Note: Descriptions are shown in the official language in which they were submitted.
~Z:~828
-- 1 --
This is a divisional application of Ser. No. 418,192
filed December 21, 1982.
This invention relates to tetrabutylammonium
6-[D-(2-~1-methyl-2-methoxycarbonylvinylamino]-2-pphenol- or
-2-[4-hydroxyphenyl]acetamido)]penicillanate, of the formula:
o
HC-COCH3
C-CH3
NH
Roy C - CON SHEA
N kiwi N (Byway
(wherein Roy is hydrogen or hydroxy).
The present invention also relates to a process for
producing the tetrabutylammonium salt mentioned above. The
process comprises treating 6-(2-amino-2-phenyl- or -2- [4-
hydroxyphenyl]acetamido)penicillanic acid with tetrabutylammonium
hydroxide, followed by the treatment with methyl acetoacetate.
This first step is typically carried out by reacting
the acid with an equimolar amount of tetrabutylammonium
hydroxide in the presence of a water immiscible organic solvent,
preferably chloroform. The solvent layer is separated and the
product isolated by evaporation of solvent.
-- 2
Then in the second step, the resulting salt is treated
with methyl acetoacetate. A most convenient method of this
step involves reflex of the salt in methyl acetoacetate in
the presence of a dehydrating agent, such as an hydrous
magnesium sulfate.
The compound of the present invention is useful as
an intermediate for producing the compound (I), described
below, in which P is
R2NH OH
So
I N / 3
O ""
in which R is
R4 CHICO-
Al
in which Al is l-methyl-2-methoxyearbonylvinylamino.
~2;36~3Z8
--3--
The parent application relates to compounds of the
formula (I) which aye antibacterial agents and certain
intermediates therefore. The antibacterial compounds of
formula (I) are efficiently absorbed from the mammalian
gastrointestinal tract and are then rapidly transformed
into the component penicillin, POOCH, and/or beta-
lactamase inhibitor, KIWI, or salts of the respective
components. Said compounds are of the formula
R3
10RCOC~OC=O
\
A ---(I)
or a pharmaceutically acceptable cat ionic or acid addition
salt thereof wherein A is ~Cl-C12)alkylene, (Cl-C12)alkyli-
done, (C3-C7)cycloalkylene, phenylene, naphthalene,
, , , or
said alkaline or alkyiidene substituted by phenol or
car boxy;
R3 is or (clocklike
n is zero or 1,
R and Al are different and
- ~236828
-4-
R is P or B,
when n is zero, Al is H, (Cluck ) alkyd, bouncily,
Creakily SHARI or tetra~utylammonium, and when n is 1,
Al is P or B;
P is R NH CX3
N
OUCH
where R is I, ' 6 5 2
OUCH
R4 CHICO or -C CO
Al is H, NH2~ No, benzyloxycarbonylamlno,
4-nitrobenzyloxycarbonylamino or 1-methyl-2-methoxy-
carbonylvinyl~m;no; R4 is H, OH, (C2-C7)alkanoyloxy,
(C2-C7)alkoxycarbonyloxy or R C6H4COO, and R5 is H,
~Cl-C4)alkyl, (Cl-C4)alkoxy, I, Of, By or ON;
and B is 1 O O
I SHEA
Ho I or
~;8Z8
--5
where,
when Y is H, Al is H, SHEA or SHRINKS where R
is H or SHEA;
when Y is Of or SCHICK, Al is H;
and X is Of By or I.
The pharmaceutically active compounds and salts of
formula (I) are those wherein
a. when n is zero, Al is (Cl-C4~alkyl, H or an
alkali metal salt thereof; preferred such salts are the
sodium and potassium salts; and
b. when n is l, one of R and Al is B and the
other is P where R2 and R4 are as defined above and Q
is H or No
Particularly preferred such antibacterial agents
are those wherein when n is zero, Al is or a cat ionic
or acid addition salt thereof and when n is l, R2 is
R4 CHICO
No
i.e., compound of the formulae (II) or (III) where
is H, and (IV)
BCoCH(R3)oC=o ---(II)
AQUARIA
O
PCoCH(R3~oC=o ---(III)
ACTOR
R4- -CHICANO ~HH33
Ox N -oCH(R3)oC=o
O
O / ---(IV
BCOCH(R'~OC=O
.
~Z3682~3
-6-
Particularly preferred values for A are (Cl-Cl2¦-
alkaline, (Cl-Cl21alkylidene, ~C3-C7)cycloalkylene
or phenylene. More particularly preferred compounds of
formula (I) are those wherein A is tC~2lm,
- 5 Shucks cyclohexylene or phenylene where m is
1-8, x and y are each zero or 1-6, R6 is or
(Cl-C4)alkyl and R7 is CCl-C4)alkyl.
oven more particularly preferred values of A are
(C~2)2' SHEA' (C~2)4, (QUEUE, C(C~3l2, 1~4-phenylene
and trans-1,4-cyclohexylene.
Particularly preferred carboxylic acids, BOO
are 6-beta-bromopenicillanic acid, clavulanic acid
and the l,l-dioxo acids of the formula
Ho ---(i)
O I KIWI
where Y and Al are 25 previously dew nod.
ore particularly preferred values of B are those
derived from the carboxylic acids of formula (X) wherein
Y is H and Al is or SHEA and most particularly
preferred ore those wherein Y and X are both H, i.e.
those derived prom penicillanic acid l,l-dioxide.
In the compounds of the formula (IV),
above, and (VI) below, wherein R is 4-R4C6~4CH(Ql~Co,
R N CoC~(R3)oC=o ---(VI)
o ACTOR
lZ36~Z8
--7--
particularly preferred values for R4 include I,
ox, acoloxy, t-butylcarbonyloxy or isobuto:;ycarbonyloxy.
Particularly referred values for Al in the compounds
containing this variable are H, NH2,
5 No, benzyloxycar~onylamino and l-methvl-2-methoxy-arbon
vinyl amino, and H or No being es?eciallv preferred
values in the antibacterial agents.
Other particularly preferred commends provided herein
are of the formulae TV) and (Viol
O o
N 3 0 0 ---(V)
o ~COOCYOC-ACOR-
R3
R NO S SUE
C~3
I N Rococo
, O R3
O /0
SUE ---(VOW
O,, N ROCOCO
o R3
where Al is I, (Cl-C4)alkyl, bouncily, C'~2Cl, KIWI or a
carboxylate salt forming cation. Particularly preferred
such cations are tetrabutylammonium or an alkali metal
cation. Preferred alkali petal cations aye Swede and
potassium.
Particularly preferred kimonos are those wherein
R is H.
~28
--8--
The compounds containing one of the
moieties P or B, as defined above, aye allowably as
intermediates or as active pro drugs for the particular
penicillin or beta-lactamase inhibitor contained
- ; therein. For example, compounds of formula yule wherein
A and R3 are as defined above and I is CCi-C41alkyl,
I, or a pharmaceutically acceptable cation are valuable
pro drugs for sulbactam; the compounds or phyla VOW
wherein I is 4-R4C6H4C~(Ql)Co and R4 is or Ox, Al is
NH2; A and R3 are as previously defined and Al is
(Cl-C4)alXyl or H or pharmaceutically acceptable
cat ionic or acid audition salts thereof, are useful
pro drugs for ampicillin (R OH) or amoxicillin (R OWE).
Those compounds (V) and (VI) wherein Al is, for example,
C~2Cl, bouncily or tetrabu_ylammonium and compounds TV
having a Q group, that is other than or I are
useful as intermediates.
Likewise, the compounds containing both
B and P moieties are of value either as intermediates
or as antibacterial agents which are efficiently
absorbed in the mammalian gastrointestinal Tokyo where
they are rapidly transformed into the component
penicillin and beta-lactamase inhibitor in Susan
tidally equimolar amounts. The compounds of
formula (I) having a free amino grout in one or both
of the moieties P and B, as defined above, are capable
of forming acid addition salts. Such salts with
pharmaceutically acceptable acids are included in the
invention. examples of such acids are hydrochloric,
hydrobromic, hydriodic, sulfuric, phosphoric, citric,
mafia, tartaric, malefic, fumaric, gl~conic, saccha-ic,
benzenesulfonic, D-toluenesulfonic, p-chlorobenzene-
sulfonic and 2-naph.halenesul-onic acids.
~236~28
g
This invention relates to derivatives o- ensoul-
panic acid which is represented by the following
structural formula:
S SHEA
1 1 c~3
Ox N KIWI
In derivatives of penicillanic acid, broken line
attachment (''') of a substituent to the bicyclic
nucleus indicates that the substituent is below the
plane of the nucleus. Such a subs-ituen. is said to
be in the alpha-configuration. Conversely, brood line
attachment ( _ 3 of a substituent to the bicyclic
nucleus indicates that the substituent is above the
plane of the nucleus. This latter configuration is
referred to as the beta-configura.ion. As used herein
a solid line attachment ( ) of a subs_-tuent to 'he
bicycle nucleus indicates that the substi~uent can be
in either the alpha-conCiguration or the beta-configurz-
lion.
Compounds of formulae (I) - (IX)
are named as divesters of the dicarboxylic acids of
formula HOOC-A-COOH where A is as previously defined.
For example, the compound of formula (VIII) where R4 is
hydrogen, Al is NH2 and A is (SHEA is designated as
6-(2-amino-2-phenylacetamido)penicillanoyloxymethyye
Z5 l,l-dioxopenicillanoyloxymethyl succinate; the compound
(VIII) where R4 is hydroxy, A is (SCHICK end Q is Acadia
is designated as 6-[2-azido-2-(D-hydroxYPhenyl)acetamido]-
penicillanoyloxymethyl 1,1-dioxopenicillanoyloxymethyl
123G~328
--10--
dimethylmalonate; arid the kimono of formula (V) where
Al is bouncily, R3 is H and A is (Kiwi is designated
bouncily l,l-dioxo?enicillanoylo~ymethyl glutamate.
R - -C CON SHEA
I N ~COC~20C=o
O O
C~3 / ---(VIII)
I, N ~COC~20C=O
O
Additionally, throughout this specification,
whenever reference is made to compound
having a penicillin moiety, P as defined above wherein
R2 is the substituent
It=\
R4- -CHICO
where R4 and Al are as defined above (but Al is other
than H), if not already so indicated, it is understood
that this refers to a compound in which said subs-ituent
has the D-configuration.
~236~28
The compounds of formula Gil can be prepared by
many of the methods known in the art for synthesis of
esters. However, the preferred method involves salt
formation by condensation of a carboxylate salt and
- 5 . halo methyl ester wherein n halo" is a leaving group X.
Preferred values of X are Of, Bra I, CHIHUAHUAS, I-
CZECHS. For example, four general methods are
outlined below for the case where R3 is I, R is P,
Al is B and P is
R4_~--CHCoNH~ ccH3
Ox N
where Q is No, C6~5CH20CONH, ~-N02C6H40CONH or
SHEEHAN
C02CH3
B is
0\ I
SHEA
Ox
M is a carboxylate salt forming cation, preferably Nay
K or N(C4Hg)4 cations and X is as dunned above.
.
1236~28
--12--
1. PCOOM + XCH20CO PCOOCH20CO
Al A A
BCOCH20CO BCOCH20CO
O O
(II " (VOW ) '
Remove R4_~-CHCoNH S SHEA
protecting No SHEA
group from 0, N ~COOCH20CO
O O PA
No SHEA
(VIII, Ql=NH2 )
2.PCOOCH2X + MOO --MY
(VIII) ' -_ tVIII,
tXII ) BCOCEI20CO Ql=NH2 )
o
(II) '
3 . PCOOCH20CO --MY
A + BCOOCH2X yo-yo) ' (VIII,
MOO . Q =NH2 )
(III) ' ZOO
4 .PCOOCH20C\ -MY
A + BROOM ---I (VIII) '--(VIII,
XCH20C Q Ho )
(III) " (XIV)
~236~;28
-13-
In each of the above reactions to form the amino-
protected product of formula VOW)', the respective
carbo~ylate salt and wholemeal ester are contacted in
approximately e~uimolar amounts in toe presence of a
polar organic solvent at a temperature of from about
0 to 80C. and preferably from about 2~ to 5Q~C.
While, as stated above, approximately equimolar
amounts of reactants are employed, an excess of either
the carbox~late salt or halo methyl ester, up to a ten-
fold molar excess can be employed. A wide variety of solvents can be used for this reaction; however, it is
usually advantageous to use a relatively polar organic
solvent to minimize the reaction time. Typical
solvents which can be employed include N,N-dimethyl-
formamide, N,N-dimethylaceta~ide, N-methylpyrrolidone,
dimethylsulfoxide, ethyl acetate, dichloromethane,
acetone and hexamethylphosphoric trimmed. The time
required for the reaction Jo reach substantial come
pletion varies according to a number of factors, such
as the nature of the reactants, the reaction temperature
and solvent. However, at about 25C. reaction times
of from about 10 minutes to about 24 hours are commonly
employed.
The desired amino-protected compound of formula
(VIII)' is then isolated by methods well known to those
of skill in the art. For example, the reaction
mixture is taken up in a water immiscible solvent,
e.g. ethyl acetate, chloroform or dichloromethane,
washed with water, brine and dried. Evaporation of
solvent provides the intermediate of formula (~III)'
which can be purified, if desired, e.g. by cremate-
graph on silica gel.
So
-14-
The removal of the amino-protecting group prom
the intermediate VOW)' is carried out by methods well
known in the art, see, go Gross _ at. in "The
Peptizes, Analysis, S~nth2sis, 3ialogy", Academic
Press, New York, NAY., Vol. 3, 1981, but due regard
must be given to the lability of the beta-lactam ring
and to the ester linkages. For example, when Al is
1-methyl-2-methoxycarbo~ylvinylam~no, the protecting
group U-methyl-2-methoxycarbonylvinyl~ can be removed
simply by treating the compound of formula (VIII)' with
one equivalent of a strong aqueous acid, e.g. hydra-
caloric acid, in a reaction inert solvent, at a
temperature in the range of from -10 to 30C. In a
typical procedure, the examine intermediate is
treated with one equivalent of hydrochloric acid in
aqueous acetone. The reaction is usually complete
within a short time, e.g. within one hour. Then the
acetone is removed by evaporation in vacua, and the
methyl acetoacetate by-product is removed by extraction
with ether. Finally, the compound of formula (VIII,
Ql=N~2) is recovered by lyophilization as its hydra-
chloride salt.
Intermediate compounds of formula (VIII) wherein
Al is Acadia, benzyloxycarbonylamino or 4-nitrobenzyl-
oxycarbonylamino can be converted to the corresponding amino compound (VIII, Ql=NH2) by subjecting the inter-
mediate compound (VIII) to conditions commonly employed
for catalytic hydrogenolysis. The intermediate is
stirred or shaken under an atmosphere of hydrogen, or
hydrogen, optionally mixed with an inert fluent such
as nitrogen or argon, in the presence of a catalytic
amount of a hydrogenolysis catalyst. Convenient
solvents for this hydrogenolysis are lower-alkanols,
~236~28
-15-
such 25 methanol an isopropanol; ethers, such as
tetrahyaro~uran and Dixon; low molecular weight
esters, such as ethyl acetate and Boyle acetate:
chlorinated hydrocarbons, such as dichlo-ome~ane and
chloroform; water; and mixtures of these solvents.
However, it is usual to choose conditions under which
the starting material is soluble. The hyd-ogenolysis
is usually carried out at a temperature in the range
from 0 to 60~C. and at a pressure in the range from 1
to 10 atmospheres, preboil about 3-4 atmospheres.
The catalysts used in this hydrogenolysis reaction are
the type of agents known in the art 'or this kind of
transformation, and typical examples are nickel and
the noble metals, such as palladium, platinum and
rhodium. The catalyst is usually used in an amount
from 0.5 to 5.0, and preferably about 1.0, times the
weight of the intermediate formula (VIII). I' is often
convenient to suspend the catalyst on an inert support,
a particularly convenient catalyst is pzlladi~
suspended on an inert surety such as carbon.
The remaining compounds containing a
penicillin moiety, P, such as compounds of phyla (III),
(VI), (VII) or (VIII), wherein R2 is OOZE
KIWI
OOZE
C6HSCH2C or R C CO where Q1 is and not
containing an amino soup in B, are made, for example,
by the same methods described above, except, o_ course,
the last step, removal of the amino-?rotectin~ srou?,
is not require.
~Z36~2~
-16-
All of the remaining beta-lactamase containing
compounds of formula (I) or (II) are also
prepared by the above procedures starting prom the
appropriate precursors, except for those wherein B is
of the formula
Al O O
H S 2
Ox " .3
where Y is H and Al is SHOWROOM and R8 is or SHEA.
A preferred procedure for preparing the compounds (I)
or (II) containing the latter beta-lactamase moieties
starts with the amino protected beta-lactamase such as
e.g. 6-alpha-~benzyloxyca-bonylaminomethyl)penicil-
lunate 1,1-dioxide. This is converted into 2 salt,
BROOM, where M is Nay K ox tetrabutylammonium end the
salt is then reacted as described above, for example,
with an intermediate of formula (III)' or of the
formula XCH(R )OCOA-COOR . The amino-protecting group
is subsequently removed, e.g. by hydrogenolysis as
described above, to provide the desired pharmaceutically
active compound wherein X is CHAR )NH2. Of course, if
the desired product is of the formula
R NO "S SHEA
` C~3
O ROCOCO
O R
A TV
O R.
~236~328
where R2 is or R CHICO , any amino-protec'ing
group present in the penicillin moiety can be removed
simultaneously.
An alternate process or preparation of anti-
bacterial compounds of formula (yo-yo) where Al is
employs an intermediate of formula
R9 SHEA
C~3
o' N Rococo
,. .3
10 0 0
I Rococo
o R3
where I is Q or R C Kiwi and I is assay,
benzyloxycarbonylamino or D-nit.obenzyloxyca_bonyl-
amino; R10 is I, Of, By or I and Roll is Of, or or I.
The intermediate (XVI~ upon catalytic hydrogenation,
U.S. by the method described above for hydrogenolysis of
Acadia, or benzyloxycarbonylamino compounds of formula
(VIII), is simultaneously hydrogenolyzed at the Q2' Rl
and/or R substituents to provide compounds
of formula (VIII), Ql=NH2.
~36~ZB
-18-
The intermediates (XVI) are obtained by methods
analogous to those described above for preparation of
intermediates o' formula CVIII~', but employing a
R10,Rll-subs~ituted l,l-dioxopenicillanate in place of
the corresponding unsubstituted 1,1-dioxopenicillanic
acid, its salts or derivatives of formulae IT (II)"
or (XIII).
Methods for preparation of the requisite R10,Rll- .
disubstituted 1,l-dioxopenicillanic acids and salts
thereof are taught in U.S. 4,234,579, U.S. 4,342,772
and Belgian Patent No. 882,028.
The intermediates of formula IT can be obtained,
for example, as outlined below for the case where R3=H.
--OX
C6H5CH20CO--A--COOM + BC2CH2X ''I
(XVII) ZOO
,
C6H5CH2OC\ H PA MOHAWK\
BCOOCH20CO BCOOCH20CO BCOOCH20CO
(II, R = C6H5CH2)(II, Al = I) IT
XCH2
BCOOC1~20CO
(II) n
where A, B, M and X are as defined above and x2 is X
or a better leaving group than X, e.g., when X is Of,
x2 may be Of, Bra I, OSO2Cl, OSO2CH3 or CZECHS.
Particularly preferred values for X are By and I.
~236~28
The first step illustrated above, wherein the
salt of the b~nzyl half ester is reacted with the
halo methyl ester of l,l-dio~openicillanic acid to form
compounds of formula IT where Al is bouncily, is
carried out as described above for preparation of the
intermediates of formula (VOW.
The selective removal of bouncily group is typically
carried out by catalytic hydrogenolysis by the same
methods and conditions as those described above for
the conversion of compounds of formula (VIII) wherein
is Acadia, benzyloxycarbonylamino or 4-nitrobenzyloxy-
carbonylamino to the corresponding invention compounds
of formula (VIII) where Ql=N~2. An especially preferred
method employs palladium-on-carbon catalyst at 3-4 atom-
spheres pressure and use of tetrahydrofuran or ethyl acetate as solvent. The carboxvlic acid of formula
(II, Al is H) may then be isolated by standard methods
or the acid can be conveniently reacted with an appear-
private base to form the corresponding salt of formula
(II)' where M is a carboxy~ate salt forming cation as
defined above. A preferred method for obtaining the
sodium and potassium salts of formula (II)' employs
the sodium or potassium salt of 2-ethylhexanoic acid
as base. Typically, the carboxylic acid of formula (II)
is dissolved in ethyl acetate, an equimolar amount of
sodium (or potassium) 2-ethylhexanoate added with stirring
and the precipitated salt of formula (II)' collected by
filtration and washed.
The salts of formula (II)', wherein is tetrabutyl-
ammonium can be obtainer from the corresponding acid sodium or potassium salt. For example, when a carboxylic
acid of formula Clip is employed, it is typically reacted
~236~328
-20-
with an equimolar amount of tetrabutyl~mmonium hydroxide
in the presence o- a water immiscible organic solvent,
preferably chloroform. The solvent layer is separated
and the product isolate by evaporation of solvent.
- 5 The intermediates of formula SUE are obtained by
elimination of the elements of MCCOY in the reaction of
the corresponding compounds of formula " and XC~2X ,
where I X and X are as defined above The reaction
is carried out employing the same methods and conditions
as described above for preparation of intermediates of
formula (VIII).
The intermediates ox formula (III) can be obtained
by employing the same methods and conditions described
above for preparation of intermediates of formula (II),
but using the analogous penicillin derivatives,
PCOOCH~R OX instead of BCOOC~tR OX, e.g. as outlined
below for the case where R3 is H.
lox
C6H5CH20CO-A--COOM + PC02CH2X
~XVII) (XII)
I
2 2 2 2 6 5 catalyst 2 2 A Coo
(III, R = C6H5CH2) (III, Al = H, Q NH2)
-MY
20 ~PCO2CH2OCO-A-COOM ---
. XCH~X
(III, R = M)
Al No
PC02C~20CO-A--COOC~2X
(III, Al = C~2X, Al No
where A, M, X and x and P are as defined above. The
amino-protecting group can be removed as described
above for the conversion of intermediate compounds of
formula (VIII) to amino compounds of the same formula.
~236~328
-21-
The compounds wherein R4 is acyloxy or
alkoxycarbonyloxy as defined above can be prepared
starting with the appropriate ~acylamox-cillin or I-
alkyloxycarbonylamoxicillin prepared, e.g. by acylation
of 6-aminopenicillanic acid with the appropriate acid
of the formula
R SCHICK
Q
where Al is as defined above and R4 is forelocks,
alkanoyloxy or alkoxycarbonyloxy, or a carboxvl
activated derivative thereof by methods disclosed in
U.S. 4,053,360. Alternatively, the intermediates of
formula (Vend their precursors of formula (VI) and
(XIII) wherein R4 is hydroxy can be prepared as described
above and the intermediate of formula (VIII', R4 = Ox)
lo subsequently assaulted or alkoxycarbonylated to provide
the corresponding compound of formula (yo-yo) wherein
R4 is formyloxy, alkylca~rbonyloxy, alkoxycarbonyloxy
or R5C6H4CoO as defined above.
The acylation or alkoxycarbonylation of the
intermediate of formula (VIII)' wherein R4 is hydroxy and
Al is as previously defined can be carried out e.g., by
reacting said compound of formula (VIII)' with the
appropriate acid chloride or acid arhydride or mixed
android. The reaction is ordinarily carried out in
the presence of a reaction-inert solvent system. In a
typical procedure, from 0.5 to 2.0 molar equivalents,
and preferably about 1 molar equivalent, of the
appropriate acid chloride or acid android is contacted
with the starting compared of formula (VIII) wherein I
is hydroxy, in a reac~ion-inert solvent, in the presence
~Z36~28
-22-
of a tertiary amine, at a temperature in the range from
-10 to 30~C. Reaction-inert solvents which can be used
in this acylation are: chlorinated hydrocarbons, such
as chloroform and dichloromethane; ethers, such as
S deathly ether and tPtrahydrofuran; low molecular weight
esters, such as ethyl acetate and bottle acetate; low
molecular weight aliphatic tones such as acetone and
methyl ethyl kitten, tertiary asides, such as N,N-di-
methylformamide and N-~ethylpyrrolidone; acetonitrile;
and mixtures thereof. The tertiary amine is normally
used in an amount equivalent to the starting acid chloride
or acid android, and typical-tertiary amine which can
be used are triethylamine, tributylamine, diisopropyl-
ethyl amine, pardon and 4-dimethylaminopyridine.
