CA1089470A - Oxazolidine compounds - Google Patents

Abstract

A B S T R A C T
Compounds represented by the following formula prepared from 6-aminopenicillanic acid are key intermediates in a stereo-specific synthesis of 1-oxadethiacephalosporins, highly active antibiotics:

Description

This invention relates to a new synthetic route along the reactions sequence of the following chart for preparing highly bactericidal l-oxadethiacephalosporins from penicillins, and literally unknown intermediates thereof.

~COA

2 ~ 5 CH3 (1) . ~ ~ CH3 ~ ) >

O ~ CH3 O
COB COB

COA CO~ :
COA
CONH ~ CH (3)~ ~ CH3 (4) ~ ~,CH3 N-C=C < 3 O 1 CH3 I \ CH3 CO~ ' ' Acyl- ~ o CH Diazoketone synthesis, Grignard ~ 3 ._ _ O ~L--N-C=C~ reaction~ or the like reactions ; `~
COB

COCHQZ

Acyl- ~ OEI reducing Acyl- ~ ocH2cocHQz f 3 ~-f-c~ 3 COB ` COB

._-- Acyl-~
I
O ~N~CHQZ
COB
(wherein COA and COB each is carboxy or protected carboxy;

Hal is a halogen; . : :

Q is hydrogen, lower alkyl or aryl; and ~ :

Z is a hydrogen or nucIeophilic group) l-oxadethiacephalosporins have been synthesized from penici-llins by Saul Wolfe et al.: Canadian Journal of Chemistry, Volume ' .

V1~3'~

52, 3996 (1974); and by total synthesis in Journal of Heterocyclic Chemistry, Volume 5, 779 (1968) by J.C. Sheehan and M. Dadiq;
German Patent Application OLS No. 2,219,601 (1972) and Journal of American Chemical Society, Volume 96, 7582 (1974).
The present inventors have found some promising l-oxadethia-cephalosporins and explored a method for producing same.
However, all the methods referred to above were not practical, because of low overall yield, some by-products separable only difficulty, and long steps to be elaborated.
In order to avoid the formation of sterochemical isomers as by-products, the present inventors conceived a stereoselective synthetic method for preparing said l-oxadethiacephalosporins.
The method, the embodiment of this invention, is disclosed hereunder in this specificatlon.
The novel intermediates for preparing l-oxadethiacephal-osporins are shown by the following formula:
- COA
ICOA

~ ,CH3 CONH ~ ~Hal N 'CH ; CH3 (I) COOR (II) COB

COA COX
~5 COH \ CH3 CO~ ~ CE3 ~ (II) (IV) ~V~9fl~(~

[wherein COA and COB each is carboxy or protected caxboxy;
CoX is carboxy, protected carboxy including halocarbonyl, or a gxoup of the formula: -COCQ=N2 or ~COCHQ-Z (in which Q is hydrogen, lower alkyl or aryl; Z is a hydrogen or nucleophilic group);
Hal is halogen;
R is lower alkyl or aralkyl; and Y is hydrogen or acyl].
The GrouP R is Compound I
The lower alkyl for R includes straight, branched, or cyclic lower alkyl optionally substituted by halogen. Preferable lower alkyl groups are those containing 1 to 8 carbon atoms. Represen-tatives of the specific lower alkyl include mèthyl, ethyl, iso- -propylg butyl, isobutyl, t-butyl, pentyL, l-methylcyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclohexyl, cycloheptyl, chloromethyl, chloroethyl, bromoethyl, :iodoethyl, trichloroethyl, chlorocyclohexyl, chlorocyclopentyl, bromocycloheptyl, and bromo-octyl. The lower aralkyl for R includes mono-, di-, or tricyclic aralkyl groups optionally substituted by an inert group (e.g.
lower alkyl, haloalkyl, cyano, aminoalkyl, hydroxy, alkoxy, acyl-oxy, aralkoxy, nitro, or halogen). Preferable aralkyl groups con-tain from 6 to 20 carbon atoms. Representatives of the speaific aralkyl include benzyl, methoxybenzyl, nitrobenzyl, diphenylmethyl, di-(p-methoxyphenyl)methyl, trityl, phthalidyl, tolyl, xylyl~
dihydroanthryl, anthrylmethyl, furylmethyl, thienylmethyl, q:uin--:
olylmethyl, pyridylmethyl, pyrimidylethyl, and isoxazolylpropyl. ~ ~ ~

Most preferable R are Cl to C3 alkyl and chloroalkylg benzyl, ~ -methoxybenzyl, nitrobenzylg diphenylmethyl, and tolymethyl.

Haloqen Hal in ComPound II

The halogen for Hal is chlorine~ bromine, or iodine~ in which ~U13~70 chlorine is the most preferable.
Acyl qroup for Y in Compound IV
The acyl group for Y includes a monovalent acyl group derived from inorganic or organic acid and preferably those constituting the side chain of natural or synthetic penicillins or cephalospor-ins reactive group if any can be protected in a conventional manner.
Representative acyl group can be selected from the following groups: -1) Cl to C10 alkanoyl;
2) Cl to C5 haloalkanoyl;

3) azidoacetyl or cyanoacetyl;

4) acyl groups of the following formuia:
Ar-cQ Q2_Co-[in which Q and Q each-i~ hydrogen or methyl and Ar is phenyl, dihydrophenyll or mo~ocyclic heteroaromatic group containing from 1 to 4 hetero ring atoms selected from ~, o, and/or S atoms, and each can optionally be substituted i by an inert group [e.g. Cl to C5 alkyl, trifluoromethyl, cyano, aminomethyl, optionaliy protected carboxymethylthio, carboxy, hy~roxy, Cl to C3 alkoxy, Cl to C10 acyloxy, C7 to C10 aralkoxy, chlorine~ bromine, iodine, fIuorine, nitro]: i

5) (4-pyridon-1-yl)acetyl or (2-iminothiazolin-4-yl)acetyl;

6) acyl groups of the following ormula: -A~-G-CQlQ2-Co-in which Ar, Q , and Q are defined above and G is O or S atom]; ~ :`

7~) acyl groups of the following formula:
AR-CHT-CO- .
0 lin which Ar is as defined above and 0 1'~
T is i) hydroxy or Cl to C10 acyloxy;
ii) carboxy, C2 to C7 alkoxycarbonyl, C2 to C15 aralkoxycarbonyl, Cl to Cl~ aryloxycarbonyl, Cl to C7 alkanoyloxy-Cl to C3 alkoxycarbonyl, S cyano, Or carbamoyl; or iii) sulfo or Cl to C7 alkoxysulfonylJ;

8) acyl groups of the following formula:
Ar-fH-C0 W -~-W .
in which Ar is as defined above and W and W each is hydrogen or amino substituent ~ -[including C2 to C10 alkoxycarbonyl, C3 to C10 cycloalkyl- ~`
C2 to C3-alkoxycarbonyl~ C5 to C8 cycloalkoxycarbonyl, Cl to C4 alkylsulfonyl-Cl to C4-alkoxycarbonyl, halo-Cl to C3-alkoxycarbonyl, Cl to C15 aralkoxycarbonyl, Cl to C10 alkanoyl, ' or C2 to C15 aroyl, each optionally substituted by an lnert ~ -group (e.g. hydroxy, Cl to C5 alky]., Cl ko C10 alkanoyloxy, halogen, Cl to C3 hydroxyalkyl, trifluoromethyl); pyronecar-bo~yl, thiopyronecarbonyl, pyridonecarbonyl, carbamoyl, guanidinocarbonyl, optionally substituted ureidocarbonyl (e~g. 3-methyl-2-oxoimidazolidin-1-ylcarbonylJ 3-methane-~ulfonyl-2-oxcimidazolidin-1-ylcarbonyl, 3-methylureidocar-bonyl, l-methylureidocarbonyl), optionally substituted amino-oxalylcarbamoyl (e.g. 4-methyl-2,3-dioxopiperazin-1-ylcar-bonyl~ 4-ethyl-2J3-dioxopiperazin-1-ylcarbonyl) optionally substituted thioureidocarbonyl equivalents of above ureido- ~
1 2 ~ -carbonyl-or aminooxalylcarbamoyl], or W , W , and the nitrogen atom combined together represent phthalimido, male-imido, or enamino derived rom enolizable carbonyl compound (e.g. C5 to C10 acetoacetates, C4 to C10 acetacetamides, ~-acetoacetanilides, acetylacetone, acetoacetonitrile, a-acetyl-r-~utyrolacetone, 1~3-cyclopentanedione);

9) acyl groups of the ~ollowing formula:
Ar ~ -CO-NOE , (in which Ar is defined above and E is hydrogen or Cl to C5 alkyl);

10) 5-aminoadipoyl, N-protected 5-aminoadipoyl tprotected by e.g. Cl to C10 alkanoyl, up to C10 aralkanoyl, C2 to Cll aroyl, Cl to C5 haloalkanoyl, or C~ or Cll alkoxycarbonyl), or 5-aminoadipoyl protected at the carboxy (protected by e.g.
Cl to C5 alkyl, C2 to C21 aralkyl, up to C10 aroyl, C2 to C10 trialkylsilyl, C2 to C5 dialkyl-Cl to C5-alkoxy silyl, .
and each protecting group for amino or carboxy can optionally be substituted by Cl to C5 alkyl, Cl to C5 alkoxy, halogen, or nitr o and

11) acyl groups of the following formula:
L-O-CO-Lin which ~ is an easily removable and optionally substituted Cl to C10 hydrocarbyI group (e.g. t-butyl, l,l-dimethylpxopyl, .,_ .
cyclopropylmethyl, l-methylcyclohexyl, isobornyl, 2~Cl to C2-alkoxy-t-butyl, 2,2,2-trichloroethyl, benzyl, naphthylmethyl, p-methoxybenzyl, pyridylmethyl, diphenylmethyl)3.
Typical examples of Ar in said definitlons include furyl, thienyl, pyrryl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thiatriazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidyl, pyrazi~yl, pyridazinyl, triazinyl, dihydrophenyl, each optionally .

~ 0 be substituted by halogen, Cl to C5 al]cyl, hydroxy, C to C5 acyl-oxy, C7 to C15 aralkoxy e.g. benzyloxy, methoxybenzyloxy, amino-benzyloxy), aminomethyl, Cl to C5 alkoxy and C7 to C12 aralkoxy-carbonyl.
Representatives of the monovalent specific acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, t-valeryl, hexanoyl, heptanoyl, octanoyl, cyclopentylcarbonyl, cyclopentylacetyl, cyclohexylcarbonyl, cyclohexylacetyL, cyclo-hexylpropionyl, cyclohexadienylcarbonyl, cyclohexadienylacetyl, cycloheptylcarbonyl, cycloheptylacetyl, cycloheptylpropionyl, chloroacetyl, chloropropionyl, fluoroacetyl, bromoacetyl, difluoro-acetyl, dichloroacetyl, dibromoacetyl, trifluoroacetyl~ trichloro-acetyl, chloropropionyl, acryl, methacryl, butenoyl, hexenoyl, mcthoxyacetyl, isopropoxyacetyl, pentyloxyacetyl, hexyloxyacetyl, cyclohexyloxyacetyl, cyclohexadienyloxyacetyl, phenoxyacetyl, phenoxypropionyl, phenoxybutyryl, diphenoxyacetyl, methylthiophcn- .
oxyacetyl, carboxymethylphenoxyacetyl, sulfophenoxyacetyl, tetra-hydronaphthyloxyacetyl, methylthioacetyl, butylthioacetyl, allyl~
thioacetyl, propenylthioacetyl, cyclohexylthioacetyl, cyclohexa-dienylthioacetyl, phenylthioacetyl, phenylthiopropionylj fluoro-phenylthioacetyl, chlorophenylthioacetyl, carboxymethylphenylthio- ~ ~
acetyl, pyridylthioacetyl, pyrimidylthioacetyl, benzoyl, methyl- . .
,. ........................................................... ~ . :
benzoyl, dimethylbenzoyl, carboxybenzoyl, aminobenzoyl, methoxy~
ben20yl, chlorobenzyl, guanidylaminobenzoyl, dimethoxybenzoyl, trimethoxybenzyl, methylenedioxybenzoyl, phenylbenzoyl, naphthoyl, . methylnaphthoyl, methoxynaphthoyl, ethoxynaphthoyl~ tetrahydrona-phthoyl, acetylnaphthoyl, furylcarbonyl, thienylcarbonyl, isoxa- ;~
zolylcarbonyl, phenylisoxazolylcarbonyl, dimethylisoxazolylcar-bonyl, methylbutyli~oxazolylcarbonyl, phenylmethylisoxazolylcar-bonyl, chlorophenylmethylisoxazolylcarbonyl~ dichlorophenylmethyl-~ 7 .~ ~J~ 7~

isoxazolylcarbonyl, chlorofluorophenylisoxazolylcarbonyl, guanidyl-phenylisoxazolylcarbonyl, guanidylaminophenylfurylisoxazolylcarbo-nyl, carboxyquinolylcarbonylJ carboxyquinoxalinylcarbonyl, phenyl-acetyl, phenylpropionylJ phenylbutyrylJ hydroxyphenylacetyl, S methoxyphenylacetylJ acetyloxyphenylacetylJ aminophenylacetyl, ' fluorophenylacetylJ chlorophenylacetyl, bromophenylacetyl, methyl-thiophenylacetyl, sulfophenylacetyl, carboxymethylphenylacetyl, mcthylphenylacetylJ dimethylphenylacetylJ aminomethylphenylacetyl, acetaminomethylphenylacetyl, diphenylpropionyl, triphenylacetyl, guanidylaminophenylacetyl, guanidylcarbamoylphenylacetyl, tetra-zolylphenylacetyl, cinnamoylJ phenylethynylcarbonyl, naphthylacetyl, tetrahydronaphthylacetyl, furylacetyl, nitrofurylacetyl, thienyl-acetyl, methylthienylacetyl, chlorothienylacetyl, methoxythienyl-acetyl, sulfothienylacetyl, carboxymethylthieny1acetyl, oxazolyl-acetyl, isoxazolylacetyl, methylisoxazolylacetyl, chlorophenyl-methy1isoxazolylacetyl, isothiazolylacetyl, imidazolylacetyl, thia-diazolylacetyl, chlorothiadiazolylacety:L, methylthiadiazolylacetyl, methoxythiadiazolylàcetyl, tetrazolylacetyl, benzofurylacetyl, benzothienylacetylJ indolylacetyl, pyridylacetyl, a-phenyl-a-20 1uoroacetyl, a-chlorophenylacetyl, a-bromophenylacetyl, a-sulfo- :
phenylacetyl, a-phosphophenylacetyl, a-azidophenylacetyl, mandeloyl, o-formylmandeloyl, a-thienylglycolyl, a-chlorothienylglycolyl, a-thiazolylglycolyl, a-isothiazolylglycolyl, a-thiadiazolylglycolyl, a-oxadiazolylglycolyl, a-benzothienylglycolyl, a-phenylmalonyl, a-thienylmalonyl, a-furylmalonyl, is a-thiazolylmalonyl, a-iso-thi.azolylmalonyl, a-oxadiazolylmalonyl, a-isothiazolylmalonyl, a-thiadiazolylmalonyl~ a-benzothienylmalonyl, a-isothiazolyl-a-sulfoacetyl, a-phenylglycyl, a-phenyl-N-methylglycyl, N-sulfo-a phenylglycyl, N-methyl-N-sulfo-a-phenylglycyl, a-chlorophenyl-glycyl, a-hydroxyphenylglycyl, a-aminophenylglycyl, a dichloro-phenylglycyl, -chlorohydroxyphenylglycyl, a-thienylglycylJ a-iso-oxazolylglycyl, a-pyridylglycyl, a-benzothiazolylglycyl, ~-hydroxy-iminophenylacetyl, a-methoxyiminophenylacetyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, cyclohexyloxycarbonyl, chloro-s ethoxycarbonyl, trichloroethoxycarbonyl, tribromoethoxycarbonyl, bromoethoxycarbonyl, iodoethoxycarbonyl, cyclopropylmethoxycarbonyl, cyclopropylethoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxy-carbonyl, cycloheptyloxycarbonyl, cyclohexadienyloxycarbonyl, iso-bornyloxycarbonyl, methanesulfonylethoxycarbonyl, ethanesulfonyl-propoxycarbonyl, phenoxycarbonyl, methylphenoxycarbonyl, dimethyl-phenoxycarbonyl, diphenylmethoxycarbonyl, naphthyloxycarbonyl, benzyloxycarbonyl, bromobenzyloxycarbonyl, chlorohenzyloxycarbonyl, nitroben2yloxycarbonyl, methoxybenzyloxycarbonyl, dimethylbenzyloxy-carbonyl, methylenedioxybenzyloxycarbonyl, furyloxycarbonyl, pyridylmethoxycarbonyl, quinolyloxycarbonyl, aminoadipoyl, acetyl- -aminoadipoyl, benzoylaminoadipoyl, trichloroethoxycarbonylamino-adipoyl, carbobenzoxyaminoadipoyl, oxoaclipoyl, trimethylsilylamino-adipoyl,~trimethylsilyloxycarbonyltrimethylsilylaminopentanoyl, carboxybutyrylJ methanesulfonyl, ethanesulfonyl, benzenesulfonyl9 methylben~enesulfonyl, and benzylsulfonyl.
The acyl group in Y of Compound IV is a protective group for the reactions, and if required removable at a desired stage of . .
synthesis for exchanging with another acyl suitable for the use of the final l-oxadethiacephalosporins. In other words, easily introducable and removable groups are preferable ones of the groups. The procedures for the introduction and removal of such groups are well documented in the field o~ ~-lactam chemistry~
From other aspect, the acyl group can be widely changed within the gist of this invention. When the acyl group has a reactive func- -~

tional group, the latter can be protected by conventional methods .

