Note: Descriptions are shown in the official language in which they were submitted.
736~
SY-1767A
BACKGROUND OF THE IN~ENTION
1. Field of the Invention
The present in~ention is directed to a new process for
the preparation of carbapenem antibiotics having a 2-substituent
of the formula
-S-~ ~ 5
in which A represents a C1-C6 straight or hranched chain alkylene
group; R represents an optionally substituted aliphatic, cyclo-
aliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, hetero-
aryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic
radical; and
~3
represents a nitrogen containing axomatic heterocycle attached to
the alkylene group A at a ring carbon atom and ~uaternized by
substituent R5.
2. Descri~tion of the Priox Ar~
.
I'he carbapenem derivatives prepared by the process o~
the present invention are disclosed and claimed by my colleague,
,
...
-- 3 --
~3~
Choung J. Ki~, in U.S. Patent No. 4,644,061 which issued
February 17, 1987.
In U.S. Patent No. 4,644,061 there is disclosed
the preparation of carbapenem antibiotics o~ the formula
}~l~S-A ~ 5
N 2
~ COOR
wherein R8 is hydrogen and R1 is selected from the group consist-
ing of hydrogen; substituted and unsubstituted: alkyl, alkenyl
and alkynyl, having from l-lO,carbon atoms; ~ycloalkyl and
cycloalkylalky~, having 3-6 carbon a~oms in the cycloalkyl xing
and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl,
xalkenyl and aralkynyl wherein the aryl moiety is phenyl and the
aliphatic pcr~ion has 1-6 carbon a~oms; heteroaryl, he~ero-
aralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero
atom or atoms in the ahove-named heterocyclic moieties are
seleotea from the group consisting of 1-4 oxygen, nitrogen ox
sulfur atoms and the alkyl moieties associated with said hetexo-
cyclic moieties have 1-6 carbon atoms; wherein the substituent or
substituents relative to the abo~e-named radicals are indepen-
dently selected ~xom the group consisting o~
,
Cl-C6 alkyl optionally substituted by amino, halo, hydroxy ox
carboxyl
halo
-oR3
-oCNR3R4
~ RNR3 R4
.. . .
~3~
-NR3R
_~NR
NR3 R4
- S~NR3R4
.~ .
-NHCNR3R4
R3 CNR4 -
-C~2
-o~R3
-SR
-~R9
-~R9
-CN
-oSo3R3
o
-O~-R~ '
-NR3~-R9
_op (O) (oR3) (OR )
-NR3C-NR
-NR3Co2R4
-N02
where n, relative to the above-named substituents, the groups R3
and R are independently selected from hydrogen; alkyl, alkenyl
.
~ 5 - ~2~3~
and alkynyl, having from ~-10 carbon atoms; cycloalkyl~ cyclo-
alkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the
cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety
is phenyl and the aliphatic portion has 1~6 carbon atoms; and
heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl
wherein the hetero atom or atoms in the above-named heterocyclic
moieties axe selected from the group consisting of 1-4 oxygen,
nitrogen or sulfur atoms and the alkyl moieties associated with
said heterocyclic moieties have 1-6 carbon atoms, or R3 and R4
taken togethex with the nitrogen to which at least one is at-
tached may form a 5- or ~-membered nitrogen-containing hetero-
cyclic ring; R9 is as defined for R3 except that it may not be
hydrogen; or wherein Rl a~d R8 taken together represent C2-C10
alkylidene substituted by hydroxy; R is selected from the group
consisting of substituted and unsubstituted: alkyl, alkenyl and
alkynyl, having from 1-10 carbon atoms; cycloalkyl and cyclo-
alkylalkyl, having 3-6 carbon atoms in the cycloal~yl ring and
1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aral-
kenyl and aralkynyl whe.rein the aryl moiety is phenyl and the
aliphatic portion has l-Ç carbon atoms; heteroaryl, hetero-
aralkyl, heterocyclyl ànd heterocyclyalkyl wherein the hetero
atom or atoms in the ahove-named heterocyclic moieties are
selected from the group consisting of 1-4 oxygen, nitroge~ or
sulfur atoms and the alkyl moieties associated with said hetero-
cyclic moieties have 1-6 carbon atoms; wherein the above named R5
radicals are optionally substituted by 1-3 substituents indepen-
dently selected fxom:
Cl-C6 alkyl optionally substituted by amino, fluoro, chloro,
carboxyl, hydxoxy or carbamoyl;
fluoro, chloro or bromo;
-oR3;
-oCo2R3;
-ocoR3;
-ocoMR3R ;
- 6 ~ '73~
o
-0~ -R9;
--oxo;
NR3R4
R3 ::ONRJs-; .
-NR3 C02R;
-NR3CûNR3R4;
-N~3 11 R9;
-SR3: .
O
-~-R;
O O
- S- R9;
-S03R;
C2 R
--CoNR3 R4,
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro, bromo, Cl-C6
alkyl ~ -oR3 ~ -NR3R4, -So3R3, -Co2R3 or -CoNR3R4, wherein R3, R4,
and R9 in such R5 substituents are as defined above; or RS may be
attached to
~ N-
at another point on the ring so as to form a fused heterocyclic
or heteroaromatic ring, which ring may contain additional hetero
atoms selected from 0, S and N;
R15 is selected from the group consisting of hydrogen;
substituted and unsubstituted: alkyl, alkenyl and alkynyl,
having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and
alkylcycloalky~, having 3-6 carbon atoms in the cycloalkyl ring
and 1-6 carbon atoms in the alkyl moieties; spirocycloalkyl
haviny 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralky~yl
wherein the aryl moiety is phenyl and the aliphatic portion has
1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and
, . ..
.
'
~2t73~
- 7 -
heterocyclylalkyl wherein the hetero atom or atoms in the
above-named heterocyclic moieties are selected from the group
consisting o~ 1-4 oxygen, nitroger and sulfur atoms and the alkyl
moieties associatPd with said heterocyclic moieties have 1-6
carbon atoms; wherein the substituent or substituents relative to
the above-named radicals are selected from the group consisting
o~: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl,
mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino,
nitro,-chloro, bromo, fluoro, cyano and carboxy; and wherein the
alkyl moieties of the above-recited substituents have 1-6 carbon
atoms;
A is O1-C6 straight or branched chain alkylene; R2 is hydrogen,
an anionic charge or a conventional readily remo~able carboxyl-
protecting group, providing that when R2 is hydrogen or a pro-
tecting group, there is also present a counter ion; and
r~
represents a substituted or unsubstituted mono-, bi- or poly-
cyclic aromatic heterocyclic radical containing at least one
nitrogen in the ring and attached to A through a ring carbon atom
and having a ring nitrogen which is quaternized by the group R5;
and pharmaceutically acceptable salts thereof, by the process
shown in the ~ollowing reaction scheme-
R8 ~ ~,
Rl ~ O R-~ >
.~ N COOR2
III
-- 8 --
R8 ~1 RlS f~
R~
o~ COOR2'
~Y 15
- Rl = N 5
N oOR
II
8 Rl~
Rl ~ ,S-A ~ N -R5 X' e
optional
- ~ ~ COOR2 de-bl~cking
Rl ~ 5-~ ~ N -R5
O~ COOR
.
In a preferred variant of the above process, the scheme
is modified as shown below:
.
.
...
. ..
- 9 ~
~ de-block
N COOR2
R ~
COO~ :
IIa lS
l ~ -R5
O COOe
Ia
To elaborate on the above process, starting material
III is reacted in an inert organic solvent such as methylene
chloride, acetonitrile or dimethylformamide with about an e~ui-
molar amount o~ an agent R-L such as p-toluenesulfonic acid
anhydride, p-nitrobenzenesulfonic acid anhydride, 2,4,6-
triisopropylbenzenesulfonic acid anhydride, methanesulfonic acid
anhydride, tri~luoromethane sulfonic acid anhydride, diphenyl
chlorophosphate, toluenesulfonyl chloride, p-bromobenzenesulfonyl
chloride, or the like, wherein L is the corresponding leaving
group such as toluenesulfonyloxy, p-nitrobenzenesulfonyloxy,
diph~noxyphosphinyloxy, and other leaving groups which are estab-
lished by.conventional procedures and are well-known in the art.
The reaction to establish the leaving group at the 2-position o~
intermediate III is advantageously carried out in the presence of
a base ~uch as diisopropylethylamine, triethylamine, 4-
dLmethylaminopyridine, or the like, at a kemperature o~ from
about ~20 to ~40C, most preferably at about 0C. The leaving
group L of intexmediate IV may also be halogen in which case such
group is established by reacting interm~diate III with a halo-
genating agent such as 03PC12, ~3PBr2, (0O)3PBr2, oxalylchloride
or the like in a solvent such as CH2C12, C~3CN, T~F, ~r the like,
in the presence of a base such as diisopropylethylamine, tri-
ethylamine, 4-dimethylaminopyridine, or the like. Intermediate
,
IV may be isolated if desired, but is conveniently used for the
next step without isolation or purification.
Intermediate IV is next converted to intermediate II by
a conventional displacement reaction. Thus, intermediate IV may
be r~acted with approximately an equimolar amsunt of a hetero-
aralkyl mercaptan reagent of the formula
r~ ..
HS A
.-
wherein A represents Cl-C6 straight or branched chain alkylene
and
~ ~ ' ''''' ' .
.
represents a mono-, bi- or polycyclic aromatic hetero~ycl.ic
radical containing a quaternizable nitroge~ in the ring, said
ring ~ei.ng attached to A through a ring carbon atom, in an inert
organic solvent such as dioxane, dimethylformamide,
dimethylsulfoxide or acetonitrile and in the presence o~ a base
suh as diisopropylethylamine, triethylamine, sodium hydrogen
carbonate, potassium carbonate or 4-dLmethylaminopyridine. The
temperature for the displacement is not critical, but an advanta-
geous temperature range is from about -40C to 25C. Most
conveniently, the reaction is carried out with cooling, e.g. at
about 0C to 10C.
Quaternization of the ring nitrogen:in the hetero-
aralkyl group o intermediate II is carried out by reacting
intermediate II in an inert organic solvent with at least an
equivalent (up to about a 50% molar excess) of an alkylating
agent of the formula
R5 X'
., ;.. ,:.. ' .
3L~73~
s
wherein R is as defined above and X' is a conventional leaving
group such as halo (chloro, bromo or iodo, most preferably iodo)
or a sulfo~ate ester moiety such as a mesylate, tosylate or
triflate. Examples of suitable non-reactive organic solYents are
chloroform, methylene chloride, tetrahydrofuran, dioxane,
acetone, dimethylsulfoxide and dimethylformamide. The
temperature for the alkylation reaction i5 not criti al and
temperatures in the range of from about 0C to 40~C are
preferred. Most conveniently, the reaction step i5 carried out
at room temperature.
Intermediate I' will have a counter ion X' (e.g.
derived from the alkylating age~t used) associated with it which
at this stage or at a later stage, i.e. following the de-blocking
step, may be substituted by a different counter io~, e.g. one
which is more pharmaceutically acceptable, by conventional
procedures. Alternatively, the counter ion may be subseguently
removed during the de-blocking step.
The de-blocking step to remove the carboxyl-protecting
group R2 of intermediate I' is accomplished by conventional
procedures such as solvolysis, chemical reduction or hydro-
genation. Where a protecting group such as p-nitrobenzyl,
benzyl, benzhydryl or 2-naphthylmethyl is used which can be
removed by catalytic hydrogenation~ intermediate I' in a suitable
solvent such as dioxane-water-ethanol, tetrahydrofuran-aqueous
dipotassium hydrogen phosphate-isopropanol or the like may be
treated under a hydrogen pressure of ~xom 1 to 4 atmospheres in
the presence o~ a hydrogenation catalyst such as palladium on
charcoal, palladi-un hydroxide, platinum oxide or the like at a
temperature of from 0 to 50C for from about 0.24 to 4 hours.
When R2 is a group such as o-nitrobenzyl, photolysis may also be
used for de-blockiny. Protecting groups such as 2,2,2-
trichloroethyl may be removed by mild zinc reduction. The allyl
protecting group may be removed by using a catalyst comprising a
mixture of a palladium compound and triphenyl phosphine in a
suitable aprotic solvent such as tetrahydrofuran, methylene
chloride or diethyl ether. Similarly, other conventional
73~
12 ~
carboxyl-protecting groups may be removed by methods known to
those skilled in the art. Finally, as mentioned above, compounds
of Formula I' whera R is ~ physiologically hydrolyzable ester
such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl,
methoxymethyl, etc., may be administered dixectly to the host
without de-blocking since such esters are hydrolyzed in YiVo
under physiological conditions~
The above-described process has several disad~antages.
Thus, for example, the process involves several steps which
advantageously could be reduced in number~ The overall reaction
yield is also quite low and the quaternization step is performed
on the carbapenem compound per se. It would be desirable to have
a new process for producing compounds of Formula I which (1)
involves fewer steps, (2) gives higher yields, (3) allows the
quaternized amine to be formed first and then attached to the
carbapenem nucleus at a later stage in the synthesis nd (4) can
be used to more easily form quaternary amine products with a wide
varie~y of amines, i.e. amines with steric hindrance and those
with low pKb values.
:' '
.- 13 _ ~73
.
The present invention provides a novel process for
preparation of carbapenem derivatives of the formula
R I~S~A~_R5
COOR2
wherein R3 is hydrogen and Rl is selected from the group consist-
ing of hydrogen; substituted and unsubstituted: alkyl, alkenyl
and alkynyl, having from 1-10 carbon atoms; cycloalkyl and
cycloalkyl21kyl, having 3-6 carbon atoms in the cycloalkyl ring
and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl,
aralkenyl and aralkynyl wherein the axyl moiety is phenyl and the
aliphatic portion has 1-6 carbon atoms; heteroaryl, hetero
aralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero
atom or atom~ in the above-named heterocyclic moieties are
selected from the group consisting of 1-4 oxygen, nitrogen or
sulfur atoms and the alkyl moieties associated with said hetero-
cyclic moieties have 1-6 carbon atoms; wherein the substituent or
substituents relative to the above-named radicals are indepen-
dently selected from the group consisting of
Cl-C6 alkyl optionally substituted by amino, halo, hydroxy or
caxboxyl
halo
-OR
-o~NR3R
IINR3R4
-NR3R4
NR3
NR3R4
" .
.
' ~' .
, ,: .
~L2~3~
. - 14 -
-S-NR3R4
~NH~NR3R4
-CO~R s
--O
-ollR3
SR3
O
-SR9
~ 9
-~R
--CN
N3 3
-oso3R,
R g
-Ofi-R
d
-N~,3R-R9
~ .
P ~0) (oR3) ~oR4
-NR3~NR4
R3
-NR3Co2R4
-N02
wherein, relative to the above-named substituents, the groups R3
and R4 are independently selected from hydrogen; alkyl, alkenyl
and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cyclo-
alkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the
cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aral,kenyl and aralkynyl wherein the aryl moiety
, . . .
.
.. . ...
~ ;~
" .
:;
.. ' -.'
, .
~:,. . "
.-- 15 ~
is phenyl and the aliphatic portion has 1-6 carbon atoms; and
heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl
wherein the hetero atom or atoms in the above-named heterocyclic
moieties are selected from the yroup consisting of 1-4 oxygen,
nitrogen or sulfur atoms and the alkyl moieties associated with
said heterocyclic moieties have 1-6 carbon atoms, or R3 and R4
taken togethex with the nitrogen to which at least one is at-
tached may form a 5- or 6-memb~red nitrogen-containing hetero-
cyclic ring; Rg is as defined for R3 except that it may not be
hydrogen; or wherein Rl and R8 taken together represent C2-C10
alkylidene substituted by hydroxy; R is selected from the group
consisting of substituted and unsubstituted: alkyl, alkenyl and
alkynyl, having from i-10 carbon atoms; cycloalkyl and cyclo-
alkylalkyl, havins 3-6 carbon atoms in the cycloalkyl ring and
1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aral-
kenyl and aralkynyl wherein the aryl moiety is phenyl and the
aliphatic portion has 1-6 carbo~ atoms; hetexoaryl, hetero-
aralkyl, heterocyclyl and heterocyclyalkyl wherein the hetero
atom or atoms in the above-named hetervcyclic moieties are
selected from the group consisting of 1~4 oxygen, nitrogen or
sulfur atoms and the alkyl moieties associated with said hetero-
cyclic moieties have 1-6 carbon atoms; wherein the above-named R5
radicals are optionally substituted by 1-3 substituents indepen-
dently selected from:
C1-C6 alkyl optionally substituted by amino, fluoro, chloro,
carboxyl,. hydroxy or carbamoyl;
fluoro, chloro or bromo;
oR3;
-oCo2R3;
-OCOR ;
-ocoNR3R~;
~i g '
-O~-R ;
o
--oxo;
NR3R4;
~3~
~ 16 --
R 3 CoNR4 _;
-NR3Co2R;
--NR3CoNR3R4;
~ NR3~-R9,
''
-SR3,
-~-R9;
O
1~ 9
-S-R;
~So3R3;
C2R;
-CoNR3R4;
-CN; or
phenyl opt onally substituted by 1-3 fluoro, chloro, bxomo, Cl-C6
alkyl,. -OR , -NR R , -SO3R , -C02R or -CONR R , wherei~ R3, R4,
and R9 in such R5 substituents are as de~ined.above; or R ~ay be
attached to _ _
.
at another point on the ring so as to form a fused heterocyclic
or heteroaromatic riny, which xing may contain additional hetero
atoms selected from O, S and N;
R15 is selected from the group consisting of hydrogen;
substituted and unsubstituted: alkyl, alkenyl and alkynyl,
having from 1 10 carbon atoms; cycloalkyl, cycloalkylalkyl and
alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring
and 1-6 carbon atoms in the alkyl moieties; spirocycloal~yl
having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl
wherein the aryl moiety is phenyl and the aliphatic portion has
1-6 carbon atoms; heteroaryi, heteroaralkyl, heterocyclyl and
heterocyclylalkyl wherein the hetero atom or atoms in the
above-named heterocyclic moieties are selected from the group
consisting of 1-4 oxygen, nitrogen and sulfur atoms and the alkyl
moieties associated with said heterocyclic moieties have 1-6
carbon atoms; wherein the substituent or substituents relative to
.;
:
.
...
- 17 -
the above-named radicals are selected from the group consis~ing
of: amino, mono-, di~ and trialkylamino, hydroxyl, alkoxyl,
mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino,
nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the
alkyl moieties of the above-reci~ed substituents have 1-6 carbon
atoms;
A is Cl-C~ straight or bxanched chain alkylPne; R2 is hydrogen~
an anionic charge or a conventional readily removable carboxyl
protecting group, providing that when R2 is hydrogen or a pro-
tecting group, there is also present a counter ion; and
... , . . _ .
represents a substituted or unsubstituted mono-, bi or poly-
cyclic aromatic heterocyclic radical containing at least one
nitrogen in the ring, said ring being attached to A through a
ring carbon atom and having a ring nitrogen which is ~uaterni2ed
by the group R5; and pharmaceutically acceptable salts thereof,
which process comprises reacting an intermediate of ~he formula
R8 15 ..
Rl~[L
. ~ N COOR2'
IV ,,
wherein Rl, R8 and R15 are as defined above, R2 is a
conventional readily removable carboxyl protecting group and L is
a conventional leaving group such as toluenesulfonyloxy, p-
nitrobenzenesulfonyloxy~ diphenoxyphosphinyloxy or halo with a
thiol compound of the ~ormula
HS-A- ~ -0R5 VII
- 18 -
wherein A and
R
~~
are as defined above and ~ is a counter anion in an inert
solvent and in the presence of base to produce a
carbapenem product of the formula
R15
Rl ~S~ R5
(g-- CC:~OR2
wherein Rl, R8, R15 R2' A
~3 5
~ -R
and ~ are a6 defined above and, if desired, removing the
carboxyl protecting group R2 to give the corresponding de-
blocked compound of Formula I, or a pharmaceutically
acceptable salt thereof.
Thus in one embodiment of the pre~ently claimed
invention the invention provides a process for the
preparation of a compound of the formula
OH ~ Rl5
SC~I~R5
~ 0
wherein R15 i8 methyl and
.
:
.
