 5.90 ppm (doublet o~
doublets, C-6 hydrogen), 5.65 ppm (doublet, C-5 hydrogen),
5.40 ppm (doubIet, C-3 hydrogen), 1.68 ppm (doublet, C-2 ~-
- .
methyl hydrogens~ and 1.00 ppm (doublet, C-2 methyl
hydrogens). --
.`:
-248-
,~
:~-
105~9g;~
EXAMPLE CXXXV
6-(2-Carboxy-2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam _ _
Reaction of 500 mg. (2.69 mmole) of 2-(3-thienyl)
malonic acid (British Patent No. 1,125,557) with 645 mg.
(2~69 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, -
according to the procedure of Example LXXXIV, affords 810
mg. (67% yield) of 6-(2-carboxy-2-[3-thienyl]acetamido)-2,-
2-dimethyl-3-(5-tetrazolyl)penam as its disodium salt. The
infrared spectrum of the product ~Br disc) shows absorp-
tions at 1775 cm (~-lactam), 1670 cm (amide I), 1620
cm 1 (carboxylate) and 1525 cm (amide II). The NMR
spectrum (D2O) shows absorptions at 7.80-7.00 ppm
(multiplet, thienyl hydrogens), 5.88 ppm (doublet, C-6
hydrogen), 5.65 ppm (doublet of doublets, C-5 hydrogen),
5.40 ppm (doublet, C-3 hydrogen), 1.60 ppm (doublet, C-2
methyl hydrogens) and 1.00 ppm (doublet, C-2 methyl
hydrogens).
-249-
lOS~99Z
E~AMPLE CXXXVI
6-(2-Sulfo-2-phenylacetamido)-2,2-dimethyl-3-(5-tetra-
zolvl)~enam
,. _ . .
To a stirred slurry of 240 mg. of 6-amino-2,2-
dimethyl-3-(5-tetrazolyl)penam in 5 ml. of methylene
chloride is added 0.254 ml of triethylamine. This is
stirred for a further 45 minutes, and then it is cooled to
about 0C. To it is then added a solution, in 6 ml. of
methylene chloride, of 389 mg. of the mixed carbonic-
carboxylic anhydride formed by reacting the bis-triethyl-
amine salt of 2-sulfo-2-phenylacetic acid with one equiv-
alent of ethyl chloroformate (Nicolaus, et al., Annali di
Chimica [Rome], 53, 14 [1963]). The reaction mixture is
then stirred at about 0C. for a further 1.5 hours after
the addition of the anhydride salution. At this point, the
reaction mixture is filtered and then a solution of 288 mg
of sodium 2-ethylhexanoate in ethyl acetate is added. The
precipitate which forms is filtered off, giving the crude
-prodiuct as its disodium salt. The crude product is
purified by dissolving it in water and adding the solution
: to a column of 25 g of Sephadex LH-20 (Pharmacia Fine
Chemicals, Inc.) made up in water. The column is eluted
with water, taking fractions, and the composition of the ~ -
fractions is assayedi by thin-layer chromatography. The
fractions containlng the pure product are combined and
lyophiIized, giving 117 mg. of the disodium salt of 6-(2- -
sulfo-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)-
penam. The infr~ared spectrum (~Br disc) of the product
shows absorptions at 1765 cm (~-lactam carbonyl) and
1660 cm 1 (amide I band). The NMR spectrum (in D2O) shows --
absorptions at 7.60-7.-20 ppm (multiplet, aromatic
-; ~.
10~99;~
hydrogens), 5.70 and 5.50 ppm (2 multiplets, C-5 and C-6
hydrogens~, 5.20 ppm (multiplet, methine hydrogen), S.00
ppm (singlet, C-3 hydrogen), 1.50 ppm (2 singlets, C-2
methyl hydrogens) and 0.95 ppm (2 singlets, C-2 methyl
hydrogens).
EXAMPLE CXXXVII
- 6-(2-[5-Indanyloxycarbonyl]-2-phenylacetamido)-2,2-
dimethyl-3-(5-tetrazolyl)-penam
Reaction of 592 mg. (2.0 mmole) of 5-indanyl 2-
phenylmalonate with 480 mg. (2.0 mmole) of 6-amino-2,2-
dimethyI-3-(5-tetrazolyl)penam, according to the procedure
of Example CXXXIV, affords 680 mg. (63% yield) of 6-(2-[5-
indanyloxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam as its sodium salt. The infrared spectrum
(KBr disc) of the product shows absorption bands at 1780
cm (~-lactam), 1705 cm (ester), 1680 cm 1 (amide I) and
1565 cm (amide II). The NMR spectrum (D2O) shows
absorption bands at 7.80-6.80 ppm (multiplet, aromatic
hydrogens), 5.70 ppm (multiplet, C-5 and C-6 hydrogens),
5.25 ppm (doublet, C-3 hydrogen), 2.60-2.00 ppm (multiplet,
C-l and C-3 indanyl hydrogens), 2.00-1.80 ppm (multiplet,
C-2 indanyl hydrogens), 1.35 ppm (doublet, C-2 methyl
hydrogens) and 0.90 ppm (doublet, C-2 methyl hydrogens).
-251-
... , . ~ ,. . ~ . . .. . ,- ~ . -- , .. . .... .. . . . .
lV55~99~
EXAMPLE CXXXVIII
6-(2-Phenoxycarbonyl-2-phenylacetamido)-2,2-dimethyl-3-
(S-tetrazolyl)penam
A stirred solution of 1.80 g of phenyl chloro-
carbonyl ketene (United States Patent No. 3,679,801) in 20
ml. of chloroform is cooled to -40C, and then 0.94 g of
phenol is added. Stirring is continued at -40C. for a
further 20 minutes, and then a solution of 2.40 g. of 6-
amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 1.40 ml of
triethylamine in 50 ml. of chloroform is added dropwise.
The cooling bath is removed, and the mixture is stirred for
a further 30 minutes. The mixture is filtered, and the
chloroform is evaporated in vacuo to give crude 6-(2-
phenoxycarbonyl-2-phenylacetamido)-2,2-dimethyl-3-(5-tetra-
zolyl)penam, as its triethylamine salt.
-252- ` -~
105~99~
EXAMPI,E CXXXIX
-
The procedure of Example CXXXVIII is repeated
except that the phenyl chlorocarbonyl ketene used therein
i5 replaced by an equimolar amount of ~-chlorophenyl
chlorocarbonyl ketene, 2-furyl chlorocarbonyl ketene and
3-thienyl chlorocarbonyl ketene, respectively. There is
produced:
6-(2-phenoxycarbonyl-2-[P-chlorophenyl]acet-
amido)-2,2-dimethyl-3-(5-tetrazolyl)penam,
6-(2-phenoxycarbonyl-2-[2-fur.yl]acetamido)-2,2-
dimethyL-3-(5-tetrazolyl)penam, and
6-(2-phenoxyoarbonyl-2-[3-thienyl]acetamido)-2,-
2-dimethyl-3-(5-tetraz-olyl)penam,
respectlvely.
When the proce:dure of Example CXXXVIII is
repeated, and the phenol used therein is replaced by an
equimolar amount of the appropriate substituted phenol,
the products are: -
6-(2-[m-methoxyphenoxycarbonyl]-2-phenylacet--
amido)-2,2-dimethyI-3-(5-tetrazolyl)penam,
6-(2 -EmethyIphenoxycarbonyl]-2-phenylacetamido)- .
2~2-dimethyl-3-(5-tetrazolyl)penam,.
6-(2-[5-indanyloxycarbonyl]-2-phenylacetamido)-
2,2-dimethyl-3-(5-tetrazolyl)penam,
6-(2-[~-nitrophenoxycarbonyl]-2-phenylacetam~do)- .
2,2-dimethyl-3-(5-tetrazolyl)penam,
6-(2-lm-bromophenoxycarbonyl]-2-phenylacetamido)-
2,2-dimethyl-3-(S-tetrazolyl)penam,
6-~2-~o-fluorophenoxycarbonyl]-2-phenylacet-
amldo)-2,2-dimethyl-3-~5-tetrazolyl)penam
6-~2-[~-cyanophenoxycarbonyl]-2-phenylacetamido)-
2,2-dimethyI-3-~5-tetrazolyl)penam, and
6-~2-13,4-dichlorophenoxycarbonyl]-2-phenylacet-
amido)-2,2-~dimethyl-3-~5-tetraz-olyl)penam.
,
~' ~oss`~g;~
EXAMPLE CXL
6-(2-Carbamoyl-2-phenylaCetamido)-2,2-dimethyl-3-(5-tetra-
zolyl)penam
To a stirred solution of 523 mg. ~0.001 mole) of
6-(2-[p-nitrophenoxycarbonyl]-2-phenylacetamido)-2,2-di-
methyl-3-(5-tetrazolyl)penam and 101 mg of triethylamine in
50 ml. of chloroform i9 added 1 ml of a lM solution of
ammonia in methanol,-at -30C. Stirring is continued for
4 hours without external cooling and then evaporation in
vacuo leaves the crude product as its triethylamine salt.
,
-,
,~,...
;~ ~ ~ '''''` ''.
~ ~ ` -254- ~
: ' ' '''' ''.
, . . .
1()5~9~
EXAMPLE CXLI
6-(D-2-sulfoamino-2-phenylacetamidO)-2,2-dlmethyl-3-(5-
tetrazolyl)penam
To a stirred suspension of 2.13 g. (0.005) mole
of 6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-
tetrazolyl)penam in 50 ml. of methylene chloride is added
0.84 ml. (0.006 mole) of triethylamine. The mixture is
stirred until most of the solid dissolves. To this
solution is then added approximately 2 g. of pulverized
Linde 4A molecular sieves, and stirring is continued for
an additional one hour. The molecular sieves are removed
by filtration, and the filtrate is coaled to 0CO To this
cooled solution is added, portionwise, over 5 minutes,
0.84 g. (0.006 mole) of trimethylaminesulfur trioxide
complex. The solution is stirred at 0C. for 5 minutes,
and then at ambient temperature for 2.25 hours. A solution
of 2.5 g. of sodium 2-ethylhexanoate in 10 ml. of
l-butanol is then added. The resulting precipitate is
filtered, dissolved in 20 ml. of water and cooled to 0C.
The pH of the reaction is adjusted to 5O0 (glacial acetic
acid) and the resulting cloudy solution is stirred for 1
hour-. After filtration through diatomaceous earth, the
filtrate ls added dropwise with stirring to 700 ml. of cold
(0C.) acetone. The resulting precipitate i9 collected,
and dried, to yield 1.80 g. (65.3~ yield) of 6-~D-2-sulfo-
amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)-
penam as its disodium salt. The infrared spectrum
(KBr disc) shows absorptions at 1770 cm (~-lactam), 1660
cm 1 (amide I) and 1550 cm (amide II). The NMR spectrum
(D2O) shows absorptions at 7.46 ppm (S, 5H aromati~
hydrogens), 5.64 ppm (q, 2H, C-5 and C-6 hydrogens),
-255-
105~9~'~
5,33 ppm) S, lH, methine hydrogen), 5.10 ppm (S, lH, C-3
hydrogen), 1.58 ppm (s, 3H, C-2 methyl hydrogens) and 1.00
ppm (S, 3H), C-2 methyl hydrogen~). [X]25 = 108 (H2O).