:~.U~39'~t7f,3 and afterwards deprotected to give desired acyls.
Some of the most preferable acyl groups for Y include phenyl-acetyl, phenoxyacetyl, benzoyl, toluoyl, carbo~enæoxy, and benzyl-sulfonyl. Another preferable acyl group for Y is one of most pre-ferable side chain in the objective l-oxadethiacephalosporins.
Reactive functional group if any can be protected by conventional manners. Representatives of them are a-phenyl~t-benzylo~ycarbonyl-acetyl, ~-p-hydroxyphenyl-a-diphenylmethoxycarbonylacetyl, a-p-acyloxyphenyl-a-benzyloxycarbonylacetyl, a-p-benzyloxyphenyl-~-t-butoxycarbonylacetyl, a-p-benzoyloxyphenyl-a-indanyloxycarbonyl-acetyl, and a-p-tolylmethoxyphenyl-a-tolyloxycarbonylacetyl.
PrQtected Carboxy GrouP COA, COB and CoX for ComPounds I. II, III, and IV
The protected carboxy for COA in Compounds I, COA and COB in Compounds II and III, and COB and COX in Compounds IV include those forming salts including alkali metal salts, alkaline earth ; `
metal salts, salts with organic bases; esters including lower alkyl esters, aralkyl esters, aryl esters, organometallic esters, acid anhydrides; acid halides; thiol esters; thiono esters; amides;
hydrazides; azide; and like carboxy derivatives.
The protective part of the protected carboxy groups contain preferably up to 20 carbon atoms including optional substituent e.g. alkyl, acyl, carboxy, protected carboxy, hydroxy, alkoxy, aryloxy, aralkyloxy, acyloxy, alkylthio, arylthio, aralkylthio, ~5 acylthio, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, amLno, alkyl-amino, arylamino, acylamino, nitro, and halogen, and can further be unsaturated.
Representatives of the specific protected-carboxy groups in-clude those forming salts (e.g. lithium, sodium, potassium, magne-sium, calcium, acetoxycalcium, stearoyloxycalcium, trimethylammo-L0 ~ ~

1'3~9'~

nium, triethylammonium, dicyclohexylammonium, morpholinium, N-methylmorpholinium, pyridinium, quinolinium, picolinium, and colli-dinium salts), esters (e.g. methyl, ethyl, propylJ iso-propyl, butyl, t-butyl, lJl-dimethylpropyl, cyclopropylmethyl, cyclopropyl-ethyl, cyclopentylmethylJ cyclopentylJ cyclohexyl, cycloheptyL, -norbornylJ bornylJ vinylJ propenylJ butenyl, pentenyl, pentynylJ
lJl-dimethylpropargylJ tetrahydrofurylJ tetrahydropyranylJ dihydro-pyranylJ chloromethylJ bromomethylJ iodoethylJ trichloromethylJ :
trichloroethylJ tribromoethylJ methoxymethyl, ethoxym~thylJ ethoxy-ethylJ t-butoxymethylJ t-butoxyethylJ methoxyvinyl, l-dimethyl-amino-3,3-dimethyl-2-buten-1-yl, phenoxymethylg chlorophenoxyethyl, methylthiomethyl~ methylthioethyl, methylsulfinylmethyl, methyl-sulfonylethyl, ethylsul~onylpropyl, ethylthiomethyl, phenylthio- ~ .
methyl, nitrophenylthiomethyl, chlorophenylthiomethyl, dimethyl- ~ :
15 aminoethyl, diethylaminoethyl, acetylmethyl, propionylmethyl, ;~
pivaloylmethyl, phenacyl, nitrophenacylJ chlorophenacylJ bromo-phenacylJ methylphenacyl, methanesulfonylphenacylJ acetoxymethylJ
propionyloxymethylJ butyryloxypropyl, methoxycarbonyloxyethyl, ethoxycarbonyloxyethyl, pivaloyloxymethyl, succiniminomethyl, 20 phthaliminomethyl, cyanomethyl, l,l-dimethyl~yanomethylJ benzyl, :
chlorobenzyl, nitrobenzyl, methoxybenzyl, dimethoxybenzylJ
dimethoxynitrobenzyl, trimethoxybenzyl, hydroxy-di-t-butylbenzyl, trichlorobenzyl, pentachlorobenzyl, phenethyl, benzhydryl, dimethoxybenzhydryl, a,a-dimethyldimethoxybenzyl, trityl, furyl-methyl, guinolylmethyl, l-oxidoquinolylmethyl, thienylmethyl, 9,10-dihydroanthryl, phenyl, tolyl, xylyl, indanyl, trichloro- :
phenyl, pentachlorophenyl, nitrophenyl, di.nitrophenyl, diazophenyl, phenylazophenyl, methanesulfonylphenyl~ naphthyl, benzotriazolyl, ~ ~ -trimethylsilyl, methoxydimethylsilyl, diethoxymethylsilyl, ethylenedioxymethylsilyl, trimethylstannyl, and triethylstannyl ~a 1l ~J~
-esters), acid halides (e.g. chloride and bromide)J acid anhydrides (e;g. anhydrides with methoxyformic acid, cyclohexyloxyformic acid) J amides (e.g. with ammonia and methylamine) and hydrazides (e.g. isopropylhydrazide, diisopropylhydrazideJ and di-secondary butylhydrazide).
Particularly important protected carboxy are those inert in . the reaction condition and removable without undesirable change in other parts of the moleculeJ exemplified by haloalkyl, acylalkyl, alkoxyalkylJ acyloxyalkylJ aralkyl esters, dialkylhydrazide, alkali metal saltsJ alkylamine saltsJ and like groups.
The lower alkyl and aryl for Q in Compounds IV
The lower alkyl for Q includes Cl to C5 alkyl e.g. methyl ethyl, propyl, and isopropyl; and aryl for Q can be phenyl or optionally substituted phenyl e.g. tolyl, methoxyphenyl, chloro- -phenyl, and isopropylphenyl. Most preferable Q is hydrogen.
The nucIeoPhilic qroup of Z in Compounds IV
Representatives of nucleophilic groups Z include halogen (e.g.
chlorine, bromine, iodine), oxygen unctions (e.g. alkoxy, aralkoxy, aryloxy, organic or inorganic acyloxy, hydroxy) J sulfur ~unctions (e~g. alkylt~io, aralkylthio, arylthio, organic or inorganic acyl-thio, mercapto, sulfo, alkylsulfonyl), nitrogen functions (e.g.
azido, aliphatic or aromatic amino or ammonio, amino, nitro, .
nitroso) and other nucleophiles. Among these, aryls can be phenyl, naphthyl, or heterocyclic aromatic group which can be substituted by a inert substitutent. Preferable nucleophiles contain up to - 10 carbon atoms.
Representatives of typical specific nucleophilic groups in~

clude fluorine, chlorine, bromine, iodine, hydroxy, methoxy, -~ .
ethoxy, propoxy, isopropoxy, butoxy, acetoxy, propionyloxy, buty- ~

30 ryloxy, isobutyryloxy, pivaloyloxy, cyclobutylcarboxy, carbamoyl- - - -

12 .
, .

7l~
oxy, methylcarbamoyloxy, ethylcarbamoyloxy, chloroethylcarbamoyl-oxy, trichloroethoxycarbamoyloxy, dimethylcarbamoyloxy di-(methoxy-benzyl)carbamoyloxy, phenylcarbamoyloxy, anisylcarbamoyloxy, sulfo-phenylcarbamoyloxy, carboxymethylphenylcarbamoyloxy, methanesul-fonyloxy, sulfonyloxy, methanesulfinyloxy, benzyloxy, phenethyloxy,toluenesulfonyloxy, benzoyloxy, chlorobenzyloxy, tolylcarbonyloxy, cinnamoyloxy, hydroxycinnamoyloxy, sulfocinnamoyloxy, napthoyloxy, tetrahydrofurylacetyloxy, methylthio, ethylthio, aminoethylthio, propylthio, dimethylpropylthio, isobutylthio, dithioacetyl, thio- ..
10 propionylthio, propylthiocarbonylthio, xanthoyl, cyclopentyloxy- -thiocarbonylthiocarbonylthio, thiocarbamoylthio, dimethylthiocarba-moylthio, phenylthio, aminophenylthio, nitrophenylthio, benzylthio, tosylthio, furylthio, furylcarbonylthio, pyrrolidinylthio, pyrrolyl-thio, isoxazolylthio, isothiazolylthio, thiazolylthio, imidazolyl-thio, methylimidazolylthio, pyranylthio~ pyridylthio, pyrimidyl-thio, methylpyrimidylthio, oxadiazolylthio, methyloxadiazolylthio, methyloxadiazolylthio, propyloxadiazoly:Lthio, thiadiazolylthio, ethylthiadiazolylthio, ethylthiothiadiazolylthio, aminothiadiazol-ylthio, triazolylthio, cyanotriazolylthio, methyltriazolylthio, methoxytriazolylthio, tetrazolylthio, methyltetrazolylthio, indolyl-thio, benzoxazolylthio, benzothiazolylthio, methylamino, ethyl-amino, diethylamino, trimethylammonio, acetamido, chloroethylamino, . . _ . .
ureido, thioacetamido, thiopropionamido, thiocarbamoylamino, methyl- ;
ureido, ethylthiocarbamoylamino, cyclohexylaminothiocarbonylamino, anilino, tolylamino~ methylnitrophenylamino, thiobenzoylamino, naphthylamino, pyrrolidyl, methylpyrrolyl, pyridazinyl, triazinyl, ~:
; pyridinium, chloropyridinium, methylpyridinium, nicotinium, di-methylpyridinium, quinolinium, trifluoromethylpyridinium, and carbamoylpyridinium.

Representatives or specific compounds include the following o compounds-(1) Compounds of the formula:

fOA

SCo ~ CN3 ~2) ., COOR

(wherein COA is lower alkoxycarbonyl or aralkyloxycarbonyl and R is lower alkyl or aralkyl) 0 More specific compounds (2) include those wherein i) COA is methoxycarbonyl and R is benzyl, ii) COA is benzyloxycarbonyl and R is methyl, or :iii) COA is methoxycarbonyl and R is diphenylmethyl;
(2) Compounds of the formula:
: . -COA
o ~ ~ al ¦ ~ CH (3) COB

~wherein COA and COB each is lower alkoxycarbonyl or aralkoxy-carbonyl and Hal is halogen) ~ore specific compounds (3) include those wherein il COA is methoxycarbonyl, COB is ben~yloxycarbonyl, and ;
Hal is chlorlne;
ii) COA is benzyloxycarbonyl, COB is methoxycarbonyl, a~nd ~al is chlorine; or iii) COA is methoxycarbonyl, COB is diphenylmethoxycarbonyl ~ ~ -.and ~al is chlorine. - -:~

~3) Compounds of the formula~
`~ 14 ~ ' .
.
COA ~ ~ :
~ O H~ o O ~ ~f=C~ CH orO ~ N-C=C \ 3 COB OB 3 : .
(4) (5) (wherein COA and COB each is lower alkoxycarbonyl or aralkoxy-carbonyl) . .
More specific compoundq (4) and (5) include those wherein i) COA is methoxycarbonyl and COB is benzyloxycarbonyl,: ~ .
ii) COA is benzyloxycarbonyl and COB is methoxycarbonyl, or : . ~
iii) COA is methoxycarbonyl and COB is diphenylmethoxy~
carbonyl.
~4) Compounds of the formula: ` :
: ~ :

COA . ~ O~
Acyl-~ ~o Acyl o COB 3 O ~ -I-C< 3 ~6) - ~7) ~ COHal COCHQ=N
Acyl O Acyl-~ g ~ CH ~ CH

. ~ 3-C=C~ 3 lO CH3 ~ ~8) ~g) : :
~ ~;
(wherein COA and COB each lS lower alkoxycarbonyl or araLkoxy- ; ;`
carbonyl; Acyl is alkanoyl~ aralkanoyl, aroyl, sulfonyl, or ;
carbonic acyl; Hal is halogen; and Q is hydrogen, alkyl, or:arylj More specific compounds (6) incLude those wherein ij CO~ is methoxycarbonyl, COB is benzyloxycarbonyl:, and ., ~

~v~

Acyl is phenylacetyl, benzoyl, benzyloxycarbonyl, or benzylsulfonyl;
ii) COA is ben~yloxycarbonyl, COB is methoxycarbonyl, and Acyl is phenylacetyl; or iii) COA is methoxycarbonyl, COB is diphenylmethoxycarbonyl, and Acyl is phenylacetyl.
More specific compounds t7i include those wherein:
1) COB is benzyloxycarbonyl and Acyl is phenylacetyl, benzoyl, benzyloxycarbonyl or benzylsulfonyl;
ii) COB is methoxycarbonyl and Acyl is phenylacetyl; or iii) COB is diphenylmethoxycarbonyl and Acyl is phenylacetyl.
Mor.e specific compounds (~) include those wherein:
i) COB is benzyloxycarbonyl, Acyl is phenylacetyl, benzoyl, ben~yloxycarbonyl or benzylsulfonyl and Hal is chlorine; or ii) COB is methoxycarbonyl, Acyl is phenylacetyl and Hal is chlorine;
iii) COB is diphenylmethoxycarbonyl, Acyl is phenylacetyl, and Hal is chlorine.
More specific compounds -(9) include those wherein:
i) COB is benzyloxycarbonyl, Acyl is phenylacetyl, benzoyl, benzyloxycaxbonyl or benzylsulfonyl and Q is hydrogen;
ii) COB is methoxycarbonyl, Acyl is phenylacetyl, and Q is hydrogen; or iii) CO~ is diphenylmethoxycarbonyl, Acyl is phenylace~yl, and Q is hydrogen.
t5) Compounds Qf the formula~
~ HQZ
Acyl-N
~ / 3 I ~ CH

L7~) ~ ..
(wherein COB is lower alkoxycarbonyl or aralkoxycarbonyl; Acyl is alkanoyl, aralkanoyl, aroyl, sulfonyl, or carbonic acyl; Q is hydrogen, lower alkyl, or aryl; and Z is hydrogen or nucleophilic group).
More specific compounds (10) include those wherein:
i) COB, Acyl, and Q are as defined above; and Z is acetoxy or chlorine;
ii) COB, Acyl and Q are as defined above, and Z is hydrogen.
iii) COB, Acyl and Z are as defined above, and Q is hydrogen;
iv) COB is benzyloxycarbonyl, Acyl is phenylacetyl, benzoyl, benzyloxycarbonyl or benzylsulfonyl and Z is hydrogen, `` chlorine, or acetoxy; or v) COB is methoxycarbonyl, or diphenylmethoxycarbonyl, Acyl is phenylacetyl and Z is hydrogen or chlorine.
The Compounds IV (where COX is -COCHQZ in which Q and Z are as defined abofé) were found to be reduced with e.g. aluminium ;
amalgam and acetic acid to give Compo~ds 11 according to Reaction

13 as described later.