~3~
- 18a -
represent~ a radical of the formula
R5 ~6
+ ~ ~7
whersin R5 is C1-C4 alkyl and R6 and R7 each independently
represent hydrogen or C1-C4 alkyl, or a pharmaceutically
acceptable salt or ester thereof, which process comprises
reacting an intermediate of the formula
o~ ~oOR2
wherein L i~ a conventional leaving group, R15 is as
defined above and R2 is a conventional readily removable
carboxyl protecting group, with a thiol compound of the
formula
HS.-CH2 l ~ _ R7
10 wherein R5, R6 and R7 are a~ defined above, in an inert
solvent and in the prssence of base to produce a
carbapenem product of the formula
~ ScH2~5
rr Ir
~ ~co~2
. .~,
:, ; ' "
. ~
. . .
.: :
'
- 18b -
~ ~ 5
wherein R15, R2 and are as defined above
and, if desired, removing the protecting group R2 to give
the corresponding de-blocked carbapenem product, or a
pharmaceutically acceptabl2 salt thereof.
In another embodiment ~he invention provides a
process for the preparation of a compound of the formula
CH
~H ~ e~3 ~ 3
SCH
I
or a pharmaceutically acaeptable salt thereof, which
process comprises reacting an intermediate of the formula
~R2
wherein L is a oonventional leaving group and R2 is a
conventional readily removable carboxyl-protecting group
with a thiol compound of the ~ormula
H
~5-c~2~ 3 ~
wherein ~ i8 a counter anion, in ~n inert solvent and in
the presence of ba~e to produ¢e a ¢arbapenem product of
the formula
'~,3
~2~3~
- 18c -
~00~
wherein R2 and ~ are as defined above and, if desired,
removing the protecting group R2 to give the
corresponding de-blocked compound of Formula I, or a
pha~maceutically acceptable salt thereof.
Also provided by the present invention are
intermediates of Formula VII.
The carbapenem compounds of Formula I are potent
antibacterial agents or intermediates useful in the
preparation of such agents.
DE~AILED DESCRIPTION
The compounds of Formula I above contain the
carbapenem nucleus
~ !13
and may thus be named as 1-carba-2-penem-3-carboxylic aaid
derivatives. Alternatively, the compounds may be
considered to have the basic structure
6, ~ ~3
17
0~ '
and name as 7-oxo-1-azabiayclo (3.2.0)hept-2-ene-2-
aarboxylic acid derivatives. While the present invention
includes compounds wherein the relative stereochemistry of
the 5,6-protorts i8 aia as well as ~ , the preferred
compounds have the 5R,6S (~an~) stereochemistry as in the
case of thienamyain.
The compounds of formula I may be unsubstituted in
:,
: , ; ' .~
:.
:: ,
`' ' ~ .
.: .,;
.,, : .
-- 19 --
the 6-position or substituted by 6 ubstituent groups
previously disclosed for other carbapenem derivatives.
More specifically, R8 may be hydrogen and R1 may be
hydrogen or a non-hydrogen substituent disclosed, for
example, in European Patent Application 38,869 (see
definition of R63. Alternatively, R8 and ~1 taken
together may be C2-C10 alkylidene or C2-C10 alkylidene
substituted for example, by hydroxy.
The compounds of Formula I may also be unsubstituted
10 in the 1-position (R15=H) or substituted by substituent
groups previously disclosed ~or other carbapenem
derivatives. More specifically, R15 may be hydrogen or
any of the non-hydrogen 1-substituents dlsclosed, for
example, in European Patent Application 54,917 (see
15 definition of R1 or R2 therein) or in U.S. Patent
4,350,631. Preferred non-hydrogen R15 6ubstituents
include C1-C6 alkyl, most pxeferably methyl; phenyl; and
phenyl (C1-C6) alkyl. ~he non-hydrogen R15 substituent
may be in either the a- or B- configuration, and it is
20 intended that the present invention include the individual
a- and B-iaomers, a~ well as mixtures thereof.
To elaborate on the definitions for R1, R8 and R15;
(a) The aliphatic "alkyl", "alkenyl" and "alkynyl"
groups may be straight or branched ahain having 1-10
25 carbon atoms; preferred are 1-6, most preferably 1-4,
carbon groups; when part of another substituent, e.g. as
in cycloakylalkyl, or heteroaralkyl or aralkenyl, the
alkyl, alkenyl and alkynyl group preferably contalns 1-6,
mo6t preferably 1-4, carbon atoms.
(b) "he~eroaryl" include~ mono-, bi- and polycyclia
aromatic heteroayolic group~ aontaining 1-4 O, N or S
atoms; preferred are 5- or 6-membered heterocyolic rings
such as thienyl, furyl, thiadiazolyl, oxadiazolyl,
triazolyl, isothiazolyl, thiazolyl, imidazolyl,
35 isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl,
~3~
- 20 -
pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, etc.
(c) "heterocyclyl" includes mono-, bi- and
polycyclic saturated or unsaturated non--aromatic
heterocyclic groups containing 1-4 O, N or S atoms;
preferred are 5- or 6-membered heterocyclic rings such as
morpholinyl, piperazinyl, piperidyl, pyrazolinyl,
pyrazolidinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl,
eta.
(d) "halo" includes chloro, ~romo, fluoro and iodo
and is preferably chloro, fluoro or bromo.
The term "conventional readily removable carboxyl
protecting group" refers to a known ester gro~p which has
been employed to block a carboxyl group during the
chemical reaction steps described below and which can be
removed, i~ desired, by methods which do not result in any
appreciable destruction of the remaining portion of the
molecule, e.g. by chemical or enzymatic hydrolysis,
treatment with chemical reducing agents under mild
conditions, irradiation with ultraviolet light or
catalytic hydrogenation. Examples of such ester
protecting groups include benzhydryl, allyl, p
nitrobenz,vl, 2-naphthylmethyl, benzyl, trichloroethyl,
silyl such as trimethylsilyl, phenacyl, p-methoxybenzyl,
acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C1-C6 alkyl
such as methyl, ethyl or t-butyl. Included within such
protecting groups are those which are hydrolyzed under
physiological conditions such as pivaloyloxymethyl,
acetoxymethyl, phthalidyl, indanyl and methoxymethyl. A
particularly advantagaous aarboxy protecting group is p-
nitrobenzyl which may be readily xemoved by aatalytia
hydrogenolysis.
~he pharmaaeutically acceptable salts re~erred to
above include the nontoxic acid addition salte, e.g. salts
with mineral acids such as hydrochloric, hydrobromic,
hydroiodic, phosphoric, sulfuric, etc. and salts with
, .
,~ .
: . :
- 21 -
organic acids such as maleic, acetie, citric, suacinic,
benzoic, tartaric, fumaric, mandelic, ascorbic, lactic,
gluconic and malic. Compounds of formula I in the form
of acid addition salts may be written as
Rl ~ 5 ~ X~
R2 = H or protecting group
where X ~ represents the acid anion. The oounter anion
may be selected BO as to provide pharmaceutically
acceptable salts for therapeutic administration but, in
the case of intermediate compounds of formula I, X may
also be a toxie anion. In sueh a ease the ion can be
sub~eguently removed or substituted by a pharmaeeutically
aeceptable anion to form an active end produet for
therapeutic use. When acidic or ba~ic groups are present
in the R1 or R5 group or on the
~~\e3
~--
radical, the pre6ent invention may also include suitable
base or acid salts of these functional group~, e.~. acid
addltion salts in the case of a ba~ic yroup and metal.
salts (e.g. sodium, potassium, ealeium and aluminum), the
ammonium ~alt and salts with nontoxic amines (e.g.
trialkylamines, procain0, dibenzylamine, 1-ephenamine, N-
benzyl-B-phenathylamine, N,N'-dibenzylethylenediamine,
etc.) in the case of an acidic group.
,~
`
'
- 22 -
Compounds of formula I wherein R2 i8 hydrogen, an
anionic charge or a phy6iologically hydrolyzable ester
group together with pharmaceutically acceptable æalts
thereof are useful as antibacterial agent~. The remaining
compounds of formula I are valuable intermediates which
can be converted into the above-mentioned biologiaally
active compounds.
A preferred embodiment of the present invention
comprises compounds of formula I wherein R8 is hydrogen
and R1 is hydrogen, CH3CH2-
CH3 ~ OH
~ CH- / C- or CH3CH-
CH3 CH3
Among this 8 ubclass, the preferred compounds are those in
which R is
OH
CH3CH ~ mo6t preferably compounds having
the absolute configuration 5R, 6S, 8R.
Another preferred embodiment comprise~ aompounds of
formula I in whiah R1 and R8 taken together form an
alkylidene radiaal of the formula
HOCH2 C=
CH3 /
The alkylene ti.e. substituent "A") radical in the
compounds of formula I may be straight or branched chain
and may contain from 1 to 6 carbon atoms. A preferred
embodiment comprises those compounds in which A is
-(CH2~-n in which n is 1 or 2 and a partiaularly preferred
embodiment comprises those aompounds where A is -CH2-.
~! .,
- 23 ~ ~ 3~
The alkylane moiety ".~ attaahed vi.a a ring
earbon atom to an N-sub6tituted ~uaternized aromatic
heterocycle of the ~eneral formula
N ~ R
wherein the R5 substitue~t i 6 preferably an optionally
substituted C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl,
C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, phenyl,
phenyl-C1-C6 alkyl, phenyl-C2-C6 alkenyl, phenyl-C2-C~
alkynyl, heteroaryl, heteroaralkyl in whieh the alkyl
moiety has 1-6 earbon atoms, heterocyclyl or
heterocyelylalkyl in which the alkyl moiety has 1-6 carbon
atoms. The heteroaryl (or heteroaryl portion of
heteroaralkyl) R5 substituent may be a mono-, bi or
polyeyelie aromatic heteroeyclie group eontaining 1-4 O, N
or S atoms; preferred are 5- or 6-membered heterocyelie
rings sueh as thienyl, furyl, thiadiazolyl, oxadiazolyl,
triazolyl, i~othiazolyl, thiazolyl, imidazolyl,
isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, pyrrolyl and pyrazolyl. The
heteroeyclyl (or heteroeyel yl portion of
heterocyalylalkyl) R5
~0~
.
.
:
- 24 ~
substituen~ may be a.mono-, bi- or polyoyclic saturated or
unsaturated non-zrc)matic he~erc:cyclic group cc~II.zining 1-4 O,
N or S 2toms; pre~erred are 5- or 6-m~mbere~ heter~cycllc rings
su~h as morpholinyl, piperazinyl, piperidyl, pyrazolinyll
pyr2zolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl and
pyrrolidinyl.
The R5 subs~ituent may be op~ionally subs.itu.ed by 1-3
su~s'i~uen~s independently selected frc:m:
(a) Cl-C6 al};yl optionally substituted by, preferably 1-3,
amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl
groups;
(b) fluoro, chloro or bromo;
( c) -oR3
(d) -OC02R
(e) -OCOR
(f) -ocoNR3R ;
(g) n
-OS-R
c~ .
(h) -oxo ;
(i) -NR R
( i ) R3CoNR4-
(k) -NR3Co2R4 ;
(1) -NR CONR R
(m) o
-NR3S-R9 ;
O
.(n) -sR3;
(o) -SOR9 ;
P ll g
--S--~ ;
~q) -503R
(r) -CO~R
(5 ) -CoNR3R4
(t) -CN ; or -
- 25 ~ 7~L
(u) phenyl optionally substituted by 1-3 substituents in
deper~dently selected from fluor~, chloro, bromo, Cl-C6
alkyl r -oR3~ -NR R4, -So3R3, ~Co2R3 or -CoNR3R4, wherein,
relative to the abovio-named R substituents, the groups
R3 and R4 are independently selected from hydrogen; allcyl,
A~kenyl a~ad alkynyî, ha~i~g 1-10 C?r~O~a atoms; cyclo
- alkyl, c:ycl~alkylal)cyl and al~ylcy~loal~l ~ ha~i~g
3-6 carbon atoms in the cycloalkyl ring 2nd 1-6 c2r~0~
a~ms in 'che alkyl moieties; phenyl; ?r~lkyl, ~ Xe:~lyl
znd 2ra~cynyl wherein t~e aryl moiety is phenyl ~ the
21iphatic p~r.io~ has ~-6 caxbon atoms; and hetero ~yl,
heteroaralcyl, he.-erocyclyl 2nd heter~ycly~alkyl wherea~
,he he,eroaryl 2nd he,er~cyclyl group o~ p~rtion of a
sroup is 25 de-ined zbo~e ~os R~ ~nd ~he ælkyl ~oieties
associated wi~h said he'erocyclic moieties hz~e 1-6
carbon at~ms; or R3 and R4 ~Xe~ togethe~ with ~he ~itr~gen
~o which at least one is at.2ched m2y form a 5- or
6-membered nitr~ge~-contai~i~g heter~yclic (2S defi~ed
abo~e ~or ~) ring;-'and R9 is 2S defi~ed abo~e for R3
except th2t it may n~t be hydrogen. A m~st pre~e_re~ X~
subs~i~uent is Cl-C6 alkyi, especially ~ethyl.
In addition, the R substituent, together with. another
ring atom of the /,-
~
( N3
moiety, may form a ~used heterocyclic or heteroaxomatic ring,which ring may contain additional, preferably 1 or 2, he~ero
ato~s selected ~rom 0, N and S. ~or example,
CN~_R may be ~
~ or ~ ~
- 26 - ~3~
The group
preferably represents a substituted or unsubstituted mono-, bi-
or polycyclic aromatic heterocycle containing at least one
nitrogen in the ring and 0-5 additional ring hetero atoms selected
from 0, S and N, said heterocyclic ring being attached to A
thxough a ring carbon atom and havi~g a ring nitrogen atom
quaternized by the group R5.
The heteroaromatic
~ N-
ring may be optionally substituted at available ring carbo~
atoms by preferably 1-5, most preferably 1-3, substituents in-
dependently selected ~rom the group consisting of Cl-C4 alXyl;
Cl-C4 alXyl substituted by, preferably 1-3, hydroxy, amino,
Cl-C4 alkylamino, di(Cl-C4)alkylamino t Cl-C4 alkoxy, carboxy,
halo (hereinafter intended to mea~ chloxo r bromo, fluoro or iodo;
preferably chloro, bromo or fluoro) or sulfo; C3-C~ cycloalkyl;
C3-C6 cycloalkyl(Cl-C4)alkyl optionally substituted by 1-3
substituents mentioned abo~e in connection with.Cl-C4 alkyl;
Cl-C4 alkoxy; Cl-C~ alkylthio; amino; Cl-C4 alkylamino;
di(Cl-C~)alkylamino; halo; Cl-C4 alkanoylamino; Cl~C4 alkanoyloxy;
carboxy; sul~o; O
-~-O-Cl~C~ alkyl;
hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1-3
substituents independently ~elected from amino, halo, hydroxy,
trifluoromethyl, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 alkylamino,
di~Cl-C4)alkylamino, ~arboxy and sulfo; phenyl(Cl-C4)-
alkyl in which the phenyl portion may be optionally
substituted by 1-3 substituents mentioned above in
connection with phenyl and the alkyl portion may be
optionally substituted by 1-3 substituents mentioned above
in connection with Ci-C4 alkyl; and heteroaryl or hetero-
aralkyl in which the hetero atom or atoms are selected from
the group consisting of 1-4 O, S or N atoms and the alkyl moiety
,:;
~ : .... . .
''; '~ "
,, :.
:~
.',~
- 27 -
associated with heteroaralkyl has 1-6 carbon atoms t said
heteroaryl and heteroaralkyl groups being optionally substituted
in the he~erocyclic rin~ moiety by 1-3 substituents independently
selected from hydroxy, a~ino, halo, trifluoromethyl, Cl-C4 aIkyl,
Cl-C4 alkoxy, Cl-C4 alkylamino, di (Cl-C4~alkylamino, carboxy and
sulfo and in the alkyl moiety by 1-3 substituents selected ~rom
hydroxy, amino, Cl~C4 alkylamino, di tCl C4) alky 1 4
alkoxy, carboxy, halo and sulfo. In addition, available ring
nitrogen atoms (other than the quaternized nitrogen) may be
substituted by 1-3 substituents independently selected from the
group consisting of Cl-C4 alkyl; Cl C4 alkyl substituted by,
preferably 1-3, hydroxy, zmino, Cl-C4 alkylamino, di(Cl-C4~-
alkyl~mino, Cl-C4 alkoxy, carboxy, halo or sulfo groups;
C3-C6 cycloalkyl; C3-C6 cycloaLkyl (Cl-C4) alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with Cl-C~ alkyl: phenyl; phenyl
substituted by 1-3 substituents independently selected ~rom
amino, halo, hydroxy, trifluoromethyl, Cl-C4 alkyl, Cl-C4 alkoxy,
Cl-C4 alkylamino, di(Cl-C4)alkylamino, ~arboxy and sul~o;
phenyl(Ci-C4)alkyl in which the phenyl portion may be optionally
substituted by 1-3 substituents mentioned above in co~nection with .
phenyl and the alkyl portion may be optionally substituted by
1-3 substituents mentioned above in connection with Cl-C4 alkyl;
and heteroaryl or heteroaralkyl in which the hetero atom or
atoms are selected from the group consisting o~ l-A 0, S or M
atoms and the alkyl moiety associated with heteroaralkyl has
1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being
optionally substituted in the heterocyclic ring moiety by 1-
~substituents independently selected from hydroxy, amino, halo,
tri f luoxomethyl, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 alkylamino,
di(Cl-C4)alkylamino, caxboxy and sul~o and in the alkyl moiety
by 1-3 substituents selected from hydroxy, amino, Cl-~4 alkylamino,
di (Cl-C4) alkylamino, Cl~C4 alkoxy, carboxy, halo and sulfo. The
most prefexred ring carbon and nitrogen substituents are Cl-C6 alkyl,
especially methyl.
- 28 -
Within the abQve-d~scri~ed pre.erred embodiment, the
preferred compounds are those in which A is -(C~2.)n in which
n is ~ or 2, most preferably. those in which A is -~H2- and
wherein ~ 2) Rl and R8 taken t~gether represent
2 ~
~C=
C~3
or tb) R8 is hydrogen and Rl represents hydrogen, C~3C~2 ,
c~3 CH3 0~ 0~
C~3 C~ .-' C- . , or CH3C~-
Particula~ly pre,erred are the compounds wherein ~8 is
hydrogen and Rl ~s
p$
CH3C~- , especially compounds
ha~ing the zbsolute configuration 5R, 6S, 8R.
In a preferred embodiment the group
~ .
.
V ..
represe~ts an aromatic 5- or 6- membered, N-cont~ining hete,o-
cyclic ring containing 0-3 additional hekero atoms selected fxo~
O, S or ~ Such aromatic heterocycle may, where possible, ~e
fused to another ring which may be a saturated or unsaturated
~axbocyclic ring, preferably a C4-C7 carbocyclic ring, a~ aromatic
carbocycli~ ring preferably a phenyl ring, a 4-7 membered hetero-
cyclic ring (saturated or unsaturated) containing 1-3 hetero atoms
selected fro~ 0, S, N or NRll in which R 1 is hydrogen, Cl-C6 alXyl
option211y substituted by 1-2 substituents independently selected
~rom -0~3, -NR3R4, -C02R3, oxo, phenyl, fluoro, c~loro, bromo,
: .: . . .. . . .
.: '
, :
.
~73~
-- 2~ --
-So3R3 and -CoNR3R4, or phenyl optionally substituted by 1-3.
subs .ituents independently selected ~rom Cl C6 alkyl, -oR3,
-NR3~4, :luoro, chlc:ro, bromo, -sQ3R3, -Co~R3 a~d -CoNR3R4,
wherein R3 and.R4 i~ such Rll substituents are 2S ~ei~ed above
in connection with su~stituen~ R, or a 5-6 membër.ed hëter~
zrom2'ic rin~ c:ontaining 1-3 hetero atoms selected ~rom 0, S,
N or N~ which Rll is as defined abo~e_ The S or 6- membered
zromztis:: ~Euaternized ring or, where appropria~e, the carbocycl~c,
heterocyclic or heteroaromati~ r~ng ~used thereto, or both such
rings ~ may be optionally substi.uted on a~ail2ble riny
a~oms b~, preferzbly up to a total of fi~e substituents for
t}le totzl ri~g syste~, the s~stituents mentioned a}ove iD.
connection with the group
~ .
