GB2042515A - Antibacterial agents - Google Patents

Abstract

This invention relates to 2- substituted and 2,6-disubstituted penem compounds of the formula: <IMAGE> wherein Y is a hydrogen or halogen atom or certain specified groups and X represents certain specified groups. Also included in the invention are pharmaceutically acceptable salts of the above compounds and derivatives of the above-compounds in which the carboxyl group at the 3-positions protected as by an easily removable ester protecting group. The compounds of the present invention are potent antibacterial agents and can be incorporated into pharmaceutical compositions, or are of use as intermediates in the preparation of such agents.

Description

1

SPECIFICATION

Antibacterial agents GB 2 042 515 A 1 The present invention relates to certain novel 2-substituted and 2,6- disubstituted penem compounds which possess potent antibiotic activity. Also provided are various novel intermediates useful in preparing the biologically active penem derivatives and various processes for the production of the intermediates and active compounds. 4 The penern ring system has the formula: 5151 5 and systematically can be designated as 7-oxo-4-thia-1 ' -azabicyclo [3.2, 01 hept-2-ene. For the sake of simplicity, it is named "2-penem" in the present application and the numbering system used is as follows:

L 1 ilt 2 2 t, 3 0:

There is th us provided by the present i nvention the novel pene m cc m Po u n ds havi ng the fo rm u 1 a Y X 1..),z 1 wherein Z is hydrogen or an easily removable ester protecting group; X is (a) a radical of the formula (i) -OR, in which R, is hydrogen; 00 -CORb in which Rb is hydrogen, hydroxy, optionally substituted (lower)alkyl or optionally ringsubstituted phenyl or heterocyclic, the substituents on the alkyl group being one or more (preferably 1 or 2) of halo, hydroxy, oxo, carboxy, carb(lower)alkoxy, carbamoyl, (lower)alkoxy, amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic rings being one or more (preferably 1 or 2) of hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, oxo, (lower)alkylthio, amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; or (iii) -OCOR, in which Rc is amino, (lower)alkylamino, di(lower)alkylamino or optionally substituted (lower)alkyl in which the substituents are as defined under (ii); or (b) a substituted (lower)aliphatic, (lower)cycloaliphaticor(lower)cycloaliphatic(lower)aliphatic radical or a ring substituted phenyl, phenyl(lower)alkyl, heterocyclic, heterocyclic(lower)alkyl or heterocyclic thio(lower)alkyl radical, substituents forthe above-mentioned aliphatic, cycloaliphatic, phenyl or heterocyc lic groups being NR, d (i) -CNR2R3or-N=C-NR2R3 i I R, in which R, is hydrogen, (lower)alkyl or phenyl and R2 and R3 are each independently hydrogen, (lower)alkyl, 50 phenyl or benzyl; (ii) -ORd in which Rd is amino, (lower)alkylamino, di(lower)alkylamino, substituted (lower)alkyl, (lower)alkenyl or optionally ring-substituted phenyl, phenyl(lower)alkyl, heterocyclic or heterocyclic (lower)alkyl, the substituents on the alkyl, phenyl and heterocyclic groups being as defined under (a) (ii); (iii) -O(CH2)nOR, in which n is an integer from 1 to 6 and Rr is optionally substituted (lower)alkyl or optionally ring-substituted phenyl or heterocyclic, the substituents on the alkyl, phenyl or heterocylic groups being as defined under (a) (ii); (i) -OCORr' in which Rr' is amino, (lower)alkylamino, di(lower)alkylamino or Rr, with the proviso that Rr' may not be unsubstituted (lower)alkyl; 1 2 GB 2 042 515 A 2 (V) -OSO3H; 0 t M) -OP(OH)2; (Vii) -OSO2R,in which R,is as defined under (b) (iii); 0 t.

(viii) -OP(ORJ (OR,) in which % is (lower)alkyl and R, is as defined under (b) (iii); (ix) -S(O),,Rd in which n is 0, 1 or2 and Rd is as defined under (b) (H) or isinthe casewhere n=0 N134 11 -C-NR5R6 in which R4 is hydrogen or (lower)aikyl and R5 and R6 are each independently hydrogen or (lower)alkyl, with the proviso that Rd may not be unsubstituted phenyl; (x) -CORf in which Rf is amino(lower)aikyi, (lower)alkylamino(lower)alkyi, di(lower)alkylamino(lower)ai- 15 ky], -NHNH2, -NRJ7NR,8, -NHOR19, -S-R17, -O(CH2)n-A-R,, or-N%R9 in which R17, R18 and R. are (lower)aikyl, R19 is hydrogen or (lower)alkyl, A is 0, S, NH or NCH3 and n and R. are as defined under (b) (ill) and (b) (viii); (A) -PC(ORJ2 in which Rw is hydrogen or(lower)aiky]; (xii) -NHRh in which Rh is optionally substituted phenyl, optionally substituted heterocyclic, -CH=NH, -SO3H, -OH, (lower)alkoxy, amino, (lower)aikylamino, di(lowedalkylamino, -NI-ICOCH3, -CS2CH3, -S02CH3, S S 11 H -S02NH2, -CNH2,-CNHCH3, NH 11 -C-NR7R. in which R7 and 1313 are each in independently (lower)alkyl, phenyl or phenyl(lower)alkyl, NH 11 -C-Rq in which R9 is (lower)alkyl, phenyl or phenyl(lower)alkyl, or 0 11 -C-Rj in which Ri isamino(lower)alkyl, -NH2, (lower)alkylamino, di(lower)alkylamino, 0 -NH-C-R,() in which Rjo is (lower)alkyl or optionally substituted phenyl or heterocyclic, the phenyl and heterocyclic substituents being defined under (a) (ii), NH 11 (lower)alkoxy, -NH-C-NH2, -c NR--l \ ' _WH 2-(/ \02 or -O(CH2)2Si(CH3)3; 0 11 Wii) -S-C-Rll in which R,, is (lower)aikyl substituted by amino, (lower)alkylamino ordi(lower)aikylamino; (xiv) -NRjRkin which Rj is (lower)aikyl and Rkis (lower)alky], (lower)alkoxy, heterocylic, amino, or 50 0 11 -C-R, in which Ri is as defined under (b) (A) or, when taken together with the nitrogen, Rj and Rk represent so I 1 0 providing that when Rk is amino or -CH2CH2NH2, Ri is methyl and also providing that Rj and Rk may not both be (lower)aikyl; (xv) -NRI'%'in which Rj'is (lower)alkoxy and Rk'is (lower)alkyi, heterocyclic, amino(lower)alkyl, (lower)aikylamino(lower)alkyi, di(lower)aikylamino(lower)aikyl or 0 -C-Ri in which Ri is as defined under (b) (A) or, when taken together with the nitrogen, Ri' and Rk' represent 65 3 GB 2 042 515 A 3 e (xvi) -NR,R.. % in which R,, R,, and Rn are each independently (lower)alkyl or when taken together with the nitrogen, represent (xvii) -N=CH-Rx in which Rx is flower)alkyl or optionally ring- substituted phenyl or heterocyclic, the 5 substituents on the phenyl or heterocyclic ring being as defined under (a) (ii); (xviii) -N=CRxRy in which Ry is (lower)alkyl or optionally ringsubstituted phenyl or heterocyclic, the phenyl and heterocyclic substituents being as defined under (a) (ii), and R,, is as defined under (b) (xvii); (xix) =N-Rp in which Rp is hydroxy, (lower)alkoxy, amino, di(lower)alkylamino or -NR-C or 10 NOH 11 (xx) -C-(CH2)nNR,rR16 in which n is an integer from 1 to 6 and R15 and R16 are each independently hydrogen or (lower)alkyl; and Y is hydrogen or a radical selected from the group consisting of (a) optionally substituted (lower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower)aliphatic, the substituents being one or more of hydroxy, (lower)alkoxy, optionally substituted phenyloxy, optionally substituted heterocyclicoxy, optionally substituted (lower)alkylthio, optionally substituted phenylthio, optionally substituted heterocyclicthio, mercapto, amino, (lower)alkylamino, di(lower)alkylamino, (lower)al- 20 kanoyloxy, (lower)alkanoylamino, optionally substituted phenyl, optionally substituted heterocyclic, car boxy, carb(lower)alkoxy, carbamoyl, N-(Iower)alkylcarbamoyl, N,N- di(lower)alkylcarbamoyl, halo, cyano, oxo, thioxo, -S03H, -OS03H, -S02-(Iower)alkyl, (lower)alkylsulfinyl, nitro, phosphono or 0 T -OP(ORj (013r) in which R. and Rr are as defined above, the substituents on the (lower)alkylthio group being one or more of halo, hydroxy, (lower)alkoxy, amino, (lower)alkanoylamino 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)alkyl, methanesulfonyl, (lower)alkylthio, amino, (lower)alkanoylamino, (lower)alka- 30 noyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; (b) -ORs in whicl R,, is optionally substituted (lower)alkyl or (lower)alkanoyl or optionally substituted phenyl or heterocyclic, the substituents on the alkyl and alkanoyl being one or more of halo, hydroxy, (lower)alkoxy, (lower)alkylamino, di(lower)alkylamino, amino, oxo, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic being one or more of 35 hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, (lower)alkylthio, (lower)alkyla mino, di(lower)alkylamino, amino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; (C) -S(O)nRs in which n is 0, 1 or 2 and Rs 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)alkyl, methanesulfonyl, (lower)alkylthio, amino, (lower)alkylamino, di(lower)a Ikyl amino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; or a pharmaceutically acceptable salt thereof, with the proviso that when Y is hydrogen, X may not be -CH20CH2CH20CH3.

The compounds of formula 1 wherein Z is hydrogen (and their pharmaceutically acceptable salts and physiologically hydrolyzed esters) are potent antibacterial agents. The remaining compounds are useful intermediates for preparation of the biologically active penems.

Substituent groups disclosed above for the 2- and 6-positions of the penem ring may be further defined as follows:

(a) by the term "halogen" is meant chlorine, bromine, fluorine and iodine. Preferred halogen substituents are chlorine and fluorine; (b) by the term "(Iower)alkyl" is meant both straight and branched chain saturated aliphatic hydrocarbon group having from 1 to 6 carbon atoms inclusive, e.g. methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and n-hexyl. Preferred (lower)alkyl substituents have from 1 to 4 55 carbon atoms and most preferably 1 or 2 carbon atoms; (c) by the term "(Iower)aliphatic" is meant acyclic straight and branched chain saturated or unsaturated hydrocarbon groups having from 1 to 6 carbon atoms inclusive. The unsaturated groups may contain one or more double or triple bonds, but preferably contain either one double bond or one triple bond. Examples of (lower)aliphatic groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, n-pentyl, isobutyl, 60 vinyl, 1 -propenyl, 2-propenyl, isopropenyl, 2-methyl-2-propenyl, ethynyl, and 2-propynyl. The most preferred aliphatic radicals are (lower)alkyl as in (b); (d) by the term "(Iower)cycloaliphatic" is meant alicyclic saturated and unsaturated hydrocarbon 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, 4 GB 2 042 515 A 4 cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclopententyl, 1,3-cyclohexadienyl and cyclohexenyl; (e) by the term "(fower)cycloaliphatic(lower)aliphatic" is meant cycloaliphatic-aliphatic 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 cyclopropylmethyl, cyclo pro pyl ethyl, cyclopropylpentyl, cyclobutylethyl, cyclo pentyl m ethyl, cyclohexyImethyl, cyclopropeny1methyl, cyclopentenylethyl, cyclopropylethenyl and cyclopropylethynyl. The most preferred groups of this type are cycloalkylalkyl 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 Cj-C6 alkoxy groups, the alkyl portion of which is defined as in (b). Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and n-pentyloxy. Preferred groups are Cl-C4 alkoxy and the most preferred are Cl-C2 alkoxy; (g) by the term "(Iower)alkylthio" is meant Cl-C6 alkylthio groups in which the alkyl portion is as defined in (b). Examples include methylthio, ethylthio and n-butylthio; N by the term "(Iower)alkylamino" is meant Cl-C6 alkylamino radicals in which the alkyl portion is 15 defined as in (b). Examples are methylamino, ethylamino, n-propylamino and n-butylamino; M by the term "di(lower)alkylamino" is meant di Cl-C6 alkylamino in which each alkyl group is as defined in (b). Examples are dimethylamino and diethylamino; (j) by the term "(Iower)alkanoyloxy" is meant groups of the formula 0 i! (lower)alkyl-C-0 in which alkyl is as defined in (b); (k) by the term "(Iower)alkyloylamino" is meant groups of the formula 0 (lower)alkyl-C-NHin which alkyl is as defined in (b); (1) by the term "carb(lower)alkoxy" is meant 0 -C-0ower)alkoxy in which (lower)alkoxy is as defined in (f); (m) by the term "halo(lower)aikyl" is meant alkyl groups in which one or more hydrogen atoms are 35 replaced by a halogen atom; (n) by the term "suifo(lower)aikyi" is meant -(CHAnSO3H in which n is 1 to 6; (o) by the term "carboxy(lower)aikyi" is meant -(CH2)rC001-1 in which n is 1 to 6; (p) by the term "phenyl (lower)ai kyl" is meant x' in which n is 1 to 6; (g) by the term "(fower)aikylamino(lower)alkyi" is meant -(CH2)nNH- (lower)aikyl in which n is 1 to 6 and 40 alkyl is as defined in (b); (r) by the term "di(lower)aikylamino(lower)aikyl" is meant -(CH2),,N -- (lower)aikyl (lower)aikyl in which n is 1 to 6 and each alkyl is as defined in (b); (s) by the term "(iower)aikanoyi" is meant (lower)alkyl 50 0 1 -Cin which alkyl is as defined in (b); (t) by the term "N-(lower)aikylearbamoyi" is meant 0 et. (lower)aikyl iL Ii lk.