COCHQZ
, Y ~ reduciny agent Acyl-N ~ I \ CH

(IV) COB 3 ~11) COB 3 ~ ~

(wherein Acyl, COB, Q and Z are as defined above). ~ -The Compounds (11) can be used for synthesizing so-called antibacterial l-oxacephalosporins, for example, according to the process illustrated in the following chart.

~ 17 .~

1~3B9~70 ~ .
. CHART 2 ACyl-NH ~ ~Oc~12coc~l2Q ACyl-NH~ n ~OcH2cOc~l2Q
O N-C=C < ~o ~ N~C_O , ~11) COB CH3 iL) (CH3)2s , COB

i) Zn/CH3COOH Y ~ CH2COOCH2Q i) P(C6H5)3 ii) SOC12 O ~ -CHCl ii) heat' COB
.' ,', ' ' , Acyl-NH O~
Oxacephalosporins: ) O ~ N ~ 1CH Q
COB ' ~ .
(wherein COB, Q, and X are as defined above) Compounds (1) through (IV) can also be useful !
) as intermediates for preparing other useful compounds within .
or beyond the scope of the compounds given hereinabove according to thè given or known methods. ' ~ , '' ,Compounds (11) have been prepared by us from ', ~; ~
e.g. known 6-tritylaminopenicillanic acid ac~ording to the ~ ', following reaction sequence of Chart 3, but the reaction , ~; ' (iv) usually takes place from the both of ~ and B sides , ~ ' at a ratio close to 1:1. Therefore, overall yield of the' ~' ~ ~ ' final products cannot theoretically exceed 50%, and ' , usually less than 20~. The process of this invention, has ; no neck of the process, and generally the overall yield is ab,out ~30% to 50%~ accompanied by scarce of uneasily ~;
.
separable by-products. ~ -~
'.

; :' ~ :IU~LY7~3 CE~RT 3 ( 6 5)3 ~ ~ CH3 3 ( 6 5)3 ~ 3 CH . 2_~ .
0 ~ CH3 o f CH3 COB COB

(C6H5)3CMH ~ ~Cl iii) H20 2 ~ iv) HOCEI2C_CH
O N-CI=C~ 3 f < CH3 COB 3 . COB

H N OCH C-CH Acyl-~H OCH C-CH
2 ~ 2 v) acylatlon~ ~ vi) H20 O ¦ ~CH O~--N I C~ CH3 C03 . COB .

Acyl-NH ~ OCH2COOCH3 O ~ Cl C ~CH3 - ~11; Z--H, Q=H) COB
; .

Compounds ~I) through (IV) are use~ul as indispensable inter-mediates for the processes of this invention~ ~
The compounds of this invention can be prepared by the fol- ~ :
lowing reactions ~rom known compounds.
(Reaction 1) A reaction of 6-aminopenicillanic acid lower alkyl or aralkyl ester: (1) with an oxalic acids (i) or reactive derivatives thereof ;
gives oxalylaminopenicillanate (2) according to the process of the~
following reaction scheme: .

:30 :

3~e~

.
COA COA

H2NS CH COOH (i) or CONH
~ ~ 3 _~ ~ ~ ~ CH3 o ~1--N CH3 reactive deriva- o~__N CH3 (1) COOR tive thereof (2) COOR

(wherein COA is carboxy or protected carboxy and R is lower alkyl or aralkyl) The reactive derivatives of the oxalic acids ~i) include the following reagents:
1)` the free acid--in the presence of a condensing reagent such as carbodiimides (e.g. N,~'-diethylcarbodiimide, ~,~'-dipropyl-carbodiimide, N,N'-diisopropylcarbodiimide, N,~'-dicyclohexylcar-bodiimide, and ~-ethyl-~'-3-dimethylaminopropylcarbodiimide), carbonyl compounds (e.g. carbonyldiimidazole), isoxazolinium salts ~ ;
(e.g. N-ethyl-5-phenylisoxazolinium-3'-sulfonate and N-t-butyl-5-methylisoxazolinium perchlorate), acylam:ino compounds (e.g. 2- ;
ethoxy-l-ethoxycarbonyl-1,2-dihydroquino:line), or like condensing reagents---utilizable in a nonprotic solvent (especially halohydro-carbon, nitrile, ether, and amide solvents or mixtures thereof) at about -30C to +lOO:C (preferably from -10C to 50C) for 10 minutes to 24 hours, and preferably at a molar ratio of 1 to 2 of the ~ree acid and 1 to 2 of the condensing reagent against 6-._ .
aminopenicillanic acid lower alkyl or aralkyl ester (1). ~ -Q) an acid anhydride--including symmetrical anhydrides; mixed ~S anhydrides with a mineral acid e.g. a half ester of carbonic acid e.g. lower alkyl (e.g. methyl, ethyl~ propyl, i~opropyll butyl, isobutyl, sec-butyl, pentyl, cyclopropylmethyl, cyclopentyl,~ and cyclohexyl) half esters of carbonic acid; mixed anhydrides with alkanoic acids (e.g. formic acid, acetic acid, pivalic acid, trifluoroacetic acid, and trichloroacetic acid), mixed anhydrides O ' with sulfonic acid (e.g. toluene--p-sulfonic acid), and intramole-cular anhydrides (e.g. ketene and isocyanate)--utilizable prefer-ably in the presence of an acid acceptor including inorganic base [e.g. hydroxides, carbonates, or bicarbonates of alkali metal (e~g. sodium and potassium)f~r alkaline earth metal (e.g. magne-sium and calcium)~; alkaline earth metal oxides; organic bases including tertiary amines (e.g. trimethylamine, triethylamine, dimethylethylamine, propyldimethylamine, tripropylaminej N-methyl-morpholine, and dimethylaniline), and aromatic bases (e.g. pyri-di~ne, quinoline, collidine, and picoline)]; oxiranes (e.g. ethy-lene oxide, propylene oxide, and cyclohexene oxide)--in a nonpro-tic solvent (especially halohydrocarbon, nitrile~ ether, and amide solvents or mixtures thereof) at about -30C to +100C (preferably from -10C to 50C) for 10 minutes to 2~ hours, and preferably at a molar ratio of 1 to 2 of the anhydride and l to 10 of the acid acceptor against the 6-aminopenicillanic acid lower alkyl or -aralkyl ester (l);
3) an acid cyanide, acid azide, or acid halide (e.g. chloride and bromide)--preferably ln the presence of an acid acceptor mentioned for the acid anhydrides--in a solvent`(especially halohydrocarbon, nitrile, ether, ketone, water, and amide solvents or mixtures thereof) at about -30C to +100C (preferabl~ ~rom -10C to 50C) for 10 minutes to 6 hours--preferably at a molar ratio of 1 to 2 of the reactive derivatives and 1 to 10 of the acid acceptor against the 6-aminopenicillanic acid lower alkyl or aralkyl ester (l); ' .
4) a reactive ester--including enol esters (e.g. vinyl and iso-propenyl esters), aryl esters (e.g. chlorophenyl, bromophenyl, nitrophenyl, dinitrophenyl, nitrochlorophenyl, and pentachlo~ro-phenyl esters), heterocyclic aryl esters (e.g. benzotriazolyl Zl esters~, and diacylamino esters (e.g. succinimido and phthalimido esters);
5) a reactive amide--including amide with an aromatic amine (e.g.
imidazole, triazole, and 2-ethoxy-1,2-dihydroquinoline), and N-sub-5 stituted-N,N-diacylamines (e.g. diacylaniline); .
6) a formimino compound including N,N-dimethyliminomethyl deriva-tive of the oxalic acid (i) and other reactive derivatives.
The reactive ester, reactive amide, and formimino compounds can be used in a non-protic solvent tespecially halohydrocarbon, ether, ketone, amide, and ester solvencs or mixtures thereof) by merely mixing with the reagents at a molar ratio of 1 or more against the starting material (1) at about -30C to ~100C for 30 minutes to 6 hours.
The starting material tl) may be subjected to this acylation after protecting or activating the amino group by conventional groups e.g. silyl (e.g. trimethylsilyl and dimethylmethoxysilyl), stannyl (e.g. trimethylstannyl), l-haloalkylidene, 1-haloaralkyli-dene, l-alkoxyalkylidene, l-alkoxyaralkylidene, carbonyl, sulfenyl, or readily removable acyls, and the groups can be removed a~ter the reaction to give the objective compounds.
The group COA and COOR are usually replaced by carboxy separately at a desirable stage of synthesis of final objective compounds. The structure of the two groups can be varied widely so far as they are stable to the reaction and removable at a re-quired stage, as is described above.
When R is hydrogen, the reaction has been described inJapanese Patent Application Publication ~o. 39-6678.
tReaction 2) The Oxalylaminopenicillanate (2) can be treated with a halo-genating reagent to give a ~aloazetidinone (3) according to the a 22 7~:) following reaction schemeO

COA ÇOA H H
10NH ~ 6 \ CH3 halogenating reagent CON~I ~ CH3 O ~ CH3 o f ~ H3 (2) COB (3) COB

(wherein COA and COB each is carboxy or protected carboxy; and - Hal is halogen) The halogenating reagent include molecular halogen (e.g.
chlorine and hromine), hypohalogenous acid source (e.g. hypohalides~
M-haloamides e.g. N-chlorosuccinimide, N-bromosuccinimide, N-iodo-succinimide, ~-chlorophthalimide, N-bromophthalimide, N-chloroace-tamide, ~-bromoacetamide, and Chloramines B and T); iodobenzene dihalodes, sulfuryl halide; as a solution in non-polar solvent (e.g. halohydrocarbon, ether, ester solvents or mixtures thereof).
This reaction applied to 6~-phthalimidopenicillanic acid esters has been reported in Journal of the American Chemical Society, 93, 6267 (1971), ~ 7590 (1972); Canadian Journal of Chemistry, 50, 2894, 2898, ~902 (1973), 53, 497 (1975); Journal of Chemical Society 1975, 1932, but not known in the cases of oxalylaminopenicillanic acid derivatives.
Haloaæetidinone (3) may also be prepared from a-~3~-(oxalyl-amino)-4~-alkylthio-2-oxoazetidin-1-yl]--isopropylideneacetic acid or derivatives thereof on the action of said halogenating reagents. For example9 a solution of molecular halogen dissolved in carbon tetrachloride is added to a methylene chloride solution of the 4~-alkylthio compounds under ice cooling, and the mixture is stirred to give the haloazetidinone (3) in good yield.

In a preferable example, Oxalylaminopenicillanate (2) is stirred with 1 to 5 mole equivalents of chlorine in a nonprotic inert solvent (especially halohydrocar~on solvents) at -50~C to ~ gfl7~) ~10C (especially at -20C to 0C) for 10 to 60 minutes to give Haloazetidinone (3) in 60 to 90 % yield.
(Reaction 3) The Haloazetidinone (3) can be treated with a dehydrohalo-genating reagent to give a oxazolinoazetidinone (4) according tothe following reaction scheme:

COA
I H H ~
CONH ~ Hal dehydrohalogenating ~ CH3 _I-C~ 3 reagent o -f-C~CH
(3) (4) (wherein COA and COB each is carboxy or protected carboxy and Hal is halogen) Representatives of the dehydrohalogenating reagen~s are salts 15 of a metal having an affinity to halogen ion (e.g. silver, zinc, `
tin) aluminumg titanium, iron, alkali metal, alkaline earth metal in forms of mineral acid salts~ alkanoate salts, haloalkanoate salts, sulfonate salts, Lewis acid salts, and like salts, espec-ially those being lipophillic are suitable for the reaction.
Preferable dehydrohalogenating reagents are zinc chloride, titanium chloride, aluminium chloride, ferrous chloride, ferric chloride, stannous chloride, zinc sulfate~ ferric nitrate, titanium bromide silver tetrafluoroborate, sodium hydrogencarbonate, potassium hydrogencarbonate, calcium carbonate, sodium carbonate, potassium carbonate, zinc aFetate, and like salts.
Sometimes, the dehydrohalogenation also takes place by the action of basic compounds (e.g. lower alkylamine, N-methylmorpho-line, N-methylpiperidine, pyridine, sodium carbonate, and calcium oxide) or adsorbents (eOg. silica gel and alumina), or by merely refluxing under heating in a solvent in moderate yield of the ~ 7~
product (4). These dehydrohalogenating reagents are also included in the scope of the reagents for this Reaction 3.
Compounds (4) substituted by a phenoxymethyl or benzyl in place of COA have beeh described in some literatures (Journal of Chemical Society, Chem. Comm. 1972, 229; Canadian Journal of Chemistry, 50, 2902 (1972); ~ournal of Chemical Society, 1975, 883 and 1932; Canadian Journal of Chemistry, 53, 497 (1975)).
Particularly, the oxazolinoazetidinone (4) have been prepared by Wol~e et al. from a compound analogous to those of the formula (3) by shaking or refluxing in an organic solvent with an aqueous solution of sodium hydrogencarbonat~. It has been confirmed that this reaction is also applicable to the present invention, that is, the location of a carbonyl group adjacent to the amidocarbonyl did not interfere with the proceeding of the reaction.
Both of isomers of the 4a- and 4~-halogenated starting com-pounds give the same Oxazolinoazetidinone (4) in approximately the same yield. `
In a representative example, Haloazetidinone (3) is dissolved ~ ;
in an inert solvent (e.g. ether, ketone, and amide solvent) at a temperature of -50C to +100C (especially -30C to 30C), mixed with the dehydrohalogenating reagent (especially silver tetrafluo-roborate, zinc chloride, and stannous chloride)" if required in the presence of a base (e.g. methylmorpholine), and let react for .

10 minutes to 12 hours (especially 15 minutes to 60 minutes) to give Oxazolinoazetidinone (4) in 80 to 99 % yield.
(Reaction 4) The Oxazolinoazetidinone (4) can be treated with a reducing reagent to give an Oxazolidine (5) according to the following reaction scheme~: `

.' ' .

9~70 ,CH3 reducing reagent~ ~ I \C33 (4) COB t5) COB
(wherein COA and COB each is carboxy or protected carboxy) Representative reducing reagents are metals in-.
cluding alkali metal (e.g. sodium, potassium and lithium), ' alkaline earth metal (e.g. magnesium and calcium), metals of Group III in the periodical table (e.g. boron and aluminium), and transition metals (e.g. iron, cobalt, and nickel) or amal~ams thereof in the presence of a proton source (e.g.
water, alcohol, acid, and alkali); borane derivatives (e.g.
.
pyridine borane); complexes oE aluminium hydride or boron ' ' hydride with metal'hydride ~e.q. lithium aluminium hydride, `~
.
potassium aluminium hydride, sodium methoxyalumin-ium hydride, lithium t-butylaluminlum hydride, and sodium borohydridej;
salts, carbonyl compounds or organomet:allic compounds involving ~ . . : . .
multivalence metal (e.g. iron, nickel, chromium, and cobalt) ' ~ at low valence stage; hydride donating reduclng reagents, elèctrolytlc reduction; and other reducing reagents and methods.
Most preferable reducing reagents for this reaction are-zinc and mineral acid, al'uminium amalgam and water, sodium cyanoborohydride, and like reducing reagents.
. .
This typè of the reaction is known on 3-substituted-alkyl- ;~
thiazolinoazetidine compounds (Vnited States Patent 3,681,380) but not in the case where COA is carboxy or~protected carboxy.
The present inventors have discovered that the reduction of oarbonyl group bound directly to the 3-position is preceded by reductlon of~the oxazoline ring, and when the degree of carbonyl ~

3~' ' ' `' ~ 26 - ' ' ' ' '~ " '~`' " ' ' .
.'~ ' .
~ ......................................................................... ..

