GB2106113A - Azetidinones - Google Patents

Abstract

Azetidinones of the formula <IMAGE> wherein Y is hydrogen, halogen or a specified organic group; X is a hetero-interrupted alkyl radical with a terminal NHOH, NR22R23 (R22 and R3 are each independently H or lower alkyl) or NO2 group; Q is phenyl or lower alkyl; and R'' is an easily removable ester-forming protecting group. The azetidinones are useful for preparing 2-substituted or 2,6-disubstituted penems which are antibacterial agents.

Description

1 GB 2 106 113A 1

SPECIFICATION

Azetidinones The present invention relates to novel azetidinones which are useful as intermediates in preparing certain 2-substituted and 2,6-disubstituted penem compounds which possess antibiotic activity.

More specifically the present invention comprises novel compounds of the formula 0 11 Y S-cx -N i:i '1Y p (Q) 3 0 ii C0 2 W' wherein Q is phenyl or (lower) alkyl; W' is an easily removable ester forming protecting group; X is -(Alk)A-(Aik')-R20 wherein Alk represents a Cl-C2 alkylene group optionally substituted by a Cl-C, alkyl radical; A is 0, S, SO, S02 or NR21 in which R21 is hydrogen, (lower)aikyi, phenyl or phenyl(iower)aikyi; Alk, is a C2-C, alkylene group; R2. is a polar substituted selected from the group consisting of -NHOH, -NI122R23 in which R22 and R23 are each independently hydrogen or (lower)aikyl and -N02; and Y is hydrogen or a radical selected from the group consisting of (a) optionally substituted (lower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower)al iphatic, the substituents being one or more of hydroxy, (lower)aikoxy, optionally substituted phenyloxy, optionally substituted heterocyclicoxy, optionally substituted (lower)aikylthio, option ally substituted pheny[thio, optionally substituted heterocycliothio, mercapto, amino, (lower)aiky 30]amino, di(lower)alkylamino, (lower)aikanoyloxy, (lower)aikanoylamino, optionally substituted 30 phenyl, optionally substituted heterocyclic, carboxy, carb(lower)alkoxy, carbamoyl, W(lower)a] kylcarbamoyl, N,N-di(lower)aikylcarbamoyi, halo, cyano, oxo, thioxo, -SO, H, -OSO3H, -S02 (lower)aikyi, (lower)aikyisuifinyl, nitro, phosphono or 0 T -OP(OP(OR.) (OR,), the substituents on the (lower)alky[thio group being one or more of halo, hydroxy, (lower)aikoxy, 40 amino,(iower)aikanoylamino or optionally substituted phenyl or heterocyclic and the phenyl or heterocyclic substituents above being one or more of hydroxy, (lower)- alkoxy, halo, (lower)alkyi, halo(lower)aiky], methane sulfonyl, (lower)aikyithio, amino, (lower)aikanoylamino, (lower)aikanoy loxy, carboxy, carboxy(lower)aikyi, sulfo, or sulfo (lower)alkyl, R. being a (lower)aikyl group and R, being an optionally substituted (lower)alkyl group or optionally ring- substituted phenyl or 45 heterocyclic group, the substituents on the alkyl group being one or more of a halogen atom, a hydroxy oxo, carboxy, carb(lower)alkoxy, carbamoy], (lower)alkoxy, amino, (lower)aikylamino, di(lower)aikylamino, (lower)alkanoylamino group, and the substituents on the phenyl or heterocy clic rings being one or more of a halogen atom, a hydroxy, (lower)aikoxy, (lower)aiky], halo(lower)aikyi, methanesulfonyl, oxo,(iower)aikythio, amino, (lower)aikylamino, di(lower)aiky- 50 ]amino, (lower)aikanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyi, sulfo, or sulfo(lower) alkyl group.

(b) -OR. in which R, is optionally substituted (lower) alkyl or (lower)aikanoyl or optionally substituted phenyl or heterocyclic, the substituents on the alkyl and alkanoyl being one or more of halo, hydroxy, (lower)alkoxy, (lower)aikylamino, di(lower)aikylamino, amino, oxo, (lower)alka- 55 noylamino or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic being one or more of hydroxy, (lower)alkoxy, halo, (lower)aikyl, halo(lower)alkyl, methanesulfonyl, (lower)alkyithio, (lower)aikylamino, di(lower)aikylamino, amino, (lower)aikanoy [amino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or suifo(lower)aiky]; (c) -S(O).R. in which n is 0, 1 or 2 and R, is as defined above; (d) halo; and (e) optionally substituted phenyl or heterocyclic in which the substituents are one or more of hydroxy, (lower) alkoxy, halo, (lower)alkyl, halo(lower)aikyl, methane-suifony], (lower)aikyithio, amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoylamino, (lower)- alkanoyloxy, carboxy, carboxy(lower)aikyl, sulfo or sulfo(lower)alkyl.

2 GB 2 106 113A 2 Substituent groups disclosed above may be further defined as follows:- (a) by the term -halogen- is meant chlorine, bromine, fluorine, and iodine. Preferred halogen substitutents are chlorine and fluorine; (b) by the term "(iower)alkyi" is meant both straight and branched chain saturated aliphatic 5 hydrocarbon groups having from 1 to 6 carbon atoms inclusive, e.g. methyl, ethyl, r)-propy], isopropyl, n,-butyl, isobutyl, sec-butyl, tert-buty], ri-pentyi, isopentyl and r-hexyi. Preferred (lower)alkyl substituents have from 1 to 4 carbon atoms and most preferably 1 or 2 carbon atoms; (c) by the term "(lower)aiiphatic" is meant acyclic straight and branched chain saturated or unsaturated hydrocarbon groups having from 1 to 6 carbon atoms inclusive. The unsaturated 10 groups may contain one or more double or triple bonds, but preferably contain either one or double bond or one triple bond. Examples of (lower)aliphatic groups are methyl, ethyl, ri-propyi, isopropyl, ri-butyl, t-butyi, sec-butyl, r-t-kpentyi, isobutyl, vinyl, 1- propenyl, 2-propenyl, isoprope nyi, 2-methyi-2-propenyl, ethynyl and 2-propynyi. The most preferred aliphatic radicals are (lower)aikyl as in (b); (d) by the term "(iower)cycloaliphatic" is meant alicyclic saturated and unsaturated hydrocar bon groups having from 3 to 8 ring carbon atoms, preferably 3 to 6 ring carbon atoms. The unsaturated ring may contain one or more (preferably one) double bond. Examples of this group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy], cycloheptyl, cyclooctyl, cyclopropeny], cyclopentenyl, 1,3-cyclohexadienyl and cyclohexenyl; (e) by the term "(iower)cycloaliphatic(lower)aiiphatic" is meant cycloaliphatic-atiphatic groups having from 3 to 8 carbon atoms (preferably 3 to 6 carbon atoms) in the cycloaliphatic ring and 1 to 6 carbon atoms (preferably 1 to 4 and most preferably 1 or 2 carbon atoms) in the aliphatic portion. Examples include cyclopropyl methyl, cyclopropyl methyl, cyclopropylpentyl, cyclobutylethyl cyclopentyl methyl, cyclo hexylem ethyl, cyclopropenyl methyl, cyclopentenylethyl, 25 cyclopropylethenyl and cyclopropylethynyl. The most preferred groups of this type are cycloal kyi-alkyl groups in which the cycloalkyl portion contains 3 to 6 carbon atoms and the alkyl portion contains 1 or 2 carbon atoms; (f) by the term -(lower)alkoxy- is meant C,-C, alkoxy groups, the alkyl portion of which is defined as in (b). Examples include methoxy, ethoxy, n-.propoxy, isopropoxy, no-butoxy, isobu- 30 toxy, sec-butoxy and, ri-pentyloxy. Preferred groups are C,-C, alkoxy and the most preferred are Cl-C2 alkoxy; (g) by the term "(lower)aikyithio" is meant Cl-C, alkythio groups in which the alkyl portion is as defined in (b). Examples include methylthio, ethylthio and r-butyithio; (h) by the term "(iower)aikylamino" is meant Cl -C, alkylamino groups in which the alkyl 35 portion is defined as in (b). Examples are methylamino, ethylamino, n- propylamino and n butylamino; (i) by the term di(lower)aikiamino" is meant di Cl-C6 alkylamino in which each alkyl group is as defined in (b). Examples are dimethylamino and diethylamino; d) by the term (lower)aikanoyloxy" is meant groups or the formula 0 11 (lower)aikyi-t--u- in which alkyl is as defined in (b); (k) by the term "(iower)aikanoyfamino" is meant groups of formula 0 11 (lower)aikyi-C-NH- in which alkyl is as defined in (b); (1) by the term "carb(tower)aikoxy" is meant 0 11 -,-,-kiower)alkoxy in which (lower)alkoxy is as defined in (f); (m) by the terms "halo(lower)aikyi" is meant alkyl groups in which one or more hydrogen atoms are replaced by a halogen atom; (n) by the term "suifo(lower)aikyl" is meant -(CH2),S03H in which n is 1 to 6; (o) by the term "carboxy(lower)alkyl" is meant -(CH2)nCOOH in which n is 1 to 6; 65 (p) by the term "phenyi(iower)aikyl is meant 3 GB 2 106 113A 3 - (CH 2 1 5 in which n is 1 to 6; (q) by the term -(lower)alkanoyl- is meant 0 10 11 (lower) alKY1-,- in which alkyl is as defined in (b); (r) by the term "N-(iower)aikylcarbamoyl" is meant 0 11 (lower)aikyi-HI-4-i,- in which alkyl is as defined in (b); (s) by the term "N,N-di(lower)carbamoyl" is meant (lower)alkyl 0 11 25 (lower)aikyl in which each alkyl group is as defined in (b); (t) by the term "(iower)alkylsuifinyl" is meant 0 1 -S-(lower)alkyl in which (lower)alkyl is as defined in (b).

By the term -heterocyclic- as used herein is meant heteromonocyclic and heterobicylic residues of aromatic character as well as appropriate partially or wholly saturated residues, the heterocyclic residues containing at least one heteroatom selected from oxygen, sulfur and nitrogen and being bonded to the penem ring carbon atom via a ring carbon atom. The 40 preferred hetrerocyclic groups are ether 5- or 6-membered monocyclic radicals or fused 6,6 or 5,6 bicyclic radicals. Illustrative of suitable heterocyclic radicals are the following:

0 N N N QN N l N L eN N 55 (15n LZJ1 - H N 600 GC H. 2 6C 4 GB 2 106 113A 4 N N N N N, 5 0 N 10 N N H H N=N N-N S 0 N-N N-N 15 N N'_ L1N N N H H 11 - N 20 N R-N N-N N,5,,N S 0 N-- 25 N-,o.,N UJ, N.;N N-" 5 H H 30 H CN N 3 5 N and 35 H Similarly, by the terms "heterocycliclower)aikyi, heterocyclic- thio- (lower)alkyl, heterocycli coxy and heterocyclic-thioare meant -(CH2)n-Hetrocyclic, -(CH2)n-S- Heterocyclic, -0-Heterocyclic and -S-Heterocyclic, respectively in which n is 1 to 6 preferably 1 or 2).

The term -easily removable ester-forming protecting group- is one which has acquired a definite meaning within the 8-lactam and peptide art. Many such groups are known which are used to protect the carboxyl group during subsequent chemical reactions and which may later be removed by standard methods to give the free carboxylic acid. Known ester forming protecting groups include 2,2,2-trichloroethy], tertiary alkyl of from 4- 6 carbon atoms, tertiary alkenyl of from 5-7 carbon atoms, tertiary alkynyl of from 5 to 7 atoms, alkoxymethyl, alkanoyimethyl of from 2 to 7 carbon atoms, N-phthalimidomethyl, benzoyimethyl, halobenzoyl methyl, benzyi, p-nitrobenzyi, o-nitrobenzyl, benzhydryl, trityl, trimthylsilyl, triethylsilyl and trimethylsilylethyl.

Choice of an ester-forming protecting group is dependent on the subsequent reaction conditions the group must withstand and the conditions desired for removing it. Selection of a suitable group is well within the ability of one skilled in the art. The most preferred ester is the p-nitrobenzyl ester which can be readily removed by catalytic hydrogenation. For preparation of compounds containing functional groups reducible under such removal conditions, a preferred 55 alternative is the fl-trimethylsilylethyl ester removable by treatment with fluoride ions.

The azetidinones of the invention are useful in the preparation of novel 2-substituted or 2,6 disubstituted penems having the formula GB 2 106 113A 5 Y 0 :NQ/ (Alk) -A- (Alk') -R 20 CO 2 wherein Z is hydrogen or an easily cleavable ester-forming protecting group. These penems are 10 claimed in our copending Patent Application No. 204 2514.

The penem ring system has the formula 4 3_ i-N:

0 7.1 2 and systematically can be designated as 7-oxo-4-thia-l-azabicyclo [3.2. 0]hept-2-ene. For the sake of simplicity, it is named -2-penern- in the present application and the numbering system 20 used is as follows.

1 6 5 S 2 7 1 NQ 4 3 0 The preferred compounds of the present invention are those wherein Y is hydrogen or (lower)aikyl optionally substituted (preferably at the a-carbon) by Kydroxy. More preferred 30 compounds within the above group are those wherein Y is hydrogen, ethyl or a-hydroxyethyl.

Still more preferred compounds of formula 11 are those wherein Y is hydrogen or a-hydroxyethyl.

The most preferred compounds are those wherein Y is a-hydroxyethyl.

A preferred embodiment of the present invention consists of the compounds of formula 11 wherein X is -(Alk)-0-(Aik')-R20 in which Alk, Alk' and R2. are as defined above. Examples of substituents included within this class include -CH20CH2CH2NH2, -CH2CH2OCH2C1-12NH2, -CH20CH2CH2NHCH3, CH20CH2CH2N(CHI, -CH20CH2CH2NHC2H,, -CH20CH2CH2N(C2H1)2, -CH20CH2CH2NHC3H,, -CH20CH2CH2N(C3H1)2, -CH20CH2CH2CH2NH2, -CH20CH2CH2CH2CH,NH2, -CH20CH2CH2CH2CH2NHCH3, CH20CH2CH2CH2CH2N(CH3)2, -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2N(CHI, -CH20CH2CH2C1-12NH2, -CH2CH2OCH2CH2CH2NHCH3, -CH2CH2OCH2CH2CH2N(CH3)2, -CH2CH-OCH2C1-12NH2, -CH2CH-OCH2CH2NI-ICH3, 1 1 CH3 CH3 -CH2CH-OCH2CH2CH2N(CH3)2, -CH20CH2CH2NHOH, CH20CH2CH2CH2NHO 1 C,H, -CH2CH2OCH2CH2NHOH, -CH20CH2C1-12NO21 -CH20CH2CH2CH2CH2NO2, -CH2CH2OCH2CH21\102, -CH2CHOCH2CH2NHOH, -CH2CHOCH2CH21\102 CH3 i C2H, and -CH20CH2CH2C1-12NHOH. Within this class of compounds, the preferred members are those wherein Y is hydrogen, ethyl or a-hydroxyethy]. Most preferred members have Y = hydrogen or 65 a-hydroxyethyl and especially Y = a-hydroxyethyL 6 GB 2 106 113A 6 Another preferred embodiment of the present invention consists of the compounds of formula 11 wherein X is -(Alk)-S-(AW)-R20 in which Alk, AW and R20 are as defined above. Examples of substituents within this class include -CH2SCH2CH2NH2, -CH2CH2SCH2CH2NH2, - CH2SCH2CH2C1-12NH2, -CH2SCH2CH2CH2CH2NH2, -CH,SCH2CH2NHCH3, - CH2SCH2CH2N(CH3)2, -CH2SCH2CH2NHC2H,, -CH2SCH2CH2N(C2H1)2, -CH2SCH2CH2NHC,H,, -CH2SCH2CH2N(C,H,),, - CH2SCH2CH2CH2NI-ICH3, -CH2SCH2CH2CH2N(CH3)2, -CH2SCH2CH2CH2N(C3H1)2, - CH2SCH2CH2CH2CH2NHCH3, -CH2CH2SCH2CH2CH2NH2, -CH2CH2SCH2CH2NH2, -CH2CHSCH2CH2NH2, 1 CH3 -CH2SCH2CH2NHOH, -CH2SCH2CH2C1-12NHOH, -CH2SCH2CH2CH2CH2NI-10H, -CH2CH2SCH2CH2NHOH, -CH2CH2SCH2CH2CH2NHOH, -CHPHSCH2CH2NHOH, 1 C3H7 -CH2SCH2C1-12NO2, -CH2SCH2CH2CH2NO2, -CH2SCH,CH2CH2CH2NO2, -CH2CH2SCH2C1-12NO2 and -CH2CH2SCH2CH2C1-12NO2. Within this class of compounds, the preferred members are those wherein Y is hydrogen, ethyl or a-hydroxyethyl. Most preferred members have Y = hydrogen or a- hydroxyethyl and especially Y = a-hydroxyethyl. An especially preferred embodiment of the present invention consists of the following compounds included within formula ll:

(a) Y = H; 2-CH2OCH2CH2NH2; (b) Y = a-hydroxyethyl; 2-CH2OCH2CH2NH2; (c) Y = H; 2-CH2OCH2CH2NHOH; (d) Y = a-hydroxyethyl; 2-CH2OCH2C1-12NHOH; (e) Y = H; 2-CH2SCH2C1-12NH2; (f) Y = a-hydroxyethyl; 2-CH2SCH2CH2NH2; (g) Y = H; 2-CH2SCH,Cl-12NHOH; (h) Y = a-hydroxyethyl; 2-CH2SCH2C1-12NHOH; is 0 40 11 (i) Y = H; /--k'r'2b'-M2CH2NH2; 0 45 11 (j) Y = a-hydroxyethyl; 2-CH,SCH2C1-12N H2; 0 50 11 (k) Y = H; 2-CH2SCH2CH2NHOH; 0 55 11 (1) Y = a-hydroxyethyl; 2-CH2SCH2C1-12NHOH; (m) Y H; 2-CH2OCH2C1-12NO2; (n) Y oz-hydroxyethyl; 2-CH2OCH2C1-12NO2; (o) Y H; 2-CH2SCH2CH2NO2; (p) Ya-hydroxyethyl; 2-CH2SCH2C1-12NO2; 7 GB 2 106 113A 7 0 11 (q) Y = H; 2-CH2SCH2C1-12NO2; and 0 11 (r) Y = a-hydrOxyethyl; 2-CH2SCH2C1-12N02.

Most preferred compounds of the present invention are those where Y = hydrogen or, more preferably, a-hydroxyethyl, and X is -CH20CH2CH2NH2, most especially the free acids, pharmaceutically acceptable salts thereof and physiologically cleavable esters thereof.

In the intermediates of formula 11, reactive functional groups such as mercapto, amino and hydroxy in substituents X and Y may be protected by conventional blocking groups during conversion of the intermediates to biologically active end- products.

Compound 1 may be prepared by one or more of the reaction routes discussed below. The various synthetic routes may be divided into three main processes depending on the stage of incorporation of the 6- substituent, i.e. Y. Thus, in Process 1, the 6-substituent is incorporated in the basic starting material; Process 11 involves incorporation of Y at the end of the synthesis and 20 in Process Ill substituent Y is incorporated in mid-synthesis. Each of the three main processes in turn can vary in the procedure for incorporating the desired 2-substituent, i. e. X in the schemes shown below. In general, it is preferred to incorporate substituent Y in mid-synthesis and to incorporate substituent X by acylation of the mercaptide intermediates Ill or Ill. shown below since these procedures have been found to be the most generally useful.

The steps of Process 1 may be seen from the following scheme: Process I (Variation I): Early incorporation of 2-substituent 0 OAC 11 -SNa 30 Y-CH=CH-OAc CS1 XC IN PH 7.5 H 0 0 11 X Y 11 35 Y 2_ >, _T SC-X CHO 50C1 1 N 2 0 -.4 55 0 - '.

C0 R" 40 2 0 0 Y 11 -X Y 11 -X SC po 3 SC liN cl base NPO 0 0 1 Y C0 2 R" C02We a 1 8 GB 2 106 113A 8 Y Y X X de-protec t C0 5 2 C0 2 R 0 11 Ac = CH 3 c- 10 0 = c 6 H 5- Process I (Variation 2): Late incorporation of 2-substituent 0 2Y-CH=CH-OAc CSI OAC CH 3 C-SNa 20 0 > Y)l N H pH 7 5 Y SAC Y 5Ac CHO SOC1 2 P.N X_:IN, H 30 H 2 0 C0 2 W' SAC PO 3 Y SAC MA 35 N, c 1 base N Dri base :1 3 0 0 Y' C0 2 R- C0 2 W' 40 0 Y 0 Y.11 SM 11 SC-X NyPO X-C- (9 DO 3 45 if' 3 0 0 C02 11p - C02W' 50 Y S Y S -Q/ 0 N -de-protect 0 NQ/ 55 C0 2 C0 2 H 60 0 11 X-C- acylating agent MA = heavy metal salt 65 9 GB 2 106 113A 9 Process 1 (Variation 3): tate incorporation of 27substituent- Y-CH=CH-OAC Y Y 1)1f SCO 3 N, 6 C0 2 Rn 0 SM H X-C NYPO )if' 3 0 C0 2 W# Y 5 X -N C0 2 Rte Y)::: SC03 CHO > N H 2 Y: n0AC N H P03 > base de-protect 0 3 C514a - - H 75 Y SCO 3 0 c 0 2 R..

SCO 3 MA 1 PO base > Y: Y 3 1 0 C0 2 RU Y SC-X NyP03' ::vf, 0 SOC1 2 C0 2 RU 1 X -N )0i c 0 2 h a 4 20 In Process 1 a vinyl ester (Y = H or a radical as defined in connection with compounds 1) containing the desired 6-substituent is converted to the optionally 1 -substituted 4-acetoxy-2azetidinone by a cycloaddition reaction with chloro sulfonyl isocyanate (CSI) followed by reduction with an organic reducing agent such as sodium sulfite. The CSI reaction is conveniently carried out in an inert organic solvent such as diethyl ether at a temperature of OC 35 or below. The reduction step may be conducted in an aqueous or aqeuous-organic reaction mixture at a temperature of 0 or below and at a slightly basic pH.

Following formation of the 4-acetoxy-2-azetid i none, Process 1 may be separated into three different paths. In one route (Variation 1) the azetidinone is reacted with a thiolic acid 0 11 X-C-SH wherein X is as defined in connection with compounds 1, or a salt thereof, in a suitable solvent 45 (e.g. aqueous or aqueous organic). Displacement of the acetoxy group results in incorporation of the desired 2- substituent in the azetidinone at this stage. The displacement reaction is preferably carried out at room temperature or below and at a slightly basic pH (7.5). When Y = H, cis and trans isomers of the resulting azetidinone are preferably separated (e.g. by chromatography) 50 at this point in the process. Variations 2 and 3 depicted above convert the 4acetoxy-2azetidinone into the 4-acetylth io-2-azetid i none and 4tritylth io-2-azetid i none products, respectively, by nucleophic displacement with thioacetic acid or triphenyimethyl mercaptan (or a salt thereof such as the sodium salt), respectively.

The 4-thio azetidinone is next reacted with a glyoxylate ester 0 11 rX-C02Ft" wherein R" is an easily removable ester protecting group such as p- nitrobenzyl or trimethylsilyle- 60 thyl, or a reactive oxo derivative thereof such as a hydrate, in an inert organic solvent (e.g. benzene, toluene, xylene, and the like) and preferably at an elevated temperature (e.g. 50C. up to most preferably reflux temperature). When a hydrate of the ester is employed, resulting water may be removed azeotropically or with molecular sieves. The hydroxy ester product is formed as a mixture of epimers which can be optionally purified as by chromatography or used directly in 65 1 GB 2 106 113A 10 the next step.

Conversion of the hydroxy ester to the corresponding chloro ester is achieved by reaction with a chlorinating reagent (e.g. SOC12, POCI,, PCL,, and the like) in an inert organic solvent (e.g. tetrahydrofuran, diethyl ether, methylene chloride, dioxane, and the like) in the presence or absence of a base, preferably an aliphatic tertiary amine (e.g. triethylamine) or a heterocyclic tertiary amine (e.g. pryidine or collidine). The reaction is advantageously run at from about - 1 WC. to room temperature. Chloro ester product is obtained as a mixture of epimers which can optionally be purified before use in the next step.

The phosphorane intermediate may be obtained by reaction of the chloro ester with a suitable phosphine (preferably tri phenyl phosphine or a tri(lower)aikyl phosphine such as triethylphosphine or tri-n-butyl phosphine) in an inert organic solvent such as dimethylformamide, dimethyisuffoxide, tetrahydrofuran, dimethoxyethane, dioxane or an aliphatic, cycloaliphatic or aromatic hydrocarbon (e.g. hexane, cyclohexane, benzene, toluene, and the like) in the presence of a base, preferably an organic tertiary amine such as triethylamine, pyridine or 2,6-1utidine. The reaction is advantageously carried out at temperatures from room temperature to the reflux temperature of the solvent system.

At this stage the process again diverges into two routes. In Variation 1 (where the 2substituent has already been incorporated), the phosphorane intermediate is converted to the desired penem by thermally cyclizing in an inert organic solvent at a temperature of from just above room temperature to the reflux temperature of the solvent system. Most conveniently, the 20 cyclization is carried out under reflux conditions. Suitable inert organic solvents include aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. benzene, toluene, hexane, cyclohexane), halogenated hydrocarbons (e.g. methylene chloride, chloroform, carbon tetrachloride), ethers (diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane), carboxylic acid amides (e.g. dimethylformamide), di C,-C, alkylsulfoxides (e.g. dimethylsulfoxide) or a C,-C, alkanol (e.g. methanol, ethanol, 25 t-butanol), or a mixture thereof.