A~y~ - Calcd. for C1 H 7N7O5S2Na2 (percent): C, 34.85;
6 1
H, 4.20; N, 17.78; S, 11.63. Found: (Percent): C, 35 02;
H, 4.31; N, 17.82; S, 11.91.
EXAMPLE CXLII
Reaction of the appropriate 6-(2-amino-2-sub-
stituted-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam with
the sulfur trioxide-trimethylamine complex, according to
the procedure of Example CXLI, provides the following -
compounds:
SO3H ~ N~ ;
HN _ N ~-
R7 ;
methyl
isopropyl --
cyclopentyl -
3-cyclohexenyl -
1,4-cyclohexadienyl -
benzyl
p-chlorobenzyl
~-hydroxyphenyI
m-methoxyphenyl
m-bromophenyl
o-fluorophenyl
p-tolyl
3-chloro-4-hydroxyphenyl
3,4-dichlorophenyl
3,4-dimethoxyphenyl
2-thienyl
3-thienyl
2-furyl
3-pyridyl -256-
. .
,;
lOSg99;~
EXAMPLE CXL I I I
-
6-(D-2-~Carboxymethoxy]acetamido-2-phenylacetamido)-2,2-
dimethyl-3-(5-tetrazolvl)~enam
.. ...
To a stirr~d solution of 2.59 g. (6.0 mmole) of 6-(D-2_
amino-2-phenylacetamido)-2,2-dimethyl 3-(5-tetrazolyl)penam
trihydrate and 1.70 ml. (12.2 mmole) of triethylamine in
70 ml. of methylene chloride, at 0-5Co, is added a solu-
tion of 1.40 g. (12.0 mmole) of diglycolic anhydride in 30
ml. of methylene chloride. The solution is stirred at ;-
0-5C. for 1 hour and then it is extracted with 200 ml. of
10% sodium bicarbonate solution. The pH of the aqueous
phase is adjusted to 2.0 and the product is extracted into
ethyl acetate. The solvent is dried (MgSO4), and then
concentrated in vacuo, to give 820 mg. (28~ yieLd) of the
title compound. IR (KBr disc): 1780 cm 1 (~-lactam) and
1650 cm (amide I). NMR (in DM5O-d6): 7.41 ppm (m, 5H),
5.55-5.90 ppm (m, 3H), 5.24 ppm (S, lH), 4.17 ppm (S, 2H),
4.10 ppm (s, 2H), 1.57 ppm (s, 3H), 0.99 (s, 3H)o
. . .
-257-
1055~S~9~ :
EXAMPLE CXLIV
6-(D-2-14-Carboxy-2,3-propionamido]-2-phenylacetamido)-2,-
2-dimethyl-3-(5-tetrazol-5-yl)penam
The title compound i9 prepared in 73% yield from
6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetra-
zolyl)penam and epoxysuccinic anhydride, using the method
of Example CXLIII. IR (RBr disc): 1790 cm (~-lactam)
and 1665 cm (amide I). NMR (in DMSO-d6): 7.42 ppm
(m, 5H), 5.55-5.85 ppm (m, 3H), 5.27 ppm (s, lH), 3.87 ppm --
(s, 2H), 1.60 ppm (s, 3H), 1.02 ppm (s, 3H).
-258-
~(~5~
EXAMPLE CXLV
6-(2-[2-(Carboxymethyl)phenyl]acetamido)-2,2-dimethyl-3-
(5-tetrazolvl)~enam
An ice-bath cooled, stirred mixture of 1.94 g
(10 mmol) of o-phenylenediacetic acid, and 60 ml. of water
is adjusted to pH 5.5 by the careful addition of 6N sodium
hydroxide. The resulting solution is treated with 1.92 g
(10 mmiol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride and stirring is continued for 30 minutes,
with the pH being maintained at 5.5 by the addition of 6.ON
hydrochloric acid. A solution consisting of 2.4 g. (10
mmol) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 30
ml. of water (adjusted to pH 7) is added to the first
mentioned solution and stirring and cooling is continued
for an hour. The aqueous solution is washed three times -~
with 30 mI. portions of ethyl acetate, and is then
adjusted to pH 2.5 with 6N hydrochloric acid. This
solution is extracted twice with 40 ml. portions of ethyl -
acetate, and the combined extracts are washed with 50 ml. - -
of water. After being dried over anhydrous s~dium sulfate,
the extract is evaporated under reduced pressure to :
furnish a colorless foam: yield 3 g. The foam is
dissolved in 50 ml. o ethyl acetate and then it is treated
with 2.4 g. (14.5 mmol) of sodium 2-ethylhexanoate in 30
ml. of ethyl acetate. The title compound precipitates as
the 90dium salt: ~ield 3.4 g (74%) IR ~XBr) 1770, 1667,
and 1587 cm NMR (D2O): 7.25 ppm (s, 4H), 5.70 (d, lH),
5.40 (d, lH), 5.25 (s, lH), 3.70 (s, 2H), 3.60 ~s, 2H),
1.50 (s, 3H), 1.00 (s, 3H).
-259-
- :'
9'~
EXAMPLE CXLVI
6-(2-Acetyl-2-phenylacetamido)-2,2-dimethyl-3-(5-tetra-
zolvl)~enam
To a solution of 700 mg (3.92 mmole~) of 2-
5 carboxy-3-phenyl-2-propanone in 35 ml. of dry tetra-
hydrofuran is added 453 mg (3.92 mmoles) of N-hydroxy-
succinimide (dissolved in a small portion of dry tetra- -~
hydrofuran), followed by 811 mg. (3.92 mmoles) of ~
dicyclohexylcarbodiimide dissolved in a small portion of ; ;
10 dry tetrahydrofuran. The reaction mixture is allowed to -
stir at room temperature for approximately three hours.
The reaction mixture is then filtered and the yellow ~--
filtràte is added dropwise, with stirring, to a cooled - ~`-
(0C) solution of 720 mg. (3 mmoles) of 6-amino-2,2-
dimethyl-3-(5-tetrazolyl)penam and 606 mg. of triethylamine
in 15 ml. of methylene chloride. The result~ng solution is
stirred for 45 minutes, and then the solvent is removed by
evaporation in vacuo. To the residue is added 50 ml. of
water and 50 ml. of ethyl acetate, and the pH is adjusted
to 7.8 using sodium bicarbonate solution. The ethyl
acetate layer is-removed and discarded. To the aqueous
phase is added a further quantity of ethyl acetate and the
pH is adjusted to 2.5.
The ethyl acetate is removed, washed with water,
washed with sodium chloride solution, and then dried using
anhydrous sodium sulfate. To the dried solution i~ added
0.4~2 ml. (3 mmole) of triethylamine, and then the æolvent
is removed giving the title compound as its triethylamine
salt. The yield is 540 mg. (36%). IR (CHCI3 solution): -
1780 cm . NMR (CDC13): 7.6-7.2 ppm (m, 5H), 6.0 - 5.6
(m, 4H), 5.4 ppm (s, lH~, 3.4-3.1 ppm (q, 6H), 2.2 ppm
-260-
105~9'~
(s, 3H), 1.8 ppm (s, 3H), 1.6-1.3 tm, 9H) and 1.0 ppm
(s, 3H).
EXAMPLE CXLVII
6-Phenylpyruvamido 2,2-dimethyl-3-(5-tetrazolyl)penam
To a stirred solution of 960 mg. (4 mmole) of
6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 1.2 g.
(12 mmole) of triethylamine-in 20 ml. of methylene
chloride, is added a solution of 728 mg. (4 mmole) of
phenylpyruvoyl chloride in 5 ml. of methylene chloride, at
0C. The co~ling bath is removed, and when the reaction
mixture has attained room temperature, the solvent i~
removed by evaporation in vacuo. The residue is -
partitioned between ethyl acetate and water, the pH is --
adjusted to 7.8, and then the ethyl acetate layer is
separated and discarded. The pH of the residual aqueous ~ :
phase is adjusted to 2-5! and the product is extraoted into
ethyl acetate. The ethyl acetate is washed with water,
followed by brine, and then dried using sodium sulfate.
To the ethyl acetate is added 404 mg. of triethylamine, and
then the solvent is evaporated to dryness in vacuo. This
affords 1.26 g. (65% yield) of the title compound as its
triethylamine salt. IR (KBr disc): 1760 and 1670 cm
NMR (in CDC13): 7.4-7.0 ppm (m, 5H); 6.0-5.2 ppm (m, 3H),
3.6 ppm (s, 2H), 1.6 ppm (s, 3H), 1.1 ppm (5, 3H).
-261-
105~9'~
EXAMPLE CXLVIII
Following the procedure of Example CXLVII, and
reacting either 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam
or 6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam with the appropriate acid chloride, the
following compounds are prepared~
Rl_NH S CH3 ~ :.
~ ~ CH3
~7 ;''''''',.
+ -N .
. (CH3CH2)3NH
., , ,:
'.
. - .
'.
` -262-
~ ,
105999
u~
-- , ~
O ~D u
o o o ~., ~,
, ~ o
,, ~ _ ~ a~
o U~ o
,, -- uq m
~ O ~ I ~ ~
~ " O ~ e o ' '
t,q ~1 o ~~
00 _ ~ o o ~,
_ _ o
~n ~ ~ ~ _
o ~ ,
.o ~ ~ bq ~ e
.~_I tn ~ ~ O
-- O ~r 1` o~ o ~
I ._ _ O
U_ ~7 o
C~Ul _ ~ O
~ ~ q _ o 1` '` `
_ r~ - ~ _ _e ul O
o
_ O
~ ~ ~ e ~ n ~
~q O _ O ~O ~ u~ o
o~ oco o o o-- ~
~CD I-- ~I ~
~n . O ~ _ CD ` ` ' ~ `
u~ oCO ` __ ~,q O 6q
p ou~
o
o
e ~, e.~ n e
r In~ N It~ N ~ l N ~ u~
O OOO _~ O O O _ ~. _ ,
oo o ~nO :~ ~ O O ~ ~ Ul ~ :
O _ ~ ~ ~ O L~
~ - .
O O O O O O O U~ O O ~1
_I ~' I` O r~
o I o 11~ Is) In o ~) o u~ O U~
q~ a) e ~ 0 ~0 co
~ ~ .
' O m ,.
~ _ ' ' O U~ I` 000 0 U~ ~ rl '
:: : l o
~ ' e ~
~a n ~ a.~ I ou ~
U A $
~ U ~ '~ : "
o ~ a) o a~ ~ ,q u
P~ h
`: 5 ~ 2 ~ N ~
O N ~ ~ $Q, .~ g ~ ,, p - -
U ~ 0 ~ 0 ~ 0 ~ "
2 6 3--
~ , . . .
:: :
.,
lOS~
EXAMPLE CXLIX
6-(D-2-[2-carboxy-3-(2-thienyl)acrylamido]-2-phen
acetamido)-2,2-dimethvl-3-(5-tetrazolYl)Penam
To 20 ml. o~ water at ca. 0CO~ is added 0.99 g.