7~
unsaturation is decreased in forms of carboxy, esters~ amides, salts, and the like, the reduction proceeds more easily. The pre-sent process is based on this discovery.
In a representative example, the Oxazolinoazetidinone (4) is dissolved in an inert solvent (e.g. ether, ester, and alcohol sol-vents), mixed with water and aluminium amalgam at 0C to 50C for 30 minutes to 5 hours (preferably 1 to 3 hours) to give the Oxa-zolidine (5) in high yield.
(Reaction 5) The Oxazolidine (5) can be acylated with an acylating reagent to give N-Acyloxazolidine (6) according to the following reaction scheme:

COA COA

HN O Acyl-N O
~ CH3 Acylating reagent ~ CH
O 10B~CH3 O ~N_f=C~C
- COB
(5) (6~) ~wherein COA and COB each is carboxy or protected carboxy) The acyl groups to be introduced are, as is described above, preferably those constituting the optionally protected side chain of natural or synthetic penicillins or cephalosporins in which a .
functional group if any, may be protected from following reactions according to conventional manner and may be deprotected for use of final products.
The acylating reagent is a reactive derivative of an acid having the desired acyl group. The reaction is easily carried out by applying the reaction conditions and reactive derivatives similar to those described above in relation to Reaction 1 for the preparation of the Oxalylaminopenicillins (2).

~ 70 Particularly preferred acyl groups are those increasing selec-tivity and reactivity of the subsequent reactions and readily re-movable at a required stage of synthesis if desired.
In a preferable example, 1 mole equivalent of an Oxazolidine (5) is treated with 1 to 2 mole equivalents of an acid chloride of phenylacetic acid, benzoyl chloride, benzylsulfonyl chloride, or benzyl chloro~ormate, 1n the presence of 1 to 2 mole equivalents of an organic base (e.g. triethylamine and pyridine) at -50C to 30~C (especially from -30C to 10C) for 10 minutes to 5 hours ;
(especially from 30 minu`tes to 2 hours) in an inert solvent (especially halohydrocarbon, ether, ketone, amide, and ester sol-vents).
(Reaction 6) The N-Acyloxazolidine (6) can be deprotected at COA group selectively to give Free acid (7) according to the following reaction scheme: -COA COOH

AcyI-~ O Acyl ~ ~CH3 partial deprotection ~ CH
200 ¦ \ C~3 ¦ \ CH
COB COB
(6) (7) ~herein COA and COB each is carboxy or protected carboxy) The ~-acyloxazolidine (6) is much more stable to various reaction conditions than those having penam or cephem structure, and it tolerates such deprotection conditions as hydrolysis including hydrolysis even with mineral acids (e.g. hydrochloric acidj sul~uric acid, phosphoric acid, nitric acid, perchloric acid) and alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide), ~ `
solvol~sis (with e.g. trifluoroacetic acid and cation scavenger;

30 hydrogen bromide and acetic acid), hydrogenolysis over catalysts ~ -~

,.~

7~
o (e.g. palladium, platinum, and nickel), reduction (with e.g. sodium borohydride, lithium aluminum hydride, sodium borohydride), oxida-tion (with e.g. chromium trioxide and manganese oxides), dealkyla-tion (nucleophilic dealkylation e.g. with lithium iodide, lithium thiophenoxide, and lithium t-butylmercaptide), anion or cation exchange reaction, and other conventional reaction conditions.
These reactions are applicable to the said partial deprotection.
As it is necessary to make the 3-carboxy group free while a-carboxy being protected, the protecting groups in COA and COB in N:acyloxazolidine (6) are different each other, and deprotected by diferent means or conditions. It is preferable therefor to select such COA and COB at the stage of introduction of said pro-tected carboxy groups in former reactions. Such procedure is conventional in the synthetic chemistry.
In a preferable example, 1 mole of ~-Acyloxazolidine (6) is treated with diluted sodium hydroxide in water (e.g. ~rom 0.1 to 10) in a soLution of an inert solvent ~e.g. ether or ketone solvent, or mixtures thereof), at -20C to 100C (especially from -10C to 50C) for 30 minutes to 5 hours to give the Free acid (7) up to 95 % yield.
In another preferable example, when COA is benzyloxycarbonyl, the N-Acyloxazolidine (6) is hydrogenated over palladium carbon in tetrahydrofuran at room temperature until the consumption of hydrogen ceases to give the Free acid (7)~
In other preferable example, when COA is diphenylmethoxy-carbonyl, the N-Acyloxazolidine (6) is dissolved in trifluoroacetic acid in the presence of anisole at room temperature, and the solu-tion is evaporated after 30 minutes to give the Free acid (7).

Reactions from 7 to 10 are conventional diazoketone synthesis for preparing a Ketone (10) from a Free acid (7) in 85 to 90 %

~v~9~7 O
over-all yield.

(Reaction 7) The Free acid (7) can be treated with a halogenating reagent for preparing acid halides to give a Acid halide (8~ according to the following reaction scheme-.
COOH COHal ~ ~ .
Acyl-N O Acyl-~ o ~ ~CH3 halogenating ~ ~ 3 OsL--N-I=C \ reagent ~ - - N-f=C<
(7) COB (8) COB

(whlsrein COB is carboxy or protected carboxy and Hal is halogen) The halogenating reagents for this reaction 7 are those which are usuaLly used in preparlng acid halides from carboxylic acids;
particularly preferable ones are Vilsmeier type reagents (e.g.
dimethylformamide and phosgene or thionyl chloride), thionyl halides, phosphorus pentaha1idèsJ pho~phorus oxyhalides, oxalyl halides, and triphenylphosphine in carbon tetrachloride).
~0 The Free acid (7) may first be converted into an alkaIi metal salts prior to the ac'cion of the halogenating reagent.

Preferable halogens for the halogenating reagent or Hal are ; ~;
chlorine or bromine.
In a preferable example, the Free acid (7) is treated with ;

oxalyl chloride, thionyl chloride, or phosphorus pentachloride in an inert solvent (especially hydrocarbon, halohydrocarbon, or~amide `
solvents and mixtures thereofJ at 0C to 100C for 10 minutes to 5 hours to give the Acid halide (8).
(Reaction 8) The Acid halide (8) can be treated with a diazo compound (ii) .

~3~

to give a Diazoketone (9) according to the following reaction scheme:

COHal C0CQ=N2 ~ ~
Acyl-N ~ d d Acyl-~ o CH3 _ P ~ ~ CH
~ ~-f=C <CH HCQ=~=N (ii) ~ N-IC= ~

(8) COB (g) OB 3 (wherein COB is carboxy or protected carboxy; Hal is halogen;
and Q is hydrogen, lower alkyl or aryl) The diazocompound (ii) is a diazoalkane or diazoaralkane.
The reaction proceeds well in a solvent in which both of reactant and reagent are brought to contact according to conventional manner preferably at -10C to 50C for 10 minutes to 5 hours to give the Diazoketone (9) in high yield.
The product may be isolated in a conventional manner without decomposition or ~or the further synthesis, it may be subjected to the ollowing reaction 9 without isolation.
In a preferable example, the Acid halide (8) is dissolved in an inert solvent (especially ether and halohydrocarbon solvents or mlxtures thereof), mixed with a solution of diazomethane at 0C
to 30C for 20 minutes to 2 hours to glve the Diazoketone (9) in high yield.
(Reaction 9) The Diazoketone (9) can be treated with a nucleophilic com-po~nd ~iii) to give an optionally substituted methylketone (10) according to the following reactiOn scheme: ~

~ :.
_____--~~~~~~

d ` -iO
~ `
~CoCQ=N2 COCHQZ

Acyl-~ o nucleophilic Acyl-N O
~ CH3 ~ H
o ~ -f-C~ compound HZ (iii~ O ~ ¦ CH

COB COB
5 (9) (10) ' (wherein COB is carboxy or protected carboxy; Q is hydrogen, alkyl or aryl; and Z is hydrogen or nucleophilic group) The nucleophilic compound tiii) represented by the formula HZ
is that having the Z group to be introduced, and are exemplified by a hydrogen halide, hydrogen azide, alcohol, phenol, organic acid, inorganic acid, water, mercaptane, thiophenol, thiol acid, hydrogen sulfide, amine, or the other nucleophilic compounds rep-rese~nted by the formula HZ in which Z is as defined above for the Compounds IV.
A compound forming a nucleophilic compound (iii) under the reaction condition is also included in the definition of the nucleophilic compounds for this reaction, as a reactive derivative.
In a preferablè case, a Diazoketone (9) is dissolYed in an inert solvent (especially ether, ketone, halohydrocarbon, or mix- :
.~
20 tures thereof) and mixed with ether saturated with hydrogen :
chloride at -10C to 50C for 15 minutes to 5 hours to give a chloromethylketone (10, Z=Cl). : ~
In another example, a ~iazoketone (9) is dissolved in acetic .. ~.
acid containing boron trifluoride etherate to give an acetoxy-2S methylketone (10~ Z=-OCOCH3).
(Reaction 10) , .
The Haloketone (10; Z--Hal ) can be treated with a reducing -reagent to give a ketone (10: Z=H) according to the following ~ ~ .
reaction scheme~

COCEIQ-~al2 COCH2Q

Acyl-N o Acyl-N o ~ CH3 reducing reagent ~ N-C=C <

(lO; Z=Hal ) (lO; Z=H) (wherein COB is carboxy or protected carboxy; Hal is halogen;
and Q is hydrogen, lower alkyl, or aryl) The preferable reducing reagents include a combination of reducing metal (e.g. zinc, iron, tin, and aluminium), or their amalgams and proton donor (e.g. acids, alcohols, and water);
catalytic hydrogenation over a catalyst (e.g. palladium, platinum, and nickel), electrolytic reduction, and reduction with hydrides (e.g. sodium borohydride, potassium borohydride, zinc borohydride, and lithium methoxyaluminum hydride). The reduction can also be carried out by the treatment of the Haloketone (10; Z=Hal ) with an alkali metal iodide, hydrogen iodide, or the like, followed, by, if required by reduction.
The reduction carried out under more drastic condition than those specified above sometimes gives Compounds tll) as a result of accompanying Reaction 13.
In a preferable example of Reaction lO~ a Haloketone (10;
Z--Hal ) is dissolved in acetic acid and stirred with zinc powder at room temperature or 30 minutes to 2 hours yielding the Ketone (11) in high yield.
(Reaction 11) The ~-Acyloxazolidine (7) cain be treated with an organomet-allic compound (iv) to give Ketone (10; Z--H) according to the following reaction scheme: ~

- - -: .

~3t~ 0 Acyl-~ o organometallic compound Acyl-N
~ ~ _C-C / 3 QCH M --(iv) ~~~ ~ 3 ¦ CH3 2 ~1--N-C-C

(wherein COA and COB each is carboxy or protected carboxy;
Q is hydrogen, lower alkyl or aralkyl; and M is a monovalent metal or monohalodivalent metal or a half of divalent metal) The organometallic compound (iv) is that capable of introdu-cing a lower alkyl or aralkyl into a carboxy or protected carboxy to give a methylketone derivative. Representatives of the reagent (iv) include LiCU(CH2Q)2, QCH2MgHal:CuHal, Cd(CH2Q)2, CH3SOCHQNa, and like organom~tallic reagents for introducing QCH2-group.
These organometallic reagents are brought to contact with an N Acyloxazolidine (7) in a nonprotic solvent (especially hydro- ~ `
carbon or their solvent or mixture thereof) under exclusion of : `
moisture~ if required in the presence of amine, to give objective Ketone (lQ; ~=H) in high yield. `~ `
20The reaction may be classified into one of Grignard reaction, BIaise reaction, Corey reaction, or like reactions for ketone synthesis. ~;
~ This route is more efficient than said Diazoketone synthesis described above (Reactions 7 through 11) as the process is simple 2S and high yield. ~ -(Reaction 12) Compound (10) having Z being a nucleophilic group, can be subjected to exchange reaction with other type of nucleophilic reagent to give a Compound (10) where Z is more strong nucleophilic than that of the starting material;
d 34 Acyl-N O Acyl-N O
~ nucleophilic reagent ~ CH3 0~ - N-l=C~ 3 e.g. HXlO ~ N-C=C

COB COB
(10; Z=Zo) (10; Z=Zl) (wherein COB is carboxy or protected carboxy; Q is hydrogen, lower alkyl or aralkyl; ZO is the starting nucleophilic group; and Zl is the introduced nucleophilic group) This reaction can be utilized for introduction of z group in Compound (10) suitable for the purpose of the subsequent reactions or the use of the final products. For example, when the starting zO is a halogen, the Compound (10) is treated with an alkali metal alkanoate or alkali metal heterocyclic mercaptide to give the cor- -responding compounds where Z is an alkanoyloxy or heterocyclic thio group.
(Reaction 13) -The optionally substituted ketone (10) can be treated with a reducing reagent to give an Acetonylazetidinone (11) according to the following reaction scheme:

COCHQZ

Acyl- ~ O Acyl-N ~ OCH2COCHQZ
I ~CH3 _ _; ~ CH3 N~f=C~cH O,~ N IC C <CH3 COB COB

( 10) ( 11) (wherein COB ls carboxy or protected carboxy; Q is hydrogen, lower alkyl or aryl; and Z is hydrogen or nucleophilic group) All of the reducing xeagents which effectively cleave the oxazolidine ring without reduction of the carbonyl group attached to the 3-position may be utilized in this reduction step. This is a novel reaction never described in the chemistry of carbonyloxa-zolidines.
For example, the reduction can be carried out under the action of a reducing metal (e.g. zinc, iron, tin, magnesium, aluminium, ' and titanium) with a proton donor (including a hydrogen halide e.g.
hydrogen chloride, hydrogen bromide, ammonium halide, ammonium chloride, ammonium bromide, sulfonic acid e.g. toluene-p-sulfonic acid, benzenesulfonic acid, methanesulfonic acid, mineral acids e.g. sulfuric acid, phosphoric acid, and nitric acid, acetic acid, trichloroacetic acid, and trifluoroacetic acid, in a solvent such as ether, amide, ester, alcohol, carboxylic acid solvents, or `
mixtures thereof. The addition of water sometimes promotes this reaction. Solvent such as hydrocarbons, esters, or halohydrocar-15 bons may be used in order to dissolve the starting material. -~
Besides, organometallic reducing r~eagents of polyvalent metals (e.g. iron, cobalt, nickel) chromous salts, or electrolytic reduc-tion may also be used for the reducing reagent speci~ied above, which are included in the reaction of this step.
When the group Z is a readily reducible nucleophilic group, the group Z of a part of the product may be different rom that of the starting material and probably Z is reduced Z or hydrogen.
_,. .
In order to avoid such reductive change of Z group, it is appropriate to select suitable reducing reagents and reaction conditions according to conventional methods.
~ nsecutive application of the aforementioned processes st;arting from 6-aminopenicillanic acid down to Compound-tll) gives th~se wherein the substituents at the 4-position of azetidine structure have single configuration. According to the prior art processes, the reaction gives a mixture of stereoisomers (epimers) ~ ;~