In addition to being useful intermediates for
production of the conjugate antibacterial compounds of
formula I) where n is 1, the carboxylic acids and salts
of formula (II) through (VI) wherein R is H or an alkali
metal cation, e.g. No or R, are useful pro drug forms of
the beta-lactamase inhibitors, BOOR, or penicillin,
POOCH where B and P are as previously defined. Paretic-
ularly preferred such beta-lactamase inhibiting compounds
are those of the formula (V) where R is I, No or K and
A and Al are as previously defined, which are useful
pro drugs of penicillanic acid 1,l-dioxide (sulbactam).
Likewise, the penicillin derivatives of formula (VI)
wherein Al is H, No or R and R2 is 2~6-(CH3O22C6H3CO~
C6H5OCH2CO or 4-R -C6H4CH~NH21CO and the pharmaceutically
acceptable acid addition salts of such compounds wherein
R2 has the latter value, are useful pro drugs for the
corresponding penicillins. Particularly preferred such
derivatives are ox the formula (VI) where R2 is
4 /==~
R COO
NH2
~Z36~28
-23-
and especially three wherein R4 is or OH which are
useful pro drug forms ox the elm known antibacterial
gents ampicillin and amoxicillin.
The compounds ox the formula Gil which contain a
free amino group will form acid addition salts, and
these acid addition salts are considered to be within
the scope and purview of this invention. Said acid
addition salts are prepared my standard methods or
penicillin compounds, for example by combining a
lo solution of the compound of formula U) -in a suitable
salivate (e.g. water, ethyl acetate, acetone, methanol,
ethanol or buttonhole) with a solution containing a
stoichiometric equivalent of the appropriate acid. If
the salt precipitates, it is recovered by filtration.
Alternatively, it can be recovered by evaporation of the
solvent, or, in the case of aqueous solutions, by
lyophilization. Of particular value are the sulfate,
hydrochloride, hydrobromide, nitrate, phosphate, citrate,
tart rate, pamoate, per chlorate, sulfosalicylate,
benzenesulfonate, 4-toluenesulfonate and 2-naphthylene-
sulfonate salts.
The compounds of the formula (It, and the salts
thereof, can be purified by conventional methods for
penicillin compounds, e.g. recrystallization or
chromatography, but due regard must be given to the
lability of the beta-lactam ring systems and the ester
- linkages.
123~28
I
Certain of the compounds of formula (IV)
which contain a beta-lactamase inhibitor residue, I, are
not adequately stable to the hydrogenolysis conditions
described above, for example, certain of such compounds
- 5 wherein B is
okays
Ox N I",
O o . .3
of I
where X3 is Of, Bra or I. An especially per erred method
for preparing invention compounds (rev) containing one
I of the above B moieties involves 'he use of a protect-
in group which is removable by mild hydrolysis or by
mild reduction methods, for example as outlined
below.
~:~36~2~
--25--
R4 -CHICANO S 'EYE
NOR 2 3 I BCO2CH2I
COO
R CHICANO SHEA
N~R12 f SHEA 0 H20
Ox N PA
(XVIII ) 3COCH20C=O
n
where A, B and R4 are as defined above, is a
cation, preferably sodium, potassium or tetrabutyl-
S ammonium, and R12 is an amino protecting soup which irremovable by mild hydrolysis or mild reduction methods.
Examples of suitable groups are triphenylmethyl and
SHEA
Corey
where R13 is alkoxy having from one to three carbon
atoms or NH2
Alternatively, the compounds of formula IVY
which are not stable to hydrogenolysis conditions can
be prepared by the following method.
:~Z36~328
-26-
14
CRY o
A + 3C02C.~ CO I CC
COO Jo
Corey
(YUCCA
R4-~6~4c~co~a S C
N~R12 C~3 + SLY ~(XVIIII---~(rv)
one C02C~2I
where A, M and R12 aye as defined above, 3 is the
residue of a beta-lact~m2se inhibitor as defined above,
preferably one which is unstable to hyarogenolysis
conditions and R14 is 2 tiebacks protecting guy? removable
by mild hydrolysis or reduction such as ?-N02C6~CY2,
RaRb~CSi or R Rb~CSiC~2CY2 where each of R , R and R
is allele having from one to twelve carbon atoms, aureole
or aralkyl having rum jive to eight carbon atoms.
Many of 'the beta-lzctæmase inhibitors employed
as starting material fox syntheses of the compounds of
the parent application are known in the art. 6-alpha-
~ydroxymethylpenicillanic acid l,l-cioxide is prepared
by reaction of bouncily 6,6-dibromopenicillanato in
reaction-inert solvent at -70 to -20 C. with t-bu'.yl-
lithium or t-butylmagnesium chloride. The resulting
enolate is then treated with formaldehyde and the
resulting mixture Ox bouncily 6-bromo-6-hydroxymeth
penicillanate issuers is isolated. This mixture is
oxidized to the corresponding l,l-dioxide, e.g. employing
an organic pursued such as m-chloroperben-oic acid. The
isolated cellophane is hydrogenated in the presence of a
palladiur,-on-calcium c2~~0na~e catalyst which results
in formation ox the desired 6-al?ha-hyd-oxymeth
penicillanic acid cellophane.
~Z36~32~3
-27-
As noted above 6-beta-hydroxymethylpenicillanic
acid cellophane is provided in U.S. 4,342,768 issued
August 3, 1~82.
A preferred method for preparing the 6-amino-
S methyl- and 6~Cl-amino~ethyl-penicillanic acid
l,l-d~oxides also starts with bouncily 6,6-dibromopenicil-
lunate. Thus is reacted with one molar equivalent of
methyl magnesium bromide in an ether solvent at -100 to
-50 C; for a rough of time. The resulting one-
Grignard reagent is contacted with about-0.5 molar
equivalents of benzyloxycarboxamidomethyl acetate or
l-benzyloxycarboxamidoethyl acetate at the some
temperature for about 0.5 to 2 hours to afford a mixture
of epimers of, e.g. bouncily 6-bromo-6-benzyloxycarbonyl-
aminomethylpenicillanate. This is reacted in the next step or the mixture can be separated by column chrome-
tography. In the next step the bromide atom is removed,
e.g., by halogenolysis with tri-n-butyltin hydrides
optionally in the presence of a small amount of a free
radical initiator, preferably 2,2'-azobisisobutyro-
nitrite (AIBN), and hydrocarbon solvent, e.g., Bunsen
or Tulane at 60-100 C. The 6-beta-benzyloxycarbonyl-
aminomethylpenicillanate ester is then recovered by
crystallization (if a mixture of epimers is employed as
starting material) and the 6-alpha epimer is recovered
by evaporation of the mother liquor and chromatography
of the residue. The epimeric sulfides are then oxidized
to sulfones, e.g., as described above for the 6-hydroxy-
methylpenicillanates and the bouncily protecting groups
removed by standard hydrogenolysis methods.
~Z36~
-28-
When contemplating therapeutic eye Jo- a I. o
an antlbac~erial compound disclosed herein! it is
necessary to use a pharmaceutically-acce?taDIe set_;
however, salts other than these con ye used Jo- a
variety of purposes. Such purposes include isolating
and purifying particular compounds, and inter convert-
in pharmaceutically-accept2ble salts and their non-
salt counterparts.
The conjugate compounds of formula (I)
lo where n is l, one of R and Al is B and the other is P,
as defined above where R2 is 2,6-di~.ethoxybenzoyl,
phenoxyacetyl or 4-R4C6~4C~Co; the car~oxylic a do,
No
lower alkyd esters and the alkali metal salts thereof
of the formula IT or (V) as well as the ca-b~xylic
acids, lower alXyl esters, and alkali metal salts of
the compounds of formula (VI) where R is 2,6-d~metho~-
bouncily, phenoxyacetyl or 4-R4C6~C;iCo, US well as 'he
No
acid addition salts of those compounds containing a
free amino (NH2) group, all possess in viva antibacterial
activity in mammals. This activity can be demonstrated
by standard techniques for penicillin compounds. Jo_
example, the above compound of formula (I), IT (V)
or VOW) is administered to mice in which acute infections
have been established by intraperitoneal inoculation with
a standardized culture of a pathogenic bacterium.
Infection severity is standardized such that the mice
receive one to ten times the LDlCo (LDloo: the minimum
inoculation required to consistently Kill lo percent
of control mice). At the end of the test, the activity
of the compound is assessed by counting 'the number of
survivors which have been chall2nsed by the bacterium
and also have received 'he invention co~Dound. The
~236~28
I
2ntibacte-ial compounds of formula I US wet as the
carboxylic acids, esters and alkali metal salts of
formulae (II), TV and (yip) can be administered by both
the oral (pro.) and subcutaneous (Scholl route.
The in viva activity of the antibacterial come
pounds makes them suitable for the
control of bacterial injections in mammals, including
man, by both the oral and parenteral modes of ad minis-
traction. The compounds are useful in the control of
infections caused by susceptible bacteria in human
subjects.
The above compound, for example, one of
formula (VIII, Al = NH2) wherein R4 is other than
hydrogen breaks down to 6-(2-amino-2-[4-hydroxyphenyl]-
acetamido)penicillanic acid (amoxicillin) and ensoul-
panic acid l,l-dioxide (sulbactam) after administration
to a mammalian subject by both the oral and parenteral
route. Sulbactam then functions as a beta-lactamase
inhibitor, and it increases the antibacterial elective
news of the amoxicillin' Similarly, a communed formula (VIII) wherein R4 is hydrogen breaks dorm to
6-t2-amino-2-phenylacetamido2penicillanic acid
(ampicillin) and sulbactam. Thus, the conjugate anti-
bacterial compounds of the formula (I) will fund use in
the control of bacteria which are susceptible to an
approximately equimolar mixture of penicillin, POOCH,
and BCOOH, for example a 1:1 mixture of amoxicillin and
sulbactam for the compound (VIII) where Q is No and
R is HO or ampicillin and sulbactam 'or the coarsened-
in compound where R is H. Example of such bacteria are susceptible strains of shrewish golf and
Sta~hvlococcus Ayers.
~Z36~Z8
-30-
The carboxylic acids of the formula SHEA, an
especially those of the formula
O J
I N 'Co~CH20C-A-COOH
TV, Al = R3 =
the alkyd esters having from one to four carbon atoms
S in said alkyd, and the alkali metal salts, especially
the sodium and potassium salts thereof, are useful as
oral or parenteral pro drug forms of sulbactam and as
such have the therapeutic applications as a beta-
lactamase inhibitor, for example, the applications
disclosed for sulbactam in U.S. 4,234,579.
The antibacterial carboxylic acids, esters and
salts of the formula (VI) as defined above, especially
those of the formula
R4- NH2 C~3
Ox N 2 2 "
(XX)
(Cl-C4)alkyl esters and the pharmaceutically acceptable
acid addition and cat ionic salts thereof, are useful
as oral and parenteral pro drug forms of amoxicillin
(when R4 is other than hydrogen and ampicillin (when
R4 is hydrogen).
ZIG
Examples Ox photo Cole actable acid
addition salts of ye compounds of formula
(I) containing a free No grout in Q1 I clue the
salts of hydrochloric, hycro~~omic, sup icky, oozier,
acetic, Molly, matte, fumes, Seiko, tactic,
Tartar, eta, Glenn, Syria e, ben-enesulCor.-e~
~-toluenesulfonie, p-ehlorobenzenesul onto and
2-naphthalenesulfonie acids.
Examples Ox pharmaceutically aeee?t_ble eationie
salts of the earboxylie acid compounds en Formulae (II),
SHEA), TV or (I) include the alkali metal salts such
as the sodium, and potassium salts; as well as the
a~monium salt and salts o- pha~maeeutieally ayatollah
amine such as N-methylglucamine, N,N-dibenzylethylene-
Damon, ethanol amine and procaine.
The above pro drugs of formula tip) and (III) whereRl = (Cl-C4~alkyl, or a pharmaeeutieall~ actable
salt thereof can also be administered as physical
mixtures of the two emends, preferably said mixture
is one having a weight ratio in the range o_ from
about 1:3 to 3:1. Such mixtures Upon a~minlst-ation to
a mammalian subject by either the oral o- Darenteral
route would also break down to form mix ryes of the
beta-lactamase inhibitor (KIWI) and the penicillin
tPCOO~).
In determining whether a particular strain of
Essayer colt or StaDhvlocoeeus assay is sensitive
to a particular therapeutic compound or mixture, the
in viva test described earlier can be used. Alto--
natively, ens., the minimum inhibitory concent_ation(MIC1 of a 1:1 mixture of amoxicillin and sulbactam or
ampieillin/sulbactam can be measured. The Micas can
~Z3G~Z8
-32-
be measured by the procedure recommended by the
International Collaborative Study on Analytic
Sensitivity Testing reaction and Cheerios, cat
Patholo~ica et Microbial Scanain2v, Sup. 217,
Section I: 64-68 ~1971]1, which employs train heart
infusion (BYWAY) ajar and the inkwell replicating device.
Overnight growth tunes are diluted 100 fold for use as
the standard inoculum C20,Q00-lQ,00Q cells in ap?roxi-
mutely 0.~02 ml are placed on the ajar surface; 20
ml of PHI agar/dish~. twelve 2 fold dilutions O r the
jest compound are employed, with initial concentration
of the test drug being 200 mcg/ml Single colonies
are disregarded when reading plates after 18 his. at
37C. The susceptibility (ICKY of the test organism
is accepted as the lowest concentration of compound
capable of producing complete inhibition ox growth as
judged by the naked eye.
When using an antibacterial compound disclosed in
this specification, or a salt thereof, in a mammal, part-
ocularly man, the compound can be administered alienor it can be mixed with other antibiotic substances
and/or pharmaceutically-acceptable carriers or delineates.
Said carrier or delineate is chosen on the basis of the
intended mode of administration. For example, when
considering the oral mode of administration, an
antibacterial compound can be used
in the form of tablets, capsules, lozenges, torches,
powders, syrups, elixirs, aqueous solutions and
suspensions, and the like, in accordance with standard
pharmaceutical practice. The proportional Allah of
active ingredient to carrier will naturally depend on
lZ36B~
-33-
the chemical nature, volubility and Steele ox the
active ingredient, as well as the dosage kenneled.
In the case of tablets for oral use, Crusoe which
are commonly used include lactose, sod us citrate and
- 5 salts of phosphoric acid. various dozier.... --cranks such
as starch, and lubricating agents, such as magnesium
Stewart, sodium laurel sulfate and talc, are commonly
used in tablets. or oral administration in capsule
form, useful delineates are lactose and hush molecular
weight polyethylene glycols, e.g. polyethylene glycols
having molecular weights of from 2000 to 4000. Lyon
aqueous suspensions are -erred for oral use, the
active ingredient is combined wow emulsi'yins and
suspending agents. If desired, certain sweetening
and/or 'favoring agents can be added. For parenteral
administration, which includes intramuscul2_, intro-
peritoneal, subcutaneous, and intravenous use, sterile
solutions of the active incident are usually prepared,
and the pi of the solutions are suitably adjusted and
buffered. For intravenous use, the total concentration
of solutes should be controlled Jo rondo- the preparation
isotonic.
As indicated earlier, the antibacterial compounds
are of use in human subjects and the
daily dosages to be used will not differ significantly
from other, clinically-used, penicillin antibiotics.
The prescribing physician will ultimately determine
the appropriate dose for a given human subject, and
this can be expected to vary according to the age,
weight, and response of the individual patient as well
1236828
- I -
as the nature and the severity of the patient's symptoms. The
antibacterial compounds will normally be used orally at dosages
in the range from 20 to about 100 my per kilogram of body weight
per day, and parenterally at dosages from about 10 to about 100
my per kilogram of body weight per day, usually in divided
doses. In some instances it may be necessary to use doses
outside these ranges.
The following examples and preparations are provided
solely for further illustration.
These include working examples of the present invention,
(i.e., Examples 11 and 12) as well as others which are related
to the present invention and helpful in understanding the
present invention.
Nuclear magnetic resonance spectra (NOR) were measured
for solutions in deuterated chloroform (CDC13) or deuterated
dim ethyl sulfoxide (DMSO-d6), and peak positions are reported
in parts per million downfield from tetramethylsilane. The
following abbreviations for peak shapes are used: by, broad
singlet; s, singlet; d, doublet; t, triplet; q, quartet; m,
multiple.
1236828
EXPEL 1
Monobenzvl Esters of Dicarbox~lic Acids
A. trans-1,4-Cycloh Of anedicarboxylic acid monobenzyl
ester
- 5 To a solution of 1.0 g (2.8 Molly dibenzyl trays-
1,4-cyclohexanedicarboxylate in 20 ml tert.-butanol
(warm) is added a solution of 1.9 g potassium hydroxide
in 10 ml tert.-butanol. After stirring at room them-
portray overnight the cloudy mixture is evaporated to
remove solvent, taken up in water and acidified to
pi 5.3; then, after 30 minutes, acidified to pi 5.25
with dilute hydrochloric acid. The precipitated solid
is collected on a filter, redissolved in dilute sodium
bicarbonate solution and this readjusted to pi 5.25 to
precipitate the purified monster l~_NMR (D~SO-D6) ppm
delta): 1.1-2.3 (m, 10~), 5.1 (s, lo), 7.35 (s, I
B. Monobenzyl terephthalate
To a warm solution of 10 g dibenzyl terephthalate
in 200 ml t-butanol is added a solution of 1.9 g
potassium hydroxide in 100 ml t-butanol and 10 ml water.
The resulting mixture is stirred at room temperature
for 60 hours. The solvent is evaporated in vacua, the
residue taken up in water and acidified to pi 5.3 and
worked up as in Part A, above, to provide the desired
monster in 56% yield, mop. 178 C. NOR ~DNSO)
ppm (delta): 5.3 us, OH), 7.4 (s, I 8.1 (s, I
infrared absorption peaks at 1690 cm 1 and 1710 cm 1.
Saponification of dibenzyl terephthalate C15 g) in
bouncily alcohol (225 ml2 containing an equimolar amount
of potassium hydroxide by stirring overnight at room
temperature and trituration with ethyl ether affords
a 75% yield of the potassium salt of monobenzyl
terephthalate.
123G828
-36-
C. Monobenzyl isophthalate
Dibenzyl isophthalaie is converted to the moo-
bouncily ester, potassium sat if. 75~ yield by the above
procedure employing bouncily alcohol as solvent. NOR
(DOW ppm (delta): 5.1 (so OH), 7.2 (s, I 7.6-7.8
(m, OH), 8.4 (t, lo).
D. The monobenzyl esters of the following dicarboxylic
acids are obtained similarly by the above procedures.
1,2-cyclopropanedicarbox~lic acid
1,3-cyclobutanedicarboxylic acid
trans-1,2-cyclobutanedicarboxylic acid
1,3-cyclopentanedicarboxylic acid
trans-1,3-cyclohexanedicarboxylic acid
1,4-cycloheptanedicarboxylic acid
1,3-cycloheptanedicarboxylic acid
1,4-naphthalenedicarboxylic acid
2,6-pyridinedicarboxylic acid
2,4-pyridinedic~rboxylic acid
2,5-pyridinedicarboxylic acid
3,5-pyridinedicarboxylic acid
2,5-pyrazinedicarboxylic acid
2,5-furandicarboxylic acid
2,5-thiophenedicarboxylic acid
~rans-1,2-cyclohexanedicarboxylic acid
1,12-dodecanedicarboxylic acid
l,10-decanedicarboxylic acid
_-butylmalonic acid -
methylmalonic acid
ethvlmalonic acid
isotropy Masonic acid
die~hylmalonic acid
~Z36~328
-37-
di-n-butylmalonic aria
3-methylglutaric acid
3-ethylglutaric acid
3-ethyl-3-methylglutaric acid
2-methylglutaric acid
2,2-dimethylglutaric acid
2-methylsuccinic acid
2-phenylsuccinic acid
3-methyladipic acid
3-n-butyladipic acid
3~3-di-n-propylglutaric acid
3,3-diisobutylglutaric acid
phenylmalonic acid
tricarballylic
~Z36~328
-38-
EXAMPLE 2
C -1,2-cyclohexanedicarboxylic acid
monobenzyl ester
To 15.4 g (0.10 mole cis-1,2-cyclohexanedicar-
boxlike android in 200 ml Tulane is added drops solution of 10.8 g C0.10 mole bouncily alcohol in
50 ml of Tulane. The mixture is stirred at room them-
portray for one hour then warmed to 60~ C. and held
at this temperature for one hour. The solvent is
evaporated to a small volume and the product monster
obtained upon cooling and filtration of the precipitated
solid.
Alternatively, the reaction mixture in Tulane is
treated with an equimolar amount of ethanolic potassium
lo hydroxide to obtain the potassium salt of the monobenzyl
ester. The sodium salt is obtained by use of methanolic
sodium hydroxide in like manner.
The corresponding monobenzyl esters or their sodium
or potassium salts are obtained from the hollowing
dicarboxylic acid androids by the above procedure.
succinic android
glutaric android (reflexed in Tulane overnight)
cis-1,2-cyclobutanecarboxylic android
phthalic android
1,2-naphthalenedica-boxylic android
3,4-furandicarboxylic acid
2,3-pyridinedicarboxylic acid
2,3-pyrazinedicarboxylic acid
~l23~;~328
-39-
EXAMPLE 3
Bouncily l,l-dioxopenicillanoYloxymethyl succinate
To a mixture of 9.2 g ~.044 mole) bouncily succinate
half ester in 200 ml ox chloroform and 25 ml water
was added 40~ aqueous tetrabutylammonium hydroxide
with vigorous stirring until a pi of 8.5 was obtained.
The chloroform layer was separated and the aqueous
layer extract (1 x 100 my with chloroform. The
combined chloroform extracts were dried Nazi) and
concentrated in vacua to an oil. The oil was combined
with 200 ml .oluene and 16.5 g (.044 mole) iodomethyl
penicillanate l,l-dioxide was added. The mixture was
stirred 30 minutes, diluted to 400 ml with ethyl
acetate and the precipitated tetrabutylammonium iodide
removed by filtration. The filter cake was washed
with 100 ml ethyl acetate and the combined filtrates
were washed with saturated Nikko (1 x 100 ml), water
(1 x 100 ml), brine (1 x 100 ml), dried (Nazi)
and concentrated in vacua to an oil. Chromatography
on silica gel (1 kg), eluding with 1:1 (v/v) ethyl
acetate/hexane), gave 8.5 g (43%) of a white solid.
lH-NMR (CDC13) ppm (delta): 1.45 (s, OH), 1.63
(s, OH), 2.77 (s, OH), 3.47 (d, OH), 4.43 (s, lo),
4.62 (t, lo), 5.17 (s, I 5.84 JAB quartet, OH), 7.4
(s, OH).
In the same manner the following compounds were
also prepared from the appropriate monobenzyl ester:
a. Bouncily l,l-dioxopenicillanovloxymethyl qlutarate -
(61% yield) - lH-NMR (CDC131 ppm (delta): 1.42 (s,
30 OH), 1.6 (s, OH), 1.8-2.2 (m, OH), 2.28-2.68 (m, OH
3.45 (d, OH 4.4 (s, lo), 4.5 (t, lo), 5.14 (s, lo
5.8 JAB quartet, OH), 7.37 (s, OH).
- :
lZ368Z8
-40-
b. Bouncily lll_dioxopenicillanoylox~methyl adipate -
(47% yield) - H-NMR (CDC132 ppm (dental: 1.46 (s,
OH), 1.63 (s, OH), 1.53-1.86 em, OH), 2.22-2.6 em,
OH), 3.46 (d, OH), 4.42 (s, lo), 4.6 (t, lo 5.13 Us,
- 5 2Hl, 5.82 JAB quartet, OH), 7.33 (s, OH).
c. Bouncily l,1-dioxo~enicillanovloxYmethYl dim ethyl-
malonate - ~73.8% yield - lH-NMR ~CDC131 ppm dental
1- 4 (s, OH), 1.53 us, OH), 3.45 Cud, OH), 4.4 us, lHl,
4.56 (t, lo), 5.22 (s, OH), 5.78 JAB quartet, OH),
7.35 (s, OH).
d. Benzvl l,l-dioxopenicillanoYloxYmethyl malonate
(45% yield) - HER (CDC13) ppm (delta): 1.43 (s,
OH), 1.6 (s, OH), 3.46 (d, OH), 3.53 us, OH), 4.42 (s,
lo), 4.6 (t, lo), 5.2 (s, OH), 5.85 JAB quartet, I
7.39 (s, OH); infrared spectrum (nujol) cm 1 1795,
1790.
e. Bouncily l,l-dioxo~enicillanoyloxymethvl subacute -
(54% yield), oil lH-~R (CDC13) ppm (delta): 1.2-1.9
(m, 18H), 2.1-2;5 (m, OH), 3.4 (d, OH), 4.4 (s, lo),
4.6 (t, lo), 5.1 (s, OH), 5.8 (q, OH), 7.3 (s, OH).