In variations 2 and 3 the phosphorane is converted to a heavy metal mercaptide of the formula - -1"" 5 -- 0 E N 'Y P(Q)3 C0 2 R- III 0 r 5H9CO0CH m X ' n p (Q) 45 0 'Y 3 C0 2 W' wherein Q is preferably phenyl or (lower)alkyi, x is 1 or 2 and M is Cu(11), Pb (11) or Hg(ii) when 50 x is 2 or Agfl) when x is 1. Mercaptide formation is accomplished by reaction of the phosphorane with a salt of Hg(I1), Pb(ii), Cufli) or Ag(l) or with (methoxycarbonyi) mercury (11) acetate in a methanol-containing solvent and in the presence of an organic or inorganic base such as aniline, pyridine, collidine, 2,6- 1utidine, an alkali metal carbonate, and the like. A 55 preferred base is pyridine. The reaction may be carried out at room temperature or, if desired, with moderate cooling or heating. The anion (A) of the heavy metal salt may be any anion which gives a soluble salt in the selected solvent, e.g. NO,-, CH,COO-, BF,-, F-, CIO,-, N02-, CNO-, etc. The mercaptide intermediate is then reacted with an acylating agent capable of introducing the moiety 0 11 X-C- wherein X is the desired penem 2-substituent. The acylating agent 11 GB 2 106 113A 11 0 11 kA-k,- 9 may be the acid 0 11 X-C-OH or a reactive functional derivative thereof such as an acid halide (preferably acid chloride), acid azide, acid anhydride, mixed acid anhydride, active ester, active thioester, etc. Acylation is conducted in an inert solvent (e.g. a halogenated hydrocarbon such as methylene chloride or an ether such as dioxane, tetrahydrofuran or diethyl ether) and, when an acid derivative is used, in 15 the presence of an acid acceptor such as a tri(lower)aikylamine (e.g. triethylamine) or a tertiary organic base such as pyridine, collidine or 2,6Autidine. When the free acid is employed, the acylation is conducted in the presence of a suitable condensing agent, for example a carbodiimide such as N,N'-dicyclohexylcarbodiimide. Acylation of the mercaptide can be achieved over a wide temperature range, but is preferably carried out from about 20 to 20 + 25T. Following acylation, the resulting phosphorane is cyclized as described above to give the desired penem ester.

Formation of the phosphorane via the mercaptide intermediate (Variations 2 and 3) has been found to result in product of much better purity than that obtained by the more conventional route of Variation 1.

Once the carboxyl-protected penem is formed, the protecting group may be removed by conventional deblocking procedures (e.g. hydrolysis, hydrogenation or photolysis) to give the de blocked penem. Removal of the p-nitrobenzy] ester, for example, may be achieved by catalytic hydrogenation in the presence of a noble metal catalyst such as palladium or rhodium, including derivatives thereof such as oxides, hydroxides or halides, said catalyst being optionally supported on a conventional carrier such as carbon or diatomaceous earth. A non-reducible aqueous or non-aqueous inert solvent such as water, ethanol, methanol, ethyl acetate, tetrahydrofuran, diethyl ether or dioxane is used. Hydrogenation may be conducted at atmospheric or elevated pressure and is conveniently run at room temperature for a period of from about 1 -5 hours depending on the solvent and catalyst used. If an equivalent weight of a 35 base such as an alkali metal or alkaline earth metal hydroxide or an amine is employed during the hydrogenation, the product may be recovered in the form of a carboxylic acid salt. Removal of the fl-trimethylsilylethyl ester, another useful protecti ' ng group, is conveniently achieved by treatment with a source of fluoride ions. Other ester protecting groups can be similarly removed by methods well-known to those skilled in the art.

In a second main process (Process 11), the reaction sequence is as shown below:

Process II (Variation 1)-: Early incorporation of 2-substiti-e 0 0AC 11 45 XC-5Na CH 2 =CH-OAc CS1-, -T I- N_ P11 7.

0 1 H --- J:-X c " HO fS SC-X SOC 1 2 > 1 N, H 0 c. 0 2 0 '11 C0 2 R. 55 12 GB 2 106 113A 12 11 SC-X PO base 0.--r c' co 2 R,.

0 SAX N,,,C P 0 3 Oil 01 R" 10 S y y:> 1 X base N C-0 2 W' 0 c- 0 W' 15 A y 20 de-orotect co 7 Fl 25 Process-11 (Variation 2): Late -incorporation of 2-substituent 0Ac 30 CHfCH-0Ac CSI AcSNa pH 7. 5 H SAC SAC 35 CHO Socl 2 H 0 H 2 0 co 2 R" 40 SAC PO SAC MA 3 - > 45 _YDO base base 0 IIN,' cl 0 CO R" 3 co 2 R" 2 50 0 0 11 SM 11 SC-X X-c 3 > -00 3 55 0,5EN,yPO 0 v C02R" C02 R" 13 GB 2 106 113A 13 y 5 y base 0 CO 2 Rn 0 CO 2 C y X 10 de-protect 0- CO 2 R PO'Cess 11 (Var r _iation 3): Late incorporation of 2-substl 0Ac Na N 03CS 20 CH =CH-OAC CS1 f 2 7.5 H 25 SCO S C0 3 3 CHO 5CCl 2 1 N H 0 H eu 2 0 30 CO 2 Re.

35 SC03 P03 SC.03 MA.

N, cl base Opm41 P03 -a 5 e YR. 40 CO CO 2 W' 2 0 0 9 SM 19 SC-X 45 X-C(D N P03 JINyPO3 TO-R" CO R., 2 2 50 14 GB 2 106 113A 14 X N C)p-N CO 2 W' base de-protect Y 5 0 CO 2 R Y -LI- 5 N i co:l.

As can be seen Process 11 is substantially the same as Process 1 (except that Y must be H) up through the thermal cyclization step which produces the 2-substituted penem. A 6-substituent, however, if desired, is now incorporated at this stage by reaction of the 2-penern with a suitable 20 electrophile in an inert solvent (e.g. tetrahydrofuran, diethyl ether, dimethoxyethane, and the like) and in the presence of a strong base. In this procedure the 2-penem can be reacted in the form of the free acid (obtained by de-blocking as described above) in the presence of about two equivalents of base or, alternatively, a suitable 2-penern ester may be used in the presence of about one equivalent of base. Any ester inert to anion chemistry (the reaction involves anion 25 formation with base followed by reaction of the electrophile with the penern anion) may be employed, e.g. (lower)aikyl such as methyl, ethyl, n-propyl or t-butyl, phenyl, trichloroethyl, methoxymethyl, silyl such as trimethylsilyl or t-butyidimethyisilyi, and the like. Penem esters having activated methylene groups such as p-nitrobenzyl are not suitable and, if the 2-penern ester is of this type, it must be first de-blocked and either used as the free acid or converted to a 30 suitable ester. The particular base used is not critical and the usual strong bases such as sodium hydride, phenyl lithium or butyl lithium are suitable. Most preferably, however, a lithium disilylamide or a lithium dialkylamide such as lithium dicyclohexylamide (LDCA), lithium diethylamide, lithium dimethylamide or lithium di-isopropylamide (LIDA) is used. The electrophile is selected so as to generate the desired Y-substituent upon reaction with the anion andmay be, 35 for example, a halogen (e.g. Br, 1,), an alkyl halide (e.g. CH31) or a similar halide such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenyi(iower)alkyi, heterocyclic, heterocyclicthio, hererocyclicthio-(lower)aikyl, or heterocyclic-(iower)aikyi, halide, a tosylate or mesylate (e.g.

CH 3 CH 2 OSO 2_.aCH3' CH3CH26SO2Ct'3' C OSO 2 so 2 0 OCH 2 CH 2 CH 2 OSO 2 CF 3# etc.), an epoxide (e.g. M), an S episulfide (e.g. an aldehyde (e.a. CH C-i10, C H CHT CHO), 3 6 5 2 a ketone (e.g. CH 3 COCH 3' (::::0) or an ester (e.g.

CH3CH2CO0CH3 or C61-15CO0CH3). Representative examples of other suitable electrophiles are shown below:

GB 2 106 113A 15 CH 2 -CH-CH2 Br 0 11 CH 3 Cch=CH2 5 Br Br CH 3 CH -CF 3 n OCH Br 10 cl 2 PCHO 0c=_CCH2 Br 15 0 CH 2 SCH2 cl CH 3 SSO 2 CH 3 OOCH2C1 20 0 OCH=CHCHO 0 --Q 0 - m CH CCH 2 cl 25 3 v 1 ".S,-"-c-CH Cl.

11 2 0 A most preferred electrophile is acetaldehyde which gives rise to the hydroxyethyl 6-substituent. 30 Introduction of the 6-substituent by this process is preferably carried out with cooling (e.g. - 80 to WC.) according to the general procedure described in Canadian Journal of Chemistry, 50 (19), 3196-3201 (1972).

After formation of the desired 2,6-penem, any ester protecting group may be removed as 35 discussed above to give the de-protected product.

The third main reaction process (Process 111) can be understood from the following scheme:

Process 111 (Variations 1 and 2):

SCO 3 SC03 40 Of 0 B 45 Y Y SCO 3 50 base)0_ N, B de-protect biAlb.tse 55 16 GB 2 106 113A 16 y _f SCA3 1 Y)/im '13 0 H 5 0 HO a x-r co 2 10 0 y C03 y x I-S 15 01- b 1 'Yo 0.

co 2 R" socl 2 Y-'- -5co 3 0 co 2 R" 0 0 P03 30 bas e CHO 1 1 cl 0 2 W.

35 Y-, y sco 3 c - 1 3 OH J-J 0 0 40 co 2 cc) 2 R" s ric 1 2 45 SM 14 P03 0 0 y 1.

c co 2 R- 17 GB 2 106 113A 17 0 11 X-c- (D 3 Pboase SC-X 5 Y: 1, SC-X Ny3 01 mr,3 C0 Roe YR. 10 2 C0 2 y 5 Y 5 15 )INQ/ X N X 0 0)14 C0 Roe 0 2 2 20 ide-protect de-Protect y 25 X X )INQ/ 0 0 30 C0 2 H C0 2 H B = blocking group for rIng nitrogen The 4-tritylth io-2-azetid i none Of Process Ill is formed as described in Process 11 (Variation 3). The ring nitrogen of the azetidinone is then protected by a conventional easily removable blocking group such as triorganosilyl (e.g. trimethylsilyl or t-butyidimethyisiiyi), methoxymethy], methoxymethyl, tetra hyd ropyra nyi, and the like. Introduction of the desired Y-substituent at the 40 1 -position of the azeidinone is then achieved by reaction of an appropriate electrophile with the N-protected azetidinone in the presence of a strong base (reaction conditions as described above in connection with Process 11). At this point the process diverges into two routes depending on the time of de-blocking the azetidinone.

In one route the N-protected intermediate is de-blocked by conventional procedures (e.g. acid 45 hydrolysis) and then converted to the 2,6-penem via ester formation, chlorination of the hydroxy ester, conversion of the chloro ester to a phosphorane, conversion of the phosphorane to a heavy metal mercaptide, acylation of the mercaptide with 0 11 X-C- +, thermal cyclization of the resulting phosphorane to give the 2,6-penem ester and removal of the carboxyl-protecting group. Reaction conditions for these steps are as disclosed in connection 55 with Process 11 (Variation 3).

An alternative route involves the steps of converting the N-protected azetidinone to a heavy metal mercaptide, acylating the mercaptide with the moiety 0 11 X-C- +, removing the N-protecting group, reacting the de-protected azetidinone with the glyoxylate ester, 65 chlorinating, reacting the chloro ester with the phosphine to give the phosphorane, cyclizing the 65 18 GB 2 106 113A 18 phosphorane to give the penem ester and removing the carboxyl-protecting group to give the 2,6-penem. Reaction conditions for these steps are as disclosed previously.

In preparing the 2-penem or 2,6-penem compounds according to the above processes, free functional groups in substituents X or Y which do not participate in the reaction may be 5 temporarily protected in a manner which is itself known, such as free amino groups by acylation, tritylation or silylation, free hydroxyl groups, for example, by etherification or esterification, metcapto groups by esterification, and free carboxyl or sulfo groups, for example, by esterification, including silylation. After the reaction has taken place, these groups can, if desired, be liberated, individually or jointly, in a manner which is itself known.

Additionally, it is possible in compounds of formula 1 to functionally modify the 2- and/or 2,6-substituents during or at the conclusion of the reaction procedures according to known processes to obtain other substituents included within the scope of the present invention. Thus, for example, carbonyl groups can be reduced to alcohol groups, unsaturated aliphatic groups can be halogenated, amino groups can be alkylated or acylated, nitro groups can be converted 15 to hydroxyamino and amino groups, hydroxyl groups can be etherified or esterified, etc.

Illustrative examples of the preparation of starting materials and endproducts of the present invention follow. All temperatures are in degrees Centigrade. For the sake of convenience, certain abbreviations are employed in the examples. Definitions of the less obvious of these abbreviations are as follows:

20 CSI chloro sulfonyl isocyanate pet. ether petroleum ether b. p. boiling point n. m. r. nuclear magnetic resonance h hour 25 ether diethyl ether (unless otherwise indicated) Celite Trademark of Johns-Manville Product Corporation for diatomaceous earth psi pounds per square inch 30 r.t. room temperature PNB p-nitrobenzyl M. p. melting point LAH lithium aluminum hydride n-BuLi n-butyl lithium 35 M113K methyl isobutyl ketone Et CA Tr -C(C,HJ3 Me CH3 THF tetrahydrofuran 40 Ph phenyl DIVIP dimethylformamide TEA triethylamine PN13G p-nitrobenzylglyoxylate THP tetra hyd ropyra nyl 45 TFA trifluoroacetic acid HMPT hexamethylphosphorus triamide (or HMPA) LDA lithium diisopropyl amide Ac CH,CO- 50 Ms CH3S02 DMAP 4-dimethylaminopyridine Preparation of Starting Materials Preparation of 4-Tritylthio-2- azetidinone Intermediates 1. 1 -(Trimethyisilyl)4-trityithio-2-azetidin one C 3 C:' 60 of!<N11 5 i (Me) A solution of 4-tritylthio-2-azetidinone (345 mg, 1 mmole), 1,1,1, 3,3,3, -hexa methyl d isi lazane (80 mg, 0.5 mmole) and chlorotrimethyisilane (55 mg, 0.5 mmole) in dichloromethane (20 mi) 65 19 GB 2 106 11 3A 19 was heated under reflux for 18 h. Concentration of the reaction mixture left virtually pure title compound. 8 (ppm, CDC13): 7.32 (1 5H, m, aromatics), 4.22 (1 H, dd, H-4), 2.67 (1 H, dd, J = 4. 11 J = 16, H-3), 2. 22 (1 H, dd, J = 2.2, J = 16, H-3), 0.3 (9H, s, CH3).

Example 1 1-(p-Nitrobenzyloxycarbonyimethyltriphenylphosphoranyl)-4(silver mercaptidyl)-2-azetidinone SA9 10 p CV114B OAC Tr5H STr 15 1 NaO.4a dFfl, oj: N 1 20 A methanol (90cc) suspension of triphenyimethyl mercaptan (13.8 g, 0.05 mmole) was degassed for 0.5 hour with a nitrogen stream. The mixture was cooled down at 0' and sodium hydride (2.4 g, 0.05 mole, 50% oil dispersion) was added portionwise. The resulting solution 25 was stirred for 5 min and 4-acetexyazetidi none (7.7 g, 0.059 mole) in water (55 cc) was added rapidly. Precipitation of 4-triphenyl methyl merca ptoazem id i none (2) occurred immediately. The mixture was stirred for 4 h at room temperature. The solid was filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution was washed with diluted HCI, water, aqueous sodium bicarbonate water and brine and dried over M9S04 (89.8%, m.p.: 30 146.5-147.5'C) Anal. CaWd for C22H19NOS: C, 76.49; H, 5.54; N, 4.05; S, 9.28 Found: C, 7.54; H, 5.60; N, 4.00; S, 9.36.

8 (ppm, WC13) 7.60-7.10 (15H, m, H-trityl), 4.62 (1 H, bs, NH), 4.40 (1 H, dd, J4-31m. == 3.0, J4-3 ci, = 5, H-4), 3.24 (1 H, ddd, J96M = 151 J3-40. = 5, J3-NH = 1.8, H- 3), 2.81 (1 H, ddd, igem = 15, J3-4trans = 3,0, J3-NH = 1.2, H-3) t,, -,, (CI-IC13) 1760, %H 3340.

STr HO Tr STr - OPPNB ___+ OH + C PH j N, of:72 1 40 0 Y02 PNB '10 2 t33 2 3 Hydrated p-nitrobenzy] glyoxylate (4.54 g, 0.02 mole) and azetidinone 2 (6.90, 0.02 mole) 45 were refluxed in benzene through a Dean Stark condenser filled with 3A molecular sieves for 24 h. Further glyoxylate (2 X 454 mg, 2 mmoles) was added with reflux period (18 h) after each addition. The mixture was diluted with ether, washed with 5% aqueous HQ water, aqueous 5% NaHC03 water and brine. It was dried over M9S04 (12, g, quantitative). A small fraction of the epimeric mixture was separated on a silica gel plate (CH2C12-ether 6:4). Isomer A:

Rf = 0.87, m.p. = 170.5-171.5 (ppm, WC13) 8.07 (21-1, d, J = 9, Hm aromatic), 7.45 (part of d, Ho aromatic), 7.40-7.00 (1 5H, m, Trityl), 5. 25 (21-1, s, CH2-PNB), 4.75 (1 H, s, H-C-0), 4.37 (1 H, dd, J3-4trans -"" 3, J3-1cil = 4, H-3), 2.83 (1 H, dd, Jgem = 16, J4-3 ci. = 4, H-4), 2.10 (1 H, dd, Jgem = 16, J1-3 trans 3, H-4), 1.42 (b.s., OH).,pc-.(CHC'3) 1770, 1760 (shoulder), P,O, 1525, POH 3475.

Isomer B:

Rf = 0.75, m.p. = 152-153' & (ppm, CDC13), 8.13 (21-1, d, J = 9, Hm aromatic), 7.47 (21-1, d, J = 9, Ho aromatic), 7.40-7.00 (15H, m, trityl), 5.30 (31-1, s, CH2-PNB, H-C-0), 4.45 (1 H, t, J = 3.5, H-4), 2.90-2.70 (21-1, AB part of A13X, H-4), 1.55 (b.s., OH).

Pr 1525, I'OH -,, (CI-IC13) 1767, 1755 (shoulder), PNO, 3500.

GB 2 106 113A 20 S Tr STr SOC1 2 OH p yridine MC c i "f02 PNB TO 2 PNB, 5 3 4 A cold ( - 15') THF (150 cc, dried over molecular sieves) solutions of azetidinone 3 (12 9, 10 21.7 mmoles) was treated with pyridine (1.9 g, 24.1 mmoles, 1.94 cc) and dropwise with thionyl chloride (2.86 g, 24 mmoles, 1.88 cc) under a nitrogen atmosphere. The mixture was stirred for 45 min at - 1 W. The precipitate was filtered off and washed with benzene. Evaporation of solvent gave a residue which was taken up in benzene and treated with activated 15 charcoal (11.7 g 94%, crystallized out from chloroform). 8(ppm, WC1,) 8.17 (2H, J = 8, Hm aromatic), 7.67-7.00 (17H, m, Ho aromatic, Tr-H), 5.80 (s, H-C-CI), 5.37, 5.33 (2s, H-C-Cl, CH2-PNB), 4.81 (1 H, m, H-4), 3.27-2.40 (2H, m, H-3) j,,-. (KBr film) 1785, 1770 %0, 1525.

' STr 0, cl "ro?- NB 03P 2,6-Lutidine 4 5 STr o-f PO 3 Y co 2 PNB A TH F (100 cc, distilled over LAH) solution of chloroazetidinone 4 (11.6 g, 20.2 mmoles) was treated with triphenyl phosphine (7.86 g, 30.0 mmoles) and 2,6- 1utidine (2.36 g, 2.56 cc, 22.0 mmoles). The mixture was refluxed for 72 h. The precipitate was filtered off and washed 30 with ether. The organic solution was washed with 2% aqueous HCI and 5% aqueous bicarbonate and dried over MgSO, Evaporation of solvent gave a residue which was purified through silica gel pad (200 g). The desired phosphorane was eluted with 30, 40 and 50% ether-benzene (11.4 g, 70.4%, m.p.: 201-202').

Anal. Calc'd for C,^ON205SP: C, 73.57; H, 5.04; N, 3.50; S, 4.01. Found: C, 73.58; H, 4.91; N, 3.44; S, 3.87.

(CHCI,) 1740, P phosphorane (16 20, 1610), PN02 1525.

Tr A9NO 3 SA9 40 pyridine p 3)IN 3 PNB Y VO 2 CO 2 PNB 5 45 4-Tritylmercapto azetidinone 5 (1.6 g, 2 mmoles) was dissolved in CH2C12 (20 cc) and the solvent was flushed down at W-60. Phosphorane 5 at 55-60' was dissolved in preheated (55-60') methanol (32 cc). Immediately after the obtention of a methanolic solution of 6 it was treated with a preheated (55-60') mixture of methanolic 0. 15 M silver nitrate solution (16 cc, 50 1.2 cq) and pyridine (174 mg, 178 gi, 2.2 mmoles, 1. 1 eq). The warming bath was then immediately removed. The mixture was stirred at room temperature for 2 h and at WC for 1 h.

The silver mercapatide 6 was filtered off, washed twice with cold (0') methanol and three times with ether. (1. 12 g, 84.5%, m.p.: 130-135 dec.). x,,, (CHC'3) 1795, 1725 (shoulder), j, phosphorane (1620, 1605), %0, 1530.

Example 2 1-(p-Nitrobenzyloxycarbonyimethyitriphenylphosphoranyl)-4(silver mercaptidyl)-2-azetidinone 21 GB 2 106 113A 21 SCOCH SA9 3. K 2 C011A91m 1 MeOll fN, ipph 3 -0 pph 3 5 COOPN3 COOPNB 7 6 A solution of phosphorane 7 (1.796 g, 3.0 mmoles) in chloroform (3 mi) was diluted with 10 methanol (90 mi), cooled at WC under nitrogen atmosphere and treated successively with silver nitrate (0.51 g, 3.0 mmoles) and potassium carbonate (0.33 g, 2.4 mmoles). The reaction mixture (protected from light) was stirred at OT for 15 min., then the cooling bath was removed and stirring was continued for 3 h. The reaction mixture was cooled down to - 1 WC, stirred for 1 h and filtered; the silver mercaptide was successively washed with cold methanol and ether; 1.91 g, M.P.: 138-14WC dec, 96%. [.R. (nujol) em-': 1748, 1620 and 1605. Nusol is a Registered Trade Mark. An analytical sample was obtained by preparative TLC (ethyl acetate): M.P.: 140-5T dec, caic'd for C3,1-124N205 SPA9: C, 54.31; H, 3.65; N, 4.22; S, 4.83. Found: C, 54.11; H, 3.48; N, 3.92; S, 4.62.

Example 3 1-(p-Nitrobenzyloxycarbonyimethyltriphenylphosphoranyl)-4(silver mercaptidyl)-2-azetidinone A. Use of aniline as base SCOCH 3 Aniline, A9NO SA9 25 :L MeOH pph Pph 3 3 LOM 30 7 6 A solution of phosphorane 7 (1.8 9, 3.0 mmoles) in chloroform (4 mi) was diluted with methanol (90 mi), cooled to - 1 WC under nitrogen atmosphere and treated successively with 35 silver nitrate (0.56 g, 3.3 mmoles) and aniline (1.5 mi, 16.5 mmoles). The reaction mixture (protected from light) was stirred at - 1 WC for 0.5 h and then the cooling bath was removed and stirring was continued for 24 h. The reaction mixture was cooled to - 1 OC and stirred for 1 h before being filtered; the silver mercaptide was successively washed with cold methanol and ether; 1.55 g, M.P. 11 4-WC dec. 77.9%. IR (nujol)cm - 1; identical to compound of Example 40 2.

Silver- 1-(1,-paranitrobenyl oxycarbonyl-l,. triphenylphosphoranylidenemethyl 2-azetidinone-4-thi olate B. Use of 4-dimethylaminopyridine (DMAP) as base 45 SCOCH 3 AgNo /DMA_.

CH cl ICII N PO 2 2 300 OEN 3 Y CO ?NB CO 2 PNB 2 50 A solution of the above S-acetyl phosphrane (17.90 g, 30 mmol) in methanol and dichloromethane (1:2, 450 mi) was purged with nitrogen (5-10 min), cooled to 5T and treated successively with silver nitrate (5.35 g, 31.5 mmpl) and 4-dimethylaminopyridine (3.85 g, 31.5 mmol). The ice-bath was removed and the solution refluxed vigorously for 2 h and then stirred at room temperature for 1 h. The colored reaction mixture was treated with charcoal, filtered and evaporated. The residue was redissolved in the minimum amount of dichloromethane and added dropwise, with stirring to cold methanol (300 mi). The precipitated silver salt was collected by filtration, washed with ether and dried; 18.1 g (91 %); in (CHCI,) 1745 (C = 0 of P-lactam) and 1607 em - 1 (C = 0 of ester). Silver1-(paranitrobenzyl 2-triphenylphosphoranylidene-2'.-acetate)-2-Azetidinone-4-Thiolate C. Use of 1,8 diazabicyclo [5.4.0jundec-7-ene (D8U) as base 22 GB 2 106 113A 22 SCOCH 3 SA9 O,ENC, o 3 DBU. MCOH P6 PN3 -fo MB 5 2 2 The above S-acetylphosphorane (36.0 g, 0.060 mol) was dissolved in methylene chloride 120 mi. The solvent was evaporated in order to obtain an oil. The resulting oily residue was dissolved in warm (WC) methanol (240 mi) and treated rapidly with a methanolic (420 mi) 10 solution of silver nitrate (10.68 g, 0.0628 mol). The resulting solution (or suspension) was stirred at room temperature for 5 min, cooled down (ice bath) and a DBU (8.96 mi, 0.060 mol) solution in methanol (20 mi) was added over a 5 min period. The mixture was stirred for 5 min. The solid was filtered, washed once with cold (O'C) methanol and ether and dried under 15 vacuum; 37.0 g (93%); ir (nujol mull) tn,,, (c= 0) and 1600 cm-1 (phosphorane) D. Use of pyrrolidine as base Silver 1 -(1 - paranitrobenzyl oxycarbonyl- 1 -triphenylphosphoranyimethyl-2-azetidinone- 4-thiolate SCOCII SA9 Pyrrolidine 20 oj::(C=Pph A9NO 3 3 L 3 OOPNB To a cold (O'C) solution of 4-acetylthio-l-(paranitrobenzyi oxyca rbonyl- 1 '-tri phenyl phosphoranyl methyl-2-azetid i none (0.60 g, 1.0 mmol) in CH2C12 (2 mi) was added MeOH (4 mi), a solution of AgNO, in MeOH (0.14N, 7.86 m], 1.1 mmol) and a solution of pyrrolidine (0.92 m[, 1.1 mmol) in MeOH (2 mi). The cooling bath was removed and the reaction mixture was stirred for 1.75 h, cooled to - 1 O'C, stirred for 0.25 h and filtered. The solid was washed with cold MeOH and dried in vacuo; 0.548 g, m.p. 115'C, 82.4% ir (nujol) 1755 (C = 0) and 1600 30 cm-1 (aromatics).