~f~ '7~

at the position 4; since the epimers are closely resemble each other in their property, a special techniques for separation such as precisiOus chromatograph is required. The processes of this invention does not require such troublesome procedures.
Each reaction as mentioned above may preferably be carried out in a solvent. The solvent may be selected according to the starting materials, reagents, reaction temperature, reaction time, the scale of the reaction, and other reaction conditions, and belong to conventional solvents i~cluding hydrocarbon (e.g. pentane, hexane, petroleum ether, cyclohexane, cycloheptane, isooctane, benzene, toluene, xylene, and cyclohexane), halohydrocarbon (e.g.
dichloromethane, chloroform, trichloroethane, pentachloroethane, chlorobenzene, dichlorobenzene, and fluorobenzene), ether (e.g.
diethyl ether, methyl isobutyl ether, dloxane, tetrahydrofuran, ethylene glycol diethyl ether, and anisole), ester ~e.g. methyl acetate, ethyl acetate, butyl acetate, methyl benzoate, and dimethyl phthalate), ketone (e.g. acetone, methyl ethyl ketone, cyclohexanone, acetophenone, and benzophenone), nitrohydrocarbon (e.g. nitromethane, nitroethane, nitrobenzene, nitrntoluene, and nitroxylene), water, alcohol (e.g. methanol, ethanol, propanol, butanol, isobutanol, pentanol, cyclohexanol, cyclohexylmethanol, and octanol), nitrile (e.g. acetonitrile, propionitrile, and benzonitrile), and amide (e.g. formamide, acetamido, dimethylfor-mamide, dimethylacetamide, benzamide, dimethylbenzamide, and benzoylmorpholine), solvents, and like solvents for chemical reactions.
The products in each step may be separated from the reaction mixture containing the unreacted starting materials, unreacted reagents7 by-products, solvents, by conventional methods e.g.
extraction, filtration, drying, concentration, adsorption, crystal-lization, chromatography, and like manners, and purified in con-ventional methods e.g. recrystallization, reprecipitation, chroma-tography, counter-current distribution, and like methods.
The following examples are provided to illustrate this inven-tion in detail. The elemental analyses and physical constants of the products in each example are consistent with the given structures.
I. I~TRODUCTION OF OX~LYL

COOR
2 ~; CH3 LOOH CO~H 5F 5\~ 3 O~ ~CH3 or reactive 3 COB derivative COB

Example I-l ~R =-CH3 COB = -COOCH2Ph) To a suspension of 80 g of benzyl 6-aminopenicillanate p-toluenesulfonate in 680 ml of tetrahydrouran is added 51. 3 ml of triethylamine under ice cooling with stirring, and then dropwise added a solution of 18. 3 ml of the acid chloride of monomethyl oxalate in 20 ml of tetrahydrofuran to the mixture over a period of 20 minutes. The mixture is stirred for 30 minutes under ice cooling, diluted with 800 ml of ice water and extracted with ethyl ... .
acetate. The extract is washed with 5 % aqueous solution of sodium hydrogencarbonate, water and then brine, dried on sodium ~:
sulfate and concentrated under reduced pressure. The residue is recrystallized rom a mixture of methylene chloride and ether to yield 60 g of benzyl 6~-methoxalylaminopenicillanate melting at 113 - 114.5C in 91.3% yield.
IR: ~ HC 3 3395, 1790, 1745, 171S, 1518 cm NMR: ~ 3 1.43s3H, 1.67s3H, 3.93s3H, 4.55slH, 5.25sZH, ~v~ u 5.~-5.8m2H, 7.43s5H, 7.8brslH.
[a]D + 116.8 + 2.1 (c - 1.002, CHC13).
Example I-2 (R = -CH2Ph, COB = -COOCH3 ~
To a solution of 2.30g of methyl 6-aminopenicillanate and 1.90 g of monobenzyl oxalate in 46 ml of tetrahydrofuran is added 2.17 g of N,~'-dicyclohexylcarbodiimide under ice cooling, and the mixtureIstirred for 30 minutes. The resulting crystals are remo-ved by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on 100 g of silica gel containing 10% water and eluted with benzene containing 10% ethyl acetate to yield 1.8 g of methyl 6~-phenylmethoxalyl-aminopenicillanate in 46% yield.
IR: y 3 3380, 1790, 1750, 1720 cm NMR:S 3 1.48s3H, 1.65s3H, 3.75s3H, 4.50slH, 5.27s2H, 5.50d (3.5Hz)lH, 5.60q(3.5;8Hz)lH, 7.33s5H, 7.72dt8Hz)lH.

Example I-3 (R = -CH Ph, COB = -COOCH ) To a suspension of 16 g of sodium monobenzyl oxalate in 160 ml of methylene chloride containing 0.5 ml of N,~-dimethylforma-~ mide i5 added 6 ml of oxalyl chloride under ice-cooling and the mixture stirred for 30 minutes to yield a solution of the acid chloride. This is dropwise added to a solution o~ 15 g of methyl 6-aminopenicillanate and 11 ml of triethylamine in 150 ml of mëthylene chloride under ice-cooling and the mixture stirred for 20 minutes, washed with water, dried on magnesium sulfate and con-centrated under reduced pressure. The residue is purified ~y ~
chromatography on 250 g of silica gel containing 10 % water and eluted with benzene containing 10 % ethyl acetate to yield 16.9 g of me~hyl 6~-phenylmethoxalylaminopenicillanate in 66 % yield.
E ample I-4 (R = -CH3, COB = -COOCHPh~) To a suspension of 6Q.54 g of diphenylmethyl 6-aminopenicill-.

O
anate p-toluenesulfonate in 400 ml of tetrahydrofuran, are added 33 ml of triethylamine, and then 15 g of the acid chlcride of mono-methyl oxalate under ice-cooling, and the mixture stirred for 20 minutes and concentrated under reduced pressure to yield the residue, which is dissolved in ethyl acetate, washed with water, dried on magnesium sulfate and concentrated under reduced pressure to yield 55.91 g of diphenylmethyl 6~-methoxalylaminopenicillanate as crude product in 109.4 % yield.
NMR : ~ 3 1.30s3H, 1.67s3H, 3.97s3H, 4.63slH, 5.62d(3.5Hz)lH, 5.73q(3.5;8Hz)lH, 7.03slH, 7.43slOH, 7.83d(8Hz)lH.
II. CLEAVAGE OF PENAM RING

COORl COORl lo~H ~__~,s CH CONH ~al ~ I ~ 3 Halogen ~

COB ~ -Example~ l tR = CH3, COB = -COOCH2Ph, Hal = Cl) To a solution of 57.3 g of benzyl 6~-methoxalylaminopenicill-anate dissolved in a mixture of 120 ml of methylene chloride and ~
700 ml of carbon tetrachloride is dropwise added 347 ml of a SQlU- :
tion of chlorine in carbon tetrachloride (1.6 mole/l) with stirring under cooling at -25C, and the mixture stirred for 18 minutes, and ._ .
warmed slowly up to -15C. After 20 minutes, the mixture is poured into about 2 liter o ice cold aqueous 5 % sodium hydrogencarbonate and extracted with methylene chloride. The extract is washed with water, dried on sodium sulfate and concentrated under reduced pressure to yield 66.5 g of the residue, which is purified by chro~
matography on 280 g of silica gel containing 10 % water and eluted with a mixture of benzene and ethyl acetate ~9 : 1 - 8.5 : 1.5) to yield 38.38 g of benzyl a-(~a-chloro-3~-methoxalylamino-4-oxoazeti-.:

~V89~7(J

din-l-yl)-a-isopropylideneacetate in 66.6 % yield.
NMR : ~ 3 2.03s3H, 2.30s3H, 3.90s3H, 5.0-5.3dd(8;1.5Hz)lH, 5.25s2H, 5.83d(1.5Hz)lH, 7.40s5H, 7.90d(8Hz)lH.
ExamPle II-2 (R = -CH2Ph, COB = -COOCH3, Hal = Cl) To a solution of 16.78 g of methyl 6~-phenylmethoxalylamino~
penicillanate in 330 ml of carbon tetrachloride is added a solu-tion of 9.23 g of chlorine in 77 ml of carbon tetrachloride at -20 to -15C with stirring, and the mixture stirred for 20 minutes and shaken with an aqueous solution of sodium hydrogencarbonate. The organic layer is separated, washed with water, dried on magnesium sulfate and concentrated under reduced pressure to yield the resi-due~ which is purified by chromatography on 150 g of silica gel containing 10 % water and eluted with benzene containing 15 % ethyl acetate to yield 14.7 g of methyl a-(2a-chloro-3-phenylmethoxalyl-amino-4-oxoazetidin-1-yl)-a-isopropylideneacetate in 87 % yield.
~ max 3 3390, 1790, 1720 cm NMR :~ 3 2.10s3H, 2.30s3H, 3.77s3H, 5.17q(8;1.5H~)lH, 5.33s2H, 5.95d(1.5H~)lH, 7.42s5H, 8.3~d(8Hz)lH.
Example II-3 (R = CH3, COB = -COOCHPh2, Hal = Cl) To a solution of 55.88 g of diphenylmethyl 6~-methoxalylamino~
penicillanate in 670 ml of carbon tetrachloride is added a solution of 37~58 g of chlorine in 618 ml of carbon tetrachloride under cooling at -15 to -20C. After 30 minutes, the reaction mixture is shaken with an aqueous solution of sodium hydrogencarbonate, and the organic layer is separated, washed with water, dried on magne-. , sium sulfate and-concentrated under reduced pressure to yield the residue, which is chromatographed on 300 g of silica gel containing 10 ~O water and eluted with benzene containing 15 to 20 % ethyl ace-tate to yield 46.82 g of diphenylmethyl a-~2a-chloro-3-methoxalyl-amino-4-oxoa~etidin-1-yl~-a-isopropylideneacetate in 84 % yield.

7(;1 IR ~CHC13 3380, 1790, 1720 cm max NMR : ~ 3 2.02s3H, 2.28s3H, 3.83s3H, 5.07q(8;1.5Hz)lH, 5.70d(1.5Hz)lH, 6.85slH, 7.28slOH, 7.73d(8Hz)lH.
I I I . OXAZOL INE FORMAT ION
IOOR COORl CO ~ Hal -HHal ~ ~ -~ \ /CH3 j ~ CH

Example III-l (R = CH3, COB = -COOCH2Ph, Hal = Cl) AgBF4 To a solution of 38.38 g of benzyl a-(2a-chloro-3~-methoxalyl-amino-4-oxoazetidin-1-yl)-a-1sopropylideneacetate in 350 ml of tetrahydrofuran is added 37.84 g of a mass of silvertetrafluoro l~-borate (about 50 % purity) at -20C with stirring. After 80 minutes, the reaction mixture is poured into 5 % aqueous solution of sodlum hydrogencarbonate under ice-cooling and extracted with ethyl acetate. The extract is filtrated on Hyflo Super Cel pre-::
liminarily washed with water, and the filtrate washed with water, dried on sodium sulfate and evaporated under reduced pressura to ~ ;
yield 32.78 g of benzyl a-(3-carbomethoxy-7-oxo-4-oxa-2,6-dlaza-bicyclol3.2.0]hept-2-en-~-yl)-a-isoprolylideneacetate.
IR : Y 3 1790, 1758, 1730, 1631 cm ~MR : S C 3 1~93s3HJ 2.28s3H, 3.93s3H, 5.25ABg(15;12Hz)2H, ~ ~;
5.40d~3.5Hz)lH~ 6.17d(3.5Hz)lH, 7.40s5H.
Exam ~ (R - -CH2Ph, COB - -COOCH3J Hal - Cl) AgBF4 ~ o a solutlon of 4.80 g of methyl a-(2a-chloro-3~-phenyl~
methoxalylamlno-4-oxoazetidin-1-yl)-a-isopropylideneacetate in 96 ml of tetrahydrofuran is added 4.80 g of silve~rtetrafluoroborate (50 % purity) while stirring and cooling at -20C, and the mixture :
30 stirred for 30 minutes. The reaction mixture is poured~into an ~ ~
d ~ 42 ~ ~ ~

1?~3~ ~ ~V
aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract is washed with water, dried on magne-sium sulfate and concentrated under reduced pressure. The residue is chromatographed on 80 g of silica gel containing 10 % water and eluted with benzene contalning 10 % ethyl acetate to yield 3.42 g of methyl a-(3-benzyloxycarbonyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]
hept-2-en-6-yl)-a-isopropylideneacetate in 78.4 % yield.
IR : ~ 3 1790, 1760, 1730, 1635 cm NMR : ~ 3 1.87s3H, 2.23s3H, 3.70s3H, 5.39s2H, 5.39d(3Hz)lH, 6.17d(3Hz)lH, 7.39s5H.
Example III-3 (R = -CH3, COB = -COOCHPh2, Hal = Cl) ZnC12 To a solution of 1.41 g o~ diphenylmethyl a-(2a-chloro-3~-methoxalylamino-4-oxoazetidin-1-yl)-a-isopropylideneacetate in 20 ml of tetrahydrofuran are added 6 ml of ether solution of zinc chloride (0.61 mole/l) and 0.33 ml of ~-methylmorpholine, and the mixture stirred at room temperature for 15 minutes, diluted with ethyl acetate, washed with water, dried and then concentrated under reduced pressure tQ yield 1.371 g of diphenylmethyl a-(3-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3~2.0]-hept-2-en-6-yl)- -~
a-isopropylideneacetate as crystalline product in 91 % yield~

xample III-4 (R = -CH , COB = -COOCHPh , Hal = Cl) AgBF

To a solution of 22.70 g of diphenylmethyl a-(2a-chloro-3 methoxalylamino-4-oxoazetidin-1-yl)-a-isopropylideneacetate in 230 ml o tetrahydrofuran is added 18.8 g of silvertetrafluoro borate (50 % purity) while cooling at -15 to -20C, and the mix-tuxe stirred or 40 minutes. The reaction mixture is poured into an aqueous solution of sodium hydrogencarbonate and extracted with et~yl acetate. The extract is washed with water, dried on magne-sium sulfate and concentrated under reduced pressure to yield 20.94 g o diphenylmethyl a-(3-carbomethoxy-7-oxo-4-oxa-2~6-diaza-, , ~ ~V~
bicyclo[3.2.0]hept-2-en-6-yl)-a-isopropylideneacetate in 99 %
yield.
IR : Y m 3 1790, 1755, 1725, 1635 cm ~MR : S 3 1.88s3~, 2.23s3H, 3.83s3H, 5.30d(3.5Hz)lH, 6.00d --(3.5Hz)lH, 6.83slH, 7.27s10H.
ExamPle III-5 (R = CH3, COB = -COOCHPh2, Hal = Cl) other reagents.
Diphenylmethyl a-(2a-chloro-3~-methoxalylamino-4-~xoazetidin-l-yl~-a-isopropylideneacetate is dissolved in a solvent and allow-ed to react with the reagent. The reaction mixture is worked up in a conventional manner to yield the starting compound remaining unchanged and diphenylmethyl a-(3_carbomethoxy~7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-a-isopropylideneacetate in the xatio as described in the following table.

I
... _ .............................. . ...................... . ~ :
Rea~ent Reaction Reaction Starting material -15 (mole ratio) Solvent temperature time(hour~ Product SnC12 (1.2) glyme - rt 4.75 3 : 1 SnC12 ~1-4) THF rt 24 1 ~

SnC12 (2.8) THF rt 24 1 : 1*

SnC12 (1.2) /~~~ THF rt 7.5 4 : 1 20CH3~ ~1.0) 10 % ~aHCO3 acetone 0C ~ rt 2 ~ 2 0 : 1*

ZnC12 (1.2) THF rt 2 1 : 1 znC12 ~1.2) THF rt 24 1 : 1*

ZnCi2 (2.4) THF rt 24 1 : 1*

25ZnC12 ~2.4) DMF rt 5 - 1 : 0 ZnC12 ~1.2) THF ~t 0.25 0 : 1 CH3N O (1.0) .