W 50]W (lower)alkyi-HN-Cin which (lower)alkyl is as defined in (b); (u) by the term "N,N-di(lower)carbamoyi" is meant (lower)aikyl 0 1 ' 111.1 N-C- C n GB 2 042 515 A 5 in which each (lower)alkyl is as defined in (b); (v) by the term "amino(lower)alkyl" is meant -(CH2)nNH2 in which n is 1 to 6; (w) by the term "hydroxyamino(lower)alkyl" is meant -(CH2)nNHOH in which n is 1 to 6; W by the term "(Iower)alkylsulfinyl" is meant 0 T -S-(Iower)alkyl in which (lower)alkyl is as defined in (b); and (y) by the term "(Iower)alkenyl" is meant a straight or branched unsaturated aliphatic hydrocarbon 10 group containing one double bond and having from 2 to 6 carbon atoms inclusive, e.g. vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl.

By the term "heterocyclic" as used herein is meant heteromonocyclic and heterobicyclic residues of aromatic character as well as appropriate partially or wholly unsaturated residues, the heterocyclic residues containing at least one heteroatom selected from oxygen, sulfur and nitrogen and being bonded to the 15 penem ring carbon atom via a ring carbon atom. The preferred heterocyclic groups are either 5- or 6membered monocyclic radicals or fused 6,6 or 5,6 bicyclic radicals. Illustrative of suitable heterocyclic radicals are the following:

S J1 -s.-- -N H 20 H N ?' N N N - ---1C, F LLIN 1 N N ', N 25 C ' 'N L 0 0 N C 2 U1 -1,11 30 35 ci 0 N C1 p ".,77 P.

40 N =N N-N N- N-N, 11 - p N-"4 11 45 N N-N N-11 TI-7 F-11 N _ ', 1 N,sN -,_,,N F.

T-11; 50 N_,N 1!4" t 0 F. l! and 0 C c I-', H Similarly, by the terms "heterocyclic-(Iower)alkyl, heterocyclicthio- (Iower)alkyl, heterocyclicoxy and 60 heterocyclicthio" are meant -(CH2),,- Heterocyclic, -(CH2)n-S-Heterocyclic, -0-Heterocyclic and -SHeterocyclic, respectively, in which n is 1 to 6 (preferably 1 or 2).

Since an asymmetric carbon atom is present in the 2-substituted compounds of formula 1, such compounds may exist either in the form of racemic mixtures (R,S form) or as the individual dextrorotatory and levorotatory (R- and S- forms) optical isomers. Preferred are the compounds in which the configuration 65 of the 5-carbon atom corresponds to that of natural penicillin (513-corif igu ration). Substituents at the 5- and 6 GB 2 042 515 A 6 6-positions of the 2,6-disubstituted penems may be in the cis or trans position in relation to one another. Where the penem 6-substituent contains an asymmetric carbon atom, the resulting isomers are identified herein as isomers A, B, C and D (see Example 58 for stereochemistry). The preferred isomer in compounds of this type is isomer B. Separation of the various optical and geometric isomers may be carried out by 5 conventional separation and resolution procedures well-known to those skilled in the art.

The present invention is intended to include the compounds of formula I in the form of isomer mixtures and also in the form of the individual separated and resolved isomers.

The pharmaceutically acceptable salts referred to above include the nontoxic carboxylic acid salts, e.g. nontoxic metallic salts such as sodium, potassium, calcium, aluminum and magnesium, the ammonium salt and salts with nontoxic amines such as trialkylamines (triethylamine), procaine, dibenzylamine, N-benzy[-Pphenethylamine, 1 -ephenamine, N,N'dibenzyiethylenediamine, N-alkylpiperidine and other amines which have been used to form salts of penicillins and cephalosporins. When a basic group is present, the present invention also includes the pharmaceutically acceptable acid addition salts, e.g. salts with mineral acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric or with suitable organic carboxylic acids or sulfonic acids such as trifluoroacetic, p-toluenesulfonic, maleic, acetic, citric, oxalic, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic and malic. Compounds containing an acid group and a basic group can also be in the form of inner salts, i.e. a zwitterion. Preparation of the above-described salts may be carried out according to conventional procedures for forming salts of P-lactam antibiotics such as penicillins and cephalosporins.

The term "easily removable ester protecting group" is one which has acquired a definite meaning within 20 the P-lactam and peptide art. Many such groups are known which are used to protectthe carboxyl group during subsequent chemical reactions and which may later be removed by standard methods to give the free carboxylic acid. Known ester protecting groups include 2,2,2- trichloroethyl, tertiary alkyl of from 4-6 carbon atoms, tertiary alkenyl of from 5-7 carbon atoms, tertiary alkynyl of from 5-7 carbon atoms, alkoxymethyl, alkanoylmethyl of from 2-7 carbon atoms, N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, benzyl, 25 p-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, trimethylsilyl, triethylsilyl and P-tri m ethyl si lyl ethyl. Choice of an ester 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. For use as a chemical intermediate the most preferred ester is the p-nitrobenzyl ester which can be readily removed by catalytic hydrogenation. For preparation of compounds containing functional groups 30 reducible under such removal conditions, a preferred alternative is the P- tri m ethylsi lyl ethyl ester removable by treatment with fluoride ions. Also included within the scope of easily removable ester protecting groups are physiologically cleavable esters, i.e. those esters known in the penicillin and cephalosporin art to be easily cleaved within the body to the parent acid. Examples of such physiologically cleavable esters include indanyl, phthalidyl, methoxymethyl, g lycyloxym ethyl, phenylglycyloxymethyl,thienylglycyloxymethyI or 35 acyloxymethyl of the formula i h 0 11 -CH2C-r 40 in which Y' is Cl-C4 alkyl or phenyl. Particularly preferred esters of this type are methoxymethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.

It will be appreciated that the compounds of formula I may exist in various states of solvation and the anhydrous as well as solvated (including hydrates) forms are intended to be within the scope of the 45 invention.

With respect to the compounds of formula 1, the preferred compounds are those wherein Y is hydrogen or flower)alkyl optionally substituted (preferably at the a-carbon) by hydroxy. More preferred compounds within the above group are those wherein Y is hydroxy, ethyl or a- hydroxyethyl. Still more preferred compounds of formula I 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 I wherein substituent X is a substituted (lower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower)aliphatic radical or a ring-substituted phenyl, phenyl(lower)alkyl, heterocyclic, heterocyclic(lower)alkyl or heterocyc licthio(lower)alkyl radical, the substituents for the above-named aliphatic, cycloaliphatic, cycloaliphatic aliphatic, phenyl, phenyl-alkyl, heterocyclic, heterocyclic-alkyl and heterocyclicthio-alkyl radicals being NRi -CNIR2R3or-N=C-NIR2R3 in which 1 R, R, is hydrogen, (lower)aikyl or phenyl and R2 and R3 are each independently hydrogen, (lower)alkyl, phenyl or benzy]. Within this class, the preferred compounds are those wherein Y is hydrogen, ethyl or i 7 GB 2 042 515 A 7 a-hydroxyethyl, especially those wherein Y is hydrogen or a-hydroxyethyl and most especially those wherein Y is a-hydroxyethyl.

Another preferred embodiment of the present invention consists of the compounds of formula I wherein X is a substituted (lower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower)aliphatic radical or a ring-substituted phenyl, phenyl(lower)alkyl, heterocyclic, heterocyclic(lower)alkyl or heterocyclicthio(lower)- 5 alkyl radical, the substituents on the above-mentioned aliphatic, cycloaliphatic, cycloaliphatic-allphatic, phenyl, phenyl-alkyl, heterocyclic, heterocyclic-alkyl or heterocyclicthio-alkyl radicals being -CORf in which Rf is amino(lower)alkyi, (lower)alkylamino(lower)alkyi, di(lower)aikylamino(lower)aiky], -NHNI-12, -NRAR18, -NHOR19, -S1317, O(CH2)n-A-R or -NIR.Rg in which R17, R18, R. and R. are (lower)alkyl, R19 is hydrogen or (lower)aikyl, A is 0, S, NH or NCH3 and n is an integer from 1 to 6. Within this class, the preferred compounds are those wherein Y is hydrogen, ethyl or cc-hydroxyethy], especially those wherein Y is hydrogen or a-hydroxyethyl and most especially those wherein Y is cLhydroxyethyi.

Still another preferred embodiment of the present invention consists of the compounds of formula 1 wherein X is 0 iA' (a) - (CH in which n is an integer from 1 to 6, preferably 1 to 4; 2 n' (b) -(CH2)nNHOH in which n is an integer from 1 to 6, preferably 1 to 4; (c) -(CH2)nPO(O"Cl-C6 alkyl)2 in which n is an integer from 1 to 6, preferably 1 to 4 and alkyl is preferably methyl, ethyl or isopropyl; NH 11 (d) -(CH2)nNH-C Cl-C6 alkyl in which n is an integer from 1 to 6, preferably 1 to 4, and alkyl is preferably methyl or ethyl; (e) -(CH2)nN=C NH2 H in which n is an integer from 1 to 6, preferably 1 to 4; 0 1 (f) -(CH2)n0C(CH2),NR A R13 in which n and m are each independently 1 or 2 and R A and RB are each independently hydrogen or (lower)alkyl; or (g) -(CH2)nNHC-Rc I! NH in which n is an integer of 1 to 6, preferably 1 to 4, and R' is Cl-C4 alkyl (preferably methyl or ethyl), phenyl or.,0 in which m is 1 or 2.

- (CH 2) Within this class of compounds, the preferred members are those wherein Y is hydrogen, ethyl or a-hydroxyethyl, preferably those wherein Y is hydrogen or (x-hydroxyethyl and most preferably those 45 wherein Y is a-hydroxyethyl.

Other preferred embodiments of the present invention include the intermediates of the formulae:

(A) Y - 11 p (Q)3.11 ill 50 0 "v col.

2 X wherein Y is hydrogen or as defined above in regard to compounds of formula 1, G is phenyl or (lower)aikyl, R' is an easily removable ester protecting group, X is 1 or 2 and M is Cu(H), Pb(ll) or Hg(ii) when x is 2 or Ag(i) 55 when x is 1; Ilia C02 C 60 in which Y, G and R' are as defined above under (M and 8 GB 2 042 515 A (C) , r -T p (0) 0 Y R. 3 C02 IV wherein Y is as defined above in regard to compounds of formula 1, Q is phenyl or (lower)alkyl, W' is an easily removable ester protecting group and T is jo C6H5 0 1 11 -C-C61-15 or -C-X i Cal-15 wherein X is as defined above in regard to compounds of formula 1.

In the intermediates of formulae Ill, Ilia and IV, Q is preferably phenyl, W' is preferably p-nitrobenzyl and X and Y are preferably those substituent groups mentioned as being preferred in connection with the compounds of formula 1. Reactive functional groups such as mercapto, amino and hydroxy in substituents Y and X 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 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 general, it is preferred to incorporate substituent Y in mid-synthesis and to incorporate substituent X by acylation of mercaptide intermediate Ill or Ilia 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 1 (Variation 1):

Y OAC Y-CHCR-OAC CSI, i:, 0 CHO N 4, N I 0 11 C02 R" 0 Y 11 SC-X cl 71 IT, 0 1 CO ^ R" 1 Y PO, - base de-protect 0 CO 2 R" 0 AC - CH3 c- 0. C G H 5_ 8 1 Early rrcrFnr3-cn of 2-substituent 0 11 XC-5Na > pH 7.5 0 Y 11 SC X -> 0 -7 - H CO 2 R" t" P0, CO 2 Y 5 -t4 // N- c CO 2 F! SOCI.

6 M 9 y GB 2 042 515 A 9 PrcSeLs _I_LViriation 2): Late incorporation of 2-substituent y 0 OAC I Y-CE=CH-OAC CS I s C11 3 C-SN& > 0 r k R pli 7.5 Y _:,::SAC CHO > y SAC 1:0 R" N,'I nH 1 2 0 a y C02 R.

SOCI 2 SAC P03 5"c 0 N ' base 0;1 '4YP03 G " C, CO 2 R" CO 2 1.

0 y SM X-C- 0 ,E 1, PO ' - p 0 - ' -,r 3 0 'Y 03 CO 2 R CO 2 R.' y X d-protect CO R" 2 CO 2 9 0 11, X-C (F) - acylating agnt MA - heavy metal salt 1 _!y_ari.ation_3): ?,,lte lrcrPora"On of 2-iititunt y -5 4.

3, Y-CH=CH-0.Ac CSI rN, pH 7.5 > 0 y -I-,- SCO 3 0 H y SCO 3 Clio I ' R":a, OH -0 2C, I -r co 2 R.

y 1)7 SC03 r03 y -., SCO 3 MA N, 11, ci has, ? P03 base 0 I 0,11-1-_r 0 2 1. CO 2 R.' 0 SM 1: y L X-C- (E) tl 1 PO - 1:11, 3 3 0:j:i CO 2 W' C02 1 y 5 y S :1r- / X de-nrotect A CO 0 -_ 2 CO,E GB 2 042 515 A 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-2-azetidi none by a cycloaddition reaction with chloro suifonyl 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 OOC or below. The reduction step may be conducted in an aqueous or aqueous-organic reaction mixture at a temperature of 0' or below and at a slightly basic pH.