Example 4 Mercuric (11)-[1'-p-nitrobenzyloxycarbonyl- 1 -21Triphenylphosphoranymethyl]-2-azetidinone- 4-thiolate STr Hg (OAC) 2 2 oj:l YPPh 3 40 co 2 PNB 1 5) 2 Hq 3 02 PNB IL A solution of 1(2.4 g, 3 mmoles) in dichloromethane (15 mi) was cooled to WC and treated with a solution.

To a cold (O'C) solution of 4-acetyithio-l-(paranitrobenzy] oxyca rbonyi1 '-tri phenyl ph osphora- nyl methyl-2-azetid i none (0.60 g, 1.0 mmol) in CH2C12 (2 m]) was added MeOH (4 mi), a solution of A9N03 in MeOH (0.14N, 7.86 mi, 1.1 mmol) and a solution of pyrrolidine (0.92 mi, 1.1 mmol) in MeOH (2 mi). The cooling bath was removed and the reaction mixture was stirred for 1.75 h, cooled to - 1 WC, stirred for 0.25 h and filtered. The solid was washed with cold MeOH and dried in vacuo; 0.548 g, m.p. 11 WC, 82.4% ir (nujol) 1755 (C = 0) and 1600 cm - 1 (aromatics).

Example 4

Mercuric (11)-[1 -p-nitrobenzyloxycarbonyl- 1'-21Triphenylphosphoranymethyll-2-azetidinone-4-thiolate 23 GB 2 106 113A 23 4-thiolate STr.

Ng MAC) 2 Ypph 3 co 2 pNB 1 2 9 pph 3 MB 2 A solution of 1 (.4 g, 3 mmoles) in dichloromethane (15 m]) was cooled to WC and treated with a solution of mercuric acetate (0.525 g, 1.65 mmole) dissolved in methanol (15 mi). After stirring at WC for 2 h, the solvent was evaporated and the residue redissolved in dichlorometh- 20 ane and washed with cold water. The organic solution after being dried (M9S04) and treated with charcoal, was evaporated to give a foam which crystilized when triturated in ether. Yield: 1.73 g (91%) M.P. 123-127Q I.R. (CHC'3) 1745 cm-1 (p.

=,, P-lactam) 1608 cm (phenyl) Example 5 A. Preparation of 3-(1'-Hydroxy-1,-ethyl)-1-methoxymethyl-4- tritylthio-2-azetidinones j-f SCO 3 '0" SC3 _ N N_ 14 0". 30 0 _11^ a) (1 IS, 3S, 4R and 1 -'R, 3R, 4S)isomer (isomer C) A solution of lithium diisopropyl amide was prepared in THF (5 m]) at - MC from n-butyl lithium (1.6M, 1.0 m], 1.6 mmol) and diisopropylamine (0.25 mi, 1.84 mmol). After 30 min a 35 solution of 1 -methoxymethyi-4-trityith io-2-azetid i none (491 mg, 1.42 mmol) in THF (6 mi) was added dropwise and the solution was stirred for 15 min. Acetaldehyde (3.0 mi) was added dropwise, followed, after 20 min, by water (30 mi). The mixture was acidified to pH 3 with 2% HCl and extracted with ethyl acetate (5 X 20 mi). The combined organic phases were washed with brine, dried an concentrated to leave an oil which crystallized upon trituration with ether: 40 440 mg, 80%, mp 188.5-9'C; 11-1mr (CDC'3) 8: 7.3-(15H, m, aromatics), 4. 37 (2H, ABq, N CH20), 4.32 (1 H, d, J = 2, H-4), 3.17 (3H, s, OCH.), 3.32-2.70 (2H, m, H- 3 and H-5), and 1. 12 ppm (3H, d, J = 7, CH3); Anal. calcd for C2rH27NO3S: C 72.02, H 6. 28, N 3.23, S 7.39; found: C 71.99, H 6.02, N 3.21, S 7.40%.

b) (VS,3SAR and VR,317,4S) and (V17,3S,4R and VS,3R,4S) (isomers C and B).

A solution of lithium diisopropyl amide (0.482 mmol) is prepared at - 78C in dry ether (3 mi) from butyl lithium 0. 19 1 m] of 2.52 M solution in hexane, 0.482 mmol) and diisopropyl amine (0.067 mi, 0.482 mmol). After 20 min, a solution of (4R and 4S) 1- methoxymethyl-4 tritylth io-2-azetid i none (0. 171 9, 0.439 mmol) in a mixture of dry ether (1 m]) and dry THF (1 mi) was added dropwise and the resulting clear solution was stirred at - 78C for 15 min. A 50 solution of tetrabutyl ammonium fluoride (0.96 m] of a 0.5M solution in THF, 0.48 mmol) was then added. A precipitate was formed with the generation of a slight pink colour. After 5 min at - 78Q the reaction mixture was quenched with freshly distilled acetaidehyde (0.2 mi, excess), and the stirring continued for 15 more min. The work-up was done by adding to a saturated solution of ammonium chloride and extracting with ethyl acetate (2 X 25 H). The combined 55 organic phases were washed with brine and dried over anhydrous magnesium sulfate.

Evaporation of the solvent under vacuum gave an oil (0.228 g) which was chromatographed on g of silica gel A mixture of benzene and ethyl acetate (M) gave 0. 106 g (6 2% recovery) of substrate and a mixture of the two isomer alcohols which were separated by chromatography on thick layer plates (same solvent-system). The alcohol with the high Rf (0. 033 9, 17%) was identical to the above isomer (isomer Q: mp 186.5-189'C (Etherdichloromethane); The alcohol with low Rf (0.030 g, 16%) (isomer B), was obtained as an oil which crystallized with difficulty from hexanes: mp 94-95C. ir (CH2C12) Pn.,,: 3600 (OH), 1760 cm-1 (C = 0); Hmr (CDC13) 8:6.9-7.5 (1 5H, m, aromatics), 4.2 (2H, center of ABq, J = 11.5, CH2-0CH3), 4.28 (1 H, d, J = 2.0, 4-H), 3.65 (1 H, center of a broad sextet, H-1'), 3.3 (1 H, dd, J3,41m,'. = 2.5, J3,1, = 5.5, 65 24 GB 2 106 113A 24 H3), 3.15 (3H, s, O-CH,), 1.55 (1 H, broad s, OH-1 1), 1.05 (3H, d, J = 6. 5, 1-1-2% Anal. calcd for C2,,H2,1\103S: C 72.02, H 6.28, N 3.23, S 7.39; found: C 71.77, H 6.36, N 3.15, S 7.43%.

B. Preparation of trans 3-Acetyl-l-methoxymethyl-4-trityithio-2azetidinone C LDA CH EtOAC Lithium diisopropylamide was prepared under a nitrogen atmosphere at - 78C in the usual manner from diisopropylamine (0.34 mi, 2.4 mmol) and n- butyl lithium (1. 1 mi of a 2.2M solution in hexane, 2.4 mmol) in THF (3 mi). A solution of 1methoxymethyi-4-tritylthio-2- 15 azetidinone (0.78 g, 2 mmol) in THF (3 mi) was added dropwise and, after stirring at - 7WC for 20 min, ethylacetate (0.53 9, 6 mmol) was added in one portion and stirring continued for 0.75 h at - 7WC. The reaction mixture was diluted with ether and washed with an ammonium chloride solution, water and brine, dried and concentrated to give an oil (0.7 g). Purification was achieved by chromatography over silica gel (20 g) eluting with increasing amounts of ether in 20 benzene. The pertinent fractions were concentrated to give the title material as a colorless oil (0.32 g, 37%); 'Hmr (C13C13) 8: 7.7-6.8 (15H, aromatics), 4.85 (1 H, d, J = 2, H-4), 4.5 (21-1, s, N- CH2-0), 3.9 (1 H, d, J = 2, H-3), 3.22 (31-1, s, CH,) and 2.0 ppm (31-1, s, CH3); ir 1770, 1710 cm - C. Preparation of trans 3-Acetyl-l-(t-butyidimethylsilyl)-4-tritylthio-2- azetidinone c sc c 3 LDA 30 3 EtOAC CIr 3 C,-DU N t-DU si (CH 3 2 \(CH 3 2 Diisopropyl lithium amide was prepared in the usual manner from d i isopropyla mine (0. 18 mi, 35 1.24 mmol) and n-butyl-lithium (0.78 mi of a 1.6M solution in hexane, 1. 24 mmol) and n butyl-lithium (0.78 m] of a 1.6M solution in hexane, 1.24 mmol) in THF (8 mi). A solution of 1 (t-butyidimethyisilyl)-4-trityithio-2-azetidine (0.46 g, 1 mmol) in THF (8 mi) was added dropwise at - 7WC. After a 5 min stirring period, ethyl acetate (1 mi) was added in one portion and the mixture was stirred 3 h at - 7WC. The mixture was acidified with cold hydrochloric acid (0.5N) 40 to pH 6 and extracted with ethyl acetate (2 X 20 m]). The combined organic phases were dried and concentrated to give an oil (0.5 g) which crystallized from pentane: 200 mg total, 40%; mp 122-4'C; ir 1750, 1710 cm-l; 11-1mr (CDCI,) 8: 8-7.1 (1 5H, m, aromatics), 4.83 (1 H, d' J = 2, H-4), 3.38 (1 H, d, J = 2, H = 3), 1.80 (3H, s, CH,), 0.92 (9H, s, Bu and 0.3 ppm (6H, s, CH3).

D. Preparation of trans- 1 -(t-Butyidimethyisilyl)-3-formyl-4-tritylthio2-azetidinone 50 sc 3 3 i (CH 3) 2 (CH 3) 2 t-Bu t-Bu To a cooled ( - 7WC) solution of diisopropylamine (0.34 mi, 2.4 mmol) in tetrahydrofuran (5 mi) was added dropwise, under N2, a solution of 1.5 M n-BuLi (1.6 mi, 2.4 mmol). After stirring for 30 min, a solution of 1 -(t-b utyid i methyl si lyl)-4-tritylth i o-2- azeti d i none (1.0 g, 2.18 mmol) in tetrahydrofuran (5 m]) was added dropwise and stirring was maintained for 30 min. Ethyl formate (0.8 mi, 9.9 mmol) was added and the cooled solution was stirred for 10 min. The 60 reaction mixture was washed successively with cold 1 N hydrochloric acid (5 mi), 1 M sodium bicarbonate (6 mi), water (10 mi) and brine. The organic layer was dried (M9S0j, evaporated and crystallized from pentane to give 810 mg (76%) of formate as a white solid mp 1 32-3,C; ir (CI-ICI,) vm,: 1760, 1715 cm - 1; 1 Hmr (CDC'3) 8: 9.0 (1 H, d, J = 1. 25 Hz), 7.30 (1 5H, m), 6 5 4.7 (1 H, cl, J = 1. 5 Hz) and 3.5 ppm (1 H, t, J = 1. 5 Hz).

GB 2 106 11 3A 25 NOTE: a) diisopropyl amine was distilled over CaH and stored on KOH b) tetrahydrofuran was distilled over L.A.H. and stored on molecular sieves 3A c) ethyl formate was stirred at room temperature with K2C03, then distilled over P205 5 d) n-BuLi was titrated with 1 N hydrochloric acid Preparation of 1-(t-Butyidimethyisityl)-3-(1-hydroxy-l'ethyl)-4tritylthio-2-azetidinones. (4 isomers).

sco 3 ON SC'3' 10 -Bu tBu ",, S. Si - (Me) 2 2 15 n-Butyllithium (1.6M, 3.4 m[, 5.44 mmol) was added in 5 min to a solution of diisopropylam ine (0.847 mi, 6.23 mmol) in THF (30 mi) maintained at - 78C. After 0.5 h a solution of 1-(t butyidimethyisiiyi) 4-tritylth io-2-azetid i none (2.0 g, 4.4 mmol) in THF (20 m]) was added; after 15 min acetaidehyde (10 mi) was added in one portion; after another 15 min water (100 mi) 20 was added. The mixture was acidified (pH 5-6) with dilute hydrochloric acid and extracted with ethyl acetate (3 X 30 m]). The organic phases were washed with brine, dried and concentrated to leave an oil which was found to consist of a mixture of four isomers by Elc (labelled isomers A, B, C, D by decreasing order of polarity).

Crystallization of the oily residue in ethyl acetate-pentane gave isomers B and C as a white 25 solid and left A and D in the mother-liquors. The four pure compounds were obtained by preparative chromatography (Waters, 500) of the above solid and mother- liquors. The relative proportions were: A, 17%; B, 32%; C, 39%; D, 12%. In the above reaction, when ether was substituted for THF and the reaction quenched after 1 min at - 7WC, the relative proportions of A, B, C, and D were: 12.9, 30.5, 38.2 and 18.4%. In ether, when the reaction was allowed 30 to come to 20C in 2 h before quenching, the proportions were: 13.4, 24.6, 44, and 18%.

When one molar equivalent of anhydrous magnesium bromide was added to the reaction mixture, the proportions changed to: 19. 2, 19.7, 30.1 and 31 %.

Isomer A: This isomer possesses a cis-stereochemistry at C3-C4. It is a racemic mixture composed of the (1'S, 3R, 4R) and the (VR, 3S, 4S) enantiomers. Compounds later derived from compound A are referred to as -Isomer A-. They consist of an enantiomeric mixture and possess the same configuration at C,., C3 and C4. Compounds derived from compound A, through a reaction that proceeds with inversion of configuration, will be referred to as -Isomer D- if the inversion takes place at C, and as -isomer C- for the inversion, at C3 mp 1 52-21'C; 'Hmr (CDC'3) 8: 8.0-6.8 (1 5H, m, aromatics), 4.30 (1 H, cl, J = 5.5, H- 4), 3.78 (1 H, m, H-1'), 40 3.10 (1 H, dd, J = 5.5, J = 10, H-3), 1.22 (3H, cl, J = 6.5, CH3), 0.95 (9H, s, Bu), 0.27 (6H, 2s, CH3). AnaL calcd for: C3,H3,NO,Si; C 71.52, H 7.40, N 2.78, S 6.36%. found: C 71.28, H 7.4 1, N 2.48, S 6.19%. Isomer B This isomer posseses a trans-stereochemistry at C3-C4. It is a racemic mixture 45 composed of the (1 'R, 3S, 4R) and the (VS, 3R, 4S) enantiomers. Compounds with the same 45 configuration at C,. C3 and C4 are referred to as -Isomer 13---;ir (CI-IC13) P,,.; 1745 cm - 1 (C = 0); mp 1 58-9'C; 1 Hmr (CDC'3) 8: 7.60-7.10 (1 5H, m, aromatics), 4.02 (1 H, cl, J = 0. 8 H-4), 3.32 (1 H, dd, J = 3.0, J = 0.8, H-3), 3. 55-3.15 (1 H, m, H-1% 0.88 (12H, CH3, and tBu), 0. 16 (6H, s, CH3); Isomer C: This isomer possesses a trans-stereochemistry at C3-Cl. It is a racemate formed of the 50 (1 IS, 3S, 411) and the (VR, 3R, 4S) enantiomers. Compounds with the same configuration at Cl.' C3 and C, are referred to as -Isomer C-. mp 1 34-6C; 11-1mr (CDC'3) 8: 7.60-7,10 (1 5H, m, aromatics), 4.32 (1 H, d, J =1.8, H-4), 3.02 (1 H, dd, J = 2.7, J = 1. 8, H-3), 3.0-2.5 (1 H, dq, J = 2.7, J = 6, H-1'), 1.02 (3H, d, J = 6, CH3), 0.95 (9H, s, t-Bu), 0.27 (6H, s, CH3); ir (CHC13) Pm.x: 1735 cm - 1 (C= 0).

Isomer D: This isomer possesses a cis-stereochemistry at C3-C4. It is a racemate composed of the (1 'R, 3R, 4R) and the (1 IS, 3S, 4S) enantiomers. Compounds with the same configuration at C, C3 and Q, are referred to as -Isomer D-. mp 1 71-2C; Hmr (CDC'3): 7. 80-6.90 (1 5H, m, aromatics), 4.70 (1 H, d, J = 4.5, H-4), 3.02 (1 H, dd, J = 4.5, J = 0. 5, H-3), 2.39 (1 H, dq, J = 0.5, J = 6.5, H-1'), 1.0 (3H, d, J = 6.5, CH3), 0.97 (OH, s, t-Bu), 0. 32 (6H, s, CH3). AnaL 60 calcd for C30H3-,N02 SSi; C 71.52, H 7.40, N 2.78, S 6.36%. found: C 71. 27, H 7.43, N 2.51, S 6.31 %.

26 GB 2 106 113A 26 1 SCO 3 b) N Bu \Me 2 OH C0 0 /.t-BU \me 2 BH 4 1 A solution of trans 3-acetyl-1-(t-b utyl d i m ethyl-si ly 1)-4-tritylth i o-2-azetid i none (1.0 g, 2 mmol) in THF (30 mi) was added dropwise, under a nitrogen atmosphere, to a cooled (W) and stirred suspension of sodium borohydride (0. 38 g, 10 mmol) in TH F (120 mi). The ice bath was removed and the mixture was stirred at room temperature for 4 h. It was poured into ice-cold hydrochloric acid (1 N, pH 6), stirred for 15 min and extracted with ether (U). The combined ether extracts were dried and concentrated to give an oil (1.04 g) which was crystallized in pentane to give the title compounds as a 70:30 mixture of the C and B isomers. mp 11 g- 121 'C; 84%.

0 C) 14 i _.,i (C11 3 2 t-Bu OH sc (CH 3) 2 -Bu Isomer B A suspension of cuprous iodide (4.78 g, 15 mmol) in ether (50 m]) was cooled to WC and treated under N2, with a 1.9 M solution of methyl lithium (26 mi, 50 mmol). The brown solution was stirred at O'C for 10 min and then cooled to - WC and treated dropwise with the trans 1 - 1 (t-butyl dimethyisiiyl)-3-formyi-4-trityithio-2- azetidinone (2.43 g, 5.0 mmol) in a mixture of tetrahyrofuran (10 ml)/ether (40 mi). Stirring was continued for 3 h. The solution 30 was warmed up to - 40T and treated carefully with a 1 M solution of ammonium chloride. The mixture was filtered over Celite and the organic phase was washed with a 1 M solution of ammonium chloride (3 X 5 mi) and then brine and dried over sodium suffate. Filtration and evaporation gave alcohol, isomer B, which crystallized from warm pentane to yield 1.6 g (65%), mp 160- VC; ir (CI-IC13) 'Vmax: 1730 cm - 1. 1 Hmr (CM3) 8: 7.32 (1 5H, m), 4.05 (1 H, s), 3.4 35 (1 H, d, J = 3HZ, 3.25-3.55 (1 H, m), 1.6 (1 H, s), 0.9 (1 2H, s) and 0. 1 ppm (6H, s) NOTE:

a) tetrahydrofuran and ether were distilled over L.A.H.

b) methyl lithium was titrated with 1 N hydrochloric acid c) copper (1) iodide was purified by continuous extraction with anhydous tetrahydrofuran in a 40 Soxhiet extractor for 18 h, then dried under vacuum in a dessicator (P,O. ) for 18 h.

co 3 d) Me 2 tBU _,H SC3 CH 3 Me 3 -tBU Methyimagnesium iodide (0. 1 mi, 0. 1 mmol) was added dropwise to a cooled (O'C) and stirred solution of trans 1-(t-butyl-d i methylsi lyl)- 3-fo rmyi-4- trityith i o-2-azetid in one (25 mg, 0.05 50 mmol) in THF (2 mi). The solution was stirred 1.5 h at WC, poured onto an ammonium chloride solution, acidified with a hydrochloric acid solution (1 N) and extracted with ether. Drying and concentration of the organic extracts left an oil consisting of starting material and a small amount of a mixture of the two trans title compounds with isomer B predominating.

F. Preparation of (VS, 3S, 4R and VR, 3R,4S) 1-(t-Butyldimethyisilyl)-3(1-trimethyisilyloxy-l'-ethyl)-4-tritylthio2-azetidinone (isomer C) H ' c', 0 1 h S 3 ISC 0 A solution of (VS, 3S,41R and 'I'FI,31R,4S) 1 -(t-butyidimethyisiiyi)-3- (1 '-hydroxy-l'-ethyi)-4- 65 27 GB 2 106 113A 27 tritylth io-2-azetid i none (15 mg, 0.3 mmol) and azidotrimethylsilane (35 mg, 0.30 mmol) in dry THF (6 mi) was stirred at room temperature until disapparance of the starting material (15 min). Purification of the reaction mixture by column chromatography (silica gel, CH2C12) gave the desired compound as a white solid (128 mg, 74%) mp 144-46C. 11-1mr (CDC]3) 8: 7.10-7.60 5 (15H, m, aromatics), 4.30 (1 H, d, J = 1.5, H-4), 2.25-2.89 (2H, m, H-3, H-1 1), 0.82-1.07 (1 2H, m, t-Bu, H-2% 0.27 (6H, s, CH3), 0.10 (91-1, s, -0-Si(CHI: ir (CHC'3) I'ma,,: 1736 cm - 1 (C = 0).

G. Preparation of (1 IS, 3R, 4R and 1 -'R, 3S, 4S) 1 -'(t-Butyidimethyisiiyl)-3-(1,. methoxymethoxy ether- 1 'ethyl)-4-trityi10 thio-2-azetidinone (isomer A).

r2OC"3 SCO 3 CO 3 e (Me) 15 N111% 0 -'si. 2 S i (Me) -'t-BU 1 2 t-Bu n-Butyllithium (ca 12.5 mi of 1.6M solution in hexane, 20 mmol; just enough to obtain a 20 permanent pink coloration) was added dropwise to a solution of (1 'S,3R, 4R and 1 IR,3S,4S) 1 - (t-Butyidimethyisiiyi)-3-(1 '-hydroxy- 1 '-ethyi)-4-trityith io-2-azetid i none (isomer A) (10. 1 g, 20 mmol) in TH F (100 mi) maintained at - 78. After a 15 min stirring period a solution of bromomethoxymethyl ether (2 mi, 24 mmol) in THF (30 m[) was added dropwise. The mixture was stirred 1 h at - 78' and 2 h at room temperature and poured into an ammonium chloride 25 solution (200 m[). Extraction with ethyl acetate (3 X 200 mi), washing with brine, drying with sodium sulfate and concentration gave the crude title compound which was purified by chromatography on silica gel eluting with increasing amounts of ether in benzene (10.4 g 95%).

Hmr (CM3) 8: 7.1 -7.5 (1 5H, m, aromatics), 4.47 (1 H, cl, H-4), 4.23 (2H, ABq, J = 7, O-CH2-0), 3.11-3.4 (2H, m, H-3 et H-1 1), 3.23 (3H, s, O-CH3), 1.37 (3H, d, J = 6.5, CH3), 30 0.97 (9H, s, Bu) and 0.25 ppm (6H, 2s, CH3).

H. Preparation of (1 IS, 3S, 4R and 1 'R, 3R, 4S) 1 -(t-Butyidimethylsilyl)-3-(1 "formyloxy- 1'-ethyl)-4-tritylthio-2-azetidinone (isomer C) - H HO C 3 C 3 009 40. 40 0 S I ob i4_ A solution of (VS,3SAR and VIR,31R,4S) 1 -(t-butyidimethyisiiyi)-3-(1 1- hydroxy-1 '-ethyi)-4- tritylthio-2-azetidinone (isomer c) (50 mg, 0. 1 mmol), pbromobenzenesuifonylchloride (100 mg, 45 0.4 mmol) and 4-dimethylaminopyridine (24 mg, 0.2 mmol) in DIVIF (3 mi) was stirred at room temperature until disappearance of starting material (0.5 h). Then the reaction mixture was diluted with water and extracted with ether. The organic extracts were washed with brine, dried (MgSO,) and evaporated. The title compound was purified by column cromatography. 'Hmr (CDC'3)8: 7.80 (1 H, s, CHO), 7.20-7.66 (15H, m, aromatics) 3.90-4.36 (1 H, m, H-1% 4.07 50 (1 H, cl, J = 2, H-4), 3.22 (1 H, broad s, H-3) 1.18 (3H, d, J = 6.5, 1-1- 2% 1.0 (91-1, s, t-Bu), 0.31 (6H, s, di-CH3).