~ ?9L ;~(~
THF : tetrahydrofuran DMF : N,N-dimethylformamide rt : room temperature * : The reaction mixture colors and contains by-product.
IV. R~EI)UCTION YIELDING OXAZOLIDIN

COOR COOR

N

~ ~ CH3 ~ CH3 COB COB

Example IV-l (R - -CH3, COB = -COOCH2Ph) A solution of 32.78 g of benzyl a-(3-carbomethoxy-7-oxo-4-oxa--2,6-diaza-bicyclo[3.2.0]hept-2-en-6-yl)-a-isopropylideneace-15 tate in 500 ml of tetrahydrofuran conta:ining 5 % water is mixed ``
with aluminium amalgam which has been prepared from 22.95 g of aluminium and 0.5 % aqueous solution of mercuric chloride, and the mixture stirred at room temperature for 50 minutes. The reaction mixture is diluted with ethyl acetate and filtrated through a layer ~f Hyflo Supex Cel. The filtrate is dried on sodium sulfate andconcentrated under reduced pressure to yield the residue, which is crystallized from ether to yield 22.02 g of benzyl a-(3~-carbo-methoxy-7-oxo-4-oxa-2,6-diaza-bicyclo[3.2.0~heptan-6-ylj-a-iso-propylideneacetate in 61 % yield. ~ ;
mp. 113 - 115C
IR : ~ m x 3 3366, 1776j 1722, 1633 cm ~IR : S 3 1.88S3H, 2.15s3H, 3.17brslH, 3.75s3H, 4.~7brslH, 5.23s2H, 5.65brslH~ 5.80d(4Hz)lH, 7.40s5H.
[a3D ~94 4 + 2.7C (c = 0.5043 CHC13~
0 Example IV-2 (R = -CH3, COB = -COOCH2Ph) .. .

1~3~
~ .
A solution of 75 g o~ benzyl a-(3-carbomethoxy-7-oxo-4-oxa-2, 6-diazabicyclo[3.2.0]hept-2-en-6-yl)-a-isopropylideneacetate in 900 ml of tetrahydrofuran containing 5 % water is mixed with alu-minium amalgam which has been prepared from 26.3 g of aluminium and 2.5 % aqueous solution of mercuric chloride, and the mixture stirred under ice-cooling for 20 minutes. The reacti~n mixture is filtrated through Hyflo Super Cel, diluted with ethyl acetate, washed with an aqueous solution of sodium hydrogencarbonate and waterJ dried on sodium sulfate, concentrated and then mixed with 10 e~her. The resulting crystals are collected by filtration to ^
yield 47.02 g of ~enzyl a-(3~-carbometho~y-7-oxo-4-oxa-2,6-diaza-bicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate in 62.4 %
yiRld.
mp. 113 - 115C
Example IV-3 (R - -CH3, COB = -COOCH2Ph, Hal = Cl) In the same manner as described in Examples 1 and 2, 65.5 g of benzyl 6-aminopenicillanate p-toluenesulfonate is methoxalyl-ated to yield 59.9 g of benzyl a-(2a-chloro-3~-methoxalylamino-4-oxoazetidin-l-yl)-a-isopropylideneacetate. This is dissolved in ~^
740 ml of tetrahydrofùran and treated with a mixture of 24.24 g o zinc chloride, 16.3 ml of N-methylmorpholine and 226 ml of ether at room temperature in nitrogen atmosphere for 40 minutes. The mixture is then extracted with ethyl acetate to yield 50.79 g of benzyl a-(3-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-a-isopropylideneacetate. This is treated with aluminium amalgam in tetrahydrofuran and purified by chromatography on~
silica gel to yield 18.07 g of benzyl a-(3~-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate in 44 % yield.
mp~ 114 - 116C

~ ~ .

~t~ 7 ~

Example IV-4 (R = -CH2Ph, COB = -COOCH3) To a solution of 5.00 g of methyl a-(3-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-a-isopropylideneacetate in 100 ml of tetrahydrofuran containing 5 % water is added alumi-nium amalgam prepared from 4 g of aluminium and 0.5 g of mercuricchloride, and the mixture stirred at room temperature for 1.5 hours.
The reaction mixture is dried on magnesium sulfate and concentrated under reduced pressure to yield 4.92 g of methyl a-(3~-carbobenz-oxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropyli-deneacetate as crude product in 98.4 % yield.
IR : ~ 3 3380, 1780, 1730 cm NMR S 3 1.77s3H, 2.07s3H, 3.75s3H, 5.00d(3.5Hz)lH, 5.17S2H, 5.67slH, 5.83d(3.5Hz)lH, 7.40s5H.
Example IV-5 (R = -CH3, COB = -COOCHPh2) 15To a solution of 23.0 g of diphenylmethyl a-(3-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-èn-6-yl)-a-isopropylidene-acetate in 480 ml of tetrahydrofuran containing 5 % water is added aluminium amalgam prepared from 10 g of aluminium and 250 ml of 0.5 % mercuric chloride and the mixture stirred at room temperature for 2 hours, dried on magnesium sulfate and concentrated under reduced pressure. The residue is recrystallized from a mixture of methylene chloride and ether (1 : 5) to yield 17.5 g of diphenyl- ;
methyl a-(3~-carbomethoXy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]-heptan-6-yl)-a-isopropylideneacetate in 76 % yield.
mp. 136 - 139C
IR Ymax 3 3370, 1780, 1730, 1710~sh) cm MMR ~CDC13 1~87s3H, 2.13S3H, 3.30-2.70mlH, 3.70s3H, 4.73d (3.5Hz)lH, 5.50slH, 5.67d(3.5Hz)lH, 6.87slH, 7.30-s10H.
V. N-ACYLATION

.,~ .
, .

~V8~
.~

COORl COORl O ~ -C< 3 ~ -NC-C ~ 3 Example V-l (R = -CH3, COB = -COOCH2Ph, Acyl = PhCH2CO-) To a solution of 32.6 g of benzyl a-(3~-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.03heptan-6-yl)-a-isopropylideneacetate in 750 ml of tetrah~drofuran i5 dropwise added a solution of 9.5~ml o~ pyridine and 15.1 ml of phenylacetyl chloride in 144 ml of tetrahydrofuran over a period of 15 minutes while maintaining the temperature at -20C and stirring under nitrog~en atmosphere. The mixture is stirred for 55 minutes~ poured into 700 ml of Lce water~
stirred for 5 minutes and extracted with ethyl acetate. ~he extract is washed with an aqueous solut:ion of sodium hydrogencar-bonate and water, dried on sodium sulfate, and evaporated under~
reduced pressure to yield 46.4 g o benzyl a-(3~-carbomethoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0~heptan-6-ylj-a-isopropylideneacetate as crude product in 107 % yield.
IR CHC13 1787, 1762, 1725, 1674 cm NMR: ~ C 3~ 1.92s3H, 2.20s3H, 3.78s3H, 3.92s2H, 5.LSd(4Hz)lH, ~ ;
5;23s2H, 6.02d(4Hz)lH, 6.13slH, 7.38sSH, 7.42sSH.
ExampLe V-2 (R = -CH3, COB = -COOCH2Ph, Acyl = PhCH2OCO-) To a solution o 360 mg o benzyl a-(3~-carbomethoxy-7-oxo-4 oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropyLideneacetate lD 5 ml of tetrahydrofuran are added 0.1 ml of pyridine and then 255 mg of benzyl chloroformate under lce-cooling, and the mixture st1rred or 90 minutes, and then mixed with water and ethyl~ace-tate. The organic layer is separated, washed with water,~drled and concentrated to yield the residue, which is chromatographed on ; 48 o silica gel containing 10 % water to yield 306 mg of benzyl a-(3~-carbomethoxy-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]-heptan-6-yl)_a-isopropylideneacetate in 61.7 % yield.
IR r max 3 1785, 1750, 1720, 1635 cm .
NMR : ~ 3 1.88s3H, 2.02s3H, 3.78s3H, 5.97d(5Hz)lH, 6.07slH, 5.25m4H, 5.37d(5Hz)lH, 7.4mlOH.
ExamPle V-3 (R = -CH3, COB = COOCH2Ph, Acyl = PhCO-) To a solution of 5 g of benzyl a-(3~-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate in 100 ml of tetrahydrofuran are dropwise added 1.82 ml of pyri-dine and a solution of 2.86 g of benzoyl chloride in 20 ml of tetrahydrofuran at 0C under nitrogen atmosphere. After 20 mi~utes the reaction mixture is warmed up to room temperature. After additional 2 hours, the mixture is diluted with ice water and ex-~racted with ethyl acetate. The extract is washed with an aqueous sodium sulfate and condensed under reduced pressure to yield 7.02 g - of benzyl a-(3~-car~omethoxy-2-benzoyl-7-oxo-4-oxa-2,6-diazabicy-clol3.2.0]heptan-6-yl)-a-isopropylideneacetate as crude product.
NMR~: ~CDC13 1.93s3H, 2.22s3H, 3.82s3H, 5.18S2H, 5.22d(4Hz)lH~
6. d(4Hz)lH, 6.57slH~ 7.2-8.3mllH.
Example V-4 (R = -CH3, COB = -COOCH2Ph, Acyl = PhCH2S02-) ~o a solution of 500 mg of benzyl a-(3~-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate in 10 ml of tetrahydrofuran are added 0.27 ml of triethylamine and 343 mg of phenylmethanesulfonyl chloride under ice-coaling in nitrogen atmosphere, and the mixture stirred for 25 minutes. The reaction mixture is poured into ice water and extracted with ethyl a~etate, and the extract washed with water, dried on sodium sulfate a~d concentrated under reduced pressure to yield 756 mg of benzyl a-(3~-carbomethoxy-2-phenylmethanesulfonyl-7-oxo-4-oxa-2,6-diaza-~' ..

bicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate.
NMR : ~ 3 1.87s3H, 2.17s3H, 3.77s3H, 4.57s2H, 5.23s2H, 5.27d~4Hz)l~I, 5.95d(4Hz)lH, 6.20slH, 7.2-7.6mlOH.
ExamPle V-5 (R = -CH2Ph, COB - -COOCH3, Acyl = PhCH2CO-) To a solution of 4.90 g of methyl a-(3~-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3,2.0]heptan-6-yl)-a-isopropylideneacetate in 50 ml of tetrahydrofuran are added 2.4 ml of triethylamine and then 2.5 ml of phenylacetyl chloride under ice-cooling, and the mixture stirred for 30 minutes, poured into water and extracted with ethyl acetate. The extract is washed with water dried on magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on 150 g of silica gel containing l0 %
water and eluted with benzene containing 10 % ethyl acetate to ! `
yield 4.37 g of methyl a-~3~-carbobenzoxy-2-phenylacetyl-7-oxo-4-oxa-2,~-diazabicyclol3.2.0~heptan-6-yl)-a-isopropylideneacetate in 67.2 % yield.
IR : YmaX 3 1795, 1760, 1730, I675 cm NMR : ~ 3 1.73s3H, 2.08s3H, 3.70s3~, 3.83s2H, 5.13brs3H, 5.93d(3.5Hz)lH, 6.07slH, 7.20s5H.
Example V-6 (R = -CH3~ COB = -COOCHPh2, Acyl = PhCH2CO-) To a solution of 16.46 g of diphenylmethyl a-(3~-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylidene-acetate in 160 ml of methylene chloride are added 9.6 ml of tri-ethylamine and 9 ml of phenylacetyl chloride under ice-cooling, and the mixture stirred at room temperature for 2 hours. The reaction mixture is then washed with water, dried on magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on 200 g of silica gel containing 10 % water and eluted with benzene containillg 10 % ethyl acetate to yield 17 to ~`
19 g of diphenylmethyl a-(3~-car~omethoxy-2-phenylacetyl-7-oxo-4-J

~8~3~70 oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate in 80 to 90 % yield.
IR : ~ 3 1790, 1760, 1730~ 1675 cm NMR : ~ 3 1.90s3H, 2.17s3H, 3.70s3H, 3.83s2H, 4.g7d(3.5Hz)lH, 5.80d(3.5Hz)lH, 5.97slH~ 6.80slH, 7.20s10H.
VI. DEPROTECTION YIELDING FREE CARBOXY

COOR - COOH

Acyl ~ Acyl~ ~ C ~ 3 Exam~le VI-l (R = -CH3, COB = -COOCH2Ph, Acyl = PhCH2CO-) ~ `.
To a solution o~ 39 g of benzyl a-(3~-carbomethoxy-2-phenyl-acetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isoprop-ylideneacetate in 628 ml of acetone is added 228 ml of water and then dropwise added 90.8 ml of 1. 0N aqueous solution of sodium hyd:roxide. The mixture is stirred for 1 hour under ice-cooling, diluted with 630 ml of ice water, covered with ethyl acetate, adjusted to pH 2 with 20 % hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried on sodium sul~ate and concentrated under reduced pressure to yield 41.7 g of benzyl a-(3~-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diaza-bicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate as crude product.
IR ~CHc13 3500, 1785, 1724, 1704, 1672 cm NMR : ~ 3 1.85s3H, 2.13s3H, 3.87s2H, 5.1-5.2mlH, 5.18s2H, 6.00d(4Hz)lH, 6.03slH, 7.30s5H, 7.37s5H, 9.47brslH.
Example VI-2 (R = CH3, COB = -COOCH2Ph, Acyl = PhCH2OCO-) To a solution of 1.482 g of benzyl a-(3~-carbomethoxy-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-- ,: , ~9~

isopropylideneacetate in 20 ml of acetone is added 5 ml of 0.6 M
aqueous solution of sodium hydroxide under ice-cooling, and the mixture stirred for 45 minutes~ then neutralized with 2N hydro-chloric acid and extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure to yield 1.27 g of benzyl a-(3~-carboxy-2-carbobenzoxy-7-oxo-4-oxa-2~6-diazabicyclo[3.2~o]heptan-6-yl)-~-isopropylideneacetate as crude product in 88.5 % yield.
NMR : ~ 3 1.83s3H, 2.18s3H, 5.88d(5Hz)lH, 5.97slH, 6.90slH, 5.13s2H, 5.17s2H, 7.30mlOH.
Example VI-3 (R = C~3, COB = -COOCH2Ph, Acyl = PhCO-) To a solution of 7.02 g of benzyl a-(3~-carbomethoxy-2-ben-zoyL-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropyl-ideneacetate dissolved in a mixture of 85 ml of acetone and 26.5 ml of water is added 20 ml of 1.012~ aqueous solution of sodium hydroxide at -3 to -4C over a period o:E an hour and the mixture diluted with water and washed with ethy:L acetate. The aqueous layer is separated, adjusted to pH 2.0 with 4~ hydrochloric acid~
and then extracted with ethyl acetate. The extract is washed with water, dried on sodium sulfate, and concentrated under reduced pressure to yield 6.34 g of benzyl a-(3~-carboxy-2-benzoyl-7 oxo-4-oxa-2,6-diazabicyclo13.2.0]heptan-6-yl)-a-isopropylideneacetate as foamy material.
IR : ~ H 3 3500, 1788, 1730, 1663 cm NMR :~ 3 1.93s3H, 2.18s3H, 5.17ABqtl4;13Hz)2H, 5.20d(4Hz)lH, 6.03d(4Hz)lH, 6.57slH, 7.2-8.3mllH.
ExamPle VI-4 (R = CH3~ COB = -COOCH2Ph, Acyl = PhCH2S02-) To a solution of 756 mg of benzyl a-(3~ carbomethoxy-2-phenyl-methanesulfonyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate dissolved in a mixture of 9 ml of acetone and 2.7 ml of water is added 1.85 ml of 1.012N aqueous solution of sodium hydroxide under ice-cooling. After 15 minutes, the reaction mixture is poured into ice water, mixed with ethyl acetate, adjus-ted to pH 2 with 2N-hydrochloric acid under ice-cooling and extrac-ted with ethyl acetate. The extract is washed with water, dried on'sodium sul~ate, and evaporated under reduced pressure to yield 705 mg of benzyl a-(3~-carboxy-2-phenylmethanesulfonyl-7-oxo-4-oxa-2, 6-diazabicyclo~3.2.0]heptan-6-yl)-a-isopropylideneacetate.
IR : ~ H 3 1785, 1728, 1634, 1603 cm NMR : ~ 3 1.83s3H, 2.10s3H, 4.57s2H, 5.22s2H, 5.27d(4Hz)lH, 5.93d(4Hz)lH, 6.25slH, 7.2-7.6mlOH, 9.03slH.
ExamPle VI-5 (R = PhCH2-, COB = COOCH3, Acyl = PhCH2CO-) A solution of 4.24 g of methyl a-(3~-carbobenzoxy-2-phenyl-acetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yL)-a-isopropyli-deneacetate dissolved in 64 ml of tetrahydrofuran is catalyticallyhydrogenated on 1.3 g of 5 % palladium carbon under atmospheric pressure. The catalyst is removed by filtration and the filtrate is condeneed to yield 3.38 g of methyl a-(3~-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylidene-acetate as crude product in quantitative yield.
IR : ~ maHx 3 3500, 1790J 1735, 1685 cm NMR :~ 3 1.90s3H, 2.20s3H, 3.78s3H, 3.97s2H, 5.30d(3.5Hz)lH, _ . . .
6.13d(3.5Hz)lH, 6.15slH, 7.40s5H, 8.17brslH.
Example VI-6 (R = CH3, COB = -COOCHPh2, Acyl = PhCH2CO-) To a solution of 11.3 g of diphenylmethyl a-(3~-carbomethoxy-2-phenylacetyl-7-oxo-4-oxa-2~6-diazabicyclo[3.2.0~heptan-6-yl)-a-isopropylideneacetate in 230 ml of acetone is added a solution of 900 mg of sodium hydroxide in 36 ml of water under ice-cooling, and the mixture stirred for 1 hour, then diluted with water, acidi~ied with hydrochloric acid, and then extracted with methylene 53 ~ ~
~. :