~2368;~8
-41-
f. In like manner the remaining monobenzyl esters
provided in Examples 1 and 2 are converted to 'he
corresponding compounds of the formula
- O\ /0
_ So C~3
- OH
Ox N ~COCH2OC=O
C ITCH OOZE
where A is as defined for the starting monobenzyl ester.
g. Alternatively, the above bouncily, l,l-dioxopenicil-
lanoyloxymethyl divesters are prepared as described
below for the adipate divester.
A mixture of 17.0 g (0.0665 mole) sodium 1,1-
dioxopenicillanate, 18.0 g (0.0634 mole) bouncily
chloromethyl adipate, 6.7 g (0.020 mole) tetrabutyl-
ammonium bromide and 300 ml acetone is heated under
nitrogen at refly overnight. The acetone is evaporated
and the residual gel taken up in 300 ml ethyl acetate.
Water (150 ml) is added, the organic layer is separated
and the aqueous layer extracted with fresh ethyl
acetate (150 ml). The combined organic extracts are
washed with water (3 x 250 mull, brine (2 x 150 my
dried (Nazi and concentrated on vacua to an oil
(31.8 g). the oil is chromatographed on 7Q0 g
silica gel, eluding with 2:1 hexane/ethyl acetate to
-
lZ36~ 8
-42-
remove the less polar impurities, then with 1:1 ethyl
acetate/hexane to remove the product. Evaporation of
solvent from the product fractions affords 27.3 g
~89.5%).
- 5 By employing the corresponding methyl half ester,
or other alkyd half ester where alkyd is ethyl, n-
propel, isopropyl, bottle, or isobutyl, in place of
the bouncily half ester in the above procedure the cores-
pounding alkyd l,l-dioxopenicillanyloyloxymethyl dicer-
boxy late is provided in like manner.
~236828
-43-
EXAMPLE 4
Sodium l~l-Dioxopenicillanovloxvme-h~l Succinate
A solution of 8.4 g (.019 mole of bouncily ill-
dioxopenicillanoyloxy~ethyl succin~te in 75 ml of
tetrahydrofuran us added to a suspension of 4 g of
10% (w/w) palladium on carbon in tetrahydro~uran TO
and shaken under 50 psi (3.52 kg/cm2~ of hydrogen on
an hydrogenation apparatus. After 30 minutes the
catalyst was removed by filtration through a filter
aid and the cake washed with 75 ml of I the
combined filtrates were concentrated in vacua and
taken up in 75 ml of ethyl acetate. To this solution
was added 3.07 g (.019 mole) of sodium-2-ethylhexanoate
with stirring. After 15 minutes the precipitate was
filtered, washed with deathly ether and dried under
nitrogen to give 6.8 g (95%) of a white solid.
The following sodium salts were prepared in like
manner, except that in cases where no precipitate
forts upon addition of sodium 2-ethylhexanoate, ethyl
ether is added to effect precipitation.
a. Sodium l,l-dioxopenicillanovloxymethvl glutamate -
~93% yield) - 1H-NMR DOW) ppm delta): 1.48 us, OH),
1.63 us, OH), 1.6-2.7 em, OH), 3.22-3.98 em, OH), 4.68
(s, lo), 4.8-5.13 (m, lo), 5.86 JAB quartet, OH).
b. Sodium 1,1- -
(79~ yield) - H-NMR DOW) ppm dwelt: 1.46 (s, I
1.63 (s, OH), 1.44-1.8 (m, OH), 2.1-2.6 em, OH),
3.1-3.96 (m, OH), 4.56-4.76 SHOD peak, hides C-3H~,
5.0-5.16 I, lHl, 5.92 By quartet, OH
~Z36828
-44-
c. Sodium 1,l-dioxoDenicillanoyloxymethyl dimethvl-
Mullen - (94.5% yield* - HO Doyle ppm delta:
1.33 (s, OH), 1.44 (s, EYE), 1.58 us, 3~I1, 3.16--3.
(m, OH 4.65 (s, lo), 4.93-5.1 em, phi, 5.93 CAB
- 5 quartet, I infrared spectrum Cnujoll, 1780 cm 1.
d. Sodium l,l-dioxoPenicillanoyloxYmethvl malonate -
(88% yield) - 1~-MMR (Doyle ppm (delta: 1.45 Us, 3H1,
1.6 I 3Hl, 3.2-3.93 (m, OH 4.66 Us, I 4.96-5.13
(m, lo), 5.88 JAB quartet, OH It was noted that the
I C~2-malonate hydrogen atoms exchanged with DUO.
e. Sodium l,l-dioxoPenicillanoYloxymethyl subacute -
(80~ yield) - lH-~R (DOW ppm Delta): i.2-1.7
(m, 18~), 2.15 (t, lo), 2.45 (t, I 3.45 Ed, lo),
3.65-3.75 (dud, lHl, 4.75 (s, lo), 5.15-5.25 (m, lo),
5.8-6.0 (dud, OH); infrared spectrum (RBr) cm : 1570,
1770, 1800.
f. The remaining bouncily esters provided in Example 3
are hydrogenated and converted to the corresponding
sodium salt by the above procedure. The corresponding
potassium salt is obtained by use of potassium 2-ethyl
hexanoate in the above procedure.
Recrystallization from ethyl acetate/hexane affords
crystalline needles.
~Z36~2~
-45-
EXAMPLE PA
Christine l,l-dioxopenicillanQyloxymethyl
Adipic Acid Hydrate
To 400 ml acetone us added 48.5 g ~0.19 mole
sodium l,l-dioxopenicillanate, 48.Q g C0.17 mole bouncily
chloromethyl adipate and 19.3 g L0.06 mole tetrabutyl-
ammonium bromide. The mixture is heated at reflex under
nitrogen overnight, filtered, washed with acetone and
the filtrate evaporated. The residue is taken up in
500 ml ethyl acetate, washed alternately with brine and
water, 250 ml portions, brine again and dried McCoy.
Evaporation O r solvent in vacua afforded 89.6 g light
yellow oil. The oil is taken up in 250 I ethyl acetate,
20.0 g 10% Pd/C added and the mixture is hydrogenated
at 3.52 kg/cm2 for one hour. After adding 15 g of fresh
catalyst the hydrogenation is continued for 2.5 hours.
The catalyst is removed by filtration, the cake washed
with acetone (1500 ml) and the combined filtrate and
washings evaporated in vacua to obtain a viscous oil.
The oil is taken up in 150 ml acetone and water added
slowly to start crystallization, then continued until
800 ml water is added. After stirring 30 minutes, the
crystalline product is recovered by filtration, washing
with water and air dried to obtain 58.2 g of the title
carboxylic acid. Recrystallization from ethyl acetate
affords the crystalline MindWrite, mop. 100-102 C.
Analysis: Calculated for C15~21O~NS-X2O
C, 44.00; I, 5.66; N, 3.42.
Found: C, 43.93; H, 5.65; N, 3.42.
The crystallinity was verified by X-ray crystal-
lography.
~Z3~8Z~3
-46-
EXAMPLE 5
Sodium 1,l-Dioxopenicillanoyloxymethyl
trans-1,4-cyclohexanedicar~ox~late
,
A. Bouncily chloromethyl trans-1,4-cyclohexanedi-
carboxylate
To a mixture a 3.06 g ~0.036 motel sodium bit
carbonate, 5.46 g Cole mole) potassium Bunnell trays-
1,4-cyclohexanedicarboxylate, 50 ml water and 500 ml
chloroform is added 6.17 g (0.018 motel tetrabutyl-
ammonium hydrogen sulfate and the mixture is stirred at room temperature overnight. The layers are separated.
The aqueous layer is extracted twice with chloroform
and the combined chloroform layers are dried and e~apo-
rated to dryness. The resulting tetrabutylammonium
salt is taken up in ethylene chloride (20 ml) and the
solution added drops to 20 ml of bromochloromethane
at 0 C. The resulting mixture is stirred at ambient
temperature for 70 hours, the solvent evaporated and
ethyl acetate added to the residue. The precipitated
tetrabutylammonium bromide is removed by filtration,
the filtrate dried (Noah) and evaporated in vacua to
obtain 5 g (91%) of crude product. Purification by
silica gel chromatography, eluding with 1:3 ethyl
ether/hexane gave 1.9 g (35~) of the desired product
25 as an oil. H-NMR (CDC13) ppm (delta): 1.0-2.4 (m,
lo), 5.1 (s, OH), 5.7 (s, OH), 7~3 (s, OH).
B. Bouncily l,l-dioxopenicillanoyloxymethyl trueness-
cyclohexanedicarboxylate
A solution of 4.2 g (13.5 mole) bouncily sheller-
30 methyl trans-1,4-cyclohexanedicarboxylate, 3.63 g
(14.2 mole) sodium l,l-dioxopenicillanate, 1.45 g
(4.5 mole) and 100 ml acetone is netted at reflex
overnight. The acetone is evaporated, ethyl acetate
(100 ml) added and the solution washed with water
~Z368Z8
-47-
(3 times), brine and dried over an hydrous sodium
sulfate. The solvent is removed by evaporation in
vacua to afford 2 crude product which is purified by
column chromatography on silica gel, eluding with 1:1
- 5 ethyl acetate/hexane to provide 5.3 g C78gl of purified
product as an oil which is used in the next step.
H-NMR ~CDC13~ ppm (dwelt -1.65 Cm, I 65-
2.6 (m, Lowe, 3.4 Ed, OH 4.4 (s, I 4.55 (t, lo),
5.1 (s, OH), 5.8 (q, OH), 7.3 (s, OH infrared spectrum
10 (SCHICK) cm 1 1730, 1760, 1810.
C. To a solution of 2.5 g ~4.9 Molly of the bouncily
ester provided in Part B, above, in 50 ml ethyl acetate
under a nitrogen atmosphere, is added 1.5 g 10% Pd/C
catalyst. The resulting mixture is hydrogenated at
1-2 atmospheres pressure for about 20 minutes. The
catalyst is removed by filtration and 0.82 g (4.9 mole)
sodium 2-ethylhexanoate is added to the filtrate.
After stirring for 30 minutes at room temperature the
mixture is concentrated to one-third volume and three
volumes of ethyl ether is added. The precipitated
title compound is filtered, washed with ether and dried
under nitrogen to afford 1.7 g (79% step yield).
H-NMR (DUO) ppm (delta): 1.3-2.4 (m, 16H), 3.4-3.6
em, OH), 4.6 (s, lo), 4.9-5.0 (m, lo), 5 7 (q, OH);
25 infrared spectrum (RBr) cm 1 1565, 1760, 1810, 1780.
123682~3
-48-
EXAMPLE 6
Crystalline 1,l-Dioxopenicillanoyloxymethyl
trans-1,4-Cyclohexanec~rboxylic Acid
To a solution ox 6.07 g Us molehill Bessel l,l-dioxo-
penicillanoylaxymethyl trans-1,4-cyclohexanedicarboxylate
in 100 ml ethyl acetate under nitrogen is added 3.2 g,
10~ Pd/C catalyst The mixture is hydrogenated for
45 minutes with shaking at 50 psi (3.52 kg/cm21. The
mixture is filtered, the filtrate concentrated in vacua
to afford a residual oil which crystallizes upon stand-
in. The product is recrystallized from ethyl acetate/
hexane under a nitrogen atmosphere to obtain 2.35 g of
crystalline product which appeared to contain some oil.
This was taken up in ethyl acetate (100 ml) and an
equivalent amount of sodium 2-ethylhexanoate is added.
The precipitated sodium salt is stirred for 45 minutes,
concentrated to one-third volume and ethyl ether added
to complete the precipitation. The sodium salt is
collected by filtration, washed with ether and dried
under nitrogen. The sodium salt is taken up in water
(So ml) acidified with hydrochloric acid and the mixture
extracted with ethyl acetate. The extracts are dried
(Nazi), the solvent evaporated in vacua, the residue
crystallized from ethyl acetate/hexane and dried
25 under nitrogen to obtain 1.85 g (37~) of product,
mop. 118.5-119 C. which is found to be crystalline by
X-ray diffraction. lH-NMR (CDC13~ ppm dental 1.4
(s, OH), 1.4-1.55 (m, PHI, 1.6 (s, OH 2.05-2.15 I,
OH), 2.25-2.45 (m, 2Hl~ 3.4-3.6 to, 2Hl, 4.4 (s, 1~1,
30 4.6-4.65 (m, lo), 5.7-5.95 (odd, OH); infrared spectrum
(XBrl cm 1 1700, 1760, 1780, 18Q0.
lZ36~328
-49-
EXAMPLE 7
l,l-Dioxopenicillanoyloxymethyl Terephthalate
and its Sodium Salt
A. Bouncily chloromethyl terephthalate
To a solution of 18.53 g C0.062 mole potassium
bouncily terephthalate in 3~0 ml water is added 600 ml
chloroform, 10.38 g (0.121 mole sodium bicarbonate
and 2Q.95 g C0.062 motel tetra~utylammoniu~ hydrogen
sulfate. The resulting mixture us stirred at room
temperature for three yours, the organic layer is
separated and the aqueous phase extracted twice with
chloroform. The organic layers are combined, dried
(Nazi) and the solvent evaporated to provide the
tetrabutylammonium salt of bouncily terephthalate. This
is taken up in 25 ml ethylene chloride and the solution
added drops to 100 ml bromochloromethane at 0 C.
The resulting mixture it allowed to warm to room
temperature, stirred overnight and the product is-
fated and purified by the methods described in Example 5,
Part A to obtain the title divester, as crystals,
mop. 64-66 C. l~_NMR (CDC13) ppm delta): 5.3 (s,
I 5.9 (s, I 7.3 (s, OH), 8.1 (s, I infrared
spectrum (RBr) cm 1 1720 and 1735.
B. Benzvl 1,1-dioxo~enicillano~loxvmeth~l terephthalate
A solution of 6.34 g Tao mole) bouncily sheller-
methyl terephthalate, 5.58 g (0.022 mole) sodium 1,1-
dioxopenicillanate, 2.24 g (0.0069 mole tetrabutyl-
ammonium bromide and 2QQ ml acetone is stirred at reflex
under a nitrogen atmosphere for 18 hours. The acetone
is then evaporated, the residue taken up in ethyl
acetate, washed with water three times and dried
lNa2SO4l. Evaporation of solvent affords 11 g of crude
product which is purified by passing through an 20 x 2 cm
column of silica gel eluding with ethyl acetate/hexane,
1:1. evaporation of product fractions gave 10 g t96%~
.
~23~2~
-50-
of the desired bouncily ester as an oil. l~_NMR ~CDC131
ppm (delta): 1.4 us, I 1.5 (s, OH), 3.4 Ed, I
4.4 (s, I 4.6 (t, I 5.4 (s, OH), 6.1 (q, OH
7.4 (s, I 8.1 (s, OH infrared spectrum CCHC13l
- 5 Cal 1725, 1745, 1780, 1810.
C. A solution of 9 g of the bouncily ester obtained
in Part B in So ml ethyl acetate is evacuated to remove
air and placed under a nitrogen atmosphere. To this is
added 2.5 g 10% palladium-on-carbon catalyst and the
mixture hydrogenated at 3 atmospheres for 20 minutes.
The mixture is filtered through a filter aid, washing
with ethyl acetate. To the filtrate and washings is
added 2.98 g sodium 2-ethylhexanoate and the resulting
mixture stirred for 30 minutes. An additional 50 ml
each of ethyl acetate and ethyl ether are added to
the resulting thick mixture and this is filtered, wash-
in with ethyl ether. After drying overnight, 5.8 g
(75%) of crystalline sodium salt is obtained.
D. To a solution of one gram of the above sodium salt
in 50 ml water is added 5 ml of normal hydrochloric
acid and the resulting mixture is extracted with 75 ml
ethyl acetate. The ethyl acetate is concentrated in
vacua to obtain a slurry and sufficient ethyl acetate
added to just dissolve the precipitate. This solution
is stirred while slowly adding hexane at room temperature
to the cloud point. This is then warmed on the steam-
bath to effect solution, and a few drops of hexane
added, the mixture cooled to room temperature and
placed in the refrigerator. The resulting crystals are
collected by filtration and dried under nitrogen to
obtain go my (95~ of the title acid, mop. 167-169
(doe). H-NMR (DMSO) ppm (delta): it (s, OH), 1.5
(s, I 3.4 (d, OH), owe (s, I 5.1-5.3 (m, OH), 6.1
(g, I 8.1 (s, I infrared spectrum (X3r) cm 1
35 1700, 1750, 1780, 1810.
~Z368Z8
--51--
Example 8
Sodium 1,l-Dioxo~enicillanoyloxYmethYl isophthalate
A. sinuously chloromethyl isophtha ate
By the procedure of Example 7, Part 17.0 g
(0.058 mole) potassium bouncily isophthalate in 45 ml
water and 500 ml chloroform is converted to its twitter-
butylammonium salt and this reacted with excess broom-
chlorom~thane. The resulting crude product, 15 g, is
taken up in ethyl acetate, this added to 45 g silica
gel, the mixture slurries and the solvent evaporated.
The residual silica gel was dry-loaded on an 8 inch
column of silica gel and eluded with ethyl ether/hexane
1:3. Evaporation of solvent from the product containing
fractions gives the desired divester as an oil. l~_N~DR
(CDC13) ppm (delta) 5.3 (s, I 5.9 (s, OH), 7.3 (s,
I 8.0-8.3 (m, I 8.55 (t, I
B. Bouncily l,l-dioxopenicillanoYloxymethvl isophthalate
A mixture of 12.22 g (0.04 mole) bouncily sheller-
methyl isophthaLate, 10.75 g (0.042 mole) sodium 1,1-
dioxopenicillanate, 4.31 g (0.0134 mole) tetrabutyl-
ammonium bromide and 400 ml acetone are heated at
reflex for 30 hours. The acetone was evaporated and
replaced by ethyl acetate. The solution was washed
with water (3x), brine (lo) and dried (Nazi). Evapora-
lion of solvent and silica gel chromatography of the
residue, eluding with ethyl ether/hexane (65:35) affords
a 41% yield of product as an oil which crystallizes
upon standing. lH-NMR (CDC131 ppm (dwelt: 1.3 us, I
1.5 (s, OH 3.4 (d, I 4.5 us, lo), 4.6 it, I 5.3
(s, I 6.0 (q, I 7.4 (s, 5Hl, 7.5-7.7 em, 1~2, 8.1-
8.4 (m, I 8.7-8.8 (m, I infrared spectrum ~KBr~
Cal 1720, 1750, 1805.
,
~Z36~28
C. A mixture of 8.14 g (0.016 mole of the bouncily
ester obtained in Part B, 2.5 g 10% Pd/C catalyst and
50 ml ethyl acetate is hydrogenated by the procedure
of Example 7, Part C. The mixture is filtered to
remove catalyst and 2.70 g (OKAY mole sodium 2-ethyl-
hexanoate is added. After stirring for 20 minutes,
the thick slurry is concentrated to one third its volume
and ethyl ether added to complete the precipitation.
The resulting crystals are collected by filtration and
lo dried under nitrogen to obtain 6.33 g ~90%2 of the title
sodium salt. 1H-NMR (DMSO) ppm (delta): 1.3 (S, I
1.5 (S, OH), 3.3-3.4 (m, OH), 3.5-3.6 (m, OH), 4.55
(S , OH), 5.0-5.2 (m, OH), 6.05 (q, OH), 7.45 (t, lo),
7.8-8.3 (m, OH), 8.5 (by, lo); infrared spectrum (KBr)
Cm 1: 1575, 1620, 1740, 1810.
123G828
-53-
EXAMPLE
A. sinuously l-Chloroethyl-trans-1,4-cyclohexanedi-
carboxvlate
To I 0 g (0.10 mole) potassium bouncily trueness-
cyclohexanedicarboxylate, 16.8 g C0.20 motel sodium
bicarbonate, 300 ml water and 2.5 liters chloroform is
added 33.9 g (0.10 mole tetrabutylammonium hydrogen
sulfate. The mixture is stirred overnight, the layers
separated and the aqueous layer extracted with chloroform.
The combined organic layers are evaporated to dryness
and the residue taken up in 150 ml ethylene chloride.
The resulting solution is added drops to 100 ml
1-bromo-1-chloroethane at 0 C. and the reaction mixture
stirred at 25 C. for 48 hours. The solvent is evaporated,
lo the residue is triturated with ethyl acetate, filtered
to remove tetrabutylammonium bromide and the filtrate
dried (Nazi). Evaporation of solvent affords the
title compound.
B. In like manner reaction of the appropriate
potassium salt, ber.zyl ester and l-bromo-l-chloroalkane
by the above method provides compounds of the formula
below 3
R
COOCHCl
A
COSSACK
where A and R3 are as follows:
A R3
SHEA SHEA
C(CH3~2 SHEA
(SHEA CH(CH3~2
CH3CH H3CH2
(SHEA C~3CH2CH2
..
1236~28
-54-
A R3
(SHEA SHEA
(SHEA C SHEA
(CH3CH2)2C CH~CH3~2
1,2-C6H SHEA
1,3-C6H4 SHEA
1,4-C6H4 C~3C~
EXPEL 10
Employing the bouncily esters provided in the
preceding Example as starting materials, the indicated
products of formula (V, Al is bouncily) are obtained
and converted to the corresponding salts (V, R is
No or R) by the procedures of Example 7.
O Jo
C02CH2C6~5 C~3
A/ , I SHEA
\ 3 O N ~JCOOCHOC=O
KICKER R3
Of A
1 /
(V) R OOZE
R SCHICK ,
No or R
:~2368Z8
-55-
EX~LE_ll
Tetrabutyl~monium idiot-
methyl-2-methoxycarbonylvinylaminc3-
2-~henylacetamidol]penicillanate
To 300 ml chloroform is added 39.3 g IDEA-
amino-2-phenylacetamidol]penicillanic acid trihydrate,
50 ml of water is added end the pi of the mixture
adjusted to 8.5 by addition of 4Q~ aqueous tetrabutyl-
ammonium hydroxide. The layers are separated, the
aqueous layer is saturated with sodium sulfate and
extracted with fresh chloroform. the extracts and
initial lower layer are combined and the solvent is
evaporated to about 250 ml total volume.
Jo this is added 150 ml methyl acetoacetate and
30 g of an hydrous magnesium sulfate. The mixture is
heated at reflex for three hours, the mixture allowed
to settle and the warm organic layer decanted. The
clear chloroform solution is allowed to cool to obtain
crystals of the title compound in 52~ yield, mop.
182-184 C. (decomp.). H-NMR ~CDC13) ppm (delta):
0.8-2.0 (m, OH), 1.88 (s, OH), 3.1-3.6 (m, OH), 3.6
(s, OH), 4.17 (s, lo), 4.58 (s, lo), 5.05 (d, lo),
5.38-5.6 (m, I 6.78 (d, lo), 7.35 (s, OH), 9.4 (d,
lo).
.
:~Z3682~
-56-
EXAMPLE 12
Tetrabutylammonium 6-rD-(2-ll-methyl-
2-methoxy~ar~onyl~inylamino~-2-I4-hydroxy-
phenyl]acetamido)~enicillanate
- to 300 ml of dichloromethane was added 41.9 g ox
6-(2-amino-2-[4-hydroxyphenyl~acetamido~penicillannix
acid trihydrate and 50 ml of water, and then the pi
was adjusted to 8.5 using 40~ aqueous tetrabutyl-
ammonium hydroxide. Three layers were obtained. The
upper layer was removed, saturated with sodium sulfate
and then it was extracted with dichloromethane. The
extracts were combined with the middle layer and the
lower layer, and the resulting mixture was evaporated
in vacua to give an oil which crystallized on trotter-
lion with acetone. This afforded 44.6 g of twitter-
butylammonium 6-(2-amino-2-[4-hydroxyphenyl]acetamido~-
penicillanate.