~ N -
Within the above-described preferred emb~diment, the -
preferred compounds are those in which A is -(C~2)~ i~ which
~ is 1 or 2, most ~referably those in which A is -C~2- znd
wherein (a) Rl and R8 taken together represent
. . ~CH2 ~
Cs
or (b) R~ is hydro~en and R1 represe~ts hydrogen, C~3Ca~-,
CH3 ~ C~ o~
C~- , C- , or CH3C~-
c~3 c~3
Particularly preferred are the compounds wherein R8 is hydrogen
and Rl is
~I
C~3CH-, especially compounds having the 2bsolute
- cc~ uration 5R, 6S, 8R.
",
.
3 ~ 73~
~ Still another pre~erred embodiment of the present invention
co;nprises compound~ o~ formula I wherei~
~3 ~
_ ~ N--~ .
~ ' ,
represe~.s a xadical selected from ~he group consisting of
(a) ~ ~
. ~ ,
~ ,10
whe:cein ~6, R7 ~u~d ~10 are independently selected ~ro~n hydrogcn;
Cl-C4 alkyl; Cl-C4 alkyl substituted by, preferably 1-3, hydroxy,
4 . ~ (Cl C4 alkyl)~mino, Cl-C4 alkoxy amino lf
carbo~ or halo (chloro, bromo, fluoro or iodo; preferzbly chloro,
fluoro or bromo); C3-C6 cycloAlkyl; Cl-C4 alkoxy; Cl-C4 alkylthio;
amino; Cl-C4 aIkylamino; di(Cl-C4 alkyl)amino;.halo tchloro,
bromo, fluoro or iodo; prefera}~ly chloro, fluoro or bromo~; Cl-C4
21~canoyl~rl0; Cl-C4 al~oyloxy; carboxy;
o
-C-OCl-C4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl
substituted by one, ~wo or three amino, halo (chloro, bromo,
fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl,
trifluoromethyl, Cl C4 alkyl or Cl-C4 alkoxy grou? s;.
phenyl (C1-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
abo~e in connectio~ with phenyl and the alkyl portion
m~y be optionally substituted by 1-3 suhstituents mentioned
above i~ connection with C -C alkyl:; and heteroaryl
_ _ _ . 1 4 . .................................... ......
and heteroaxalkyl in which th2 hetero atom ox atoms.i~ the above- :
named heteroyclic moieties are selected from the gr~up consisting
o~ 1-4 oxygen, nitroge~ or sulfur atoms and the alkyl moiety
associated with said heteroaral~cyl moiety has 1-6 carbon atoms;
or wherei~ ~wo of R6, R7 or R10 taken togetXe~ may be a fused
saturated carbocyclic ring, a fused aromatic carbocyclic ring,
a fused non-aroma tic heterocyclic ring or a ~used heteroaromatic
ring, said fused rings being optionally su~stituted by 1 or 2 of
the substituents defined abo~e for R6, R7 and R ;
,, .
. .
, :'' "" `'
''
31
~I or
~x3
opti~nally su~s.itu~e~ a car}~orl ato~a by one to three sub-
stitueTlts independently selected ~rom ~l-C4..&1kyl; Cl-C4
~lkyl su~stituted }~y, prefer2hly 1-3 j hydrQxy, Cl.-C~ alkyl2~ino,
sulfo, di ( .l-C4 21~cyl) æmino, C~ 4 alkoxy, amino, ~ar~oxy ~r halo
(chloro, bromo, fluoro or iodo; pre~erably chloro, ~lu~ro or
bromo); C3-C6 ~c1021kyl; Cl-C4 ~lkoxy; el-C4 æl~cylth~ 0;
Cl C,~ aOcylami~ao; di (Cl-C4 alkyl) amino; halo (chloro, b~c~mo,
fluoro or iodo; p~eferably chloro , fluoro or b_omo); Cl-C4
al~c2noyl~no; Ct C4 alkarloyloxy; car:boxy;
. o
-C-O ~ C4 21kyl; hydro~; æmidino; gu~idi~o; phenyl; phenyl
su!~stikuted by one, I:wo or th:ree æ~ino, halo ~c~loro, bro:mo,
:Eluor~ o:c iodo; prefera}:~ly chloror :Eluoro or b:como), hydroxyl,
~rifluo~ome'chyl, C:l-C~ al~cyl or Cl . C4 xy g
phenyl (C1-C,L)alkyl in which the phenyl portion may be
optionally substiltuted by 1-3 substituents mentioned
above i~ connectio~. with phenyl and the alkyl portio~
may b~ optionally substituted by 1-3 suhsti4ue~ts mentioned
abo~r~ in co~ec~ion with Cl-C~ ~lkyl:; antl.heteroaryl
or heteroaralkyl in which the hetero atom or ~toms iri the
~ove-named heterocyclic moieties are selected ~ro:m the group
consisting o~ oxygen, ~itrogen or sulfur ~to~ns ar~d the alkyl
moiety 2ssociated wiSh szid hetero2ralkyl moiety ~as 1-~ carbor~
a'oms, ox s:pl:ionally su~stituted so 25 to fo2m a ~USE:~ carbo--
cyclic, heterocyclit: or heteroaromati~ ring optioslally substituted
~y 1 or 2 of the sul~s 'ituen~s de~ined a~ove;
,.~ . ' '' .
'~
- 32~
~5 R5 R5
~1 el
(c ~ ~ N~` ~ N ~ ~ A
N~ r t
RS ~ 5
optionally substituted on a carbon ztom by one or two su}: sti-
tuents independently selected from Cl-C4 alkyl: Cl-C4 alkyl
substituted by~ pre era~ly 1-3, hydroxy, ::1-C4 ?lkylamino, sul~o,
di (Cl-C4 alkyl) aminor Cl-C4 z.lkoxy, 2~i~0, carboxy or halo
(chloro, bromo, fluoro or iodo; preferably chloro, fluoro or
br~mo); C3-C6 cycloal}cyl; Cl-C,~ alkoxy;. Cl-C4 alkylthio; amir~o;
Cl-C4 allcylam~no; di (Cl-C4 alXyl) a~no; halo (chloro, bromo,
fluoro or iodo; preferably chloro, fluoro or bromo); CL-C4
l,'carloylamir~o; Cl-C4 alkanoyloxy; carJ: oxy;
o
-C-OCl-C4 alkyl; hydroxy, amidino; guanidino, phenyl; phenyl
substitu~ed by one, two or three ~-nino, halo (chloro, bromo,
fluoro or iodo; pre~erably chl4ro, 41uoro or bromo), hydroxyl,
trifluoromethyl, Cl-C4 alky1 or Cl-C4 alkoxy groups,
phenyl ~Cl-C4)alkyl in which the phenyl portion may be
optionally substituted ~y 1-3 substituents mentioned
abo~e in connection with phenyl and ~he alkyl portion
may be optionally substituted by 1-3 substituents mentioned
above in connection with Cl-C4 alkyl; and heteroaryl
or ~eteroaralkyl in which the hetero atom or atoms
in the abo~e-named heterocyclic moieties are selected from the
group consisting of 1-4 oxygen, nitrogen or sulfur atoms and
the alkyl moiety associated with said heteroaralkyl moiety has
1-6 carbon atoms, or optionally substituted so 25 to form a fused
carbocyclic, heterocyclic or heteroaromatic ring optionally
sub~tituted by 1 or 2 of the substituents defined abo~e;
3 3 _ ~ 2~3~
~5 ~,5 ~5
( d ) N~ '~ N ~N N~ ~N
~5 n ' ~.5 e ~s
N~ N
op'ionally substituted on a carbon atom by a eubstitue~
inaependently se~ected frc~m Cl-C4 zLkyl; Cl-C4 a~?cy.l su3~sti~uted
by, prefer2bly 1-3,..hydroxy, Cl-C4 zlkylamino, di (Cl-C4 al~cyl) -
~mino, sulfo, Cl-C4 alko~, amino, carboxy or halo (chloxo, bromo,
fluoro or ~odo; pre~erably c~iloro, luoro or bromo~; C 2-C6
cycloalkyl; Cl-C4 alkoxy; Cl-C4 zlkylthio; ~no; Cl-C,a alkyl-
amino; di(Cl-C4 aL)syl) amino; halo (chloro, bro;no, fluoro or
iodo; preferably chloro, ~luoro ox bromo); Cl-C~ alkanoyla~r~no;
Cl-C4 alkanoyloxy; carboxy;
O
-C-OC~-C4 al~yl, hydroxy; a~idino; guznidino., phenyl; phenyl
substituted by one,~two or ~hree ~mino, halo (chloro, bromo,
fluoro or iodo; pre~erably chloro, ~luoro or bromo), hydroxyl,
trif luoromethyl , C1-C~ alkyl or Cl-C4 alXoxy groups;
_, _ ~ . . . .. .
phenyl tC~-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents mentioned
above in connection with Cl-C4 alkyl.; and heteroaryl
or heteroaxalkyl in which the hetero atom or atoms
in the above-named he~erocycilc moieties are selected from ~h~
group consisting o~ 1-4 oxygen, nitrogen or sulfur ~toms and
the alkyl moiety associated with said hetero~ral~yl moiety has
1-6 carbon atoms;
, .
34
( e) r=N-RS r s~-PcS
or ~ ,~
wherein X is 0, S or NR in which R is Cl-C4 alkyl; Cl-C,~ alkyl
substituted by 1-3 hydroxy, amino, Cl-C4 alkylamino, di (Cl-C4)
alkylamino, Cl-C,~, alkoxy, carboxy, halo or sulfo groups;
C3-C6 cycloaLlcyl; C3-C6 cycloalkyl (Cl-C4) a:lXyl
optionally substituted by 1-3 substituents mentioned
above in connection with Cl-C4 alkyl; phenyl; phenyl
substituted by 1-3 substituents independently selected from
amino, halo, hydroxy, trifluoromethyl, Cl-C4 alkyl, Cl-C4 alkoxy,
Cl-C4 alkylamino, di(Cl-C4)alkylamino,-- carboxy and sulfo;
phenyl(Cl-C4)alXyl in which ~he phenyl portion may be optionally
substituted by 1-3 substituents mentioned abo~e in connection
with phenyl and the alkyl portion may be optionally substi-tuted
by 1-3 substituents mentioned ~bvve in connection with Cl-C4 alkyl;
and heteroaryl nd heteroaraIkyl i~ which the hetero atom or atoms
~re selected ~rom the group consis ting of 1- 4 0, S or N atoms a~d
the alkyl moiety associated with heteroaralkyl has 1 6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected fxom hydroxy, amino, halo, trifluoromethyl,
Cl-C4 aIkyl, Cl-C4 alkoxy, Cl-C4 alkylamino, di(Cl-C4~alXylamino,
carboxy and sul~o and in the alkyl moiety by 1-3 sukstituents
selected from hydroxy, amino, Cl-C4 alkylamino, di(Cl-C4)alkylamino,
Cl-C4 a~coxy, czLrboxy, halo and su~fo; said heteroaromatic radical
being optionally substituted on a carbon atom by one or more
substituents independently selected from Cl-C4 alkyl; Cl-C4 alkyl
substituted by, preferably 1-3, hyd.roxy, amino, Cl-C4 alkylamino,
ditCl-c4 alkyl)amino, Cl-C4 alkoxy, sulfo, carboxy or halo
~chlorol bromo, fluoro or iodo; preferably chloro, fluoro or bromo);
C3-C6 cycloalkyl; Cl-C4 alkoxy; Cl-C4 alkylthio; amino; Cl-C4
alkylamino; di(cl-c4 alkyl)amino; halo (chloro, bromo, fluoro or
iodo; preferably chloro, fluoro or bromo); Cl-C4 alkanoylamino;
Cl-C4 alkanoyloxy; carboxy; O
-C-OCl-C4 alkyl; hydroxy; amidino;
- 35 -
guanidino; phenyl; phenyl sub6tituted by one, two or three
amino, halo (chloro, bromo, fluoro or iodo; preferably
chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C1-C4
alkyl or C1-C4 alkoxy groups; phenyl (C1-C4~ alkyl in
which the phenyl portion may be optionally substituted by
1-3 substituents mentioned above in connection with phenyl
and the alkyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with C1-C4
alkyl; and heteroaryl or heteroaralkyl in which the hetero
atom or a-toms in the above-named heterocyclic moisties are
selected from the group consisting of 1-4 oxygen, nitrogen
or sulfur atoms and ths alkyl moiety associated with said
heteroaralkyl moiety has 1-6 carbon atoms, or optionally
substituted 60 as to form a fused carbocyclic,
heterocyclic or heteroaromatic ring optionally substituted
by 1 or 2 of the substituent~ defined above;
R5
R5-~ il~
~ 1'~,~
~3 5 ~) 5
X --N-R N 1... N-R
~N>~ ~X ~1
j
- 36 -
wherein X is O, S or NR in which R i~ C1-C4 alkyl; C1-C4
alkyl ~ubstituted by 1-3 hydroxy, amino, C1 C4 alkylamino,
di(C1 C4)-alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo
groups; C3-C6 cycloalkyl; C3-C6 cycloalkyl (C1-C4)alkyl
optionally ~ubstituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; phenyl; phenyl substituted
by 1-3 substituents independently selected from amino,
halo, hydroxy, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C~) alkylamino, carboxy and ~ulfo;
phenyl (C1-C4) alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned above
in connection with phenyl and the alkyl poxtion may be
optionally substituted by 1-3 substituents mentioned abo~e
in connection with C1-C4 alkyl; and heteroaryl and
heteroaralkyl in whiah the hetero atom or atoms are
selected from the group consisting of 1-4 O, S or N atoms
and the alkyl moiety associated with heteroaralkyl has 1-6
carbon atoms, said heteroaryl and heteroaralkyl groups
being optionally substituted in the heterocyclic ring
moiety by 1-3 substituents independently ~elected from
hydroxy, amino, halo, trifluoromethyl, C1-C4 alXyl, C1-C4
alkoxy, C1-C4 alkylamino, di(Cl-C4) alkylamino, carboxy
and ~ulfo and in the alkyl moiety by 1-3 substituents
selected ~rom hydroxy, amino, C1-C4 alkylamino, di(Cl-C~)
alkylamino, C1-C4 alkoxy, aarboxy, halo and sulfo; 8 aid
heteroaromatio radical being optionally ~ubstituted on a
carbon atom by a 6ubstituent selected from Cl-C~ alkyl;
C1-C~ alkyl substituted by, preferably 1-3, hydroxy,
amino; C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C4
alkoxy, sul.fo, carboxy or halo (ahloro, bromo, fluoro or
iodo; pre~erably chloro, fluoro or bromo); C3-C6
cycloalkyl; C1-C4 alkoxy; C1-C~ alkylthio; amino; Cl-C4
alkylamino; d-(C1-C4 al kyl ) amlno; halo (chloro, bromo,
fluoro or iodo; preferably chloro, fluoro or bromo); C1-C4
alkanoylamino; C1-C4 alkanoyloxy; carboxy;
~.
, ~
~3~
- 36a -
-C-OC1-C4 alkyl; hydroxy; amidino;
guanidino; phenyl; phenyl substituted by one, two or th~ee
amino, halo (chloro, brom, fluoro or iodo; preferably
chloro, ~luoro or bromo), hydroxyl, trifluoromethyl, C1-C4
alkyl or C1-C4 alkoxy groups; phenyl ~C1-C4)alkyl in which
the phenyl portion may be optionally substituted by 1-3
substituents mentioned above in connection with phenyl
and the alkyl portion may be optionally substituted by 1-
3 substituents mentioned above in connection with C1-C4
alkyl; and heteroaryl or heteroaralkyl in which the hetero
atom or atoms in the above-name heterocyclic moieties are
selected from the group consisting of 1-4 oxygen, nitrogen
or sulfur atoms and the alkyl moiety associated with said
heteroaralkyl moiety has 1-6 carbon atoms; and
.j ....... .
, ~, ,i
~2~3~
-- 37 --
) N ~ R5 ~.5-N=~ N_N
R5
N-- ~-R RS~ N-R ~----N-~
5, 11 1 0~ 55
~ M ~ N ~f ~
wherein R is Cl-C4 alkyl; Cl-C4 aL'cyl substituted by 1-3
hydroxy, amlno, Cl-C4 alkylamino, di(Cl-C4)a~kylamino,
Cl-C4 alkoxy, carboxy~ halo or sullo groups; C3-C6 cyclo-
alkyl; C3-C6 cycloa.lkyl(Cl-C4)alkyl
optionally su~stituted by 1-3 substituents mentioned
above in connection with Cl-C4 alkyl; phenyl; phenyl
substituted by 1-3 substitue~ts independeatly selected from
zmino, h~lo, hydroxy, tri luor~methyl, Cl C4 àlkyl, Cl-C4 21k0xy,
Cl-C4 2~kyl~mino, di(Cl-C4)alkyl2mino, carboxy and sulfo;
phenyl (Cl-C,l) alkyl in which the phenyl portion m2y be optionally
substituted by 1-3 substituen ~ mentioned abo~e in~cDnnection
with phenyl znd the alkyl portion may be option211y substituted
by 1-3 substituents mentioned abo~e in connectio~ with Cl-C4 zlkyl;
and he.eroaryi and heteroaraikyi 1~ which the hetero atom os ato~s
are selected ~rom the group consisting o~ 1~4 O, S os N atoms and
~he alkyl moiety associated wi~h heteroaralkyl h~s 1-6 caxbon
atoms, szid heteroaxyl and heteroaralXyl groups ~eing optionally
substituted in the heterocyclic ring moiety by~l-3 substituents
independently selected from hydroxy, amino, halo, trifluoromethyl,
Cl-C4 21Xyl, Cl-C4 alkoxy, Cl-C4 alkylamuno, di(Cl-C~)alkylamino,
car~oxy and sulfo and in the alkyl moiety by 1-3 substi~uents
selected fxom ~ydroxy, amino, Cl-C~ alXylzmino, di.(Cl-C~)alkylamino~
Cl-C4 21X0xy ,.. carboxy, halo and sulfo. The R and R5 gro~ps m~y
..
.. ~ ..
- 38 ~ 3~
also be taken together to ~onm a fused heterocyclic or
heteroaromatic ring.
Wi~hin the above-described preferred embodiment, the
preferred compounds are those in which A is -(C~2)n in which
n is 1 or 2, most preferably ~hose in which A is -C~2- and
wherein (a~ Rl and R~ taken together represent
2 C
c~3
or (b) R8 is hydrogen 2nd ~1 represents hydrogen, C~3C~2-,
C~ ~ C~3
~C~- t ~ C- , or C~3t~-
3 C~3
Particula~ly preferred are the compounds wherein R8 is
hyd:rogen and Rl is
~.
C~3~H-, espe~ially compounds ha~ing the
absolute configuration ~R, 6S, 8R.
Another more preferred embodiment comprises compounds
o~ ~oxmula I wherein .
re~resents a radical of the ~ormula
(a, R5 R7
\~ . .
Rl!~
--39--
wherein RS is Cl-C6 a~cyl and R6, R7 and Rl~ are each
independen~ly hydx;oge~ or Cl-C~ aL~cyl;
~ ~5 - o:c
~N
N
wherein R is Cl-C6 alkyl aT~d w~erein a~ailable ring ca:r~on
atoms ~re optionally substituted by 1-3 substitue~
independently selected from Cl-C4 alXyl;
(=) RS IRS
N~
S R5
N ~;7 t~N
~ t ~
R5 7'5
' ~ 3 ~
'.:"'; ,
~:~7~
--40--
wherein R is Cl-C6 alkyl and wh~rein a~Tailable ring carbon
a~oms are optiona~ly substitu.ed by 1 or 2 substituent$
independently selected ~rom C.~-C4 al~cyl;
RS ~?.5
~3 ~N~
R5 ~ ~.5
~¦ N ,~
N~ ,N,~N N
whereirl R5 is Cl C6 a~Xyl and wherein an a~tailable ri.ng
carbon atom is optionally substituted ~y Cl C4 alkyl;
(e, ~ I_R5 ~9-R5
t or ~Jj
wherein R5 is Cl-C6 alkyl, X is 0, S or NR in which R is
Cl-C4 aLkyl and wherein one or more a~railable riII~ carbon
atoms is optional1y substituted by Cl~C4, alkyl,
'El Q- ~; '
t~ N-R5 ~ ~
~t~ ~,~1 R ,)~ ~ X ~ ~N ~ .