Following formation of the 4-acetoxy-2-azetidinone, 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 (e.g. aqueous or aqueous organic). Displacement of the acetoxy group results in incorporation of the desired 2-substituent 15 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) at this point in the process. Variations 2 and 3 depicted above convert the 4-acetoxy-2-azetidinone into the 4-acetylth io-2-azetid i none and 4-tritylth io-2-azetidin one pro ducts, respectively, by nucleophic displacement with thioacetic acid or triphenylmethyl mercaptan (or a salt 20 thereof such as the sodium salt), respectively.

The 4-thio azetidinone is next reacted with a glyoxylate ester 0 H I-IC-CO2W wherein R" is an easily removable ester protecting group such as p- nitrobenzyl or tri methylsi lyl ethyl, 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. 50'C. up to most preferably reflux temperature). 30 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 the next step.

Conversion of the hydroxy ester to the corresponding chloro ester is achieved by reaction with a chlorinating reagent (e.g. POC12, POC13, PCI5, and the like) in an inert organic solvent (e.g. tetrahydrofuran, 35 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. pyridine or collidine). The reaction is advantageously run at from about - 10'C. 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 40 (preferably triphenylphosphine or a tri(lower)alkyl phosphine such as triethylphosphine ortri-n-butyl phosphine) in an inert organic solvent such as dimethy1formamide, dimethylsulfoxide, tetrahydrofuran, dimethoxyethane, dioxane or an aliphatic, cycloaliphatic or aromatic hydrocarbon (e.g. hexane, cyclohex ane, benzene, toluene, and the like) in the presence of a base, preferably an organictertiary amine such as triethylamine, pyridine or 2,6-lutidine. The reaction is advantageously carried out attemperatures from room 45 temperature to the reflux temperature of the solvent system.

At this stage the process again diverges into two routes. In Variation I (where the 2-substituent 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 cyclization is carried out under reflux conditions. Suitable inert 50 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. dimethyfforma mide), di C1-C6 alkylsulfoxides (e.g. dimethylsulfoxide) or a Cl-C6 alkanol (e.g. methanol, ethanol, t-butanol), ora mixture thereof.

In variations 2 and 3 the phosphorane is converted to a heavy metal mercaptide of the formula 9 1 11 GB 2 042 515 A 11 S - - p (Q)3 M_ 0 'v CO W' _ 1 2 5 III or HgCOOCH 3 10 0J:' p (0) 3 Y C0 2C Illa wherein Q is preferably phenyl or (lower)alkyl,x is 1 or 2 and M is Cu(11),Pb(1 I) or Hg(I1) when xis 2 or Ag(I) when x is 1. Mercaptide formation is accomplished by reaction of the phosphorane with a salt of Hg(II), Pb(11), Cuffi) or Ag(I) or with (methoxycarbonyi)mercury(I1) 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 preferred base is pyridine. The reaction maybe carried out at room temperature or, 20 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. N03-, CH3C00-, 13F4-, 17-, C104-, N02-, CNO-, etc. The mercaptide intermediate is then reacted with an acylating agent capable of introducing the moiety 0 11 X-Cwherein X is the desired penern 2-substituent. The acylating agent 0 0 1 11 (X-C- (1))may bethe acid X-C-OH ora reactive functional derivative thereof such as an acid halide (preferably acid chloride), acid azide, acid 35 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 the presence of an acid acceptor such as a tri(lower)alkyla mine, (e.g. triethylamine) or a tertiary organic base such as pyridine, collidine or 2,6-lutidine.

When the free acid is employed, the acylation is conducted in the presence of a suitable condensing agent, 40 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 +25'C. 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 ca rboxyl -protected penem is formed, the protecting group may be removed by conventional de-blocking procedures (e.g. hydrolysis, hydrogenation or photolysis) to give the de-blocked penem.

Removal of the p-nitrobenzyl 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 50 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 base such as an alkali metal or alkaline earth metal hydroxide or an amine is employed during the hydrogenation, the product may 55 be recovered in the form of a carboxylic acid salt. Removal of the 0-tri methylsi lyl ethyl ester, another useful protecting 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:

12 GB 2 042 515 A _Process 11 (Variation 1):

CH 2 -CH-OAC csi; 0 11 SC-X C0 W, 0 H 2 0 11 SC-X 7 0 j N cl Co 2 R" 0 de-protect ' Early inccrpora#ion of 2-substituent - OAC P' H XC-5Na pm 1..

0 It SC-x CHO r 1 0 H CO 2 R" 0 11 PO 3 base --51- PO 3 C02 W' S X P- / Co 2 R..

y y S y > X base / R., Co 2 --5 IG X 0 1 - / CO 2 R Process 11 (Variation 2): Late --.corporation of 2-substituent Ci 2 -CH-CAC CSL Elr SAC 0 11.4 SOCI 6 OAC 0 11 Ill AeSNa > N pH 7.5 Ac Clio CIO, it- y, H I R" Co 2 SOCII 2 -JAC; A c ,Er ---> 1 base N, ---PPase c N '-r cl 0 ' c 3 Co'.R.' co 2 R.' FTSM -M -PA3 . 'T Co'.R.

X co,it' l 12 1111 0 0;1 11 SC-X X - - a C- 0 Co,R" y l base v 'Iy, - X J 0 CO 2 H v 5 0 co:..

13 ri at ion---3 _)_: incorpuration of GB 2 042 515 A 13 CH 2 =CH-OAc CS1 ' 0AC 03C5Na E,, - -,> 0 111 5 SCO 3 SCO 3 ---> Soci 2 N 0 EC CIz, "U, 0 H 2 0 -r 10 CO 2 R.

SCO 3 P03 SCO 3 MA 15 N, Cl base ' N-PO 1 N ' N, ' 3 0 0, - CO 2 R" CO 2 1.

0 0 SM X_ 0 20 - --> -T Ny Nl-fl'P03 Oili P03 0,- CO 2 W' CO 2 R" S Y X y 11 base 0 CO 2 R" p, - / C0 2 " 30 de-protect Y -LI_ 5 J:i / X CO Ascanbeseen Process 11 is substantially the same as Process I (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-penem with a suitable electrophile in an inert solvent (e.g. 40 tetrahydrofuran, diethyl ether, climethoxyethane, 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 cle-blocking as described above) in the presence of about two equivalents of base or, alternatively, a suitable 2-penem ester may be used in the presence of about one equivalent of base. Any ester inert to anion chemistry (the reaction involves anion formation with base followed by reaction of the electrophile with the penem anion) may be 45 employed, e.g. (lower)alkyl such as methyl, ethyl, n-propyl ort-butyl, phenyl,trichloroethyl, methoxymethyl, silyl such astrimethylsilyl ort-butyldimethylsilyl, and the like. Penern 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 cle-blocked and either used as the free acid or converted to a 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 50 preferably, however, a lithium disilylamide or a lithium dialkylamide such as lithium di-cyclohexylamide (LDCA), lithium diethylamide, lithium di-methylamide or lithium di- isopropylamide (LIDA) is used. The electrophile is selected so as to generate the desired Y-substituent upon reaction with the anion and may be, for example, a halogen (e.g. Br2,12), an alkyl halide (e.g. CH31) or a similar halide such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenyl-(Iower)alkyl, heterocyclic, heterocyclic-thio, heterocyclic-thio- 55 (lower)alkyl, or heterocyclic-(Iower)alkyl, halide, a tosylate or mesylate (e.g.

CH 3 C H 20502 C H 3' (50 3' 3CH20502C11 2 '5021 CH 0 CH CH 050 ell etc.), an epaxlde (e.g. an C"'2 2 2 2 3' S opisulfide (e.g. L_\), an aldehyde (e.g. C.4 3 Cz!O, c 6 H 5 CH 2 CW a ketone (e.g. CH3CCCH3' Cro) 14 GB 2 042 515 A 14 or an ester (e.g. CH3CH2CO0CH3 or C61-15CO0CH3). Representative examples of other suitable electrophiles are shown below:

CH2=CH-CH2 Br CH 3 CC11=CH2 5 Dr 1 Br CH 3 CH-CH 3 r.

10 1W OL cl OCH2 Br HCHO OCECCH 2 Br cr 0 CH 2 sc 2 ci 15 CH3SS02 CHS 00CH 2 cl OCH-CHCHO 0 -< 20 0 11 CH 3 CCH 2 cl C-CH 2 cl.

0 A most preferred electrophile is acetaldehyde which gives rise to the hydroxyethyl 6-substituent. Introduction of the 6-substituent by this process is preferably carried out with cooling (e.g. -80'to O'C.) 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 discussed above to give the de-protected product.

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

Process!I! (Variatiens 1 and 21:

SCO 0-1:

Y > base Y 0,f--r SCO 3 B Y lli 5 C 0 3 0 ' a de-prote li SC03 0 H HO 1 CO 2 R.

base Y J_ j N 0 ' B 1 0 X-C- 0 1k y y SC03 -:-1" ' 011 C02 W' 1 SOC12 y '. C 0 3 -,-cl 0 'T 11.

co 2 PO 3 1 base SC03 _N.

P03 c v C02 R" W,.lbase SCO3 0 H h 0 co 2p,' Y_ SC"53 0 7-N, OH C^- 2 1.1 1 1 so(-, 2 y SC' 1 c 1 1 c - - P..

1 F-- 3 base 3 2 bt7/b,ise GB 2 042 515 A 15 0 Y- 0 1-1 SC-X c-N "13 .de-prctect 0 y A SC-X I Cile 1 c) ' R" 0 y 11 SC-X cc Secl, y c 11 )"-c0 0 de-protect 19 Ii Y'-_sc-x Jj, 11 Clio 1 -1,.. V --- 7, 0 Y cc. F...

51Dci 2 16 GB 2 042 515 A 16 0 Y SM Y 11 - SC - X N PO 1 3 cl IN, - f Y 0] "-r C0 2 R" C0 2 W' 5 base 0 Y d 10 11 ' 1 11r PO 3:

1 CO R2 1 Y Y iQ/ X C0 2 W' 11. derote-t S"" -X 11 - 11 - / 0 11 C0 2 R" 1:!Q-ProtRct "-s \ -1 1 -1--- - X, 25 A C0 2 R C0 2 R a - blocking Ircup for ring itr;gen 30 The 4-tritylthio-2-azetidinone 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-butyidimethyisilyi); methoxymethyl, methoxyethoxymethyl, tetrahy dropyranyl, and the like. Introduction of the desired Y-substituent at the 1-position of the azetidinone is then 35 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. 1 In one route the N-protected intermediate is de-blocked by conventional procedures (e.g. acid hydrolysis) and then converted to the 2,6-penem via ester formation, chlorination of the hydroxy ester, conversion of the 40 chloro ester to a phosphorane, conversion of the phosphorane to a heavy metal mercaptide, acylation of the mercaptide with 0 46 I X-C- e, 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 with Process 11 50 (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 X-C- E), removing the N-protecting group, reacting the de-protected azetidinone with the glyoxylate ester, chlorinating, reacting the chloro ester with the phosphine to give the phosphorane, cyclizing the 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 temporarily protected in a manner which is itself known, such as f ree amino groups by acylation, tritylation or silylation, free hydroxyl groups, for example, by etherification or esterification, mercapto groups by esterification, and free carboxyl 65 17 GB 2 042 515 A 17 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 I 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 to hydroxyamino and amino groups, hydroxyl groups can be etherif ied or esterif ied, etc.

The penem free acid compounds may be converted to pharmaceutically acceptable salts thereof orto easily removable esters thereof (particularly physiologically cleavable esters). Salts may be formed by 10 reaction of the free acid with a stoichiometric amount of a suitable nontoxic acid or base in an inert solvent, followed by recovery of the desired salt as by Iyophilization or precipitation. Esters (in particular physiologically cleavable esters) may be prepared in an analogous manner to preparation of the corresponding esters of penicillins and cephalosporins. Resulting mixtures of isomers can be separated into the individual isomers according to known methods. Mixtures of diastereomeric isomers, for example, can 15 be separated by fractional crystallization, adsorption chromatography (column or thin-layer) or other suitable separation methods. Resulting racernates can be resolved into the antipodes in the customary manner, for example by forming a mixture of diastereomeric salts with optically active salt-forming reagents, separating the diasteromeric salts and converting the salts into the free compounds, or by fractional crystallization from optically active solvents.

Accordingly, the present invention also provides for a process for the preparation of the compounds of formula I which comprises cyclizing a compound of the formula i iI 3 -C -X El 1 U2) 3 0 '_ 1 > CO,q..

wherein Q is a phenyl or (lower)alkyl group, R" is an easily removable ester group and X and Y are as defined above in an inert organic solvent at a temperature of from just above room temperature to the reflux temperature of the solvent; removing by methods known per se the removable ester group and, optionally, other protecting groups; and, if desired optionally coverting a compound of formula I where Y is a hydrogen atom to any other desired product where Y is a substituent as defined above other than a hydrogen atom by 35 treating the product with a corresponding electrophile in an inert solvent in the presence of a strong base.