(S mmole) of (2-thienyl)methylenemalonic acid followed by
1.86 g. (5 mmole) of 6-(D-2-amino-2-phenylacetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penam, and the pH raised to 7.7.
When a clear solution is obtained, the pH is lowered to
6.0, and 0.96 g. (5 mmole) of 1-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide is added. The mixture is stirred ~`
at ca. 0C. for 3 hours, with the pH being maintained at
6.0 by the addition of 6N hydrochloric acid. At this
point, the pH is again raised to 7 7, and the reaction
mixture is extracted with ethyl acetate. The extracts are
discarded, and the residual aqueous phase is acidified topH 2.6. The product is extracted into ethyl acetate, and
then the extract is treated with 1.4 ml. (10 mmole) of
triethylamineO The solvent is removed by evaporation in
vacuo, which affords 1.8 g. (55% yield) of the title com-
20 pound as its triethylamine salt. IR (CHC13 solution): -
1780, 1660 and 1600 cm . NMR (in CDC13): 11.6-10.9 ppm
(s, lH), 8.5 ppm (s, lH), 7.8-6.9 ppm (m, 9H), 5.9-5.3 ppm
(mj 4H), 1.6 ppm (s, 3H), 1.0 ppm (s, 3H). -
In like manner, starting with (p-chlorophenyl)-
25 methylenemalonic acid, there is prepared, in 71% yield, ---
6-(D-2-[2-carboxy-2-(p-chlorophenyl)aarylamido]-2-phenyl-
acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam triethyl-
amine salt. IR (KBr disc): 1780, 1670 and 1600 cm
~NMR (in CDC13): 10.5-9.0 ppm (m, lH), 8.1-7.1 ppm
(m, 10H), 5.9-5.3 ppm (m, 4H), 1.6 ppm (s, 3H), 1.1 ppm
(s, 3H).
-264-
105~99~
EXAMPLE CL
6-(D-2-Allophanamido-2-phenylacetamido)~2,2-dimethyl-3-(5-
tetrazolYl)~enam
,. . .
To a stirred solution of 1.12 g. (3 mmole) of
6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetra-
zolyl)penam and 0.485 ml. of triethylamine in 6 ml. of
water is added portionwise, during 10 minutes, 0.512 g.
(3.5 mmole) of N-methyl-N-nitrosobiuret. Stirring is con-
tinued for a further 2 hours, and then the pH is adjusted
to 2Ø The product is extracted into ethyl acetate, and
then the extract is treated with 0.42 ml. (3.0 mmole) of
triethylamine and then evaporated to dryness in vacuo.
This affords 1.4 g. (84% yield) of the title compound as
its triethylamine salt. IR (KBr disc): 1785, 1695 and
1540 cm . NMR (in CDC13): 9.4-8.4 ppm (m), 8.3 ppm (s),
7.7-7.1 ppm (m), 7.1-6.7 ppm (m), 5.9-5.3 ppm (m), 5.3-5.0
ppm (d), 4.5-4.1 ppm (d), 1.6 ppm (s), 1.0 ppm (s).
-265-
~05~99'~
EXAMPLE CLI
-
6-(3-Aminomethyl-2-phenylisocrotonamido)-2,2-dimethyl-3-
(5-tetrazolvl)~enam
..
To a stirred solution of 720 mg. (3 mmole) of
6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 0.84 ml.
(6 mmole) of triethyLamine in 15 ml. of methylene chloride,
at -20C., is added 706 mg. (3 mmole) of 3-azidomethyl-2- ~-
phenylisocrotonoyl chloride (The Journal of Antibiotics,
Tokyo, 24, 626 [1971]) dissolved in 5 ml. of methylene -~-
chloride. The cooling is removed, and the reaction mixture
is stirred as it warms to room temperature and then f~r a
further 15 minutes. The pH of the reaction mixture is then
adjusted to 7.8, and it is extracted with ethyl acetate.
The ethyl acetate i8 discarded, and the pH of the residual
aqueous phase i5 lowered to 2.5. It is then re-extracted
with ethyl acetate, and to thi~ second extract is added 3
mmoles of sodium 2-ethylhexanoate, The solvent is then
removed by evaporation in vacuo leaving a gummy solid ~ -
(1.12 g.). -
The above ~Olia i5 dis~olved in 35 ml. of water,
and 500 mg. of 10% palladium-on-carbon i8 added. The
mixture is then hydrogenated in a Parr hydrogenator, under
20 p.s.i. pressure, at-25C., for 16 hours. At this point,
the catalyst i8 removed by filtration, and the filtrate is
acidifled to pH 2Ø It i8 filtered, and the pH of the
filtrate i8 ral80d to 5.7. ~he flltrate i9 lyophlllzed, to
produco 900 mg. t87~ yiold) of the title compound. IR
~XBr di9c)s 1770 cm~l (~-lactam).
-266-
10~999'~
EXAMPLE CLII
6-(2,2-Dimethyl-S-oxo-4-phenyl-1-imidazolidinyl)-2,2-
dimethyl-3-(5-tetrazolyl)penam
A mixture of 1.0 g (2.34 mmole) of 6-(D-2-amino-
5 2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,
0.654 ml (4.86 mmole) of triethylamine and 100 ml of
anhydrous acetone is stirred at ca. 25C. for 24 hours.
At this point, the solvent is removed by evaporation in
vacuo, leaving 1.10 g of 6-(2,2-dimethyl-5-oxo-4-phenyl-1-
imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam, as its
triethylamine salt. The infrared spectrum (KBr disc) shows
absorptions at 1786 cm 1 (~-lactam) and 1709 cm 1. The
NMR spectrum (DMSO-d6/D2O) shows absorptions at 7.i6-7.15
ppm (multiplet, 5H, aromatic hydrogens), 5.22 ppm (singIet,
lH, imidazolidine methine hydrogen) 5078 and 5.10 ppm (two -
doublets, 2H, J = 4 Hz, C-5 and C-6 hydrogens), 4.69 ppm
(singlet, 3H, C-3 hydrogen), 3.10 ppm (quarter, 6H, J = 8
Hz, N-CH2-CH3), 1.62 ppm (singlet, 3H, imidazolidine
methyl hydrogens), 1.50 ppm (singlet, 3H, C-2 methyl
hydrogens), 1.40 ppm (singlet, 3H, imidazolidine methyl
hydrogens), 1.21 ppm (triplet, 9H, J = 8 Hz, N-CH2-CH3)
and 0.98 ppm (singlet, 3H), C-2 methyl hydrogens).
-267-
lOSg99'~
EXAMPLE CLII~
.
6-(2,2-Dimethyl-5-oxo-4-¦ -hydroxyphenyl~-l-imidazo-
lidinyl)-2,2-dimethyl-3-(~-tetrazolyl)penam
Reaction of 6-(D-2-amino-2-[~-hydroxyphenyl]-2-
phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, with
acetone and triethylamine, according to the procedure of
Example CLII affords 6-(2,2-dimethyl-5-oxo-4-[p-hydroxy- -
phenyl]-l-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)-
penam as its triethylamine salt. The infrared spectrum
(KBr disc) shows absorption bands at 1786 cm 1 (~-lactam)
and 1686 cm . The NMR spectrum (DMSO-d6/D2O) shows
absorptions at 6.82 and 7.35 ppm (quartet, 4H, aromatic
hydrogens), 5.16 ppm (singlet, lH, imidazolidine methine -
hydrogen), 5~71 and 5.07 ppm (two doublets, 2H, J = 4 Hz,
C-5 and C-6 hydrogens), 4.52 ppm (singlet, 3H, C-3 hydro-
gen), 3.07 ppm (quartet, 6H, J = 8 Hz, N-CH2-CH3), 1.60 ppm
(singlet, 3H, imidazolidine methyl hydrogens), 1.43 ppm
(singlet, 3H, C-2 methyl hydrogen), 1.36 ppm (singlet, 3H,
imidazolidine methyl hydrogens), 1.16 ppm (triplet, 9H,
J = 8 Hz, N-CH2-CH3) and 0.97 ppm (singlet, 3H, C-2 methyl
hydrogens).
.
` -268-
': -
:,
lOS999'~
EXAMPLE CLIV
Following the procedure of Example CLII, and
reacting the appropriate 6-(2-amino-2-substituted-acet-
amido)-2,2-dimethyl-3-~5-tetrazolyl)penam with the
requisite aldehyde or ketone, the following compounds are
prepared:
6-(2,2-dimethyI-5-oxo-4-[_-fluorophenyl]-1-
imidazolidinyl)-2,2-dimet~yl-3-(5-tetrazolyl)-
penam, -
6-(2,2-dimethyl-5-oxo-4-[o-chlorophenyl]-1-
imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)-
penam,
6-(2,2-dimethyl-5-oxo-4-lm-bromophenyl]-1-
imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)~ -
penam,
6-(2,2-diethyl-5-oxo-4-[m-hydroxyphenyl]-1-
imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)- ~ :~
penam,
6-(2-ethyl-5-oxo-4-[p-hydroxyphenyl]-1-imidazo-
lidinyl)-2,2-dimethyi-3-(5-tetrazolyl)penam, : .
6-(2,2-dimethyl-5-oxo-4-[m-tolyl]-1-imidazo-
lidinyl)-2,2-dimethyl-3-(~-tetrazolyl)penam,
6-(2,2-dimethyl-5-oxo-4-[p-amyloxyphenyl~-1-
imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)-
penam,
6-(2,2-dimethyl-5-oxo-4-[m-butoxyphenyl]~
imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)-
penam,
6-(2,2-dimethyI-5-oxo-4-[_-methoxyphenyl]-1-
imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)-
penam,
6-(2-ethyl-2-methyl-5-oxo-4-[p-n-hexyloxyphenyl]-
l-imidazolidinyl)-2,2-dimethyr-~-(5-tetrazolyl)~
penam,
6-~2,2-dimethyl-5-oxo-4-[p-isopropylphenyl]-1-
imidazolidinyl)-2,2-dimet~yl-3-(5-tetrazolyl)-
penam, .
6-(2,2-dimethyl-5-oxo-4-[p-methylthiophenyl]-1-
imidazolidinyl)-2,2-dimethyl-3-(5-tetrazoIyl)-
penam,
6-(2,2-dimethyl-5-oxo-4-cyclopropyl-1-imidazo- :: -
lidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,
-269- :
~ , .