~'1=' I JN-~ ~ N--X
, . . . .
: . .
wherein R5 is C1~6 alkyl, X is 0, 5 or NR in which R is
Cl-C4 alkyl and wherein one or mc~re a~Jailable rins~ carbon
ator~ is optisnally substituted by Cl-C4 alkyl; ana
(g~ ~ R~
~ -R . ~-R
.
R5 ~9N ~-R ~ 5
Nf R
M ~ . or R5~
wherein RS is Cl-C6 allcyl and R is Cl-C4 alkyl,
A particularly pre~erred embodime:~lt o~ t~e preserlt
invention camprises compounds o~ formula I whe.rein
a 5
~ N--R
represents a radica~ of the ~orm~la
~ R6
Rl ' ..
wherein R6, R7 and R10 are independent~y selected ~ro~ the
sroup consisting o~ hydrogen, Cl-C~ alXyl, Cl-C~ alkoxy,
carboxyl and carbamoyl and R is.as de~$ned above, and is
prererzbly Cl-C6 ~l~yl, most preferably -C~3.
` ""' "" ""' ' 1 ' "'" ' '
" 12~
-42-
Withi~ the abo~e-described preferred emb~diment, the
preferred compounds are t~ose in whi~h A is -(C~2)~- in which
n is 1 or 2, most preferz~ly those in which A is -C~2- and
wherein (a) Rl and R8 taken together represent
~C~2
or (b) R8 is hydrogen and Rl represe~ts hydrogen, C~3C~2-,
c~3~. C~3 ~ ~ ~
~ C~- , " ,C- , or C~3 ~- .
c~3 .c~3
Par.icularly preferred are the compou~ds wherein ~8 is
hydrogen and Rl is
OII
C~3C~-, especiælly compounds ~ving
the absolute configuration 5R, 6S, 8R.
Another preferred embodiment comprises compounds o~
formula I wherein
~ N-R
represents a radical o~ the formula
(a) ~ R7
wherein RS is Cl-C4 alkyl, most preferably methyl, and R6 & R7
each indepe.n~ently represènt ~ydr~gen or Cl - C4 alkyl;
'
. .: .
: : :
_43_ ~2~3~
~5
(b) ~31 6
~R
where r~ R5 is Cl-C~ alkyl, m~st prefer~ly methy~: and R~
and R are hydrogen or Cl-C4 alkyl;
( c) R~_~.5
wkerein R~ is Cl-C4 alkyl, most pre erably ~nethyl and R is
Cl-C4 aL~cyl or phenyl (Cl-C4) alkyl;
(d) ~
Il .
~6 ..
where~n R5 is C~ Xyl, n~st pre~er~bly methyl or ca~o~ (Cl ~ C4 alXyl)
and R6 c Cl - C,~ alJcyl, ItDst preferably rnet~hyl or carbo~;y (Cl - C,l,) al}~l;
R5
~e)
~?
.. ..
wherein R is Cl-C4 alkyl, most pre~erably methyl and R is
Cl-C4 alkyl, most preferably methyï;
,
., '
. ' '
-44_ ~73~
(f ) ~N
R5
wherein R5 is Cl-C4 alkyly most prefera~ly methyl~
N--N~R
'g~ ~'''1
jN= N
wherein R5 is Cl - C~, alkyl and R is Cl - C4 alkyl; or
R5 ~
1~ ~N
~h) ~</
R
wherein RS i5 Cl - C4 alkyl and R is Cl - C4 alkyl.
~' :
.
~2~
-~5-
Within the above-described embodiment, the pre~erred
compounds are those in which A is -(CH2~- in which n is
1 or 2, most preferably those in which A is -CH2- and wherein
(a) Rl and R8 ta~en together represent
~OCH~
~C=
c~3
ox (b) R~ is hydrogen and Rl represents hydrogen, C~3C~
. C~3 1~ q~
CH- , ~ C- , or C~3C~- .
CH3 CH3
Particulzrly preferred zre the compounds wherein R8 is hydrogen
and R is
0~ :
CH3CH-, especially com2ounds having. the absolu~e
configuration 5R, 6S, 8R.
A most preferred embodiment of the present in~ention
comprises compounds o~ formula I wherein
~ ~ 5
_ - N-R
represents a radical o~ the formula
~3~
-~6-
(a) ~ ,, (b)
CH3
~=~ (d) ~D C}12C1~2C133
C`3
( e ) ~ C~ 3
~, ~I C~3
CH3
C2~
CH3
CH3
' ~ .
' . i :,: .'. !:; ' .'. r. .,~" '
~2~3~
-47
l~3
(m) ~,~ ; or (n~
S 3 /N _
,rcO~
~c) ~ N\ ~ ) C~
. ~M ~/
3 . ~C2~)
f~3 C~3
(g~ _~ N (r)
c~3
t ~ CEI3 ~t) ~ ,~(3
~3
,
~36~
tu) ~; ox
3 C 1 3
... .
~3~
. _4~-
h~ithin ~his ahove-described embodiment, the preferred compounds
are those in which A is ~(CR2)n- in whi~h n is 1 or 2, most
preferably those in which A is -~C~2)- and wherein ~a) Rl and
R8 ta~en ~ge~her represent
~C~ .
",C=
or (b) R8 is hydrogen a~d Rl repxesents hydrogen, CX3C~2-, .
CR~ 1~
C~- , ~ C- , or C~3C~
c~3 c~3
Pa~ticularly preferred are the compounds wherein R8 is hydrogen
and R is 0~
C~ , especially compounds ha~ing the absolute
configuration 5R, 6S, 8R.
Specifi~ preferred compounds o the present in~entio~
are those o~ the formula
.
.- OEl R15
~R) ~ S - A ~ ~ R5
o oOR2
wherein R15 is hydrogen or methyl, R2 is hydrogen, an anionic
charge or a conventional. readily removable carboxyl group, providing
that when R2 is hydrPgen or a protecting group, there is also
present a counter ion and wherein
--S--A~ R5 is
(a) -SCE~ N~3 CH3 (b) -SCH2CH ~--C~I3
\~3
(C) sc~2--C~? (d) -SCH2~3
N
CH 3
\
~3N--\
(e)-SCH2CH2~ ~f) -SCH~CH;~CH2C~3
-so-
c\3~ CH3
) -SCH2 ~(b) -SCH2 ~ ~ ~ ~ H3
CH3
0NH3C ~ ~ ~CH3
scH2~ 3 -SCH2 S ~ C~3
c~3
( ~ -SCN2 ~ 3 CIN3 ~ 3 C~3
CIH2
(n) -SCH
CH3 CH3
ICH3 CH3
(O) /N" (p) '
-SCH2~ -SCH ~ N
N//~ 2 \ ~ CH3
CH3
wherein the lHNMR(D2O) spectrum shows characteristic peaks
at ~: 1.23(3H, d, J=6.4 Hz), 3.12(2H, q, J=1.4, 8.9 Hz),
3.39(1H, q, J=2.7, 6.0 Hz), 4.07-~.68(10H, m), 8.19(1H, s);
(q) -SCH
C 3
wherein the lHNMR(D20) spectrum shows characteristic peaks
at ~: 1.23(3H, d, J=6.4 Hz), 3.15(2H, q, J=3.7, 9.0 Hz),
3.37(1H, q, J=2.6, 6.0 Hz), 3.95-4.65(10H, m), 8.62(1H, s);
~3~
--51--
~ 00
SCH 2 ~h~cH3 -SC~2~
-SCE~2 ~
2COOe N_ N
(V) fH3 . CY3
l33 -sCE[~33
(Y~-5~2~ ' ~Y~-s~:
~ .
2~ ~N
C~3 CE~3 ~aa) SCa2.~
C~3
-52 ~L2~
A most preferred ernbodiment o:E the present invention
comprises comp~unds of formula I wherein
. ~~\~ 5
N--R
' .
repres ents
and Rl5 is hydrogen or methyl.
Withirl the abo~e-des cribed e~bodimeslt, .the pre erred
comDounds are those in which ;A is o (CEI2~ ~, in whic~ n is 1 or 2,
most pre. erably those in which A is -CH2 and wherein ~a) Rl and
R. taken together re}?resent
~ ~ioa~2
~C=
or ~};) R8 is hydrogen and.Rl represents hydrogen, CH3C1~2-,
C~ C 3 l~H ~H
~ , or CH~CEl- .
c}~3 CH3
.
. .
.
.
' ~ ,. ,
".,
.
' :. ,.
. 53- ~2~3~
Particularly preferred are the compounds wherein R is hydrogen
and Rl is OH
CH31H-, especially compounds having the absolute con~
figuration 5R, 6S, 8R.
The process of the pxesent invention utilizes the
intermediate of the ~ormula
R8 ~ R
Rl ~ L
~ M OOR2
which has been disclosed, for example, in European Patent Appli-
cation 38,a69 and European Patent Application 54,917 and which
may be prepared by the general methods described therein.
represents a conventional leaving group (defined as "X" in
European Patent Application 38,869) such as chloro, bromo, iodo,
benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzene-
sulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy,
diphenoxyphosphinyloxy or dittrichloroethoxy)phosphinyloxy ~ The
preferred lea~ing group is diphenoxyphosphinyloxy. Intermediates
of Formula IV are generally formed in situ by reacting a~
intermediate of the formula
~8 ~ R
0~-- LOOR2
III
wherein R1, R8, R15 and R2 are as defined above with a suitable
acylatin7 agent R -L. The preferred intermediate IV where L is
diphenoxyphosph.inyloxy may be prepared by reacting keto ester III
in an inert organic solvent such as methylene chloride,
acetonitrile or dimethylformamide with about an equimolar amount
of diphenyl chlorophosphate in the presence of a base such as di-
isopropylethylamine, triethylamine, 4-dimethylaminopyridine or
-54~
,
the like at a temperatuxe of from about -20C to l40C, most
preferably at about 0C. Intermediate LV may be isolated, if
desired, but is conveniently used as the starting material for
the process o the present invention without isolation ox puri~
fication.
In the present process, carbapenem intermediate I~ is
reacted with a quaternary amine thiol compound of the formula
~ ~ 5
HS-A ~ -R
VII xe
wherein
A ~ e)~5
is as defined above and ~ is a counter aAion. The reaction is
carried out in an inert solvent such as acetonitrile,
acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydro-
furan-~2O, acetonitri~e-H2O or acetone in the presence of base.
The nature of the base is not critical. Examples o~ suitable
bases include sodium hydroxide, diisopropylethylamine, 1,8-
diazabicyclo[5.4.0]undec-7-ene t 1,5-diazabicyclo~4.3.0]non-S-ene
and tri(C1-C4)alkylamines such as triethylamine, tributylamine or
tripropylamine. Reaction of intcrmediate IV and thiol VII may be
carried out o~er a wide temperature range, e.g~ ~15C up to r~om
temperature, but is preferably done at a temperature in the range
o~ from about -15C to -~15DC, most preferably at around 0CC.
The carbapenem product produced by reaction of the
quaternary amine thiol VII with intermediate IV will have a
counter anion associated with it [e.g. (C6H50)2P02 ~ , Cl ~ or
the anion associated with the quaternary thiol~ which may at this
stage be substitute~ by a different counter anion, e.g. one which
is more pharmaceutically acceptable, by conventional proceduxes.
Alternatively, the counter anion may be xemoved during the
subsequent de-blocking step. Where the quaternized carbapenem
55~ 3~
compound and counter anion form an insoluble product, the ~ro-duct
may crystallize out as it is formed and be collected pure by
filtration.
Following formation of the d~sired carbapen~m product,
the carboxyl protecting group R2 of Compound Il may be option-
ally removed by conventional procedures such as solvolysis,
chemical reduction or hydrogenation. Where a protecting group
such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl is
used which can ~e removed by catalytic hydrogenation, intermedi-
ate I' in a suitable solvent such as dioxane-water-ethanol,
tetrahydrofuran-diethylether-buffer, tetrahydrofuran-aqueous
dipotassium hydrogen phosphate-isopropanol or the like may be
treated under a hydrogen pressure of from 1 to 4 atmospheres in
the presence of a hydrogenation catalyst such as palladium on
charcoal, palladium hydroxide, platinum oxide or the like at a
temperature of ~rom 0 to 50C for from about 0.24 to ~ hours.
When R2 is a group such as o-nitrobenzyl, photolysis may also be
used for deblocking. Protecting groups such as 2,2,2-
trichloroethyl may be removed by mild zinc reduction. The allyl
protecting group may be removed by using a catalyst comprising a
mixture of a palladium compound and triphenyl phosphine i~ a
suitable aprotic solvent such as tetrahydrofuran, methylene
chloride or diethyl ether. Similarly, other conventional car-
boxyl protecting groups may be removed by methods known to those
skilled in the art. Finally, as mentioned above, compounds of
Form~la ~' where R2 is a physiologically hydrolyzable ester such
as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl,
methoxymethyl, etc., may be administered directly to the host
without de-blocking since such esters are hydrolyzed in vivo
under physiological conditions.
It will he understood that where the Rl, R8, R5 or R15
substituent or the quaternized heteroaromatic group attached to
substituent A contain a functional group which might interfere
with the intended course of reaction, such group may be protected
by a conventional blocking group and then subsequently de-blocked
to regenerate the desired functional group. Suitable blocking
groups and procedures for introducing and removiny such groups
are well-known to those skilled in the art.
-56- ~2~7~
As in the case of other B-lactam antibiotics, compounds
of general Formula I may be converted by known procedures to
pharmaceutically acceptable salts which r for purposes of the
present invention, are substantially equivalent to the non-salted
compounds. Thus, ~or example, one may dissolve a compound of
Formula I wherein R is an anionic charge in a suitable inert
solvent and then add an equivalent of a pharmaceutical~y accept-
able acid. The desired acid addition salt may be recovered by
conventional`procedures, e~g. solvent precipitation, lyo-
philization, etc. Where other basic or acidic functisnal groups
are present in the compound of Formula I, pharmaceutically
acceptable base addition salts and acid addition salts may be
similarly prepared by known methods.
A compound of Formula I where R2 is hydrogen or an
anionic charge, or a pharmaceutically acceptable salt thereof may
also be converted by conventional procedures to a corresponding
compound where R2 is a physiologically hydrolyzable ester group,
or a compound of Formula I wherein R is a conventional carboxyl-
protect ng group may be converted to the corresponding compound
where R is hydrogen, an anionic charge or a physiologically
hydrolyzable ester group, or a pharmaceutically acceptable salt
thereof.
It will be appreciated that certain products within the
scop~ of Formula I may be formed as optical isomers as well as
epimeric mixtures thereof. It is intended that the present
in~ention include within its scope all such optical isomers and
epimeric mixtures. For example, when the 6-substituent is
hydroxyethyl, such substituent may be in either the R or S
configuration and the resulting isomers as well as epimeric
mixtures thereof are encompassed by the present invention.
The thiol intermediates of Formula VII may be prepared,
for example, from the corresponding thioacetate compound of the
formula
O
CH3CS-A
. . .
.. :~' ..
-57- ~7~
wherein A is as defined above and
f- ~
~ N
/
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom. The thio-
acetate compound is quaternized by reacting it in an inert
organic solvent such as diethyl ether, dichloromethane, methylene
chloride, dioxane, benzene, xylene, toluene or mixtures thereof
with a suitable alkylating agent of the formula
R5-X'
wherein R5 is as defined above and X' is a conventional leaving
group such as halo (chloro, bromo or iodo, most preferably iodo)
or a sulfonate ester moiety such as mesylate, tosylate or
triflate. The temperature for the alkylation reaction is not
critical, and temperatures in the range of from about 0C to 40C
are preferred.
Prior to reaction with carbapenem intermediate IV, the
quaternized thioacetate compound is subjected to acidic or basic
hydrolysis to generate quaternary thiol intermediate VII. This
hydrolysis is preferably done immediately prior to coupling with
IV so as to minimize decomposition of the relatively unstable
quaternary thiol VII.
~ y proper selection of khe solvents, the reaction from
intermediate III to end product I may be carried out without
isolation of the various intermediates, i.e. in a "one-pot"
process. An example of such a process is illustrated below in
Example 7.
The carbapenem derivatives of general Formula I wherein
R2 is hydrogen, an anionic charge or a physiologically hydro-
lyzable carboxyl protecting group, or the pharmaceutica~ly
. .
,;. ~
-58- ~73~
acceptable salts thereof, are potent antibiotics active against
various gram-positive and gram-negative bacteria and they may be
used, for example, as animal feed additives for promotion of
growth, as preservatives in food, as bactericides in industrial
applications, for example in waterbased paint and in the white
water of paper mills to inhibit the gxowth of harmful bacteria,
and as disinfectants for destroying or inhibitinq the yrowth o~
harmful bacteria on medical and dental equipment. They are
especially useful, however, in ~he treatment of infectious
disease in humans and other animals caused by gram-positive or
gram-negative bacteria.
.
The pharmaceutically active compounds of this invention
may be used alone or formulated as pharmaceutical compositions
comprising, in addition to the active carbapenem ingredient, a
pharmaceutically acceptable carrier or diluent. The compounds
may be administered by a variety o means; those of principal
interest include: orally, topically or parer.terally (e.gO intra-
venous or intramuscular injection). The pharmaceutical composi-
tions may be in solid form such as capsules, tablets, powders,
etc. or in liquid form such as solutions, suspensions or emul-
sions. Compositions for injection, the preferred route of
delivery, may be prepared in unit dose form in ampules or in
multidose containers and may contain formulatory agents such as
suspending, stabilizing and dispersing agents. The compositions
may be in ready to use form or in powder form for reconstitution
at the time oX delivery with a suitable vehicle such as sterile
water.
The dosage to be administered depends to a large extent
on the particular compound being used, the particular composition
formulated, the route of administration, the nature and condition
of the host and the particular situs and organism being treated.
Selection of the particular preferred dosage and route of appli-
cation, then, is left to the discretion of the therapist. In
general, however, the compounds may be administered parenterally
or orally to ma~alian hosts in an amount of from about 5 to 200
3~
mg/kg/day~ Ad~ istration is generally carrled out in dîvided
doses, e. g. three to four times a day.
-~- ~73~`~
The following examples illustrate but do not limit
the s cope of the present invention .
. .
~ .
0~
H
~ S/ ~C53
A. PrPparation of isomer A
OH H El
SAc a) MeOT:E ~\ Me
~? ~ o~
~N 2
2PNB
d) H2/Pd-C
' ' ~ ' , "'' ~'
.., ,, ,, ,,, ~
P5ethyltrifluoromethane sulfonate (O ~ 58 ml, 5 .16
mmol~ W25 added dropwise to an ice-cooled, stirred, solu-
tion of 4 (me~hanethic~lacetate)-1-methyl-1,2,3-triazole
(590 mg, 3. 52 mmol) in dry methylene chloride (2 mL) under
nitrogen. A~ter 0. ~ h, the bath was remo~ed and aftex 1 h~
the sol~ent was removed wi~h an ~pirator. The residual
oil was dissolved in a few ~TL o:E wa~er and thi5 solu~ion
was cooled in an iceba~. A cold solution o~ sodium
hydroxide (305 mg, 7.59 ~nol) in a few mL of water was then
added and the reaction was left stirring fo~ O ~ 75 h. The
solution was diluted to 25 mI, with water and the p~l W?S
adjusted to 7. 5 by the addition o~ solid sodi~n dihydrogen
phosphate monohydrate . The~, 14 mL o~ this solution ~ ca .
1.9 ~mnol of ~he triazolium thiol) was added to an ice-
cooled, s~irred, solution Q~ the enol phospha~e (1.0 g,
1.72 mmol) in tetr~hydrofur2n (T~F) (10 mL). ~his was
left stirxing for 0.75 h (some crystalline material,
presumably Na2~P04 is deposited during the.course of this
reaction). The suspension was transferred to a pressure
bottle with the aid o~ some T~F (20 mL) and water (20 mL).
Ether ~30 mL) a~d 10% palladium on charcoal (1.0 g) were
added and the mix~ure hydrogenated (40 P.S.I.) for 1 h.