The above salt was added to 150 ml of methyl
acetoacetate and the suspension was heated at cay
65 C. until a clear solution was obtained (8 minutes).
The mixture was allowed to cool, and then the solid
was recovered by filtration. The solid was washed
with methyl acetoacetate, followed by deathly ether,
to give 49.25 g of tetrabutylammonium methyl-
2-methoxycarbonyl~inylamino~-2-14-hydroxyphenyl]-
acetamido)penicillanate crystals.
- ~Z3G828
-57-
EXAMPLE 13
A. Chloromethyl 6- ED- (2-~1-methyl-2-methoxycarbonyl-
vinylamino]-2-~henylacetamido2~penici-llanate
To 42.9 g (Q.062 mole) tetrabutylammon us old
~2-rl-methyl-2-methoxyca_~onylvinylamino]-2-phenyll-
acetamido)]penicillanate is added 500 ml sheller-
iodomethane and the mixture stirred for one hour at
room temperature. The mixture is concentrated,
chromatographed on 1 kg silica gel, eluding with
~0:20 by volume ethyl acetate/hexane, collecting
75 ml fractions. Fractions 5-13 are combined and
evaporated to dryness to afford a yellow oil. This
was re-chromatographed, eluding with a 1:1 by volume
mixture of the same solvents to afford 30.6 g (80%)
of the desired chloromethyl ester as a roam. l~-N~R
(CDC13) ppm (delta): 1.5 (s, OH), 1.57 (s, I 1.9
(s, I 3.65 (s, I 4.4 (s, lo), 4.65 (s, I
5.12 (d, I 5.42-5.7 (m, OH), 5.75 (double d, OH),
6.8 (d, I 7.4 (s, I 9.35 (d, I
B. Iodomethyl 6-[D-(2-[1-methyl-2-methoxycarbonyl-
vinYlamino]-2-phenvlacetamido)~penicillanate
The above chloromethyl ester, 4.96 g (10 mole)
and 7.5 g (50 mole) sodium iodide are combined with
50 ml acetone and stirred overnight. The mixture is
concentrated to dryness, the residue taken up in
ethyl acetate (150 ml), washed with 3 x 50 ml
water, 1 x 50 ml brine, dried (Nazi and concern-
treated to afford 6.0 g of product as a pale yellow foam.
Trituration with petroleum ether afforded a pale yellow
solid, 5.2 g (89%1.
C. Starting with tetrabutylammonium 6-~D-C2-Tl-methyl-
2-methoxycarbonylvinylamino~-2-[4-hydroxyphenyl]acact-
amido)]penicillanate in the above procedures, but using
dimethyl'ormamide as cosolvent in Part A, affords the
I iodomethyl ester o' amoxicillin examine.
-I
lZ3G~2B
-58-
EXAMPLE 14
6-[D-(2-Amino-2-phenylacetamldo~penicillanoyloxymeethyl
trans-1,4-cyclohexanedicarboxyl c Acid Hydrochloride
A. Bouncily 6-~D-~2- r l-methyl-2-methOxycarbQnylvinyl-
amino]-2-phenylacetamido~]penicillanoyloxymethyl trays
1,4-cyclohexanedicarboxvlate _ - -
A solution of 2.22 g C3 28 molehill tetrabutylammonium
6-tD-(2-Il-methyl-2-methoxycarbonylvinylam~no~-2-pphenol-
acetamido)]penicillanate and 1.~0 g C3.23 molehill bouncily
chloromethyl trans-1,4-cyclohexanedicarboxylate in 100 ml
acetone is stirred at room temperature overnight. The
acetone is evaporated and replaced with ethyl acetate.
The solution is washed with water, dried (Nazi and
the solvent evaporated _ vacua. The resulting crude
material is purified by chromatography on silica gel,
eluding with 40:60 ethyl acetate/hexane to afford 1.5 g
(53%)-
B. The bouncily ester obtained in Part A, above, 1.5 g
(Z.08 mole) is dissolved in 25 ml acetone and 20.1 ml
Own hydrochloric acid it added. The mixture is stirred
ten minutes, an additional 2.0 ml Own hydrochloric acid
is added and the solvent is evaporated. To the residue
is added 75 ml water, the resulting mixture is extracted
twice with ethyl ether containing a small amount of ethyl
acetate. To the extracts is added 0.75 g 10% Pd/C
catalyst and the mixture is shaken under hydrogen at
50 psi (3.52 kg/cm2) for 30 minutes. The catalyst is
removed by filtration and the filtrate is freeze dried
to obtain Tao my product. Infrared spectrum ~RBr~ cm 1
1680, 1700, 175Q, 1~00. lH-~R QDMSOI ppm (delta): 1.25
(s, OH), 1.45 (s, OH), 1.8-2.0 (m, 4X), 2.05-2.4 Cm, 4~1,
3.25-3.55 (m, I 4.35 us, lo), 5.07 abs, lo¦, 5.35-5.45
(m, lo), 5.55 (q, lo), 5.65-5.85 (dud, OH), 7.3-7.6 (m, PHI,
8.9 (by, lo), 5.45 Ed, OH).
issue
-59-
EXAMPLE 15
6-lD-c2-Amino-2-~4-hydroxyph~nyl]acetamidol~-
penicillanoyloxymethyl trans-1,4-cyclohexane-
dicarboxylic acid hydrochloride
- 5 A. Bouncily 6-~D-C2-rl-methyl-2-methoxycarbonylvinyl-
amino]-2-r4-hydroxyphenyl]acetamidol~penicillanoylfoxy-
methyl trans-1,4-cyclohexanedicarboxylate
A solution ox Owe g (1.61 Molly bouncily sheller-
methyl trans-1,4-cyclohexanedicarboxyiate and 1.14 g
10 (1.61 mole) tetrabutylammonium 6-~D-~2-rl-methyl-2-
methoxycarbonylvinylamino]-2-l4-hydroxyphenyl]acett-
amido~]penicillanate in 50 ml dimethylformamide is
stirred overnight at room temperature. The reaction
mixture is diluted with ethyl acetate, washed three
times with water, then with brine and dried (Nazi).
The solvent is evaporated in vacua. To the residue is
added fresh ethyl acetate, the mixture washed again
with water, brine and dried and evaporated to remove
the last of the dimethylformamide. The residue is
purified by silica gel chromatography, eluding with
7:3 ethyl acetate/hexane to yield 500 my (42%) of
purified divester.
B. To a solution of 0.5 g (0.678 mole) of the
purified divester obtained in Part A, above, in 25 ml
acetone is added 6.8 ml Own hydrochloric acid. After
stirring for 10 minutes an additional 1.0 ml of Own
hydrochloric acid is added and the acetone is evaporated
in vacua. The residue is partitioned between water and
ethyl ether and the aqueous layer washed with ether.
30 To the aqueous phase is added 0.35 g, 10~ Pd/C catalyst,
under a nitrogen atmosphere, arid the resulting mixture
is hydrogenated at 50 psi (3.52 kg/cm2) overnight. The
lZ3613~8
-60-
mixture is filtered to remove catalyst and the aqueous
filtrate is freeze dried to provide 200 my ~50~1 of
the title compound. H-NMR (DMSO-D6~ ppm Cdeltal; 1.1-
2.7 (m, 16H), 3.4-4.0 (us, lo 4.3-4.5 em, 1~1, 5.0-
5.2 (m, lo), 5.4-6.0 (m, 3H)j 6.7-7.6 (dud, PHI; infrared
spectrum (XBr) cm 1 1700, 1770, 3~00, 3500.
In like manner the analogous compounds of the
formula below are obtained by employing the appropriate
starting materials in the above procedure. The cores-
pounding tetrabutylammonium examines are also obtained by the methods of Examples 11 and 12.
R4- -SCHICK Y CcH3
Ox N ~C-OC~2OC=O
\
/
OKAY
R A
H SHEA
Y- (SUE
, C(C~3)2
OH (C~2)4
OCOC~(CH3)2 1,4-cycloheptyl
OCOOC6H5 1,2-phenylene
OCOOC(CH3)3
OKAY 1,4-cyclohexyl
OCOC(C~3)3 (SHEA
OCOCH2CY.(CH312 (C 2~4
OCOO(4--FC6H4) lCH3)2CCH2CH2
~:2368Z8
-61-
EXAMPLE 16
Sodium 6-(2-phenoxyacet~mido~penicillanoyloxymethyl
Dimwit lmalonate
A. ensoul 6-(2-phenoxyacetamido~penicillanoyloxy-
methyl dim~thylmalonate
To 50 ml of dimethy~formamide is added 3.88 g
(0.01 mole) potassium 6-(2-phenoxyacetamido~penicil-
lunate, 2.7 g (0.01 mole ensoul chloromethyl dLmethyl-
malonate and the mixture stirred at room temperature
for three hours. The mixture is poured into 150 I
ethyl acetate, washed with 3 x 50 ml water, 1 x 50 ml
brine, dried (Nazi) and evaporated to dryness in
vacua. The residue is taken up in a small amount of
ethyl acetate and transferred to a got D of silica
gel 5200 g). The column was eluded with 1:1 ethyl
acetate/hexane. The product fractions are combined and
concentrated in vacua to yield 2.0 g of product as a
colorless oil. ~H-NMR (CDC13~ ppm (delta): 1.42
(s, I 1.5 (s, OH), 4.4 (s, lo), 4.5 (s, OH), 5.13
(s, OH), 5.4-5.86 (m, OH), 6.8-7.5 (m, OH), 7.3 (s, OH).
B. A mixture of 2.0 g (3.4 mole) of the product of
Part A, above, 40 ml ethyl acetate and 2.0 g 10%
palladium-on-carbon catalyst is agitated under a hydrogen
atmosphere at 50 psi for 45 minutes. An additional gram
of catalyst is added and stirring continued for 30
minutes. The mixture is filtered, washing the cake with
ethyl acetate. The filtrate and washings are stirred
while adding 0.56 g (3.37 mole) sodium 2-ethyl-hexanoate.
Stirring is continued while adding an equal volume of
ethyl ether. The precipitated solids are granulated by
stirring for 30 minutes, filtered, washed with ether
and dried under a nitrogen atmosphere to afford 1.35 g
(77~ of the title sodium salt. lH-NMR (D20) Pam
delta): 1.33 (s, OH), 1-4 (s, OH), 4.4-4.6 (s non top
of broad singlet], OH), 5.5 (by, OH), 5.8 Lid, I
6.63-7.33 (m, OH).
~23G~3Z~
-62-
EXAMPLE 17
Sodium 6-(2-phenoxyacetamido)p~-.icillanoyloxymethyl
Glutamate
A. Bouncily 6-(2-phenoxyacetamidalpenicillanoyloxy-
methyl glutamate
To 50 ml dimethylformamide is added 3.88 g
(0.01 mole) potassium 6-~2-phenoxyacetamidolpenicil-
lunate, 2.7 g (0.01 mole ensoul chloromethyl glutamate
and the mixture stirred for three hours after which
3.0 g (0.02 mole) sodium iodide is added and stirring
continued overnight. The reaction mixture is quenched
by addition of 150 ml ethyl acetate, washed with water
to x 50 ml), brine (1 x 50 ml) and dried (Nazi).
Evaporation of solvent in vacua affords 6.0 g of oil
which is purified by column chromatography on silica
gel (300 g) with ethyl acetate/hexane solvent, 1:1.
Concentration of the product fractions affords 5.0 g
(85~) of colorless oil. ~H-NMR (CDC13) ppm (delta):
1.45 (s, I 1.55 (s, OH), 1.73-2.16 (m, I 2.16-2.6
(m, OH), 4.4 (s, lo), 4.5 (s, OH), 5.05 (s, I 5.4-
5.83 (m, 2B), 5.73 (s, OH), 6.66-7.4 (m, OH), 7.28
(s, OH).
B. The product obtained in Part A, 5.0 g (0.0085 mole),
50 ml ethyl acetate and 5 g 10~ Pd/C catalyst are
hydrogenated at 3 atmospheres pressure for one hour.
An additional 2.5 g catalyst is added and hydrogen-
lion continued for two hours. The mixture is filtered
through diatomaceous earth, washing with ethyl acetate.
The combined filtrate and washings, 200 ml, are poured
into a clean flask and 6.13 ml sodium 2-ethylhexanoate
in ethyl acetate ~0.23 gel is added. After stirring
for 30 minutes, the mixture is diluted with an equal
volume of ethyl ether and filtered to obtain 2.25 g
(51%) of sodium salt. HER (DUO) ppm (delta: 1.4
(s, OH), 1.43 (s, OH), 1.4-2.5 (m, OH), 4.4-4.8 (HOD),
5.46 (by, OH), 5.73 (by, OH), 6.64-7.4 (m, I
~L23682~
-63-
EXAMPLE 18
Sodium 6-~2,6-dimethoxybenzamido)penicillanoyloxymethyl
`Dimeth~lmalonate
A mixture of 4.02 g tool mole sodium 6-C2,6-
dimethoxybenzamido~penicillanate, 3.3 g Coequal motel
bouncily chloromethyl d~methylmalonate and 30 ml dim ethyl-
formamide are stirred at 25 C. for 60 hours, then the
product isolated and purified by the procedure of the
preceding Example to obtain bouncily 6-(2,6-dimethoxy-
benzamido)penicillanoyloxymethyl dimethylmalonate inn% yield. lH-NMR (CDC13) ppm dwelt: 1.46 (s, EYE,
1.6 (s, OH 3.78 (s, OH), 4.38 Us, lo 5.16 (s, OH),
5.5-6.1 (m, OH 6.53 (d, OH), 7.1-7.43 (m, lo), 7.3
(s, OH).
To 3.5 g (5.7 Molly of this bouncily ester in 50 ml
ethyl acetate is added 2.5 g 10% Pd/C catalyst and the
mixture hydrogenated at 50 psi pressure for one hour.
After filtering to remove catalyst, to the filtrate is
added an equimo}ar amount of sodium 2-ethylhe~anoate in
ethyl acetate. The product sodium salt is precipitated
with ethyl ether and collected by filtration to yield
1.95 g (63%) of the title compound. lH-NMR (D20) ppm
(delta): 1.33 (s, OH), 1.42 (s, OH), 1.6 (s, OH), 3.73
(s, OH), 4.4-4.8 (HOD signal), 5.5-5.8 (m, OH), 5.78
(dud, OH), 6.6 (d, OH 7.13-7.46 (m, lo); infrared
spectrum (KBr): 1787 cm 1.
~Z36~28
I
EXAMPLE 19
The procedure of the preceding example it
repeated with sodium 6-(2,6-dimethoxybenzamidolpenicil-
lunate and bouncily chloromethyl glutamate on a 2.2
molar scale to provide bouncily 6-~2,6-dimethDxybenz-
amidolpenicillanoyloxymethyl glutamate in quantitative
yield as an oil. lH-NMR ~CDC131 ppm Cdeltal: 1.48
(s, OH 1.61 (s, OH), 1.7-2.2 (m, OH), 2.2-2.62 em, I
3.8 (s, I 4.38 (s, I 5.08 (s, OH), 5.5-6.06 (m,
OH), 6.5 (d, OH), 7.1-7.38 (m, lo), 7.3 Us, 5Hl.
Hydrogenation of 1.4 g C2.2 Molly of the above
bouncily ester over Pd/C catalyst by the method used in
the previous examples and conversion to sodium salt
with sodium 2-ethylhexanoate affords 0.87 g (72.5%) of
sodium 6-(2,6-dimethoxybenzamido~penicillanoyloxy-
methyl glutamate. lH-N~R (DUO) ppm (delta): 1.43 (s,
OH), 1.;8 (s, OH), 1.5-2.5 (m, OH), 3.75 (s, OH), 4.4-
4.7 (HOD signal), 5.5-5.9 (m, OH), 6.6 (d, OH), 7.13-
7.5 em, lo); infrared spectrum ~RBrl: 1786 cm
I 28
-65-
EXAMPLE 2Q
1,l-Dioxopenicillanoyloxymethyl IDEA-
[l-methyl-2-methDxycarhonylvinylamino]-2-
phen~lacetamido)~penicillanoyloxymethyl
trans-1,4-cyclohexanedicarboxylate
A mixture of 2.33 g (3.97 Molly sodium 1,l-dioxo-
penicillanoyloxymethyl- trans-1,4-cyclohexanedicarboxylate,
1.72 5 ~3.97 mole) iodomethyl 6-rD-(2-11-methyl-2-
methoxycarbonylvinylamino]-2-phenylacetamido~]penitail-
lunate and 40 ml dimethylformamide is stirred at room temperature for five minutes. The mixture is diluted
with ethyl acetate, washed three times with small port
lions of water, once with brine and dried Nazi).
Evaporation of the solvent in vacua and chromatography
of the residue on a silica gel column, eluding with
7:3 ethyl acetate/hexane affords 1.4 g (40%) of the
desired examine. l~_NMR (CDC13) ppm (delta): ;.3-2.4
(m, 16H), 3.3-3.7 (m, I 4.3-4.i (s, I 4.5-4.7
(m, I 5.0-5.2 (d, lo), 5.3-5.4 (m, I 5.5-5.9
(m, I 6.5-6.8 (d, I 7.3 (s, OH); infrared spectrum
(KBr) cm 1 1600, 1760, 1800.
.
~Z3~8Z~3
-66-
EXAMPLE 21
1,l-Dioxopenicillanoyloxymethyl 6-ID-~2-amlno-
2-phenylacetamidolj~enicillanoyloxymethyl trueness-
cyclohexanedicarb^xylate Xvdrochloride
To a solution of 1.4 g (1.61 Molly l,l-dioxo-
penicillanoyloxymethyl 6-ID- C2_11_methY1_2_methOXY-
carbonylvinylamino]-2-phenylacetamidol]penicillanoowl-
oxymethyl trans-1,4-cyclohexane dicarboxylate in 150 ml
acetone is added 20 ml 0.lN hydrochloric acid and the
solution is stirred for five minutes. The solvent is
evaporated in vacua, the residue diluted with water and
the aqueous phase washed twice with 1:1 ethyl ether/
ethyl acetate. The aqueous phase is filtered and freeze
dried to obtain 634 my (48~) of the title compound,
mop. 155-170 (decomp.). l~_NMR (DMSO-D6 with D20
exchange) ppm (delta: 1.25-1.5 (m, 16H), 1.85-1.95
(m, OH), 2.35-2.5 (m, OH), 3.3 odd, lo), 3.7 (dud, lo),
4.4 (s, lo), 4.55 us, lo), 5.1 (s, lo), 5.2 (q, lo),
5.45 (d, lo), 5.55-5.65 (q, lo), 5.7-5.95 (m, OH), 7.4-
7.6 (m, OH), 8.85 (by, OH), 9.45 (d, lo); infrared
spectrum (KBr) cm 1 1690, 1750, 1800.
--6 7--
AMPLE 22
Bouncily Chloromethyl Socket
To a mixture of 48.67 g ~9.155 mole monobenzyl
subacute, 26 . 04 g JO. 310 motel sodium bicarbonate,
5 200 ml water and 52.55 g (0.155 mole tetrabutyl-
ammonium hydrogen sulfate is added 100 ml chloroform.
After shaking, the organic layer is separate, the
aqueous phase extracted again with chloroform and the
combined chloroform layers dried (Nazi. Evaporation
of solvent affords a residue which is taken up in 50 ml
bromochloromethane and stirred overnight at room
temperature. The mixture is evaporated in vacua, the
residue mixed with ethyl acetate, filtered and the
filtrate concentrated in vacua. The residual crude
product is purified by column chromatography on silica
gel to afford 2 g of purified monster as an oil.
(CDC13) ppm (delta): 1.1-1.9 (m, 12H), 2.2-2.5
(m, I 5.0 (s, I 5.6 (s, OH), 7.3 us, OH).
EXAMPLE 23
1,1-Dioxopenicillanoyloxymethyl 6-~D-(2-[1-methyl-
2-methoxycarbonylvinylamino]-2-phenylacetamido)]-
penicillanoYloxymethyl Subacute
To a solution of 0.59 g (1.0 mole) iodomethyl
6-~D-(2-[1 methyl-2-methoxycarbonylvinylamino]-2-phenyl-
acetamido)]penicillanate in 10 ml dimethylformamide is
added 0.47 g (1.0 Molly sodium l,l-dioxopenicillanoyl-
oxymethyl subacute and the mixture is stirred until
solution is complete. The reaction mixture is flash
chromatographed on a 23 cm silica gel column bed,
30 eluding with 7:3 ethyl acetate/hexane to obtain 200 my
~22%1 of the desired examine. lH-N~R (CDC131 ppm
(delta): 1.2-1.8 (m, 24H), 1.9 (s, OH), 2.2-2.6 (m, OH),
3.4-3.8 (m, OH), 4.4 (s, OH), 4.6-4.7 (m, OH), 5.2
(d, lo), 5.3 us, lo), 5-6-6-0 (m, OH), 6.9 (d, lo),
35 7-3 to I
123G8Z8
--68--
EX~t`lP~E 24
1,l-Dioxopenicillanoyloxymethyl 6- ED- (2-amino-
2-phenylacetamido~penicillanoylQxymethyl
Subacute Hydrochloride
to a stirred solution of 200 my (0.22 Molly
penicillanoyloxymethyl 6-~D-~2-Il-methyl-2-methoxy-
carbonylvinylamino]-2-phenylacetam;dol]penicillanoowl-
oxymethyl socket in 25 ml acuteness added 3.2 ml
Own hydrochloric acid and the mixture is stirred for
a few minutes, an additional 1.0 ml hydrochloric acid
added and stirring continued for one more minute. The
acetone is evaporated, the residue diluted with water,
and washed twice with 1:1 ethyl ether/e Hal acetate.
The aqueous layer is filtered and freeze dried to obtain
15110 my (59%) of product. lH-~R (DMSO-D6 + D20 exchange)
ppm (delta): 1~2-1.6 (m, 24H), 2.4 (q, OH), 3.3 (d, lo),
3.65-3.75 (dud, lo), 4.4 (s, lo), 4.55 (s, lo), 5.05
(s, lo), 5.2 (q, I 5.45 (d, lo), 5.55-5.65 (m, lo),
5.7-5.9 (m, OH), 7.35-7.55 to, OH), 8.65 (by, OH), 9.45
(d, lo).
-`
\
~;23G82~
I
EXAMPLE 25
1,l-Dioxopenicillanoyloxymethyl 6-ID-(2-amlno-
2-phenylacetamido~penicillanoyloxymethyl
Tere~hthalate hydrochloride
A. l,l-Dioxopenicillanoyloxymethyl 6-ID-C2-¦1-methyl-
2-methox~carbonylvinylamino~-2-phenylacetamido),~ppencil-
lanoyloxymethyl terephtha'ate
To a solution ox 0.59 g if Molly iodomethyl 6-rD-
(2-~1-methyl-2-methoxycarbonylvinylamino~-2-phenyll-
acetamido)]penicillanate in 10 ml dimethylformamide misadded 0.48 g (1.1 mole) sodium l,l-dioxopenicillanoyl-
oxymethyl terephthalate and the mixture stirred until
a solution is obtained. The solution is diluted with
ethyl acetate and washed with small portions of water
(3x), once with brine and dried Nazi). The solvent
is evaporated in vacua, the residue taken up in a small
amount of ethyl acetate and purified by silica gel
chromatography eluding with ethyl acetate/hexane, 6:4.
The product containing fractions are evaporated to
Jo provide 0.3 g (23%) of the examine protected compound.
lH-NMR (CDC13) ppm (delta): 1.1-1.5 (m, 12~), 1.7 (s,
I 3.3-3.6 (m, I 4.4 (s, I 4.4-4.6 em, OH), 5.1
(d, lo), 5.4 (s, I 5.8-6.1 (m, I 6.9 (d, lo), 7.2
(s, OH), 8.0 (s, I
B. To a stirred solution of 0.3 g ~0.35 mole) of the
above examine protected product in 25 ml Austria is
added 4.5 ml Own hydrochloric acid. The resulting
mixture is stirred for a few minutes, the solvent
evaporated and the residue partitioned between water and
ethyl ether. The aqueous phase is then washed with 1:1
ethyl ether/ethyl acetate, filtered and the filtrate is
freeze dried to obtain 222 my (78%) of the title
hydrochloride salt. l~_NMR (DMSO DUO) ppm (dental:
,
-
123~28
- 70 -
1.25 - 1.4 (d, PHI, 1.4-1.5 (d, OH), 3.2-3.3 (d, lo 3.65-
3.75 (dud, lo 4.45 (s, lo), 4.6 Lo, lo), 5.1 (s, lo),
5.2 (d, lo), 5.45 - 5.5 pa, I 5.55 - 5.65 (m, lo), 6.0-
6.4 em, PHI, 7.35-7.55 (m, Sol, 8.15 (us, I 8.85
- 5 abs , OH 9.45 (d, lo); infrared spectrum (Karl cm 1
1690, 1740, 1800.