:`\
105~9'~
6-(2,2-dimethyl-5-oxo-4-cyclopentyl-1-imidazo-
lidinyl)-2,2-dimethyl'-3-(5-tetrazolyl)penam,
6-t2,2-dimethyl-5-oxo-4-cyclohexyl-1-imidazo-
lidinyl)-2,2-dimethyl-3-t5-tetrazolyl)penam,
6-(2,2-dimethyl-5-oxo-4-cycloheptyl-1-imidazo-
lidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,
6-(2,2-dimethyl-5-oxo-4-[2-thienyl~-1-imidazo-
lidinyl)2,2-dimethyl-3-(5-tetrazolyl)penam, ~ :~
6-(2,2-dimethyl-5-oxo-4-[3-thienyl]-1-imidazo- ' '--~
lidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam, '::
6-(2,2-dimethyl-5-oxo-4-[2-furyl]-1-imidazo- .
lidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,
6-(2,2-dimethyl-5-oxo-4-[3-furyl]-1-imidazo-
lidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,
6-(2,2-dimethyl-5-oxo-4-[3-pyridyl]-1-imidazo-
lidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam, and
6-(2,2-dimethyl-5-oxo-4-E5-ethyl-2-thienyl]-1-
imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)~
penam,
6-(2,2-dimethyl-5-oxo-4-E:4-1sothiazolyl]-l-
imidazolidinyl)'-2,2-dimethyl-3-(5-tetrazolyl)~ . .
penam,
6-(2,2-dimethyl-5-oxo-4-[3-isothiazolyl]-1-
imidazolidinyl)-2,2-dimethyl-3-(5-tetrazol'yl)-
penam,
6-(2,2-dimethyl-5-oxo-4-[3-chloro-4-hydroxy-
phenyl]-l-imidazolidinyl)-2,2-dimethyl-3-(5-
tetrazoly})penam,
6-(2,2-dimethyI-5-oxo-4-[3,4-dimethoxyphenyl]-1-
imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)-
penam,
6-(2,2-dimethyl-5-oxo-4-E3-methyl-4-methoxy-
phenyl]-l-imidazolidinyl)-2,2-dimethyl-3-
(5-tetraz~lyl~)penam,
: '
: . -
-270-
.
.
~05999'~
EXAMPLE CLV
6-~5-Oxo-4-phenyl-1-imidazolidinyl)-2,2-dimethyl-3-(5-
tetrazolvl)~enam
To a stirred suspen~ion of 1.0 g. (2.26 mole) of
6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetra-
zolyl)penam trihydrate in 15 ml. of water is added 151
(2.53 mmole) of 2-aminoethanol ~ollowed by 342 ~1. (4.6
mmole) of 37% aqueous formaldehyde. The suspension is
stirred for 7 hours, and then it is lyophilized to give
0.96 g. (92~ yield) of the title compound, as its ethanol-
amine salt. IR (KBr di c): 1773 cm 1 (~-lactam) and
1681 cm~l (amide I). NMR (in DMSO-d6): 8.75 ppm
(multiplet, 2H), 7.30 ppm ~inglet, 5H), 6.00-5.60 ppm
and 4.90-4.40 ppm ~multiplet~, 4H), 4,00-3.20 ppm
(multiplet, 4H), 1.70 ppm and 1.06 ppm (2 singlets, 6H).
.,
j -271-
~os99~f~
EXAMPLE CLVI
6-(5 Oxo-4-~p-hydroxyphenyl~ imidazolidinyl)-2,2-
dimethyl-3-(~-tetrazolyl?penam
The procedure of Example CLIV is repeated,
except that the 6-(D-2-amino-2-phenylacetamido)-2,2-
dimethyl-3-(5-tetrazolyl)penamitrihydrate used therein is
replaced by an equivalent amount of 6-(D-2-amino-2-
[p-hydroxyphenyl]-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)-
penam trihydrate. This affords 0.96 g. (92% yield) of the
title compound as its ethanolamine salt. IR (KBr disc):
1776 cm (~-lactam) and 167S cm 1 (amide I). NMR (in
DMSO-d6): 8.52 ppm (multiplet, 2H), 7.14 ppm (multiplet,
4H), 5.90-5.00 ppm and 4.80-4.40 ppm (multiplets, 4H),
3.80-3.00 ppm (multiplet, 4H), 1.67 ppm and 1.06 ppm (2
singlets, 6H).
-272-
~ .
,-: . ' :
~05~9~
EX~MPLE CLVII
Following the procedure of Example CLV, and
reacting the appropriate 6-(2-amino-2-substituted-
acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam with the
requisite aldehyde, the following compounds arè prepared:
6-(5-oxo-4-~p-chloropheny~ -imidazolidinyl)-2
2-dimethyl-3-(5-tetrazolyl)penam,
6-(2-methyl-5-oxo-4-[3-chloro-4-hydroxyphenyl]-
l-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)-
penam,
6-(5-oxo-4-[p-n-hexylphenyl]-1-imidazolidinyl)-
2,2-dimethyl-3-(5-tetrazolyl)penam,
6-(2-methyl-5-oxo-[m-n-propylthiophenyl]-1-
imidazolidinyl)-2,2-dlmethyl-3-(5-tetrazolyl)
lS penam and
6-(2-ethyl-5-oxo[p-n-hexylthiophenyl]-1-imidazo-
lidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,
6-(5-oxo-4-[2-thienyl]-1-imidazolidinyl)-2,2-
dimethyl-3-~5-tetrazolyl)penam and
6-(5-oxo-4-[3-thienyl]-1-imidazoLidinyl)-2,2
dimethyl-3-(5-tetrazolyl)penam,
respectively
- -
-:
. .:
.
~osgg~
EXAMPLE CLV I I I
-
6-([Hexahydro-l-azepinyl~methyleneamino)-2,2-dimethyl-3-
(5-tetrazolyl)~enam
To a stirred solution of 1.2 g (5 mmole~) of
6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 1.0 g (10
mmole) of triethylamine and 30 ml of dichloromethane,
cooled to 0C, is added 0.54 g (5 mmole) of chloro-
trimethylsilane. After 15 minutes, 0.86 (5 mmole) of l-
(dimethoxymethyl)hexahydroazepine (~ritish Patent No.
1,293,590) is added, and stirring is continued for a
further 1 hour. The volatile components are removed by
evaporation in vacuo, and then the residue is extracted
with 25 ml of acetone. The insoluble material is filtered
off, and the acetone is evaporated in acuo to a yellow
foam, which changes to a white powder on trituration with
ether. This affords 1.44 g (82% yield) of 6-([hexahydro-
l-azepinyllmethyleneamino)-2,2-dimethyl-3-(5-tetrazolyl)_ -
penam. The infrared spectrum of the product (K~r disc)
shows abs-orption bands at 1795 cm 1 (~-lactam), 1706 cm 1 -
and 1645 cm . The NMR spectrum (CDC13) shows absorpti~n
bands at 8.00 ppm (singlet,- lH, N-CH-N), 5.90 and 5.60 ppm
(two dou~lets, 2H, J = 4 Hz, C-5 and C-6 hydrogens), 5.40
ppm (singlet, lH, C-3 hydrogen), 3.90-3.50 (multiplet,
4H, CH2-N-CH2), 2.00-1.50 ppm (multiplet, llH, C-2 methyl
hyarogens and [CH2]4) and 1.20 ppm (singlet, 3H, C-2 methyl
hydrogens). Examination of the product by thin-layer
chromatography(0.2M NaOAc: acetone; 1:6) showed a single
spot (Rf 0.23).
-274-
lOS~99'~
EX~MPLE CLIX
6-([Dimethylaminolmethyleneamino)-2,2-dimethyl-3-~5-tetra-
zolvl ) nenam
Reaction of N,N-dimethylformamide dimethyl acetal
with 6-amino-2,2-dimekhyl-3-(5-tetrazolyl)penam, according
to the procedure of Example CLVIII, on a 5 mmole scale pro-
duces 1.47 g (89% yield) of product. The product is a 3:1
complex of 6-(~dimethylamino]methyleneamino)-2,2-dimethyl-
3-(5-tetrazolyl)penam with triethylamine. The infrared
spectrum of the product (KBr disc) shows absorption bands
at 1780 cm 1 (~-lactam), 1710 cm 1 and 1640 cm 1. The NMR -~
spectrwm shows absorptions at 8.00 ppm (singlet, lH, N-CH=N),
5.80 and 5.50 ppm (two doublets, 2H, J = 4 Hz, C-5 and C-6
hydrogens), 5.30 ppm (singlet, lH, C-3 hydrogen), 3.40-3.00 ~ ;
ppm (multiplet, 8H, N(CH3)2 and N-CH2-CH3), 1.70 ppm (singlet,
3H, C-2 methyl hydrogens), 1.30 ppm (triplet, 3H, N-CH2-CH3),
1.70 ppm (singlet, 3H, C-2 methyl hydrogens). When examined
by thin-layer chromatography (0.2M NaOAc: acetone; 1:6),
showed a single spot (Rf 0.26).
-275- ~ `
lOSg99'~
EXAMPLE CLX
6~ 2-[Dimethylaminomethyleneaminol-2-phenylacetamido)-2,-
2-dimethvl-3-(5-tetrazolYl)Penam
_
To a stirred solution of 3.73 g. (10 mmole) of
S 6-~D-2-amino-2 -phenylacetamido)-2,2-dimethyl-3-(5-tetra-
zolyl)penam and 2.02 g. (20 mmole) of triethylamine in 50
ml. of methylene chloride, at 0C., is added 1.08 g. (10
mmole) of trimethylsilyl chloride Stirring i8 continued
for 20 minutes at 0C~, and then 1.2 g. (10 mmole) of N,N-
dimethylformamide dimethyl acetal i~ added. Stirring i8
continued for a further 2 hours, and then 2 ml. of -
methanol is added. The solvents are removed by evaporation
in vacuo, and acetone i8 added to the re~idue. After
filtration, the filtrate is evaporated to dryne~s. ~h~ B :: .
latter residue is dissolved in 25 ml. of methylene chloride
containing 1.4 ml. of triethylamine, and then the solution
i8 added dropwise with stirring to 400 ml. of ether The
solid whlch precipitates is filtered off, giving 4.83 g.
~30% yield) of the title compound as its triethylamine
salt. IR (KBr disc): 1786, 1710 and 1652 cm . NMR
(in D20): 7.8 ppm (8, lH), 7.6 ppm (8, 5H), 6.0 ppm
(d, 2H), 5.8 ppm (d, 2H~, 5.5 ppm (8, lHl, 5.4 ~pm (s, ~H),
3.3 ppm (q, 6H), 3.2 ppm (~, 6H), 1.8 ppm (8~ 3H), 1.4 ppm
(t, 9H), and 1.2 ppm (~, 3H).
. . .
-276-
-,:
lOS~99Z
EXAMPLE CLXI
6-(D~-2-[2-(VHexahydro -l-azepinyl]methyleneamino)acetamido]-
acetamido)-2-dim~thyl-3-(5-tetrazolyl)penam
A procedure analogous to that of Example CLX is
used to obtain the title compound from the reaction 1.07 g.
(2.5 mmol) of 6-D-[2-(2-aminoacetamido)-2-phenylacetamido]-
2,2-dimethyl-3-(5-tetrazolyl)penam and 0.43 g.