The present invention also comprises those embodiments according to which compounds used as intermediate products are used as starting materials and the remaining process steps are carried out with these, or the process is discontinued at any stage. Furthermore, starting materials can be used in the form of derivatives or can be formed during the reaction.

The free acid penem compounds provided by the present invention and pharmaceutically acceptable salts and physiologically cleavable esters of said acids have been found to be potent broad-spectrum antibacterial agents useful in the treatment of infectious diseases in animals, including man, caused by both Gram-negative and Gram-positive organisms. The compounds are also of value as nutritional supplements in animal feeds and as agents for the treatment of mastitis in cattle.

The 2-penem acids (and physiologically cleavable esters and pharmaceutically acceptable salts thereof) provided according to the present invention (i.e. compounds of general formula I wherein Y = H) possess antibacterial activityperse and are also useful intermediates (preferably in their ca rboxy- protected form) for preparing the 2,6-disubstituted penems I via anion formation and reaction with an electrophile.

The active compounds provided by the present invention may be formulated as pharmaceutical compositions comprising, in addition to the active ingredient, a pharmaceutically acceptable carrier or diluent. The compounds may be administered both orally and parenterally. The pharmaceutical preparations may be in solid form such as capsules, tablets or dragees, or in liquid form such as solutions, suspensions or emulsions. In the treatment of bacterial infections in man, the active compounds of this invention may be administered orally or parenterally in an amount of from about 5to 200 mg. /kg./day and preferably about 5 55 to 20 mg./kg./day in divided dosage, e.g. three or four times a day. They are administered in dosage units containing, for example, 125, 250 or 500 mg. of active ingredient with suitable physiologically acceptable carriers or diluents.

The present invention also provides a method of combatting bacterial infections in animals, particularly warm-blooded animals, which comprises administering an acid of formula I or a physiologically cleavable ester thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to an infected host in an amount sufficient to combat such infection.

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 areas follows:

18 GB 2 042 515 A 18 Csi chloro sulfonyl isocyanate pet. ether petroleum ether b.p. boiling point 5 n.m.r. nuclear magnetic resonance h hour 10 ether diethyl ether (unless otherwise indicated) Celite Trademark of Johns-Manville Products Corporation for diatomaceous earth 15 psi pounds per square inch r.t. room temperature PNB p-nitrobenzyl 20 m.p. melting point LAH lithium aluminum hydride 25 n-BuLi n-butyl lithium MWK methyl isobutyl ketone Et C2H5- 30 Tr -C(C6H5)3 Me CH3 35 THF tetrahydrofuran Ph phenyl DIVIF dimethylformamide 40 TEA triethylamine PNBG p-nltrobenzylgiyoxylate 45 THP tetrahydropyranyl TFA trifluoroacetic acid HMPT (or HMPA) hexamethyl phosphorus triamide 50 EtOAc ethyl acetate DIVISO di methyl su IfoxIde 55 Ac CH3CO Ms CH3S02- DMAP 4-dimethylaminopyridine 60 PY pyridine LDA lithium diisopropyl amide 19 GB 2 042 515 A 19 EXAMPLE 1 2'-(2'-Diethylphosphono-l'-ethyl)penem-3-carboxylicAcid 0- (CH 2(OEt) 2 0 0 2 11 11 (EtO)2-P-(CH2)2CO2CH3)(R0)2P-(CH2)2C02H 1 2 10 0 0 (C0)2P-(CH2)2COCI (EtO)2-P-CH2)2COSH 3 4 Amixtureof 1(11.29,5Ommoles)and5N NaOH (10 mi) was stirred and cooled (ice-bath) for 15 min and at room temperature for 15 min. The mixture was extracted with ether and the extract discarded. The aqueous solution was acidified with 5N HCl and extracted wht CH2C12 to give after drying and evaporation of solvent 20 10.0 g (95%) of oil 2, nmrb (CDC13),4.1 (4H, m), 1.8-2.9 (4H, m) 1.2 (6H, t).

To a cooled (ice-bath) solution of 2 (2.26 g, 10.76 mmoles) was added dropwise oxalyl chloride (2.74 g, 1.88 mi, 21.5 mmoles). The mixture was kept at room temperature for 6 h and then it was evaporated to dryness.

The traces Of (C0C02 were removed azeotropically with benzene to give 2.4 g (quantitative yield) of crude 3.113v ,A c cl 1800; 1735 cm-1. nmr 6 4.3 (4H, m), 3.0 - 3.7 (2H, m) 2.0 - 3.0 (2H, m), 1.4 (6H, m). This was treated with H2S/TEA in a standard procedure to give 1.9 g (80%) of oil 4 estimated to be 80% pure. Nmr: 6 4.1 (4H, q), 2.7 - 30 3.5 (2H, m), 1.7 2.5 (2H, m) 1.33 (6H, t).

0AC (EtO) ?-(CH 95 ly, (CH 3 1,LEt)2 i of-f 35 --- i t To 4 (1.9 g, 8.4 mmoles) was added under N2 1 M solution of NaHC03 (10 ml), followed by addition of 5 (0.813'g, 6.3 mmoles) in H20 (3 mi). The pH of the mixture was adjusted to 7-8 by adding more NaHC03. After standing for 4 h the mixture was extracted with CI-IC13tO give after drying and concentration 1.05 g (56.4% 40 based on 5) of solid 6, m.p. 64-67% nmr 6 7.7 (NH), 5.3 (1 H, q), 4.2 (4H, ) 3.8 (1 H q) 3.5 (1 H q), 2.6-3.2 (2H, m) 13-2.4 (2H, m), 1.3 (6H,) (CH 2) 2 LEC 2 'CH 2) 2-5- "Ft) 2 2 6 7 A mixture of 6 (260 mg, 0.88 mmole) and p-nitrobenzy] glyoxalate (198 mg, 0.88 mmoie) was refluxed in 50 benzene (6 mi) under a Dean Stark apparatus for 16 h to give after evaporation of benzene 453 mg of heavy oil 7, nmr 6 8.3 (2H, d) 7.6 (2H, d) 53-5.7 (4H,) 4.9 (OH), 4.2 (4HJ 3.55 (1 H g), 3.4 (1 H, g), 2.5-3.2 (2H, m) 1.7-2.5 (2H, m) 1.3 (6H) 55;: 5 (CH 2) 2 (OEt) 2 5 T (cif 2) 2 1 (CEt) 2 55 N ' oPNB ', 02 PNB 0 0 'U',1 2 A crude 7 (504 mg, 0.88 mrriole) was dissolved in 1 M solution of pyridine in THF (0.9 mi). To this was added dropwise with stirring and cooling (ice-bath) 1 M solution Of SW2 in THF (0.9 mi) and the mixture was stirred in the cold for 15 min and at room temperature for 40 min. To it was added benzene (10 mi), and the solid was filtered off. The filtrate was concentrated in vacuo to give 463 mg (quantitative yield) of crude 8, nmr 6 65 8.3 (2H, d), 7.6 (2H, d), 6.1 (1 H, s), 5.7 (1 H, m), 5. 3 (2H, d), 4.2 (4H), 1.8-3.6 (6H, m) 1.3 (6H).

GB 2 042 515 A ?-(OE:t) Sly(CH) --(0Et) (C11 2) 2 2 2 2 - 0 ' c; 3 v 2 CO 2V'" 5 2 To a solution of crude 8 (463 mg, 0.88 mmole) in THF (4 mi) was added trip henyl phosphi ne (236 mg, 0.9 mmole) and 2,6 lutidine (96 mg, 0.9 mmole) and the mixture was allowed to stand at room temperature for 65 h. Then it was filtered, the filtrate concentrated and the residual oil chromatographed on a silica gel column with ethyl acetate-2% EtOH as eluent, to give 203 mg (30.6%) of oil 9, which solidified on standing, m. p. 126-128'C.

(CH) LEd N P(P 3 (CH 2 3 2 LEt) 2 15 CO -JS T._ PND 2p 2 9 A solution of 9 (470 mg, 0.635 mmole) in toluene (30 mi) was refluxed for 5 h followed by concentration and chromatography on silica gei-ethyl acetate to give 167 mg (56%) of 10 as oil, [R 1795,1710 cm-1. nmr 8 8.3 (2H, d) 7.7 (2H, d) 5.7 (1 H, m), 5.38 (2H, d) 4.1 (4H) 1.8-3.8 (6H, 1.35 (6H).

CH 2) 2_ f- (OEt) (C4 1 R - 25 2 2 eta-ti 2 C02 p 88 C02M 11 To a solution of 10 (59 mg, 0.126 mmole) in THF (3 mi) and ether (1 mi) was added NaHCO3 (9 mg, 0.107 30 mmole), water (1 mi) and 10% Pd/celite (60 mg) and the mixture hydrogenated at 30 psi for 2 h. The product was isolated as usual to give 36 mg (86%) of 11 as oil, IR (CHC13) 1798, 1730,1710 cm-1, nmr 6 9.0 (C02H), 5.6 (1 H, m) 4.4 (4H), 3.6 (1 H, q), 3.15 (1 H, q) 1.7-3.0 (4H, m), 1.3 (6H).

EXAMPLE 2 6-Acetoxymethyl-2-methylpenem-3-carboxylicAcid Acolls - CH 3 -.,H 40 Preparation of 1,3-diacetoxypropene 1 (Ref. L^ McTeer U.S. 2,866,813. CA 53 9063) AC20 CH2CH-CHO U - --- --. AcOCH2CH=CH-CAc+CH2=CH-CH(OAc)2 at at. 45 Preparation of catalyst: A solution of boric acid (6.2 g) and oxalic acid (12.6 9) in water (44 m]) was evaporated to dryness to give the solid catalyst. Procedure: Acrolein (140 g; 2.5 mol) was mixed with acetic anhydride (256 g, 2.5 mol) at r.t. A 5 mi portion of this mixture was transferred to a one-liter Erlenmeyer flask and treated with a few drops of catalyst, prepared by dissolving 1.0 9 of solid catalyst in 5 mi acetic anhydride. A vigorous exothermic reaction set in and the reaction mixture was kept at a temperature of 40 60' (controlled by cooling with ice-bath), and the rest of the acrolein-acetic anyhdride mixture was introduced into the flask in portions of 10 to 15 mI followed by a few drops of catalyst. The resulting mixture was distilled to remove unreacted starting materials followed by 1,1-diacetoxy-propene. The product 51.6 g (13.06%) was obtained next, b.p. 54 - 57'C/1.2 mm. NMR: 6 (ppm, WC13),7A (H, d, J = 12), 5.3 - 5.8 (H, m), 4.5 (2H, d, J = 7), 2.16 (3H, s), 2.05 (3H, s). IR: vc _. 1770,1750, vc 1680.

ACOCH _C"c - C51 A c a'"')- OAC 2CliCH NH - c 1,./,, 1 2b - 60 Procedure:

CSI (16.92 g; 0.12 mol) was added dropwise to cooled (ice salt bath, -1 5'C) 1 (18.96 g; 0.12 mol). The pale yellow mixture was kept at 5'for 5 h whereby it changed to deep yellow. This was diluted with ethyl acetae (20 mi), cooled to -30'C, and added in portions to a cooled (ice salt bath) mixture of water (3.4 m]); ice (17.0 65 21 GB 2 042 515 A 21 g) NaK03(0.3 g) and Na2S03(3.4g). After addition, the resulting mixture was stirred vigorously for 20 m in and some additional NaHC03 was added to keep pH at 7-8. The layers were separated, and aqueous layer was extracted with ethyl acetate (2 X 50 mi). The combined organic phase was dried (Na2S04; NaHC03; 1: 1). It was filtered and evaporated to give 17.4 g of an oil. This was distilled under high vacuum (0.01 -0.05 mm) in a hot a i r bath. (tem p. 55' - 85') to remove 1. The u nd isti 1 led 1 ig ht brown oi 1 was cool ed, taken u p i n ether a nd filtered over celite-charcoal to give, after evaporation to dryness 5.28 g (22%) of 4:1 mixture of 2a and 2b (determined by nmr) as colourless oil. NMR: 7.25 (H, NH), 6.0 (0.25H, d, J = 4.3), 5.8 (0.75H, cl, J = 15j,4.5 (0.5H, d, J = 6. 5), 4.4 (1.5H, cl, J = 4.5), 3.8 (0.25H, m), 3.5 (0.75H, m), 2.13 (3H, s), 2.1 (3H, s). IR: v,:=,, 1780, 1740.

CA 10 ACcr E I_ C"ICOS,41 A N NH -NH 0, 0 0 it lb 3,C Procedure:

Sodium thioacetate was prepared by addition of thioacetic acid (2.22 mi, 2.363 g) to a solution of IM 20 NaHC03 (31.0 mi) under nitrogen. This was added to a cooled (ice bath) solution of 2 (5.2 g; 25.9 mmoles) in water (20 mi) and stirred for 4 h at room temperature. Some acetone (20 mi) was added to render the reaction mixture homogeneous. The mixture was concentrated in vacuo to remove acetone and then extracted with methylene chloride. The extract was dried and evaporated to give 5.6 g of a mixture of isomers (83.14%) of 3a and 3b. The NIVIR spectrum of the crude oil showed that there were one trans and two 25 cis compounds present in the mixture. A sample (550 mg) was chromatographed on silica gel (30 g, 10% H20) and eluted with benzene-ether-methanol to give 200 mg of a mixture of 3a and 3b in the ratio of 7A, followed by 150 mg of an unknown cis compound (6 5. 55, cl, J = 4.3) to which structure 3c was tentatively assigned. NIVIR: 6. 78(H,NH),5.52 (0.17H,d,J =4.3),5.18(0.83H,d,J = 1.5),4.37(2H,d,J = 4.5),3. 45(H,m), 30 2.35 (3H, s), 2.05 (3H, s). IR: v,. 1765,1740,1600 cm-1.