1. Preparation of (11R,3SAR and VS, 3R, 4S) 11(t-Butyidimethyisilyl)-3-1.-acetoxy-l-ethyl)- 4-tritylthio-3-azetidinone (Isomer B) OH 0Ac STr Tr A50 60 Pyriaine S A solution of (VIR,3S,4S and 1 IS 3R 4S) 1 -(t-butyidimethyisiiyi)-3-(1 1- hydroxy-1 1-ethyl)-4 tritylth io-2-azetid i none (13.85 g, 27.5 mmol) in pyridine (75 mi) acetic anhydride (50 m]) 65 99 poup 'auijq ql!AA paqsem sem uoilnios aqi "N japun q L joj ainieiodwal leqI le Buinils j.914v cig W8 'B LT0) Gulwel419M PUB (10ww 98 'B W0) OPPOW 1Auojinsaueqlew'q' le poleall sem (Itu 08) GURq19 I!M '3.9 W0J01q31p ul (Ioww -V 6 O.U) (0 Jewosi) GUOUIP!Igze-:-oiql]AI!JI pue dt'SE 'S,) o uoilnios V 09 ne-1 09 z ú TA Hi) TS wil ú 99 swo HO 99 (,q jewosi) auouip.ijeeze-j-Tqj 1 -XxolAuojins-eueqjaw-,, (Sp,'UE'U, 1 pue Ut,'SE'S, 1) jo uo.ijejedgjd.>i 0Z 09 '6 Tt, S '9 6T N '8:'9 H '9 T9 9:D 09 :punol 'OL't, S '0 Vt, N 'OU'9 H 'E8'99 3 SIS 9OzNzt'H'3E:0 JOI POIEO 'leuV j.U-OE L dw (EHO S 'H9) wdd 9C.0 pue (ng-l s 'H6) WL 'NO '99 = r 'P 'HE) CO'L U-H '9 = r '90 = r 'PP H L) gTZ L-H 'q0 = r '99 = r 'bp 'H 0 OTE '(CH '9 = r 'P 'H 0 W.V '(11auaq 'bqV 'Hz:) OUS '(s3IlewOJB 'w 'H6 L) LS-C'8:9 (ú13C13) Jw H L '%06 'GuOu[P!Igz-U- OiqliAl!jl--V-(1Aqla-, L g-V -1AuoqjeoAxoipiAzueqojl!uejed-, L jo,(] jawosl,, aind eAe6 'auouip!laze L-AxojpAq-, L)-C-IAI!silqlawipilInq-1)- L o,(] jewosi,, asiAAal!l,,a ia' fHO 'SZ 'H9) wdd Z.0 pue (ngl s H6) 960 '(T9 = r 'P 'HE) tt,'L '(E-H 'TL = r '9 = r 'PP 'H L) WE '(t,-H '9 = r 'P 'H L) L E:'t, -, L-H 'TL = r 'TL = r 'd 'H L) Eg't, '(1AzuE)q 'bqV 'HZ) 96't, '(s31lewOJe 'w 'H6 L) LS-E's ot,:9 (Ej(]3) JUJH, %96 'N ue se guoulp!leze-:-olqliAl!jl-t,-(1Aqla-, LJA, uoqjec)Axoipilzueqojl!uejed OV O-E-JAI!SlAqiewi plAinq-1)- L 10---Vjewosi, , aind E6 9Aoqe paq!j3sap se poiegil 'GUOUIP L-AxOlPAt4-, L)-E- ill!siAqiewipilxinq-1)- L jo j wosi,, eqj. i a ---Vawosil, o=o -W3OVLL S9LL:xewIl (WIWA:CHO 'S 'H9) wdd E0 pue ng 's 'H6) L'0 'NO 'P 'HE) LA '(E-H SS = r 'TL = r 'PP 'H L) 8TE '(V-H SA = r 9E 'P 'H L) LTE % L-H 'W 'H L) O:'t,-99 t7 '(iAzuaq 's 'HZ) V9 '(SOllew0Je 'w 'H6 L) 06-9-ZES gc JUJH, '%96 'weOJ e SR guoulp!laze-z-oiqiiAi!ji-t,-(1Aqle-, L1Auoqje3Axoipilxzuoqojl!uejed L)-E:-(IAI!511%qiawiplAinq-1)- L o---q jewosi,, aind GAE6 GAoqe peq!josep se paleall ououlp L -AxwPAq-, L)-ú-(IAI!silqlewiplAinq-1)- L;o _q jewosi,, aqj_---9 igwos,' 69't, S 'L Vt, N '9i'9 H '06S9 0:punol 69"V S '0 L 'V N 'OZ9 H 'EW99 3 S!SVN oú "H"O JOJ P3193 'leuy f(o = 3), -LUD gtL L:'ew,' (EIJHD) JI (:HO 'SZ: 'H9) wdd 0E.0 pue oc (nE] 'S 'H6) 0 L 'CAD SS = r 'P 'HE) EA '(E-H 'WL = r 'Z = r 'PP 'H L) 0 VE % L-H 'U = r 99 = r 'bp 'H L) TE-V 'WH 'WL = r 'P 'H 0 80't, '(ihzugq 'S 'Hz) Z L 9 '(soilewOJE 'W 'H6 L) L-9ú8:R CIDG3) JwHL GqIG) 0.6-8 L L dw '%C6 auezueq ui jaqla o slunowe 6uiseaioui Wm Builnia (6 OZZ) lab eoii!s uo Aqdej60lew0J43 Aq pauielqo sem punodwoo ail!l aind aq_l 9Z ieijalew apnjo jo 6 L L 1491 uoilejlueouoo pue BuiAip 'auijq qi!AA Buiqsem (1w 00 L X E) Glelooe 9 1419 Wm uOllOW1x3.(iw 00 L) uoiinlos ap!joiqo wniuowwe ue olui painod PuE JAL - le q L panils sem ainixiw aq SeAA (1W 0 _1 asiAAdojp pappe E) J H 1 ul (10LULU Tt L 'B UT) GleLUJOJOJON3 1Azuaqojl!uejed lo uoilnios e popad Buimls uiw 9 L e jG'14V '3.8L - 19 PGUMIUMU1 Ow 01) JH1. ul (10LULU E L '6 99 1!siAqlewipiAinq OA -l)- L jo -3 Jewosi- o U01Inlos e 01 asimdojp pappe SRAA (Uoilejoioc) juid lueuew'jed e OZ uielqo ol q6noue isn[ 'loww t, L auexaq ui uoilnios Vy 9, L;o 1w 99) wniql!iiAing-u,,D jewosl,, nal rs ENJO (siewos.1 0 L t -AxolXuoqjeoAxolAzuaqoij!uejed-, 0 L jo uo.ijejedaid r (o = 3) U13 0.17L L '9LL L:"w,' MOH3) 11 fCH3 's 'H9) U L 0 (1Alnq-1 's 'H6) 8TO 'CAD q = r P 'HE) WO '(ODEHD 'S 'HE) 6L L U-H '9 = r 'u = r 'PP 'H L) 9TE '(V-H 'z = r 'P 'H L) UTE: % L -H '9 = r 'w 'H 0 OTt, '(0119w0JR H 'w 'H9 L) EWL-tWL:9 93C13) ILUH, '(%9'L6) punodwoo oil!l aind GA16 01 GInixiw jaqla wngiojlE)d-jaqla Ue W0J1 PWII1e15/J3 59M GAlleAlJGP apnjo Pq05 el!qm AlieGU R BUIAeGI (sewil ú auaniol qliAA AllpoidoiloozL, PGAOLUW Buiaq saiLijl Isel aql) go pejejodUAG 9AAA SJUGBeal gql. -q O-V io ainieiadwal wooi ie panils sem (.0 le poiedaid) 8Z YELL 90L Z99 8Z 29 GB 2 106 113A 29 (M9S04) and evaporated to dryness. After crystallization from ether-petether, 1.9 g (81.9%) of mesylate was obtained mp 120-22C; 11-1mr (CDC'3) 8: 7.13-7.61 (15H, m, aromatics), 4.50 (1 H, d, J = 2, H-4), 3.62 (1 H, dq, J = 6.5, 2-1-1-11), 2.96 (1 H, dd, J = 2, 2, H-3), 2.84 (31-1, s, methanesulfonyl) 1.22 (31-1, d, J = 6.5, H-2% 0.99 (91-1, s, Si-t-Bu) and 0.30 ppm (61-1, s, Si5 (CH3)2); ir P... (CI-IC13): 1746 (C = 0), 1343 and 1180 cm - 1 (S02).

L. Preparation of (11R,3SAR and VS,3MS) 1-(t-Butyidimethyisilyl)-3(1'methane-suifonyloxy-1'ethyl)-4-trityithio-2-azetidinone (Isomer 8) 10 -0 1f5C0 3 Si 1. 15 A solution of (1'R,3S,4R and 1 IS,311,4S) 1 -(t-butyidimethyisiiyi)-3-(1'- hydroxy-1 '-ethyl)-4tritylth io-2-azetidi none (isomer B) (5.03 g, 10 mmol), methanesuifonylchloride (2.52 g, 22.0 mmol) and triethylamine (2. 23 9, 22.0 mmol) in CH2C12 (200 mi) was stirred at WC for 1 h.

Then the solution was washed with brine, dried (M9S04) and evaporated to leave a residue which crystallized as a white solid when triturated in ether (5.40 g, 93%) mp 127-31 'C. 11-1mr (CDC'3) 8: 7.20-7.63 (15H, m, aromatics), 4.51 (1 H, dq, J = 5.0-6.2, H-1 1), 4.10 (1 H, d, J = 2.0, H-4), 3.60 (1 H, dd, J = 5.0-2.0, H-3), 2.03 (31-1, s, -CH3), 1. 01 (31-1, d, J = 6.2, H 21), 0.90 (9 H, s, t-Bu), 0. 12 (6 H, s, -CH3); ir (CHC'3) 17 4 5 cm - 1 (C = 0).

M. Preparation of (VS,3S,4R and VR,3RAS) 3-(1,-p-Bromobenzenesutfonyloxy1,1ethyi)-1-(t-butyidimethylsilyi)-4tritylthio-2-azetidinone (Isomer Q 0SO 2 Or 30 C 3 SC4) 3 0 A solution of (1 IS,3S,4R and VIR,311,4S) 1 -(t-butyidimethyisiiyi)-3-(1 '-hydroxy-l'-ethyi)-4 tritylthio-2-azetid i none (Isomer Q (2.5 g, 5 mmol) in dry THF (100 mi) was cooled to - 7WC and treated with 2.52M butyllithium/hexane (2.38 mi, 6 mmol). After 3-4 min p-bromoben zenesulfonylchloride (1.53 g, 6 mmol) dissolved in THF was added dropwise. The solution was stirred at - 78C for 3 h and then allowed to come to room temperature. Then the solvent was 40 evaporated and the desired product purified by column chromatography (silica gel, CH2C12) (3.36 g, 94.6%) mp 142-44Q 'Hmr (CDC'3) 8: 7.68 (41-1, s, benzenefulsonyl), 7.28-7.60 (1 5H, m, aromatics), 4.59 (1 H, d, J = 1.8, H-4), 3.68 (1 H, dq, J = 6.2, H-1 1), 2.99 (1 H, dd, J = 1.8, 2.0, H-3), 1.18 (31-1, d, J = 6.2, H-2% 1.08 (91-1, s, t-Bu), 0. 40 and 0.38 (61-1, 2S, -CH3); ir (CHC'3) 1749 cm - 1 (C = 0).

N. Preparation of (1 IS, 3R, 4R and 1 'R, 3S, 4S) 3-(1..Methoxymethyloxy1.-ethyl)-4- tritylthio-2-azetidinone (isomer A).

50 0C312M13 O-n2CPC"3 sc-3 3 N Me N 5 to ci' 2 55 ti,Su A cold (OC) HIVIPA-1-120 (116 mi-1 3 m]) solution of Isomer A of 1 -(tbutyidimethyisiiyi)-3-(1' methoxymethyloxy- 1 '-ethyl)-4-tritylth io-2-azetid in one (11 g, 20 mmol) was treated with sodium azide (2.7 g, 42 mmol). The cold bath was removed and the mixture was stirred for 30 min. It 60 was then poured into cold water (1.3 1) and dried. The title compound recrystallized from ethyl acetate-hexanes (7.2 g, 83%) as a white solid mp 173-174C. 11-1mr (CDC'3) S; 7.10-7. (15H, m, aromatics), 4.85 (21-1, A13q, J = 7.4, O-CH2-0), 4.53 (1 H, d, J = 5.2, H-4), 4.42 (1 H, s, N H), 4.15 (1 H, m, H-1% 3.5 (1 H, m, H-3), 3.47 (31-1, s, O-CH3), 1.5 (31- 1, d, J = 6, CH3). ir (KBr) 3400-3500 (N-H) and 1760 cm - 1 (C = 0).

GB 2 106 113A 30 0. Preparation of (VS, 3S, 4R and 1 'R, 3R, 4S) 3-(1 -Methoxymethyloxy- 1 -ethyl)-4-tritylthio-2-azetidinone (Isomer Q JH ST OCH 2 OCH 3 Tr OCH 2 OCH 3 STr 5 BrCH OCH NaN 2 3 1:N Si + 0 10 A cold (dry ice-acetone bath) solution of (VS,3S,41R and VIR,3R,4S) 1-(tbutyidimethyisilyl)-3 (1 '-hyd roxy- 1 '-ethyi)-4-tritylth i o-2-azeti d in one (5.03 g, 10 mmol) in THF (50 mi, distilled over LAH) was treated dropwise with a 1.6 solution of n-butyl lithium in hexane (13.0 mi) until a pink coloration persisted. A THF (20 mi) solution of bromomethyl methylether (1.49 g, 0.97 mi, 1. 19 mmol) was added dropwise. The mixture was stirred at - 7WC for 30 min and for a 3 h 15 period at WC. It was poured in an ice cold ammonium chloride solution and extracted with ether. The ether extracts were combined, washed with water, dried (MgSOJ and concentrated to give crude (VS,3S,41R and VIR,31RAS) 1-(t-butyidimethyisiiyi)-3-(1 '- methoxymethyloxy- 1 '-ethyl) 4-tritylthio-2-azetidinone (5.83 9, 100%) which was deprotected as described below:

A cold (ice bath) solution of the above derivative (5.83 g, 10 mmol) in HIVIPA-H,0 (90 mi-1 0 20 mi) was treated with sodium azide (1.365 g, 21 mmol). The cooling bath was removed and the mixture was stirred at room temperature for a 2 h period. It was then poured slowly into ice cold water (900 mi) and stirred for 30 min. The precipitate was collected by filtration and redissolved in methylene chloride. The solution was washed with water and brine and dried (MgSO,,) to give the title compound (3.0 g, 69.3%), mp 172-2.5 (ethyl acetate-hexane); ir (CHO tm,,.: 3400 (W H) and 1760 cm (C = 0); 11-1mr (CDC'3) 8: 7.67-7.12 (1 5H, m,H aromatics), 4.63 (2H, center of ABq, J 6, O-CH2-0), 4.49 (1 H, s, N-H), 4.40 (1 H, d, J = 3, H- 4), 4.25-3.80 (1 H, m, H-1% 3.35-3.15 and 3.26 (4H, s + m, CH, and H-3) and 1.30 ppm (3H, cl, J = 6, CH3).

P. Preparation of (VR, 3S, 4R and 1 -'S, 3R, 4S) 3-(1 '-Formyloxy- 1 ethyl-4-tritylthio-2-azetidinone (Isomer B) __S02 C 3 OCHO SC 35 op N,'S 0 H A solution of (VS,3SAR and VIR,31R,4S) 3-(1 '-p-bromobenzenesu Ifonyloxy- 1 '-ethyl)- 1 -(tbutyidimethyisiiyl)-4-trityithio-2-azetidinone (isomer C) in DIVIF (3 mi) was heated at WC for 48 h and then at 1 OWC for 4 h. The reaction mixture was then diluted with H20 and extracted with ether. The ethereal extracts were washed with brine, dried (MgSOJ and evaporated. The title compound was obtained as white crystals after purification by column chromatography (silica gel, 5% CH3CN-CH2C12) (2 mg, 4.8%) mp 131-32'C; 1 Hmr (CDCI,) 8: 8.07 (1 H, s, CHO), 7.24-7.56 (1 5H, m, aromatics), 5.23 (1 H, dq, J = 6.4, 7, H-1 1), 4.38 (1 H, dm J = 2.4, H-4), 4.25 (1 H, s, NH), 3.20 (1 H, dd, J = 7, 2.4, H-3), 1.43 (3H, d, J = 6.4, H-2'); ir (CI-ICI,) 3400 (NH), 1765 (C = 0), 1725 cm - 1 (C = 0).

Q. Preparation of (1 -'R, 3S, 4R and VS, 3R, 4S) 3-(V-Acetoxy- 1 -ethyl)4-tritylthio-2-azetidinone (isomer B) OAC 0A c STr Nal43 ill - STr 55)il tBD-4S EMPT 0:1S4 55 Pure derivative (VIR,3SAR and VS,3R,4S) 1-(t-butyidimethyisilyi)-3-(1'- acetoxy-l'-ethyi)-4- tritylth io-2-azetid i none (5.77 g, 10.57 mmol) was dissolved in warm HIVIPT-water (60 mi, 10 mf). The solution was cooled down at room temperature and NaN3 (1.2 g was added in. It was 60 stirred for 45 min (reaction progression was followed by fic) and poured slowly in stirred cold water (800 mi). The mixture was stirred for 20 more min. The crystalline material was collected and washed with water. It was redissolved in CH2C12, washed with water (twice) and brine and dried over MgSO, Solvent evaporation left a foam which crystallized out from ether-petroleum ether (4.90 g, 96.5%, mp 143-44.5'C).

31 GB 2 106 113A 31 ir (CH2C12)p z: 3395 (N-H), 1772, 1738 cm-1 (C 0). 'Hmr (CIDC13) 8: 7.9-6. 8 (15H, m, H aromatic), 5.12 (1 H, center of dq, J = 6.5, 7.5, H-1 4.33 (1 H, d, J = 2.8, H-4), 4.20 (1 H, bs, N-H), 3.17 (1 H, ddd, J3-11 = 7.5, J3-4 = 2.8, J3-NH = 1, H-3), 2.1 (31-1, s, CH3CO), 1.35 (31-1, d, J-6.5, CH3).

R. Preparation of 3-(1'.Hydroxy- 1 -ethyl)-4-tritylthio-2-azetidininone. Mixture of four isomers) OH 0Ac sc 3 LDA Cl3 SC.3 Ac 2 0 SCO 3 10 ojlf Pyridirie N, si (CH) CH3dHO 0 3 3 1 C si-ci 3 + j 15 15 DIC -N (Et) 3 + A solution of lithium diisopropyl amidel (0.74 mmol) was prepared at - 78C in dry tetrahydrofuran (5 mi) from diisopropyl amine (0. 103 mi, 0.74 mmol) and BuLi (0.29 mi of a 20 2.52 M in hexane). After 30 min at - 78T, a solution of the (R and S) 1- trimethylsilyl-4 tritylth io-2-azetid i none (0.292 g, 6.99 mmol) in dry tetrahydrofurane (2 mi) was added dropwise. After 5 min, excess of freshly distilled acetaidehyde (0.2 m]) was added all at once.

After 20 min at - 78T, tie indicated complete disappearance of starting materials and the reaction mixture was quenched by adding to a saturated solution of ammonium chloride.

Extraction with ethyl acetate (2 X 25 m]) followed by washing of the combined organic phases with saturated NI-14C1, brine and drying on anhydrous magnesium sulfate gave, after evaporation of the solvent, a yellow oil. Filtration of this oil on silica gel (10 g, elution CA): EtOAc, 6:4) gave a mixture of alcohols (0.215 g, 80%). This mixture ('Hmr) cannot be separated either by hplc or by tic.

a: Acetylation Acetylation of an aliquot of the mixture (0.065 g) with excess acetic anhydride (1.0 mi) and pyridine (1.4 mi) gave a mixture of acetates. hplc Analysis indicated four componentS2: a) 34.6% b) 17.4% c) 30.1 %; d) 17.9%. Compound a) was identical to the isomer B by direct comparison (hpIC).4 b: t-Butyidimetyl silyl derivatives The mixture of alcohols (0. 121 g, 0. 34 mmol) was treated with t-butyl d i methylchlorosi lane (0.117 g, 0.776 mmol) and triethyl amine (0.10 mi, 7.14 mmol) in dry dimethyiformamide (1 mi) for 36 h at room temperature. After dilution with ethyl acetate, the solution was washed with saturated ammonium chloride and dried over anhydrous magnesium sulfate. Evaporation 40 gave an oil (0.716 9) which contains 4 components by HPLC. a= 3.7%; b = 60.6%; c= 3 1.1 %; d = 4.6% (the identity of each one has not been established)4 NOTE:

Butyl lithium and lithium hexamethyl disilazane were ineffective 20rder of increasing polarity 3 Acetylation of the product derived from 1 -t-butyid i methyisi 1y14- tritylth io-2-azetid i none gave the following ratio: d= 29.5%; c= 24.1%; b= 33.8%; a= 12.6% 4Reaction of a mixture of alcohols derived from (R and S) 1-(t- butyidimethyisilyi)-4-trityithio-2azetidinone gave the following proportions: a= 5.2%; b= 41.3%; c= 48%; d= 4.6% 50 S. Preparation of (1,1R, 3S, 4R and 1 IS, 3R, 4S) 3-(V-8enzoyloxy1 - ethyl)-4-tritylthio-2-azetidinone (Isomer 8) 55 C0 3 C H SH A solution of (1 'S,3S,4R and VIR,3R,4S) 3-(1 '-methanesuifonyloxy-1 'ethyi)-4-trityithio-2- azetidinone (isomer C) (035 mg, 2 mmol) and sodium benzoate (432 mg, 3 mmol) in 10% H20-DMF (10 m]) was heated at 90C for 7.5 h. Then the reaction mixture was diluted with H20 and extracted with ethyl acetate. The organic extracts were washed with brine, dried (M9S04) and evaporated. The residue, purified by column chromatography (silica gel, 5% CH3 65 32 GB 2 106 113A 32 CN-CH2C12) gave the title compound as a white solid (108 mg, 23.2%) mp 1 WC. 1 Hmr (CDC'3) 8: 7.03-8.25 (20H, m, aromatics), 5.32 (1 H, dq, J = 6. 1, 9, H- l'), 4.40 (1 H, cl, J = 2.5, H-4), 4.30 (1 H, s, N-H), 3.40 (1 H, dd, J = 9, 2.5, H-3), 1.50 (3H, cl, J = 6. 1, H-21); ir (CI-IC13) 3400 (N-H), 1765 (C-0), 1715 cm-1 (C= 0).

T. Preparation of 3-(1"Paranitrobenzyioxycarbonyloxy-l'-ethyl)-4tritylthio-2-azetidinone (4 isomers).

co 3 N S -,,Me, sk.X - tBU -Isomer C a) A solution of -Isomer C- of 1-(t-butyid i methyisiiyl)-3-(1 '-pa ran itrobenzyioxycarboxyloxy- 1 ethyl)-4-trityi-thio-2-azetidinone (1.3 g) in a mixture of TFA (5 mi), water (5mi), dichloromethane (20 mi) and methanol (30 mi) was stirred for 2 days at room temperature. The solution was diluted with water and the aqueous phase extracted with d ich loro methane. The combined organic phases were washed with sodium bicarbonate and water, dried and concentrated to 20 leave an oil. Crystallization from ether gave the pure title compound (902 mg), mp 78-80'C; Hmr (CDC'3): 8.25-6.75 (19H, m, aromatics), 5.21 (2H, s, benzyi), 5.05 (1 H, m, H-1% 4.40 (1 H, s, N-H), 4.27 (1 H, cl, J = 2.8, H-4), 3.37 (1 H, dd, J = 5.3, 2.8, H-3) and 1.37 ppm (3H, cl, J = 6.5, CH3); ir (CHC13) P z,,:3390 (N-H), 1765 and 1745 (shoulder) (C = 0, and 1525 cm-1 (N02).

b) A cold (O'C) I-IMPT-1-120 (90 M'-' 9 mi) solution of---IsomerC- of 1 (t-butyidimethyisiiyi)-3 (1 '-paranitrobenzyioxycarbonyloxy- 1 '-ethyi)-4-tritylth i o-2-azet i d in one (9. 11 g, 13.3 mmol) was treated with sodium azide (1.82 g, 27.9 mmol). The cold bath was removed and the mixture was stirred for 30 min. It was then poured into water (11) and extracted with ether (5 X 200 mi).

The ether fractions were combined and washed with water (5 X 200 mi), brine and dried over 30 M9S04. Alternatively since the title compound precipitated out on water dilution, it was filtered off and recrystallized from ether; 7.22 g, 89%, mp 78-80'C.

---IsomerB -Isomer B- of 3-(1 '-pa ran itrobe nzyl oxyca rbonyloxy- 1 '-ethyi)-4- trity[th io-2-azetid in one was pre pared as described above for the -Isomer W; 92%; mp 1 55.5-WC (ether); 'Hmr (CDCI,). 8: 35 8.25-6.80 (19H, m, aromatics), 5.20 (2H, s, benzyi), 4.95 (1 H, m, H-1% 4. 35 (1 H, d, J = 2.9, H-4), 4.17 (1 H, s, N-H), 3.20 (1 H, dd, J = 10.8, J = 2.9, H-3) and 1.40 ppm (3H, d' J = 7.5, CHj; ir (CHCI,) 3480, 3390 (N-H), 1772, 1750 (C = 0), and 1525 cm-1 (N02).

Anal. calcd for C12H2,N20,,S: C 67.59, H 4.96, N 4.93, S 5.64; found: C 67.48, H 4.98, N 4.92, S 5.67. -Isomer A--- -Isomer A- of 3-(1 '-pa ran itrobe nzyi oxyca rbo nyloxy- 1 '-ethyi)-4- tritylth i o-2-azeti d i none was prepared as described above for the - Isomer W; mp 205-6C. 'Hmr (CDCI,) 8: 8.2-6.7 (19H, m, aromatics), 5.22 (2H, A13q, benzyl), 5.57-4.85 (1 H, m, H-1% 4.65 (1 H, N-H), 4.50 (1 H, d, J = 6.5, H-4), 3.65 (1 H, dd, J = 6.5, 12, JN-1 = 1, H-3) and 1.52 ppm (3H, cl, J = 7.5). ---IsomerD-Isomer D- of 3-(1 '-pa ran itro be nzyi oxyca rbonyloxy- 1 '-ethyl)-4trityith i o-2-azeti d i none was prepared as described above for -Isomer W; 11-1mr (C13C13) 8: 8.15-6.70 (19H, m, aromatics), 5.23 (2H, ABq, benzyi), 5.20 (1 H, m, H-1'), 4.75 (1 H, NH), 4.52 (1 H, d, J = 5.5, H-4), 3.42 (1 H, J = 5.5, 3, H-3 and 1. 5 ppm (3 H, cl, J = 6.5, CH3). (J value for H-3 taken after D20 exchange).