The orgænic phase was separated and washed with w~ter
~2 x 5 mL)~ The combined aqueous phases were filtered
and the filtxate was concentrated under high vacuum (ca.
O.S mm, 1.5h). The yellow solution was ~hen chromatographed
(medium pressure reverse phase column, 35 x 90 mm, ~2 as
eluent) to a~ford, after lyophilization, 39~ mg ~ ~he
carbzpenem slightly contaminated with some inorganic
materislO It was puri~ied by ~P~C 110 x 300 mm'Waters
Microbo ~ pack" C-18 colu~m, multiple injections, ~2 as
*Trad~k
.. D ' "
. :'~' , , ,
, '~'
-62-
eluent~ to gi~e 310 mg (57~) of isomer A as a tan-colored
powder: ~ NMR (D20) ~, 1.23 (3~, d, J=6.4 ~) 9 3.10 ~2~,
d, J=9~1 ~z), 3.24 (lX, ~, J=2.7, 6.1Hz), 4.03-4.71 (lOH,
m~, 8.4S (1~, s); I~ ujol") 1760 cm 1; uv (p~ospha~e
buffer, pR 7.4, M-O.O~)~ax: 296 (~=7,500).
B. Preparation of isomer B and isomer C
b~ q. NaO~ ) ~ 5 ~ ~ e2
Me ~ ,~ C0
(tentati~e ~ N ~ ~(~)
structure) CO~PNB
d) ~ ~Pd-C
Methyltrifluoromethane sulfonate tl. 60 mL, 1~ . O
mmol) was added dropwise to an ice-cooled solution of 4-
(methanethiolacetate)-2-methyl-1,2,3-txiazole (1.20 g,
7.02 mmol) in dry methylene chloride (6 mL) under nitrogen.
This was allowed to warm to room tempexature and le~t
stirring ~or 16 h. Additional methyltrifluoromethan~
sul~onate tO . 40 mL, 3.56 mmol) was added and after 3 h at
room temperaturey the solvent was r~moved with an aspirator.
The residual oil was triturated wi~h ether and the resulting
gum W2S dissolved in water 55 mL). This was cooled in an
icebath and a solution o~ sodi~m hydroxide ~844 mg, 21.1
~nol) in water ~5 mL) was added. After stirring ~or O.75 h,
this solu~io~ was diluted to 60 mL with water and the pH
adjusted to 8 by ~he ~ddi~ion o~ solid potassium dihydrogen
phosphate. Then, 40 mI of this solution ~ca. 4,7 ~mnol of
a mixtu~e of isomeric tria~olium thiols) was added to an
*Trademark for liquid pa-aff.Ln. See Gardner's Chemical Synony~s and Trade
Na~ s, (1987) Ninth Edition, Gbwer Technicai Press, page 593, for further
detalls.
~ I .
' J
~273~
--63--
..;,
ice-cooled, stirred, solution o~ the ç~ol phosphate
(2.00 g, 3.45 mmol) in 5~IF 169 mL~. This mixture was
le~t ~irring in the ic~ebat:h for 0.5 h af er which it
was transferred to a pressure bottle containing a sus-
pension of 10% palladium on charcoal (2.0û g) and ether
~60 mL~ O The mixture was hydrogeIlat~d (40 P-S .I . ) for
1 h. The organi~ phase was sepæated and washed with
wa~er ( 2 x lû r~L), The combined a~aueous phases were
~iltered and the ~iltrate wa~ conoentrated under high
vacuum (ea. 0 . 5 mm, l. 5 h) . ~he reraaininy solutio~ was
then chromatographed (medium pressure reverse phæe colwnn,
45 x 130 rmn, ~2 as ~luent) to 2~ford, after lyophilization,
595 mg of ~ ~ixture of isomerit:: c rbapenems which were
coita;~inated with a little inorganic material. These were
separated and purified by ~IPLC (lO x 300 man Waters ~icro-
bon~apack~ C-18 colu~ , multiple injections, ~2 as eluent)
to afford, i~ order oi~ elution: isomer B; 153 mg (13%);
(D2O) ~: 1.23 t3~, d, J=6.4 Hz), 3.12 (2~, q, J-l:4,
8.9 ~z) , 3.39 (1~, q, J-2.7, 6.û l~z), 4.07-4.68 ~lO~, m),
8.l9 (lH, s); IR ("Nujol"), 755 c3n l; u~r ~phosphate buffer,
p~=7.4~ M=û.û5) ~ a.x 296 r~ 6,7ûû); and isomer C; 284 mg
(24%); }~NMR (D20) ~: 1023 (3H~ d~ H-6.4 Hz) ~ 3.15 (~I, q~
J=3.7, 9.û El2), 3.37 (l~I, g, J~2.6, ~.0 Hz), 3.95-4.65 (lOEI,
m), 8. 62 (l:EI, s); IR (~Nujol") 1750 cm l; uv (phosphate buffer,
pH 7.4, M=0.05) ~`m2Lx 29B nm (E=7~600).
*~ademark
.
. ..
" : . . .~. :'
~. .
~64-
~.
.. ..
(SR,6S) 6~ hydroxyethyl)-3~2-methyl-1,2,3-thladlazolium-
9~'` ~
~ ~ C~3
A. Ethyl 1,2,~-thiadiazol-4-ylcarb~
N~' 5^12 b~gC\E~
C~3 ~OEt
A solution o~ e~hyl ~-N-car~ethoxyhydrazonopxopiona~
(31.2 g, 0.154 mol) in thionyl ch~oride (80 mL) wns stirred at
23C for 3 h and heated at 70C for 20 min. Thionyl chloride was
evaporzted and the residue was triturated in he~ane (4 x 30 mL).
m e red solid was dissol~7ed in dichloromethane (150 ~L) and ~he
solution was washed with satl~ated sodium bicarbonate solutio~
and water. ~ter drying over Na2S04 the solution was concentrated
until ~he compound crystalli~ed. ~ter standing at ~3C ~or a
while, the crystals were ~iltered; 16.8 g, mp 86C, 69%. The
:Eiltra~e was concentra~ed and.purified by chromatography orl a
silica gel col~ wit:h dichloromethane as elut;rlg sol~ren~ ~o gi~e
3.17 g, mp 86~::, 13%, ir (~C~r)vmax: 1720 (ester~ cm 1; ~Hmr (CDC13)
~: 1.52 (3H, t, J=7.1 Hz, CH3CH20), 4.57 (2H, q, J--7.1 ~z, UI3C~2O),
9. 47 (l~i, s, ~ o~ thiadiazole) .
C.D. Hurd and R.I. Mori, J. Am. Chem. So~., 77, 5359 (19~5).
, ' ''I .
- ~s -
B .
~OE~ i20E~
Ji~ ~ N~ ~ :
To a suspension of ethyl 1,2,3-~hiadiazol-4-ylcarboxyl~e
(18. 35 g, 0 .116 mol) i~ ether ~400 mI,) was added portionwise
lithium aluminum hyaride (2.47 g, 0.065 moi) oYer a 1 h period. The
rea~tion mixture was stirred at 23C for 7 h and t2eated with
lithium alumirlum hydride (2.47 g, 0,.065 mL). The stirring w~s
corltinued for 24 h be~ore adding successi~7ely water t7 mL), 15%
sodium hydroxide solutio~ (7 mL) and watex ~21 mI,). After stirring
for 1~ min, ~he ethe:r solution was ~lec2:nted and the gum W2S
extraeted wi~ ether ( 5 x 100 mL). Th~ ether extracts were
~ombined, dried (MgS04) ~md concent-rated t5.4 g). The crude
material was.purified o~ a silica ~1 ~1~ (120 g, 4 x 16 ~l),
with ether as eluting sol~ent to gi~e 103 g (7~) of ethyl 1,2,3
~hiadiazol~4-~lcarboxylate and 2.4~ y (18%) of 1,2,3-thiadiazol-4-
ylmeth~nol; ir ~ilm)~max: 3380 (O~) cm ; ~mr (CDC13)~: 2.31
(1~, s, 0~), 5.22 (2~, s, C~2O), 8.50 ~1~, s, ~ o~ thiadiazole). ,
lS.I. R~msby, S.O. Ogren, S.B. Ross and N.E. Stjernstrom,
Acta Pharm. Succica., 10, 285-96 ~1973); C.A., 79, 137052W (1973).
~3~
--66--
C. 1,2,3-thiadiazol-4-ylmethanol methanesulfonate
CH OH . 5H ~Ms
N ~ 2 . N ~ 2
S~ Ms ~ f ,~
A solution of 1,2,3-thiadiazol-4-ylmethanol ~0.75 g,
6.5 mmol) in dichlorometharle (20 mL) was cooled to 5~C undex a
nitrogen atmosphere a~d treated with triethylamine (1.018 mL,
~.3 mmol) and methanesulfonyl chloride (0.56~ ml, 7.3 ~ranol).
After 15 min, the ice-bath was removed and the reaction mixture
was stirred for 2 h. The solution was washed with lN hydrochloric
acid solution (2 x 2 mL) ar~d water, dried (MgS04 + MgO) and
concentxated. The residue was purified by chromatography (silica
gel colu~M 1.5 x 21 cm) with ether as Pluting solvent to gi~e
0.90 g (71%) o 1,2,3-thiadiazol-4-ylmethanol methanesulfonate;
ir (film)~ma~c: 1350 (S02) cra 1, 1172 (S02) cm 1; l~Imr (CDC13)~:
3.09 (3H, s, CH3), 5.75 (2H, s, CH2), 8.72 (lH, s, H o~ thia-
diazole); uv (CH2C12)~ma~c: 251 (El990) . Anal. calcd Eor
C6H6N2O3S: C 24.73, H 3~11, N 14.4Z, S 33.02; found: C 24.78
EI 3.09, N 14.66, S 31.94 and 0.13 g (19%) of di-(1,2,3-thiadiazol
4-ylmethyl)ether; ir (film)vmax: 1272, 1242, 1200, 986, 805,
728 cm 1; lHmr (CDC13)~: 5.16 (s, 4H, CH2), 8.42 (s, 2H, H's o
thiadiazole).
~2~73~
~67-
;" .
. .
D. ~
~ ~ N ~ C~2s8c~
To a solution o~ 1,2,3-thiadiazol-4-ylmethanol
methanesulfonate (0.90 g2 4.6 mmol) in tetrahydrofuran (9 ~L~
w2s added an aq~eous solution (2 mL) of sodium thiolacetate
[prepared from thiolacetic acid (0.38 mL, 5.3 mmol) and sodium
bicarbonate (0.445 g, 5.3 mmol)~. The r~sulting mixture was
stirred at 23~C for 1 h and diluted with ether (75 mL). The
organic solution was washed with water (3 x 3 mL), dried
(MgSO4) and co~centrated. The crude ~nixture was purified
by chromatography (sillica gel column: 1.4 x 19 cm) with 50%
ether in h2xane as eluting solvent to gi~e 0.60 g (75~); ir
(film)vma~: 1675 (C=O) cm 1; 1Xmr (CDC13)~: 2.37 (3H, s, CH3),
4.58 t2E, s, CE2~, 8.4~ s, H o~ thiadiazole). Anal. calcd
for C5R6N20S2: C 34.47, H 3.47, N 16.08, S 36.80, found:
C 34.48, ~ 3.83, N 16.28, S 36.80.
~2~3~ ~
E. 4-acetylthiomethYl-2-meth~ 2. 3-thiadiazolium trifluoro-
methanesulfonate and 4-acet~vlthiomethY1 3-methvl-1,2 t 3-
.
thiadiazQlium trifluromethane sulfonate
~i S~ ' S~ H S~
1~ ~ 2 3 OE SO Ne ~ 3 .~ 2 3
~5 ~ ~ ~5~ CF35O3 ~S~ 3 3
To a solution o~ 4-acetylthiomethyl-1, 2,3-thiadi2120le
~ 0.60 g, 3.44 mmol) in a mixture of ether ~4 mL) and dichloro-
methane ~0. 4 mL) were ~dded a few crystals of t:he title compounds
and trifluoroIoethanesul~onate ~0.407 ~, 3.6 mmol) over 5
period. The reaction mixture was stirred at 23C unde:c a
nitrogen atmosphere ~or 6 h. The white solid that was a mixture
of the two kitle co~pou~ds was ~iltered and washed with ether,
1. 05 g, 90%; ir lxBr)~max: 1675 (C=0) cm l; ~ DMS0, d 6) ô:
2.43 (3~, 5, C~3t::0S), 3,33 (s, C~13 on N-3), 4.57 Is, C~3 or~ N-2),
4.66 t2~, s, C~2), 9.55 (~ on thiadiazolium N-2), 9.66 ( ~1 on
thia~iazo~:ium N-3). A~al. calcd ~or C7~N20453F3: C 24-85, H 2.68,
N 8.28, S 28.43; found: C 24.61, H 2.57, N 8.47, S 28.21.
.. ..
.. .
~':
'' "
~2~73C)~
_~9_
.,
F. 4-merca~tomethyl-?-methyl-1,2,3-thL~ oli-- t~iSI~or~
_ =~
thiadiazolium trifluoromethanesul~onate
,~H2S~3 ~25
HCl, 6N ~ Me ~
A solution of a mixture of 4-acetylthiomethyl-2-
methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-
acetylthiomethyl-3-me~hyl-1,2,3-thiadiazolium trifluorometha~e-
sulfonate (l.OS g, 3.1 mmol) in 6N hydrochloric acid ~10 mL)
was heated at 65~C under a nitrogen atmosphere ~or 1.75 h.
The solvent was evaporated under reduced pressure lea~ing a.
yellow syrup O.91 g. This compound was used in the next step
without purification.
~L2~
--70--
G. (SR,6S) 6- (lR-hydrox~ethyl~-3 ~2-methyl-1,2,3-thiadiazolium-
carboxv late
ON O~(OPh) .~5~353 10 ~8
~ ~~C 2 pB 7.2 ~:the~ iF,
00~3 2 COO S
A cold (5C) solution of (5R, 6S) paranitrobenzyl 6-
( lR-hydroxyethy 1) -3-(diphenylphosphono)-7-oxo-1-azabicyclo(3.2.9)-
hept-2-ene 2-carboxylate ~1.7 g, 2.92 Imnol) in tetrahydrofuran
(10 m~ was treated with a solution of a crude ~xture of 4-
mercaptomet~hyl- 2-methyl-1, 2, 3-thiadi azolium trif luorometl~ane-
sulfonate and 4-mercaptomethyl-3-methyl-1,2,3-thiadiazolium
~rifluoxomethanesulfonate (0.9 g) in a mixture o~ phosphate
~uffer ~p~ 7.2, 0.3M, 15 mL) and tetrahydrofuran (5 ~L). The
reaction mixture was stirred for 1 h and the p~ was kept at 7.2
with 2N sodium hydroxide solu~ion. ~he stirring was continue~
for one ~ore houx before adding ether (50 m~) and 10% palladiu~
on charcoal (l g). The result~ng mixture was hydrogenated at
23C under 45 psi or 2 h and filtered through a "Celi~e" pad.
~he oxganic phase was separated, diluted with ether (SD mL) and
phosphate bufiEer (p:~ 7.2, 0.3M, 20 nL) and hydrogen2ted (2 g of
10 % palladium on ~harcoal) ~or 2 h under 50 psi . The aqueous
phases were cor~bined (~ro~ the first and second hydrogenolysis),
washed with ether and puri~ied by chroma~ography on "PrepPak"
500-C~18 with wa~er as~eluting sol~ t to give D.22 g o~ crude
material. It was rep-~rified ~y hplc with water as eluti:ng
*Trademark or diatomaceous earth
**~radRm~rk
,.,.. ~ .
:.
. .' - .
~,.,~
. : :
.. ~,............ .
.. ~ '
... .
--71--
solverat to give O . 040 g (4%) of the title coTn~ouIld aftex
lyophilization, ir ~KBr)~max: 3400 (br, OH), 1745 (C=O of
B-lact~n), 1580 (carboxylate) cm 1; ~Imr (D20) ô 1. 23 (3H,
d, J-6.3 Hz, CH3C~0~1), 3.04, 3.05, 3.16 (2~I, m~ ~I-4), 3:38
(l~I, dd, J=2.8 Hz, J=6.0 }Iz, ~I-6), 3.9-4.6 (2~, m, H-5,
C~I3CHO~I), 4.51, 4.53 (2"s", SC~I2), 4.6~ (s, N C~3); uv
(~I20) ~ma:~c 224 (E4345), 262 (~49 80), 296 (E6885) ' [~D 18
(c o.i~, H2t:)); Tl/2=9. 8 h ~meas-~red at a concentratio~ o~
10 4 M in phosphate buf~er p}I 7. 4 at 36. 8C) .
--72--
Exa~nple 3_
Potassium 3- ~ 5~ carboxylatomethy1-3 methyl-1 J 2, 3-
triazolium) methanethio]-6~ 1- (R) -hvdroxvethvl]-7-
oxo l-azabic:yclo~3~.0]hept-2-elle-2 car~e
~ }~ H ~C2
J~ S ~CN ~
.. 2 .
cS ~e~ ~
Nl 2) MsCl/NEt3
XSCC~3
~rC~2~0
. ' ' ~
~ ; 2Bt
b) ~ (~ 2
C2P~ ,
,
' " :
.. .
.. .
~:
: :
.. ~: ,
: . . ..
:.. ..: .... ....
3~
Lithium aluminum hydride ~2.83 g, 70.9 mmol) was
added in small poxtions to a stixred suspension of l-methyl-
1,2,3-triazole-4-carboxylic acid~ (9.00 g, 70.9 mmol) in dry
THF (200 mL). The mixture was left stirring at room t2~perature
for 15 h after which a 20~ aqueous solution of sodi~m hydroxide
(20 mL) was carefully added in ca. 1 mL aliquots. The resulting
granul2r suspension was ~iltered ar.d the solid w2shed with
additional TE}F (5 x 75 mL). The combined T~F solutions were
dried (MsSO4~ and the solvent removed. The residual yellGw oil
was flash chromatographed o~ a silica gel column (90 x 35 mm)
~100 mL portions o~ hexane, mixtures of ethyl acetate-hexane
(1:1) and (1:3), and lastly ethyl acetate-methanol (9:1~ as
eluent]. This a~forded 4-hydroxymethyl-1-methyl-1,2,3 tria~ole
(3.18 g, 40%) as a colourless oil: ~ MR (CDCl~) ~ 4.07 (3~r 5)
4.73 (2~, d), 7.52 (I~, s); IR (neat) 332C cm ..
Methanesul~onyl chloride (3.82 mL, 49.6 mmol) was
added dropwise to an ice-cooled, stirred, solution of the ~lcohol .
(4.67 mL, 41.3 mmol) and triethylamine (7.47 mL, 53.7 mmol) in
methylene chloride (20 mL). After 0.5 h, the solvent was removed
and the residual solid was taken up in acetonitrile ~30 mL).
Potassiu~ thiolacetate (7.06 g, 62.0 mmol) was then added and the
suspension was left stirring at room temperature for 3 h. An
additional quantity of potassium thiolacetate (3.0 g, 26.3 mmol)
was added and the suspension was left stirring for a ~urther
16 h. The dark-coloured suspension was then concentrated and
water ~10 mL) was added. This mixture was extracted with methylene
chloxide (5 x 40 mL)I The combined çxkracts were dried (MgSO4)
and the sol~ent removed. The residual oil was flash chromatographed
on a silica gel column (90 x 36 mm) ~hexane followed ~y a mixture
lC. Pederson, Acta. Chem. Scand., 1959, 13, 888
~3~
--74--
o~ hexa~e~ethyl acetate (1: i) being used as ~lue~t~ O This
af~orded 4- (me~hanethiolacetate~ methy1-1,2,3-triazole
(5.9~ g, 84%) s a faint pink colc)ure~l solid~ (CDC1
2. 40 ~3~I, s), 4. 1~ (3~, s), 4. 20 (2~, s) / 7. 53 (1~, s~;
~R ("~jol" ~null) 1675 cm 1,
A solution of the 'criazole (1. 00 g, 5. 85 mmol) a~d
ethyl brc~moacetate (1. 48 ml, 13. 3 ~¢Qol) in dry aceto~trile
(10 snL) was heated at 60 for 9o h ~mder nitroger~. The
solvent W2S remo~red and the residual oil was triturated with
ether (4 x 2~ mL) to lea~re l-methyl-3- (ethyl carbo~ hyl)-4-
methaslethiolace~ate-l, 2, 3-txiazolium bromide as a .brc~wnish
gum which W2S used directly.