AC 0 2 N -@- 2 CO 2 CH LOH) 2 SA.

NH CO 2 PNV 35 2 4 Procedure:

A mixture of crude 3 (2.17 g; 10 mmoles) and p-nitrobenzyl glyoxylate (2. 5 g; 11 mmoles) in benzene (200 m]) was refluxed 20 h under a Dean Stark water collector followed by concentration in vacuo to give 3.4 9 of 40crude 4 as oil. This was used as such without further purification. NIVIR: 6 7.5 - 8.5 (4H), 5.2 - 5.8 (M), 3.4 - 5.1 (411), 2 - 2.4 (6H). IR: v,. 1665,1740,1740,1730,1700.

S' c SOC 12 45 C,L 0 PND 4 Procedure:

To a cooled (ice-bath) solution of crude 5 (3.3 g; 7.75 mmoles) and pyridine (0.67 g; 8.5 mmoles) in benzene (20 mi) was added dropwise thionyl chloride (1.01 g; 8.5 mmoles) in benzene (10 mi) and the mixture stirred at the above temperature for 15 min and at r.t. for 15 min. The benzene solution was decanted, and the residual semi solid washed three times with 15 mi portions of benzene. The combined benzene solution was evaporated to give 1.90 9 crude 5(55%). NIVIR: 6 7.5 - 8.5 (4H), 6.12 and 6.2 (111), 5.66 55 (1H,m),5.4(2H,d,J=6),4.3-4.7(2H,m),3.63(H,m)2.4(3H,d),2.1(3H,s).IR:vc=. 1765, 1740,1730,1700.

CO 2 P14B SAC C02p' 5 6 22 GB 2 042 515 A 22 Procedure:

A mixture of crude 5 (1.90 g; 4.27 mmoles) trip henyl phosph i ne (1.572 g; 6 mmoles) and 2,6-1utidine (0.642 g; 6 mmoles) in dioxane (20 mi) was heated at 55'for 18 h. It was cooled, filtered and evaporated to give 3.8 g of a crude dark oil. This was chromatographed on silica gel to give 1.2 9 (42%) of 6.

5Ac 5 ACO CO 2 PNB "S 6 7 10 Procedure:

A solution of crude 6 (1.20 g; 1.79 mmoles) in toluene (15 m[) was refluxed for 5 h. It was cooled and evaporated to give an oil which was chromatographed on Si02 (30 g) and eluted with benzene to give 0.4 g of 15 7 (57%). Anal. Calc'd for C171-116N207S. C 52.04; H 4.11; N 7.14. Found: C 51.77; H 4.08; N 7.30.

Separation of the cis and trans isomers was achieved through careful chromatography on silica gel (60 g) eluting with benzene. cis-isomer: 6 (ppm, C13C13): 7.5-8.5 (41-1, aromatics), 5.67 (11-1, d, J = 5, H-5),5.28 (2H,AB quartet, benzyi),4.33 (2H,d,AcOCH2),4.20 (1H,dt, H-6),2.31 (3H,s, CH3),2.0 (3H,s, CH3CO).vc=0 1770,1740, 1730 cm-1. trans isomer: 6 (ppm, WC13): 7.5-8.5 (41-1, aromatics), 5.53 (1 H, d, J = 2, H-5), 5.30 (21-1, AB quarter, 2o benzyi),4.32(2H,d,AcOCH2),4.27(1H,dt,J=5,J-2,H-6),2.31(3H, s,CH3),2.0(3H,s,CH 3C0).vc=,1770, 1740,1730 cm-1.

CH 3 ':"2p"" C:02"a 25 2 a Procedure:

To a solution of trans 7 (119 mg; 0.3 mmole) in ethyl acetate (15 ml) and water (7 ml) was added NaHC03 30 (25.2 mg, 0.3 mmole) and Pd/C (110 mg) and this was hydrogenated 4.5 h at 30 psi. The mixture was filtered and layers separated. The aqueous layer was washed with ether and then lyophilized to give 40 mg of solid 8 (48%).

Y,=,1765,1740,1600cm-l.b(ppm,D20):5.52(1H,H-5),4.85(2H,AcOCH2),4.0(1H,H6),2.65(3H,CH3),2.40 35 (31-1, CH3CO).

11 If 3 C" 1 CH 3 ----- 6 C02k 40.7 40 3 11 Procedure:

To a solution of crude trans 8 (100 mg) in cold water (2 mi) was acidified with cold 1 N HCI and extracted 45 with CHC13. The extract was dried (Na2S04) and evaporated to give 30 mg of a pale yellow solid. M.P.

111-1 13'with decomposition. IR: v... 1780,1750,1680. (Neat). IR: (KBr): v,,=. 1775 (Strong), 1745,1670.

Treatment of cis paranitrobenzyl 6-acetoxymethyi-2-methyl-penem-3carboxylate according to the above procedure gives the cis sodium salt and free acid.

EXAMPLE3 Potassium 6-(2'-Hydroxyisopropyl)-2methylpenem-3-carboxylate (anion process) H C02r' 1 k c 1r, 5 LDA V.9 CO 21 4a 23 GB 2 042 515 A 23 A solution of acid 1(116mg,0.627mmoles) in anhydrous TH F (4cc, freshly distilled over LAH) was added dropwise at -78'C to a THF (2ec) solution of LDA (from diisopropylamine, 70.7 mg, 98 lil, 0.699 mmoles, and n BuLi 1.6 M, 0.440cc, 0.704 mmole stirred at -78'C for 30 min). The mixture was stirred for 5 min. followed by successive addition of diisopropylamine (70.7 mg, 98 111, 0.699 mmole) and 1.6 M n BuLi (0.440cc, 0.704 mmole) at -78'. It was then stirred for 10 min. at -780 and treated rapidly with acetone (5cc). The mixture was allowed to react with acetone for 10 min. It was acidified (pH=2) with 1 % HQ diluted with ethyl acetate (40 cc) and washed with brine (3 x 20 cc). It was dried over Na2S04. Solvent evaporation gave a crude residue (3a) which was taken up in CH2C12 (crude yield 90 mg). The crude acid was dissolved in cold M113K (2 cc) and treated dropwise with potassium 2-ethyl hexanoate. It gave two batches of potassium salt (36.4 mg, 26%) as a cis and trans mixture, the trans isomer being predominant. 6 (ppm, DIVIS0c16) 5.60 (1 H, d, J5-6 cis = 10 4, H-5), 5.55 (1 H, d, J5-6 trans = 2, H-5), 3.93 (1 H, cl, J6-5 cis = 4, H-6), 3.62 (1 H, d, J6-5 trans = 2, H-6), 3.50 (b.s.,OH), 2.34 (3H, s, CH3), 1.47, 1.40 (6H, 2s, 2CH3), 1.35,132 (611, 2s, 2CH3) Vc=o (nujol mull) 1765, 1582, VOH 3600 3100 LIV (EtOH) kmax 257 (F- = 3920), 300 (8 = 4020).

EXAMPLE 4 Potassium 6-Hydroxybenzyl-2-methylpenem-3-carboxylate (anion process) 0 N:: 5 N H 3 C021. 20 OCHO C0,21 CO2r. 25 1 4h A solution of acid 1 (100 mg, 0.540 mmole) in anhydrous THF (6 cc, distilled over LAH) was added dropwise to a cold (-78') THF (2cc) solution of LDA made from diisopropylamine (84 pd, 60.6 mg, 0.599 mmole) and 1.6 30 M n-BuLi (0.380 cc, 0.608 mmole). The mixture was stirred for 5 min, followed by successive addition of diisopropyl amine (84 RI, 60.6 mg, 0.599 mmole) and 1.6 M n-BuLi (0.380 cc, 0.608 mmole). It was then stirred for 7 min at -78'and treated rapidly with benzaldehyde (300 [d). The mixture was allowed to react at -78'for min. It was acidified with 1% HCI (pH2), diluted with ethyl acetate (40 cc), washed with 1: 1 H20-brine (3 x 20 cc) and brine (1 x 20cc). It was dried over Na2S04. Solvent evaporation gave a residue which was dissolved in M113K (2cc). It was treated dropwise with potassium 2-ethyl hexanoate. It gave 4b (35 mg) in 20% yield as a diastereoisomeric mixture. 6: (ppm, DIVIS0c16) 7.95 (5H, s, H-aromatic) 5.57 (d, J5-6 trans 1.5, H-5), 5.45 (d, J5-6 trans 1.5, H-5) 5.35 (df J5-6 cis 4, H-5), 5.0 (m, C-H hydroxybenzyi), 4.25 (dd, J6-5 cis 4, J6-CM hydroxy benzyl = 10, H-6), 3.90 (m, H-6), 3.65 (b.s., OH). 2.35 (3H, 2s, CH3) vc=,,(nujol mull) 1760,1590, VOH 3600 - 3100. UV (H20) km,x 252 (c = 5,100), 296 (E = 3,300).

EXAM P LE 5 Potassium 6-Thiomethyl-2-methylpenem3-carboxylate (anion process) 5M 45 C02K j CH L5A C.4 3 CP 35SO2CA-3 3 50 H X + C02K 1 4c A sol ution of acid 1 (100 mg, 0.540 m mole) in an hydrous TH F (5cc, distilled over LAH) was added dropwise to a cold (-781 THF (2cc) solution of LDA made from diisopropylamine (84 RI, 60.6 mg, 0.599 mmole) and 1.6 55 M n-Butyl lithium (0.380 cc, 0.608 mmole). The mixture was stirred for 7 - 8 min, followed by successive addition of diisopropylamine (84 [11, 60.6 mg, 0.599 mmole) and 1.6 M n- Butyl lithium (0.380 cc, 0.608 mmole). It was then stirred for7 min at -78'and treated rapidly with methyl thiomethyisuifonate (300 [ti, excess). The mixture was allowed to react at -78'for 5 min. It was acidified with 1% HCI (pH-2), diluted with ethyl acetate (40 cc), washed with 1: 1 H20-brine (3 x 20 cc) and brine (20 cc). The organic solution was dried 60 over Na2S04. Solvent evaporation gave a residue which was dissolved in cold M113K (2cc). The cold solution was treated dropwise with potassium 2-ethylhexanoate. It gave 4c (40 mg) in 28% yield as a 8:3 mixture of cis and trans isomers (decomp.) 11 1200) 8 (ppm, DIVIS0c16) 5.85 (1 H, cl, J5-6 Cil = 4, H-5), 5.57 (1 H, d, J5-6 trans 1.5, H-5),4.87 (1H, d, J6-5 cis = 4, H-6),432 (1 H, d, J6-5 trans = 1.5, H-6),142 (b.s., OH), 2.37 (s, SCH3), 2.33 (s, CH3),2.25(s,SCH3)-Vc=o(nujoi mull) 1770,1600,UV(H20)Xrna,<252(e=4200), 297(e =3700).

24 GB 2 042 515 A EXAMPLE 6 1-(p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4- (silver mercaptidyl)-2-azetidinone 5A9 ):-.I- Y_ M oj STr 0 1 2 A methanol (90ec) suspension of tri phenyl methyl 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 was stirred for 5 min and 4-acetoxyazetidinone 15 (7.7 9, 0.059 mole) in water (55 cc) was added rapidly. Precipitation of 4-triphenyl methyl mercaptoazetidinone (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.:

146.5 - 147.5OC). 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. 6 (ppm, CDC13) 7.60 - 7. 10 (15H, m, H-trityl), 4.62 (1 H, bs, NH), 4.40 (1 H, dd, J4-3 trans = 3. 0, J4-3 cis 5, H-4),124 (1 H, ddd, Jgem = 15, J3-4 cis 5, J3-NH = 1.8, H3),2.81 (1 H, ddd, J9em 15, J3-4trans = 3AJ3-NH = 1.2, H-3) v,.

(CHC13)1760,VNH3340.

24 57 r ATr STr OH ro PNB 0 C02"13 2 2 i 30 Hydrated p-nitrobenzyl glyoxylate (4.54 g, 0.02 mole) and azetidinone 2 (6.90,0.02 mole) 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 HCI, water, aqueous 5% Nal-IC03 water and brine. It was dried over M9S04 (12 g, 35 quantitative). A small fraction of the epimeric mixture was separated on a silica gel plate (CH2C12-ether 6:4) IsomerA:

Rf = 0.87, m.p. = 170.5 - 171.50 6(ppm,CDC13)8.07 (2H,d,J=9,Hm aromatic), 7.45 (part of d, Ho aromatic), 7. 40-7.00 (15H, m,Trityi), 5.25 (2H,s,CH2-PNB),4.75(1H,s, H-C-0),437 (1H,dd, J3-4trans = 3,J3-4cis =4, H-3),2.83(1H,dd,Jgem 16,J4-3cis =4,H-4),2.10 OH, dd,Jgem = 16,J4-3trans = 3, H-4),1.42(b.s.,OH). vc=,, (CHC13) 1770,1760 (shoulder), VNO2 1525,VOH 3475.