(2.5 mmol) of l-(dimethoxymethyl)hexahydrozRpine. The
product is isolated as its triethylamine salt: yield 0.68 -
g (43%); IR (KBr) 1780 and 1695 cm 1; NMR (D2O) 8.05 ppm
(s, lH), 7.75 (s, 5H), 6.0-5.6- (m, 2H), 5.50 (s, lH), 4.50
(s, 2H), 4.20 (s, lH), 4,05-3.65 (m, 4H), 3.4 (q, 6H),
2.3~75 ~ 8H~, 1.70 ~m, 8H),~s~ 3~ .55,(t7 9H),
.l0 (s, 3H)-
-277-
:`
" .
lOSg99'~
EXAMPLE CLXII
6-(D-2-~Dimethylaminomethyleneaminol-2-[~-hydroxyphenyl]-
acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam
To a stirred solution of 1.95 g. (5 mmole) of
6-(D-2-amino-2-]~-hydroxyphenyl]acetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam and 0.5 g. (5 mmole) of triethylamine
ln 12 ml. of methylene chloride, at 0C., i5 added 0.6 g.
of N,N-dimethylformamide dimethyl acetal. Stirring is
continued for 1 hour at 0C., and then the reaction mix-
ture is poured into 100 ml. of ether. This causes a gummy
solid to precipitate. The sol~ent is decanted from the
solid, and then the solid is dissolved in 50 ml. of
methylene chloride and 2 ml. of triethylamine. The
selution is treated with activated charcoal, filtered, and
then added dropwise to 100 ml. of ether. The solid which
precipitates is re-dissolved in methylene chloride con-
taining triethylamine, again treated with activated
charcoal, and again added dropwise with stirring to ether.
The solid which precipitates is filtered off, giving 450
mg. (17~ yield) of the title compound as its triethylamine
salt. IR ~KBr disc): 1786, 1715 and 1652 cm 1. NMR (in
D20-NaHC03): 7.7 ppm (8, lH), 7.3 ppm (d, 2H), 6.9 ppm (d,
2H), 5.8 ppm (d, lH), 5.5 ppm (d, lH), 5.3 ppm (28, 2H),
3.2 ppm (q, 6H), 3.1 ppm (8, 6H), 1.3 ppm (t, 9H), 1.0 ppm
(~, 3H).
In like manner, startlng with 6-(D-2-12-amino-
açetamidol-2-phenylaaetamido)-2,2-dlmethyl-3-(5-tetrazolyl)
ponam, thore i9 pr-pared a 29~ yleld of a 2:1 complex of
6-(D-2-12-(dimethylaminomethyleneamino)acetamido]-2-
phenylaçetamido)-2~2-dimethyl-3-(5-tetrazolyl)penam-tri-
ethylamine. IR (X~r di~c): 1780, 1715 and 1667 cm 1. NMR
-278-
:
lOS~9'~:
(in D2O): 7.9 ppm ~s, lH), 7.5 ppm (8, 5H), 5.6 ppm (s,lH), 5.7 ppm (d, lH), 5.5 ppm (d, lH), 5.3 ppm (s, lH),
4.3 ppm (s, 2H), 3.3 ppm (s, 3H), 3.2 ppm (9, 3H), 3.2 ppm
(q, 3H), 1.5 ppm (s, 3H), 1.3 ppm (t,4.5H) and 1.0 ppm
(s, 3H).
EX;!~MPLE CLX I I I
6-(2-Phenylacetamido)-2,2-dimethyl-3~ pivaloyloxy-
methyl]-tetrazol-5-yl)penam and 6-(2-Phenylacetamido)-2,2-
dimethyl-3-(2-[plvaloyloxymethyl]tetrazol-5-yl)penam -
To a stirred suspension of 10.0 g. 10.0264 mole)
of 6-(2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam
sodium salt, in 105 ml. ~f acetone, is added 2.6 ml. of 25%
aqueous sodium iodide, followed by 4.35 g. (0.0290 mole) of ~`
chloromethyl pivalate. The mixture is refluxed for 4.5
hours, and then it is cooled to ambient temperature. To
the mixture is then added 100 ml. of water, and the
resulting suspension is extracted with ethyl acetate. The -
extracts are dried and evaporated to give 6.3 g. of a white - -
foam. The MIC of this mixture of the title compounds
against Strep. p~ogenes is 0.2 ~g./ml.
The white foam is re-dissolved in a small volume
of 80s20 chloroform-ethyl acetate and absorbed on a column
of 180 g. of chromatographic grade silica gel. The column
i8 then eluted with 80:20 chloroform-ethyl acetate taking
fractions. Each fraction consists of 700 drops of solvent.
Fractions 55-95 are combined and evaporated in
vacuo to glve 2.03 g. of 6-(2-phenylacetamido)-2,2-
dimethyl-3-~2-[pivaloyloxymethyl]tetrazol-5-yl)penam.
Fractions 100-164 are combined and evaporated in vacuo to
give 0,80 g. of 6-(2-phenylacetamido)-2,2-dimethyI-3- -
(1-lplvaloyloxymethyl~tetrazol-5-yl)penam.
-279-
::~ ','; 1 ~
lOS~95'~
Ul
U~
OD
. 5~
,,
~ __
p~
m In m
__
o ~o
.~ p~ .
I In~ ~,~
~m 13
_~ --_
~ o~
.~ ~ ~a~
O
m~ In m
_ I _
o ~ o~
U~ _. o ~7
.~ . .
O ~ a~
u~ ~m
~ _-- __
C~
_ ~ ~
e ~ m m
_ __
o ~ ou~
CD _ I` ~D ,,,
U . p~
I , , "
~ .
~n ~ m
C X ~'"
If~ N , . ~.
æ ~
m ,~ m m
_ __
o ~ o~
u~ _ In co
.
ou~ ou~
~a e r~
-~ ~ ~
~ U I 0 0 U~ O
q~ ~ e c~
1` ~ 1` ~
~ o . .
m
.~1 rl
I ~ I :
~ I '' ~
:
,~
~ l
-l ~
-280-
. .
. .
105999'~
EXAMPLE CLXIII A
6-(2-Phenylacetamido)-2,2-dimethyl-3-(1-12]-[1-acetoxy-
ethyl]-tetrazol-5-yl)penam
Reaction 6-(2-phenylacetamido)-2,2-dimethyl-3-
(S-tetrazolyl)penam sodium salt with l-acetoxyethyl chlor-
ide, according to the procedure of Example CLXIII produces
the title compound as a mixture of isomers, m.p. 55-70C.,
yield 28%. IR (KBr disc): 1780, 1770, 1670 and 1515 cm 1.
NMR (CDC13): 7.20 (~, 6H), 6.25 (m, lH), 5.75-5.40 (m, 2H),
5.20 (s, lH), 3.60 (s, 2H), 2.00 (m, 6H), 1.45 (s, 3H) and
0.95 (s, 3H) ppm. ~
EXAMPLE CLXI I I B ~ :
6-(2-Phenylacetamido)-2,2-dimethyl-3-(1-12]-[3-phthalidyl~
tetrazol-5- 1) enam
Y P
Reaction of 6-(2-phenylacetamido)-2,2-dimethyl-3-
(5-tetrazolyl)penam sodium salt with 3~bromophthalide,
according to the procedure of Example CLXIII produces the
title compound as a mixture of isomers, m.p. 70-85~C.,
yield 91%. IR (KBr disc): 1785, 1675 and 1500 cm 1. NMR
(CDC13): 8.05 - 7.10 (m, 9H), 6.55-6.20 (m, 2H), 5.80
(m, 2H), 5.20 (m, lH), 3.60 (s, 2H), 1.60 (s, 3H) and 1.00
(s, 3H) ppm.
-281-
.
, .,,,".
~05~99'~
EXAMPLE CLXIV
Reaction of the appropriate 6-acylamino-2,2- -
dlmethyl-3-(5-terazolyl)-penam with the requisite alkanoyl-
oxyalkyl chlor~de or with 3-bromophthalide, according to
the procedure of Example CLXIII, provides the following
congeners. In each case, the product i8 a mixture of
monoal~ylated compounds, in which the alkanoyloxyalkyl or
phthalldyl substituent is located at either the l- or the
2-po~itlon of the tetrazole ring.
6-acetamido-2,2-dimethyl-3-(1[2~-acetoxymethyl-
tetrazol-S-yl)penam,
6-propionamido-2,2-dimethyl-3-(1-[2]-isobutyryl-
oxymethyltetrazol-5-yl)penam,
6-(2-phenylacetamido)-2,2-dimethyl-3~ 2]-
propionyloxymethyltetrazol-5-yl)penam,
6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1~2]-n- - :
hexanoyloxymethyltetrazol-5-yl)penam,
6-(2-cyclohexanecarboxamido)-2,2-dimethyl-3-
(1~2]-pivaloyloxymethyltetrazol-5-yl)penam,
6-(2-p-chlorophenylacetamido)-2,2-dimethyl-3-
(1~2]~acetoxymethyltetrazol-5-yl)penam,
6-(2-m-methoxyphenylacetamido)-2,2-dimethyl-3-
(1~2]-propionyloxymethyltetrazol-5-yl)penam,
6-(2-[3-chloro-4-hydroxyphenyl]acetamido)-2,2-
aimsthyl-3~ 23-pivaloyloxymethyltetrazol-5-
yl)penam
6-(2-[2-thienyl]acetamido)-2,2-dimethy1-3-(1-
[2]-acetoxymethyltetrazol-5-yl)penam
6-(3-furancarboxamido)-2,2-dimethyl-3-(1-[2]-n-
butyryloxymethyltetra201-5-yl)penam,
6-(2-phonylproplonamido)-2,2-dimethyl-3~ 2]-
plvaloyIoxymothyltetrasol-5-yl)penam,
6-~2-phenoxyacetamido)-2,2-dimethyl-3~ 2]-
plvaloyloxymethyltetrazol-S-yl)penam,
-282-
, ~ ,
lV~i~99'~
6-acetamido-2,2-dimethyl-3-(1{21-11-acetoxyethyl]-
tetrazol-5-yl)penam,
6-(2-cyclohexylacetamido)-2,2-dimethyl-3-(1{2]-
ll-propionyloxyethyl]tetrazol-5-yl)penam,
6-(2-phenylacetamido)-2,2-dimethyl-3-(1~21-11-
pivaloyloxyethyl]tetrazol-5-yl)penam,
6-(2-phenoxyacetamido)2,2-dimethyl-3-(1{2]-[1-n-
hexanoyloxyethyl]tetrazolyl)penam,
6-(2-[3-thienyl]acetamido)-2,2-dimethyl-3-(1-[2]- :~ -
[l-acetoxyethyl]tetrazolyl)penam, ~ .
6-propionamido-2,2-dimethyl-3-(1[2]-phthalidyl- ~`-
tetrazol-5-yl)penam ~:
6-(2-phenylacetamido)-2,2-dimethyl-3-(1-[2]-
phthalidyltetrazol-5-yl)penam, :~
lS 6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1{2]- :
phthalidyltetrazol-5-yl)penam, :~
6-(2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3- ~:.
(1~2]-phthalidyltetrazol-5-yl)penam,
6-(2-[2-furyl]acetamido)-2,2-dimethyl-3-(1{2]-
phthalidyltetrazol-5-yl)penam and --~
6-(2-[5-methyl-2-thienyl]acetamido)-2,2-dimethyl- :~:
3-(~{2]-phthalidyltetrazol-5-yl)penam, .
respectively.
; -283- .
~ :'
.
lOS~99'~
EXAMPLE CLXV
6-Amino-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-
penam __ _
To a stirred solution of 0.932 g. (7.21 m mole)
of quinoline in 8.0 ml. of chloroform is added 0.840 g.