123G8;~8
-71-
EXAMPLE 26
1,l-Dioxopenicillanoyloxymethyl 6-rD-~2-amino-
2-phenyla-etamido)penicillanoyloxymethyl
_ Isophthalate Hydrochloride
A. l,l-Dioxopenicillanoyloxymethyl 6-lD-C2-~l-methyl-
2-methoxycarbonylvinylamino]-2-phenylacetamidol]peentail-
lanoyloxymethyl isophthalate
To a solution of 0.59 g (110 Molly iodomethyl
6-~D-(2-[1-methyl~2-methoxycarbonylvinylamino]-2-
phenylacetamido)]penicillanate in 10 ml dimethylform-
aside is added 0.43 g (1.0 mole) sodium l,l-dioxo-
penicillanoyloxymethyl isophthalate and the mixture is
stirred at room temperature until solution is complete.
The reaction mixture is worked up by the procedure of
15 the preceding example (Part A) to provide 200 my (23%)
of the coupled examine. lH-NMR (CDC13) ppm (delta):
1.3-1.6 (m, 12H), 1.85 (s, OH), 3.6 (s, OH), 3.4-3.55
(m, OH), 4.i5 (s, OH), 4.6-4.7 (m, OH), 5.2 (d, lo),
5.4-5.7 (m, OH), 5.9-6.2 (m, I 6.9 (by, lo), 7.3
20 (s, OH), 7.5-7.7 (m, lo), 8.1-8.4 (m, OH), 8.7 (by,
lo), 9.4 (d, lo).
B. The examine protecting group is removed and the
hydrochloride salt formed by the method of the previous
Example, Part B in 94~ yield. lH-NMR ~DMSO + D20) ppm
25 (delta): 1.3 (d, OH), 1.5 (d, OH), 3.7 odd, lo), 3.3
(d, lo), 4.5 (s, lo), 4.65 (s, I 5.1 (s, lo), 5.2
(d, lo), 5.45 (d, lo), 5.55-5.65 (m, lo 6.0-6.2 (m,
OH), 7.35-7.55 (m, OH 7.8 (t, lH2, 8.25-8.35 (m, I
8.48 (t, lo), 8.85 (by, OH), 9.45 (d, LO infrared
30 spectrum (KBr): 1750-1800 cm l (Rudy.
,
1231~3Z8
-72-
EXAMPLE 27
6-rD-t2-Amino-2-phenylacetamido~]-
penicillanoyloxymethyl l,l-dioxo-
penicillanoyloxymeth~1 succ~nate hydrochloride
rVIII, R = I, Al = NH2, CC~2)2]
To a solution of 5.9 g ~0.01 motel iodomethyl 6-
lD-c2-[l-methyl-2-methoxycar~onyl~inylamino~-2-pheen
acetamido~]penicillanate in 3Q ml d~methyl~ormamide
was added 5.5 g C.014 mole) ox sodium l,l-dioxo-
penicillanoyloxymethyl succinate with stirring. After minutes 150 ml of ethyl acetate was added and the
mixture washed with water C3 x 50 my brine C50 ml),
water (2 x 50 ml), brine C50 mull, dried (Nazi)
and concentrated to 6.3 g of a yellow foam. The
product was dissolved in 60 ml of acetone and hydra-
lazed by stirring with 80 ml of Own hydrochloric
acid for 15 minutes. The acetone was removed in vacua
and the aqueous residue extracted with ethyl acetate
(50 ml), ethyl acetate/ethyl ether toll 75 ml) and
ethyl acetate (50 ml) again. The aqueous phase was
filtered to give a clear solution which produced
2.95 g of a solid mixture upon freeze drying.
Chromatography on Sephadex*L~-20 (water) gave 0.26 g
(3%) of pure hydrochloride salt. lH-NMR -(perdeutero
25 dimethylsulfoxide) ppm (delta): 1.4 (s, PHI, 1.52 (s,
OH), 2.7 (s, OH), 3.1-3.95 (m, I 4.4 (s, lo), 4.52
(s, lo), 5.0-5.28 (m, OH), 5.3-5.68 (m, PHI, 5.68-6.0
(m, OH), 7.43 (broad s, OH); infrared spectrum (nujoll
cm 1 1810-1730 Cbroadl.
* Trade Mark
~23~82~3
-73-
a. 6-[D-(2-Amino-2-ohenylacetamido)]penicillanoylox
methyl l,l-dioxo~e~icillanovloxvmethyl glutamate hydra-
chloride IVY, R4 = H, Al = NX2, A = CCH2~3~
Similarly, 2.94 g C5 Molly of the same idea-
methyl ester of methyl acetoacetate examine protected
ampicillin and 3.0-g t7.5 Molly sodium l,l-dioxo-
penicillanoyloxymethyl glutamate were stirred in
20 ml dimethylformamide for five minutes and quenched
with 150 ml ethyl acetate. The mixture was washed
with water (3 x 50 ml), Kline C50 my dried (Nazi
and evaporated to dryness in vacua. The residue was
purified by chromatography on silica gel (100 g),
eluding with ethylene chloride/ethyl acetate (60:40
by volume) taking fractions every 60 seconds. tractions
16-24 were combined and the solvent evaporated to
afford 1.8 g of foam. This was dissolved in 30 ml
acetone, 21.5 ml Own hydrochloric acid was added and
the mixture stirred for 20 minutes. The acetone was
evaporated at reduced pressure, the aqueous phase
extracted with ethyl ether (30 ml) and 1:1 ethyl
acetate/ethyl ether. The aqueous layer was filtered
through diatomaceous earth and the filtrate loopholes-
Ed to afford 1.45 g (37%) of the desired hydrochloride
salt.
lH-NMR (perdeutero dimethylsulfoxide) ppm delta):
1.4 (s, OH), 1.52 (s, OH), 1.5-2.0 (m, OH), 2.2-2.5
(m, OH), 3.06-3.9 (m, OH¦; 4.38 (s, I 4.5 (s, I
5.03-5.26 (m, OH), 5.33-5.63 em, OH 5.63-5.g3 em,
OH), 7.43 (broad s, SO); infrared spectrum CNujol)
cm 1 1815-1730.
The following compounds are also obtained by the
above method:
* Trade ark
~236,~Z~3
-74-
b.6-[D-(2-Amino-2-phenylacetamido)]penicillznoylox~--
methyl l,l-dioxopenicillanoyloxvmethyl adipate hydra-
chloride IYIII, R4 - I, Al - NH2, A = (SHEA t50
yield)* - H-NMR Cperdeutero d;methylsulfoxidel ppm
(dental: 1.4 (s, 6~1, 1.5 Us, OH Cloth ox these sing-
lets are on top of a multiple for I atoms, 2.2-2.6
em, EYE, 3.06-3.g3 (I, I 4.4 Us, I 4.53 Us, lo),
5.06-5.26 (m, I 5.36-5.96 I, 6~1, 7.46 Broad s, SHIV
infrared spectrum ~nujol~ cm 1 1815-1725.
c. 6- I ~2-~mino-2-phenylacetamido)]penicillanoyloxY-
methyl l,l-dioxoPenicillanoyloxymethyl dimethylmalonate
hydrochloride [VIII, I = H, Al = No A = (SCHICK]
- (76% yield) - 250 MHz l~-NMR (perdeutero dim ethyl-
sulfoxide) ppm (delta): 1.341 (s, OH), 1.366 (s, OH),
1.48 (s, OH), 3.0-3.9 (m, PHI, 4.41 us, lo), 4.53
(s, lo), 5.116 (broad s, lo), 5.2 (broad s, lo), 5.46
(d, lo), 5.55-5.65 (m, lo), 5.7-6.0 (m, OH), 7.33-7.64
(m, OH), 8.88 (broad s, I 9.45 (d, lo); infrared
spectrum (nujol) cm 1 1815-1770.
d. 6-[D-(2-Amino-2-Phenvlacetamido)~enicillanoYloxy-
methyl l,l-dioxoPenicillanoYloxYmethYl malonate hvdro-
chloride VOW, R4 = H, Al = NH2, A = SHEA] - (80% yield)
- lH-NMR (dimethylsulfoxide) ppm (delta): 1.33 (s, OH
1.46 (s, I 3.0-3.9 (m, OH), 3.73 (s, OH), 4.36 (s, I
4.46 (s, I 5.0-5.26 (m, OH 5.3-5.96 (m, I 7.4
(broad s, OH
* Upon purification by chromatography on Sephadex LH20
(Pharmacia Fine Chemicals Kiwi, material is obtained
which is 95% pure Dye high pressure liquid chromatography
assay
.
SUE
-75-
EXAMPLE 28
6-~D-(2-Amino-2-phenylacetamido~penicillan-
Qyloxymethyl l~l-dioxopenicillanoyloxymethyl
glutamate hydrochloride
Lo R = Al = I A = (SHEA
A. 6-[D-C2-Azido-2-phenylacetamidol~penicillanoyloxy--
methyl l,l-dioxopenicillanoyloxvmethyl glutamate
To a mixture of 1.18 g C.0023 mole) ox iodomethyl
6-[D-(2-azido-2-phenylacetamido~]penicillanate and
1.2 g (.Q03 mole) ox sodium l,l-dioxopenicillanoyloxy-
methyl glutamate was added 15 ml of dimethylformamide
and the mixture stirred into solution. After one hour
an additional 1.0 g of sodium salt was added and the
solution stirred an additional 30 minutes, diluted
with ethyl acetate ~100 ml) and washed with brine
(2 x 30 ml), water (2 x 30 ml), brine (1 x 30 ml),
dried (Nazi) and concentrated in vacua to a foam.
Chromatography on silica gel (100 g), elm_ no with
7:3 ethyl acetate/hexane, gave 0.72 g (43%) of
purified Acadia compound. lH-NMR (CDC13) ppm (delta):
1.41 (s, OH), 1.5 (s, I 1.6 (s, OH), 1.63 (s, OH),
1.77 - 2.23 (m, OH), 2.26-2.66 (m, OH), 3.42 (d, OH
4.38 (s, lo), 4.43 (s, lo), 4.58 (t, lo), 5.06 (s,
lo), 5.4-5.9 (m, OH), 7.1 (d, I 7.33 (s, OH).
~Z36~28
-76-
B. The aside product obtained above was dissolved in
15 ml of dichloromethane and 15 ml of isopropyl
and com~inefl with 0.5 g ox lo% palladium on carbon.
The mixture was hydrogenate under 50 pi C3.52
kg/cm2) ox hydrogen for 45 minutes. After addition
of another 0.25 g Ox catalyst, hydrogenation was
continued for another 30 minutes. the catalyst was
removed by filtration, washed with dichloromethane/
isopropanol and the filtrate concentrated Lo vacua to
give about 3 ml ox a suspension. Addition of 30 ml
of deathly ether gave a precipitate which, after
stirring for 5 minutes and filtration, gave a. 24 g
(35%) of free base. A 0.21 g portion of the base was
dissolved in 2.8 ml of Own hydrochloric acid and
freeze dried after filtration through diatomaceous
earth to give 0.14 g of hydrochloride salt.
A sample of the free base was used to obtain
H-NMR ~perdeutero dimethylsulfo~ide) ppm (delta):
1.38 (s, OH), 1.43 (s, OH), 1.5 (s, I 1.6 (s, OH),
1.65-2.0 (m, OH), 2.25-2.6 (m, OH partially obstructed
by DMSO), 3.1-3.9 (m, 2H),-4.43 (s, lo), 4.5 (broad s,
OH), 5.03-5.2 em, lo), 5.36-5.6 (I, I 5.6-5.9 em,
OH), 7.26 (road s, OH).
I`
lZ3~8Z8
-77-
EXAMPLE 29
6-ID-c2-Amino-2-phenylacetamidol]-
penicillanoyloxymethyl 1,l-dioxopenicillanoyl-
oxymethyl adiPate hvdrochIoride
A. By employing sodium 1,1-dioxopenicillanoyloxy-
methyl adipate in place of sodium l,l-dioxopenicillan-
oyloxymethyl glutamate in the procedure of Example 5,
Part A afforded 6-~D-(2-azido-2-phenylaCetamidO2~-
penicillanoyloxymethyl 1,l-dioxopenicillano~loxymethyl
adipate in 37.7% yield, lH-NMR (CDC13) ppm Cdeltal:
1.45 (s, OH), 1.55 (s, OH), 1.63 (s, OH 1.68 (s,
OH), previous singlets on top of m, OH), 2.2-2.6 em,
OH), 3.48 (d, OH), 4.43 (sly), 4.48 (s, lo), 4.65
(t, lo), 5.12 (s, lo), 5.5-5.95 (m, OH), 7.15 (d, lo
7.38 (s, OH).
B. The free base ox the title compound was obtained
upon hydrogenation of the Acadia compound obtained in
Part A by the procedure of Example 5, Part B. It was
converted to the hydrochloride salt as also described
in Example 5B, identical to that obtained in Example 4,
Part b.
C. The following Acadia compounds are obtained in
like manner and hydrogenated to provide the cores-
pounding 2-amino compounds
.
1236B28
-78-
3 I o
- ox N ~COCH20C
~CC1l2
R4 A
H (SHEA
I CEIL
ECHO C(CH3)2
OCOCH2CH3 C(C2H5)2
OCOCH(CH3)2 (SHEA
OCO(C~2)3CH3 (SHEA
OCO(CH2)5rH3 (SHEA
oCo(cH2)3cH(c~3)2 (C 2)12
OCOOCH3 CHCH3
OCOOC2H5 CHCH2CH3
OCOOCH(CH3)2 CH2CH(C~3)
OCOOCH2CH2c~3 (CH3)CHCH(CH3)
OCOOCH2CH(CH3)2 CH2C(cH3)2cH2
OCOOC(CH3)3 - C~2CH(CH3)CH2
OCOOC(c~3)2c~2c~3 CH2C(C2H5~2c~2
OCOOCH2CH2C~CH313 CH2C(CH3)(C2H51CH2
OCOO(CH2)5CH3 CH2CH(CH3lc~2c~2
OCOOC(CH3)3 CH(CH31CH2CH2
OCOOC6H5 CH2C~(cH3)c~2
OC00(4-FC6H41 ~CH3)2Cc~2cH2
ocoO(2-ClC6H4) C~2C~C~3)2c~2
OCO(3-BrC6H4) CH(CH3)C~2
lZ36~;~8
-79-
R4 A
OCO(4-IC6H4) (SHEA
OcO(4-clc6H42 ~223
oco(4-c~c6H42 SHEA
OCO(2-C~3C6H41 C~CH3)2
- OCo~4-(cH322cHc6H4~ CHCH3
Ocoo~4-(CH323cc6~4] I
OCOOC4-CH30C6H4) SHEA
OCO(3--C2H50C6H4) SHEA
0coo(2-n-c3H7oc6H42 C 2 512
OC0~2-n-C4HgOC6H4) (C~2)4
to (CH3)3cc6~4] (SHEA
OCol4-(cH3)2cHcH2oc6H4] (CH3)CHCH2
ECHO CRY
ECHO (C~2)4
ECHO SCHICK
H .1,4-cyclohexyl
- OR 1,3-cyclobutyl
OCOCH(CH3)2 1,4-cycloheptyl
OCOCH3 1,4-phenylene
OCOC2R5 1,3-phenylene
OCOOC6H5 1,2-phenylene
OCOOC(CH3)
OCOOCH2CH2CH
H
No
HO ON
H . CH2cH(c6H52cH2
HO . CH2CH(COOH)C~2
OCOCH3 (CH2llocH(c6Es2cH2
H ,C(CH32(CH2C6H5)
HO ~CHCH2CH2C6H5
123G828
-80-
EXAMPLE
Chlorom~thyl l,l-dioxo-
penicillanoyloxymethYl qlutarate
A solution of 3.9 g C.0084 motel ox Hansel 1,1-
dioxopenicillano~loxymethyl glutamate in 50 ml ox
tetrahydrofuran OF) was hydrogenated in the presence
of 3.0 g of 10~ palladium on carbon under 5Q psi
(3.52 kg/cm2) of hydrogen with a Pear hydrogenation
apparatus. The catalyst was removed by filtration and
the cake washed with THY and the filtrates concentrated
in vacua to 3.5 g of a viscous oil. the oil was
dissolved in 25 ml of chloroform, overlaid with
10 ml of water, the mixture stirred and adjusted to
pi 8.0 by addition of 40% tetrabutylammonium hydroxide.
The chloroform layer was separated and the aqueous
layer extracted with chloroform to x 30 ml). The
combined chloroform layers were dried (Nazi) and
concentrated in vacua to give 5.8 g of an oil, which
was dissolved in 35 ml of iodochloromethane and
stirred 15 hours. Concentration in vacua and cremate-
graph on silica gel (ethyl acetate/hexane) gave
0.20 g (6%) of the title compound. lH-NMR (CDC13)
ppm (delta): 1.44 (s, OH), 1.63 (s, OH), 1.82-2.2
(m, OH), 2.26-2.7 (m, OH), 3.48 (d, OH), 4.43 (s, I
4.63 (t, lo), 5.72 (s, OH), 5.83 I quartet, I
~Z3~82~3
--81--
EXAMPLE 31
6- D- (2-~ino-2-ph~ylaceta~.idol~-
penicillanoyloxymethyl 1,l-dioxo-
penic~llanoyloxymethyl
5glutarate hydrochloride
VOW, R4 = H, Al = NH2, A = CC~2~3]
To a solution of 0.2 g C0.0~05 mole ox sheller-
methyl 1,l-dioxopenicillanoyloxymethyl glutamate in
2 ml of acetone was added 0.323 g ~0.0005 motel of
lo tetrabutylammonium 6-rD-~2-rl-methyl-2-methoxycarbonyl-
vinylzmino]-2-phenylacetamido)]penicillanate with
stirring. After stirring 20 hours at room temperature
the solvent was removed in vacua and the residue
chromatographed on silica gel, eluding with 7:3 ethyl
acetate/hexane, to give 0.18 g of an oil. To a
solution of the product oil in 15 ml of acetone was
added 2 ml of Own hydrochloric acid followed by an
additional S ml of water and the mixture (pi 1.2~ was
stirred 30 minutes. Acetone was removed in vacua and
the aqueous residue was washed with ethyl ether to x
30 ml), filtered, and freeze dried to give 0.12 g
(75~ based on examine) of hydrochloride salt.
lZ3~8:Z8
-82-
EXAMPLE 32
Iodomethyl 1,1-dioxopenicillan-
oyloxymethvl dimethylmalonate
A. Chloromethyl l,l-dioxopenicillanoyloxymethyl
dimethylmalonate
To a solution of lo g (.025 motel of sodium 1,1-
dioxopenicillanoyloxymethyl dImethylmalonate in 25 ml
of water was added 150 ml of chloroform followed by
8.5 g (.025 mole) of tetrabutylammonium hydrogen
sulfate. The aqueous layer was adjusted with stirring
to pi 7.5 by addition of sodium bicarbonate. The
chloroform layer was separated and the aqueous phase
extracted with chloroform I x 100 ml2. The combined
chloroform layers were dried Nazi) and concentrated
in vacua to give 19.5 g of a viscous oil still
containing chloroform. The oil was dissolved in
95 ml of chloroiodomethane and stirred overnight.
Concentration in vacua and chromatography on 300 g of
silica gel, eluding wit ethyl acetate/hexane 1:1 by
volume, gave 7.4 g (70%) of chloromethyl ester as an
oil. lH-NMR (CDC13) ppm (delta): 1.43 (s, OH), 1.5
(s, OH), 1.6 (s, OH), 3.45 (d, OH), 4.38 (s, lo), 4.6
(t, lo), 5.68 (s, OH), 5.8 JAB quartet, OH).
123&828
-83-
B. To a solution of 7.4 g (.0156 mole of cbloro-
methyl 1,l-dioxopenicillanoyloxymeth~l dimethylmalonate
in 50 ml of acetone was added 11.75 g C.Q78 mole of
sodium iodide and the solution stirred on hours.
Concentration in vacua gave an oily solid which was
partitioned between 50 ml of wales and 100 ml ox
ethyl acetate. The aqueous layer was separated and
the organic layer washed with water C50 ml2, brine
C50 mull, dried (Nazi and concentrated in vacua to
a yellow oil. Chromatography on 150 g of silica gel,
eluding with 1:1 ethyl acetate/hexane by volume
gave 8.3 g (100%1 of iodomethyl ester as a clear
viscous oil. lH-N~R (CDC132 ppm Delta): 1.48 is,
OH), 1.52 (s, I 1.65 (s, OH 3.46 (d, OH 4.45
(s, lo), 4.65 (t, I 5.83 KIWI quartet, OH), 5.93 us,
OH); infrared (neat) cm 1 1810-1735.
C. The above procedures are repeated, but starting
with one of the remaining sodium or potassium salts
provided in Example 4, to provide the following
compounds
C02CH2X /
A SHEA
C02CH20--C
o
where A is as defined in Example 4 and X is Of or I.
issue
-84-
EXAMPLE 33
6-lD-(2-Amino-2-~p-hydroxyphenyl~-
acetamido~penic~llanoyloxymethyl
1,l-dioxopenicillanoyloxymet~yl
- 5 dimethylmalonate hydrochloride
IVlII, R4 = Ox, Al = No A - LC~312C~
A. 6-¦D-(2-rl-methyl-2-methoxycar~onylvinylamino~-
2-tp-hydroxyphenyl]acetamido~]penic~llanoyloxymethHal
l,l-dioxopenicillanoyloxymethyl dimethylmalonate
To a mixture of 1.83 g C.0026 motel tetrabutyl-
am~onium 6-~D-(2-ll-methyl-2-methoxycarbonylvinyl-
amino]-2-~p-hydroxyphenyl]acetamidol]penicillanatee and
1.35 g (.0026 mole) iodomethyl l,l-dioxopenicillanoyl-
oxymethyl dimethylmalonate was added 10 ml of dim ethyl-
formamide. After stirring for 15 minutes, the solution
was diluted with 100 ml of ethyl acetate, washed with
brine (25 ml), water (3 x 25 ml), brine (25 my
dried (Nazi) and concentrated to a foam. The foam
was taken up in ethyl acetate and chromatographed on
100 g of silica gel, eluding with 1:1 by volume ethyl
acetate/hexane, to give 1.2 g (54%) of examine
protected adduce. lH-NMR (CDC13) ppm (dental:
1.4-1.66 (m, 18H), 1.96 (s, OH), 3.45 (d, OH), 3.66
(s, OH), 4.46 (s, lo), 4.5 (s, lo), 4.56-4.73 (m, OH),
5.02 (d, lo), 5.43-5.96 (m, OH), 6.7 (d, OH), 7.13 (d,
OH); infrared spectrum (nujol~ cm 1 1810-1725
(broad).
lZ36~28
-85-
B. To the above examine product (1.2 go dissolved
in 30 ml of acetone was added 14 ml of 0.lN hydra-
caloric acid, after 20 minute acetone was removed in
vacua and the aqueous residue extracted with ethyl
S ether (2 X 50 ml2 and ethyl acetate L30 ml2,
Freeze drying the aqueous phase gave 0.8 g U2~2 of
the title hydrochloride salt. lH-N~R (perdeutero
dimethylsulfoxide2 ppm delta: 1.42 broad s, 12H2
1.53 (S, I 3.05-3.9 (m, OH), 4.36 (S, lH2, 4.48 I
lo), 4.83-5.26 (m, OH), 5.26-6.0 (m, OH), 6.73 Ed,
2~2, 7.23 (d, OH); infrared spectrum (nujol2 cm 1
1815-172S (broad).
C. By repeating the procedure of Part A above but
starting with the appropriate examine protected alpha-
15 aminobenzylpenicillin tetrabutylammonium salt and one
of the iodomethyl l,l-dioxopenicillanoyloxymethyl dip
carboxylates provided in Example 32, Part C, provides
the corresponding compound of the formula below.
R4 - - CHICANO SHEA
O C OUCH
~OCE~20C~
20 where Q is OH NH
~C02CH3
A is as defined in Examples 1-4 and R is hydrogen
or hyrax.