Isomer B:

Rf = 0.75, m.p. = 152 - 153' 6(ppm,CDC13),8.13(2H,d,J = 9, Hm aromatic),7.47 (2H,d,J = 9, Ho aromatic), 7.40 - 7.00 (15H, m,trityi), 50 5.30 (3H,s, CH2-PNB, H-C-0), 4.45 (1H,t, J = 3.5, H-4),2.90 - 2.70 (2H,A13 part of A13X, H-4),1.55 (b.s., OH). vc=. (CHC13) 1767,1755 (shoulder), VN02 1525,VOH 3500.

S,rr -r SOC12 - -------- l5 f-f pyridine CC4, cl C.,-.4 CH r. 1,m 2 2 1 4 A cold (- 15') THF (150 cc, dried over molecular sieves) solution of azetidinone 3 (12 g, 21.7 mmoles) was treated with pyridine (1.9 9, 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 -15'. 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 charcoal (11.7 g, 94%, crystallized out from chloroform).

6 (ppm, CDC13) 8.17 (21-1, d, 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-PN B), 4.81 (1 H, m, H-4) 3.27 - 2.40 (2H, m, H-3) vc=. (KBr film) 1785,1770 YNO2 1525. 65 GB 2 042 515 A 25 STr STr 03P 1 cl 2,6-Lutidine -fily PO 3 C02pr'a i i 5 A THFOO0 cc, distilled over LAH) solution of ch loroazetid i none 4(11.6 g, 20.2 mmoles) was treated with triphenyl phosphine (7.86 g, 30.0 mmoles) and 2,6-lutidine (2.36 g, 2.56 cc, 22.0 mmoles). The mixture was refluxed for 72 h. The precipitate was filtered off and washed with ether. The organic solutiori was washed with 2% aqueous HCI and 5% aqueous bicarbonate and dried over M9S04. 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. CaWd for C49H4ON205SP: 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.

Y,:=.(CHC13)1740,vphosphorane(1620,1610),VNO2 1525.

.Tr,, A SA9 9"03 NN 03 pyridine ^3 2PN13 C027!:B 20 4-Tritylmercapto azetidinone 5 (1.6 g, 2 mmoles) was dissolved in CH2CI2 (20 cc) and the solvent was flushed down at 55'-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, 1.2 eq) and pyridine (174mg, 178 [d, 2.2 mmoles, 25 1.1 eq). The warming bath was then immediately removed. The mixture was stirred at room temperature for 2 hand at OOC for 1 h. The silver mercaptide 6 was filtered off, washed twice with cold (0o) methanol and three times with ether. (1.12 g, 84.5%, m.p.: 130-135 dec.).

v,. (CHC13) 1795,1725 (shoulder), v phosphorane (1 620,1605),VN02 1530.

EXAMPLE 7 1-(p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4(silvermercaptidyl)-2-azetidinone SCOCH 3 K2C01'Agkf3 SAg HeOH 35 Cf COOPUB i 6 A solution of phosphorane 7 (1.796 g, 3.0 mmoles) in chloroform (3 mi) was diluted with methanol (90 mO, cooled at O'C 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 O'C for 15 min., then the cooling bath was removed and stirring was continued for 3 h. The reaction mixture was cooled down to -1 OOC, stirred for 1 h and filtered; the silver mercaptide was successively washed with cold methanol and ether; 1.91 g, M.P.: 138 - 145'C dec, 96%. I.R. (nujol) cm- l: 1748,1620 and 1605. An analytical sample was obtained by preparative TLC (ethyl acetate); M.P.: 140 - 5'C dec, caic'd for C30H24N205SPAg: 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 8 1-(p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4(silver mercaptidyl)-2-azetidinone A. Use of aniline as base SCOCH 3. Aniline, A9NO SA9 FIf' 5-pph 3 MOH 2P.3 55 C00PN3 LPhNB 2 6 - A sol ution of phosphora ne 7 (1.8 9, 3.0 m moles) in chloroform (4 ml) was di luted with methanol (90 mi), cooled to - 1 YC under nitrogen atmosphere and treated successively with silver nitrate (0.56 g, 3.3 mmoles) and anil i ne (1.5 mi, 16.5 m moles). The reaction mixtu re (protected from lig ht) was stirred at - 1 5'C 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 O'C and stirred for 1 h before being filtered; the silver mercaptide was successively washed with cold 65 methanol and ether; 1.55 g, M.P. 114-WC dec. 77.9%]R (nujol) cm-l; identical to compound of Example 7.

26 GB 2 042 515 A Silver- 1-(paranitrobenzyl 2'-triphenylphosphoranylidene-2'-acetate)-2- azetidinone-4-thiolate B. Use of 4-dimethylaminopyridine (DMAP) as base 26 SCOCH 3 A940 /DhIA. Shg 0 or: -i- 03 CH2 C12 /CS 3ON Cy g. 3 CO 2 PNB cc rt:B z A solution of the above S-acetyl phosphorane (17.96 g, 30 mmol) in methanol and dichloromethane (1:2, 450 ml) was purged with nitrogen (5-10 min), cooled to 50C and treated successively with silver nitrate (5.35 g, 31.5 mmol) and 4dimethylaminopyridine (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 ml). The precipitated silver salt was collected by filtration, washed with ether and dried; 18.1 g (91 %); ir (CHC[3) Vmax: 1745 (C=O of P- lactam) and 1607 cm-1 (C=O of ester).

Silver- 1-(paranitrobenzyl2'-triphenylphosphoranylidene-2"-acetate)-2- C. Use of diazabicycloundecene (DBU) as base SCOCH 3 A9NO3 SA9 103 DBU. M.OH 0,[::,- 3 -r.2ptiB f.

2 25 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) solution of silver nitrate (10.68 9, 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 WC) methanol and ether and dried under vacuum; 37.0 g (93%); ir (nujol naill) vmx (c=o) and 1600 cm-1 (phosphorane) D. Use ofpyrrolidine as base Silver 1-(paranitrobenzyl2'-triphenylphosphoranylidene-2"-acetate)-2azetidinone-4-t hiolate SCOC11 3 Pyrrolidine SA9 A9NO 3 0 C-PPh 3 -C-Pph 1 3 COOPR:5 40 OOPNB To a cold WC) solution of 4-acetyithio-l-(paranitrobenzyi T- tri phenyl phosphoranyl idene-2"-acetate)-2azetidinone (0.60 g, 1.0 mmol) in CH2C12 (2 mi) was added MeOH (4 mi), a solution of AgNO3 in MeOH (0.14N, 7.86 mi, 1.1 mmol) and a solution of pyrrolidine (0.92 mi, 1.1 mmol) in MeOH (2 m]). 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) vr,,x: 1755 (C=O) and 1600 cm-1 (aromatics).

EXAMPLE 9 Mercuric (1l)-[2'-Triphenylphosphoranylidene-2'-acetatej-2azetidinone-4-thiolate ST 1 3 55 C02p:;e 1 5) Hq -11 r_rl. p h 3 60 C02p"P A solution of 1(2.4 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 ml). After stirring at 5'C for 2 h, the solvent was evaporated and the residue redissolved in dichloromethane and washed with cold water. The 65 t 27 GB 2 042 515 A 27 organic solution after being dried (M9S04) and treated with charcoal, was evaporated to give a foam which crystallized when triturated in ether. Yield: 1.73 g (91%) M.P. 123'- 127'C, I.R. (CHC13) 1745 cm-1 (vc=o P- lactam) 1608 cm-1 (phenyl).

EXAMPLE 10 2-Methylpenem-3-p-nitrobenzyl-carboxylate (from mercaptide intermediate) 5) Hq.Ji,--f.,Ph 3 C02P14n 11 2CHICOCI 2g S--C-OCH. 3 pyxidine N -, I Ph 3 r - C02PrJL ill A solution of H (262 mg, 0.2 mmol), acetyl chloride (35 mg, 0.44 mmole) and 2 drops of pyridine in 10 ml of dichloromethane was stirred at 5'C for 1 h. The precipitated mercuric chloride was then filtered off and the 15 filtrate washed successively with cold dilute hydrochloride acid, sodium hydroxide and finally brine. The organic solution was submitted to a stream of hydrogen sulfide for 2 minutes at 5'C and stirred at that temperature for an additional 10 minutes in order to precipitate the last traces of mercuric salts. Some charcoal was added to the black mixture which was then filtered through a pad of celite. Evaporation of the clear filtrate left 193 mg (80.7%) of ffl as a foamy material. I.R. (CHC13) 1755 (vc=, P-lactam) 1692 NSCOCH) 1620(phenyl).- ccc '3 COZAIN13 ill J1 C., 3 J ', --),-i.;-, 1 ' 1 Phosphorane /11 (75 mg, 0.126 mmole) in toluene (10 cc) was refluxed over a 2.5 h period under nitrogen 30 atmosphere. Solvent evaporation and purification of the residue afforded a crystalline derivative (25 mg, 63%) whose physical and spectral data were in complete agreement with those of the title product.

Product IV may if desired be subjected to catalytic hydrogenation (30% Pd on celite) to produce the corresponding 3-carboxylic acid product.

EXAMPLE 11 2-Aminomethylpenem-3-carboxylic Acid (from mercaptide intermediate) d - f-prb 3 COOP:.B i cleocitH, COCH 2113 1 CH2C12 p 1,-c.PPI, 1 3 COWNB A Asolution of silver mercaptide 1 (1.25 g, 1.99 mmole) in dichloromethane (15 mi) kept under nitrogen atmosphere was cooled at O'C and treated dropwise with a 2M solution of azidoacetyl chloride in dichloromethane (1.13 mi, 2.26 mmoles). The reaction mixture was stirred at O'C for 1 h; the cooling bath was removed and stirring was continued for 5 h. The reaction mixture was filtered over a celite pad and the solids were washed with dichloromethane (35 mi). The filtrate and washings were combined, washing with sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to an orange syrup which was purified by column chromatography (30 g of silica gel 60, eluate; ether-2% ethyl acetate (200 m]), ether -6% ethyl acetate (200 ml) and ether -20% ethyl acetate (500 mi), fraction size: 10 mi). The combination and evaporation of fractions 49-80 gave a yellow powder; 0.73 g, M.P. 61-70', 60.8%.

:c "2"' J Pph 3 C0CP:19 i 21; 3 i 28 GB 2 042 515 A 28 A solution of phosphorane 2 (0.593 g, 0.93 mmole) in toluene (20 ml) was heated at 105C for 1 h, cooled to 23C and concentrated to a semi- crystalline compound which was purified by column chromatography 0 2 g of silica gel 60, Eluate: benzene (100 ml), benzene-2% ether (100 ml) and benzene-4% ether; fraction size: 10 ml). The combination and evaporation of fractions 18 26 gave a yellow syrup which crystallized on standing; 0.18 g, M.P.: 127-8'C, 53.7%. NMR (CDC13) 8 8.22 (2H, d, JHo, Hm = 8.8 Hz, Ho of p-nitrobenzyl), 7.60 (2H, d, JHm, Ho = 8.8 Hz, Hm of p- nitrobenzyl), 5.710 H, dd, J5,6 cis = 3.6 Hz, J5,6 trans = 2.1 Hz, H-5), 5.33 (2H, center of ABq, Ja,b = 14.0 Hz, CH2 of p-nitrobenzyl), 4.58 (2H, center of ABq, Ja,b = 15.0 Hz, CH2on C-2) 3.88 (1 H, dd, J6,5 cis = 3.6 Hz, Jgem = 16.5 Hz, H-6 cis) and 3.55 (1 H, dd, J6,5 trans = 2.1 Hz, Jgern = 16.5 Hz, H-6 trans). I.R. (Nujol) cm-1: 2115 and 2090 (N30780 (c=o) of P-lactam) and 1685 (c=o of p-nitrobenzyl ester).

An analytical sample was obtained by preparative T.L.C.; M.P. 127-8'C, calc'd for C14HjjN505S: C, 46.54; H, 3.07; N, 19.37; S, 8.87. Found: C, 46.43; H, 3.08; N, 19.37; S, 8.90.

H N 301 Pd/ceUte -CM2NH2 2 3 TEF, ether, Ho 1:0OPN9 15 i 4 Toa solution of penem 3 (0.18 9,0.5 mmole) in tetrahydrofuran (6 mi) was successively added ether (6 mi), water (6 mi) and 30% palladium on celite (0.18 g). The reaction mixture was hydrogenated under 30 p.s.i. at 23% for 2.5 hand filtered over celite pad; the pad was washed with water and the filtrate and washings were 20 combined, washed with ether-THF mixture and lyophilized to give 30 mg, 30%, of compound 4. [Water and ether insoluble compound were dissolved in chloroform and the organic solution was washed with water and dried over anhydrous sodium sulfate. The evaporation of solvent under reduced pressure gave 77 mg (42.8%) of starting material 31. NMR (DMSO d-6) 6: 5.7 (dd, J5-6 cis - 3. 5 Hz, J5-6 trans 1.5 Hz, H-5). I.R. (nujol) U.V. XH20 rnt:

em-': 1775 (c=o of P-lactam) and 1615,1585. max (E=2320) and 307 (E=2685). Title product 4was also obtained from intermediate 3 by the following route:

H 2t:3 H2.Pd1D.E. 5 0 THF, Ether, .E.- - P.c COOPNr 1 CoaH 30 2 4 To a solution of penem 3 (2.4 g, 6.89 mmoles) in tetrahydrofuran-ether- water mixture (MA, 165 mi) was added 30% palladium on diatomaceous earth (4.8 g). The reaction mixture was hydrogenated under 45 p.s.i.

at 23C for 2.5 h and filtered over celite pad. The filtrate and washings were combined, washed twice with ether, centrifugated and filtered several times to give a clear solution which was lyophilized; 0.622 g, 45%. The crystallization of the compound was induced by the addition of water (0.8 mi); the suspension was centrifuged and the water was removed leaving an orange solid. This solid was washed twice with water and Mg, 19.8%. UV XH20 a slightly yellow solid was obtained after drying: 0.273 max, 307 (E=4318) and 257 (E=2650).