) 0 2 PNB SCO 3 W H U. Preparation of (1 'R, 3S, 4R and 1 S, 3R, 4S) 3-(1 1- methanesulfonyloxy- 1'-ethyl)-4-tritylthio-2-azetidinone (isomer 55 8) M50 M50 C 3 " 3 ^N N 0 60 A solution of (VR,3SAR and VS,3R,4S) 1-(t-butyidimethylsiiyi)-3-(1'- methanesuifonyloxy-l'ethyl)-4-trithyithio-2-azetidinone. (isomer B) (4.95 g, 8.5 mmol) and sodium azide (1. 11 g, 17.0 6 5 mmol) in 10% H20-H M PA (50 mi) was stirred at room temperature for 30 min. Then the 65 33 GB 2 106 113A solution was diluted with water (250 mi) and extracted with ether. The organic extracts were washed with brine, dried (M9S04) and evaporated. Crystallization of the residue (ether-pet-ether) gave the title compound (3.33 9, 83.8%). mp 130-31 C. 11-1mr (CM3) 8: 7. 20-7.62 (15H, m, aromatics), 4.9 7 (1 H, dq, J = 6.4, 6. 1, H- 1 % 4.5 6 (1 H, d, J = 2. 8, H-4), 4.2 2 (1 H, m, N H), 3.27 (1 H, dd, J = 6.1, 2.8, H-3), 3.0 (3H, s, -CH3), 1.63 (3H, d, J = 6.4, H-2'); ir (nujol) 5 319 5 (n-H), 17 6 8 cm - 1 (C = 0).

V. Preparation of (1,1S,3SAR and 1"R,3R,4S)3-(11methanesulfonyloxy-1,ethyl)-4-tritylthio-2-azetidinone. (Isomer C) MS sc 3 C, 3 N.' 0 ri (CH 3) 2 15 t-Du A sol ution of (1 IS, 3 S, 4 R a nd 1 1 R, 3 R, 4S) 1 -(t-butyid i methyisiiyi)-3-(1 '-methanesu Ifonyloxy- 1 '- ethyl)-4-trityith io-2-azetid i none (isomer C) (2.85 g; 4.9 mmol) in 10% aqueous HMPA (25 M1) was treated with sodium azide (0.65 g, 10 mmol) and stirred at 25'C for 0. 5 h. By diluting the 20 solution with water (250 mi), the reaction product was forced to crystallize out. The crude mesylate was redissolved in dichloromethane, washed with brine, dried (M9S04) and evapo rated. Trituration in ether gave the title compound as white crystals mp 1 55-60C 1.80 g; 78.6%; 11-1mr (CDC'3) 8: 7.43 (15N, m, aromatic), 5.02 (1 H, dq, J = 6 4. 9, H-1 1), 4.55 (1 H, s, N-H), 4.95 (1 H, d, J = 3, H-4), 3.33 (1 H, dd, J = 4. 3, H-3), 1.51 (3H, d' J = 6.9, H-2'); ir 25 p..: 3395 (N-H), 1768 cm - 1 (C = 0); AnaL calcd for C251-12.NO,S. C 64. 22, H 5.39, N 3.00; found: C 63.93, H 5. N 3.24%.

W. Preparation of (11S,3S,4R and VR,3R,4S) 3-(11p-Bromobenzenesuffonyloxy-l'-ethyl)-4- trityithio-2-azetidinone 30 (Isomer Q oso 0Br 050 0Br C3 ?C, 3 35 2 N Si+ 0 A solution of (1 IS,3S,411 and VIR,31R,4S) 3-(1 1-p- bromobenzenesuifoxyloxy- 1 '-ethyl- 1 -(t-butyid i methylsi lyl)-4-tritylth io-2-azetid i none (isomer C) (1.42 g, 2 mmol) and sodium benzoate (0.865 40 g, 6 mmol) in 10% H20 H M PA (40 m]) was stirred at room temperature for 1 h. Then the solution was diluted with H20 (100 mi) and extracted with ether. The ether extracts were washed with brine, dried ^SOJ and evaporated. The crude crystalline title compound was triturated in a small volume of ether and collected by filtration (0.92 g, 77%) mp 1 25-26C.

1 Hmr (C13C13) 8: 7.80 (4H, s, benzenesulfonyl), 7.30-7.65 (1 5H, m, aromatics), 5.13 (1 H, dq, J = 6.5, 4.0, H-1 1), 4.50 (1 H, d, J = 2.9, H-4), 4.40 (1 H, s, N-H), 3. 40 (1 H, dd, J 4.0, 2.9, H-3), 1.50 (3H, d, J = 6.5, H-2'); ir (CHC13) 3400 cm - 1 (N-H), 17 70 cm - 1 (C 0).

X. Preparation of (1 'R, 3SAR and 1 'S, 3R,4S) 3-(1'Hydroxy- 1 'ethyl)-4-triylthio-2- azetidinone (Isomer B) 2 0Br OH C 55 i+ To a warm solution of (1 IS, 3S,41R and VIR,31R,4S) 3-(1'-pbromobenzenesuifonyloxy-l'- ethyl)- 1 -(t-butyid i methylsi lyi)-4-trityith io-2-azetid i none (isomer C) in HMPA (5 m]) was added dropwise 1 mi of H20. The reaction mixture was kept at 90C for 20 h, then diluted with ether 60 and washed 4 times with brine. The organic solution was dried (M9S04), evaporated and the crude title compound purified by column chromatography (silica gel, 15% CH3CN-CHIC12). A white solid was obtained (122 mg, 44.5%) mp 187-189C which was found to be identical to a sample of the title compound prepared by another method.

34 GB 2 106 113A 34 Y. Preparation of 3-(1.-Hydroxy- 1-ethyl)-4-tritylthio-2-azetidinone 4 c '5:NSC 3 5 L S o):!N 5 i- 11ft 10 Both isomers, (VS,3SAR and VIR,31R,4S) 3-(1 '-hyd roxy- 1 '-et hyl)-4tritylth io-2-azeti d i none (Isomer C) and (VIR,3S,41R and VS,31R,4S) 3(1 '-hydroxy- 1 '-ethyl)-4-trityithio-2-azetid i none (isomer B) were prepared by the same method. For example, a solution of (VS,3S,41R and VIR,31R,4S) 1 -(t-butyid i methyl s i lyl)-3-(1 '-hyd roxy- 1 '-ethyl)-4tritylth io-2-azetid i none (Isomer C) (1.0 g, 2 mmol) and sodium benzoate (0.865 9, 6 mmol) in 10% H20-DMF (40 mi) was stirred15 at room temperature for 18 h. Then the reaction mixture was diluted with H20 and extracted with ether. The organic extracts were washed with brine, dried (M9S04) and evaporated. The crude title compound was crystallized from cold ether (0.47 g, 61 %) mp 1 34-35T. ' Hmr (CDCI,) 8: 7.12-7.56 (1 5H, m, aromatics), 4.48 (1 H, s, N-H), 4.28 (1 H, d, J = 2.13, H-4), 2.94 (1 H, dq, J = 6.5, 6.2, 1-1-1% 3.06 (1 H, dd, J = 6.2, 2.8, H-3), 2.18 (1 H, s, -OH), 1.30 (31-1, 20 cl, J = 6.5, 1-1-2% ir (CHCI,) vm: 3400 (n-H), 1760 cm-1 (C = 0). Similarly (VIR,3S,41R and VS,3MS) 1 -(t-butyid i methylsi lyi)-3-(1 '-hyd roxy- 1 '-ethyi)-4- trityith io-2-azetid i none (isomer B) mp 1 90-92T. 11-1mr (CDC'3) 8: 7.10-7.55 (15H, m, aromatics), 4.45 (1 H, cl, J = 2.5, H-4), 4.28 (1 H, s, NH), 4.10 (1 H, dq, J = 6.4, 5.3, 1-1-1% 3.08 (1 H, dd, J = 5.3, 2.5, H-3), 1.50 (1 H, s, -OH), 1.30 (31-1, cl, J = 6.4, H-2'); ir (CHC'3) 3400 (N-H), 1760 cm - 1 (C = 0) 25 Z. Preparation of WS,3RAR and VR,3SAS) 3-(1 -Methoxymethyloxy- 1 -ethyl)1-(paranitrobenzyl 2"-hydroxy-21 acetate)-4-tritylthio-2-azetidinones (Isomer A) 30 OCH OCH OCH2OCH3 CO 3 C, CH OH 35 CO 2 P14B A mixture of Isomer A of 3-(1 '-m eth oxy methyl oxy- 1 '-ethyl)-4- trityith io-2-azetid in one (7.5 g, 17.3 mmol), paranitrobenzyl glyoxylate hydrate (4.7 g, 20.8 mmol) and toluene (300 mi) was heated under reflux for 1 h in a Dean and Stark apparatus filled with 3A molecular sieves. The 40 solution was cooled in ice and triethylamine (0. 24 mi, 1.7 mmol) was added dropwise. The mixture was stirred for 1 h, washed with diluted hydrochloric acid, sodium bicarbonate and brine, dried and concentrated to give the title compound as a foam (10.5 9, 94%). 11-1mr (CDCI,) 8: 8.25-6.84 (1 9H, m, aromatics), 5.24 (21-1, s, benzyis), 4.67-4.83 (31-1, m, O-CH2 and H-4), 4.34-4.55 (1 H, m, H-2"), 4.02 (1 H, m, 1-1-1% 3.54 (1 H, m, H- 3), 3.40 (31-1, s, 45 O-CH3), 1.38 (31-1, d, J = 6.5, CH3); ir (KBr) v,,,: 3360 (01-1), 1770 (C = 0 offl-lactam), 1735 (C = 0 of ester) and 1605 cm - 1 (aromatics).

AA. Preparation of WS,3SAR and VR,3R,4S) 3-(1'-Methoxymethoxy-l'-ethyl)-1-(1- paranitrobenzyioxycarbonyl-1' 50 hydroxy-methyl)-4-tritylthio-2- azetidinone (Isomer C) OCP 0C13 3 CHO OCH OCH 3 55), STr o 2 PNB STr oj::r - 55 OH 0 PNB A solution of hydrated paranitrobenzyl glyoxylate (1.73 g, 7.11 mmol) was refluxed in toluene 60 (90 mi) using a Dean Stark condenser filled with 3A molecular sieves for a 2 h period. To the boiling solution was added (VS,3S,41R and VIR,31R,4S) 3-(1'- methoxymethyloxy-l'-ethyi)-4- tritylth io-2-azetid i none (3.0 g, 6.93 mmol) and the mixture was refluxed for 2 h more. The mixture was cooled to room temperature, triethyl amine (70 mg, 97 [LI, 0. 69 mmol) was added and it was stirred for 2 h. The reaction mixture was diluted with ether, washed with 1 % 65 GB 2 106 113A aqueous HCI, water, 1 % aqueous Nal-IC03, water and brine, dried (M9S04) and concentrated to give the title compound (4.60 g, 100%); ir (CI-IC13) 3530-3100 (O-H), 1765, 1750 (C = 0) and 1525 cm-1 (N02); 11-1mr (CDC'3) 8: 8.22, 8.18 (2H, 2d, J = 8, Hm aromatics), 7.67-7.0 (17H, m, H-aromatics), 5.3 (2H, bs, CH2-PNB), 5.30-5.02 (m, H- 211), 4.89-4.52 (m, HA' and 0-H), 4.63, 4.69 (1 H, 2d, J 2, H-4), 4.33, 4.30 (2H, 2 center of 2 A13q, J = 7, J = 7, O-CH2-0), 4.1-3.67 (1 H, m, H-1 3.2 (1 H, H-3), 3.1, 3.6 (3H, 2s, CH3-0), and 1. 15 ppm (3H, d, J = 6.5, CH3).

BB. Preparation of (11R,3S,4R and 1S,3R,4S) 3-(1"Acetoxy-l'.ethyi)-1-(1'paranitrobenzyl- oxycarbonyl-ll-hydroxy-10 methyl)-4-tritylthio-2-azetidinone 0Ac Ac 1) 5Tx. HO STr PNB 15 TEA 0 H 01 CO Phla 2 -Isomer 8--- A solution of hydrated p-nitrobenzyl glyoxiate (triturated with ether) (1. 82 9, 30 mol) was refluxed in benzene through a Dean Stark condenser filled with 3A molecular sieves for 2 h. To that was added azetidinone (V11,3SAR and 1 'S,3RAS) 3-(1'-acetoxy-l'-ethyi)-4-trityithio- 2azetidinone (10.88 g, 25.2 mmol) and the mixture was refluxed for 1 h more. The solution was cooled at room temperature and triethyl amine (0.35 mi, 2.5 mmol was added. It was then stirred for 2 h; the reaction progression being followed by tic. Solvent evaporation afforded a white foam in quantitative yield (100%, mixture of epimers) Alternatively the solution can be acid and base washed. ir (CH3C12) 3520 (OH), 1775, 1745 cm-1 (C = 0); 11- 1mr (CDC13) 8:

8.2, 8.18 (2H, 2d, J = 8, Ho aromatic), 7.80-6.90 (17H, m, H-aromatic), 5. 28, 5.17 (2H, 24, CH2-PNB, 4.89 (0.67H, d, J = 7.2, CHO), 4.80 (center of m, H-1 1), 4. 38 (0.33 H, 2d, 30 J = 8.8, CHO), 4.22 (D. 33H, d, J,-, = 2.5, H-4), 4.09 (0.67H, d, J,-, = 2.1, H-4), 3.65 (D.67H, dd, J3-1 = 5.8, J3-1 = 2. 1, H-3). 3.47 (0.33H, dd, J,-, = 5.5 J3- 4 = 2.5, H-3), 3.33 (0.33H, d, J = 8.8, OH), 3.23 (0.67H, d. J = 7.5, OH), 1.38, 1.86 (3H, 2s, CH,,CD), 1. 10, 1.06 (3H, 2d, J = 5.8, 6.3, CH3) CC. Preparation of 3-(1 'Paranitrobenzyloxycarbonyloxy- 1 "ethyi)- 1 -(1'. paranitrobenzyl oxycarboxyi- 1'hydroxy-methyl) 4-tritylthio-2-azetidinone (4 isomers).

OCO PNB 03 OCO 2 PNB sco 40 01 N Y CO 2 p 45 -Isomer C A mixture of -Isomer C- of 3-(1 1-paranitrobenzyi-oxycarbonyloxy 1'ethyi)-4-trityithio-2-azetidi- none (1.70 g, 0.3 mmol), paranitrobenzy] glyoxylate hydrate (815 mg, 3.6 mmol) and toluene (50 mi) was heated under reflux 7 days in a Dean and Stark apparatus filled with 3A molecular sieves. The cooled solution was washed with dilute hydrochloric acid, sodium bicarbonate and 50 brine, dried and concentrated to give the title compound (2.1 9) as an epimeric mixture at carbon-2". Purification was effected by chromatography over silica gel. Alternatively the title compound could be prepared by using a catalytic amount of triethyl amine. Less polar epimer at 2'.'. 11-1mr (CD) 8: 8.25-6.80 (23H, m, aromatics), 5.30 and 3.12 (4H, 2s, benzyi 4.65 (1 H, cl, J = 9, H-211), 4.45 (1 H, d, J = 2.5, H-4), 4.454.10 (1 H, m, H-1% 3.50 (1 H, d, J = 9, 211- 55 OH), 3.28 (1 H, dd, J = 2.5, J = 2.5, H-3) and 1.23 ppm (3H, d, J = 6.5, CH3); ir (CI-IC13) 3530 to 3200 (D-H), 1765, 1750 (C = 0) and 1525 cm-1 (N02). More polar isomer at C2 Hmr (CDC'3) 8: 8.25-6.85 (23H, m, aromatics), 5.25 and 5.08 (4H, 2s, benzyis), 5.05 (1 H, d, J = 7, H-2"), 4.35 (1 H, d, J = 2.5, H-4), 4.40-4.05 (1 H, m, H-1'), 3. 42 (1 H, J = 7-1 211 OH) 3.33 (1 H, dd, J = 2.5, 2.5, H-3), 1.23 (3H, d, J = 6.5, CH3); ir (CI- IC13) 3520 to 60 3200 (O-H), 1755 (C = 0) and 1525 cm - 1 (N02).

---Isomer8-- A mixture of hydrated paranitrobenzylgiyoxylate (1.74 g, 7.66 mmol) and (1 'R,3S,4R and VS, 311,4S) 3-(1'-paranitrobenzyioxycarboxyi-oxy-1 '-ethyi)-4-trityith io- 2-azetid i none (3.63 g, 6.38 mmol) was refluxed in toluene (70 ml) on a Dean Stark condenser filled with 3A molecular 65 36 GB 2 106 113A 36 sieves for 3h. The solution was cooled down to room temperature and triethyi amine (64.5 mg, 89 m], 0.639 mmol) was added. It was then stirred for 4 h, diluted with ether and washed with 2% aqueous HCI, water, 2% aqueous NaHC03, water and brine. It was dried and concentrated to give pure title compound (5.02 g, 100%). Separation of the 2 epimers was effected on preparative silica gel plate. Less polar epimer at 2": ir (CHC13) 3500 (O- H), 1772, 1750 5 (C = 0) 1525 cm- 1 (N02); 'Hmr (CDC13) 8: 8.30-8.0 and 7.65-6.80, (23H, m, aromatics), 5.27 and 5.13 (4H, 2s, benzyis), 4.71 (1 H, m, J = 6.5, 6.5, H-1'), 4.28 (1 H, d, J = 2.2, H-4), 4.23 (1 H, cl, J = 8.7, H-2"), 3.50 (1 H, dd, J = 2.2, 6.5, H-3), 3.28 (1 H, cl, J = 8.7, 0-H) and 1. 18 ppm (3H, d, J = 6.5, CH3). More polar epimer ir (CI-ICI,) 3480 (O- H) 1772, 1750 (C = 0) and 1525 cm - 1 (N02); 'Hmr (CDC'3) 8: 8.35-6.90 (23H, m, aromatics), 5.15 (4H, 10 benzyis), 4.72 (1 H, d, J = 7.5, H-2"O), 4.90-4.50 (1 H, m, J = 6.5, 6.5, H-1% 4.10 (1 H, d' J = 2, H4), 3.68 (1 H, dd, J = 2, 6.5, H-3), 3.28 (1 H, cl, J = 6.5, 0-1- 1) and 1. 15 ppm (3H, cl, J = 6.5, CH3).

-Isomer A-- The -Isomer A- of 3-(1 '-paranitrobenzyloxycarbonyloxy-l'-ethyl)-4- tritylthio-2-azetidinone like- 15 wise gave a mixture of---IsomerA- of 3-(1 '-paranitrobenzy[oxycarboxyloxy- 1 '-ethyi)- 1 -(1 ' paranitrobenzy] oxycarboxyl-l'-hydroxymethyl)-4-trityithio-2-azetidinones. 11-1mr (C13C13) 6:

8.3 -6.7 (2 3 H, m, aromatics), 5.17 (2 H, benzyis), 5. 0 (1 H, m, H- 1 % 4.9 and 4.8 (1 H, 2 D, J = 6, H-4, two epimers), 4.32 and 3.96 (1 H, 2s, H-2", two epimers), 3. 68 (1 H, dd, J = 6, 6, H-3(and 1.47 ppm (3H, 2d, J = 6.5, CH, two epimers).

-Isomer D The -Isomer D- of 3-(1 '-para n itrobenzyloxycarbonyloxy- 1 '-ethyl)-4- tritylth io-2-azetid i none like wise gave a mixture of---IsomerD- of 3-(1 '-paranitrobenzyioxycarbonyloxy- 1 '-ethyl)- 1 -(1 paranitrobenzyloxycarbonyl-l'-hydroxymethyl)-4-trityithio-2-azetidinones. 'Hmr (CDC13) 8:

8.30-6.60 (23H, m, aromatics), 5.20 (4H, rn, benzyis), 4.83 (1 H, 2d, J = 5, H = 4), 5.50-4.30 (2H, m, HA' and H-2"). 3.48 (1 H, m, H-3), 3.15 (1 H, m, 0-H), 1.37 and 1.30 ppm (3H, 2d, CH3).

DD. Preparation of (VS,3SAR and I'R,3R,4S)3-(1'Methanesuffonyloxy-l'ethyl)-1-(1- paranitrobenzyI oxycarbonyl- 30 1'hydroxy-methyl)-4-tritylthio-2- azetidinone (isomer C) (epimers at C,").

OMS CO 3 0MS sc N OH 35 0 H PNB A solution of paranitrobenzyiglyoxylate hydrate (9.72 g; 42.6 mmol) in benzene (350 mi) was refluxed for 2 h, removing the water azeotropically in a Dean-Stark trap. To that solution was added the (VS,3S,4R and 1'R,3R,4S)3-(1'methanesuifonyloxy-l'-ethyi)-4-trityithio-2-azetidinone (16.62 9, 35.5 mmol) and the reflux maintained for an additional 0.5 h. Then the reaction mixture was cooled to room temperature, treated with triethylamine (0.5 mi; 3.5 mmol) and stirred for 3 h in order to complete the reaction. Evaporation of the solvent left a white foam which was used as such in the next step. 11-1mr (CDC'3) 8: 8.12 (2H, d, J = 9, Hm aromatic), 7.28 (1 7H, part of cl, Ho aromatic, trityl), 5.28 (2H, s, -CH2- PNB), 4.88 (0.5 H, s, H-1 '), 4.62 (1.5H, rn, H-2" and H-4), 4. 00 (2H, m, HA', -OH), 3.15 (1 H, m, H-3), 2.73 (3H, s, mesylate and 1.30 ppm (3H, cl, J = 6 Hz, H-2'); ir 7'ma: 3520 (O-H), 1775 (C = 0) and 1765 cm - 1 (C = 0).

EE. Preparation of (1,'S,3RAR and VR,3SAS) 3-(1-Methoxymethyloxy-l'ethyl)-1-(1'-paranitrobenzyl-oxycarbonyl1'chloromethyl)-4-triylthio-2azetidinone (isomer A) ocn C&-, OCH OCH 55 2 3 2 3 sc 3 SCO 3 cl 0 - CO P" 2 co 2 PNB 60 Pyridine (1.1 mi, 14.2 mmol) was added dropwise to a solution of Isomer A of 3-(Vmethoxymethyloxy-1 '-ethyl)-1 -(1'-paranitrobenzyloxycarbonyl- 'I '-hydroxymethyl)-4-triyithio-2-azetidinone (7 g, 10.9 mmol) in THF (350 m]) cooled to - 1WC. Immediately after thionyl chloride (1,0 mi, 14.0 mmol) was added dropwise and the mixture was stirred at - 15' for 0.5 h. The 65 37 GB 2 106 113A 37 precipitate was removed by filtration and washed with benzene. The combined filtrates were concentrated, the residue dissolved in fresh benzene and the solution treated with activated charcoal, filtered and concentrated to leave to title compound as an oil (6.5 g, 90%), 'Hmr (CDC'3) 8: 6.65-8.35 (19H, m, aromatics), 5.24 (2H, s, benzyi), 3.43 (3H, s, OCH3) and 1.42 5 ppm (3H, d, J = 6, CH3).

FF. Preparation of (1 IS, 3S, 4R and 1 "R, 3R, 4S) 3-(1,-methoxymethyloxy1 Imethyl)- 1 -(1 I.-paranitrobenzyi oxycarbonyl1 'chforomethyl)-4-trit thio-2-azetidinone (Isomer C) 'C2 OCH 3 OCH 2 OCH 3 10 ST, SOC12 STr N ()H Cl 15 CO 2 PNB CO 2 PHD A cold (ice-MeOH bath) THF (60 m], distilled over LAH) solution of (1 'S, 3S,4R and VR,3MS) 3-(11 '-methoxymethyloxy- 1 '-ethyi)- 1 -(1 '-pa ran itrobenzyl oxycarbonyi-ll-hydroxyme thyi)-4-trityithio-2-azetid i none (4.25 g, 6.62 mmol) was treated dropwise with pyridine (0.696 20 mi, 8.61 mmol) and thionyl chloride (0.530 m], 8.61 mmol). The mixture was stirred for 30 min at - 1 5C. The precipitate was collected by filtration and washed with benzene. The THF benzene solution was concentrated and the residue was dissolved again in benzene. The resulting solution was treated with charcoal. Removal of charcoal on a Celite pad and subsequent benzene evaporation afforded the title compound (4.86 g, 100%); ir (CHC13) 25 1770 (C = 0) and 1525 cm-1 (N02); 'Hmr (CDC13) 8: 8.15, 8.12 (2H, 2d, H- aromatics), 7.70-7.00 (17H, m, H-aromatics 5.62, 5.02 (1 H, 2s, H-2"), 5.27 (2H, s, CH2-PNB), 4.7 (1 H, d, H4), 4.7-3.7 (m, O-CH2-0, H-1% 3.5-2.8 (m, H-3), 3.08 (3H, 2s, O-CH3), and 1.30-0.96 ppm (3H, m, CH3).