(4.05 m mole) of phosphorus pentachloride. The suspension
is cooled to -15C., and then 1.81 g. (3.84 m mole) of 6-
(2-phenylacetamido)-2,2-dimethyl-3-(2-[pivaIoyloxymethyl]--
tetrazol-5-yl)penam is added. Stirring is continued for a
further 30 minutes, at ca.-5C., and then 2.15 g. ~35.7 m
mole) of n-propanol is added. Stirring is continued for a
further 30 minutes, again at ca~ -5C., and then 25 ml. of
90:10 isopropyl ether-acetone is added, followed immediately
by a solution of 1.35 g. of sodium chloride in 6.02 ml of
water. The temperature rises to 15C. and then it is
lowered again to -15C. The precipitate which has formed
is filtered off and dried, giving 1.33 g. (88~ yield) of
6-amino-2,2-dimethyl-3-(2-lpivaloyloxymethyl]tetrazol-5-
yl)penam hydrochloride. The infrared spectrum (KBr disc)
shows absorptions at 1785 cm (~-lactam) and 1750 cm 1
(ester). The NMR spectrum (DMSO-d6) shows absorptions at
6.70 ppm (singlet, 2H, pivaloyloxy methylene hydrogens),
5.75 ppm (doublet, lH, C-5 hydrogen), 5.50 ppm (singlet,
lH, C-3 hydrogen), 5.70 ppm (doublet, lH, C-6 hydrogen),
1.75 ppm ~singlet, 3H, C-2 methyl hydrogens), 1,20 ppm
~singlet, 9H, _-butyl hydrogens) and 1.10 ppm ~singlet,
3H, C-2 methyl hydrogens).
'
~ ~ .
~i -284-
~ ` .
105~39'~
EXAMPLE CLXVI
6-Amino-2,2-dimethyl-3-(1-[pivaloyloxymethyl]tetrazol-5-
~l)penam
The title compound is prepared as its hydro-
chloride, in 90% yield, from 6-(2-phenylacetamido)-2,2-
dimethyl-3-(1-~pivaloyloxymethyl]tetrazol-5-yl)penam,
using the method of Example CLxV. The infrared spectrum
(KBr disc) shows absorptions at 1780 cm 1 (~-lactam) and
1740 cm (ester). The NMR spectrum (DMSO-d6) shows
absorptions at 6.71 ppm (singlet, 2H, pivaloyloxy methylene
hydrogens), 5.88 ppm (singlet, lH, C-3 hydrogen), 5.83 ppm
(doublet, lH, C-5 hydrogen), 5.20 ppm (doublet, lH, C-6
hydrogen), 1.80 ppm (singlet, 3H, C-2 methyl hydrogens),
1.20 ppm (singlet, 9H, t-butyl hydrogens) and 1.16 ppm
(singlet, 3H, C-2 methyl hydrogens). ~
-285- :-
'.
10S~5~9~
EXAMP~E CLXVII
6-~D-2-Amino-2-tp-hydroXyphenyl]acotamido)-2,2-dim-thyl-
3-~2r-lpivaloylo~ymethyl]totrazol-5-Yl)penam
To a ~tlrr~d ~u-penslon o~ 287 mg ~1 0 m ~ol-)
of sodlum N-(2-m thoxycarbonyl-1-methylvlnyl)-D-2-amino-2-
(~hydroxyphenyl)acetate (Long, et al , Jouranl of th
Chemical Soclety tLondon], Part C, 1920 119711) and 1 drop
of N-methylm~rphollne ln 6 ml of ethyl acetate, i~ add~d
0 97 ml~ (1 03 m~lc) o~ ethylchloroformat-, at -15C
Stirring i- continued for a further 30 minutes at -15C
This mixture i8 thon add-d to a pre-cooled (-15C ) u--
pension of 390 5 mg (1 0 m mole) o~ 6-amino-2,2-dimnthyl-
3-(2-lpivaloyloxym thylltetrazol-5-yl)penam hydrochlorld
in 2 ml of thyl acetate containing lOl mg ~1 0 m ~ol-)
o~ triethylamine m e reaction mixture is then ~tirr-d ~t
-15 C for l hour followed by 5C for 1 hour The thyl
acetate i8 removed by evaporation in vacuo, and the whit-
solid thus obtained is suspended in lO ml of 1 1 wator-
tetrahydrofuran The suspension is cooled to 0C~, ana
then its pH is adjusted to 2 1 The suspension is stirred
at 0C for 45 minutes, with further acid being added to
maintain the pH at 2 1 as necessary At- thi- point, th-
tetrahydrofuran is removed by evaporation in v~cuo, th- -
r-sidual aqueou# pha~e i8 saturated with ~odium chlorid-,
and the product i- extr-oted into ~thyl acetat- m
ethyl ac-tato i- dri-d and ovaporated in vaouo g~ving,
a~ter trlturatlon of the r-sidue with ~th-r, ~25 mg ~8l~
yield) o~ 6-(D~2-àmino-2-[~-hydroxyphenyl]acetamido)~2,2-
dlmethyl-3-(2-[plvaloyloxymethyl]-tetrazol-5-yl)penam
hydroch10rlde The ln~rared spectrum (XBr disc) show~
-286-
lOS~9'~
ab~orptions at 1780 cm 1 (~-lactam) 1755 cm 1 ~e~tor),
1682 cm 1 (amide I). The NMR spectrum (DMS0-d6) shows
absorptions at 7.09 ppm (~uartet, 4H, aromatic hydrogens),
6.59 ppm (singlet, 2H, pivaloyloxy methylene), 5.52 ppm
S (multiplet, 2H, C-5 and C-6 hydrogens), 5.22 ppm (singlet,
lH, side chain methine hydrogen) 5.00 ppm (singlet, lH,
C-3 hydrogen), 1.47 ppm (singIet, 3H, C-2 methyl hydrogen),
1.07 ppm (singlet, 9H, t~butyl hydrogens), and 0.95 ppm
(singlet, 3H, C-2 methyl hydrogens~
The MIC of the.title compound against Strep.
pyogenes is 0.39 ~g.~ml.
: -287- --
, ~
~OS5~9'~;~
EXAMPLE CLXVIII
6-(D-2-Amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-
(l-~pivaloylox~ethyl]tetrazol-5-yl)penam
The title compound i8 prepared a~ lt~ hydro-
chloride, in 50% yield, from 6-amino-2,2-dimethyl-3-(1-
[pivaloyloxymethyl]tetrazol-5-yl)penam, using the procedure
of Example CLXVII. The infrared spectrum of the product
(KBr disc) shows absorptions at 1780 cm 1 (~-lactam) and
1680 cm 1 (amide I). The NMR spectrum (DMS0-d6) shows -
absorptions at 7!09 ppm (quartet, 4H, aromatic hydrogens),
6.55 ppm (singlet, 2H, pivaloyloxy methylene hydrogens),
5.61 ppm (multiplet, 3H, C-3, C-5 and C-6 hydrogens), 5.06
ppm (slnglet, lH, side-chain methine hydrogen), 1.55 ppm
(singlet, 3H, C-2 methyl hydrogen), 1.10 ppm (singlet, 3H,
C-2 methyl hydrogen), 1.10 ppm (singlet, 9H, t-butyl hydro-
gens) and 1.03 ppm (singlet, 3H, C-2 methyl hydrogens).
- -288-
:~ .
,~,,.... ,, .. " .. , ,,- . . , - .. , . ., . - . . .. . . . . ~ .
l()S~99'~
EXAMPLE CLXIX
Using the procedure of Example CLXVII, reaction
of the appropriate 6-amino-2,2-dimethyl-3-(pivaloyloxy-
methyltetrazol-5-yl)penam with the requisite sodium N-(2-
methoxycarbonyl-1-methylvinyl)-2-amino-2-substituted-
acetate provides the following compounds:
6-(D-2-amino-2-phenylacetamido)-2,2~dimethyl-3-
(l-pivaloyloxymethyltetrazol-5-yl)penam,
6 (D-2-amino-2-phenylacetamido~-2,2-dimethyl-3-
(2-pivaloyloxymethyltetrazol-5-yl)penam,
6-(D-2-amino-2-[2-thienyl]acetamido)-2,2-dimethyl-
3-(2-pivaIoyloxymethyltetrazol-5-yl)penam
6-(D-2-amino-2-[3-chloro-4-hydroxyphenyl]acet- :-~
amido)-2,2-dimethyl-3-(2-pivaloyloxymethyl-
tetrazol-5-yl)penam and
6-(D-2-amino-2-[3-thienyl]acetamido)-2,2- ~
dimethyl-3-2-pivaloyloxymethyltetrazol-5-yl)penam, ~ .
reJpectively, ~
," '
'"''
-289- ~
''.
. .
1(~5~399'~
EXAMPLE CLXX
6-Amino-2,2-dimethyl-3-(1-pivaloyloxymethyltetrazol-5-yl)
penam and
6-Amino-2,2-dimethyl-3-(2-pivaloyloxymethyltetrazol-5-yl)
nenam
.
To a stirred suspension of 2.40 g. of 6-amino-2,-
2-dimethyl-3-(S-tetrazolyl)penam in 15 ml. of N,N-dimethyl-
formamide, is added 2.8 ml. of triethylamine. Stirring is
continued for a further 15 minutes, and then 2.68 g. of
chloromethyl pivalate is added. The mixture is stirred at
ambient temperature for 5 hours, and then it is diluted with
100-ml. of water. It is then extracted with ethyl acetatè.
The extract is washed with water, dried usin~ anhydrous
sodium sulfate, and then it is evaporated in vacuo to give
a mixture of the title compounds. The individual isomers
are obtained by chromatographic separation of the crude
product.
-290-
~S1399'~
EXAMPLE C~XXI
_
6-(2-[3-(2-[~-Chlorophenyl]acetimidoyl)ureido~acetamido)-
2,2-dimethyl-3-(5-tetrazolyl)penam
To a stirred solution of 480 mg. of 6-amino-2,2-
dimethyl-3-(5-tetrazolyl)penam and 404 mg. of triethylamine,
in 6 ml. of N,N-dimethylformamide, is added 650 mg. of
2-(3-[2-(p-chlorophenyl)acetimidoyI]ureido)acetyl chloride
hydrochloride. Stirring is continued for 1 hour, and then
the reacti~n mixture is filtered. The filtrate is added to
300 ml. of ether, and the solid which precipitates is
filtered off. The solid is washed thoroughly with -
methylene chloride, and dried, giving 585 mg. of the title
compound, m.p. 150-162C. IR spectrum (Nujol mull): 1780
cm 1 (~-lactam). NMR spectrum (DMSO-d6): 8.90 ppm (d, lH), -
8.00-7.20 ppm (m, 8H), 5.80-5.20 ppm (m, 3H), 4.10-3.60 --
ppm (m, 4H), 1.65 ppm (s, 3H), 1.10 ppm (s, 3H). ;
.
-291-
''
, .:
~05~9g~
EXAMPLE CLXXII
Using the procedure of Example CLXXI, and
reacting either 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam
or 6-(D-2-amino-2-phenylacetamido)-2~2-dimethyl-3-(5-
tetrazolyl)penam with the appropriate acid chloride hydro-
chloride, the following compounds are produced.