Some crude starting material (1.2 g, 50%) was recovered. The compound (50 mg) can also be purified by column chromatography [Sephadex G1 0, column size: 1.6 x 100 cm, flow rate: 10 mi/h, eluent: distilled UV XH20 water, fraction volume: 1.5 mi, detector: refractive index]. max: 307 (E=3597) and 255 (8=2424). The stability of the compound in aqueous solution was checked by:

t UV: 6 h 307 (E=3545) and 255 (E=2773) 45 21 h 307 (E=3467) and 255 (E=2411 28 h 307 (E=3337) and 254 (e=2398) 46 h 307 (E=3259) and 254 (E=2398) h 307 (c=3076) 94 h 307 (E=2842) 50 h 307 (E= 1900) UV XH20 A sample of compound 4was kept at 230C for 3 days and the UV was taken: max: 307 (F,=3055) and 255 (6=2008).

Compound 4 was converted as described below to two additional 2-penem derivatives.

1 J1.1 ', 2WH:10 0 C 4 HaHCO 3 '1120. CH 'H2 CP. r- I ' '-cji 3 3 COA.0 29 GB 2 042 515 A 29 A suspension of compound 4 (50 mg, 0.25 mmole) in distilled water (0.5 mi) was treated with one equivalent of sodium bicarbonate (21 mg) followed by the addition of ethyl acetimidate (21.8 mg, 0.024 mi). The reaction mixture was stirred at 230C for 20 min and lyophilized giving 52 mg of a yellow solid. NMR (D20) U.V. XD20 8: 5.7 (m, H-5) and 2.23 (b.s., CH3 of amidine). I.R. (KBr)cm-l: 1772 (c=o of P-lactam). rnaxm[L: 305 5 (E=3116) and 253 (E=2525). The compound 5was applied on a column (Sephadex G10, column size: 1.6 X 100 cm-1, Eluent: H20, detector: I.R. fraction sizes: 1.6 mi) and lyophilization of appropriate fractions gave 23 U.V. XH20 mg 45% of slightly yellow powder. max m[t: 303 (E=2960) and 248 (e=2885).

2. RUHCO3, it' 0 A C..::='/N 1 + d2H43 2 'f7C_ HCI O'EIL/1 0 H-IN "C -j 10 -OEt AP A suspension of compound 4 (50 mg, 0.25 mmole) in distilled water (0.5 ml) was treated with sodium bicarbonate (21 mg, 0.25 mmole) and stirred for 1.5 min before the addition (2 min) of a mixture of sodium bicarbonate (126 mg, 1.5 mmole) and ethyl formimidate hydrochloride (164 mg, 1.5 mmole). The reaction H20 mixture was stirred for 10 min at 23"C and lyophilized giving an orange powder. U.V. X,,,.m[v 304 (E=2300).

EXAMPLE 12

Sodium 2-Hydroxyaminopropylpenem-3-carboxylate i 11:JaCH 51 21 NCL A To a cold 5% aqueous solution of sodium hydroxide (320 ml) was added ester 1 (21.6 g, 0.134 mole). The resulting mixture was stirred at room temperature for 2 h and then concentrated to 250 ml and acidified with concentrated HCL The mixture was extracted with ethyl acetate (4 x 200 ml) and the organic extracts were dried over sodium sulfate. Concentration on rotary evaporator left an oil. Yield 13.2 g (75%).

02NI-__^CO 2 q. SOCI, ------ - -------- 0 2 cl- C 2 3 40 A solution of acid 2 (13.2 9, 0.1 mole) in SOC12 (25 mi) was stirred for 2 h at 300C. After evaporation of thionyl chloride, the residue was distilled under vacuum T = 76-78'C (P=0. 2 mm Hg). Yield 8.8g (58.3%) as a colourless liquid: n.m.r. (CDC13) 6 ppm: 2.40 (21-1, m, P-CH2); 3.15(2H,t, ct-CH2); 4.50 (2H,t,y-CH2) i.r. (neat): 45 1550 cm (YN02); 1790 cm-1 (v.

=., acid chloride).

2 L) i:

AC 50:ICC)31 115 0 50 0-- H i i A solution of 3 (19.46 g, 0.128 mole) in methylene chloride (200 mi) was added rapidly to a cold (0-101 stirred solution of triethylamine (36 mi, 0.256 mole) in methylene chloride (500 mi) which had been saturated 55 at 0-50 with H2S. The mixture was stirred at -100 for 1 hand then a stream of nitrogen was passed through the solution to eliminate the excess of H2S. The mixture was washed with 10%HCl, the organic extract was concentrated to about 150 mi and then sodium bicarbonate (10.9 g) and water (500 mi) was added. The pH was adjusted to about 7.5 with NaHCO3 or HCL The resulting mixture was cooled to O'C and 4-acetoxy-2-azetidinone (16.8 g, 0.13 mole) in water (20 mi) was added with vigourous stirring. After 4 h the 60 mixture was extracted with ethyl acetate. The extracts were washed with 10% HCl, sat. Nal-IC03, brine, dried (Na2S04) and evaporated. The residue was purified by column chromatography (Si02; eluent: ether then ether-ethyl acetate 5%) giving an oil which crystallized in ethyl acetate- hexanes yielding 4 (3.5 g, 12.5%) as a white powder. (m.p. 45-47'C).

GB 2 042 515 A 30 H C02 PN8 5 A mixture of azetidinone 4 (1.09 g, 5 mmoles) and p-nitrobenzyl glyoxylate hydrate (1.2 g, 5.25 mmoles) in benzene (100 mi) was heated at reflux with a Dean-Stark trap filled with 4A molecular sieves for 18 h. 10 Evaporation of the solvent gave the glyoxylate adduct 5 (2.1 g) as an oil.

6 2 PY U-cl 32 P"3 15 i L Azetidinone glyoxylate 5 (2.1 g) was dissolved in tetrahydrofuran (50 mi) and pyridine (0.57 m], 7 mmoles) was added to the solution. The mixture was cooled to OOC and SOC12 (0.5 mi, 7 mmoles) was slowly added.

The mixture was stirred 1 h at OOC and then filtered before evaporation to dryness. Filtration of this material over a pad of silica gel with CH2C12 gave a foam; yield 1.9 g (85%).

NO C-Cl 25 CO PN6 3 2 C02 P:42 f 7 To a solution of chloroazetidinone (6.2 g, 14 mmoles) in THF (300 mi) was added triphenyl phosphine (5.5 30 g,0.02 mole) and 2,6-1utidine (2.4 mi, 0.02 mole). The mixture was heated at WC for 20 hours. Lutidine hydrochloride was filtered off and washed with ether. The filtrate was then evaporated. The residue was purified by chromatography through a silica gel columna and eluted with dichloromethane and dichloromethane-ethylacetate (1: 1). Evaporation of eluent gave a white solid (2.9 g, 30%).

"02 5 W -8, E N 0 co,p:,,-. 2P"!' A 40 i Phosphorane 7 (2.0 g, 3 mmoles) in toluene (150 mi) was refluxed for 2.5 h. Evaporation of solvent afforded an oil which was purified by chromatography through a silica gel column and eluted with dichloromethane and dichloromethane-ethylacetate (M). Evaporation of the solvent gave a syrup which crystallized in 45 ethylacetate-hexanes as a white solid (0.82 g, 40.7%).

301 Pd/DE 0 j Ir S 2 -a-"20-'%'HCO3 C02 r4 a 1 2 To a solution of ester 8 (50 mg, 0.127 mmole) in tetra hydrofu ra n-ether mixture (2-3,25 mi) was added water (10 mi), sodium bicarbonate (10 rng, 0.127 mmole) and 30% palladium on diatomaceous earth (50 mg).

The reaction mixture was hydrogenated under 50 p.s.i. for 3 h at WC, filtered over a celite pad and washed with ether. Aqueous solution was lyophilized yielding a yellow powder (30 mg) of hygroscopic compound. 60 i.

c 1 31 GB 2 042 515 A 31 EXAMPLE 13 6-Ethyl-2-aminomethylpenem-3-carboxylic Acid (cis andtrans isomers) L C1:2121'2 1 and 2H S / U. 2 1111 2 l-k 211 a. Silver cis and trans 3-ethyl- 1-(p-nitrobenzyl-2triphenylphosphoranylidene-2-acetate)-2-azetidinone-4thiolates A solution of cis and trans 3-ethyi-l-(p-nitrobenzyi-2'-phosphoranylidene2'-acetate)-4-acetyithio-2- azetidinones (1.88 g., 3.0 mmoles; Example 1, structure 7) in chloroform (4 mi.) was diluted with methanol (90 mi.), cooled to Wand treated successively with finely powdered silver nitrate (0.51 g., 3.0 mmoles) and potassium carbonate (0.33 g., 2.4 mmoles). The mixture was stirred vigorously 15 min. at 00, 3 h at room temperature and 1 h at -1 O'C. The precipitated silver mercaptide was collected by filtration, washed with methanol and with ether and dried in a vacuum. The title product was obtained as a greyish solid, m.p. 112-135' d. vc=o 1750,1620,1605.

b. Cis and trans 3-ethyl- 1-(p-nitrobenzyl-2'phosphoranylidene-2-acetate)4-azidoacetylthio-2-azetid inones A solution of the above crude mercaptide (1.31 g, 2 mmoles) in dichloromethane (15 ml) was cooled to 0' and treated, under a nitrogen atmosphere, with a 2M solution of azidoacetyl chloride in dichloromethane (1.13 ml. 2.26 mmoles). The mixture was stirred at 0 for 1 hand at room temperature for 5 h. The insoluble silver salts were removed by filtration over Celite and washed with dichloromethane. The combined filtrates were washed with dilute sodium bicarbonate solution and water, dried and concentrated. The oily residue was purified by chromatography over silica gel (35 g) eluting with etherethyl acetate. The pertinent fractions were concentrated to give a mixture of cis and trans acylated compounds as a semi-solid; 0.62 mg. v (CDC13):

2105,1760,1690,1621 cm-1.

c. Cis and transp-nitrobenzyl-2-azidomethyl-6-ethylpenem-3-carboxylates A solution of the above crude phosphorane (0.60 g) in toluene (30 mi) was kept at 105'for 1 h, cooled and 30 concentrated to leave an oily residue which was purified by column chromatography over silica gel (20 g) eluting with increasing proportions of ether in benzene. The pertinent fractions were concentrated to give both the cis and trans isomers.

cis isomer: 6 (ppm, CDC13): 8.25 (2H, d, J = 8.8, Ho of paranitrobenzyl), 7.65 (2H, d, Hm), 5.93 (1 H, cl, J = 4.1, H-5),5.38 (2H, AB quartet, J = 14.0, benzyl), 4.68 (2H, AB quartet, J = 15.0, CH2-N3),14 (1H, m, H-6),2.0 (2H, 35 m, CH2CH30.1 (3H, t, J = 7.4, CH2CH3).

trans isomer: 6 (ppm, CDC13): 8.18 (2H, d, J = 8.8, Ho), 7.59 (2H, d, Hm) 5.52 (1 H, d, J = 1.4, H-5), 5.33 (2H, AB quartet, J = 14.0, benzyl) 4,58 (2H, AB quartet, J = 15.0, CH2-N3), 3.7 (1 H, dt, J = 1.4, J = 7.4, H-6),1.9 (2H, m, CH2CH30.1 (3H, t, J = 7.4, CH2CH3.

d. Trans 2zAminomethyl-6-ethylpenem-3-carboxylicAcid A mixture of the above trans p-nitro benzyl ester (0.20 g, 0.5 mmole), THF (6 ml), ether (6 ml), water (12 ml) and 30% palladium on celite (0.20 g) was reduced at 23'for 2.5 h at an initial hydrogen pressure of 30 psi. The catalyst was removed by filtration over celite and washed with water. The combined filtrates were washed 45 with ether-THF and Iyophilized to give the crude trans acid (12 mg). Chromatography over a column of Sephadex G-10 eluting with water gave the pure trans acid (6 mg) as a hygroscopic powder. vc=o 1775,1615 Cm-1. kma,, = 306 (F_ = 3465). 6 (ppm, D20-DMSO): 5.40 (1 H, d, J = 2.0, H-5),2.0 (2H, m, CH2CH30-1 (3H, t, J = 7.4, CH2CH3).