~ IL7V

1 chloride. The extract is washed with water, dried on magnesium sulfate and concentrated under reduced pressure to yield 12.54 g of diphenylmethyl ~-(3 ~-carboxy~2-phenylacetyl-7-oxo-4 oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)--isopro-pylideneacetate as crude product. -NMR : ~ CDC13 1.89s3H, 2.17s3H, 3.89s2H, 5.08d(3.5Hz)lH, 5.92d (3.5Hz)lH, 6.09slH, 6.93slH, 7.33s10H, 7.53brsl~1.
This product can be converted into the starting material on treatment with diazomethane in ether.
VII. ACID ~IALIDE FORMATION
VIII. DIAZOKETONE
IX. HALOMETHEYL KETONE

COOH COHal AcylN ~ ~ CH3 Hal ~ NC=C ~ 3 O NCaC\ > I ~ CH VIII

COB -.
.
~ N2 ' - . COCH2Z
Acyl ~ CN3 HZ Acy1l ~ /C33 f ~ CH IX ¦ ~ CH
COB
Example IX-l (COB a COOCH2Ph, Acyl _ PhCH2OCO-, Z = Cl) To a solution of 435 mg of benzyl -(3 ~ -~iazoacetyl-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo [3.~2.3]heptan-6-yl)--isopropylideneacetate in 4 ml of m~hylene chlori~e i5 added 1 ml of ether containing 16~ `
hydrogen chloride~ and the mixture stirred at room temperature for 30 minutes and ~hen concentrated under ~ ~
-.:

q~

reduced pressure to yield 433 mg of benzyl a-(3~-chloroacetyl-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabi~yclo[3.2.0~heptan-6-yl)-a-isopropylideneacetate as crystals.
IR yCHC13 1785, 1720 cm max NMR : ~ 3 1.80s3H, 2.20s3H, 4.43s2H, 5.08m4H, 5.43d(5Hz)lH, 6.10d(5Hz)lH, 6.43slH, 7.3mlOH.
Exa~ple (~II-VIII)-2 (COB = -COOCH2Ph, Acyl = PhCH20CO-, Hall = Cl) To a solution of 1.44 g of benzyl a-(3~-carboxy-2-carbobenz-oxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropyli-deneacetate in 15 ml of benzene is added 0.09 ml of N,N-dimethyl-formamide and then dropwise added 0.3 ml of oxalyl chloride under ice-cooling, and the mixture stirred at room temperature for 30 minutes. The resulting solution of benzyl a-(3~-chlorocarbonyl-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabic~clo[3.2.0]heptan-6-yl)-a-isopropylideneacetate is concentrated under reduced pressure to yield the residue~ which is dissolved in 10 ml of methylene chlor-ide and mixed with ether solutio~ of diazomethane under ice-cooling and then stirred at room temperature for 30 minutes. The mi~ture is concentrated under reduced pressure to yield 1.519 g of the residue, which is purified by chromatography on silica gei contain-ing 10 % water to yield 886 mg of benzyl a-(3~-diazoacetyl-2- ;
carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-y~-a-isopropylidene acetate as yellow solid in 58.6 % yield.
IR : ~ 3 2200~ 1780, 1720, 1650 cm t ~MR : ~CDC13 1.87s3H, 2.18s3H, 5.05m4H, 5.43d(5Hz~lH, 5.75slH, 6.05d(5Hz)lH, 6.08slH, 7.3mlOH.
Exa~-ple ~II, VIII, IX)-3 (COB = -COOCH3, Acyl = PhCH2Co-, Hal = Cl, ~ = Cl) To a solution of 1.4S g of methyl a-(3~-carboxy-2-phenylacetyl-, 7-oxo~4-oxa-276-diazabicyclo[3.2.0~heptan-6-yl)-~-isopropylidene-acetate in 7 ml of methylene chloride is added 1.2 ml of thionyl chloride, and the mixture refluxed under heating for 2 hours and concentrated under reduced pressure. The resulting residue [methyl-a-(3~-chlorocarbonyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo-[3.2.0]heptan-6-yl)-a-isopropylideneacetate] is dissolved in 20 ml of tetrahydrofuran and mixed with 15 ml of ether solution of diazo-methane which has been prepared ~rom 1.5 g of nitrosomethylurea, and the mixture is kept at room temperature for 30 minutes. Into the resulting solution of methyl a-(3~-diazoacetyl-2-phenylacetyl-7-oxo-4 oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylidene-acetate is introduced hydrogen chloride gas under ice-cooling until the spot of diazo ketone disappears. The mixture is concentrated under reduced pressure, and the residue is purified by chromatog-raphy on 17 g of silica gel containing 10 % water and eluted with benzene containing 10 % ethyl acetate to yield 1.19 g of methyl a-(3~--chloroacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]-heptan-6-yl)-a-isopropylideneacetate in 75.3 % yield.
IR : Y m 3 1790, 1725, 1705, 1670 cm NMR S 3 1.83s3H, 2.15s3H, 3.77s3H, 3.92s2H, 4.37s2H, 5.25d(3.5Hz~lH, 6.10d(3.5Hz)lH, 6.29slH, 7.37s5H.
ExamPle (VII. VIII. IX)-4 (COR = -COOCHPh2, Acyl =
PhCH2CO-, Hal = Cl, Z = Cl) To a solution of 1.774 g of diphenylmethyl a-~3~-carboxy-2-`phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo~3.2.0]heptan-6-yl)-a-isopropylideneacetate dissolved in a mixture of 18 ml of benzene and 0.1 ml of N,N-dimethylforMamide is added 0.43 ml of oxalyl chloride, and the mixture stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue 30 (diphenylmethyl a-(3~-chlorocarbonyl-2-phenylacetyl-7-oxo-4-oxa- -~

' ~ '.

'7V
o 2,6-diazabicyclo~3.2.0]heptan-6-yl)-a--isopropylideneacetate) is dissolved in 10 ml of methylene chloride and mixed with 15 ml of ether solution of diazomethane~ which has been pxepared from 1.5 g of nitrosomethylurea, under ice-cooling, and the mixture stirred for 30 minutes. To the resulting solution of diphenylmethyl a-(3~-diazoacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]-heptan-6-yl)-a-isopropylideneacetate is added an ether solution of hydrogen chloride until the spot of diazoketone disappears, and the mixture concentrated under reduced pressure. The residue is purified by chromatography on 40 g of silica gel containing 10 %
water and eluted with benzene containing 10 % ethyl acetate to yield 1.59 g of diphenylmethyl a-(3~-chloroacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6~diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylidene-acetate in 84.7 % yield.
IR : ~ mH 3 1785, 1730, 1670 cm ~MR: ~ 3 1.80s3H, 2.12s3H, 3.78s2H, 4.25s2H, 5.00d(3.5Hz)lH, 5.83d(3.5Hz)lH, 6.13slH, 6.85slH, 7.23slOH.
Exam~le IX-5 (COB - -COOCHPh2, Acyl = PhCH2CO-, Z = OAc) To a solution of 20~ mg of diphenylmethyl a-(3~-diazoacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate in 2 ml of acetic acid is added 0.045 ml of boron trifluoride etherate. After the termination of gas evolution, the reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is washed with water, an aqueous solu-tion of sodium hydrogencarbonate and then water, dried on sodium sulfate and evaporated. The residue t205 mg) is purified by thin-la~er chromatography to yield 65 mg of diphenylmethyl a-(3~-acetoxy-acetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate in 30 % yield.

IR : y 3 1788, 1752, 1730sh, 1675 cm NMR ~CDC13 1.80s3H, 2.03s3H, 2.15s3H, 3.80s2H, 4.80s2H, 5.00brlH, 5.82d(4Hz)lH, 6.08slH, 6.80slH, 7.20s10H.
X. REDUCTION YIELDI~G METHYLKETONE

Acyl ~ Acyl ~

~ I \ CH3 O ~ I \CH

xamPle (VII, VIII, IX, X)-l ~COB = COOCH2Ph, Acyl = PhCH2CO-, Hal = Cl, ~ = CI--~H) To a solution of 10 g of benzyl a-(3~-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-~-isopropylidene-acetate in 120 ml of benzene are added 0.25 ml of ~,N-dimethylfor-mamide and 2.2 ml of oxalyl chloride, and the mixture stirred at `
room temperature, for 45 minutes. The resulting solution of benzyl-a-(3~-chlorocarbonyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo-13.2.03heptan-6-yl)-a-isopropylideneacetate is concentrated to about 1/2 volume~ then dropwise added to a solution of diazomethane in 250 ml of ether (which has been prepared from 13 g of nitroso-methyl-urea) under ice-cooling, and stirred for 20 minutes. The resulting solution of benzyl a-(3~-diazoacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclol3.2.0]heptan-6-yl)-a-isopropylideneace-ta~e is mixed with 10 ml of ether containing 16 % hydrogen chloride and after 85 minutes, the mixture is concentrated under reduced pr~ssure. The residue lbenzyl a-(3~-chloroacetyl~2-phenylacetyl-7-oxo-~-oxa-2,6-dia2abicyclo[3.2.0]heptan-6-yl)-a-isopropylidene-acetate (IR: ~ max 3 1786, 1724, 1674 cm )], is dissolved in 100 ml of acetic acid and mixed with 10 g of zinc powder which has J

~U~
?
preliminarily been washed with hydrochloric acid, water, ethanol and ether, and stirred at room temperature for 1.5 hours. The reactiOn mixture is filtrated, and the filtrate poured into 90 ml of ice water and extracted with methylene chloride. The extract is washed with water, an aqueous solution of sodium hydrogencarbo-nate and then water, dried on sodium sulfate and concentrated under reduced pressure. The residue (9.68 g) is purified by chromatog~
raphy on 200 g of silica gel containing 10 % water and eluted with a mixture of benzene and ethyl acetate (7 : 1) to yield 7.208 g of benzyl a-(3~-acetyl-2-phenylacetyl~7-oxo-4-oxa-2,6-diaæabicyclo-[3.2.0]heptan-6-yl)-a-isopropylideneacetate in 79.7 % yield.
IR : ~ 3 1785, 1727, 1703, 1670, 1603, 1585 cm 1 N~R : S 3 1.85s3H, 2.18s3H, 2.28s3H, 3.92s2H, 5.15d(4Hz)lH, 5.23ABq(14;13Hz)2H, 6.03d(4Hz)lH, 6.15slH, 7.38s5H, 7.42s5H.
Example X-2 (COB = -COOCH2Ph, Acyl = PhCH20CO-, Z = Cl--~H) To a solution of 433 mg of benzyl a-(3~-chloroacetyl-2-carbo-benzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopro- ~ ;
pylideneacetate dissolved in a mixture of 4 ml of methylene chloride and 4 ml of acetic acid is added 450 mg of zinc powder, and the mixture stirred at room temperature for 1 hour. The reac-tion mixture is filtrated and the filtrate diluted with water and extracted with methylene chloride. The extract is washed with water, dried and èvaporated to yield 375 mg of benzyl a-(3~-acetyl-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-~-isopropylideneacetate as an oily material in 98 % yield.
NMR : ~ 3 1.80s3H, 2.17s3H, 2.26s3H, 5.17m4H, 5.37d(5HzjlH, 5~97sl~) 6.0d(5Hz)lH, 7.3mlOH.
Example _(VII, VIII, IX, X)-3 (COB = -COOCH2Ph, Acyl = PhCO-, z = Cl ~H) ~ -d 7~1 To a solution of 5.8 g of benzyl a-(3~-carboxy-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylidene-acetate dissolved in a mixture of 70 ml of benzene and 0.14 ml of N,N-dimethylformamide is added 1.33 ml o~ oxalyl chloride at room 5 temperature under nitrogen atmosphere, and the mixture allowed to stand for 30 minutes, and concentrated to 1/2 volume. The result-ing solution of benzyl a-(3~-chlorocarbonyl-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl) ~-isopropylideneacetate is mixed under ice-cooling with an ether solution of diazomethane 10 prepared from 4 g of N-nitrosomethylurea. The resulting solution of benzyl a-(3~diazoacetyl-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo-13.2.0]heptan-6-yl)~-isopropylideneacetate is mixed with 2.1 ml o~ ether containing 0.47 g of hydrogen chloride at 0C, and after 2 hours, evaporated to yield 6.3 g of benzyl a-(3~-chloroacetyl-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo13.~.0]heptan-6-yl) ~-isopro-pylLdeneacetate as an yellow-brown oil.
This product dissolved in 60 ml of acetic acid is mixed with 5.8 g oE activated zinc under nitrogen gas at room temperature, and the mixture stirred for 25 minutes, poured into ice water and extracted with ethyl acetate. The extract is washed with an aqueous solution of sodium hydrogencarbonate and water, dried on sodium sulfate and evaporated to yield S.04 g of benzyl a-(3~:-acetyl-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl) -~-isopropylideneacetate. This is purified by chromatography on 200 g Oe silica gel containing 10 % water and eluted with a mixture of ~enzene and ethyl acetate (5 : 1) to yield 2.9 g of the pure product in 46.5 % yield.
~ r max 3 1785, 1732, 1660 cm NMR : ~ 3 1.85s3H, 2.17s3H, 2.30s3H, 5.17d(4Hz)lH, 5.22ABq 30(15;12Hz)2H, 6.05d(4Hz)lH, 6.50slH, 7.2-8.lmllH.

l~V~

[a]21.5 -91.7 (c = 0.412, CHC13) Example (VII VIII~ IX, X)-4 (COB = -COOCH2Ph, Acyl = PhCH2S02-, Hal = Cl, Z = Cl -~H~
To a solution o 600 mg of benzyl a-(3~-carboxy-2-phenyl-methanesulfonyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate in 12 ml of benzene are added 40 ,ul of dimethylformamide and 0.12 ml of oxalyl chloride, and the mixture kept at room temperature for 20 minutes. The reaction mixture is concentrated to 1/3 volume, diluted with 6 ml of methylene chloride, and mixed with an ether solution of diazomethane under cooling at -20C. After 30 minutes, the reaction mixture is mixed with 1 ml of ether solution containing 0.24 g of hydrogen chloride at -20C, and after 50 minutes, evaporated in vacuo under ice-cooling. The residue, benzyl ~-(3~-chloroacetyl-2-phenylmethanesulfonyl-7-oxo- ~"
. . ~ .
4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate, is dissolved in 6 ml of glacial acetic acid, mixed with 600 mg of activated zinc powder,-and stirred at room temperature ~or 140 minutes. The reaction mixture, from which zinc powder is removed, is poured into ice water and extracted with methylene chloride.
The extract is washed with water, an aqueous solution of sodium hydrogencarbonate and then water, dried on sodium sulfate and con-centrated under reduced pressure to yield 563 mg of the res-idue, which is purified by chromatography on 17 ~ of silica gel contain-ing 10 % water and eluted with a mixture of benzene and ethyl ace-~25 tate (7 : 1) to yield 377 mg of benzyl a-(3Y~-acetyl-2-phenylmethane-sulfonyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-iso-propylideneacetate in 64 % over-all yield from Example 48.
IR r'cacl3 179~l 1735, 1634, 1608 cm~
~MR :~ 3 1.77s3H, 2.13s3H, 2.18s3H, 4.57s3H, 5.17d(4Hz)lH, 5.23ABq(14;12Hz)2H, 5.97d(4~z)lH, 7.2-7.6mlOH.