Rl ~
-292-
lOS9~9
e e e _m
oo Inln o_ ~In ~In
N ~ l O _I m ,1 n ~ Ln
O ~ . . O ~ ~ O ~ O
Ln ,1~n ~I I è ~e ,, ~ ~1
o ~n ~ o~ o ~ o ~
ICD ~ d' O O-- ~ _
m ~mo~
n ~n ~oo O ~ n
` bq ` In ` I O E~ O E~
__ _-- _In ~1~ ,1~
m Ln :~ Ln ~ O . O O O
l ~ er O
o ~ ~ ~ ~I~
ca _ ~
o--m P:o P~o
N _N _ OD m ~ ,1 o _I
I ~ . O ....
~- N~ IS) CD U~ ~ d' ~,~r-- -
o El n E~ ~~o o ~ ~ o
~~ o~ _Ln o ~
~ ~ o ~ o m ,~ d m ~ . . -
~ . . ~ O -~ .
~ e, ~ ~ e ~ o
~ -- I -- I --O _ _ _ ~
mo mu oa~m :coo mo,~ .
~ ~ O N ~ ~1 _J O
Z ~ n ~
o ~ o ~ o _u~ o O ~ o o
o~ In ~ o
~ m ~ O O u~
~e . .
a~ ~ . ..
~_
~_I o Ln o Ln Ln
~, CO t~ CO
~ ~U
~ ~r co ~ ~D ~ . ,,
.,,1 ~ _ LD LD LD ~ .
~ ~:
~1 ~ ~ ~ N O O C~)
î ': '
~_ ~ O Ln ~r
P c~ ~_ Ln
-- '.
I I O ' ~ '
I ~1 _1 ~ I , .
Il) N I
I N O ~ .g
N~ 0~ N ~ yq~ O
IJ) I t~ N I ~ I IU
P. ~-- ~ I~ --1~ h ~d
~ O _4 ~
I oI S~ I U ~ I O I O ~: 3
N rON ~J N td tlJ N 0 N r~
-29 3- -
.
~OS~992
EXAMPLE CLXXIII
6-(3-Phenylureido)-2,2-dimethyl-3-(5-tetrazolyl)penam
To a stirred slurry of 724 mg. of 6-amino-2,2-
dimethyl-3-(5-tetrazolyl)penam in 10 ml. of methylene
chloride i9 added 1.3 ml. of triethylamine. The mixture
is stirred for 40 minutes, and then filtered. To the
filtrate is added 0.35 ml. of phenyl isocyanate. Stirring
is continued for a further 45 minutes, and then the
reaction mixture is cooled in an ice-bath for 30 minutes.
The solid which precipitates is filtered ~ff, washed with
ether, and dried, giving 935 mg. of the title compound as
its triethylamine salt, m.p. 110-120C. IR spectrum (Nujol
mull): 1775 cm 1 (~-lactam), 1700 cm 1, 1600 cm 1 and 1550
cm . NMR spectrum (DMSO-d6): 9.00 ppm (s, lH), 7.50-6.70
ppm (m, 7H), 5.65 ppm (m, 2H), 5.10 ppm (s, lH), 3.10 ppm
(q, 6H), 1.80 ppm (s, 3H), 1.18 ppm (t, 9H), 1.00 ppm
(s, 3H).
In like manner, using ethyl isocyanate, there is
obtained a 70~ yield of 6-(3-ethylureido)-2,2-dimethyl-3-
(5-tetrazolyl)penam triethylamine salt, m.p. 80-90C. IR
spectrum (KBr disc): 1785 cm (~-lactam). 1668 cm and
1570 cm . NMR spectrum (DMSO-d6): 7.80 ppm (m, lH), 6.50
ppm (m, 2H), 5.60 ppm (m, 2H), 5.10 ppm (s, lH~, 3.10 ppm
(q, 8H), 1.60 ppm (s, 3H), 1.40-0.70 ppm (m, 15H).
-294-
~o~
EXAMELE CLXXIV
Reactlon of 6-tD-2-amino-2-phenylacetamido)-2,2-
dimethyl-3-t5-tetrazolyl)penam with the appropriate acid
chloride, according to the procedure of Example CXLVII,
provides the following compounds, which are isolated as the
free aclds by elimination of the final triethylamine
treatment.
Rl-NH S H3 ~ .
\ ~ ~ CH3
N
_ N
-295-
~ , , -.
1()5~9~'~
o o ~ ~o o
o ~ o o~
m ~
m~ u~ O ~ .
_ P: ~ ~ ~ o ~ o ~ _ u~
~ O _ ~
_I m m ~ _ O t:q o m _I m ~
P ~ _I X
I --$ --~ O ~ 5
U ~o~ o,l ~~ o,l ~ I ~~ oo oo~ o~ ~
a .~ u~ D O ~
U ~ O ~ Ul r~. ~D oq . O ~ ~ o ~q
` OD ~ r~ ~ o ~ o ,
~ _ ~ O ~ e ~ O ~ 0
l :q _ _ _ ~ -- _ ~ _~_ __ _ _ ~ .o _I m _l m un m ~ m--~ m m ~ m m_l m u u
U~ ~ ~ O ~ I ~ O ~_ -
a --e_ e-- e- ~ e ~n ~'d- e-~
_ ~ ~ m --m --5~ --m o ~ ~
o~ o~ ~ o~ o--~ ooo ~u~ o~
o ~ o ~ o
~ , ~ ~ ~ e ~: tn e :1: O ~ m ~ o ~
J~ ~ I~O ~ O O ~ ~ o ~
o _ ~ e ~ O Oq _~
~ m ~ m
o _I m ~ m U~ m $ m ~ DO ~
u~ ~ o ~ m ~ N _I ~D `_
~ ~ m ~ p e ~ ul e e
æ ~ ~ ~ O _t ~ 0 ~ 0 ~_l o ~ o ,~ o _l ~ o l~ ~ ~ e _
o . U~ m - ~ e P~
u~ o u~ o u~ o o u~ o
e u~
U I o U~ o U~ U- oUl o o o U~ U~ o U~ o U- o U~
~ ~ e o~ o o-ro 0~ ~0 a~
~ o u~ o oIn u~
~ l l l l l l l l l
r o
n~ o o ~ ~ ~P~r ~r ~ ~ ~ I` .
~ P4--
-' I '' :,
~_
_l I I ' .
o I ~ -
t~ a o
I u u ~ .
~1 0 ~ .
. ~
~
~ 8
~ Q
_I ~ o o ~a u ~
~ a ~ ~ 04 t) .C U ~ O
O U
:~ 1~ 1 . ~1 ~u o IIJ ~ 0
u e ~ u ~
r~ 0
P4--I N ~ ~ a ~4 ~ ~ ~.i
a~ u ~ ~ ~ ~ ,1:: ~ .~ ~ .¢
~ .C
,q ~ ~u ~ P4 --P4 '~
P4
I .C I I I I .C I I I I I I I I
4 ~ ~ ~ ~ ~ ~ C~
29 5a-
lOS~992
~ . ~ ~
~ _ o
~a u~ m ~ w ~ ~ o ~ ~
O _ ~
a ~ m r~
q ~ N
h ~ ~ O `
00 ~,q 1`--~ CO ~-- ~ ~--I 00 $ E~ ~
O -- a~ `r~ 0 --1 CO ~I N CO ~ N
u~ ~ m ~u~ ~u m ^~
~1 ~ ~ ~ ~ O ~ N ~ ~t CO N ~ U~ ~ m m
Z _ ~ m ~q ~o m--
OD ` O ~ I ~ _ ` ~--0 0 _ 1` CO O ~ ~ _I O 1~
e ~ :~ x ~ . O ~
~` N~O 1'~ ~ ~ 1-- 0 Il~
~ e ~
h O I oco ~r)u) u~ m In o r` o l`
3 o a~ ~ o
O CO ~ t` t` t` N ~D _I W :
H tq-- ~1 ~1 ~1 _I _I ~ ~I N ~
t7~ ~ o o o ~r c~ oo 11~ 1` .
~D 10OD r` ~ r` N
o l l l l l l l l I .
~1 ~rl ~ o ~ O1~ O 0. U) ~D . ':
~ ~ ~ D N
_I
IU--In O N a~
~ u o ~
a~ a N _
~
Q~ u El J~
~ N
l a a~ ~ O ~
~1N ,~ ~1~ ~h O ~ Q~
P~ I~ .¢ 1 a~~.4 h ~~ :~ X
._ a) ~~ u ~ O o ~ oo ~ o
~ ~ e I.~
I ~ ~ I ~ O ~~ ~ ~ U
~ ~1 ~r I~ ~ ~ IN ~1rl ~0.C~ 1 N 1~
~ e ~_Q. ~ u ~ 0 ,,
: ~ I 01 0 1 ~I O I ~ I ~ I I ~ I
~: : ~ ~ N ~~ ,tt~l ~ N ~C~r 1: N N ~: N t
I u I E~I II 1~I I I ~ II .¢ I ~
.: ~ 0 N IdN ~ 1 nN t~ N ~ N~ P~ N ~
29 5b-
`
::: .
lOS~S~g;~
EXAMPLE CLXXV
6-(2-Phenylacetamido)-2,2-dimethyl-3-~1-[4-benzyloxybenzyl]-
tetrazol-S-yl)penam _ __
To a ~tirred ~olution of 189 mg of 6-amino-2,2-
dlmethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam in 4
ml o~ chloro~orm" is added, at ambient temperature, 0.038
ml of pyridine followed by 0.057 ml of phenylacetyl
chloride. Stirring is continued for a further 45 minutes,
and then the reaction mixture is diluted with 25 ml of
chloroform and then washed with water. The organic phase
is dried using anhydrous magnesium sulfate and then
evaporated in vacuo. The residue is 209 mg (86% yield) of
6-(2-phenylacetamido)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]-
tetrazol-5-yl)penam. The NMR spectrum (in CDC13) shows
absorptions at 7.50-6.70 ppm (multiplet, aromatic hydro-
gens), 6.4 ppm (doublet, amide hydrogen), 5.80-5.20 ppm
(multiplet, benzyl hydrogens and C-5 and C-6 hydr~gens),
5.10 ppm (singlet, C-3 hydrogen), 5.05 ppm (singlet, benzyl
hydrogens), 3.60 ppm (singlet, phenylacetyl methylene
hydrogens), 1.30 ppm (singlet, C-2 methyl hydrogens) and
0.85 ppm (singlet C-2 methyl hydrogens).
-295c-
lOS'3~9~
EXAMPLE CLXXVI
Reaction of the appropriate 6-amino-2,2-dimethyl-3-
(l-substituted tetrazol-5-yl)penam with the requisite acid
chloride, according to the procedure o~ Example CLXXV provides
the following compounds:
Rl-N~ ~ 3
R2 ~ , ' '
," ," ",
Rl . R2
. _ .. . . .
acetyl p-methoxybenzyl .:
acetyl _-ethoxybenzyl -
propionyl ~-acetoxybenzyl ..
acryloyl p-benzyloxybenzyl
cyclohexanecarbonyl benzyl ~ : -
benzoyl 2-furylmethyl
~-chlorobenzoyl 3-furylmethyl .. :: .
m-bromobenzoyl m-propionoyloxybenzyl
o-fluorobenzoyl ~-isopropoxybenzyl
~-phenylacetyl ~-hydroxybenzyl
3-phenylpropionyl ~-methoxybenzyl :. .~
2-(~-tolyl)acetyl o-methoxybenzyl ::: . :-
2-(2-isopropylphenyl)acetyl ~-furylmethylbenzyl :: :
2-(m-chlorophenyl)acetyl ~-n-butoxybenzyl
2-(~,5-dibromophenyl)acetyl pivaloyloxymethyl ::~.:: ..