GG. Preparation of (VR,3SAR and VS,3RAS) 3-(1,.Acetoxy-l"ethyl)-1(paranitrobenzyloxycarbonyl-lichioromethyi)-4-tritylthio-2-azetidinone 3 5 JAc Ac STX 35 Tr SOC1 OH Pyricline X1 Cl M PNB co 2 -ro 2 40 -Isomer 8--A TH F (distilled over LAH) solution of (VR,3S,4R and 1 'S, 3R, 4S) 3-(1'-acetoxy-l'-ethyi)-1-. (1 1-paranitrobenzyioxycarbonyi- 1 'hydroxymethyi)-4-tritylth io-2-azetid i none (from 10.88 g of NH) was treated at - 1 WC (ice-methanol bath) under nitrogen atmosphere with pyridine (2.19 g, 2.24 m], 27.7 mmol) and thionyl chloride (3.3 9, 2.02 mi, 27.7 mmol) and thionyl chloride (3.3 g, 2.02 mi, 27.7 mmol). The mixture was stirred for 20 min at - 15. The salt was filtered off and washed with benzene. Solvent (THF + benzene) evaporation afforded a residue which was taken up in benzene (warm) and treated with charcoal. The suspension was filtered through a celite pad and solvent evaporation left a foam; ir (CHIC12) 1780, 1740 cm (C = 0) 'Hmr (CM, 8: 8.17, 8.21 (2H, 2d, J = 8, Ho aromatic) 7.76-6.88 (1 7H, m, Haromatic), 5.31, 5.16, 5.12, 4.73 (3H, 4s, CH2-MB, CHQ, 5.12-4.55 (1 H, m, H-1 1), 4.35-4.25 (1 H, m, H-4), 3.80-3.45 (1 H, m, H-3) 1.90 (3H, s, CH3CO), 1. 12 1.0 7 (3 H, J = 6.5, CH3).

HH. 3-(1,-Paranitrobenzyloxycarbonyloxy- 1 '-ethyl)- 1 -(1'paranitrobenzyloxycarbonyl- 1 Iwchlororne- 55 thyl)-4-tritylthio-2azetidinones (mixture of epimers at W).

OCO PNB 0 PNB 2 ' sCO.A C SC4) 3 0 N,,rcs. N Cl 60 0 CO 2 PNB 'YO2' M -Isomer C Pyridine (58 mg, 0.73 mmol) was added dropwise to a solution of Isomer C- of 3-(V- 65 38 GB 2 106 113A 38 paranitrobenzyloxycarboxyloxy-1 '-ethyi)- 1 -(1 '-paranitrobenzyl oxycarbonyl-l'-hydroxymethyi)-3tritylthio-2-azetidinones (470 mg, 0.6 mmol; mixture of epimers at C2") in THF (15 mi) cooled to - 1 5"C. Immediately after thionyl chloride (86.5 mg, 0.73 mmol) was added dropwise and the mixture was stirred at - 1 WC for 0.5 h. The precipitate was removed by filtration and washed with benzene. The combined filtrates were concentrated, the residue dissolved in fresh benzene and the solution treated with activated charcoal, filtered and concentrated to leave the title compound as an oil. 530 mg; 100%. 1 Hmr (CDC'3) 8: 8.7-6.8 (23H, m, aromatic), 5. 33 (1 H, s, H-2"), 5.30 and 5.17 (41-1, 2s, benzyis), 4.52 (1 H, d, J = 2, H-4), 4.20-3.70 (1 H, m, 1-1-1% 3.31 (1 H, dd, H-3), 1.27 and 1.21 ppm (31-1, 2d, J = 6.5); ir (CI-IC13) 1,.x: 1780, 1750 (C = 0) and 1525 cm (N02). -Isomer 8- -Isomer B- of 3-(1-paranitrobenzyioxycarbonyloxy-l'-ethyi)-1-(1'paranitrobenzyioxycarbony i1'-chloromethyi)-4-trityithio-2-azetidinones (mixture of C-2" epimers) was prepared as described above for the -Isomer C- in quantitative yield. 'Hmr (CDC'3) 8: 8.25-6.90 (23H, rn, aromatics), 5.40-5.0 (41-1, m, benzyis), 5.40-4.45 (1 H, m, H-1% 4.82 and 4.57 (1 H, 2s, H-2"), 4.36 and 4.31 (1 H, 2d, J = 2.5, H-4), 3.63 (1 H, m, J = 2.5, J = 6.5, H-3), 1. 25 and 1. 18 ppm (31-1, 2d, J = 6.5, CH3); ir (CI-IC13) 1780, 1750 (C = 0), and 1525 cm - 1 (N02).

Isomer A- -Isomer A- of 3-(1 '-paranitrobenzyioxycarbonyloxy- 1 '-ethyi)1 '-(1 '-paranitrobenzy foxycarbonyi-l'-chloromethyi)-4-trityithio-2-azetidinones (mixture of C2" epimers). 'Hmr (CDC'3) 8: 8.30-6.80 (23H, m, aromatics), 5.45-4.80 (1 H, m, H-1% 5.18 and 5.21 (41-1, 2s, benzyis), 20 4.87 (1 H, 2d, H-4), 4.22 and 3.87 (1 H, 2s, H- 2"), 4.05-3.40 (1 H, m, H-3), 1.57 and 1.50 pprn (31-1, 2d, CH3). -Isomer D-Isomer D- of 3-(1 "-paranitrobenzyioxycarbonyloxy- 1 '-ethyi- 1 '-(1 'paranitrobenzyioxycarbonyi25 1 1-chforomethyl)-4-trityithio-2azetidinones (mixture of C-2" epimers). 1 Hmr (CDC'3) 8: 8.30-6.70 (23H, m, aromatics), 5.32-5.10 (41-1, m, benzyis), 5.48 and 5.30 (1 H, 2s, H2"), 4.82 (1 H, d, J = 5, H-4), 5.30-5.20 (1 H, m, 1-1-1% 3.15 (1 H, m, W3), 1.40 and 1.30 ppm (31-1, 2d, J = 6.5, CH3); ir CH0J Pm,: 1780, 1750 (C = 0) and 1525 cm -1 (N02) 11. Preparation of 11S,3SAR and 1'R,3R,4S)3-(1-Methanesuffonytoxy-lethyl)-1-(paranitrobenzyfoxycarbonyl-l chforomethyl)-4-tritylthio-2azetidinone (isomer C) (epimers at Cj.

sco 3 0MS sc 3 35 OH N l 0 "YO 2 MB 02 P14B To a cold solution (5C) of (VS, 3S, 4R and VIR, 3R, 4S)3-(1 '- methanesuifonyloxy- 1 '-ethyi)1-(1'-paranitrobenzyioxycarbonyi-l'-hydroxymethyI 4-tritylth io-2-azetid i none (24.0 g, 35.5 mmol) in dry tetrahydrofuran (350 mi) was added pyridine (3.65 g, 46.2 mmol) in dry tetrahydrofuran (350 mi) was added pyridine (3.65 g, 46.2 mmol) and thionyl chloride (5.5 g, 46.2 mmol) dropwise. After stirring for 45 min, ether (100 m]) was added to precipitate the hydrochloride salt which was filtered off. The filtrate was evaporated and the residue redissolved 45 in benzene (200 mi) and treated with charcoal. Evaporation of the solvent left a nearly white foam which was used as such in the next step. 11-1mr (CDCI,) 8: 8.18 (21-1, cl, J = 9, Hm aromatic), 7.72 (1 7H, m, part of d, Ho aromatic, trityl), 5.57 and 5. 12 (1 H, s, H-2"), 5.28 (21-1, s, -CH,PNB), 4.73 (1 H, 2d, H-4), 3.21 (1 H, 2dq, H-3), 2.78 (31-1, 2s, mesylate and 1.21 ppm (31-1, 2d, H-6H,; 1-1-2% ir 1Wa. 1779 cm - 1 (C = 0) JJ. Preparation of (1 -'S, 3R, 4R and 1 'R, 3S, 4S) 3-(1 '-Methoxymethoxy- 1 '-ethyl- 1 -(1 -paranitrobenzyloxycarbonyl- 1 1 triphenylphosphoranyimethyl-4-tritylthio-2-azetidinone (Isomer A) 55 OCH2OCH3 0C1120CT3 sc 3 C 3 cl N"f"3 60 0 2 PNB CO 2 PNB A mixture of Isomer A of 3-(1 '-methoxymethoxy- 1 '-ethyi)- 1 -(1 - paranitrobenzyl oxycarbonyl-Vchloromethyl)-4-tritylth io-2-azetid i none (6.6 g, 10 mmol), triphenylphosphine (3.3 9, 12.5 6 5 mmol), 2,6-1utidine (1. 3 mi, 11 mmol) and dioxane (140 mi) was heated under reflux for 2 65 39 GB 2 106 113A 39 days. The solution was diluted with ether, Washed with dilute acid (5% HCI), water, dilute sodium bicarbonate solution and brine, dried and concentrated. The residue was purified by chromatography on silica gel eluting with 10% ether in benzene. Concentration of the pertinent fractions left the title compound as a foam (1.4 g, 13.7%) ir (KBr) 1750 (C = 0) and 1660-1650 cm - 1 (C = C, aromatics).

KK. Preparation of (1,1S, 3S, 4R and 1 'R, 3R, 4S) 3-(1,-Methoxymethyloxy1 "methyl)- 1 -(1 -paranitrobenzyl oxycarbonyl1,triphenylphosphoranyllidenemethyl-4-tritylthio-2-azetidinone (isomer C).

10 OCH 2 OCH 3 OCR 2 OCII 3 STr) STr 3 p cl C -02 N13 15 '%1C0 2 PNB yl> 3 A dioxane (100 mi, distilled over LAH) solution of (VS,3S,411 and VR,3R, 4S) 3-(V methoxymethyloxy- 1 '-ethyl)- 1 -(1'-paranitrobenzyl-oxycarbonyi-l'- chloromethyi)-4-trityithio-2-azetidinone (4.86 g, 6.62 mmol), tri phenyl phosph i ne (2.60 g, 9.93 mmol) and 2,6Autidine (770 20 mg, 0.837 m[, 7.20 mmol) was heated under reflux for 4 h and kept in a hot bath (1 OWC) for 16 h. The mixture was diluted with ether, washed with 1 % aqueous HCI, water, 10% aqueous NaHC03, water and brine and dried (M9S04). The solution was concentrated and the residue filtered through a silica gel (65 g) column (5%, 10% and 20% etherbenzene) to give the title compound (2.8 g, 48%). ir (CHC13) Vnn.: 1795 (C = 0), 1620 and 1605 (phosphorane) and 1515 cm-1 (N02).

LL. (VR,3SAR and VS,3R,4S) 3-(1.-Acetoxy-l'.ethyl)-1-(1'. paranitrobenzyloxycarbonyl-l'triphenylphosphoranyimethyl-4-tritylthio-2azeditinone (isomer B) 30 OAC OAC 51'r 0 3 P 'i STr cl 2,6-lutidine 0 0 3 Y02 PNB CO 2 PN13 35 A dioxane (100 mi, freshly distilled over LAH) solution of crude (VR,3SAR and VS,3R,4S) 3-0 1-acetoxy- 1 '-ethyl)- 1 -(V-paranitrobenzyl oxycarbonyl- 1 '-ch loromethyl-4-tritylth io-2-azetid i none was treated with 2,6Autidine (2.97 g, 3.23 mi, 27.72 mmol) and triphenyl phosphine (9.91 g, 40 37.8 mmol). The mixture was refluxed (oil bath 130) for 18 h. The solvent was evaporated and the residue was redissolved in methylene chloride. The resulting solution was successively washed with diluted HCI, H20, diluted aqueous Nal-1C03, H20 and brine. Drying and solvent evaporation left the title compound as a solid which was triturated with ether and collected by filtration (14.6 9, 65.9%); ir (CH2C12) 1'm.,,: 1750 (C = 0) and 1620, 16 10 cm - 1 (phosphorane).45 MM. 3-(1.-Paranitrobenzyloxycarbonyloxy-11-ethyl)-1-(1'- paranitrobenzyloxycar bonyl-lltriphenylphosphoranyimethyl-4-tritylthio-2- azetidinone.

OCYNB sco OCO 2 P N-S sco 50 3 3 0 1r0CPiNB 0 N%If03 2 co 2 PNB 55 ISOMER 8 A mixture of (VR,3S,4R and VS,3R,4S) 3-(V-pa ran itrobenzyioxycarbonyloxy- 1 '-ethyl)- 1-(Vparanitrobenzyloxycarbonyi-l'-chloromethyi)-4-trityithioazetidinone (isomer B) (4.96 9, 6.22 mmol, mixture of epimers at C-2"), triphenyl phosphine (2.47 g, 9.42 mmol) and 2,6Autidine 60 (740 mg, 0.80 mi, 6,91 mmol) was refluxed in dioxane (freshly distilled over LAH) for 30 h.

The solution was diluted with ether and ethyl acetate, washed with 5% aqueous HCl, water, 10% aqueous Nal-1C03, water and brine and dried (M9S04). Solvent evaporation afforded a residue which was passed through a silica gel (10 times its weight) column (10% ether-benzene, ether, and ethyl acetate). The title compound was obtained as a crystalline solid (3.1 g, 49%), 65 GB 2 106 113A 40 mp 189-190 (ether); ir (CHC'3) Pmu: 1750 (C = 0), 1620, 1605 (phosphorane) and 1522 cm-1 (N02). ISOMER C Isomer C of 3-(1 '- paranitrobenzyioxycarbonyloxy- 1 '-ethyl)- 1 -(1 'paranitrobenzyloxycarbonyi- 1 5 phenyl phosphora nyl methyl-4-tritylth io2-azetid i none was prepared as described above for isomer 5 B. ir (CHC13) Pmm: 1750 (C = 0), 1610 (phosphorane) and 1520 cm- 1 (N02); 11- 1mr (CDC'3) 8: 8.6 = 6.7 (H, aromatics), 5.22 and 4.95 (benzyis), 4.70 (H4), 2.6 (H-3), 1.19 and 1.07 ppm (CH3). ISOMER D A mixture of Isomer D of 3-(1'-p-nitrobenzyioxycarbonyloxy 1 '-ethyl)- 1 - (p-nitrobenzyl 2"chloro-2"-acetate)-4-trityfthio-2-azetidinone (4.598 g, 4.45 mmol; purity 77%, mixture of epimers at W"), triphenylphosphine (1.425 g, 5.44 mmol; Aldrich) and 2,6-lutidine (0.63 m], 580 mg, 5.40 mmol; Anachemia) in dioxane (65 mi; distilled from LAH) was heated at gentle reflux under N2 for 41 h, monitoring the reaction by tic (benzene: ether = 3: 1). The dark reaction mixture was cooled, diluted with COAc and washed successively with 0. 1 N HCI, water, 15 2% Nal-IC03 and then brine. Drying (Na2S04) and evaporation of the solvents gave 4.18 g of a dark coloured oil which was purified by column chromatography (S'02, 88 g; eluent 10-25% ether in benzene), yielding 1. 108 9 (1.08 mmole, yield 24.3%) of the title compound as a yellowish foam: 11-1mr (CDC'3) 8: 1.08 (d, J = 6Hz, V-CH3); ir (neat) tm..: 1745 cm- 1 (s, C = 0).

NN. Preparation of (VS,3S,4R and V17,3R,4S) 3-(1-Methanesulfonyloxy-lethyl)-1-(1,.pananitrobenzyloxycarbonyl- 1 'triphenylphosphotanyimethyl-4tritylthio-2-azetidinone (isomer C) 0MS ms sco 3 f sc 3 25 N PO N, cl y 3 1 co 2 PM 30 A solution of (VS,3S,4R and 1 'R, 3 MS)3-(1 '-methanesuifonyloxy- 1 '- ethyl)- 1 -(1 '-paranitro- benzyloxycarbonyl- 1 '-ch loromethyl)-4-trityithio-2-azetid i none (24.7 g, 35.5 mmol), triphenyl phosphine (11.2 9, 42.7 mmol) and 2.6Autidine (4.2 g, 39.1 mmol) in dry dioxane (350 m[) was refluxed under nitrogen for 19 h. The solvent was evaporated and the crude product redissolved in ethyl acetate and washed successively with dilute I-ICI, NaHCO, and brine.

Purification was completed by chrometography on a silica gel column (8.5 X 12 cm). Elution with 10% ether-dichloromethane (1.51) and then ether (1.51) gave the purified phosphorane; 12.36 g (40%). 'Hmr (CDCI,) 8: 2.53 and 2.93 ppm (3H, 2s, mesylate); ir rmn: 1749 and 1620 cm- 1 (C = 0) 00. Preparation of WR,3SAR and VS,3R,4S) 3-(1 'Hydroxy- 1 '--ethyl)- 1 - (1 '-paranitrobenzyloxycarbonyl- 1 -triphenylphosphoranyimethyl 4tritylthio-2-azetidinone (isomer B).

Co OH STr NaOR 45 )iNY PO 3 0 N PO 3 0 C02 PNB Y PNB C02 50 A solution of phosphorane (VR,3SAR and VS,3RAS) 3-(1 '-acetoxy- 1 '- ethyl)1-(V-paranitro- benzyioxycarbonyi-l'-triphenylphosphoranylidenemethyI 2 "-a cetate)-4- aritylth io-2-azetid in one (4.43 g, 5.00 mmol) in methanol (10 mi) THF (60 mi) was treated at room temperature with 1 % aqueous NaOH (1 eq, 200 mg in 30 mi H20). The reaction progression was followed by tic.

The mixture was diluted with ether-ethyl acetate and washed with HCI, H20, aqueous Nal-IC03, 55 H20 and brine. Solvent evaporation afforded a residue which was crystallized from benzene- ether (3.7 9, 87.7%) mp 169.5-1 70.WC. ir (CH2C12) 1745 (C = 0) and 1620 cm-1 (phosphorane).

Heating the mixture increased the reaction rate.

PP. Preparation of (1 'S, 3R, 4R and V17, 3S, 4S) Silver 3-(1 "methoxymethyi- 1 -ethyl)- 1 - (1'mparanitrobenzyloxycarbonyl- 1 "triphenylphosphoranyimethyl-2- azetdinone-4-thiolate (Isomer A) 41 GB 2 106 113A 41 OCE2OCH3 c, CO 3 0 OCH20C113 SAV N 0 ≥PO 3 co 2 PNB Silver 3-(1 1-methoxymethylA '-ethyi)- 1 -(1 1-para n itrobenzyloxycarbonyl- 1 '-tri phenyl phosphora nyimethyl-2 "-acetate)-3-arityith io-2-azetid in one (isomer A), was prepared as described elsewhere 10 for the isomer C of the paranitrobenzyioxycarbonyloxy derivative. Yield 50%. ir (neat Pm,,,,: 1745 cm - 1 (C= 0).

QQ. Preparation of 1 'S, 3S, 4R and VR, 3R, 4S) Silver 2-(1 'methoxymethyloxy- 1'methyl)- 1 - (1.-paranitrobenzyloxycar- 15 bonyl- 1 '-triphenylphosphoranyimethyl-2-azetidinone-4-thiolate (Isomer C).

OCH 2 OCR 3 0CH,0C11 3 STr AgNO SA9 20 PO 0 3 y C 0 2 PNB co 2 PIM (1 IS,3S,41R and VIR,31R,4S) 3-(1 1-methoxymethyloxy- 1 '-ethyi)- 1 -(1 1paranitrobenzyioxycarbonyl- 25 1 1-tri phenyl phosphora nyl methyl-4tritylth io-2-azetid i none (887 mg, 1.0 mmol) was first dissolved in hot (40C) methanol (30 mi), treated with pyridine (103 mg, 0. 105 mi, 1. 3 mmol) and, after cooling, was treated with a 0. 15 M methanol solution of silver nitrate (8.7 mi, 1. 3 mmol). The mixture was stirred for 1 h at 2WC, cooled (ice bath) and stirred for 20 min. The salt was filtered and washed successively with cold methanol and ether (3 times, 671 mg, 87%). ir (CI-IC13 Pm..,: 1745 (C = 0), 1605 (phosphorane) and 1520 cm - 1 (N02).

RR. Preparation of Silver 3-(1,.paranitrobenzyloxycarbonyloxy- 1 'ethyl)1- 1 -paranitrobenzyloxycarbonyl- 1,'triphenyl35 phosphoranylozmethyl-2azetidinone-4-thiolate.

0C0 2 PNB sc C0 2 MS 3 SA9 PO 0.9 PS 3 40 "f02 pr13 2 PNB -Isomer 8-(V11,3S,4R and VS,3RAS) 3-(11-paranitrobenzyioxycarbonyloxy-1 '-ethyi)- 1(11-paranitroben zyloxycarbonylA 1-tri phenyikphosphora nyl methyl)-4-trith io-2-azetid i none (1.02 g, 1 mmol) was first dissolved in CH2C12 (3 m[) and diluted with hot (55C) MeOH (20 mi). The hot solution was treated first with pyridine (120 mi, 117 mg, 1.48 mmol) and a hot (55T) 0. 1 5M methanolic solution of silver nitrate (8 mi, 1.2 mmol). The mixture was stirred at room temperature for 15 min, then at OC for 2 h. It was then concentrated to a 10% solution on the rotary evaporator 50 (no bath). The mercaptide was filtered and washed twice with cold ( - WC) methanol and three times with ether. (917 mg, 100%). ir (nujol mull) Pm..: 1745 (C = 0), 1600 (phosphorane) and 1517 cm-1 (N02).

-Isomer C Silver 3-(1 '-paranitrobenzyioxycarbonyloxy-1 '-ethyi)- 1-(1'paranitrobenzyioxycarbonyi-ll-triphenylphosphoranyimethy]-2-azetidinone-4-thiolate, -Isomer W, was prepared as described above for the -Isomer 13---;ir (nujol) Pm.,: 1745 (C = 0) and 1600 cm (phosphorane).

-Isomer D A solution of Isomer D of 3-(1 '-p-nitrobenzyioxycarbonyloxy-1 -ethyl)- 1 -(1 '-p-nitrobenzyioxycar boxyl-tri phenyl phosphora nyl methyl)-4-trityith io-2-azetid i none (145 mg, 0. 142 mmol) was prepared by first dissolving it in CH2C12 (5 mi), removing the CH2C12 at W60 and adding hot MeOH (4 mi). To the above solution was added a hotsolution of AgNO, in MeOH (0. 15 M, 1. 14 mi, 0. 17 mmol, 1.2 eq), followed by pyridine (14 td, 0. 17 mmol, 1. 2 eq). The silver mercaptide started to precipitate immediately. The mixture was stirred 2 h at room temperature and 1 h at 0. The mercaptide was collected by filtration and washed with ice-cold MeOH and 65 42 GB 2 106 113A 42 ether, yielding 99 mg (0. 11 mmol, 78%) of the title compound as a brownish solid: ir (Nujol) 17 5 0 cm - 1 (s, C = 0).

SS. Preparation of W17, 3SAR and VS, 3RAS) Silver 3-(1 -hydroxy1'-ethyl)- 1- (1'paranitrobenzyloxycarbonyl- 1 5 triphenylphosphoranyimethyl)-2-azetidinone-4-thiolate (Isomer 8) OH OH STr SAg AgNO 3 _ -, 1J - 10 lfN_ P03 C 5 H 5 N f p 3 -Y 0 'Y co 2 PNB co 2 M A solution of (VIR,3SAR and VS,3R,4S) 3-(1 '-hyd roxy- 1 '-ethyl)- 1 -(1 '-pa ran itrobenzy[oxycar- 15 bo nyl- 1 '-tri phenyl ph osph o ra nyl m ethyl-4-tritylth io-2-azeti d in one (1 g, 1. 19 mmol) in MeOH (10 mi), was treated with pyridine (124 gi, 121.3 mg, 1.53 mmol) and at 1 WC with a 0. 1 5M solution of silver nitrate in MeOH (15 mi, 2.25 mmol-or until no more precipitation of the silver mercaptide occurred). The mixture was stirred for 1 h and concentrated on the rotary evaporator (no bath) to approximatively 10% concentration. The solvent was filtered off. The 20 cake was washed once with MeOH and 3 times with ether, and pumped under high vacuum (954 mg, 100%). ir (Nujof mull) Pm,,: 3500-3400 (O-H), 1752 (C= 0) 1595 (phosphorane) and 1525 cm (N02) The crystalline material was first dissolved in CH2C12.

Example 6 (1 'R, 5R, 6S and 1 'S, 5S, 6R) 6-(1 -Hydroxyethyl)-2-(2aminoethoxymethyl)penem-3-carboxylic Acid (isomer 8) 3 0 CT H OCH CH NR 0 N, 2 2 2 2 co 2 H (1 -'R, 3S, 4R and 1 'S, 3R, 4S) 4-(2-Azidoethoxy)acetylthio-3-(1 - hydroxyethyi)- 1 -(1 "p-nitrobenzyloxycarbonyl- 1 - triphenylphosphoranylmethyi)-2-azetidinone (Isomer 8) OH OSIMP3 cl Me sic, Et N 1) ' 1 j 3 3 ",,A OU S 40 3 p 3 lin7THF 2) TYA to o-Q PNB 2 co 2 PhIB co 2 PN3 45 To a stirred solution of (VR,3S,41R and VS,31RAS) silver 3-(1'- hydroxyethyi)-1-(1'-p-nitrobenzyioxycarbonyi-l'-triphenylphosphoranyimethyi-2-azetidinone-4-thiolate (isomer B) (820 mg, 1. 16 mmol) in THF (20 mi) was added at - 15' (MeOH-ice bath) under N, atmosphere successively triethylamine (0 1648 mi, 4.66 mmol, 4.02 eq), chlorotrimethyl silane (0. 589 mi, 4.64 mmol, 4.00 eq) and imidazole (81.2 mg, 1. 12 mmol). The mixture was stirred at room 50 temperature for 18 h (overnight) and then cooled to - 10- 1 W. To this was added pyridine (0.220 mi, 2.72 mmol) and then a solution of 2-azidoethoxyacetyl chloride (372 mg, 2.27 mmol, 1.96 eq) in CH2C12 (20 mi). It was stirred at room temperature for 1 h. After filtration of the precipitate, the filtrate, diluted with EtOAc, was washed successively with 1 N HCI, brine, saturated NaHC03 and brine, dried (Na2SO,) and evaporated yielding 748 mg an oil. This oil dissolved in wet CH2C12 (20 mi with 3 drops of water) was treated with trifluoroacetic acid (2 drops) at room temperature for 30 min. The mixture was washed with saturated NaHCO, and then brine, dried (Na2SOJ and evaporated yielding 695 mg of a crude oil. This oil was purified by column chromatography (Si02 15 9, eluent EtOAc: CH2C12 = 1: 1) collecting 538 mg (0.739 mmol, yield 63.7%) of the title compound as a yellowish oil: 11-1mr (CM.) 8: 1.22 (d, J = 6Hz, 60 CH,-1% 5.6 (2d, H-4) and 7.3 = 8.4 ppm (aromatic Hs); ir (neat) 3420 (011), 2100 (-N3), 1750 (C = 0) and 1690 cm-1 (thioester); Rf 0.20 (CH2C12: EtOAc = 1.1).