~2368Z8
-86-
EXAMPLE 34
6-ID-(2-Amino-2-~p-acetoxyphenyl]-
acetamido)]penicillanoyloxymethyl
l,l~dioxopenicillanoyloxymethyl
dimethylmalonate
. VOW, R4 = SCHICK., Al = NH2, A = SCHICK]
A. 6-~D-~2-rl-methyl-2-methoxycar~onylVinylamino~-
2-~p-acetoxyphenyl]acetamido~penicillanoyloxymethyye
1,l-dioxopenicillanoyloxymethyl d~methylmalonate
6-ID-t2-tl-methyl-2-methoxycarbonylvinylamino]-
2-~-hydroxyphenyl~acetamiao)~penicillanoyloxymethyye
1,l-dioxopenicillanoyloxymethyl dimethylmalonate,
prepared by the procedure of Example 33, Part A,
(2.55 g, 0.003 mole) and 0.366 g ~.003 mole) 4-
dimethylaminopyridine were dissolved in 30 ml dip
chloromethane and 0~28 ml (.003 mole) of acetic
android was added. The solution was stirred for
25 minutes, diluted to 100 ml, washed with water
(30 ml), brine (30 ml), dried (Nazi) and concern-
treated to give 2.1 g (78%) of a yellow foam. H-NMR
(CDC13) ppm (delta): 1.46 (s, OH), 1.52 (s, OH), 1.56
(s, OH), 1.64 (s, OH), 1.92 (s, OH), 2.33 (s, OH),
3.48 (d, OH), 3.66 (s, OH), 4.46 (s, lo), 4.5 (s, lo),
4.6-4.76 (m, OH), 5.13 (d, lo), 5.4-6.0 (m, OH), 7.1
(d, OH), 7.43 (d, OH); infrared spectrum (nujol)
cm 1 1810-1725.
~23~
-87-
B. The foam obtained in Port I, above, 2.1 g, was
dissolved Lo 50 ml of acetone and 23 ml of Q.1
hydrochloric acid was added. Aft Of stirring 20
minutes, the acetone was removed in vacua and the
- 5 aqueous layer was washed with ethyl ether I x 30 my
filtered through diatomaceous earth and freeze dried
to give 1.77 g C71~) of the title hydrochloride-salt.
1~_NMR ~erdeutero dimethylsulfoxide) ppm Cdeltal:
1.23-1.64 (m, 18Hl, 2.26 (s, 3~1, 3.0-3.9 em, 2~1,
10 4.36 is, I 4.46 (s, lo 5.0-5.23 em, I 5.23-5.96
(m, I 7.1 (d, I 7.5 (d, I
EXAMPLE 35
A. By repeating the procedure ox Example 34, Part A
on the same 3 millimola~ scale, but using pivaloyl
chloride in place of acetic android gave a crude
product which was purified by chromatography on
100 g silica gel, eluding with 60:40 (v/v) ethylene
chloride/ethyl acetate. Concentration of product-
containing fractions gave 2.3 g (82%) of colorless
foam which is 6-[D-(2-rl-methyl-2-methoxycarbonyl-
vinylamino]-2-[p-pivaloyloxyphenyl]acetamido)]penii-
cillanoyloxymethyl 1,1-dioxopenicillanoyloxymethyl
dimethylmalonate. 1~_NMR (CDC13~ ppm (delta):
1.3-1.7 (m, 27~), 1.93 (s, OH), 3.48 (d, OH), 3.68 (s,
25 I 4.48 (s, lo), 4.51 (s, lo), 4.6-4.73 (m, I
5.13 (d, lo), 5.46-6.03 (m, I 7.1 (d, OH), 7.43 (d,
I infrared spectrum (nujoll cm 1 1820-1710.
--88--
B. To 2. 2 g (2.35 mole) of the examine obtained in
Part A in 30 ml acetone was added 24 ml Own hydra-
caloric acid. The mixture was stirred at ambient
temperature for five minutes, the acetone evaporated
in vacua and the aqueous residue washed with ethyl
ether (3 x 50 my The residual ether was removed
from the aqueous layer by evaporation in vacua. The
aqueous solution was then clarified by filtration and
freeze dried to afford 1.61 g ~8Q%~ of 6-ID-~2-amino-
2-~-pivaloyloxyphenyl]ace~amido)]penicillanoyloxymmethyl
1,l-dioxopenicillanoyloxymethyl dimethylmalonate
- hydrochloride. l~_NMR (perdeutero dimethylsulfoxide)
ppm (delta): 1.16-1.66 (m, 27~), 3.03-3.93 em, I
4.43 (s, if), 4.53 us, I 5.02-5.26 (m, OH), 5.33-6.03
(m, I 7.13 (d, I 7.63 (d, OH); infrared spectrum
(nujol) cm 1 1820-1725 Broad).
C. By employing formic-acetic android as assault no
agent in Part A and removal of protecting group by the
above method, 6-lD-(2-amino-2-~-formyloxyphenyl~-
acetamido)]penicillanoyloxymethyl l,l-dioxopenicillanoyl-
oxymethyl dimethylmalonate hydrochloride is obtained.
~Z36~ZB
-89-
EXAMPLE 36
In like manner the examine compounds of the
formula below where Al is NHC=CHC02CH3 are prepared
c~3
by the procedures of Example 34, Part A and Example
35, Part A by employing the appropriate acid android,
acid chloride or chloroform ate ester in place of
acetic android and pivaloyl chloride.
Q HH33 0
Ox N ~COOC~20C
Go I' PA
R4 A
OCOCH3 SHEA
C(cH2)2cH3 (SHEA
OCO(C~2)3CH3 tC~2)4
ECHO (SHEA
OCo(cH2)3cH(cH3)2 (SHEA
OCO(CH2)5CH3 (C~2~10
OCOC6H5 SCHICK
OCO(3-CNC6H4) (CH3)CHCH(CH31
OCO(2-CH3C6H4) (:C2H5)CHCH(C2H5)
OCO0(4-CH30C6H4~ ~C~3)2C-C(CH312
OCOOCH(CH3)2 (CE~3)CHc(c2H5)2
OCOOC(CH3)3 C~CH3~2.
OCOOC(CH3)3 (SHEA
OCooc(cH3)2cH2cE3 (n-C5H112C~CH225CH3
OCOOC6H5 (SUE
OC00(4-FC6H4) (n-C3H7)C~CH(n~c3H7)2
:~23~2~3
--so--
EX~lPLE 37
6-[D-t2-~senzyloxycarbonylamino~-2-I~-
hydroxyph~nyl]acetamido~]penicillanoyloxymethyl
l,l-dioxopen~cillanoyloxym~thy--malonate
To 7.40 g (a . of o mole tetrabutylammonium 6- ID-
(2-~benzyloxycarbonylamino~-2-1~-hydroxyphenyl]aceet-
amido)]penicillanate and 4.56 g C0.010 mole) idea-
methyl 1,l-dioxopenicillanoyloxymethyl malonate is
added 50 ml dimet~ylformamide and the mixture is
stirred for thirty minutes. The reaction mixture is
diluted with ethyl acetate (500 my washed in turn
with brine, water, brine again and dried over an hydrous
sodium sulfate. The solvent is evaporated in vacua
and the crude residue purified by chromatography on
silica gel.
EXAMPLE 38
6-[D-~2-[4-Nitrobenzyloxycarbonylaminol-
2-[p-hydroxyphenyl]acetamido)]penicillanoyloxy-
methyl l,l-dioxopenicillanoyloxymethYl malonate
The title compound is obtained from tetrabutyl-
ammonium 6-[D-(2-[4-nitrobenzyloxycarbonylamino]-2-~p-
hydroxyphenyl]acetamido)]penicillanate by the above
procedure.
~23~828
-91-
EXAMPLE 39
Employing the appropriate iodomethyl 1,l-dioxo-
penicillanoyloxymethyl dicar~oxylate ester in place of
iodomethyl l,l-dioxopenicillanoyloxymethyl malonate in
the procedures of Examples 37 and 38 provides. the
corresponding compound ox the formula below in like
manner.
~IO--~--CHCONH~C~6~C~I3
ox N C2cH2--c
\
\/ C~3 A
o 3
I No COCH20-C=o
O O
6 5 ~2CN~ or 4-N02C6H4CH20CNH and A has
the values given in previous Examples.
-
123~28
-92-
EXAMPLE 4Q
6-~D-~2-Amino-2-~p-isobutoxycarbonyloxyphenyl~-
ace~amido)]penicillanoyloxym~thyl 1,1-
dioxopenicillanoyloxymethyl malonate
S VOW, R = I SCHICK, = No A = C~2]
A. 6-[D-C2-~Benzyloxycarbonylamino]-2-f~-isobutoxy-
carbonyloxyphenyl]acetamido)~pen;cillanoyloxymethyye
malonate
To a stirred solution of 2.48 g (0.003 mole) 6-
~D-2-~benzyloxycarbonylamino]-2-[p-hydroxyphenyl]--
acetamido)]penicillanoyloxymethyl l,l-dioxopenicillæn-
oyloxymethyl malonate, Q.437 g (0.003 mole) diisopropyl-
ethyl amine and 30 ml dichloromethane is added 0.410 g
(0.003 mole) isobutyl chloroform ate. The resulting
15 mixture is stirred 10 minutes then about 30 my 4-
dimethylaminopyridine is added and stirring continued
for 30 minutes. The solvent is evaporated in vacua, .
the residue dissolved in ethyl acetate, the solution
washed with water, brine, dried (Nazi) and evaporated
to dryness in V2CUO.
B. A mixture of 2.0 g of the product obtained in
Part A, 50 ml dichloromethane, 50 ml isopropanol and
2.0 g 10% palladium-on-carbon is hydrogenated at
three atmospheres (3.52 kg/cm2) until hydrogen
uptake ceases. An additional 2.0 g of Pd/C is added
and hydrogenation is continued for 30 minutes. The
reaction mixture is filtered through Solute diatom-
assess silica product) washing with 1:1 dichloromethane/
isopropanol. The combined filtrate and washings are
evaporated in vacua to afford the crude title compound
which can be purified, if desired, by chromatography
on Sephadex L~-20*.
*A registered trademark of Pharmacia Fine Chemicals,
Pussycat, NO
** Trade Mark
issue
-93-
EXAMPLE 41
By employing the appropriate starting material
selected from those provided in Examples. 38 and 39 in
the above procedure or the procedure of Example 34,
Part A followed by hydrogenation by the procedure of
Example 4Q, Par R, the following compounds are
obtained in like manner.
' .
R4- -CHICANO C~3
2 I SHEA O
I N C02CH20C
O O A
C~3
where R4 is as defined in Example 36 and A is as
defined in Examples 1-4 and 36.
-94-
EXAMPLE 42
Bouncily 6-rD-~2-11-Methyl-2-methoxycarDonyl-
vinylamino~-2-1~-hydroxyphenyl]acetamido~]-
PenicillanovloxymethYl dim~'hYlmalonate
; To a mixture of 22.2 g Kiwi mole ensoul
dimethylmalonate half ester in 500 ml ethylene
chloride and 75 ml water is added 40% tetrabutyl-
ammonium hydroxide with vigorous stirring until the pi
is U.S. The organic layer is separated, the aqueous
layer extracted with ethylene chloride C2s0 ml) and
the combined extracts dried (Noah. Evaporation of
solvent gives a residue which is taken up in 500 ml
Tulane and 54.1 g (0.10 mole) iodomethyl 6- rod- (2- Al-
methyl-2-methoxycarbonylvinylamino]-2-[p-hydroxy-
phenyl~acetamido)]penicillanate is added and the mixture stirred for one hour, diluted with ethyl
acetate (1000 ml) and the precipitated tetrabutyl-
ammonium iodide is removed by filtration. The filtrate
is washed with water, brine, dried (Nazi) and concern-
treated to dryness in vacua. The residual product maybe purified by chromatography on silica gel.
123~82B
EXAMPLE 43
Bouncily 6-~D-C2- r 1-m~thyl-2-methoxy-
carbonylvinylamino2-2-phenyl-
acetamidol]~enicillanoyloxymethyl glutamate
1. Bouncily chloromethYl_glutarate
A mixture of 1.5 g C3.75 molehill tetrabutyl-
ammonium ensoul glutamate and 20 ml c~loro~odomethane
is stirred at room temperature for three hours and
concentrated in vacua to a viscous oil The oil is
taken up in 20 ml ethyl acetate and 30 ml hexane and
filtered to remove ~etrabutylammonium iodide. The
solvent is evaporated in vacua and the residue purified
by chromatography on 75 g silica gel, eluding with
70:30 ethyl acetate/hexane by volume. Fractions
(lo ml) were collected every 0.7 minutes. The
fractions containing the desired product tractions
8-11) are combined and the solvent evaporated in vacua
to yield 0.55 g (62.5~) of the desired product.
lH-NMR (CDC13) ppm (delta): 1.65-2.2 (m, OH), 2.26-2.64
(m, OH), 5.1 (s, I 5.65 (s, I 7.3 (s, I
2. A mixture of 0.55 g (2 mole) of bouncily sheller-
methyl glutamate, 1.37 g (2 mole) tetrabutylammonium
6-~D-(2-[1-methyl-2-me~hoxycarbonylvinylamino]-2-
phenylacetamido)]penicillanate and 20 ml acetone is
stirred overnight at room temperature. The acetone is
evaporated and the residue purified by chromatography
on silica gel, eluding with 60:40 ethyl acetate/hexane
by volume to yield 1.2 g (88%) of product as an oil.
lH-N~R (CDC13) ppm Delta 1.45 Us, 3H2, 1.53 (s,
3XI, 1.9 Us, 3H2, 1.8-2.2 (m, I 2.22-2.62 em, OH
3.64 Us, OH 4.4 Us, lo), 4.62 Us, lo), 5.Q5-5.22
Us, OH), 5.4-5.73 em, OH), 5.78 Us, OH), 6.84 (d, lo),
7.3 (s, SO), 7.34 Us, OH), 9.3 (d, lo).
!
3 2
-96-
EXAMPLE 44
Sodium 6-[D-C2-aminO-2~
hydroxyphenyl]acetamido~]penicillan-
oyloxymet~yl dimethylmalonate
A. Benzyl-D-L6-C2-amino-2-I~-hydroxyphenyl]aCetamidOllo
penicillanoyloxmethyl dimeth~lmalonate hydrochloride
Bouncily 6- rod- ~2-ll-methyl-2-methoxycarbonylvinyl-
amino]-2-L~-hydroxyphenyl]acetam~do~penicillanoyloox-
methyl dimethylmalonate (6.35 g, 10 molehill is dissolved
in 200 ml acetone, 95 ml 0.lN hydrochloric acid is
added and the mixture stirred for 25 minutes. The
acetone is then evaporated at reduced pressure, the
aqueous residue extracted with ether and filtered to
obtain a clarified aqueous solution of the title
bouncily ester hydrochloride salt. The solution may be
freeze dried if desired to obtain the solid product.
B. To the aqueous solution of bouncily ester hydra-
chloride obtained in Part A is added 2.5 g of 10~
palladium-on-carbon and the mixture is hydrogenated at
a pressure of 3-4 atmospheres hydrogen for one hour.
The catalyst is removed by filtration, and the filtrate
is freeze dried to obtain the hydrochloride salt. The
freeze dried solids are taken up in 50 ml ethyl
acetate, two equivalents of sodium 2-ethylhexanoate
added and the precipitated sodium salt recovered by
filtration and dried.
C. In similar manner the product obtained in Example
43 is converted to sodium 6-~D-(2-amino-2-phenylacet-
amidol]penicillanoyloxymethyl glutamate.
lZ3~Z8
-97-
EXAMPLE _
6-[D-~2-Amino-2-~p-hydroxyphenyl~-
acetamido~]penicillanoyloxymethyl
l,l-dioxopenicillanoyloxymethyl
dimethylmalonate hydrochloride
IVY, R4 = OH, Q1 = NX2., = CC~3~2C~
To a solution of 5.32 g C0.010 mole sodium 6-
r2-~2-amino-2-r~-~ydroxyphenyl]acetamidol]penicillfan-
oyloxymethyl dimethylmalonate in 20 ml water is added
100 ml ethylene chloride and 3.2 g C0.010 motel
tetrabutylammonium hydrogen sulfate. The mixture is
adjusted to pi 7.5 with solid sodium bicarbonate, the
organic layer is separated, the aqueous layer extracted
with ethylene chloride, the combined organic layers
dried (Nazi) and evaporated in vacua. The residue
is added to 20 ml methyl acetoacetate, the mixture is
heated at 65C. for ten minutes, allowed to cool and
the examine derivative collected by filtration, washed
with ethyl ether and air dried. The recovered examine
derivative is taken up in 35 ml chloroiodomethane and
stirred overnight at room temperature. The mixture is
then concentrated and the residue purified by chrome-
tography on silica gel to provide the corresponding
chloromethyl ester.
The chloromethyl ester 5.8 g, is dissolved in
acetone (50 ml), 1.5 g sodium iodide is added and
the solution is stirred overnight. Evaporation of
solvent, partitioning the residue between water and
ethyl acetate and evaporation of solvent affords idea-
methyl ester of suitable purity for use in the next
step.
1~3~
-98-
To a mixture of 6.7 g of the iodomethyl ester
obtained above and 4.5 g (0.010 motel tetrabutylammonium
1,l-dioxopenicillanate is added 50 ml dimethylform-
aside and the mixture is stirred for 30 minutes at
room temperature. The solution is diluted with
300 ml ethyl acetate, washed with brine, water, brine
again and dried over an hydrous sodium sulfate.
Evaporation ox solvent in vacua affords a residue
which is taken up in lo ml acetone, 100 ml
lo hydrochloric acid is added and the mixture stirred for
25 minutes. The acetone is evaporated in vacua and
the aqueous residue extracted with ethyl acetate/ethyl
ether, then clarified by filtration. The filtrate is
freeze dried to afford crude solid product which is
purified by chromatography on Sephadex L~-20*.
In like manner sodium 6-~D-(2-amino-2-phenyl-
acetamido)penicillanoyloxymethyl glutamate is con-
vented to examine protected-iodomethyl ester and this
reacted with tetrabutylammonium l,l-dioxopenicillanate
to provide 6-~D-(2-amino-2-phenylacetamido)penicillan-
oyloxymethyl l,l-dioxopenicillanoyloxymethyl glutamate
hydrochloride VOW, R4 = I, Al = No A = (C~2)3].
*A registered trademark of Pharmacia Fine Chemicals,
Pussycat, N . J .
- . .
. .
I?
'12~82B
99
EXAMPLE
Bouncily 6-(D-2-azido-2-phenylacetamido~-
penicillanoyloxymethyl adipate
To 11.8 g Tess motel bouncily adipate half ester
in 250 ml chloroform and 4Q ml water is added 4Q~
aqueous tetrabutylammonium ~ydr~x~de with vigorous
stirring until the mixture is pi 8.5. The organic
phase us separated, the aqueous layer extracted with
chloroform and toe combined extracts dried over
an hydrous sodium sulfate. Evaporation of solvent
gives tetrabutylammonium ensoul adipate as an oil.
The oil is mixed with Tulane (250 ml) and 2.56 g
(0.05 mole) iodomethyl 6-~D-~2-azido-2-phenylacetamido~]-
penicillanate is added. The mixture is stirred for
one hour, diluted to 500 ml with ethyl acetate and
the precipitated tetrabutylammonium iodide removed by
filtration, washing with ethyl acetate. The filtrate
and washings are washed with sodium bicarbonate
solution, water, brine and dried (assay). Evapora-
lion of solvent affords the title compound which is purified by silica gel chromatography.
~23682~
--100--
E AMPLE 47
-
- 6-[D-(2-Amino-2-phenylacetamido)-
penicillanoyloxymothyl adipate half ester
To 2.0 g of bouncily 6-~D-(2-azido-2-phenylacet-
amido)]penicillanoyloxymethyl adipate, obtained in the
preceding Example, dissolved in 50 ml each of dichloro-
methane and isopropanol, is added 1.0 g of 10% palladium-
on-carbon and the mixture hydrogenated at 3-4 kg/cm2
with agitation for two hours. The catalyst is removed
by filtration, the filtrate and washings concentrated
in vacua to afford the desired product which is
purified by chromatography or by recrystallization.
EXAMPLE 48
Potassium 6-~D-(2-rl-methyl-2-methoxy-
carbonylvinylamino]-2-phenyl-
acetamido)~enicillanoYloxymethyl audit
To a suspension of 7.6 g (0.055 mole) potassium
carbonate in 75 ml dimethylformamide is added 10.8 ml
(0.10 mole) methyl acetoacetate and 24.6 g (0.05 mole)
6-~D-(2-amino-2-phenylacetamido)]penicillanoyloxymmethyl
adipate half ester and the mixture is stirred at room
temperature for two hours, then at 0-5C. for 4 hours.
Ethyl acetate (250 ml) is added, the mixture stirred
for 5 minutes and allowed to stand at 0-5~C. for one
hour. The solvent phase is decanted. The residue is
washed twice with ether by recantation, dissolved in
150 ml acetone and filtered through a filter-aid.
The filtrate is diluted with 150 ml isopropanol and
set aside at 0-5~C. The precipitated product is
recovered by filtration, washed with ethyl Ethel and
dried in zip.
~Z3G~828
--1 01--
EXAMPLE 49
6-[D-(2-Amino-2-phenylacetamido~]
penicillanoyloxymethyl Dixie-
penicillanoyloxymethyl adipate
VOW, R = I, Al - NH2, A = CC~2L
To 35 ml dimethylformamide is added 1.86 g
~0.005 mole) iodomethyl 1,1-dioxopen~cillanate and
3.14 g (0.005 motel potassium 6-lD-(2-~l-methyl-2-
methoxycarbonylvinylamino]-2-phenylacetamidolpeni--
cillanoyloxymethyl adipate and the mixture is stirred at room temperature for two hours. Ethyl acetate
(150 ml) is added, the mixture washed with brine,
water, brine again, dried (Noah) and concentrated in
vacua. The residue is taken up in acetone (100 ml),
50 ml of Own hydrochloric acid added, and the
mixture is stirred for 20 minutes. The acetone is
evaporated in vacua, the aqueous residue is washed
with ethyl acetate and ethyl ether, cooled, neutralized
with sodium bicarbonate solution and quickly extracted
with ethylene chloride. The combined extracts are
dried (~gS04) and the solvent evaporated in vacua to
afford the title compound as the free base.
1~:36~Z8
-102-
EXAMPLE 50
The procedure of Example 46 is repeated but
using the appropriate bouncily half ester in place of
bouncily adipate half ester and the appropriate halo methyl
6-[2-(Ql-su~stituted~-2-(R4-phenylacetam~dol~penicsilent
to provide the compounds of the formula below:
R4--~ -CHICANO "kiwi
Ox N COOCH2OC-O
C02CH2C6H5
where Al is Acadia, benzyloxycarbonylamino or nutria-
benzyloxycarbonylamino and A and R4 are as define
previously.
In the starting halo methyl ester "halo' may be
idea, broom, sheller, methylsulfonyloxy or Tulane
sulfonyloxy.
owe
-103-
EXAMPLE 51
By repeating each of the procedures of Examples 47,
48 and 49 in turn with the products provided in the
previous Example, thy following compounds are obtained
-- 5 in like manner:
R --~--CHCONH~f SHEA o
N ""'COOCH20C
'\
Ox I PA
So C~3
I COOK OX/
o
where R4 and A are as defined in the preceding Example.
~236~
-104-
EXAMPLE 52
6-~D-~2-Amino-2-phenylacetamido~]-
penicillanoyloxyme~hyl l,1-dioxo-
penicillanoyloxymethyl dimetnyl-
malonate p-toluenesul_onate
A. 6-~D-(2-Il-methyl-2-me'hoxycarbonylvinylamino]-
2-phenylacetamidol]penicillanoyloxyme~hyl 1,l-dioxo-
penicillanoyloxymethyl dimethylmalonate
To 4.0 g Owl mole sodium 1,l-dioxopenicillan-
oyloxymethyl dimethylmalonate and 6.0 g ~0.01 mole
iodomethyl 6-~D-~2-~1-methyl-2-methoxycarbonylvinyl-
amino]-2-phenylacetamido)]penicillanate is added
40 ml dimethylformamide and the mixture is stirred at
room temperature for 30 minutes. The mixture is
poured into 300 ml ethyl acetate, washed with water
(4 x 10~ ml), brine (1 x 100 ml), dried (Nazi)
and concentrated in vacua to afford 9.3 g of foam.