2,6-dimethoxybenzoyl o-acetoxybenzyl .
2-(p-chlorophenoxy)acetyl ~-methoxybenzyl
2-thienylcarbonyl o-methoxybenzyl :
2-(3-thienyl)acetyl p-methoxybenzyl ;.: .
2-(2-furyl)acetyl ~-hydroxybenzyl
2-(3-pyridyl)acetyl p-n-hexyloxybenzyl ~ ~
2-(5-tetrazolyl)acetyl 2-~urylmethyl :. -:: :
2-azido-2-phenylacetyl ~-methoxybenzyl ~.::
2-(~-cyanophenyl)acetyl ~-benzyloxybenzyl ~ : :
dodecanoyl p-methoxybenzyl : :~
aQryloyl ~-ethoxybenzyl
~'-octenoyl o-methoxybenzyl .: :
~ undecenoyl m-methoxybenzyl
2-dodecenoy~ urylmethyl
2-(phenylthio)acetyl p~methoxybenzyl ::.
2-phenylacetyl ~-phenylbenzyl .:
2-phenylacetyl diphenylmethyl ~ :
2-phenoxyacety} 3-chlorobenzyl :
2-phenoxyacetyl 3-chloro-4-methoxybenzyl . :
:~ 2-(2-thienyl)acetyl 2,4-dimethoxybenzyl - :~. .
2-(3-thienyl)acetyl 4-n-hexylbenzyl
.
;50
. - 296 -
'
: ' .
.~ .
. . .
~OS~9~'~
Rl ~2
2,6~-diethoxyben~oyl 4-fluorobenzyl
2-(~-thienyl)acetyl 3,4-dimethoxybenzyl
2-ethoxy-l-naphthoyl l-phenylethyl
5 2-n-butoxy-l-naphthoyl 4-nitrobenzyl
4-i~othiazole carbonyl l-(4-methoxyphenyl)ethyl
2-cycloheptylacety 3,5-dichlorobenzyl
2-(cyclohex-3-enyl)- 3-chloro-4-ethoxybenzyl
acetyl
lO 3-phenylpropionyl 4-isopropylbenzyl
2-phenylthioacetyl 4-iodobenzyl
2-(2-furyl)acetyl 4-methoxymethoxybenzyl
2-(l-pyrazolyl)acetyl 4-n-hexylbenzyl
2-(l-pyrrolyl)acetyl 4-n-hexyloxybenzyl
lS 2-(1,2,4-triazol-l-yl~ 4-biphenylylmethyl
acetyl
2-(3-sydnonyl)acetyl 4-bromophenyl
2-(2,4-dimethylthiazol- 2-formyloxybenzyl
5-yl)acetyl
20 2-bromoacetyl l-(4-chlorophenyl)butyl
2-bromoacetyl 4-ethylbenzyl
2-phenylacetyl 4-(n-hexyloxymethoxy)benzyl
cycloheptatrienyl- 3-formyloxybenzyl
carbonyl
25 2-phenylacetyl diphenylmethyl
2-phenoxyacetyl 4-(2-chlorophenyl)benzyl
2-(3-thienyl)acetyl 4-(4-tolyl)benzyl
2-(3-chlorophenyl)acetyl 2-(4-methoxyphenyl)benzyl
2-phenylacetyl COOC2H5
30 2-phenylbutyryl COOCH3
2-phenoxyacetyl COOC2H5
2-phenylthioacetyl COOC2H5
2-phenylacetyl COO-n-C6H3
2-thlenylacetyl CCH2 6 5
,35 3-thienylacetyl COOC6H5
3-thienyIacetyl C00-[4-(n-C4Hg)C6H4] : .
2-bromoacetyl C00-[4-N02C6H4]
2-chloroacetyl C00-(3-BrC6H4
4-bromobutyryl C00-14-(i-C3H70)C6H4~ .
2-(4-fluorophenyl)acetyl C00-[2,4-Cl2C6H3)
phenoxycarbonyl C00-(2-CH30C6H4)
benzyloxycarbonyl Co~-[4-(n-c6Hl3o)c6H3]
2-(4-fluorophenyl)acetyl Coo-(2-Fc6H4)
2,6-diethoxybenzoyl C00-(2-CH3C6H4)
2-~4-pyrldylthio)acetyl C00-14-(t-C4Hg)C6H4]
5-methyl-3-phenyl-4- COO [2,4 (N2)2C6H3]
l~oxazolylcarbonyl
2-cyanoacetyl COOCH3
2-(5-tetrazolyl)acetyl COOC2H5
2-(l-tetrazolyl)acetyl COO-n-C4Hg.
-297-
'.
~: .. i - :: ..... ,. : , . . .
~o~9~
Rl R2
2-azi.do-2-phenylacetyl CCH2C6H5
2-~ulfo-2-phenylacetyl C00-[2-N02-4-~C3H70)C6H3]
4-methyl-1-(2,6-diehloro-
phenyl)-5-pyrazolyl-
carbonyl COOC2H5
~12 -dodecenoyl CCH2C6HS
aeryloyl COOC6 5
cyclobutylcarbonyl COOC2H5
2-phenylacetyl S2CH3
. 2-phenoxyacetyl S02CH2(cH2)4cH3
2-(3-thienyl)acetyl S2CH2C6H5
2--eyanoaeetyl S02C6H5
2-(2-fluorophenyl)acetyl S02-[4 N02)C6H4] :: -
2-(3,4-dichlorophenyl~ so2-(4-Brc6H4) ~:
aeetyl
2-(3-bromophenyl)acetyl So2-(2-ClC6H4) ::
2-(3-tolyl)aeetyl S2~~2~C2Hs)C6H4)
2-(4-isopropylphenyl)- S02-[3-(n-C4Hg)C6H4)
aeetyl
2-(4-amyloxyphenyl)acetyl So2-[4-(cH3o)c6H4]
aeryloyl so2_(2,4_
2-(4-eyanophenyl)aeetyl So2-[3-cH3-4-(cH3o)c6H3J :
2-(2-furyl)aeetyl So2-l2~4-(No2)2c6H3]
ethoxyearbonyl S02-[2-CH30-5-(N02)C6H3]
aeetyl So2-cH2-(4-clc6H4)
butyryl S02-CH2-(2-Brc6H4)
benzoyl S02CH2-(3-CH3C6H4)
eyelopentaneearbonyl S02C2H5
1,4-eyclohexadienyl~ S02C2H5
earbonyl
2-(2-tetrazolyl)aeetyl S02-[4-(n-C4HgO)C6H4]
2-(4-ehlorophenyl) S02C6H5
thioaeetyl
2-phenylaeetyl phthalidyl
2-(2-thienyl)aeetyl "
2-(3-thienyl)aeetyl "
2-phenoxyaoetyl "
2-bromoaoetyl "
1,4-eyelohexadienyl-
earbonyl
. ',
.
,
-298-
10~
EXAMPLE CLXXVII
Reaction o the appropriate 6-amino-2,2-dimethyl-
3-~1-substituted tetrazol-5-yl)penam with the re~uisite
sodium N-(2-methoxycarbonyl-1-methylvinyl)-2-amino-2-sub-
stituted-acetate, according to the procedure of Example
CLXVII, affords the followlng co g
R -fH-CONH ~ ~ H3
2 :
R
R7 R2
methyl p-methoxybenzyl
isopropyl ~-hydroxybenzyl
cyclopentyl ~-methoxybenzyl
1,4-cyclohexadienyl ; p-acetoxybenzy
phenyl m-ethoxybenzyl
pheny} ~-hydroxybenzyl
phenyl p-methoxybenzyl
phenyl benzyl
phenyl 2-furylmethyl
~-hydroxyphenyl p-methoxybenzyl
~-hydroxyphenyl p-hydroxybenzyl
3-chloro-4-hydroxyphenyl 2-fùrylmethyl
2-thienyl p-methoxybenzyl
3-thienyl ~-hydroxybenzyl
2-furyl 2-furylmethyl -:`
~.
..
:: ,
-: .
~:' i , ' . .
:.: ~
: ~:
'''.~
. : ~
105~
Rl - R2
4-methoxyphenyl 3-chloro-4-methoxybenzyl
4-N,N-dimethylaminophenyl 3-chlorobenzyl
4-nitrophenyl diphenylmethyl
3-pyridyl 4-benzyloxybenzyl
4-fluorophenyl l-phenylethyl
phenyl 4-phenylbenzyl
benzyl 2,4-dimethoxybenzyl
3-indolylmethyl 4-iodobenzyl
2,4-dichlorophenyl 4-n-hexylbenzyl
3-bromophenyl 1-(4-chlorophenyl)butyl
3-tolylphenyl 4-bromophenyl
2-methoxyphenyl 4-ethylbenzyl
4-(n-butoxy)phenyl 2-formyloxybenzyl
3,5-dimethoxyphenyl 4-biphenylylmethyl
4-isopropylthiophenyl phenyl~(4-methoxyphenyl)methyl
4-methylthiophenyl 1-(4-methoxyphenyl)ethyl
3-furyl 4-nitrobenzyl
4-methylthiophenyl 2-fluorobenzyl
cycloheptyl l-phenylbutyl
cyclohexyl 4-methoxybenzyl
phenyl COOC2H5
3-thienyl
1,4-cyclohexadienyl "
p-hydroxyphenyl COOCH3
3-chloro-4-hydroxypheny COOC2H5
phenyl COOC6H13
phenyl COOC6H5
4-chlorophenyl CCH2C6H5
cyclohexyl COo-[4-(CH3)C6H4]
3-thienyl C00-[2-(CH30)C6H4)
phenyl C00-[2-N02-4-(c3H70)c6H3]
methyl C00-[2,4-(N02)2C6H3]
n-octyl COO-[2-FC6H4~
cyclopropyl C00-(3-BrC6H4)
~2-propenyl C00-[4-(n-C4Hg)C6H4]
Q2-butenyl COO-[4-Cl-3-CH3C6H3]
5-ethyl-2-thienyl COO-COO-i-C3H7
4-dimethylaminophenyl COOCH3
phenyl S2CH3
phenyl S2C2H5
2-thienyl ~'
methyl
n-butyl S2 n C6H13
dodecyl 2 6H5
cyclobutyl S2CH2C6H5
-300-
DEMANDES OU BREVETS VOLUMINEUX
LA PRÉSENTE PARTIE DE CETTE DEMANDE OU CE BREVET
COMPREND PLUS D'UN TOME.
CECI EST LE TOME / DE
.
:'.
NOTE: Pour les tomes additionels, veuillez contacter le ~ureau canadien des
. -
breveta
. ~ ' ':
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