U

Example X-5 (cos = -COOCH3, Acyl = PhCH2CO-, Z = Cl--~H) To a solution of 1.28 g of methyl a-(3~-chloroacetyl-2-phenyl-acetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropyl-ideneacetate in 13 ml of acetic acid is added 2 g of zinc powder, and the mixture stirred at room temperature for 1 hour. The reac-tion mixture is filtrated, and the filtrate poured into water and extracted with methylene chloride. The extract is washed with water, dried on magnesium sulfate and concantrated under reduced pressure to yield 1.125 g of a-(3~-acetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo~3.2.0]heptan-6-yl)-a-isopropylideneacetate in approximately 95.7 % yield.

IR ~ CHC13 1780 1730 1670 -1 max NMR : ~ 3 1.82s3H, 2.17s3H, 2.27s3H, 3.78s3H, 3~92s2H, 5.30d(3.5Hz)lH, 6.10d(3.5Hz)lH, 6.13slH~ 7.37s5H.
Example X-6 (COB = -COOCHPh2, Acyl = ;PhCH2CO-, Z = Cl-~H) To a solution of 1.59 g of diphenylmethyl a-(3~-chloroacetyl-2-phenyLacetyl-7-oxo-4-oxa-2,6-diazabicyclo~3.2.0]heptan-6-yl)-a-isopropylideneacetate in 16 ml of acetic acid is added 1.5 g of `
zinc powder, and the mixture stirred at room temperature for 1 hour, then poured into water and extracted with methylene chloride.
The extract is washed with water, dried on magnesium sulate and concentrated under reduced pressure. The residue is purified by chromatography on 30 g of silica gel containing 10 % water and eluted with benzene containing 10 % ethyl acetate to yield 1.21 g of diphenylmethyl a-(3~acetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate in 81 %
yield.
IR : ~ ~HC13 1785~ 1730, 1670 cm~

NMR :~ 3 1.82s3H, 2.15s3H, 2.22s3H, 3.87s2H, 5.07d(3.5Hz~lH, 5.90d(3.5Hz)lH, 6.10slH, 6.97slH, 7.33sl0H.

XI. OXAZOLIDINE CLEAVAGE

Acyl ~ Acyl ~ 2 2 f ~CH3 ~ Nf =c ~ CH3 COB COB

Example XI-l (COB = -COOCH2Ph, Acyl - PhCH2CO-, Z = h) To a solution of 550 mg of benzyl a-(3~-acetyl-2-phenylacetyl-7 oxo~4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylidene-acetate in 8 ml of tetrahydrofuran is added 5 % palladium carbon7 and the mixture catalytically hydrogenated under atmospheric pressure for 2 hours. The insoluble material is removed by fil- ~ ` ~
tration, and th~ filtrate concentrated under reduced pressure. The `
residue (471 mg) is crystalllzed from a mixtuxe of ether and petro~
leum ether to yield 421 mg of a-(3~-acetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetic acid in 9S % yield.
mp. 80 - 88C.
~0 IR : ~ H 3 1783, 1741, 1674, 1626, 1498, 1455 cm 1 NMR : ~ 3 1.87s3H, 2.22s3H, 2.27s3H, 3.92s2H, 5.23d(4Hz)lH, 5.80d(4Hz)lH, 7.33s5H, 7.52slH.
Example XI~2 (COB = -coocH2ph~ Acyl = PhCH2CQ-, Z = H) A solution of 1 g of benzyl a-(3~acetyl-2-phenylacetyl-7- ~ ~
oxo-4-oxa-2,6-diazabicyclo[3.2.0~heptan-6-yl)-a-isopropylidene- ;~ ` ;
.
ace ate dissolved in a mixture of 8 ml of t-butanol and~2 ml of tri1uoroacetic acid is mixed under ice-cooling with aluminium amalgam prepared from 3 g of aluminium7 and the mixture stirred for 2 hours. The supernatant solution from which amalgam has been removedg is mixed with water and extracted with methylene chloride.

-7(3 The extract is wa~hed with an aqueous solution of sodium hydrogen-carbonate, water, and a saturated aqueous solution of sodium chloride, dried on magnesium sulfate and evaporated. The residue (737 mg) is chromatographed on silica gel containing 10 % water to yield 228 mg of the starting material and 326 mg of benzyl a-(2~-acetonyloxy-3~-phenylacetamido-4-oxoazetidin-1-yl)-a-isopropylidene-acetate in 32.2 % yield.
Example XI-3 (COB = -COOCH2Ph, Acyl = PhCH2CO-, Z = H) A solution of 9.62 g of benzyl a-(3~-acetyl-2-phenylacetyl-7`oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylidene-acetate in 20 ml of benzene is diluted with 254 ml of t-butanol and then mixed with 48.4 g of active zinc powder. Then 22 ml of 16 % hydrogen chloride in ether is dropwise added thereto with stirring in nitrogen atmosphere. After the termination of dropwise addition, the mixture is filtrated, and the filtrate shaken with water and ethyl acetate. The organic layer is separated, washed with water, dried on sodium sulfate and concentrated under reduced pressure. The residue ~11.2 g ) is chromatographed on 500 g of silica gel containing 10 % water to yield 1.03 g of the starting material and 4.3 g of benzyl a-(2~-acetonyloxy-3~-phenylacetamido-~
4-oxoazetidin-1-yl)-a-isopropylideneacetate in 44.7 % yield.
IR : ~ m 3 3420, 1778, 1724, 1684 cm ~MR :~ 3 1.90s3H, 1.97s3H, 2.25s3H, 3.61s2H, 3.85brs2H, 5.05-5.40m4H, 6.35d(8Hz)lH, 7.33s5H, 7.28s5H.
[~JD -8.0 ~ 1.0 (c = 0.476, CHC13) Example XI-4 (COB = -COOCH2Ph, Acyl = PhCH2CO-, Z = H) A solution of 100 mg of benzyl a-(3~-acetyl-2-phenylacetyl- ;
7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylidene-acetate in 1 ml of trifluoroacetic acid is mixed with aluminium amalgam prepared from 300 mg of aluminium, and the mixture stirred 3~3~47~
at room temperature for 2 hours, then poured into ice water and extracted with methylene chloride. The ex-tract is washed with water~ dried on sodium sulfate and concentrated to yield 68 mg of the residue containing 60 to 70 % benzyl a-(2~-acetonyloxy-3~-phen-ylacetamido-4-oxoazetidin-1-yl)-a-isopropylideneacetate.
The same reaction as mentioned above is carried out in a mix-ture of ethanol or t-butanol and formic acid (9 : 1) in place of trifluoroacetic acid to yield about 60 to 90 mg of the residue containing about 30 % of the objective compound.
ExamPle XI-5 (COB = -COOCH2Ph, Acyl = PhCO-, Z = H) To a solution of 107 mg of benzyl a-(3~-acetyl-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylideneace-tate dissolved in a mixture of 0.5 ml of benzene and 3 ml of t-butanol i~ added 550 mg of activated zinc powder at 15C under nitrogen atmosphere, and then dropwise added 0.75 ml of ether con-taining 16 % hydrogen chloride. The reaction mixture is poured into ice water and extracted with methylene chloride. The extract is washed with water, dried on sodium sulfate and evaporsted. The residue (107 mg) is purified by chromatography on silica ~el con-taining la % water to yield 45 mg of benzyl a-(2~-acetonyloxy-3R-benzamido-4-oxoazetidin-1-yl)-a-isopropylideneacetate as colorless syrup in 42 % yield.
IR : ~ x 3 3430J 1775, 1720, 1664, 1600, 1580 cm NMR : ~ 3 1.93s3H, 2.00s3H, 2.23s3H, 4.03s2H, 5.17ABq (l4;l2Hz)2HJ 5.20d(4Hz)lHJ 5.23dd(8;4Hz)lH, 7.17d ~8Hz)lHJ 7.2-8.0mllH.
lalD -12.4 + 1.1 (c = 0.491, CHC13) Example XI-6 ~COB - -COOCH2Ph, Acyl = PhCO-, Z = H) A solution of 100 mg of benzyl ~-(3~-acetyl-2-benzoyl-7-oxo- ~ ;
304-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropylideneacetate ____ ___ .

~ 9~7~31 dissolved in 1 ml of a mixture of trifluoroacetic acid and t-butanol (1 : 4) is mixed with aluminium amalgam prepared from 300 mg of aluminium, and the mixture stirred at room temperature for 3.5 hours. The reaction mixture is diluted with methylene chloride washed with water, dried on sodiumsulfate and evaporated to yield 69 mg of a residue, which is a mixture of the starting material and benzyl a-(2~-acetonyloxy-3~-benzamido-4-oxoazetidin-1-yl)-a-isopropylideneacetate (about 2 : 3).
Example XI-7 (COB = -COOCH2Ph, Acyl = PhCH2SO2-, Z = H) ~ To a solution of 67 mg of benzyl a-(3~-acetyl-2-phenylmethane-sulfonyl-7-oxo-4-oxa-2,6-diazabicyclol3.2.0]heptan-6-yl)_-isopro-pylideneacetate dissolved in a mixture of 0.3 ml of benzene and 2 ml of t-butanol is added 335 mg of activated zinc powder under nitrogen atmosphere while the reaction temperature is maintained at L0C. Then 0.3 ml of ether containing 16 % hydrogen chloride is dropwise added thereto and the mixture stirred at room tempera-ture for 40 minutes. The reaction mixture, from which zinc powder is removed, is poured into water and extracted with ethyl acetate.
The extract is washed with water, dried on sodium sulfate and con~
centrated under reduced pressure to yield 65 mg of benzyl a-(2 acetonyloxy-3~-phenylmethylsulfonylamino-4-oxoazetidin-1-yl)-a-isopropylideneacetate. This is purified by thin layer chromatog-raphy to yield 30.3 mg of the pure product in 45.2 % yield.
IR : Y m x 3 3370. 1782, 1730, 1634 cm ~MR : ~ 3 2.02s6H, 2.28s3H, 4.13s2H, 4.43s2H, 4.67q(10;4Hz)lH, 5.20d(4Hz)lH, 5.25ABqtl5;12Hz)2H, 5 45d(10Hz)lH, 7.3-7.6mlOH.
~xample XI-8 (COB = -COOCH3, Acyl = PhCH2CO-, Z = H) To a solution o 300 mg of methyl a~(3~-acetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopr~pylidene-9L7~

acetate in 3 ml of acetic acid is added 1.5 g of activated zinc powder and then dropwise added 3 ml of acetic acid saturated with hydrogen chloride at room temperature~ and the mixture stirred for 30 minutes, then poured into water and extracted with methylene chloride. The extract is washed with water, dried on magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel containing 10 % water and eluted with benzene con-taining 20 to 40 % ethyl acetate to yield the starting material remaining unchanged and methyl a-(2~-acetonyloxy-3~-phenylacetami-do-4-oxoazetidin-l~yl)-a-isopropylideneacetate in 20 to 30 % yield.
IR : ~ 3 3400, 1780, 1730, 1680 cm NMR : ~ 3 1.97s6H, 2.23s3H, 3.63s2H, 3.73s3H, 3.97s2H, 5.26d(3.5Hz)lH, 5.33q(8;3.5Hz)lH, 6.74d(8Hz)lH, j.33s5H.
Example (X, XI)-9 (COB = -COOCH3, Acyl = PhcH2co-~ z = H) To a solution of 233 mg of methyl a-(3~-chloroacetyl-2-phenyl-acetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.200]heptan-6-yl)-a-isopropyl-ideneacetate in 2 mi of acetic acid is added 1 g of activated zinc powder and then dropwise added 2 ml of acetic acid saturated with hydrogen chloride at room temperature. The mixture is stirred for 30 minutesj poured into water and extracted with methylene chloride.
The extract is washed with water, dried on magnesium sulfate and concentrated under reduced pressure to yield the residue containing about 40 % methyl a-(2~-acetonyloxy-3~-phenylacetamido-4-oxoa&eti-din-l-yl)-a-isopropylideneacetate.
Example XI-10 (CO~ = -COOCH3, Acyl = PhCH2CO-, Z = H) A solution of 208 mg of methyl a-(3~-acetyl-2-phenylacetyl-7 -oxo-4 -oxa-2.6-diazabicyclo[3.2.0~heptan-6-yl)-a-isopropylidene-acetate in 2 ml of acetic acid is mixed with aluminium amalgam prepared from 0.2 g of aluminium, and the mixture stirred at room ~?~ 70 temperature for 1 hour, poured into water and extracted with methy-lene chloride. The extract is washed with water, dried and con~en-trated under reduced pressure to yielcl 166 mg of the residue con-taining about 50 % methyl a-(2~-acetonyloxy-3~-phenylacetamido-4-oxoazetidin-l-yl)-a-isopropylideneacetate.
Example XI-ll (COB = -COOCHPh2, Acyl = PhCH2CO-, Z = H) To a solution of 544 mg of diphenylmethyl a-(3~-acetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-a-isopropropylideneacetate in 5.5 ml of acetic acid is added aluminium amalgam prepared from 0.5 g of aluminium and 5 ml of 0.5 % aqueous solution of mercuric chloride, and the mixture stirred at room temperature for 2 hours. After the reaction completed, the mixture is poured into water and extracted with methylene chloride. The extxact is washed with water, dried and filtrated. The filtrate is concentrated to yield the residue, which is purified by chroma- ~ -tography on silica gel to yield 120 mg of the starting material and 191 mg of diphenylmethyl a-(2~-acetonyloxy-3~-phenylacetamido -4-oxoazetidin-1-yl)-a-isopropylideneacetate.
Y max 3 3425, 1774, 1735sh, 1720, 1676, 1510 cm NMR : ~ 3 1.83s3H, 1.97s3H, 2.23s3H, 3.60s2H, 3.60 + 3.97q (8Hz)2~, S.03d(4H~)lH, 5.27dd(8;4Hz)lH, 6.5Od(8Hz) ~ ~ ~
lH, 6.93slH, 7.30 + 7~33ml5H~ ;
.
'~ ' .. , ~ .

Claims (10)

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

1. A process for preparing compounds of the formula:

wherein COA and COB are carboxy or protected carboxy, comprising treating a compound of the formula- with a reducing agent.

2. A process according to claim 1, wherein COA and COB
are lower alkoxycarbonyl or aralkoxycarbonyl.

3. A process according to claim 1, wherein COA is methoxy-carbonyl and COB is benzyloxycarbonyl.

4. A process according to claim 1, wherein COA is benzyloxy-carbonyl and COB is methoxycarbonyl.

5. A process according to claim 1, wherein COA is methoxy-carbonyl and COB is diphenylmethoxycarbonyl.

6. Compounds of the formula:

wherein COA and COB are carboxy or protected carboxy, when prepared by the process of claim 1.

7. A compound according to claim 6, wherein COA and COB
are lower alkoxycarbonyl or aralkoxycarbonyl, when prepared by the process of claim 2.

8. A compound according to claim 6, wherein COA is methoxy-carbonyl and COB is benzyloxycarbonyl, when prepared by the process of claim 3.

9. A compound according to claim 6, wherein COA is benzyloxy-carbonyl and COB is methoxycarbonyl, when prepared by the process of claim 4.

10. A compound according to claim 6, wherein COA is methoxy-carbonyl and COB is diphenylmethoxycarbonyl, when prepared by the process of claim 5.