The foam is purified by chromatography on silica gel
(300 g), eluding with 60:40 ethyl acetate/hexane
taking 25 ml fractions. Fractions 39-65 are combined
and evaporated in vacua to yield 4.3 g (51%) tan
foam. 1H-NMR (CDC13) ppm (delta): 1.43 (s, OH), 1.46
(s, OH), 1.53 (I, OH), 1.6 (s, OH), 1.9 (s, OH), 3.42
(d, OH), 3.63 (s, OH), 4.4 (s, lo), 4.42 (s, lo),
4.53-4.57 (m, OH), 5.06 (d, lo), 5.35-5.93 (m, OH),
6.73 (d, lo), 7.33 's, OH), 9.4 (d, lo).
:~23~28
-105-
B. To 30 ml ethyl acetate is added 0.836 g Lo
molehill ox the examine obtained in Hart I, above, and
the mixture stirred to obtain a solution. solution
of 0.19 g (1 mmQle~ p-toluenesulfonic acid hydrate in
- 5 5 ml ethyl acetate is added and the mixture stirred for
lo minutes, and the solvent evaporated to yield a hard
gum. The gum is triturated Wyeth ml ethyl ether,
stirred overnight, filtered, washed with ethyl ether
and air dyed to give 0.84 g C92%1 of tessellate salt.
10 lH-~R (DMSO.D61 ppm Cdeltal. 1.4 Us, 12~1, 1.5 (s,
I 2.3 (s, 3~1, 3.1-3.9 em, I 4.36 Us, lo 4~5
(s, I 5.0-5.26 (m, Al 5.33-6.0 em, 6~1, 7.06 Ed,
OH), 7.3-7.63 (I, I
-
1236X32~
-106-
EXEMPT I 5 3
6-beta-Bromopenicillanoyloxymethyl
6-rD-(,2-~mlno-2-phenyl)aceta~ido~
penicillanoyloxymeihyl Glutamate
A lodomethyl 6-he*a-bromopenicillanate
To a stirred solution of 0.96 g I molehill potassium
6-beta-bromopenicillanate and 1.8Q g (18 Molly
potassium bicarbonate in 9 ml each of water and ethyl
acetate is added 0.10 g ~0.3 Molly tetrabutylammonium
hydrogen sulfate, followed by 0.45 g C4.5 molehill sheller-
methyl chlorosulfonate and the mixture stirred for
lo hours. The organic phase is separated, the aqueous
phase extracted with ethyl acetate and the combined
organic layers are washed with water, dried and concern-
treated in vacua to about 5 ml. The crude product is
purified by chromatography on silica gel (petroleum
ether/ethyl acetate 9:1) to afford chloromethyl 6-beta-
bromopenicillanate as a nearly colorless oil.
To a solution of 0.82 g (2.5 mole) of this sheller-
methyl ester in acetone (5 ml) is added 0.75 g (5 mole)
sodium iodide and the mixture stirred for 24 hours. The
precipitated salt is removed by filtration, the filtrate
evaporated in vacua, and the oily residue taken up in
ethyl acetate. The solution is washed with water, dried
(McCoy), concentrated toga small volume and purified in
the same manner as the chloromethyl ester to provide the
desired iodomethyl ester as a yellow oil. l~_NMR
(CDC13) ppm (delta):, 1.55 (s, I 1.6~ (s, I 4.5
(s, lo), 5.34 and 5.57 Cud, J=4~z, OH), 5.97 aback,
J=5~z, OH).
lZ3G~Z8
-107-
B. 6-beta-Bromopenicillanoyloxymethyl 6-~D-(2-C2-
methyl-2-methoxycarbonylvinylamino]-2-phenylacetammud
penicillanoyloxvmethyl glutamate
To a stirred solution of tetrabutylammonium ED
- 5C2-methyl-2-methoxycar~onylvinylamino]-2-phenylaceetamido~]-
penicillanoyloxymethyl glutamate C832 my, l molehill on
3 ml each of ethyl acetate and dichloromethane is added
a solution of 430 my Of molehill iodomethyl 6- eta-bromo-
penicillanate in 5 ml ethyl acetate. After stirring for
lo a few minutes, the resulting slurry is concentrated to
remove dichloromethane, filtered to remove precipitated
salt and the filtrate is washed with water I ml). To
the organic phase is added fresh water (10 ml) and the
pi adjusted to 3 with lo hydrochloric acid. The aqueous
phase is separated and freeze dried to afford the title
compound as the hydrochloride salt.
~Z31&8Z8
-108-
C. In similar manner the compounds of the formula
below are obtained prom the appropriate starting
materials
R -SCHICK C~33
Ox ~COCHOC=O
n 3
x2 OH A
SHEA
~COCHOC=O
R 3
O R
A R3 R4 x2
_
SHEA H H Of
(SHEA H H Of
(C~2)8 H OH By
(SHEA SHEA OH By
10 (C~3)2c C2~5 OCOCH3
(n-C4Hg)C(CH2C6H5) H OCOCH(CH3)2 Of
C(CH3)2 C3H7 OCOC(CH3) 2 By
1,4-phenylene H H
1,3-phenylene C~3 OCOOCH3 By
15 1,4-cyclohexylene i C3~7 OCOOCH(CH3)2 By
H ` OH C
Owe
H OH Of
C6H5CHC~2 SHEA By
lZ3G8Z8
--109--
EXAMPLE 54
Employing the appropriate starting compound of
formula BCOOH or its sodium Or potassium salt it the
procedures of Preparations C and D or Part A ox the
- 5 preceding Example, the corresponding compounds ox
formula BROOCH clue or BCOOCH~R31I are obtained in
like manner, where R3 is H, SHEA, C2H5 or C3H7 and B is
as defined below
BOO or salt
obtained by
B Procedure of
C S SHEA
C~3 U.S. 4,342,772
" N k",
ITS SHEA
SHEA U.S. 4,342,772
O O
HOC~\SJ SHEA
SHEA U.S. 4,342,768
O'
O O
CH2J, SHEA
ox N J ""SHEA Preparation I
1:~3~28
--110--
BCOO~I or salt
obtained by
B Procedure of
O O
S SYKES
C~3 u. S . 4 256, 733
N I
o O
S ~C~2Cl
Q~'/"CEI . G . B . 2, 0 7 0, 5 9 2
OKAY
U. S . 4, 342, 772
N ~"~
lZ3~il32~3
EXAMPLE 55
Employing one of the halo methyl esters provided
if. the preceding Example and an appropriate monobenzyl
ton f for via HOOT A C2CH2C6H5 as reactants in the
- 5 procedure of Example 3, the corresponding compound of
formula
BCooCH~R3loc=o
Charlie
is obtained wherein Al is bouncily, B and R3 are as
defined in Example 54 and A is as defined in Examples
1-3 and 9. Hydrogenolysis by the method of Example 4
provides the corresponding carboxylic acid or salt
where Al is H or Nay
Alternatively, a cat ionic salt, e.g., the sodium
salt of the compound BCOOH, is reacted with the moo-
idea ester of the acid, AWOKE, where A and B are as defined above, to directly provide the compounds of the
above formula where Al is H. The Monday esters of
the dicarboxylic acids, AWOKE, are obtained, for
example, by hydrogenolysis of the corresponding bouncily
chloromethyl divester over Pd/C catalyst and subsequent
reaction of the resulting monochloromethyl ester with
sodium iodide in acetone.
I
~23~82~
-112-
EXAMPLE 56
1,1-Dioxo-6-beta-hy~roxymethylpenicillanoyloxy-
methyl 6-lD-~2-amino-2-phenylacetamLdo~-
- penicillanoyloxymethyl trans-1,4-cyclohexane-
5dicarboxylate Hydrochloride
A. Reaction of equimolar amounts ox sodium l,l-dioxo-
6-beta-hydroxymethylpenicillanoyloxymethyl trueness-
cyclohexanedicarboxylate and iodomethyl 6-rD-C2-
[l-methyl-2-methoxycarbonyl~inylamino~-2-phenylaceet-
amido)]penicilianate in dimethylformamide by the
. - procedure of Example 20 affords the corresponding
coupled examine: l,l-dioxo-6-beta-hydroxymethylpenicil-
lanoyloxymethyl 6-tD-(2-tl-methyl-2-methoxycarbonyl-
vinylamino]-2-phenylacet~;do)]penicillanoyloxymethHal
trans-1,4-cyclohexanedicarboxylate. hydrolysis of the
amino protecting group by the procedure of Example 21
affords the title hydrochloride salt.
. In like manner the following compounds are prepared
and isolated as the hydrochloride salt of the formula
below.
R4 2 SHEA
Ox N -oCH(R3)oC=o
.. . \
O
BCoCH(R3)oC=o
where R3, R4, A and B are as defined below.
~239~8Z8
-113-
A BOO R3 R4
1,2-phenylene 6-beta-chloro- H
penicillanoyl
1,3-phenylene 6-beta-bromo- H OH
penicillanoyl
1,4-naphthalene butted- SHEA OH
penicillanoyl
(SHEA Dixie- C2H5 OCOCH2CH3
beta-hydroxymethyl-
penicillanoyl
(SCHICK Dixie- n-C H OCOCH(CH I
alpha-hydroxymethyl- 3 7 3
penicillanoyl
(SHEA 1,1-dioxo-2-beta- i-C H OH
acetoxymethyl-2-alpha- 3 7
methylpenam-3-alpha-
carbonyl
(SHEA 1,1-dioxo-2-beta- H H
chloromethyl-2-alpha-
methylpenam-3-alpha-
carbonyl
. (SHEA clavulànoyl H OH
n-C4Hg(CH3)C clavulanoyl SHEA H
clavulanoyl C2H5 OC~OCH3
No 1,1-dioxo-2-beta H H
chloromethyl-2-alpha-
ON - methylpenam-3-alpha-
carbonyl
1,4-cycloheptyl 6-beta-bromo- SHEA OH
penicillanoyl
1,3-cyclopentyl 6-beta-chloro- H OH
penicillanoyl
1,4-cyclohexyl 1,1-dioxo-6-beta H OCOCH3
hydroxymethyl-
penicillanoyl
~23~
-114-
EXAMPLE 57
Iodomethyl clavulanate, provided in Example 54, is
reacted with an equimolar amount of sodium 6- phonics-
acetamido~penicillanoyloxymethyl glutamate, provided in
S Example 17 my the method of Example 28, Part A, to
provide the coupled product of toe formula
R N C 3
I N C~2c-
BCOC~I20C=O
o
where A is (C~2)3, B is clavulanoyl and I is
C6~50C~2CO. In like manner compounds of the above
formula are obtained from the appropriate starting
materials where A, B and R are shown below.
- ~23~i~328
-115-
A BOO R2
Trans-1,4-cyclohexylene 6-beta-chloro 2,6-dimethoxy-
penicillanoyl bouncily
1,4-phenylene 6-beta-bromo phenoxyacetyl
penicillanoyl
(CUR ) C butted- Acadia-
5 2 penic~llanoyl phenylacetyl
( 3)2 1,1-dioxo-6-~eta
hydroxymethyl-
penicillanoyl
(CH3)CHCH2 1,1-dioxo-2-beta phenoxyacetyl
acetoxymethyl-2-
alpha-methylpenam-
3-alpha-caxbonyl
CH2C(COOH)CH2 1,1-dioxo-2-beta- 2,6-dimethoxy
chloromethyl-2- bouncily
alpha-methylpenam-
3-alpha-carbonyl
(SHEA cla~ulanoyl 2,6-dimethoxy-
bouncily
(SHEA clavulanoyl 2-carboxy-2-
phenylcarbonyl
~Z3b~8~3
-116-
EXAMPLE 58
Iodomethyl 6-alpha-(benzyloxycarbonylaminomethyll-
~enicillanic acid l,l-D~oxide
A. 6-alpha-~Benzyloxycarbonylaminomethyl~penicillanicc
acid l,l-dioxide - _
6-alpha-(~minomethyl~penicill~n~c acid 1,l~dioxide
(2.62 g, 0.01 motel is added to 20 ml water and 80 ml
acetone at 15-20 C., and the pi adjusted to 8 with
dilute Noah. A solution of bouncily chloroform ate U.88 g,
10 ~.011 mole in 20 ml acetone is added drops at
15-20~ C. while simultaneously maintaining the apparent
pi of the reaction between 7 and 8 by the periodic
addition of dilute Noah. The reaction mixture is allowed
to stir for 30 minutes, and is then concentrated in
vacua to remove most of the acetone. The aqueous solution
is extracted twice with ethyl acetate and the extracts
discarded. Fresh ethyl acetate C100 ml) is added to the
water layer and the pi adjusted to 2 with dilute hydra-
caloric acid, with stirring. The organic layer is
removed, washed with brine, dried over Nazi, and con-
cent rated in vacua to provide the title product.
B. Chloromethyl 6-alpha-(benzyloxycarbonylaminomethyl)-
penicillanate l,l-dioxide
The product of Part A, above, (1 g) is combined with
10 ml of ethylene chloride and 2 I of water and the
pi adjusted to 8.0 with 40% tetrabutylammonium hydroxide
over a period of 15 minutes. The ethylene chloride
layer is separated and the aqueous layer extracted with
three 2 ml portions of fresh ethylene chloride. The
ethylene chloride layers are combined, dried over
Nazi, and concentrated in vacua to yield tetrabutyl-
ammonium salt. The salt is combined with 10 ml of sheller-
iodomethane, the mixture stirred for 16 hours, and
concentrated to dryness in vacua to yield the desired
ester.
.
kiwi
owe
-117-
C. The chloromethyl ester obtained in above (0.24 g)
is combined with 3 ml of acetone and sodium iodide
(0.58 go and the mixture stirred for 16 hours. The
reaction mixture is concentrated in vacua and the
- 5 residue distributed between 7.5 ml of ethyl acetate
and 5.0 ml of water. The ethyl acetate is separated,
washed in sequence with two 25 ml portions of water and
one 25 ml portion of brine, dried over Newsweek and con-
cenirated in vacua to provide present title product.
By the above procedure the analogous compounds of
the formula below are obtained in like manner.
0 0
H So 3
C~3
I COUCH
" '3
O R
Al R3
beta-CH2NHCO2CH2C6H5 H
beta-CH(CH3)NHCO2CH2C6H5 SHEA
alpha-CH(CH3~NHC02CH2C6H5 C2H5'
alpha-CH2NHCO2CH2C6H~ c3~7
beta-CH2NHCO2CH2C6H5 SHEA
!, . . .. __. .
~23~828
--118--
F~X~PLE 5
1,1-Dioxo-6-alpha-(aminomethyl~penicillanoyloxymetthy
Adipic Acid, Sodium Salt
A. Employing bouncily adipate half ester and iodomethyl
- 56-alpha-(benzyloxycarbonylaminomethyllpenicillanatlo
l,l-dioxide as reactants in the procedure of Example 3
affords bouncily 1,1-dioxo-6-alpha-~benzyloxycarbonyl-
aminomethyl~penicillanoyloxymethyl adipate.
B. ~ydrogenolysis and reaction of the resulting
carboxylic acid with sodium-2-ethylhexanoate provides
the title sodium salt. Use of potassium 2-ethylhexanoate
affords the corresponding potassium salt.
C. In like manner employing the remaining idyllically
6-benzyloxycarbonylaminomethyl (or benzyloxycarbonyl-
aminoethyl)penicillanate l,l-dioxides provided in
Example 58, Part C, the corresponding salts of the
formula below are obtained.
O~COCHOC=O
O R Awaken
. .
- 12~i828
--119--
A Al R3
C~2 beautician
(SHEA ~eta-CH2N~2 H
trans-1,4-cyclo-
5 hexylene alpha-CH2N~ H
trans-1,4-cyclo-
hexylene beautician
1,4-phenylene beta-c~(cH3lNH2 SHEA
1,2-naphthalene beta-cHtcH3INH2 C~3
1,3-ph~nylene ~eta-C~(CH31N~2 SHEA
SHEA alpha-cH~cH3~N~2 C2H5
(SUE alpha-cH(cH3lNH2 C2H5
trans-1,4-cyclo-
hexylene alpha-cH~cH3)NE2 C2H5
(SCHICK alpha-C~2N~2 C3H7
(SHEA alpha-cHzNH2 n-C3H7
(SHEA alpha-CH2N~ 3 7
SHEA alpha-CH2NH2 3 7
trans'l,4-cyclo-
20 hexylene alpha-CH2N~ n C3H7
trans-1,4-cyclo-
hexylene beautician c~3
(SHEA beach NO c~3
(SHEA beautician c~3
(C~2)8 beautician c~3
(C 2)12 beautician c~3
SHEA beautician c~3
(Schick beautician SHEA
trans-1,4-cyclo-
30 hexylene beautician c~3
1,4-phenylene beautician c~3
123~828
-120-
EXAMPLE 6Q
6-~D-~2-Amino-2-phenylacetamido~penicillanoyloxymeethyl
1,1-dioxo-6-alpha-(aminometh~l~penicillanoyloxymetthy
,. Adipate Hydrochloride
5Iodomethyl 6-alpha-CbenzyloxycarbonylamLnomethyl~-
penicillanate 1,l-dioxide and tetrabutylammonium 6 ID
(2-benzyloxycarbony-lamino-2-phenylacetamido~]penitail-
lanoyloxymethyl adipate are coupled by the procedure of
Example 37 to afford the bis-benzyloxycarbonyl inter-
mediate which is hydrogenated over palladium-on-carbon
catalyst by the procedure of Example 40, Part B to
obtain the free base which is taken up in ethyl acetate
and acidified with ethanolic hydrogen chloride. Evapora-
lion of solvent or addition of a non-solvent such as
ethyl ether affords the title compound.
In like manner the compounds below are obtained
by the above procedure.
ON L_____ " S SHEA
I C~3
Ox N ~COCH2OC=O
O
Al O O OH A
SHEA
Ox N ~COCH2OC=O
O
1 2
where A and X are as defined in Example 54 and is
as defined in Example 57 and is R4 CHICO where R4
NH2
is as defined in Example 53.
~23~i82~ -
-121-
EXAMPLE 61
Crystalline acid of Formula I, Al R3 - H
A. l,l-Dioxo~enicillanovloxymethY1 glutaric acid
Bouncily l,l-dioxopenicillanoyloxymethyl glutamate
is subjected to hvdrogenolysis my the method of
Example PA. Aster evaporation ox ethyl acetate from
the filtrate, the residual oil is taken up in isopropanol,
the mixture stirred at 22 C. or I minutes and held
overnight at 50 C. The resulting solid is taken up in
isopropanol, filtered and washed with cold isopropanol
and hexane. The resulting crystals of l,l-dioxopenicil-
lanoyloxymethyl glutaric acid are vacuum dried at room
temperature to obtain a 63% yield, mop. 76-78 C.
B. l,l-Dioxopenicillanoyloxvmethyl dimeth~lmalonic acid
lo A solution of 10 g sodium l,l-dioxopenicillanoyl-
oxymethyl dimethylmalonate in 100 ml ethyl acetate is
treated with hydrochloric acid ~23 ml lo in 50 ml
water). The mixture is stirred, then allowed to stand.
The organic layer is separated, dried, the solvent
evaporated in vacua and the residue chromatographed on
400 g silica gel, eluding with 1:1 ethyl acetate/acetone.
The product fractions are combined and solvent evaporated.
The resulting viscous oil is dissolved in ethyl ether,
filtered to remove insoluble and the filtrate is evapo-
rated to obtain an oil which crystallizes upon screeching g of white crystals, mop. 121-123 C.
Analysis Calculated for C14HlgOgNS
C, 44.56; I, 5.07; N, 3.71.
Found: C, 44.13; H, 5.19; N, 3.65.
-
123~28
-122-
PREPARATION A
Dibenzyl dimethylmalonate
To 75 ml water containing 4.0 g sodium hydroxide
is added at 0C., 17.~ g ~0.05 mole) tetrabutylammonium
hydrogen sulfate, the mixture is stirred 15 minutes,
allowed to war. and lea ml chloroform containing
14.2 g ~0.05 motel densely malonate and 6.6 ml
(0.10 mole) methyl iodide is added. The mixture
(initial pi >12) is stirred for I minutes at which
time the mixture is pi cay 8. Stirring is continued
for ten minutes, the organic phase is separated. To
the organic layer is added another charge of 4.0 g
sodium hydroxide, 17.0 g tetrabutylammonium hydrogen
sulfate in 75 ml water and 6.6 g methyl iodide.
The resulting mixture is stirred at room temperature
for 30 minutes, the chloroform layer is separated,
dried (Nazi) and concentrated in vacua. The
resulting residual oil is triturated with 500 ml
ethyl ether, the resulting solids are filtered,
washed well with ether and the filtrate and washings
evaporated to afford 15.0 g (96%) of product which
is identified by l~_NMR spectrum.
J
123~328
-123-
PREPARATION B
Bouncily dimethYlmalonate half ester
A solution of 3.12 g L48 mole) of 85% potassium
hydroxide in 75 ml bouncily alcohol is added to
- 5 15.0 g dibenzyl dimethylmalonate on 75 ml bouncily
alcohol. The resulting solution is stirred for
60 hours, 1.5 liters of ethyl ether added and the
resulting mixture extracted twice with 100 ml
portions of water. The combined aqueous layers are
10 washed with 100 ml ether. To the aqueous layer is
added 100 ml ethyl ether and the Tory is acidified
to pi 2.5 with ON hydrochloric acid. The ether layer
is separated and the aqueous phase extracted again
with ether. The ether extracts are dried (Nazi)
15 and solvent evaporated to afford the product as a
colorless oil, 8.6 g ~81%). Of Owl (TLC, 2:1
hexane/ethyl acetate). S rupture verified by l~_NMR.
-
123~828
-124-
PREPARATION C
Chloromethyl Penicillanate l,l-Dioxi~e
A mixture of 4.66 g of penicillanic acid 1,1-
dioxide, 50 ml of dichlorome*hane and 35 ml ox
water was treated with sufficient tetra~utylammonium
hydroxide ~40% in water to give a pi of 6Ø The
dichloromethane layer was separated and the aqueous
phase extracted with fresh dichloromethane I x
50 ml). The organic layers were combined, dried
over sodium sulfate and concentrated to give 10.1 g
of the tetra~utylammonium salt of penicillanic acid
l,l-dioxide.
The above tetrabutylammonium penicillanate lo
dioxide was added to 50 ml of chloroiodomethane and
the reaction mixture allowed to stir at ambient
temperature overnight. The reaction mixture was
concentrated to half volume n vacua, and cremate-
graphed on 200 g of silica gel using ethyl acetate/
hexane as the eluant, 12 ml cuts being taken every
30 sec. tractions 41-73 were combined and concentrated
to dryness to give 3.2 g of the title compound.
The NOR spectrum (CDC13~ showed adsorptions at
1.5 (s, OH), 1.66 (s, OH), 3.42 (d, OH), 4.38 (s,
lo), 4.6 (t, lo) and 5.7 (dud, OH) ppm.
- Jo
~23G828
-125-
- PREPARATION D
Iodomethyl Penicillanate l,l-Dioxide
To a solution of 7.9 g of chloromethyl penicillin-
ate l,l-dioxide in lQ0 ml of dry acetone maintained
under a nitrogen atmosphere was added 21_0 g ox
sodium iodide, and thy reaction mixture was allowed
to stir overnight at room temperature. The reaction
mixture was concentrated in vacua, and the residue
was dissolved in 150 ml ethyl acetate and 150 ml
water. The organic layer was separated an the
aqueous layer was extracted with fresh ethyl acetate.
The organic extracts were combined, washed with water
(1 x 500 ml) and brine (1 x 50 my and dried over
sodium sulfate. Removal of the solvent gave 10.5 g
of the title product, mop. 100-102~C.
The NOR spectrum (CDC13) showed adsorptions at
1.55 (5! OH), 1.68 (s, OH), 3.5 (d, OH), 4.4 (s, lo),
4.65 (t, lo) and 6.0 (dud, OH) ppm.
lZ3~32~
--126--
PREPARATION E
Te_rabu'ylammonium 6-C2-Benzyloxycarbonyl-
amino-2-~4-hydroxyphenyl]acetamidolpenic~llanate
To a rapidly stirred mixture of 1.0 g o 6-~2-
benzyloxycarbonylamino-2-l4-hydroxyph~nyl]acetamiddo-
penicillznic acid, 30 ml of dichloromethane and
20 ml of water was added 40~ aqueous tetrabutyl-
ammonium hydroxide until a pi ox 8.Q was obtained.