A cold solution of KO~I (0.66 g, 12 ~aol) in watex
(5 mL) w c added to an ic~ ooled, stirred, solution o~ the
triazolium brosnide in water (20 mL). After 20 ~in, this was
diluted to 35 mL and sufficient solid potassium dihydroges~
phosphate was a~ded to bring the pB of this solution to 8Ø
This was then added to a stirred, ice-cooled, solution of the
enol phosphate in T~IF (35 mL). After 0.5 h, this mixture was
transferred to a pressuxe bottle containing ether (35 mL) and
10% palladium on charcoal (1.5 g),. It W25 hydrogenated 2t:
40 p.s.i. for 55 minO The organic phase was then separated
and washed with water t2 x 5 mL). The ~:o~ibined a~[ueous phases
were filtered and the filtrate concentrated u~der high vacuum.
The residual material was ~hromatographed on a reverse phase
~ol~Dn (35 x 120 ~n) with watex as eluent. Lyophilization Q.
the carbapenem contairling ~ractions left 1. 20 g of a green-
coloured so~i~. This was rechromatographed on a Waters Prep.
500 HPLC ("PrepPAK" -500/C18 column) with 2% acetonitrile-wa~er
as eluent. l`he fractions containing t:he carbapener~ were
combined and lyophili zed. This material was again ~echromato-
grai?hed by HPLC ~10 x 300 mm Waters Microbondapack C-18 column)
*Trademark (each wcurrence)
... .
. ;
:' '' '`' ''' ' .
. - 75--
,
.
wi~ water as eluent to afford, after lyophilization, p~e
title compound (190 mg, 17%) as a pale yellow solid~
(D20) ~ 1.24 (3~ 1, J=Ç.4 ~z3 t 3.07 (2~, d, J--9 ~z), 3.38
(lH, q, J=2.7, 6~0 ~z), 4~02-4.30 (3~, m), 4.29 (3~1, s~,
5.23 ~2~, s), 8.52 (lE~, s); IR("Nujol") mull) 1.750 an 1; W
tphospha~e bu~fer, p}I 7~ 4) ~ma~ 296 nm (E=7,520) .
Examp le 4
Potas s ium 3- ~4~ carbo~ylat~ethyl-3-me_hy~ ,3-
triazolium) -methznethio] -6u- [ 1- (R) -hydroxYethyll -7-
oxo-l-azabic~clo[3. 2. O~hePt-2-ene-2-carbo~srlate
~x
N 1~)
2 ~CO~
- HC~ ~ CO2Et
N ~ - N N ~ SQ Et
~N f ~) EtO-Cl,N~:t3 ~N~ ~ 2.
~CX N
2 3 b ) Na~3~4
~o~N~3 2
~3
,~.S~C}~3
' .
*~rademark
........ ...
. , ~ .
. . .
'' '' ` '
-76--
1~3
OH CH
. A~S ~ C~2Et
~5 ~ N
c~ b) XOB N-
~:~ ~~~32 .
C2P~3
d) H~/Pd`C
A mixture of ethyl azidoacetate (30.0 g, 0.23 mol)
and propiolic acid (14.3 mL, 0.23 m~l) in toluene (75 mL) was
stirred at room temperature. The reaction remained mildly
exothermic for 1.5 h after which it guickly became ~igorously
exothermic and cooling with an ice bath was necessary. After
this exothermic ph2se had passed, the reaction was heated at
reflux for 0.5 h. After being cooled in an ice bath, the
crystalline material was collected by filtration and washed
with a little toluene. The crude material obtained in this
manner (33.3 g, 72%) consisted of a single isomer ~ ~NMR
(DMSO-d6) ~ 1.20 ~3~, t, J=7 Hz), 4.15 (2~, q, J=7 ~z), 5.42
(2H, s), 8.67 (1~, 3)~, presumably l-(ethyl carboxymethyl)-
1,2,3-triazole-4-carboxylic acid by analogy with earlier workl.
A solution of ~he carboxylic acid (5.00 g, 25.1 mmol)
and triethylamine (3.68 mL, 26.4 mmol) in dry methylene chloride
(50 mL) was added to an ice-cooled, stirred, solution of ethyl-
chloroformate (2.52.mL r 26.4 mmol) in dry methylene chloride
(50 mL). The purple coloured solution was le~t stirring for
0.5 h a~terwhich it was washed wi~h water (10 mL), dried (MgS04)
and the sol~ent removed. The cxude mixed anhydride was dissolved
in THF (50 m~) and added 510wly to an ice-cooled suspension of
sodium borohydride ~0.72 g, 18.9 mmol) ~n THF (50 mL). After
stirring for 0.5 h, additional sodium borohydride (0.30 ~,
709 mmol) was added and the reaction was left in the ice bath
for 1 ~. Water (5 m~) was then added and after 10 min, this
was followed by 10~ aqueous HCl (3 mL). After gas evolution
had ceased, solid potassium carbonate (2 g) was added with
C. Pederson, Acta. Chem. Scand., 1959, 13, 888
;.: , ' . ' :
.. ", ~ .
-:
....
.
-77- .
.
stirring. The organic phase was ther~ removed and the residual
white paste was ~xtracted with additional T~. Th combined
organic phases were dried (~qgS04) and ~he solvent removed,.
Flash c:olumsl chromatography on silica gel, eluting with hexane,
mixtu~es o~ ethyl acetate-hexane, and fin211y ethyl acetate
afforded 1- (ethyl carboxyme~yl) -4-hydroxy~nethyl-1, 2,3-trîazole
(2.04 y, 44%) as a crystalline solid: ~NMR (CDC13) ~ 1.28
(3~, t, J=7 l~z) t 4.23 (2:~ q, J=7 E~z), 4.7~ s), 4.85
(2~I, s) ,~ 7.73 (l~I, s) .
Diisopropylazodicarbox~late (4.11 mL, 20. û mmol~ was
added dropwise to an ice-cooled solution of triphenylphosphine
(5. 47 g, 20. 8 Ir~nol) in ~ lF (100 ~nL) under nitxogen. .a~ter
0. 5 h, zn ice-cooled .solution of the alcohol (1. 93 g, 10 . 4 mmol)
and th- olacetic acid (1. 49 mL, 20 ,. 8 mmcl) in dry T~[F (~0 mL)
mder nitrogen was added to this mixture. This was left for
2 h in the ice bath and then for an additional 12 h at room
temperatur~; afterwhich the sol~ent W2S removed. The xeaction
mixture was flash chromatographed on silica gel ~40 g; eluting
with 100 ~L por~ions o~ hexane, 5%, 'L0%, 15%...50% ethyl acetate-
hexane). Fractions ~ontaining the thiolacetate were combined
and rechromatographed on silica gel (60 g~ ~elution with 200 mL
portions o~: hexane, 5%, 10%, 15%, 20% ethyl acetate-hexane and
22.5~ 25, 27.5...35~ ethyl acetate-hexane]. This afforded 1.24 g
~ 49 96 ) of 1- ~ethyl carboxyme~hyl) - 4-me thanethiolacetate-l, 2, 3- :
triazole as a crystalline so:Lid ~NMR ~ 1. 28 ~3H, t, J=7 Hz),
2~37 (3H, s), 3. 87 ~2H, s), 3.90 (2~, q, J-7 Hæ), 5.12 ~2~, s),
7-63 tlH~ s); ~R ("NlljO~ 1735, 1780 cm 1.] 3nd an additional
1.40 g of material contaminated with triphenylphosphine oxlde.
*Trad~nark
~. ' ' ' ' .
~2~3~
-78-
. _
Methyl txifluoromethane sulfonate (0.51 ~, 4.53 mmol)
was added dropwise to asl ice-cooled, stirred, solutio~ o~ the
triazole (1. 00 g, 4.12 n~Dol~ i~ dry methylene c~lorIde (5 mL~ .
The bath was removed a:Etex a . 5 h and after an add~tional 0 . 5 h,
the solvent was remo~red with an aspirator ~racuum. This 14ft a
white solid which was suspended in water (15 mL) and this stirred
mixture W2S cooled in an ice~ath. A solution of XOH (0 . 69 g,
12.4 mmol) in water. (S mL) was added arld t:he reaction was left
stirring :Eor 1 h. It was then diluted to 30 ~ with water ar~d
solid potassil~n dihydrogen phosphate was added to })ring the p~
to 8Ø A portion o this solution (22 mL, ca. 3.0 ~snol o~ the
thiolcarboxylate) was added to asl ice-coc: led, s~ rred solution
of the eT2ol phc~sphate (1.60 g~ 2.76 mmol) in T~IF (30 ~L). P~fter
0. 5 h; the reactiorl was taken a~d put undex high ~acuum to
remo~re the TEIF.. me yellow solution was then.chromatogxaphed
on a revexse phase column (3S x 120 mm) eluting with watex t300
mL) followed by 100 mL porticns of 5, 10, 15...30% acetonitrile-
water. ~yophilization of the desired fractions affoxded the p-
nitxobenzyl ester a~ a yellow solid ~930 mg). This was ~rans-
ferred to a pressure ~ottle containing ether (25 mL), T~F (25 ml),
and phosphate buf~er [25 mL, prepared by dissol~ing potassium
dihydrogen phosphate tl~36 g, 0.01 mol) i~ water (100 mL) and
adjusting ~he p~ to 7;4 by adding 45% aqueous RO~] and 10%
palladium o~ charcoal (900 ~g). The hydsogenation was conducted
at 40 p.s.i. for 1 h after whic~ the organic phase was separa~ed
and washed with water (2 x 5 mL). The ~ombined aqueous phases
were ~iltered and then concentrated under high vacuum. The
residual solution was chromatographed on a reverse pha~ column
(35 x 120 mm) eluted with water. ~ractions containing the
carbapene~m were combined and lyophilized to a~ord 1.21 g o~ a
pale greenish solid. This was then purified by HPLC (10 x 300 mm
~waters Micxobonda~a~k" C-18 col~, ~o as eluent) to give pure
title product, 480 mg ~41%): NMR (D2O) ~ 1.23 (~H, d, J=6.4 ~z),
*Tr.ad~T~k
.' `'~
. ~, ............................ . . .
. .
. .
..
:~L2~3
--79--
3.11 ~2~, d, J=9 ~Z), 3.37 (1~;, g, J=3.0, 6.1 B2), 4.02 (7~, m~,
5.18 (~I, S), 8.53 ~l~It 5) IR (~NUjO~ 750 Gm I~V
(PhOSPhate bUffer/ P~i ?.4)~aX 20~ 7~810)
EXamD1e ~-
3~ ( 1, 4-Dime ~.vl-1, 2, 4-tri2zolium) methane~io~ -6~-J l_ (R~ - .
hydro~yethyl~7-oxo-1-azabic~clo[3. 2. O~he~t-2-en~2-ca~a~e
. " ~cc(3 ~ s
methyl-~-methanethiolacetate-l, 2 t 4~txiazole
0~ a)- M8cvNEt3 /r~
---t N ~
3 ~N ~
Me~hanesul:Eonyl chloride (O . 46 mL, 6 . O :mmol) was added
dxopwise to an ice-coo1ed, stirre~, solution o l-me~hyl-~-
hydroxymethyl-1,2,4-tria~ole* (565 mg, 5.0 nmol) ~nd trie'chyla~Tine
~Oo91 mI" 6~ unol) in methylene Ghloride (~ mL). After 20 min,
zdditional triethyl2mine (1.O5 mL, 7.~ nol) ~ollowed by thiol-
a ::etic acid ~0 . 53 mL, 7. ~ ~mnol) was added and stirring was
continued f~r 45 min. The xeaction was then diluted with
,
.G. Jones 2nd C. ~.insworth, J. Amer. Chem. Soc., 1955, 77, 1938.
**Trad~rk
.~ ~
. ~ :
'....... ~ ~
.
~3~
-8~-
methylene chloxide and washed with water. The agueous phase
w2s extracted wi~h methylene chloride (3 x 5 mL) ~nd the
combined organic phases were dried (~gS04) and the solvent
removed. Column chromatGgraphy on silica gel afforded pure
l-methyl-5-methane~hiolacetate-1,2,4-triazole (570 mg~ as a
yellow oil ~in additio~, an impure fraction (200 mg) was
rechromatographed (preparative T~C, silica gel) to give a
further 100 mg of pure material (total yield: 85~)J: ~ MR
(CDC13) ô 2.38 (3H, s), 3.90 (3~, s), 4 ?5 (2~, s), 7.80
(1~, s).
B. 3-~5-(1,4-dimethyl-1,2,4-triazolium)-methanethio~-6~-
[l-(R)-hydroxyethYl]-7-oxo-1-aza icyclo[3.2.0]hept-2-
e~e-2-carboxylate
o-.
a~ MeOTf ~
N~ ~f ,~_ o; ~;
.' C02PN~,
~) ~2/~-C
.
Methyl trifluoromethanesul~onate (1.20 mL, 10.7 mmol)
was added dropwise to an ice-cooled solution of 1-methyl-5-
methanethiolacetate-1,2,4-triazole (730 mg, 4.27 mmol) in
methylene ~lloride (7 mL). The reaction mixture was slowly
allowed to warm to room temperature over 3 h after which it was
concentrated. The residual oil was triturated with ether to
leave crude 1,4-dimethyl-5-methanethiolace*ate-1,2,4-triazolium
trifluoromethanesulfonate (1.46 g) w~ich was used directly.
A solution of sodium hydroxide ~512 mg, 12.B mmol)
in water (S mL~ was ~dded to a~ ice-cooled solutio~ o~ ~he
triazolium salt (1.45 g, 4.35 mmol) in water (5 mL). After
45 min, this was diluted to 25 m~ with water and ~he p~ was
adjusted to 7. 6 with solid potassium dihydrogen phosphate.
This solution was then added to an ice-~ooled, stirred,
solution of the enol phosphate (2.00 g, 3.45 mmol) in T~F
(25 mL). A'ter 30 min, the reaction mixture was transferred
to a pressure bottle containing ether (40 mL) and ln% palladium
on charcoal ~2.0 g). This was hydrogenated (4~ p.s.i.) for
1.25 h. The reactisn mixture was ~hen diluted with ether ~25 mL)
and iltered. The organic phase was separated and washed with
wa~er (2 x 5 ~oI). The com~ined aqueous phases were washed wit~ -
ether t3 x 25 mI.) ar~d then concentrated undex vacuum. Columr
chromatography (reverse phase , 45 x 130 amn, water as eluent),
followed by lyophiliza~ion o:E the carbapenem-containing fractions,
afforded 650 mg o~ c:rude material. This was rechromatographed
to giYe pure ti~le pxoduct (450 ~g, 39%): ~NMR (D2O) ô 1.2~g
(3~I, d, J=6.4 ~z), 3.19 (2~I, dd, J~2.6, 9.2 :E~2), 3.45 (l~,dd,
J-2.~, 6.0 ~z), 3~ 3~I, s), 4.06 ~3H, s), 4.08-4.36 ~2~I, m) r
4.54 (2~I, d, ~-2.8 Hz), 8.71 (lH, s); IR ("N~ljol" nn~ll) 1755 cra~l;
W (phosphate buf~erJ P~ 7 4) ~ma~ 294 nln (E=8~202); Tl/2
(phosphate buf~er~ pH 7.4, M=0.067, T-37C) 9.1 h.
*Trademark
i .. . .
, ~
:
--82--
Examp le 6
(1' R, SR, 6S) 3- r ~1, 3-dimeth~-tetrazolium~ -methylthio~ -6
carbox~late
o~ - ~ OE
~S-C3~ 3
A.. 5-c rbethoxy-2-methyltet:razole and S carbethoxy-l-
meth~ltetrazole
,
p ~--C02~ ~ ~ N~
la. Methylation with diaz~nethane
A solution of 5-carbethoxytetrazolel t9. 17 g, 0 .064
mol) in ethyl e~her ( 80 mI.) was cooled to 0C and treated
3 . ~oderhack , ~hem. Ber ~, 10 8 , 8 87 ( 19 7 5) .
2The use of a ~Lixture of ethanol and ether gave the same rati~
of isomers.
. . .
~ ~ ~
,
`` ' '~,
~273~4
--83--
, .
dropwise (15 min) with a sc:lution of di~zomethane (3 g, 0.071 mol)
in ether (200 mI.~. The light yellQw solution W2s stixred for
30 min and the excess of aiazome~ane was destroyed by addition
of aoetic acid (1 mL). Evaporation o the sol~ent and ~istilla
tion o the ~esidue gave ~ dear oil: bp 95-100C/0 . 5 torr; 9 0 64
g~ (96~ mr indicated a ~nixture of l-methyl and ~-methyl
isomers in a ra~io 6:4. Separatio~ of the two isomers could rlot
be done by distillation nor hplc: ir (fi~l) vmax 1740 cm 1
(C=O o~ ester); L~Imr (CDC13) ~ : 1. 53 (3~, two overlapping ~,
J=7.û, ~I;~CE13), 4.46 and 4.53 (3~, 2S, C~3 of l-methyl and 2-
me.hyl tetrazoles, xatio 6:4. The methyl of the 2-isomer is at
lower field and is ~che minor product), 4.5 ppm (2~I, two. overla~ping
q' C~2~3)'
lb. 5-Carbetho~-methYltetrazole
N ~N N--~ C~3I ,~N
C1~2~ ~ C 2 1~ ~ k C0
C83 C~3 C~3
A mi~ture of 5-carbethoxy-2-methyltetrazole and 5- :
carbetho~y.l-methyltetrazole ~û.~52 g, 1.61 mmol, ratio o~ the
two i~ome~s 1~ iodomethane ~0.5 m~) was sealed , in a glass
tube and heated at lûûC ~or 15 h and at 13ûC ~or 6 h.
Distilla~ion of th~ reaction mixture gave the title ~ompound as
a light yellow oil: 0.139 g ~55%); bp 95~1ûO~C/û.5 torr ~ir
~ath temperature): ir (film) ~max 174û cm 1 (C=O of ester);
Hmr ~CDC13) ~: 1.46 ~3H, t, J=7.û, C~3CH2), 4.53 ~3H, s, CH3-2),
4.5 ~2H, q, J=7.~ CH3)-
~ . '
', ~;
'
.. . ; .
. . ~ .
~73~
--~4--
~ .
2 . Me~hy lati on wi th dimeth~l su lf ate
;~ solution OI ~-caxbethoxytetrazole (1. 42 g, O .01 mol)
in dry acetone (20 mL) was treated with anhydrous potassium
carbonate (1038 g, 0.01 mol~ and dime~hyl sul ate (1.26 g, O.Ql
mol)O The mixture was heated under re lux for 1~ h. ~he
carbonate was filtered and the sol~ent evaporated under reduced
pressure. The residue was diluted with dichloromethane (30 mL),
washed wi~h saturated sodium bicarbonate (10 mL), brine (10 m~)
and dried over anhydrous sodium sulfate. Evaporation of the
solvent and distillation under vacuum ga~e a clear oil: 1.45 g
t93%); b.p. 85-110C/0.5 torr. Hmr indica~ed the presence of
two isomers in a ratio 1:1.
B. S ~ydroxvmethyl-- 2-methy ltetxazole
c~3 ~ ~ ~C23~ _ T~; 3~ ~ N2O3
t. By reduotion of the mixture of esters.
A mixture o~ 5--carbethoxy-l-methyltetra701e and 5-
carbethoxy-2-methyltetrazole ~ratio 6:4) t7.60 g~ 0.04g mol)
in dxy tetrahydrofuran t50 mL) was cooled to 0C and treated
with lithium borohydride tl.06 g, 0.04g mmol) added i~ small
portions o~er 15 min. The n~xture was maintained at 10C for
30 additional min andthen stirred at 20C for 4 h. The mixture
was cooled to 0C and the excess hydride was carefully destroyed
by addition o 6N HCl tp~l of 7 after no more gas was evolved~.
rrhe solvent was concentrated under ~Tacuum and the residual oil
ciluted with dichloromethane (200 mL3, washed with brine (10
æ~d fi:lally dried over Na2S04. Concentration of the solvent
,
.,.' ~ ' '
'
-85-
and dis~illation of the residue under ~acuum ga~e 1.83 g
(33~) of a clear oil. lHmr of ~his makerial indicated ~he
product was 5-hydroxymethyl-2-methyltetrazolP.