W17, 5R, 6S and VS, 5S, 5S, 617) p-Nitrobenzyl 6-(1 -hydroxyethyl)-2-(2azidoethoxymethyl)penem- 3-carboxylate (Isomer B) 43 GB 2 106 113A 43 011 OR 6 toluene -H 2 OCII,CH 2 N 3 0:L N, 0 3 5 T02-p, NB CO 2 PN13 A solution of (VR,3S,4R and VS,3R,4S) 4-(2-azidoethoxy) acetyithio-3-(1'hydroxyethyl)-1- (1 1-p-n itrobenzyloxycarbonyl- 1 1-tri phenyl phosphoranyl methyl-2- azetid i none, (isomer B) (490 mg, 0.673 mmol) in toluene (80 mi) was heated at gentle reflux for 3 h. Evaporation of the solvent 10 in vacuo gave an oily residue which was purified by column chromatography (Si02, 10 9; eluent 5-10% EtOAc in CH2C12) followed by crystallization from CH2C12-ether to obtain 202 mg (0.449 mmol, yield 66.8%) of the title compound as light yellow crystals: 'Hmr (CDCI,) 8: 1.35 (31-1, d' J = 6.5Hz, CH3-1% 2.18 (1 H, br, OH), 3.2-3.9 (51-1, m, -CH2- and H-6), 3. 9-4.5 (1 H, m, H 11), 4.45-4.72-4.75-5.02 (21-1, AB type, CH2-2), 5.02-5.25-5.35-5.57 (21- 1, AB type, 15 -CH2Ar), 5.62 (1 H, d, J = 1 Hz, H-5) and 7.42-7.65-8.13-8.28 ppm (41-1, A2'132', aromatic Hs); ir (nujol) Pr..: 3460 (-OH), 2110 (-N,), 1765 ffl-lactam) and 1680 cm-1 (ester). An analytical sample was obtained by further crystallization: mp 107-8C (CH2C12-ether uv (EtOH) 264 (e 12000) and 323 mg (c 9200); Rf 962 (CH2C12:Et0Ac = 1.1); Anal. calcd for C,81-119N60,S: C 48.10, H 4.26, N 15.88, S 7.13; found: C 47.81, H 4.18, N 15.00, S 7.16 20 (1 'R, 5R, 6S abd 1 'S, 5S, 617) 6- 1'-hydroxyethyl)-2-(2azidoethoxymethyl) penem-3-carboxylic acid (Isomer 8) OH 2 5 S CH 2 OCH 2 CH 2 14 3 CO 2 PNB CH 2 OCH 2 ell 2 NH 2 0 2 H A solution of (1 IR,5R,6S and 1 IS,5S,6R) p-nitrobenzyl 6-(1'- hydroxyethyi)-2-(2-azidoethoxymethyl) penem-3-carboxylate (isomer B) (180 mg, 0.400 mmol) in THF (18 m]) was mixed with ether (19 m 1), H 20 (18 m 1) and 10% Pd-C (180 mg). It was hydrogenated (H 21 5 5 psi) at room temperature for 2.5 h. After filtering off the catalyst the aqueous filtrate was washed with EtOAc and Iyophilized to yield 84.4 mg (0.293 mmol, crude yield 73.2%) of the title compound as a crude yellowish powder: uv (H20) 305.5 (e 4800) and 255 mg (e 3800). This powder was 35 purified by hplc (Waters C,8 Micro Bondapack Reverse Phase 30 cm X 10 mm; eluent 1 % CH,Cl\1 in H20) to give 44.7 mg (0. 155 mmol, yield 38.8%) of the title compound as white powder: 11-1mr (D20) 8: 1.34 (31-1, d, J = 6.4 Hz, CH.A'), 3.26 (21-1, m, -CH,N), 3.82 (21-1, m, -OCH2CHA, 3.94 (1 H, dd, J6-1 = 6.2Hz, J.,-, = 1.4 Hz, H-6), 4.2-4.4 (1 H, m, 1-1-1% 4.52-4.70-4.84-5.02 (21-1, AB type, CH2-2) and 5.71 plam (1 H, d, J = 1.3 Hz, H-5); ir (KBr40 disc) t,,n..: 3420 (OH), 3000-2600 (br,C02H), 1765 ffl-lactam) and 1575 cm-1 (-C02H); uv (H20) 306 (c 5300) and 258 mg (e 3600).

Example 7

2-(2-Aminoethoxymethyl)penem-3-carboxylic Acid (via mercaptide intermediate) ell OCH CH NH al N 2 2 2 2 cc 2 H Ethyl 2-chloroethoxyacetate C1CH C0 Et, + TEAB C I 2 2 150-1600C 55 A mixture of ethyl chloroacetate (24.5 g, 0.200 mol), ethyleneoxide (8.80 g, 0.300 mol) and tetraethylammonium bromide (0.40 g, 1.9 mmol; dried in vacuo) was heated in a bomb at 150-1 60C for 6 h. After cooling, the reaction mixture was distilled under reduced pressure collecting 6.66 g (54.4 mmol, 27.2%) of ethyl chloroacetate, bp 22-24C (0. 5 mmHg) and 8.39 g (50.4 mmol, 25.2%) of ethyl 2-chloroethoxyacetate as a colourless oil; bp 49-53C 60 (0.1 mmhg); 11-1mr (CDC13) 8: 1.28 (31-1, t, J = 7Hz, -CH3), 15-4.0 (41-1, m, A2B2, -CH2CH2-CI), 4.15 (21-1, s, -COCH20-), 4.25 ppm (21-1, q, J = 7Hz, - OCH2CH3); ir (neat),V,,,..: 1740 cm - 1 (C = 0 ester). Procedure of D. Klamann et al, Jastus Liebig Ann., 710, 5 9 (19 6 7) (Reported: yield 42%, bp 55.5'/0.35 mmHg). 65 Ethyl 2-azidoethoxyacetate 44 GB 2 106 113A 44 1 HaN Eto 3, 0 DMF EtO 1..o ".--3 A mixture of ethyl 2-chloroethoxyacetate (7.71 g, 36.3 mmol) and sodium azide (3.31 g, 50.9 mmol) in DIVIF (100 m]) was heated at 80-90'C for 3.5 h by which time tic (hexane; ether 1: 1) indicated that the reaction was complete. The cooled mixture was poured into 1-1,0 (11) and extracted with ether (250 mi X 3). The extracts washed with H20 ( X 2) and brine ( X 1) 10 were dried (M9S04) and evaporated yielding 7.16 g (41.4 mmol 89. 4%) of ethyl 2azidoethoxyacetate as a yellowish oil: 'Hmr (CDCI,) 8: 1.30 (3H, t, J = 7Hz, -OCH2CH3), 3.21-4.0 (4H, m, -OCH2 C1-12N3), 4.13 (21-1, s, -COCH20-), 4.23 ppm (2H, q, J = 7Hz, -OCH2CH3); ir (neat)v,.,: 2100 (N3) and 1750 cm-1 (C = 0 ester). This material was used in the next step without further purification. 15 2-Azidoethoxyacetic acid EtCi, 3 NaOH ------- 4 N 3 H 2 0-MeDH cy- To a solution of ethyl 2-azidoethoxyacetate (6.56 g, 37.9 mmol) in MeOH (80 m]) was added 20 1 N aq. NaOH (80 mi) and the mixture was stirred at room temperature overnight (17 h). After removing the insoluble material, the methanol was evaporated in vacuo and this was saturated with sodium chloride and washed with ether (30 m] X 3). The aqueous layer acidified with 3N HCI (30 mf) was extracted with ether (40 mi X 4). The ether extracts were washed with brine, dried ^SOJ and evaporated to yield 4.25 g (29.3 mmol, 77.3%) of 2- azidoethoxyacetic acid 25 as a colourless oil: 11-1mr (CDCI,) 8: 3.3-4.0 (4H, m, -OCH,CH,N3), 4.22 (21-1, s, -COCH20-), 9. 52 ppm (1 H, S, -C02H, exchanged with D20); ir (neat) 2600-3300 (br, - COA 2100 (azide) and 1740 cm - 1 C = O-CO2H). This material was used in the next step without further purification.

* 2-Azidoethoxyacetyl chloride 30 SOC:12 Cl N 3 0 35 A solution of 2-azidoethoxyacetic acid (2.09 9, 14.4 mmol) in thionyl chloride (5 m]) was stirred at room temperature for 4 h. The excess thionyl chloride was removed under the vacuum of the water aspirator and the residue dissolved in benzene (10 m], dried over molecular sieves) was evaporated in vacuo. The oil so obtained was dried in vacuo (water pump) over NaOH for 1 h yielding 2.23 g (13.6 mmol, 94.4%) of 2-azidoethoxyacetyl chloride as a colourless oil: 'Hmr 40 (CDCI,) 8: 3.43 (21-1, br. t, J = 5Hz, -CH20-) 3.78 (21-1, br. t, J = 5Hz, -CH2N3) and 4.50 ppm (2H, s, -COCH20-); ir (neat) Pm.: 2100 (azide) and 1800 cm-1 (-COCI). This material was used in the next reaction without any purification.

4-(2"azidoethoxyacetylthio)- 1-(1'paranitrobenzyloxycarbonyi- 1 triphenylphosphoranyimethyl-2- azetidinone.

0 SA9 + N CO 2 PNB Pyr/CH 2 Cl 2 OYP% co 2 PNB To a stirred solution of silver 1 (1 '-paranitrobenzyi-oxycarbonyi-l '- triphenylphosphoranyimethyl)-2-azetid in on e-4-th io late (7.96 9, 12.0 mmol) in CH2C12 (100 mi) containing pyridine (1.94 mi, 24.0 mmol) was added at O-WC under nitrogen atmosphere a solution of 2-azitoethoxyace- 55 tyl chloride (2.23 g, 13.6 mmol) in CH2C12 (20 mi) and the mixture was stirred at room temperature for 2 h. After filtration of the precipitate, the filtrate was evaporated and the residual oil was purified by column chromatography (Si02, 160 g; eluent, EtOAc: CH2C12 = 1: 1) collecting 4.216 g (6.17 mmol, 51.4%) of the title phosphorane as a yellowish foam. This foam was used in the next step. An analytical sample was obtained by crystallization from CH2C12ether (1:9): mp 1 28-WC (dec.); ir (nujol) jm,x: 2090 (-N3), 1755 (plactam) and 1690 cm - 1 (thioester); Anal. calcd for C3,1-13ON50,PS: C 59.74, H 4.42, N 10.26, S 4.69; found: C 59.33, H 4.49, N 9.69, S 5.19: tic (EtOAc) Rf = 0.55.

p-Nitrobenzyl 2-(2-azidoethoxy)methyl-penem-3-carboxylate GB 2 106 113A 45 S toluene H OCH CH N Y PO 3 22 2 3 copNB Co 2 PNB 5 A solution (cloudy) of the above phosphorane (4.13 9, 6.04 mmol) in toluene (200 mi) was heated under reflux under a nitrogen atmosphere for 1.5 h. After removal of the insoluble material, the solvent was evaporated in vacuo and the residual oil was purified by column chromatography (S'02, 80 g, eluent 5% ether in benzene) collecting 2.44 g (6.02 mmol, 99.6%) of title compound as a yellowish oil. This oil was used in the next step. Crystallization from CH2C12-ether (1:9) gave an analytical sample: mp 88-89.5'C; 'Hmr (C1)C13) 8: 3.35 (2H, t, J = 5Hz, -OCHA, 3.47 (1 H, dd, J9em = 16Hz, Jtrans = 2Hz, C,-H), 3.67 (2H, t, J = 5Hz, -CH2N3), 3.85 (1 H, dd, Jgem = 16Hz, Jci., = 3.5 Hz, C,-H), 4.73 (2H, ABq, J = 16, 19 C2CH2), 15 5.30 (2H, ABq, J = 13.5, 9, -OCH2Ar), 5.63 (1 H, dd, JImn, = 2Hz, Jci, = 3.5 Hz, C,,-1-1), 7.50-7.63-8.12-8.27 ppm (4H, A2'B2', aromatic. Hs); ir (nujol) Pm.; 2100 (-N3), 1785 (p lactam) and 1695 cm- 1 (ester) uv (EtOH) Am.; 263 mtt (cl 2000), 320.5 mit (E9600) tic (benzene: ether = 1: 1) Rf = 0. 60 2-(2-Aminoethoxy)methyl-penem-3-carboxylic acid 20 CH OCH ca N H 2 /Pd-C h S CH OCH CH NH N 2 2 2 3 2 2 22 C02 PNB 0 2 H 25 A solution of the above azido ester (1.62 9, 4.00 mmol) in 1,2- dimethoxyethane (50 mi) was mixed with ether (50 m]), H20 (50 m]) and 10% Pd-C (1.62 g; Engelhard) and hydrogenated at room temperature (H2: 55 psi) for 2.5 h. After filtration of the catalyst, the aqueous layer was 30 washed with ether (50 m] X 2) and then EtOAc (50 mi X 1). The aqueous solution was lyophilized to give 817 mg (3.34 mmol, 83.6%) of the title amino-acid as a yellowish powder:

uv (H20);k,,,.,,: 304 mIt (e5000). This material was purified by hplc (Waters, C,8 Micro Bondapak Reverse Phase 30 cm X 10 mm; eluent 1 % CH3CN in H20) to give 432 mg (1. 77 mmol, 44.2%) of the title amino-acid as a white powder: 11-1mr (D20) 8: 3.19-3. 9 (4H, m, -OCH2CH2NH2), 3.54 (1 H, dd, Joem = 16.9 Hz, Jtrans = 1.9 Hz, C6-H), 3.88 (1 H, dd, igem = 16.8 Hz, Jci = 3.7 Hz, C.H), 4.52-4.70-4.83-5.01 (2H, AB type, C2- CH20-) and 5.77 ppm (1 H, dd, Jc i, = 3.6 Hz, J,,ar,, = 1.9 C,-H); ir (KBr disc) 1770 ffl-lactam) and 1580 cm -' (-C02H); uv (H20) 304 mg (c5400), 256 mg (e31 00).

Example 8

2-(2-Aminoethylthiomethyl)penem-3-carboxylic Acid (via mercaptide intermediate) CH SCH CH NH LW!, 2 2 2 2 cooll 2-Azidoethyl methanesuffonate BrCH2 20H ^CH2CH20MS A solution of 2-bromoethanol (7.5 g, 60.0 mmol) and sodium azide (5.0 g, 76.9 mmol) in HMPT (30 mi) was heated at 11 5'C for 2.5 h. The reaction mixture was cooled to 23,C and diluted with CH2C12 (100 m]). The solids were removed by filtration and the CH2C12 was evaporated on the rotary evaporator leaving a yellow liquid which was cooled to OC and successively treated with mesylchloride (5.57 mi, 72.0 mmol) and triethylamine (10.0 mi, 72.0 55 mmol). The reaction mixture was stirred at O'C for 1 h, then at 23'C for 6 h, and poured into H20 (300 m]). The aqueous solution was extracted with ether (1 X 200 mi, 4 X 100 m[); the ether extracts were combined, washed with 1 N HCl solution, H20 saturated Nal-IC03 solution and H20, dried over anhydrous MgSO, and concentrated on a rotary evaporator to an orange liquid which was distilled under high vacuum bp 95-1 OWC. 0.3 torr, 5.8 g, 58.5%; ir (neat) 60 Pm..: 2005 (s, N3), 1345 (s, S02-0), 1175 (m, S02-0) CM-'. 11-1mr (C13C13) 8: 3.03 (s, 3H, OCH3), 3.43-3.76 (m, 2H, H-2) and 4.2-4.46 ppm (m, 2H, H-1).

2,-Azidoethylthioglycolic acid 46 GB 2 106 113A 46 A solution of silver 1-(V-paranitrobenzyl 1 '-tri phenyl phosphora nyl methyl-2-azetid inone-4-thiol- ate (15.7 mmol) and pyridine (1.6 mi, 19.8 mmol) in CH2C12 (200 mi) was treated dropwise (0.25 h) with a solution of 2-azidoethyithioacetyl chloride (3.64 g, 20.3 mmol) in CH2C12 (50 mi). The reaction mixture was stirred at 23'C for 1.5 h and filtered; the solids were washed with CH2C12. The filtrate and washings were combined and washed with 0. 1 N HCl solution, H20, saturated NaHCO, solution and H20, dried over anhydrous NaSO, and concentrated on a rotary evaporator to an orange syrup. A column chromatography (300 g of silica gel G-60, eluent; EtOAc in CH2C12, 0-40%) of crude compound gave after evaporation of solvent a white powder, 7.7 g, 70%. An analytical sample was obtained after a recrystallization from CH2C12-ether-pet.

ether, mp 1 50-1'C dec. Anal. calcd for C14H,ONIOIS2p: C 58.36, H 4.32, N 10.01, S 9.17; 45 found: C 58.64, H 4.36, N 10.03, S 9.25. ir. (KBr) 2100 Is, N3), 1750 Is, C = 0 offl lactam), 1675 Is, C = 0), 1655 Is, C = 0), 1610 Is, aromatics), and 1440 cm-1 Is, P-Ph).

1. A N,Cl-12CH2OMS + NaSCH2COON&------.>N,CH2CH2SCH2COOH 2. H + Thioglycolic acid (3.14 g, 34.1 mmol) was treated with 1 N NaOH solution (68 mi, 68.0 mmol) and the resulting solution was stirred at 23T for 0.5 h and treated with a solution of 2'azidoethyl methanesulfonate (5.3 g, 32. 1 mmol) in 1,2-dimethoxyethane (15 mi). The reaction mixture was stirred at 4WC for 22 h, cooled to 23'C, washed with CH2C12 (3 X 20 mi), acidified with 6N HCI solution and extracted with CH2C12 (7 X 40 mi). The CH2C1, extracts were combined, dried over anhydrous Na,SO, and concentrated on a rotary evaporator to an oil which was distilled under high vacuum bp 11 7-22'C/0.27 torr, 4.2 g, 81.2%. ir (neat) 2100 Is, N3), 1708 Is, C = 0) cm - 1. 'Hmr (CDC'3) 8: 2.7-3.07 (m, 2H, H-1% 3. 35 Is, 2H, H-1), 3.30-3.73 (m, 2H, H-2') and 11.81 ppm Is, 1 H, COOH).

2-Azidoethylthioacetyl chloride (C0C42 N3CH3CH3SCH3COOH------3.N3CH2CH2SCH2COCl To a solution of 2-azidoethylthio glycolic acid (3.33 g, 20.7 mmol) in CH2C12 (50 mi) was added oxalyl chloride (3.9 mi) and DMF (one drop). The reaction mixture was stirred at 23C for 1.5 h and the solvent was removed on a rotary evaporator leaving a yellow liquid. ir(neat) 2100 Is, N3), 1785 (bs, C = 0). 1 Hmr (CM3) 8: 2.6-3.0 (m, 2H, H-1 1), 3.37-3.73 (m, 2H, H2% and 3.82 ppm Is, 2H, H-1).

4-(2-azidoethylthioacetyithio)- 1 -(1 -paranitrobenzyl oxycarbonyl- 1 triphenylphosphoranylmethyi)2-azetidinone SAg cl 9 N 30 9CH 2 SCH 2 C5N 'R,:,CC112SCH2CH2 3 N N f-PPh 3 'IPPh 3 COOPNB COOMB paraNitrobenzyi 2-azidoethylthiomethylpenem-3-carboxylate 9c. m 2 SCH 2 CH 2 N 3 11-s - CH SCH CH N 50 0 PPh 0 3 COOPNB OOPNB 55 A suspension of 4-(2'-azidoethyithioacetyithio)-1-(1'-paranitrobenzyl oxycarbo nyl- 1 '-tri phenyl- phosphoranyimethyi)-2-azetidinone (4.5 g, 6.43 mmol) in toluene (375 mi) was stirred at 11 OT for 2.25 h under a nitrogen atmosphere. The reaction mixture was cooled to 23'C and the evaporation of solvent on a rotary evaporator gave an orange syrup. The purification of crude 60 material was done on a silica gel column (90 g of silica gel G-60, eluent: ether-pet-ether, 1: 1 -3:2); the pure material was obtained as a yellow syrup, 2.2 9, 81 %). ir (neat)],m.,,: 2100 Is, N3), 1785 Is, C = 0 offl-lactam), 1705 cm-1 Is, C = 0 of PNB); 'Hmr (CM3) 8: 2.53-2.90 (m, 2H, H-1 "), 3.30-3.67 (m, 3H, H02", H-6 trans), 3.98 (ABq, Jb = 14.8, Hz, 2H, H-1 5.32 (ABq, J,,-b = 13.0Hz, 2H, CH,-PM0,), 5.66 (dd, JH-5,H-6i 3.6 Hz, JH- 5,H-6trans 1.9 Hz, 1- 65 47 Example 9 Silver 1-(11-(#-Trimethyisilylethytoxycarbonyl-l,. triphenylphosphoranyimethyi)-2-a zetidinone-4thiolate 1.1 ff SAg 0 CH CH H3 V02 2 2\ CH 3 GB 2 106 113A 47 H, H-5), 7.58 (d, JH,14 = 8.8Hz, 2H, Ho PNB) and 8.19 ppm (d, J1111-Ho = 8.8Hz, 2H, Hm PNB).

2-Aminoethylthiomethylpenem-3-carboxylic acid S 5 N CH 2 SCH 2 CH P3 i OP2SCH2CH2 NH 3' COOPNB c To a solution of p-nitrobenzy] 2-azidoethylthiomethylpenem-3-carboxylate (45 mg, 0. 11 10 mmol) in 1,2-dimethoxyethane (5 mi) were added ether (5 mi), water (5 m[) and 10% Pd/C (45 mg, 0. 11 mmol). The reaction mixture was hydrogenated at 23 C under 45 psi of hydrogen for 3.0 h and filtered over a Celite pad. CELITE is a Registered Trade Mark. The pad was washed with water and the filtrate and washings were combined.

di-fl-trimethyisifyiethyl fumarate 0 Cl (CH 3 Cl,, 3 3 (C-H si 30 0 Pyridine 3 3 To a cold ( - 1 OC) ether (20 m]) solution of 2-trimethylsilyl ethanol (4. 73 g, 0.04 mmol) [H.

Gerlach Heiv. Chim. Acta 60, 3039 (1977)] and pyridine (5.66 m], 0.07 mol), under nitrogen, 35 was added dropwise (15 min) fumaryl chloride (3.78 mi, 0.035 mol) dissolved in ether (10 mi).

The black mixture was stirred five minutes at - 10 C and ten at room temperature. Charcoal was added and the reaction mixture filtered on a Celite pad. The filtrate was washed with sodium bicarbonate 1 %-brine (1: 1, 150 mi). The aqueous phase was back extracted with ether (30 mi). The ether solutions were combined, washed with brine, dried over sodium sulfate, 40 filtered and concentrated under reduced pressure to give a brown solid. This compound was purified on a silica gel pad (30 g, 4 X 5 cm) with benzene (300 mi) as eluent to give an oil (4.855 g, 77%) which solidified on standing: mp 33-34C. Anal. calcd for C, ^10IS'2: C 53.12, H 8.91; found: C 53.35, H 8.91. 11-1mr (CDCI,) 8: 6.78 (2H, s, C = CH), 4.26 (4H, m, CH2-0), 1.03 (4H, m, CH2-Si) and 0.06 ppm (18 H, s, (CHISi); ir (CHC'3) P, : 1710 (C = 0 of 45 ester), 1643 (C = C), 1267, 1258, 862 and 840 cm - 1 (Si-C).

2-Trimethylsilylethyl glyoxylate hydrate 0 51 (CH 3) 3 1) 0 3 H (OH) i (CH,) 50 (CH 2) (CH 5 h 3 3 3 3 2 2 A solution of di-,8-trimethyisilYlethyl fumarate (37 g, 0. 117 mmol) in methylene chloride (1. 1 55 1) was ozonized at - 78C until a blue color persisted. The excess ozone was purged with nitrogen and dimethyl sulfide (2.57 mi, 0.351 mol) was added. The solution was allowed to gradually warm to 23C. The reaction mixture was diluted with carbon tetrachloride to 2 liters and washed with 1 % aqueous solution of sodium carbonate (500 mi). The organic phase was dried over sodium sulfate, filtered on Celite and evaporated (25C) to dryness to give 43.9 g 60 of the title compound (97%); ir (neat) 3450 (-OH), 1740 (ester, 1255, 860 and 840 cm-1 (Si-C).