Stirring was continued for 30 minutes at pi 8.0 and
then the layers were separated. The aqueous layer
was extracted with dichlorometh~ne, and then the
combined dichloromethane solutions were dried assay)
and evaporated in vacua. This afforded 1.1 g of the
title compound.
The NOR spectrum yin DMSO-d61 showed adsorptions
at 0.70-1.80 em, 34X), 2.90-3.50 (m, I 3.93 (s,
if), 5.10 (s, I 5.23-5.50 (m, I 6.76 (d, I
7.20 (d, I 7.40 (s, I 7.76 (d, I and 8.6 (a,
lo) ppm.
Tetrabutylammonium 6-(2-~4-nitrobenzyloxycarbonyl-
amino]-2-[4-hydroxyphenyl]acetamido)penicillanate is
obtained from 6-(2-r4-nitrobenzyloxycarbonylamino]-2-
[4-hydroxyphenyl]acetamido)penicillanic acid and
tetrabutylammonium hydroxide by the above method.
Tetrabutylammonium 6-rD-(2-benzyloxycarbonyl-
amino-2-phenyl)acetamido]penicillanate and tetrabutyl-
ammonium-6-[D-2-(4-nitrobenzyloxycarbonylamino)-2--
phenylacetamido]penicillanate are prepared in like
manner.
~23~i82~
-127-
PREPARATION F
Chloromethyl dozed-
phenylacetamidol]penicillanate
A solution of 12.0 g C0.03 motel 6-ID-C2-azido-
2-phenylacetamido~penicillanic acid sodium salt,
25 ml water is combined with 100 ml ethylene
chloride and lQ.17 g C0.Q3 motel tetrabutylam~onium
hydrogen sulfate. Thy mixture CUP 3-01 is adjusted
to pi 7.5 with sodium bicarbonate, toe organic layer
is separated and the aqueous layer is extracted with
2 X 100 ml ethylene chloride. The combined organic
layers are dried Nazi) and the solvent evaporated
to yield a solid residue. The residue is triturated
with ethyl acetate C300 ml), filtered, the cake
washed with ethyl acetate followed by ethyl ether and
dried under nitrogen to afford 16.5 g (89%) of
tetrabutylammonium salt.
A mixture of 12.32 g (0.02 mole) of the above
salt is combined with 70 ml chloroiodomethane and
the mixture stirred overnight at ambient temperature.
The reaction mixture is concentrated to dryness and
the residue purified by chromatography on 600 g
silica gel, eluding with 1:1 ethyl acetate/hexane by
volume to afford 8.1 g (95%) of the desired sheller-
methyl ester as a pale yellow viscous oil.
Chloromethyl 6-[2-azido-2-(~-hydroxyphenyll-
acetamido]penicillanate is obtained in live manner.
lZ3~8Z8
-128-
PREPARATION G
Iodomethyl old Acadia-
phenylacetamido)]penicillanate
In a stopper Ed flask, 1.27 g (3 mole) sheller-
- 5 methyl ED ~2-azido-2-phenylacetamido~]penicillanate,
20 ml acetone and 2.25 g. (15 Molly sodium iodide
are combined. The mixture is stirred overnight at
room temperature, the resulting suspension is concern-
treated, the residue taken up in 100 ml ethyl acetate,
10 washed with 3 x 30 ml water, 1 x 30 ml brine, dried
(Nazi) and concentrated in vacua to a pale yellow
roam. The foam is purified by chromatography on
75 g silica gel, eluding with 1:1 by volume ethyl
acetate/hexane, taking 20 ml fractions. tractions
11-15 are combined and concentrated in vacua to
afford isle g C76~) of the desired product as a pale
yellow gum.
~23~8Z~3
-129-
PREPARATION H
Bouncily chloromethyl adipate
To 350 ml of bromochloromethane cooled to ODE.
is added 67 g (~.14 motel tetrabutylammonium salt ox
- 5 bouncily adipate half ester and the mixture is stirred
overnight at 0~C. then allowed to warm to room
temperature. The excess bromochloromethane is
evaporated in vacua, 400 ml ethyl ether is added to
the residue and the mixt~Ie is stirred to form
crystals ox tetrabutyl2mmonium bromide. Toe crystals
are removed by filtration, washed with ethos, stirred
with ethyl acetate ~300 my for one hour and no-
filtered and washed with ethyl acetate. The combined
filtrates are evaporated in vacua, the residue purified
by chromatography on silica gel Of kg), eluding with
2:1 hexane/ethyl acetate, to yield 19.1 g (48%) of
the title compound. lH-NMR (CDC13~ ppm (delta):
1.58-1.9 (m, OH), 2.2-2.62 (m, OH), 5.13 (s, OH),
5.68 (s, OH), 7.38 (s, I
the remaining bouncily chloromethyl esters of the
formula below are prepared in like manner:
O O
C6H5C~20C A COCH2Cl
where A is as defined in the Examples.
,
12~6828
-130-
PREPARATION I
6-alpha-Hydroxymethylpenicillanic
Acid Cellophane
A. Bouncily 6-bromo-6-h~vdro~y~e hylpen~cillanate
A solution of 44.9 g of bouncily 6,6-dibromopenic;l-
lunate in 60Q ml of dry tetrahydrofuran was cooled to
-78 C. and 56.4 ml of t-butylmagnesium chloride was
added drops with vigorous stirring under an inert
atmosphere while maintaining the temperature at -60 C.
After stirring 30 minutes at -7~ C. the solution was
treated with gaseous- formaldehyde in a stream of
nitrogen until five molar equivalents had been added.
The reaction was quenched at -78 C. my the addition of
5.7 ml of acetic acid drops over a period of 25
minutes. The reaction solution was allowed to warm to
room temperature and was concentrated in vacua. To the
residue was added 200 ml of water and 200 ml of ethyl
acetate. The organic layer was separated and the water
layer extracted again with ethyl acetate. The organic
phases were combined, washed successively with water
(200 ml), 5% aqueous sodium bicarbonate (200 ml) and
brine (200 ml) and dried over magnesium sulfate. Removal
of the solvent under reduced pressure provides 38.2 g
of the desired product, epimeric at C-6.
B. Bouncily 6-bromo-6-hydroxymethylpenicillanate cellophane
To a solution of 500 my of bouncily 6-bromo-6-hydroxy-
methylpenicillanate in 30 ml of ethylene chloride, cooled
in an ice bath at 0-~ C., was added portions 633 my
of 85~ m-chloroperbenzoic acid over a period of
20 minutes. The reaction mixture was allowed to warm to
room temperature and allowed to stir for about 40 hours.
The solvent was removed in vacua and the residue treated
with water and ethyl acetate. The pi of the mixture was
adjusted to 7.4 with a saturated sodium bicarbonate
lZ3~28
-131-
solution, and the organic phase separated and treated
with 30 ml of fresh water. The pi of the mixture was
adjusted to 8.2 with saturated sodium bicarbonate and
the ethyl acetate layer separated and washed with a
saturate sodium bicarbonate solution and a brine soul-
lion. The ethyl acetate layer was separated, dried
over magnesium sulfate and evaporated to an oil, 500 my.
C. 6-alpha-Hydroxymethylpenic-;llanic acid cellophane
A suspension of 5Q0 my ox 5% palladium-on-charcoal-
and 500 my of bouncily 6-bromo-6-hydroxymethylpenicillanate
cellophane in 2~0 ml ox 50~ water-methanol was shaken in a
hydrogen atmosphere at an initial pressure of 48 psi for
20 minutes. An additional 500 my of fresh catalyst was
added and the hydrogen pressure adjusted to 51 psi.
After one hour of shaking the catalyst was filtered and
the methanol removed in vacua. The pi of the residual
solution was adjusted to 8.0 and extracted with ethyl
acetate. The aqueous layer was acidified to pi 2 with
ON hydrochloric acid and the product extracted with ethyl
acetate. Removal of the solvent gave 100 my of the
desired product, which was crystallized from chloroform-
ethyl acetate containing a drop of dim ethyl sulfoxide,
mop. 211-212 C(dec.~.
The NOR (100 MHz) spectrum (D~SO-D6) showed absorb-
lion at 4.93 (d, I J=2~z), 4.27 us, I 3.76 (m, OH),
1.5 (s, OH) and 1.4 (s, I ppm.
~236828
-132-
PREPARATION J
Bouncily 6-alpha-bromo-6-beta-(benzyloxv-
carbonylaminomethyllpenicillanate and
6-beta-bromo-6-alpha-(~nzyloxycarbonyl-
aminome~hyl~Penicillanate
To a solution of bouncily 6,6-di~romopenicillanat
~108.73 g, 0.242 mole in 600 ml dry tetrahydrofuran
OF cooled to -78 C., was added an ether solution
of methyl magnesium bromide C83.5 ml of 2.9~. After
stirring for 15 minutes at -78 C., a solution of
benzyloxycarboxamidomethyl acetate ~27 g, 0.121 mole) in
200 ml dry TEN was added over 10 minutes. After
stirring for an hour at -78 C., the reaction was
quenched by the addition of 14.52 ml of acetic acid. The
mixture was warmed to room temperature and volatile
removed in vacua at less than 35 C. Ethyl acetate
was added to dissolve the residue, and the solution
washed with water (100 ml), aqueous Nikko ~100 ml),
and 2 x 100 ml water, then dried over Nazi and
concentrated in vacua to 113 g of oily product. The
oil was column chromatographed on 1.2 kg silica gel,
eluding first with 6 liters of 1:1 hexane:chloroform
and then with chloroform. The first 6 liters of
equate was discarded. Further equate was collected
25 in 25 ml fractions. Fraction numbers 181-190 were
concentrate. The pnmr spectrum of the residue in
CDC13 revealed ensoul 6-alpha-bromo-6-beta-(benzyloxy-
carbonylaminomethyl)penicillanate: deltas 1.37
I s), 1.57 (OH, s), 3.86 I d, J = 6~z), 4.42
30 lo s), 5.06 OX s), 5.12 (OH, s), 5.52 I s),
7.25 (10~, s). Fraction numbers 201-249 were concern-
treated and the pnmr spectrum of this residue in CDC13
~Z3~8~3
-133-
revealed bouncily 6-beta-bromo-6-alpha-~benzyloxy-
carbonylaminomethyl)penicillanate: delta~TMS 1.36
(OH, s), 1.60 (OH, s), 3.90 I d, J easily, 4.47
(lo, s), 5.07 (2X, so, 5.14 (OH, so, 5.40 Clue, t, J -
6.2), 5.47 I so, 7.28 C5H~ sly 7.30 C5~, so. The
product from fraction numbers 171-24Q was combined
and concentrated to 22 g of foam and used in the
next experiment.
REPARATION R
Bouncily 6-beta-(Benzyloxycarbonyl-
aminomethyl)~enicillanate
To a solution of title products (epimeric mixture)
of Preparation J ~22 g, 0.0413 mole) in 100 ml Bunsen
was added tri-n-butyltin hydrides (32.7 ml, Owe mole).
The mixture was reflexed under No for 2 hours, concern-
treated in vacua to an oil and the oil triturated 4 x
100 ml hexane. the residual viscous oil was taken up in
70 ml of ether, from which title product crystallized
over 1 hour ~8.1 g in two crops] pnmr/CDC13/delta/TMS:
1.37 (OH, s), 1.57 (OH, s), 3.58 (OH, m), 4.34 (lo, s),
5.04 (OH, s), 5.12 (OH, s), 5.33 US, d, J = 4Hz], 7.32
(lo, s).
Bouncily 6-alpha-(benzyloxycarbonylaminomethyl)-
penicillanate is recovered by concentration of mother
liquors and chromatography.
123G828
-134-
PREPARATION L
ensoul 6-beta-(Benzyloxycarbonylaminomethyl2~-
penicillanate l-alpha-Oxide and
Bouncily 6-beta-(Benzyloxycarbonylaminomethyl~-
5penicillanate l-beta-Oxide -
To a solution of title product ox thy preceding
Preparation C4.54 g, 0.01 mole in 7Q I ox ethyl acetate
was added m-chloroperbenzoic acid ~2.02 g, 0.01 mole
in 30 ml ethyl acetate. Toe mixture was-stirred 30
minutes at room temperature, washed 1 x 50 ml saturated
Nikko and 2 x So ml ~2' dried over Nazi and
concentrated in vacua to a viscous oil. The oil was
dissolved in 50 ml of ether and 10 ml SCHICK and
crystallization of title alpha-oxide induced by
screeching ~2.2 g, mop. 123-124 C., pnmr~CDC13/
delta/TMS 1.22 (OH, s), 1.51 I 52, 3.7 I m),
4.34 (lo, s), 4.63 (lo, d, J = 4Hz), 5.13 I s),
5.22 (OH, s), 5.50 (lo, my, 7.34 OH s), 7.40 (OH, so
Concentration of mother liquor to dryness in vacua
20 gave the title beta-oxide as a viscous oil ~2.5 g;
pnmr/CDC13/delta/TMS 1.05 (OH, 52, 1. 60 (OH, sly 3.8
(OH, m), 4.63 I s), 4.73 I d, J = 4~z), 5.13
I s), 5.23 (OH, q), 5.70 I m), 7.35 (OH, s),
7.39 I s)].
~23~82~
-135-
PREPARATION M
Bouncily 6-alpha-(Benzyloxycarbonylamino-
methyl)Penicillanate l-beta-Oxide
To title beta-oxide of the preceding Preparation
(2.3 g, 4.g Melissa in lQ0 ml SCHICK was added 1,5-
diazabicyclo~4.3.0]non-5-ene CDBN, 0.6Q7 g, 4.9
Melissa. The mixture was stirred at room temperature
for 15 minutes, diluted with 5Q ml lo Hal, and the
layers separated. The organic layer was washed 2 x
50 ml H20, dried over Noah and concentrated i
vacua to an oil C2.3 go. The oil was column cry-
matographed on 100 g silica gel, eluding with 4:1
C~C13:ethyl acetate in 20 ml fractions. Fractions
41-70 were combined and concentrated in vacua to
yield title product as a viscous oil ~0.9 g; pnmr/
CDC13/TMS 1.03 I s), 1.60 (OH, s), 3.67 I m),
4.46 (lo, s), 4.88 (lo, m) 5.08 (OH, so, 5.17 (OH,
q), 5.39 (lo, m), 7.32 (OH, s), 7.37 (OH, s)].
î23~1!328
-136-
PREPARATION N
Bouncily 6-beta-~Benzyloxycarbonylamino-
methYl)penicillanate l,l-Dioxide
To a solution ox title product of Preparation K
(8.0 g, 0.0176 mole in 200 ml ethyl acetate cooled
to 0-5c C. was added m-chloroperbenzoic acid C10-68 g,
0.0528 mole. rho mixture was warmed to room temper-
azure, stirred for 6 hours, retooled to 0-5~ C. and
diluted with 50 ml ox saturated Nazi. The organic
layer was separated, washed 2 x 50 ml saturated
Nikko and 2 x 50 ml ~2' dried over Nazi and
concentrated on vacua to a viscous oil ~8.6 go. The
oil was chromatographed on 250 g silica gel, eluding
with 19:1 CHC13:ethyl acetate in 25 ml fractions.
Fractions 44-150 were combined and concentrated in
vacua to yield title product as a white gummy foam-
t7.6 g; pnmr/CDC13/delta/TMS 1.25 (OH, so, 1.49 (OH,
s), 3.98 I m), 4..45 I s), 4.59 I d, J =
4~z), 5.09 OH s), 5.19 I Al, 5.36 (lo, by), 7.36
(lo, s)].
~23G1~28
-137-
PREPARATION O
Bouncily 6-alpha-(Benzyloxycarhonyl-
aminomethyl~penicillanate l,l-Dioxtde
By the procedure of Preparation M, the title
l,l-dioxide of the preceding Preparation ~3.3 g,
6.79 Melissa was converted to present title product
~3.1 g crude, and purifies by column chromatography
on 150 g silica gel, eluding with 1:9 ethyl acetate:CHC13
in 20 ml fractions. tractions 26-37 were combined end
concentrated in vacua to yield purifies title product,
as a viscous oil which crystallized on standing rl.9 g;
mop. 112-113 C.; pnmr~CDC13/delta/TM5 1.20 (OH, s),
1.49 (OH, s), 3.65 (OH, my, 4.32 lo s), 4.59 (if, m),
5.07 (OH, s), 5.14 (OH, q), 5.30 lo by), 7.32
(lo, so
Present title product was also obtained by the
further oxidation of the title product of Preparation
with excess m-chloroperbenzoic acid according to the
method of Preparation N.
-`
~23~828
-138-
PREPARATION P
6-beta-cAminomethyll-
penicillanic Acid l,l-Dioxide
Title product of Preparation N Of. q go, TEN ~40 mull,
- 5 HO (40 mull and 10% Pd/C ~1.9 go were camkined and
hydrogenated at 50 prig for 1 hour. Catalyst was
recovered my filtration and EN removed from the
filtrate in assay. The aqueous layer was washed with
30 ml ethyl acetate, freeze dried to a white powder
and a first crystalline crop C0.26 go obtained by
trituration of the powder with 5 my water. A second
crop (0.14 go crystallized on addition of 10 ml of
acetone to the mother liquor and a oh; rod crop (0.35 go
by evaporating the second mother liquor to 2 ml and
adding 50 ml of acetone. Total yield of title
product was 0.75 g [pnmr/250 MXz/D20/delta/DSS 1.47
(OH, s), 1.59 I s), 3.74 I m), 4.36 I id,
J = 4, 5.5Hz), 4.45 (lo, so, 5.17 I d, J = 4Hz)].
To obtain the potassium salt, title product
(1.0 go is dissolved in 30 ml of water and cooled in
an ice water bath, one equivalent of lo KOCH is added
drops to the well-stirred solution, and the
resulting solution freeze dried.
lZ3~Z~
-139-
PREPARATIOLi Q
6-alpha-(Aminomethyll-
enicillanic Acid l,l-Dioxide
By the method of toe preceding experiment, title
product of reparation O a. 7 go was converted to
present title product, except that crystalline product
was obtained directly by concentration in vacua follow-
in the ethyl acetate extraction l a .7 g; ~nmr~250
MHz/D2O/DSS 1.44 Lo so, 1.5~ C3~, so, 3.63 (OH, d,
J = 5.5Hz~ 4.07 Clue, id, J = 2, 5.5Hz2 4.31 Clue, so,
5.06 lo d, J = I
To obtain the hydrochloride salt, product
(0.7 g) is dissolved in water C30 mull, an equivalent
of dilute hydrochloride acid is addçd.dropwise, and
lo the resulting solution freeze dried.
To obtain the sodium salt, product (0.7 g) is
dissolved in water (30 ml2. At 0-5~ C., one equivalent
of dilute sodium hydroxide is added with vigorous
stirring and the solution freeze dried.
~23~82~
-140-
PREPARATION R
Employing l-benzyloxycarboxamidoethyl acetate in
place of benzyloxycarboxamidomethyl acetate in the
procedure of Preparation J affords a mixture of isomers
- 5 of bouncily 6-bromo-6-Cl-benzyloxycarboxam~doethyl~-
penicillanate which are separated as described in
reparation J. The purified products are then carried
through the procedures ox Preparations R, N, O, P and
Q to afford the corresponding 6-alpha and 6-beta isomers
of the compound below.
, 2 \/
KIWI C~CCH3
Ox N KIWI
.
:
~3~2~ -
-141-
PREPARATION S
.
Potassium 2-beta-Chloromethyl-2-alpha-methyl-
3-alpha-carboxylate l,l-Dioxide
A. 6-al~ha-Bromo~er.icillanic acid l-oxide
6-alpha-Bromopenicillanic acid N,N'-dibenzyl-
ethylenediamine (pBEDI salt Nature, 201, 1124 CLUE;
J. Org. Chum., 27, 2668 C1~62~], 3Q g C37.5 Molly is
dissolved in 330 ml ethylene chloride and cooled to
0 C. Slowly, 13 ml (156 Molly concentrated ~ydro-
caloric acid is added and the mixture stirred for
10 minutes at 0-5 C. The precipitated DBED-~Cl salt
is removed by filtration, washing with 150 ml ethylene
chloride. As quickly as possible the combined filtrate
and washings are washed with cold water (60 ml), stirring
for five minutes before separating layers. The organic
phase is concentrated _ vacua to 65-80 ml and the
concentrate cooled with stirring to 5 C. Over a
30 minute period, 13 ml (86.9 mole) of 40% parasitic
acid is added at 15 to 18 C. (ice bath). The resulting
mixture is stirred two hours at 0-5 C., filtered and
the cake washed with 5 C. water (10 ml), ethylene
chloride at 0-5 C. and Hutton. The washed solid is
dried to obtain 16.26 g (73%) of bromosulfone.
B. ~-Nitrobenzyl 6-alpha-bromopenicillanate l-oxide
To a solution of the product of Part A, 12 g
(0.04 mole) in 100 ml acetone is added 7.5 g ~0.041
mole) potassium 2-ethylhexanoate. The precipitated
salt is collected by filtration, washed with cold
acetone and air dried. The potassium salt (10 go is
dissolved in 75 ml N,~-dimethylacetamide and 7.8 g
(0.04 motel ~-nitrobenzyl bromide is added and the
mixture. stirred at 23 C. 'or 24 hours, diluted with
~23~Z8
-142-
water (500 ml) and extracted with ethyl acetate. The
organic extracts are washed with water, dried (McCoy)
and evaporated at reduced pressure to afford an oil that
crystallizes upon standing. After slurring with ether
and filtering, 9 g (70%) of the ester is obtained,
- mop. 124-125 C. (Dick.
C. ~-Nitrobenzyl-2-beta-chloromethyl-2-alpha-methyl
6-bromopenam-3-alpha-car~oxylate
A solution of 5 g (0.012 motel of the above ester
in 120 ml an hydrous Dixon is heated at reflex under
- nitrogen with 1.5 g (0.012 motel quinoline and 1.6 g
(0.012 mole) bouncily chloride for 4 hours. The mixture
is diluted with 600 ml water and extracted with ethyl
acetate. The extracts are washed with I sodium
bicarbonate solution, 5% phosphoric acid and finally
with water. The organic layer is dried (McCoy) and the
solvent evaporated. The residual oil is washed with
ethyl ether and cold Tulane to obtain crystals, 3.5 g,
mop. 130-135 C. (doe.).
D. ~-Nitrobenzyl 2-beta-chloromethyl-2-alpha-methyl-
6-bromopenam-3-alpha-carboxylate l-oxide _ _
To a solution of 1 g (0.0022 mole) of the product
of Part C, in 50 ml ethylene chloride is added 473 my
(0.0022 mole) m-chloroperbenzoic acid and the solution
stirred at 23 C. for three hours. The solvent is
evaporated to 20 ml, the concentrate diluted with Hutton
(50 ml) and the solvent decanted. The residue is
slurries with ethyl ether to afford crystals, 250 my
(24%) mop. 136-137 C. (doe).
- ~23~28
-143-
E. To a solution ox 7 g ~0.015 motel of the product
ox Part D in 150 ml ethyl septet is added a suspension
of g of 30% palladium on diatomaceous earth and 2.8 g
sodium bicarbonate in 150 ml water. The mixture is
hydrogenated at 50 psi (3.52 kg/cm2~ for three hours.
The mixture is filtered, the aqueous filtrate is
separated and treated with 1.5 g potassium permanganate
in 50 ml water. The mixture is stirred for one hour,
250 my sodium bisulfite added and filtered. The filtrate
is adjusted to pi 2 with concentrated hydrochloric acid
and lyophilized to give an amorphous powder. The powder
is extracted with ethyl acetate, the extracts concern-
treated to 20 ml and diluted with 100 ml Hutton to
precipitate solid 2-beta-chloromethyl-2-alpha-methyl-
penam-3-alpha-carboxylic acid l,l-dioxide. The collected
acid is dissolved in acetone, treated with solid poles-
slum 2-ethylhexanoate and the precipitated crystalline
title compound collected by filtration, 170 my, mop.
140 C. (doe.).
20 Analysis: Calculated for C H Clarence
8 7
C, 28.27; H, 3.24; N, 4.12.
Found: C, 28.27; H, 3.69; N, 3.84.
lH-NMR (DUO) ppm (delta): 1.68 (s, OH), 3.2-3.9 (m,
J 2~z, J 4Hz, J 6Hz, I 4.0-4.4 (m, OH), 4.3
(s, lo), 5.02 (dud, J 4Hz, J 2Hz, lo
