CA1236828A - Tetrabutylammonium 6-¬d-(2-¬1-methyl-2- methoxycarbonylvinylamino|-2-phenyl- or -2-¬4- hydroxyphenyl|acetamido)|penicillanate - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Disclosed herewith is tetrabutylammonium 6-[D-(2-[1-methyl-2-methoxycarbonylvinylamino]-2-phenyl- or -2-[4-hydroxyphenyl]acetamido)]penicillanate, useful as an intermediate for producing antibacterial agents. The salt may be produced by treating 6-(2-amino-2-phenyl- or -2-[4-hydroxyphenyl]acetamido)-penicillanic acid with tetrabutylammonium hydroxide, followed by the treatement with methyl acetoacetate.

Description

~Z:~828 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 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.

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 So O ""

in which R is Al in which Al is l-methyl-2-methoxyearbonylvinylamino.

~2;36~3Z8 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 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 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 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 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 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 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-R NO S SUE
C~3 I N Rococo , O R3 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 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 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=\

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

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 1. PCOOM + XCH20CO PCOOCH20CO
Al A A

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 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 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 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~

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

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 C~3 o' N Rococo ,. .3 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

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\

(II, R = C6H5CH2)(II, Al = I) IT

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 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 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 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

~Z36~28 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~

R4 -CHICANO S 'EYE

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 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 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~

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 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 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~

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 - 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.

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.

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 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 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 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 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 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 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 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 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~

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 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 (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 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 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~

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 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.

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:

SHEA SHEA
C(CH3~2 SHEA
(SHEA CH(CH3~2 (SHEA C~3CH2CH2 ..

1236~28 (SHEA SHEA
(SHEA C SHEA
(CH3CH2)2C CH~CH3~2 1,2-C6H SHEA
1,3-C6H4 SHEA
1,4-C6H4 C~3C~

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

Of A

(V) R OOZE
R SCHICK , No or R

:~2368Z8 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~

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 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

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 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 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 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~

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~

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

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 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 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.

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).

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

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

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 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 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 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 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 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

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 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 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 .

3 I o - ox N ~COCH20C

~CC1l2 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 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 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) H
No HO ON

H . CH2cH(c6H52cH2 HO . CH2CH(COOH)C~2 OCOCH3 (CH2llocH(c6Es2cH2 H ,C(CH32(CH2C6H5) HO ~CHCH2CH2C6H5 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 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 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 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 A SHEA

o where A is as defined in Example 4 and X is Of or I.

issue 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 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.

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 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~

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

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.

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

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.

Ox N ~COOC~20C

Go I' PA

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 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.

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 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 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 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 O O A

C~3 where R4 is as defined in Example 36 and A is as defined in Examples 1-4 and 36.

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

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).

!

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 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~

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

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~

-- 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.

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 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 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

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 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~

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 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~

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 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 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

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 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 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 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~

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.

Ox N -oCH(R3)oC=o .. . \

O
BCoCH(R3)oC=o where R3, R4, A and B are as defined below.

~239~8Z8 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~

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 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 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 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 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.

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 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 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 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

where A and X are as defined in Example 54 and is as defined in Example 57 and is R4 CHICO where R4 is as defined in Example 53.

~23~i82~ -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 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 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 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 - 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~

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~

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 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 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 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 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 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 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.

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~

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 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 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 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~

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~

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~ -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 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 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 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

Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing tetrabutylammonium 6-[D-(2-[1-methyl-2-methoxycarbonylvinylamino]-2-phenylacetamido)]-penicillanate, which process comprises treating 6-[D-(2-amino-2-phenylacetamido)]penicillanic acid with tetrabutylammonium hydroxide, followed by the treatment with methyl acetoacetate.

2. A process according to claim 1, wherein the final product is crystallized.

3. Crystalline tetrabutylammonium 6-[D-(2-[1-methyl-2-methoxycarbonylvinylamino]-2-phenylacetamido)]penicillanate.

4. A process for producing tetrabutylammonium 6-[D-(2-[1-methyl-2-methoxycarbonylvinylamino]-2-[4-hydroxyphenyl]acet-amido)]penicillanate, which process comprises treating 6-(2-amino-2-[4-hydroxyphenyl]acetamido)penicillanic acid with tetrabutylammonium hydroxide, followed by the treatment with methyl acetoacetate.

5. A process according to claim 4, wherein the final product is crystallized.

6. Crystalline tetrabutylammonium 6-[D-(2-[1-methyl-2-methoxycarbonylvinylamino]-2-[4-hydroxyphenyl]acetamido)]-penicillanate.

7. A process for producing tetrabutylammonium 6-[D-(2-[1-methyl-2-methoxycarbonylvinylamino]-2-phenyl- or -2-[4-hydroxyphenyl]acetamido)]penicillanate, which 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.

8. A process according to claim 7, wherein the final product is crystallized.

9. Crystalline tetrabutylammonium 6-[D-(2-[1-methyl-2-methoxycarbonylvinylamino]-2-phenyl- or -2-[4-hydroxyphenyl]-acetamido)]penicillanate.