2. ~
To a solution of ~-carbethoxy-2-methyltetrazole
(0.139 g, 0.89 mmol, obtained by isomerization of ~he mixture
of esters with methyl iodide) in dry tetrahydrouran (1 mL)
at 10C was added solid lithium borohydride tO.019 g, o . R7
mmol~. The mlxture was slowly warmed up to room temperature
and stirred for 4 h. The excess borohydride was destroyed by
careful addition of 6N HCl at 0C (p~ 7). The solvent was.
evaporated and the residue dissolved in dichloro~ethane (25 mL)
and dried o~er anhydrous sodi~m sul~ate. Evaporation of the
solvent gave the ~ tle compound as a clear oil: 0.092 g (91~);
bp 90-120C/0.5 torr with decomposition; ir (film) vmaxO
3350 cm (broad, O~); ~ r (CDC13) ~: 4.4 (2H, s, C~3-2), ~.93
(2~, s, C~2-S).
C . S-AcetYlmercaE~tomethyl- 2-methYltetrazole
~l ~CH~OH _ CH~--N
'''',: '
,
" '
~2~
--86--
, . . ~ .
To a solution o~ ~-hydroxymethyl-2-methyltetrazole
(1. 83 g, 11. 7 mmol) in dry dic:hloromethane (25 mL~ at 0C was
added methanesul~onyl chloride (1. 47 g, 1209 ~nol) :ollowed by
triethylamine tl.30 g, 12.9 mmol) added dropwise o~er five min O
The mixture was stirxed at 0C for 1 h, and the~ treated wi~h
a solution of potassium thioa~etate 11~60 g, 1400 mmol) in d~
N,N-dimethylformamide ~10 mL)~ The resulting gel was stirred
at 0C for 3 h. The reaction mixture was diluted with dichloro- ~
methane ~200 mL~, washed with brine ~20 m~) and dried o~er
anhydrous sodium sulfate. Evaporation of the solvent under
vacuum and chromatography of the resulting oil over silica gel
(2 x 15 cm, eluting with dichloromethane and dichloromethane-
acetone 5~) gave ~he title compound as a clea~ oil: 1.31 g (65%);
ir (film) ~max 1696 cm 1 (CYO of thioester); ~ (CDC13) ~:
2.43 (3H, s, SAc), 4.36 (3H, s, 2-CH3), 4.38 ppm (2H, s, 5-C~2)o
D. 5-mercaptomethyl-1,3-dimethyltetrazolium trifluorome~hane~
sul~onate
N ~ CF. S0 CH CF350
h ~CH2S~c-- -3 3 3 ~ 3 ~2s~
C~3 . 3
,
A solution of 5-acetylmercaptomethyl-2-methyltetrazole
(0.400 g' 2.32 mmol) in dry dichloromet~ane (3 mL) was treated
with methyltriflate (0.76 g, 4.64 mmol) and stirred at 22C ~or
16 h. Evaporation of ~he sol~ent under ~acuum gave a red oil.
This salt was dissolved in cold oxygen-free water (5 mL) and
-87-
treated with 4 M sodium hydroxide (0.8 mL, 3.2 m~ol). The
mixture was stirred at 0C ~or 40 min, diluted with water
(7 mL), and the pH was adjusted to 7.3 with saturated XH2P04.
The clear resulting solution was maintained under nitrogen
and used immediately for the following step.
E (l'R,5R,6S) 3-[1,3-dimethY1-5-tetrazolium)-methylthio]-6-
.
(1 hydroxyethyl)-7-oxo l-azabicyclo(3.2.0)he~t-2-ene-2
carboxylate
~ 5 ~3 OH
Z ~ 2 ~
C02PI~'B C~ C02PNB 3
3 Ci~3SO3
0~ '
H2pd/c ~ ~ ~ 3
co~ C~3
A solution of enol phosphate (0.915 g, 1.58 mmol) in
tetrahydrofuran (8 mL) was cooled to 0C and treated dropwise
with the solution of 5-mercaptomethyl-1,3-dimethyltetrazolium
tri~luoromethanesulfonate (2.32 mmol, prepared above) over a
period of 20 min. The pH of the reaction mixture was stable
at 6.5 throughout the addition. After 20 additional min. the
pH of the solution was ad~usted to 7.0 with saturated sodium
bicarbonate. The mixture was transferred to a hydrogenation
..
'~'
" ,
. .
. .
,'' :,
.
-8~-
. .
bo~tle, diluted with THP` ~10 mL) ~ ether (20 sDI,) and ice (20 g).
The carbapenem was hydrogenatea oYer 10% palladium on acti~ated
carbon under 45 psi w~ile slowly increasing the tem~?erature 1:o
2~'C for 90 mirl. l`he c:atalyst was filtered and washed with cold
water (S mL) and ether ~2n mL). The a~ueous phase W2S washed
with e~er (20 mL~ a~d mairltained under vacuum for 20 min to
remove traces of organic solventO Chromatography o~ "PreP~"
500-C/18 a~d elution with water gave the title compound as a
whi~e powder after lyophilization 0. 266 g (49%); ~a}~23 +13~
(c l.D4, ~12O~; W ~I2O~ p~l 7~4) ~m2LX 294 nTtl (E7,500~ K3r)
max 1755' ~C=O of B-lactam), 1600 cm 1 (broad, C=O o~ carboxylate~;
Hmr (D2~ 1.24 (3~, ~, J-6.4 ~Iz, C~33CHOH), 3.0~3.3 (2El, m,
~-4), 3.42 ~l~I, dd, J~5.8, J=2.9, ~-6), 4~4.2 (2~lD ~ nd
0~1~, 4. 34 and 4. 57 (2 x 3~I, 2S , C}I3-1 a~d 3 c~ tetrszole),
4.49 and ~.51 t21~, 2s, C~2S). The product has a half li~e of
10 . 5 h at 37C (c of 10 ~ ~ in p~ 7. 4 phosphate ~uf~er.
*Trad~mark
"'. '
.
.
, . "
:
:: ".,
.... .
- 89 ~ 3
~e~
Preparation o~_3- ~N-Methylpyridine-2~ methanethio) -6~- [1- ~ )
hvdroxYethyl] 7~oxo-l-a2abicYclo[3.~.o]-hept-2-ene-2-carboxylate
v_n One Pot Process
J~
CF SO ~)
OH CH~ 3 3
F~ [~\SAc
C2 PNB
C~3CN ¦ Cl~ (~) 2 ¦NaOH
0C, 45 m~r~ , EtN(i~r)2 ~ 2~ 0C, 1 h.
OH
~,~CF3 50 3~)
2 PNB
~2 \ / 4
pH 6.5-7.5
THF~ H20
: i
90~
o~L~C02py~ IQi
. 5
¦ H2 Pd-C 10%
5C, 2 h.
/
0
~ CH
A. Preparation of enol phos~hate (2)
OH ~
~" ~ ~ ""' ~ ~I0)2
~ '~ -- ' ` > C02PNB
An ice-cooled solution of ketone 1 (3 g, 8.62 ~moles)
in acetonitrile (30 ml) was treated with ethyl diisopropylamine
~9 mmoles, 1.04 eq, 1~57 ml) (addition time ca. 2 minutes) and
chlorodiphenyl phosphate (9 mmoles, 1.04 eq, 1.87 ml) ~addition
time ca. 2 minutes)~ The reaction was stirred for 45 minutes and
TLC (ethyl acetate, si.lica gel) showed disappearance o~ ketone 1.
The solution was diluted with ethyl acetate (60 ml), washed with
cold water (2 x 50 m~) and brine, dried over sodium sulfate and
concentrated (bath temperature below 20C) to ~ive a foam which
was used as such.
. .. , , :
.,, ,. ~ ; .
' ',. ':
.:
. .
73~
-91-
Bo ~ ~_)
T ~ ~ I 1) N~O~/~20 ~ IH3
SAc , I b. ~ ~o ~ S~
2) KH2P4
An ice-cooled solu ion of thioa~etate 3 (3.31 g, 10
mmoles) in water purged wit~ nitrogen for S minutes was treated
dropwise (ca. 5 minutes) with a cooled solution of sodium hydrox-
ide (1.75 eq, 17.5 mmoles, 0.7 g) in water (8 ml). The mixture
became yellow. After 75 minutes under nitroge~ the p~ was
adjusted to 7.4 with saturated aqueous solution o~ K~2P04. The
reaction mixture was diluted with water (15 ml). This a~ueous
solution of thiol 4 (50 ml, O.2 mmoles/ml) was used as suoh.
C. Coupling
0~ 4
~( 2 ~HF-~2
C02PNB , 1 h.
5 ~02PNB
~ n ice-cooled solution of 2 (crude, prepared in A, 8.62
mmoles) in tetrahydrofuran (50 ml) was treated dropwise with the
aqueous solution of thiol 4 prepared in B (5 ml of solution every
5 minutes). During the course of the reaction the pH of the
reaction mixture was maintained around 6.5-7.5 (preferably 7) by
adding cooled 2N sodium hydroxide solution. The reaction was
~ollowed by TLC ~a) silica gel, ~thyl acetate; (b) reversed phase
Analtech ~PSF, ~H3C~- pH 7 buffer (4:6).
~,~r'r\ *Ira~Erk
~....................... . .
, : :,....
. ' , .'"''~ ' ~
.: '': ' '' ' -, '
-92- ~73~
At the end 1.15 eq of thiol was used (50 ml of ~o-
lution). The reaction was complete ater 1 houx at 09C an ~he
mixture was used as such for the hydrogenation after the p~ was
adjusted to 7.
D. ~y~
H ~ ~2/Pd-C 10%
N THF-~20-ether
a C02PNB ooc, 2 h~
S ~ ~_
The reaction mix~ure containing 5 (prepared in C) was
transferred into a "Parr" flask With THF (10 ml), phDsphate buffer
(p~ 7, 0.1 ~) (10 ml), ether t75 ml) and Pd-C 10~ (5 g~ and
hydrogenated at 45 psi at 3-10~C for 2 hours. Then the catalyst
was filtered, washed with water (3 x 10 ml) and the p~ adjusted
to 6.2 carefully with cold 2N NaOH. Ether was added and the
agueous phase was separated and washed again with ether. The
aqueous ph~se was purged o~ organi~ solvent under vacuum and then
purifiéd on ~ "Bondapak C-18" column (100 g, ~.5 x 13 cm) wi~ cold
distilled water. The light yellow fractions containing the
product (checked by U.V. and TLC) were lyophilized to gi~e 1.46 g
~50%)* o~ 6 as a yellow powder. ~293, E - 9000, ~ 271, E ~ 11064
, . .
*yield calculated ~rom bicyclic ketone
**Trad~E~k
~1 ,.
~.... :. .
93
ExamRle 8
o~ C~3 C~3
~'~5~
~ 02PNB ~ C5~3503~
l'ClPO (00) '
CH3 R ~ fH3 ~ CF3So3~3
OP(00)2 ~ ~O ~ H
C02PNB
\ /
OH CH3 ~ ~H3 ~ 1
02PNB
CH
'~r~ ~
I~ in the procedure of Example 7~ the keto intermediate
1 is replaced by an equimolar amount of the corresponding lB-
methyl intermediate, there is obtained the carbapenem end-product
indicated above.
,
..
.
. :''. ''
.
.. ..
. -94-
o~ CH3 ~3
~ ~J
CO~
If in the procedure o Example 7, the keto intermediate
1 is replaced by an equimolar amount of the corresponding
1~-methyl intermediate, there is obtained the carbapenem end
product indicated above~
_95 ~L~ 3~L~
~ .'
Preparatlo~ o~ (5R,6S)-3~ 1,3 dl~ethylpyridi~u~ 4-yl)methyl~h~o~-6
[I-(R)-bydroxyc ~hyl J 7-oxo-l-azabicyclot302.0]~ep~l2-ene~2~earbox~1~e~
(10
. a~t
!
(4R,5R,SS)-3-~(1,3-d~ct~lpyrid~nlu~r4-yl~et~yl3t~10~ h~ro~y~
ethyl~-4-~ethyl-7-oxo-1-a ab~c~clo~3.2.0Jhept-2-ene-2-car~Qæylate
(10 R)
.
o~ R
~ ~ 3
'' 10~
- lOB ~ 3 . ~
, r ,,
. ' ' ' ' :
..
-96
A.
~3 - f~2
3 I ) I~O~ C~1
3) ~3
The gcaeral prooedure o~ ~oekel~eidel or the preparatlo~ o~!
~ydro~ethylp~rid~ ~a~ used. ~u8~ a ~olut~oa o~ ~resh~ d~ t~led.
3~4-lu~ld~ae (46,0 g~ 0.43 Dol) ln 120 DL of gl~clal acet~ acld ua~ c~ol~d i
a O-C and ~e~ 64 ~ o~ 30X 1~202 ~Ja$ a~de~. d~op~eO T~e re~ult~
~olntion ~P~ ~eated ae 75~C (o~l-ba~h te~peratu~e) fo~ 3 h. Another 20 ~L I
f 30Z ~22 ~a8 then addea and '3eati~ ~a8 continned ~o~ 18 h. H~ally, 20
~L of 30~ ~22 was agai~ added aDd the reac~o~ ~as kept at 75-C for
another 3 h. The solut~on ~a8 then concentrated t~ ab~ut 100 ~L u~der
uater-asp~rator pres~ure9 50 ~L o~ ~0 was added a3d t~ ~ixturo ~a&,
co~centrated to about ODC 3alf ~olu~e~ The re~ultlng mixture uas cooled
(0-5~C) 2hd baslfied t~ a~out p~ 10 u~ing cold 40~ Aqueou3 ~aO~. The
~ixturc vas the~ ex~rac~ed with C~C12 (5 x~ nnd the e~ract ~a~ drie~ ;
tNa2C~3 + Na2SO4) a3~ co3centrated ~on the roto-~p to glve a yelloY
601utionc Dilutio~ o~ ~his ~olutl~ Y~th be~ane afforaed a 801ia ~hich uas
collected ~ fil~ratio~ and ~heu dr~ed ~n VLC~O ~o g~Ye 3,4-lut~di~e-N-
ox~de (48.0 g, 832~ as 8~ o~-Y3ite ~ol4d.
~97~
~ hc N-os~i~e va~ ~dde~ p~rtion~ to 60 %~L o~ aoet~ ~ab~t~lde
an~ the r~ule~ ~ar~ ~range so~utlo~ vaæ ~cated (uater ~ath~ ~t a'bout
~0C ~os 1 b.. T~ae exce~ ae~lc ~hy~r~ s t~e~ d~st~lled off usdcr
~e~uee~ pres~use a~d~ tbe ~te~al b~ t 9~120-C/D.1 ~:osr ~39.~
~ollec~d. Chro~a~ography of thls oi.l ~ Ll a gcllet~l scet~te-pet-ct~*r ;
2:3) ~for~e~ pur~ 4-aceto~ethyl-3-~cthylpyr~d~ne (19.0 g9 30~ a~ .
o~ s tueat~ 1745 ~ 11 j
~ ho ~ceta~e ~as the~ t~kc~ up ~n 100 ~L of lOZ aqueou~ BCl a~t ¦
se~luxed for 1 h. The re~ul~lng ~ol~t~o~ ~8 coole~ ~t 0C, ba~f~ed ~h '
~olia ~2C03 ~d ~he~ cx~s~cte~ ~t~ C~2C12 (3 ~ 100 ~L~- The organ~e i
extract ~8~ ~a~b~d t~3e~ dr~ed (Ra2S04) ~ e~a~orate~ to g~v~ 11.0 ~ o~
of~-~h~tc ~ol~a, ~pO 70~7~-C. T~ ol~ ~a3 ~r~turate~ Yit~ cold
ethc~ to g~ve pur~ 4N~y~ro~y~e~h71-3-mcth~lp~rid~ne (9.5 g, 672) ~ n ~hlte
colid, 2:.p. 77-80C 51~t.~ ~.p.. 81-82-C): a~r (CDC~ 8.27, 7.41 tA~
J-5~z, 2B), 13 . 18 (~ , 5 . 63 (br ~ ~ -~? 4 . 67 (~ 2 . 20 ~ 39;
lr ("Nujol"~ ~170 cm~
1. V. ~ockel~e~de~ W.J. ~ JACS, 76, 1~86 tl954) .
2. W.L.FI ~r~sregO~ B.A. ~ 0~D S.C~ Shar~a~ JCS~ 24B5 (1~7
*'~rademark
.
.... , ~ . .
..
.
(
- 9 8
~30'
c82a8 I H2SA~
~ CH3.
.
~ o a~ ~ee-~lâ, ~ccban~cally ~t~rsed 601ut-to~ o~ trlpherlylpho8- .
ph~e (~7.04 ~, 0~065 ~ol) ~a 25Q ~rL of ~ F ua~ added drop~l;e
tl~soprops~l agodlear~ox~late tl2.8 s~, 0.065 ~ol) a#d he re~
~a~ ~tir~d ~t O-C ~o~ ~ h. $o t 1~ ~tu~c u~s added drop~e a ~o~ution
o~ hyd~o:~etS~1~3-sDet~lpyr~a~ne t4~0 g, 0.0325 ~ol~ ~ 100 ~ o d~
~P, foll~ea b~ ~e~ d~t~led t~o~acctlc ~a (4.64 ~L, 0.965 ~nol9,
e~Llt~n~ sn~ture Ya~ et~e~ ~t ooe for 1 h . ~d t~e~ ~t ro~
te~peratu~2 ~o~ 1 ~ to ~l~c a~ orange ~olut~on.. T~o solut~o~Lv~s
eo~cc~trated trotar~ e~aporator) aDd thc~ d~:Luted vlth petroleu~ et~er. I,
~e re~ult~g ~xtur4 ~a8 ~lterct ~d ~ f~ltrate Yas e~aporated to g~a '
a~ o~ang~ o~. t~ro~atography ts~c~ gel/hexa~e t~er~ 102: ~ 50Z ~t~yl
4cctate-be~c~ of t~ls oll ga~e ~ . O g of sn o~l w~ich was di~t~ed
* . . :~
("~gelm~ o g~e th-: pure product ~6.,0 g, 700 Z) ao ~L yel~ow oil, b.p.
tair-ba~ t~p~rature) 9S-100-C/0.1 tor~ ~r (CDC13) ~ 8.40~ J.20 (~Bq,
J~5Bz, 2E~), 8.37 t~ , 4.08 ts. CEI2), 2.35 (~, CEt3), 2.32 (~, OE13); lr
S;~eat) 1695 e~ 1.
*Trademark
.
'' ,.
~99-- .
73~
C, Prepar tion_of 4-~Ac ~
c
2 f~l2SA~:
N3
~3
To an ice cDld ~olutio;:~ of t~e t~oacetate (2.95 g, 0.016
lû 2L of sethyleDe c~ort~e '~ta8 adaed ~op~e ~et~yl t~ uo~o~etl~ e~
rul~o~at~ (4.60 ~, 0.~4 ~ol) a~ th~ re ua~ 6tirsea ~'c O-C ~e~ ~2
for 1 h. T~e react~oa 2~xture ~a~ hc~ e~aporatea to drgne~ snd the 1 '
re~due ~las trit~rated ~t~ ethes. ~ re~ult~:ng sol~d ~as coLlected by
filtratioD. and drled ~ v~uLo to gl~e the proauct ~4.0 g, 72~ a~ a ~te
~olid~ r (CDC13) 8 8.7Z (s, 1~1), 8.58, 7.87 (~Bq, J~6~Ez, ~1), 4.39 (E~,
~-C~3~ 4.1? (~o C~)D 2-53 t6~ ~3)" 2.36 t8. ~3~; ir (~eat) 1700 c 1.
(I --100--
D. ~
~ .