1 -(1..fl-trimethyisitylethyl oxycarbonyl- 1 'hydroxymethyi)-4-trityithio2-azetidinone 48 GB 2 106 113A 48 fTr (c)H) 2 SiCH3)3 Tr N co 2 on o si (CHS 5 co 2 2-Trimethylsilyletheyl glyoxylate hydrate (4.000 g, 11.6 mmol) and the 4- trityithio-2-azetidinone (4.8 g, 24.96 mmol) were refluxed in benzene (25 m]) through a Dean Stark condenser, under nitrogen for 24 h. The solvent was evaporated under a vacuum. The product was chromatographed on a silica gel column (450 9, 8.5 X 14.5 cm) and eluted with ethyl acetate: methylene chloride (1: 19) until the title compound started to come out (- 1. 5 1) and then with ethylacetate: methylene chloride (1:9, 2 1). The fractions containing the title compound were combined and evaporated to dryness to give 5.415 g (89%) of the title compound. 'Hmr (CDCI,) 8: 7.80 to 6.70 (1 5H, m, trityl), 5.23 and 4.90 (1 H, 2s, H-C-0), 4.50 to 4.10 (3H, 15 rn, H-3 and O-CHJ, 2.60 (2H, m, H-2), 0.95 (2H, m, CH2-Si and 0.1 ppm (9H, s, Si-CH3); ir (CHC13) Pm..: 3520 (-OH), 1765 (C = 0 offl-lactam), 1740 (C= 0 of ester), 1595 (C-H, aromatic), 1257, 860 and 840 cm-1 (C-Si) 1-(1-fl-trimethyisilylethyloxycarbonyl-l'-chloromethyl)-4-tritylthio-2azet idinone STr 50121 STr 2 pyricine Cl Si (CH 3) 3 0 si (CH 3) 3 CO CO 2 25 A solution of thionyl chloride (0.74 mi, 10.37 mmol) in dry THF (9 ml) was added dropwise with stirring to a solution of 1 -(1 '-#-trim ethyl si lylethyl oxycarbony]-1 '-hydroxymethyi)-4-tritylthio- 2-azetidinone (4.9 g, 9.37 mmol), pyridine (0.84 mi, 10.38 mmol) and dry THF (40 mi) at - 1 5'C under a nitrogen atmosphere. The mixture was stirred at - 1 5T for 2 h. The precipitate was removed by filtration on a Celite pad and washed with benzene (50 mi). The filtrate was evaporated in vacuo at 3WC. The residue was dissolved in benzene (100 mi), treated with charcoal and filtered through a Celite pad. Evaporation of the solvent gave a residue which was purified through a silica gel pad (100 g, 4.7 X 11 cm): hexanebenzene (1: 1, 400 35 mi), ether-benzene (1 A 9, 11). Evaporation of the pertinent fractions gave 4.64 g of the title compound (92%). 'Hmr (CDC'3) 8: 7.30 (1 5H, m, aromatic H), 5.77 and 5.43 (1 H, 2s, CH-CI), 4.7 to 4.2 (3H, m, H-4 and CH,-0), 2.85 to 2.50 (2H, m, H-3), 1.15 (2H, m, CH,-Si) and 0.06 ppm (9H, s, Si-CH3); ir (neat) Pmax: 1760 (C = 0), 860 and 840 cm- 1 (C-Si).

1-(1'-(#-trimethyisifyiethyloxycarbonyl- 1 -triphenylphosphoranylmethyl)4-tritylthio-2-azetidinone dE N Tr cl 03 P STr 2t6-lutidizie p 45 si (CH (CH Si -ro 2 3 3 'to 2 " 3 3 A dioxane (20 mi) solution of the above ch loroazetid i none (4.12 g, 7. 568) was treated with triphenylphosphine (2.209 g, 8.424 mmol) and 2,6-1utidine (0.98 mi, 8.424 mmol). The 50 mixture was refluxed for 3.5 h. The cooled solution was filtered and the white solid washed with THF. The filtrate was evaporated to dryness. The residue was purified on a silica gel column (200 g, 4 X 31 cm) using ethyl acetate-hexa n e (17, 11; 7.3, 11) to give the title phosphorane (4.836 g, 83%). ir (film) Pm,,,: 1755 (C = 0), 1615 (phosphorane), 850 and 830 cm 1 (Si-C).

Anal. calcd for C4,H16NO3PSS': C 73.89, H 6.07, N 1.81; found: C 72.18, H 6.08, N 1.83 55 Silver 1-(1'-16-trimethyisilylethytoxycarbonyll'triphenylphosphoranyimethyl)-2-a zetidinone-4-thiolate STr SA9 60 + A9NO 3 + (nBu) 3 N + CF 3 CO 2-M ',hcr/li-0 IF C 3 2 N /^"Is i (CH 3) 3 T 3 si (CH 02 02 3 49 GB 2 106 113A 49 1 -(1 1-p-trimethyisilylethyloxycarbonyi-l'-triplienyl phosphora nyl methyl)-2-azetidi none (7.64 g, mmol) was dissolved in ether (60 m]). An aqueous solution of silver nitrate (0. 5M, 80 m], mmol) was added followed by a rapid addition (1 min) of a solution of tributylamine (3 mi, 12.58 mmol) and trif luoroacetic acid (0. 154 m[, 0. 2 mmol) in ether (20 m]). The mixture was mechanically stirred for 19 min. The precipitate was filtered, rinsed with ether (200 mi), 5 triturated in water (70 mi), filtered again and rinsed with ether (100 mi). The light brown solid was dried under vacuum (water aspirator 10 min and pump 65 min) to give the title compound (6.42 g). ir (CHC'3) 1862 (C = 0, 1630 (phosphorane), 860 and 840 cm - 1 (Si-C).

Example 10 Silver 3-(1 '-Hydroxy- 1 "ethyl)- 1-(1'.fltrimethyisilylethyloxycarbonyl- 1'-triphenylphosphoranyimethyl)-2azetidinone-4-thiolate OH SA9 le Phi 0 CO 2 3 trans 3-acetyl-l-(1'-fl-trimethyisilylethyloxycarbonyl-l,. triphenylphosphoranyim ethyl)-4-tritylthio- 20 2-azetidinone Tr 2 5 j " Pph 3 2. EtOAc 0 SiMe 3 1. LDA 0 ST'r Ple PPh 3 0 Silie 3 To a solution of diisopropylamine (0.80 mi, 5.5 mmol) in tetrahydrofuran (25 mi) at - 78C was added n-butyl lithium (4.0 mi, 6.0 mmol) with stirring. After 3 min, a solution of 1-(1 30 tri methylsi lylethyloxycarbonyl-tri phenylphosphora nyl methyl)-4- tritylth io-2-azetid i none (3.82 5.00 mmol) in tetrahydrofuran (40 m]) was added dropwise over 20 min with stirring. After 2 min, 2.5 mi (25 mmol) of ethyl acetate was added and the solution was stirred for 10 min. The cooling bath was removed and 0.2M hydrochloric (58 mi) acid was added with vigorous stirring. Water and ethyl acetate were added (65 mi each), shaken and separated. The organic 35 phase was washed with water and saturated sodium chloride (60 mi each), dried and the solvent was evaporated in vacuo to give the crude product, 4.1 g. The product was absorbed from methylene chloride onto 20 g of silica gel and placed (dry) on a 120 9 silica gel column. The column was eluted with ether/hexane 1: 1 (200 mi) then with ether (500 mi). Evaporation of the solvent from the appropriate fractions gave partially purified title compound, 2.17 g (53%); 40 ir t: 1755 ffl-lactam and ester) and 1710 cm-1 (ketone); 11-1mr (CDC13) 8: 1.67 and 1.87 peaks for 0 11 CH3(;-, trimethylsilyl and aromatic peaks; remainder poorly resolved.

3-(1,.hydroxy-l'ethyl)-1-(1-fl-trimethyisifyiethyloxycarbonyl-triphenylph osphoranyimethyl)-4-tri- 50 tylthio-2-azetidinone.

0 OH STr Tr 4 21 0 Ph 3 sime Ph 3 55 e 3 SiMe N co 3 2 A solution of the above compound (2.10 9, 2.60 mmol) in tetrahydrofuran (20 m]) was added to a slurry of sodium borohydride (160 mg, 4.3 mmol) in tetrahydrofuran (10 mi). The mixture 60 was stirred at 23C for 4 h. Water (30 mi) was added followed by the slow addition of 1 M hydrochloric acid until pH 3 was reached. The mixture was extracted with ethyl acetate (50 mi).

The organic phase was washed with 50 mi each of 0.1 M sodium bicarbonate, diluted sodium chloride and saturated sodium chloride then dried and the solvent was evaporated in vacuo to give the crude product, 2.22 g. The product was absorbed from methylene chloride onto 11 g 65 GB 2 106 113A 50 of silica gel and placed (dry) on a 44 g silica gel column. The column was eluted with ether.

Evaporation of the solvent from the appropriate fractions gave partially purified title compound, 1.43 g (68%); 'Hmr (CIDC13): peaks around 8 1 for OH 1 CH3CH-, trimethylsilyl and aromatic peaks; remainder poorly resolved.

Silver 3-(V-hydroxy- 1 'ethyl)- 1-(1 -fl-trimethyisilylethytoxycarbonyl1'-triphenylphosphoranyimethyl)-2-azetidinone-4-thiolate H Ile STr PPh A9NO 3 Me SA9 15 N SIMe 0 3 SiM.

3 Co 3 2 2 A solution of silver nitrate 1.43 g, 8.4 mmol) in water (40 mi) and a solution of pyridine (0.27 m], 3.35 mmol) and the above phosphorane (1.35 g, 1.67 mmol) in ether (40 mi) were stirred together vigorously at 23'C for 1 h. The precipitate was collected by filtration, washed with water and ether and dried to give crude title compound 1.24 g (100%); ir 3420 (OH) and 1750 cm - 1 ffl-lactarn and ester). Example 11 (1 R, 5R, 6S and VS, 5S, 6R) 6-(1 -Hydroxyethyl)-2-(2-

aminoethoxymethyl)-penem-3-carboxylic Acid (isomer B)--Altemative Procedure CH OCH CH NH 0 N 2 2 2 2 co 2 H (Isomer B) (V17,3S,4R and VS,317,4S) 4-(2-azidoethoxyacetylthio)-3(1'hydroxyethyl)-1-(1-16-trimethyisilylethyloxycarbonyl- 1 triphenylphosphoranyimethyl)-2-azetidinone H SACJ SCOCH 2 OCH 2 CH 2 N 3 40 f p 3 0 N',?3 co 2 5 co 2 45 Trimethylsityl chloride (1.54 mi, 11.8 mmol) was added to a stirred slurry of silver 3-(Vhydroxyethyl)-1-(1'-,8-trimethyisilylethyloxycarbony]-1 '-tri phenyl phosphoranyl methyl-2-azetidi none-4-thiolate (isomer B) (2.48 g, 3.34 mmol), imidazole (136 mg, 2.0 mmol) and triethylam ine (1.64 mi, 11.8 mmol) in THF (60 mi) at O'C. The mixture was stirred at 23' for 18 h.

Methylene chloride (60 mi) was added, the mixture cooled to - 1 WC, pyridine (1.32 mi, 16.4 50 mmol) and fl-azidoethoxyacetyl chloride (1.43 g, 8.70 mmol) added and the mixture stirred at - 1 WC for 0.5 h. Ether (60 mi), ethyl acetate (60 mi) and 1 M hydrochloric acid (20 m]) were added. The precipitate was removed by filtration and the organic phase was washed with 0. 1 M hydrochloric acid (100 mi), 1 % sodium bicarbonate (100 mi), and saturated sodium chloride.

Concentration of the dried solution gave crude title compound as an oil. 85%. ir P a.: 1755 and 55 1695 cm-1.

(1 'R, 5R, 6S and 1 'S, 5S, 6R) fl-trimethyisilylethyl 2-flazidoethoxymethyl-6-(1 -hydroxyethyl)penem-3-carboxylate (Isomer 8) 51 GB 2 106 11 3A 51 OH SCOCH OCH CH H 2 2 2 3 PO 3 Y SI- co 2 \ S CH 2 OCH 2 CH 2 N 3 0 C0 2 VP A solution of the above phosphorane (1.3 9) in toluene (200 m]) was heated under reflux for 103 h. Concentration of the solvent on a rotary evaporator gave the crude title compound.

Chromatography on silica gel (40 g) eluting with increasing proportions of ether in hexane gave crystalline title compound, 65%. ir 1760 and 1700 cm-l; 11-1mr indicated contamination with a second isomer.

(1117,517,6S and 1-'S,5S,6R)-2-fl-azidoethoxymethyl-6-(1-(1-hydroxyethyl)penem-3-carboxylic 15 acid (Isomer 8).

011 11 S H 2 OCII 2 CR2S 0,sit- 02 S H 0C,H 2 2CH2N3 0 2 H A solution of anhydrous tetrabutylammonium fluoride (3 mi, 1.5 mmol) in THF was added to a solution of the above ester (155 mg, 0.37 mmol) in THF (2 mi) at WC. After 5 min at WC, 25 water (10 m[) and ethyl acetate (10 mi) were added, the mixture was acidified to pH 3 (1 M hydrochloric acid) and the phases separated. The organic phase was extracted with 0.05 M sodium bicarbonate, the aqueous extracts acidified to pH 3 with hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride, dried, concentrated on the rotary evaporator and the residue triturated in ether to give the crude title 30 compound as a solid, 27 mg, 28%. ir 3500, 1785, 1670 cm-l; 11-1mr (CDC13) 8: 1.30 (31-1, d, J = 6.5, CH3-11), 2.22 (1 H, OH), 3.1 -3.9 (51-1, rn, CH2 and H6), 3.9-4.4 (1 H, m, H 11), 5.60 (1 H, d, J = 1, H-5).

3 5 (1 -R, 5R, 6S and VS, 5S, 6R) 6-(1 -Hydroxyethyl)-2-(2aminoethoxymethyi)-penem-3-carboxylic 35 acid (Isomer B) H XE CH 2 2 23 co 2 H ---------------- 11 N H 2 ocil 2 CH 2 Wiz C0 2 H A solution of the above azidocompound (150 mg) in THF (15 m]), ether (15 mi) and water (15 mi) was hydrogenated in a Parr shaker in the presence of 10% Pd/C (150 mg) at an initial H2 pressure f 60 psi. After 3 h the catalyst was removed by filtration over Celite and the aqueous phase was washed with ethyl acetate and lyophilized to give the crude title compound. Purification by hplc (Waters, Cl. Micro Bondapack Reverse Phase) gave 46.7 mg of pure title compound identical to a previously prepared sample prepared by hydrogenation /hydrogenalysis of the corresponding azido p-nitrobenzy] derivative.

6 0 oAc CSI NaHCO 3 Na 2 so 3 1 Example 12 6-Ethyl-2-(2-aminoethoxymethyi)penem-3-carboxylic Acid C 2 R 5 S /,, C H 2 OCH2 C H 2 N H 2 XC02 H 0Ac 0Ac NH 0 11 52 GB 2 106 113A 52 The 1-b utenyl acetate (about 1: 1 mixture of cis and trans isomers) was prepared according to P. Z. Bedoukian, J. Am. Chem. Soc. 66 1635 (1944).

To cooled (- 1 5T) 1(50 m]) was added dropwise 10 m] (11 g, 78 mmoles) of CSI. The mixture was allowed to warm up gradually during 30 min. to O'C. It was cooled to - 2WC and poured carefully onto a mixture of water (8 mi) ice (35 g), Nal-IC03 (18. 4 g) and Na2S03 (6.4 g). This was stirred vigorously at O'C for 30 min., treated with pet. ether (250 mi) and cooled to - 4WC. The solvent was decanted and the residue was treated with another 100 m[ of pet. ether in the same way. The combined pet. ether extracts were washed with water (30 mi) and dried (NaSOJ for recycling of 1.

The aqueous phases were combined and extracted with ethylacetate (5 X 40 mi). The extract 10 was dried (Na2S04) and concentrated in vacuo to give 7.0 g (57%) of a mixture of 28% 11 and 72% Ill, b.p. 82-85C (0.01 mm); n.m.r. 8 (ppm, CDC13) 7.3 (1 H,NH) 5.92 (0.72 H, a, J = 4.4, 11-H-3), 3.3 (0.28 H, a, J = 1.4, M-H-4), 3.3 (1 H, m, H-3), 2.24 (3H, s), 2.72 (2H, two q, J = 7), 1.1 (3H, two t, J = 7). 1775, 1755 cm-1 Anal. calcd. for C71-11,1\103 C 53.49, H 7.05, N 8.91. Found C 53.12 H 6.93, H 8.85.

o' OCOCH 3 NaSCO-^H 3 N 0 11 + ill 111 5-COCH 3 v H 0 IV Sodium thioacetate was prepared by addition of thioacetic acid (0.8 mi, 850 mg, 11.2 mmoles) to a cooled (ice-bath) IN sodium hydroxide solution (11.2 mi) under nitrogen. This was added to a cooled solution of Hand M (1. 57 g 10 mmoles) in water (5 mi) under N2. The 25 mixture was stirred for 1 h at room temperature. Since an oil was separating, acetone (9 mi) was added and stirring continued for 1.5 h. The mixture was concentrated in vacuo to remove acetone and then extracted with methylene chloride. The extract was dried and concentrated in vacuo to give 1.65 g (95%) of crude mixture of 85% trans 1Vand 15% cis /Vbp 105-110' (0.02 mm), 7.1 (1 H,NH) 5.53 (0.24H, a, J = 4.5, cis-H-4), 5.12 (0.8H, a, J 2.4 trans -H-4) 30 3.34 (1 H, two t, J = 7) 2.48 (31-1) 1.9 (1 H, two q, J = 7) 1.15 (3H, two t, J 7. V=. 1700, 1765 cm Anal. calcd for C71-1,1N C 48.53, H 6.40, N 8.07. Found C 48.18, H 6.47, N 7.77 3 5 5SCOCH3 024-' CH 2-CO 2 CH (CH) 35 V H 0 co 2 PN5 40 1V V A mixture of W(1.25 g, 7.2 mmole) and p-nitrobenzy] glyoxylate hydrate (1. 6 g, 7.5 mmole) in benzene (80 mi) was refluxed 20 h under a Dean Stark water collector followed by concentration in vacuo to give 3.01 g of crude product. This was filtered over a small amount of silica in chloroform to give 2.8 9 (quantitative yield) of slightly yellow oil Vcontaining some solvent, 8 7. 9 (4H, m) 5.3 (4H, m) 4.8 (1 H, OH) 3.2 (1 H, m) 3.37 and 3.33 (3H, two s) 1.8 (2H, m) 1.05 (3H, m) v.... 1765, 1700 cm- 1. This product was used in the next step without further purification.

COCH 3 SOC1 H-OH 0 H C 55 P.1M CO,PNB 2 V vi To a cooled (ice-bath) stirred solution of V (2.1 9, 5.5 mmole) in dry benzene (10 mi) was added thionyl chloride (3 m[) and the mixture kept at 5'C for 2 h followed by evaporation in vacuo at room temperature. The excess thionyl chloride was removed by repeated addition and evaporation of benzene and the product was purified by filtration of the benzene solution over a small amount of silica gel, to give after concentration in vacuo 1.7 g (77%) of crude slightly 65 53 GB 2 106 113A 53 yellow oil W 8 7.9 (4H, m) 6.0 (1 H, s) 5.3'(3H, m) 3.3 (1 H, m) 2.7 and 2.3 (3H, two s) 1.75 (3 H, m) 1.0 (3 H, m) P.

1700, 17 7 5 cm The product was used in the next step without further purification.

-COCIS P03 5-COCH3 N lutidine CUC1 f=p03 j _V 2 PUB co 2 PNB 10 VI Vil A mixture of V1 (1.7 g, 4.2 mmoles), tri phenyl phosphi ne (1.57 9 6.0 mmoles) and 2,6 lutidine (5.35 mg, 5 mmoles) in dry dioxane (20 mi) was heated at 55 for 19 h, followed by 15 concentration in vacuo. The dark-red residue was chromatographed on a silica gel column (35 g). Elution with benzene-ether gave 2.3 g (87%) of crude V11 as light red oil, which was used in the next step without further purification.

S COCH ASN03 SAg 20 PO 3 base PO 3 3 0 co 2 Plu C02HB Vii Viii 25 Mercaptide Vill is prepared from W by the general procedure of Example 3.

cl -519 30 0 rill 01 3 2) TRAt co PLIB 2 35 Viii 0 cri ".lii'B 2" 1X 45 S g 2 /Pd-C 0 I-Nf-li/l-CH2OCH 2 CH 2 N 3 X \ co 2 P.16 50 S co ClyCH 2 CH JR2 55 2R i XI Reaction of metcaptide VIII with 2-azidoethoxyacetyl chloride according to the procedure of 60 Example 6 gives intermediate W which may be cyclized and reduced as in Example 6 to give the title product.

Claims (21)

1. A compound of the formula:

54 GB 2 106 113A 54 0 11 S-C-X I-IN p (Q) 3 0 C0 2 R" wherein Q is phenyl or (lower) alkyl; W' is an easily removable ester- forming protecting group; X is-(Alk)-A-(Aikl)R20' wherein Alk represents a Cl-C2 alkylene group optionally substituted by a Cl-C, alkyl radical; A is 0, S, SO, S02 or NR21 in which R2, is hydrogen, (lower)aikyl, phenyl or phenyi(iower)aikyi; AW is a C2-C4 alkylene group; R21 is a polar substituent selected from the group consisting of NHOH, 15 -NR2,R23 in which R22 and R2, are each independently hydrogen or (lower)alkyl and -N02; and Y is hydrogen or a radical selected from the group consisting of (a) optionally substituted (lower)aliphatic, (lower)cycloalipatic or (lower)cycloaliphatic(lower)aiiphatic, the substituents being one or more of hydroxy, (lower)alkoxy, optionally substituted phenyloxy, optionally substituted hererocyclicoxy, optionally substituted (lower)alkylthio, option- 20 ally substituted phenylthio, optionally substituted heterocycliothio, mercapto, amino, (lower)alkylamino, di(lower)afkylamino, (lower)aikanoyloxy, (lower)aikanoylamino, optionally substituted phenyl, optionally substituted heterocyclic, carboxy, carb(lower)alkoxy, carbamoyl, N-(lower)alkylcarbamoyl, N,N- di(lower)alkylcarbarnoyl, halo, cyano, oxo, thioxo, -SO,H, -OSO,H, -SO, (lower)alkyl, (lower)aikyisuffinyi, nitro, phosphono or 0 T -OP(OR.) (OR, ), the substituents on the (lower)alkylthio group being one or more of halo, hydroxy, (lower)aikoxy, 30 amino, (lower)aikanoylamino or optionally substituted phenyl or heterocyclic and the phenyl or heterocyclic substituents above being one or more of hydroxy, (lower)- alkoxy, halo, (lower)alkyl, halo(lower)aikyl, methane suffonyi, (lower)aikyithio, amino, (lower)aikanoylamino, (lower)aikanoy loxy, carboxy, carboxy(lower)afkyi, sulfo, or sulfo (lower)alkyl, R,, being a (lower)alkyl group and R, being an optionally substituted (lower)aikyl group or 35 optionally ring-substituted phenyl or heterocyclic group, the substituents on the alkyl group being one or more of a halogen atom, a hydroxy oxo, carboxy, carb(iower)aikoxy, carbamoyl, (lower)aikoxy, amino, (lower)aikylarnino, di(lower)aikylarnino, (lower)alkanoylamino group, and the substituents on the phenyl or heterocyclic rings being one or more of a halogen atom, a hydroxy, (lower)alkoxy, (lower)alkyl, halo(lower)alky], methanesulfonyl, oxo, (lower)aikyithio, arnino, (lower)aikylamino, di(lower)aikylamino, (lower)alkanoylamino, (lower)alkanoyloxy, car boxy, carboxy(lower)aikyf, suffo, or sulfo(lower)alkyl group.

(b) -OR, in which R, is optionally substituted (lower)alkyl or (lower)alkanoyl or optionally substituted phenyl or heterocyciic, the substituents on the alkyl and alkanoyl being one or more of halo, hydroxy, (lower)afkoxy, (lower)afkylamino, di(lower)aikylamino, amino, oxo, (lower)aika- 45 noylamino or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic being one or more of hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo(lower)afkyi, methanesulfonyl, (lower)aikyithio, (lower)aikylamino, di(lower)aikylamino, amino, (lower)aikanoy lamino, (lower)aikanoyloxy, carboxy, carboxy(lower)aiky], sulfo or sulfo(lower)alkyl; (c) -S(O),,R, in which n is 0. 1 or 2 and R. is as defined above; (d) halo; and (e) optionally substituted phenyl or heterocyclic in which the substituents are one or more of hydroxy, (lower)aikoxy, halo, (lower)aikyl, halo(lower)alkyl, methanesulfonyl, (lower)aikylthio, amino, (lower)aikylamino, di(lower)aikylamino, (lower)alkanoylamino, (lower)aikanoyloxy, car- boxy, carboxy(lower)aikyf, sulfo or sulfo(lower)alkyl.

2. A compound as claimed in claim 1 wherein Y is a hydrogen atom, an ethyl or ahydroxyethyl group.

3. A compound as claimed in claim 1 or claim 2 wherein Alk is C, alkylene, A is 0, S or S = 0, AlkI is C2 aikylene and R,, is amino.

4. A compound as claimed in claim 1 wherein Y is a hydrogen atom and X is -CH,OCH2CH2NH2.

5. A compound as claimed in claim 1 wherein Y is a hydrogen atom and X is -CH20CH2CH2NHOW

6. A compound as claimed in claim 1 wherein Y is a hydrogen atom and X is -CH2SCH2CH2.

GB 2 106 113A 55

7. A compound as claimed in claim 1 wherein Y is a hydrogen atom and X is -CH2SCH2CH2NHOH.

8. A compound as claimed in claim 1 wherein Y is a hydrogen atom and X is 0 11 -CH2o,n2k-n2i,4 H2.

9. A compound as claimed in claim 1 wherein Y is a hydrogen atom and X is 0 11 -CH2SCH2CH2NHOH.

10. A compound as claimed in claim 1 wherein Y is a hydrogen atom and X is -CH20CH2CH2NO2.

11. A compound as claimed in claim 1 wherein Y is a hydrogen atom and X is -CH2SCH2CH2NO2.

12. A compound as claimed in claim 1 wherein Y is a hydrogen atom and X is 0 11 -CH2SCH2CH2NO2.

13. A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl group and X is -CH20CH2CH,NH2.

14. A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl group and X is -CH20CH2CH2NHOH.

15. A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl group and X is -CH2SCH2CH2NH2.

16. A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl group and X is -CH2SCH2CH2NHOH.

17. A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl group and X is 0 11 -CH2SCH2CH2NH2

18. A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl group and X is 0 11 -CH2SCH2CH2NHOH.

19. A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl group and X is -CH20CH2CH2NO2.

20. A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl group and X is -CH2SCH2CH2NO2.

21. A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl group and X is 0 11 -CH2SCH2CH2NO2.

Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Ltd-1 983. Published at The Patent Office, 25 Southampton Buildings, London, WC2A 'I AY, from which copies may be obtained.