:X
2 .
f~ ~ 1~ 2ta~ 21: ~ .,~
JI ~ ~S~
~1 ~C~ ~ N "~ )
~) I ;~ D~ 2
Ci'3SC~ 02PN~ ~
3 ) ~2 ~ ~?d/~ ¦
,
. Tc~ ee-cold, ~2 pu:r~ed ~olut~o of ~011 ~0.324 g, 0.008 ~nol~
~a ~D ~ of E120 ~a~ ~dded tEie t~o~cct~te (1.4D g, 0.004 ~ol) ar~d ~c
~ture s~a~ st~re~ at Q-C u;lter ~, fo~ ~ h. ~ter t~e p~ ; sd,~u~te~ ta
7.2-7.3 u~ng lO~ a~ueous pDtal;~f ~ d~ ydrogen p~o~p~Lst~ t}le rc~lt~ng j
solut~o;l ~.a~ added drop~e to aa ~ce-oolt s31ution o t~e c~ol iho~phate
~1.4~ g, 0.0025 mol~ ln 20 s~ of T~F. Thc ~ixture t.a~ ~lrred at O-C ~or S
h aTId t,-as then tra~sferr~d to ~ *es~ure bottlcO To this mlxturc ~a~ ~ddcd
20 ~sL o~ ethcr, 25 ~1 o~ 0.1~ phosp~ate bu~e~ (pB~7.~ nt 1.4 g o lO~ ~
palladlu~-or~-cha~coal. 'rhe ~ixtur~ u~c the~ hydrogeaated at 45 ps~ for 1
h. ~h~ roeactto~ ~actur~ ~as ~lltcred t~roug~ a p~t o~"Celite" ~d the pa~
~-a~ shct wie~ ~dd~tio~al ~cher ~d p~ 7.4 pho~p13ate bu~ r. ~c a~ueou~
phase ~ separa*~d aI~d ~c~ldual 60~ent~ ~ere rcmoved ,in v~ e
r~.cult~g ~ueous 601u~io~ sJac appl Led to a reverce-phase eolt= (C1~3
"BQndaPak") v~ ua~ eluted ~tb~ E120 a~d then lOX acetoDl~r~le-~I20. I~o-
ph~llzat~oa of the rc~cva~t fract~o~ gave 0.9 g o~ a~ or~ge ~olld. 1
Tra~3rk
. ~ .
--101-- (
73
~aterial U8~ rechro~atogrsphed u81ng ~2 an~ ~h~ 2~ ac~tonitr~le-~20 a~
eluane. Lyophliizatio~ a~osde~ pure .. 10 ~ t0~2S g, 57Z) as a yello~
æolid: 9~n~r ~2~ ~ 8~55 ~6~ 1~), 8.53~ 7.9~ (ABq, J~Ç.8 ~z~ 2~)~
4.30-3.99 (~ 2~)~ 4.27 (s, 5~)9 3035 (~d~ J1~2.8 ~z, J2~6.0 ~z~ / 3.05
(d,' J-8.8 ~z, 2~, 2~50 (5~ 3~ o23 (d~ J~6.3 ~ 3~ Br) 1755,
1590 c~ 1; u~ (phoæp~ate ~uf~cr, p~ 7t 295 nm tC?lBO)"
.
.
! -102-
3~
E. PreParation o~ (4R 5R,6S)-3-~t(1,3 dl~eth Ipyrld~niu~ eth llthlo~-6
. . .
~ .
OH 1) (~)2~Cl J ~
o~ ~ s~
CO~2N8 ~ 2
~o
3~ ~2' P~/C
ice-col~ 6~1utio~ o~ the blc~clic ~c~ODe (0.~06 g~ Q.0025 ~ol)
~n 10 ~L of ~ceto~itrll~ uas treated ~ucccs~el~ ~t~ dip ~71 ~hloropho~- ~
phate (0-544 ~L, 0.00263 ~ol3, diisopropylethyla~ne t0o457 ~L, 0.00263 ,'
~ol) and 4~ ethyla~inopyrid~ne t0.3 ~). After 50 ~ tbc .reactlo~
~ixture ~a~ d~luted ~t~ cold ethyl acet~te a~d then ~shed ~it~ cold ~ater !
and ~orine. The organic phaso ~as dried (NazSO4) znd e~sporated at roo~ ~
te~p~r~ture to ~lve t~e enol pho~phate a~ an off whit~ foa~. Thi6 fo~m ~a~
~ake~ u2 f~ 20 ~ of TEF, cooled at -30~C u~der N2 and the~ treated uith a~
aqueous ~olutio~ o the th~olate ~prepared a~ done pre~iousl~ ~r~ 0.3 g o~;:
~aO~ (7~5 ~mol) and 1.3 g o~ the thioacetate (3.76 ~ol) ia 10 ~L o~ ~03.
The renc~io~ m~stur~ ~a~ ~tirred at -30-C for 30 ml~ , ~he~ a~ 0-C ~or 75l
~in and fi~ally it ~as traucferred to ~ pres~ure bottle co~tai~ag 20 ~L o~'
ether, 30 sL o 0~lM phosphate buffer (p~ 7~4) and 1.5 g of 10Z pallad~2- :
on-charcoal. Aft~r hytroge~a~g at 45 p6~ for 1 h th~ ~ture ~as
.
- 1 0 3 -
~3
flltcr~ through Celite"an~ ~he ~ eQUs phase ~a~ separsted a~ con~tra~
t~ in v~!uo. The re~ul~lDg solut~or~ Ya~ appl~e~- t~a ~L ret~er~ pha~e tc~8
"BondaPak") colus3~ ~e~ ~as eluted ~ith El20. lyoph~liza~p~ o~ the r~l~t
fract~o~ gave 1.2 g o~ ~ yello~ sol~dO ~h~s ~3ter~al uas re~rD~ og
raphed ~elut:klg ~h ~2 ts 6,~: ace~ r~:Le-~20) to g~e, al~e~ l~op~ll-
satioYl~ purc 10 B (0.250 ~, 282) ~1~ 8 yello~ 6sl~d: aE~3~ (D20) ~ 8.53
(s" lE[), 8.49, 7.81 (~0 J-6.2 Bz, 2~, 4.38-3.58 (~, 4}~)~ 4.27 ~i~3 3E~
3.49-3.18 (~ ), 2~51 t6, 3~), 1.25 ~d7 J~6.7 Elz, 31I)~ 1.16 ~d" J~7.6 ~z,
3E~ r (~:c~ 1?~50, 15gS c~ l; u~ ~pho6p~ate buff~r, p~ 7) 292 DS~ (c7~30).
*Trademark
. .
~.~, . ,
~.,
, , :-,. ~........ . .
- '~ '"
-10 4-
~3~
Examl~le 11
~ )
methylthio]-6- (lR-hydrO~ ~_
~ate
~ C~
~,~ "~C~3
C 0~
--105-- !
A tl ~ 6-d'l~Qech 1 ridinius~-2- l)stleth lthiol~ ~r~fluoro~ethane~ul~r~ate salt
orf ~Cl, ~N ~,
~l Q ~ ~ If~F
3 ~J ~ s~3 E~h~ ~J ~ ~H, ~~
C~3 '
~ ~olut~03 o~ (6-~ethylp~r~d~-2-yl)~ethylthlo ~oc~ate ~1~0 g,
5.52 ~ol) ~n dry ether (5 ~L~ k~pt under a ~1tro~e~ at~osp~cr~ ~a~ tr~ate~ j
~th ~ethyl ~r~flate (0.74 ~L, 6.5 ~ol) a~d 6tisred at 23-C fo~ 4 h~ The
ethe~ ~-a~ dec~ed Rnd the w~e ~ol~d ~a~ ~ashed t~ice ~th e~her t2 ~L)
aDd d~solved ~ato ~ydrochlor$c ac~ solutioa tl~ ~L, 6~ 90.0 ~ol). The .
~esul~ng ~olutio~ ~as h~ated at 7~-C fo~ 4 ~ u~der ~ n~trogen at~osphere
8~ then co~ce~sated un~r seduce~ pr~.s~ure to ~ yello~ syrup. Trace~ o~ i
hydrochloric acid ~ere r~o~e~ ~y codist~llat~o~ ulth uat~r (2 3 1~ ~L).
Th~ cruB~ ~aterl~l v~s pu~lfied b~ re~er~et phase colu~a chro~atogr~phy
(2~2 :1~ 13.0 c~, "PrepPak C-18") w~t~ u~te~ elut~n~ ~olYe~t- Appropr~a~e
~ractions ~7ero co~bin~t ~a~ lyophiliz~l to give a uhite po~d~r; 1,,43 g~ i
85.4~; ~r tR:13r) v~: 2565 ~SE), 1626 (p~rldl~) 3 1585 (pyridlniu~) ~ ; j
u~ 20) A~: 278 (c7355); ~nal. calc'~ ~o:r CgE112N03S2F3 C 35.64, E
3.99, ~ 4~62, S 21.14; ~ouud: C 35.493 ~ 4.05, N 4.56, S 20.g9.
... . . _ . _
.;
*Trademark
. .
. . .
', ` ; ~
. . _ 1 06-- (
B.
n~hyl-7-ox
7__ _
0~ ~3 1- ~p~o~2R~ 3
aEt ~ ~ pr 3 22 ~ t ~ ~
3 ~ =O ~;~ ~ 3 ~ I ~S~r 3
~CC~O~N~ NEt( '~P~)2 ~hFes o ~ ~ ~J
.
col~ (5-C) solu~ of t5R,6$) para~tr~>~2~1 3,7--dlos~
ydrox~ct~ 4RS~met~ azablcyclDr3.2.0~hept~2-2-~-ca~o~ e
(11.l1 g, 3.06 ~ol, ~Ic: 86/14~ ~ d~ a~tD~itr~lc ~90~3 ~:cp~ de~ ~1
3~t~ogc2~ a~osp~ere was atded s~ultsDeo~ dlp~eayl c~lorop~oJip~;se (t)o~8
z;L, 3.3 ~ol) ~a d~oprop~ l~e (0.57 s~;L, 3.3 ~ol) o~er 10 ~D.
per~od. Tbe col~ (S-C) ~t~re ua~ cea ieor 1 ~, coDlcd t~ 30~ 3d
~rezted ~ lta~eou~ly uith a ~ol~;tio~ 02' (1,6-si~cth~lp~r~d~2
3:ct~yl~01, trifluoro~et~a~esul~oaate ~alt (1.03 g, 3.4 ~ Do~) in d~
ace~:o~lo t2 ~ a~a tiicoprop ~let~lssL~e ~0.59 ~, 3.4 ~ol) o~e~ 15
~ per1od.. Tbe re~ult~g ~ture ua~ ~t:~rred ~or 0.5 ~.at -30-C, wa~ed
up until O-C ~Lnd ~t~rrea for 1.0 ~ bcorc ~e~rlg ~i~ted wl~ cola ~ate~ (35
T ~) ,, 'Ih~ :ce~ t~ 3ulslo~ ~JZI; poured on top o~ ~e~cr~cd p~ase colu3~
("PrepPak C-18'', 2-5 æ lB c~ w~ch e~B8 thcrl eluted ~ a rix~ure o~ 5~2
LCCto~r t~e ~ ter. ~oph~l~zation o~ ~pprops~ate ~r~ctlo~s ga~e R
6tic~ ~ellow $olid, 1~69 % ~?1~c1:1 ~as ~olu~ zed ~'co wet tetrahy~ofura~
t40 ~ o the re~ult~ng ~o~t~o~ ua~ added ~her (7~ as~i~
~ihydrogc~phosphn~e ~d~ ydro~ide 'bu~fe~ tpEl 7~0, O.Z!I~ 50 ~? and 10~:
pallaa~yl o~ charcoal (1.6~ g) 8~ tbe result~ g ~xture ~.~a~ ~drogc;latcd
u3de~: 42 p~ t 23~S: fl~;r 2 ~ az~d thc~ ltered o~ Celite" pad. ~he tuo
*Trademark
..
-la7~
pbesc~ vcre sepa~aee~ ~d ~ aqueoll~ pha~e uas wasbed ~lt~ et~er ~2 x 20
t~ and conc~sltrated u~de~ h vacuum 8t: c23~C to 15 DL ~h~ch uas ~ppl~cd
oa eop sf re~er~ed phase oolus~ (prepPak ~ 18~. Elutio~ ~e~ 8 ~tuse oi~
U ceton~tr~le ~ ua~er ga~e ~e~ lyop~ ka~oD. o~ appro~riate ~r~c~olls
iD.23 g of ~itl~ oo~pou~d 2:Lixed ~l~h pD~sslu~odlu~ ~lpheDs~lpho6phate (24~
ln ~ole). Rcpurifloat~o~ o~ a reversed phase column (2-5 æ 14'e~, "PrepPak
C-18)" ~;lth t.~ate.r (400 2;L) n~d ~ ~xture o~ ~OX acetonl~r~c ~ ~ate~ (200
~ 2~; elut~g sol~e~ gAYC aftes lyophill~atloa o~ app~oprlate frac~oa~
a y~llov pouder~ 0.17 gO 15~3~ 1Bx~ Vs~: 1750 (C-0 o~ ~-lact~,
1625 (p~rid~ ), 1600 (C--0 of carbDxg~aq;e~ ~ (D2) ~ 12 t~-
J-7.2 i~ 3 o~ C-4~, 1.24 (d, J-6.4 ~, C~ Oa), 2.. 80 (s, ~ orl C-6 o~
p s~d~ ), 4 .18 (C:~3 on ~ o~ p~d~u~) ~ 4 q 41 (ce:~tes o~ A~ q~estet,,
,S) ~ 7.5~8.4 ~ q~ on p~ld~ ; uv ~Bu~fes 0.05~5, ~ 7.0~ 2?8 (c
11504); ~ D2~ -2~6.4 ~C 0.22, ~0); SI/2 ~ 20.8 h measuscd nt 37~C
~u~fcs (p~ 7.4) ~or a co~cç~trat~Dn ~f 10 ~.
*Trademark
,~7
~ . ~
- .
:
. . .~
,. ..... ...
-108--
Example l?
me~hvl~hio~-6- ~lR-h~d~xye~ ?-oxo-l-azabi~clo ~ 3 ~, 2. 0_~
2-ene-2-carb~?~ylate
0~ 13 ~ `
.C83""~S ~C~3
O , 0~3
-109-
A. (5R,6S) pararlitrobenzyl 3-~(1,6-d'methylpYrid~niu~Yl)lDetb lthio1 6-(lR~
~ , ,.
MeOT~ NaOH
Q Q
C~3 ~S~C~3 Ether 2 4 C~ N ~ sa ~)
C~3 ~,
.. I
1- (PhO~2P~ 5 ~3 CIH3
~=o =~ 30~ ~ , ~,
CC~OP~B 4- NEt(~r)z COOP2~B )2 2
,
To a cold (5~C) 80iut~o~ 0~ (5R,6S) para~itrobenzyl 6-(lR-hydro-
xyethyl~-3,7-dloxo-1-azabicyclot3.2.0~eptane-~R-carboxylate (2.14 g, fi.l4
~ol). i.~ ary aceto~itrile (18 mL) kept u~der a ~i~roge~ at~ospbere ~as
added diphe~yl chlorophospbate tl.37 ~L~ 6.6 ~mol), dii~opropylethylami~e
(1.15 ~L, 6~6 ~ol) at such.a rate ehat the temperature was kept at S~C
(7.-10 m~) z~d 4-d~e~hylaminopyridi~e (6 mg, 0.05 mmol). The m~xture was ..
stirre~ for 1.5 h at 5C and, ~28 used as it was; th~ mixture will bc
called ~solution A~ further in the procedure. A solutio~ Or t6-~ethyi- ,
pyridin-2-yl~methylthio acetate tl.23 g, 6.8 m~ol) ~ dry ethe~ (10 ~
kept under a ~itroge~ atmosphere was treatet wlth methyl trlflate (0.85 ~L,
7.5 ~ol) a~d ~tirred for 1.5 h at 23~C. The ether was deca~ted ~nd the
Y~lte powder uas washed ~uice uith ethe~ (2 x 10 ~L) and dissol~ed ~ uater
.. . .,.,.... : .
.~.
-110 -
~2~
(20 ~L) . Ihe resulting ague~u~ solution was oooled to O-C u~ter o~ge~
free at~Dosphere ~nd treated ~ith sodlum hydroxide (4N, 3.b, ~Lo 13.6 ~ol).
Ihe saixtur~ ~7a6 stirs~d ~t 2-C ~or 1 ~ ~d the~ the p71 was ~d~u~tl~d at 7D6
by the addition of po~ass~ dl~y~Iroge~p~osp~ate; this mixture s;ll:L be
cailed 'solutiou B~ ~ur~her in c~e proc~dureO The cold ~5C) ~solutlo~ A7
uas trcated ~th ' solu~io~ B I ~ver O . S 1~ period ~hile the pl~ ~as ~ept
beo~ee~ 702S-7r35 by the drop~l e add~tio~ of 4N sodiu~n hydrc~xide ~olutlo~
~he ~ixture ~as stlrred ~or 0.5 ~ ~nt pol2r~d on ~op of a reversed phase
colu~ 4.0 x 18 cm),("PrePak C-18"); the col= was eluted uith a ~ture
of 25-502 ~ceton~ tril~ ~ ~ater.. Lyop~illzation of appropr~ate ract~o~s
ga~e thc t~tlc co~pound as ~ yell~w pD~der~ 2.132 g (51% (PhO)2P02 ,, 49%,
C~3S03 3 ~ ~o ~9 ~ t~Br) ~ c 3700-3000 (011), 1772 ~C~0 o~ B-lacta~) D 1700
(C~0 of est~r~, 1625 (p~r~d~lwJl), 1590 (pyridl~ cm 1; l~x tD~IS0, ~
~: 1.15 (t~ J~6.2 ~lz, CE13CElOEI), 2.84 ts- ~3 on C-6 o~ py~di~Lius~), J/~.16
(s, :f~3 on N of pyridln$~), 4.i9 (s, SCP~2`~, 6.6-7.5 ~ (PhO)2PC2 ], 7.5-8.7
on pyridinlum ~d ~'~ o~ PNB ester).
111- (
3~
B. (
~C83 ~SO~ ~C~
COC~ B ' ~PbO)2~02 Bu~e~ N
C~
To a solut~on o~ (5R,6S) par~itrobe~z~ (1,6-dimethylp,~rld~
1u~-2 yl)~ct~yl~h~o~-6-(lR-~ydroxyethyl)-7-oxo~ z~bicyclo~3.2.0~hept-2-
.e~c-2-car~oxyl~te, trifluoro~cthanesulfo~ate and dlphenylpho~hate ~4g:51)
salt (0.87 g, 1.27 ~ol) is ~et tetrahydro~uran t50 ~L) uas ~dd~d cther t50
~T), potawium d~b~droge~phosphate-~od~um hydrnxide bu~fer (0.1~, 40 ~L, p~
7.O) and lO~ palladium on charcoal tO.B7 g~. The ~ixture Ra~ hydroge~ated
undcr 36 ps~ ~t 23^C for 2 h and 4iltcrcd o~ a"Celite"paa. Th~ ~o ph~cs
uere separate~ and ~queou~ pha~e uas ~ashed ~th ethcr (2 x lS ~1),
co~centrate~ under hlgh ~racuum u~t~l 30 ~L and poured on top o~ a reverse
phzse oolu~ (''Pre~?Pcak C-18", ~.Z x 13 cm)- E1utio~ o the colu~ ~as do~e
Yitb~ ~ater. Appropriate fractio~s ~crc comb~e~ a~d lyophilized to g~ a
5 e~low povder" 0.179 g, 40Z; ir (~Br~ l~æC 1755 [C-0 of ~-la~t~), 1628
(pyr~d$sl1~), 1590 (C-0 of car~oxylate) c~ ~ D20) ~: î . 25 (d,
J-6.4 ~z, CE~3C~0~, 2082 (~, C~I3 02~ C~6 of pyr~d$~ ), 3.12 (~dd~,, J~9.2
~z, J 2.9 ~2; El-4), 3.39 (dd, J~600 ~zO J-2.8 ~z, ~l-6), 3.7-4.4 (C~3CE10~, -
--112--
H-5, C~3 o~ N of pyridiniwrl), 4.48 (s, CEL~,S~ 7.6-8.4 (~'s on pyridis~
uv (!12O) ~sn8x 279 (~ 9628~ ~lth should~ at 296; [~]D~3 55.0~C tc 0.63"
~2); ~ 12.5 h s~eastsred at 37C ~n buf~er pE 7.4 for a coneesa'cration o~ i
o
., .