e. cis 2-Aminomethyl-6-ethylpenem-3-carboxylic Acid Reduction of the cis-p-nitrobenzyl ester as described above for the trans- ester gave the cis-acid as a yellowish hygroscopic power (13%) vc-0 1775, 1615 CM-1 krna,, 304 (E=3563). 8(ppm, D20-DMSO): 5.75 (1 H, d, J = 4.0, H-5), 2.0 (2H, m, CH2CH30.1 (3H, t, J = 7.4, CH2cH3)- 32 GB 2 042 515 A 32 EXAMPLE 14 The following compounds may be prepared according to the general procedure of Example 13 0 -C%1-il-1-.Z. -- Y X E C,i 3 COC1 - el.. - C.4 [,'a, H . 3 3 Ae 2 G -C!I, _c;:, Zi., H Ch 3 -Ch c 2 R 5 COC1 _Ch 3 -c, "CJ4. COC 2 3 Zia, H POCR,wCl _Ch 3 -C. 2 Go '.a, il L-COCI. -C: 3---1 '11; 1 H E7LCOC1 -C-3 F-i '.'a, h C 3 col 2' _C53 -C-- 2 \ ' - Ca 1,1 Aa. ii 3 C.4 3 Cil A--y'.ating Aqent Y -CH X z [-r -.CH 2 COCI. -CH 2 1,,;- N 1:4 S t :1 3 (,:It 2)21 Coel -CIL 3 - (ell,):jji, it COC1 -CH - (C.4 NH d 3 (C'42) 3 3 2 3 2 lie (C14 2)2 COCI. -CH 3 - (a 213 tit,.4 0 2 tl (Cit 2) 3 COC1 - W 3 - (CH 2)l NII0d Na, H 11 3 (Cl[,) 4 COCI. -CH 3 - (CH2) 4 NP. 2 I C.4 1) OCH Cocl. -CH 3 -ell 2OkC%132iH2 Z 2 2 - (CH sc.i,CZ)CI -CV -CH 5 (CH 521 h 3 2)2 3 2 2)2 2 AC11,5 (C.4 23 2 C. 2 C021.t -CH 3 (CH 2) ';""c:1a, H Cli,C0C1 -c 2 11 5 -U 3]a, H c 2 H 5 COCA. -c 2 H 5 _C2 it 5 MaL, H Pei" 2 COC1 -c 2 11 5 - C.4 20 Na, H Acen 2COC1 -c 2 H 5 -CH,00 it,,, H L-COC1 -c 2 11 5 _:i Na, H 1 N 3 (CH 2) 2 COC 1 -c 2 it 5 - (CH 2) 2:;12 N 3 ial 2) 3 COCI. -C2H5 - ((-It 2) Y4"2 H O'n (W 2) 3 COC1 _e2H5 (CH 2) 3:;Roll Na, It 1 3 (CH 2) 4 Coel -c 2 it 5 - (CU 2) 4:M 2 11 CH 3 Coel. ISO-C 3 It 7 _Ul 3 ild, 11 c 2 It 5 Coci '50-C3 it 7 -c 2 1! 5 Aa, 11 t,-CC)Cl iso-C 3H7 ---1 tla, H 33 GB 2 042 515 A 33 COCI 150-C 3'l7 0 -CC)CI ZIa, H 3 7 U 3 si S 5 IJCH 2 COCL iro-C 3 it 7 -CH 2 0 Na, It 11 3 CH 2 COC1 1GO-C 3 H 7 -CII 2.1411 2 H 3 (CH 2)2 COC1 iso-C 3 H 7 - (c I 2)2;ja 2 H 3 (CII 2) 3 COC 1 iso-C 3 H 7 -(C4,) 3 Nil, H 10 4(CH,) COC1 iso-C H - (CH 2) 3 It.

3 3 7 is EXAMPLE 15 cis- and trans-6-Acetoxymethyl-2-aminomethylpenem-3-carboxylic Acid AC0 CH 2 Nii 2 20 CO 2 H a) 3-Acetoxymethyl-4-tritylthio-2-azetidinones (cis and transisomers) A solution of a mixture of cis and trans 4-acetoxy-3-acetoxymethyl-2- azetidi none (4.7 g, 25 mmoles) (Example 2, structure 26) in water (200 ml) was added rapidly to a vigorously stirred solution of sodium triphenylmethyl mercaptide (from triphenylmethyl mercaptan, 55.2 g; and sodium hydride, 9.6 g, in methanol, 300 ml). The mixture was stirred at room temperature for4 h and the solids were collected by filtration, washed with water, and dissolved in dichloromethane. The solution was washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate and water, dried and concentrated to leave 85% of a 30 solid which was used as such in the next experiment.

b) cis and trans 3-Acetoxymethyl-l-(p-nitrobenzyl-2-hydroxy-2-acetate)-4tritylthio-2-azeti dinones A solution of the above azetidinone (8.0 g, 20 mmoles) and p-nitrobenzyi glyoxylate (4.54 g, 20 mmoles) were refluxed in benzene (100 ml) through a Dean-Stark water separator filled with 3A molecular sieves.

After 24 h a second quantity of p-nitrobenzyl glyoxylate (4.54 g) was added and the ref lux continued fora further 24 h. The mixture was diluted with-ether, washed with 5% aqueous hydrochloric acid, water, aqueous 5% sodium bicarbonate and water. Drying and concentration left 100% of the crude isomeric mixture as an oil.

c) cis and trans 3-Acetoxymethyl- 1-p-nitrobenzyl-2'1-chloro-2'1.acetate)4-tritylthio-2-azetidinones A solution of azetidinones from part b (12.2 g, 20 mmoles) and pyridine (1.9 9,24 mmoles) in dried THF (150 ml) was cooled to -150 and treated dropwise with thionyl chloride (2. 86 g, 24 mmoles) under a nitrogen atmosphere. The mixture was stirred 45 min at 15', the precipitate was removed by filtration and washed with benzene, and the filtrates were concentrated to leave a semi-solid (95%).

d) cis and trans 3-Acetoxymethyl-l-(p-nitrobenzyl2'triphenylphosphoranylidene-2-acetate)-4 -tritylthio-2- azetidinones A mixture of azetidinones from step c (12.6 g, 20 mmoles), triphenylphosphine (7.8 g, 30 mmoles) and 2,6-1utidine (2.6 cc, 22 mmoles) in THF (100 mi) was heated under reflux for 80 h. The insoluble material was 50 removed by filtration and washed with ether. The filtrates were washed with 2% aqueous hydrochloric acid, 5% aqeuous sodium bicarbonate and water, dried and concentrated. The residue was dissolved in benzene, filtered slowly through a pad of silica gel (250 g) and the pad was eluted with increasing proportions of ether in benzene. Concentration of the pertinent fractions gave a mixture of the title compounds (65%). vc=,, 1740, v,.=po,1620,1610,VN021525cm-1.

e) Silver cis and trans 3-Acetoxymethyl- 1-(p-nitrobenzyl2'triphenylphosphoranylidene-2-acetate)-2- azetidinone-4-thiolates The crude azetidinones from step d (8.5 g, 10 mmoles) were dissolved in hot methanol (55-60% A hot solution (55-60') of silver nitrate (2.04 9; 12 mmoles) and pyridine (0. 87 g, 11 mmoles) in methanol (80 mi) 60 was added. The mixture was allowed to cool down to room temperature in 2 h and stirred a further 1 h at 0% The silver mercaptide was collected by filtration, washed with ice-cold methanol and then with ether (5.7 g, 82%, melts with decomposition. vc=o 1745,1740,1625 em-' 34 GB 2 042 515 A 34 f) cis and trans 3-Acetoxymethyl-4-azidoacetylthio-l-(p-nitrobenzyl2. triphenylphosphoranylid ene-2acetate)-2-azetidinones The above silver mercaptide (from step e; 1.4 g, 2 mmoles) in dichloromethane (15 m]) treated as described in Example 28 with azidoacetylchloride (2.3 mmoles) gave 0.78 g of a yellow powder.

g) cis and trans 6-Acetoxymethyl-2-azidomethylpenem-3-carboxylicAcidpNitrobenzy1 Esters A solution of the above crude phosphorane (0.70 mg) in toluene (35 m]) was kept at 105'for 1 h, cooled and concentrated to leave an oil which was purified by chromatography over silica gel (25 g) eluting with increasing proportions of ether in benzene. The pertinent fractions were concentrated to give the cis and trans-isomers of the title compound. cis isomer: 8 (ppm, WC13): 8.5-7.5 (4H, aromatics), 5.67 (1H, d,J = 5, H-5),531 (2H,AB quartet, CH2-benzyi), 4.50 (2H,AB quartet, CH2N3),4.33 (2H, d,AcOCH2),4.26 (1H, dt, H-6),2.0 (3H,s, CH3). trans isomer: 6 (ppm,ClDC13): 8.5-7.5 (4H, aromatics), 5.62 OH, d,J = 2, H-5),533 (2H,AB quartet, CH2-benzyI),4.40 (1H, dt, H-6),4.50 (2H,AB quartet, CH2N3),427 (2H, d,AcOCH2),2.0 (3H,s, CH3).

h) trans 6-Acetoxymethyl-2-aminomethylpenem-3-carboxylic Acid Hydrogenation of the above trans isomer by the procedure described in Example 28 gave the title compound. vc=o 1775,1740,1616 cm-1 - Xmax 304 (E = 3192).

0 cis 6-Acetoxymethyl-2-aminomethylpenem-3-carboxylic Acid Hydrogenation of the corresponding cis isomer as described in Example 28 gave the title compound as an unstable hygroscopic semi-solid.

EXAMPLE 16

The following compounds may be prepared according to the general procedure of Example 15.

Y 1 N / X 0 ' CO 2 Y X Z -ell Ch3CO' _C1120"'C 3 C2115COC1 -Cll,O.-c -c,li 5 K_COC1 - CIi 2 0 c COC1 -CE OAC H 2 0 F T\. OCI _Cil OAC if h 1 1 1 '1 2 i 1 -11 3 (C11 2) 2COC 1 -cli 2 OAC - (C)1 2 2"2 11 N (Ch) COC1 -Cil OAC (Cil N111, It 3 2 3 2 2 3 - % 3 1 CH 2) 4COC1 -cm 2 0AC - (C:,) 4 NH 2 H 0 21 ( Cil 2) 3 COC 1 -elf 2 0AC - (CH 2 H elf 3 COCI. -(CH 2) 2 0A.C Cii 3 H (CH 2) 2 0AC ---1 H N 3 CH 2 COC1 (CH 2) 2 0Ac 2 WI Z H :4 3 (C11 2)2 COC L - (CH 2)2 0Ac - (CH 2)2 NB 2 H - (CH 0AC -(C11) NB H 3 (C4 213 COC1 2) 2 2 3 2 CH 3 1 CH 3 COC I: -t:H -0AC -CH 3 R CR 3 N 3 ed 2 Corl C.4 2N112 H 1 L A li EXAMPLE 17 cis andtrans 6-(1 -hydroxy1.ethyl.2-methylpenem-3-carboxylic Acid, Sodium Salts GB 2 042 515 A 35 OH 5 1 (Y = -CH-CH3; X = -CH3) To a solution of 2-m ethyl pene m-3-ca boxyl ic acid (100 mg, 0.54 mmoles) in THIF (8 ml) was added diisopropylamine (0.08 ml, 0.57 mmoles) at 0'and n-butyl lithium (0.75 ml, 1.20 mmoles) at -780. After stirring 2 min at -780, freshly distilled acetylaldehyde (0.5 ml) was added and stirring was continbed for 10 min. The reaction mixture was quenched with a saturated ammonium chloride solution (10 ml) and washed with ethyl acetate. The aqueous layer was acidified with 0.1 N hydrochloric acid (18 ml) and extracted with ethyl acetate (3 X 20 ml). Concentration of the dried ethyl acetate phases left an oil (49 mg). The oil was dissolved in methylisobutyl ketone and treated with an excess of sodium methylhexanoate in the same solvent. Addition of ether precipitated the title compounds as a white amorphous solid (25 mg). 8 (ppm, D20): 5.6-5. 83 (1 H, m, H-5, cis and trans), 2.27 (31-1, s, CH3),1.22 and 0.90 (3H, 2d, CH3)- EXAMPLE 18 cis 6-(1'.Hydroxy1'1.ethyl)-2-methylpenem-3-carboxylic Acid, Sodium Salt (isomer 'Ul 2-Methylpenem-3-carboxylic acid (100 mg) was treated with LDCA and acetaldekyde as described in Example 33. The residue (58 mg), obtained after concentration of the dried ethyl acetate phases, was extracted with ether and the ether solution concentrated to an oil (48 mg). This oil was converted to a sodium salt with sodium methyl hexanoate as described in Example 33. This yielded 29 mg of a white solid which was identified as cis-6-(1'-hydroxy-l'-ethyi)-2-methyl penem-3-carboxylic acid, sodium salt, contaminated 25 with a little sodium 5-methyl-1,3-thiazole-4-caboxylate. 6 (ppm, DIVISO- c16): 5.5 (1 H, cl, J = 4.11, H-5), 2.22 (3H, s, CH30.02'(31-1, cl, J = 5.5, CH2).

EXAMPLE 19 cis and trans 6-(2.Hydroxy-2-propyl)-2-ethylpenem-3-carboxylic Acids, Potassium Salts (Y = (C1-13)2C-; X = -C21-15) 1 OH Substitution in the general procedure of ExampleVorthe 2-m ethyl penem-3- carboxyl ic acid usedtherein of an equimolar amount of 2-ethylpenem-3-caboxylic acid gave a mixture of potassium salts. 8 (ppm, DIVIS0c16): 5.60 and 5.56 (1 H, 2d, J = 4 and J = 2, H-5), 3.92 and 3.60 (1 H, 2d, J = 4 and J = 2, H -6), 2.88 and 2.86 (21-1, 2q, CH2-CH3),1.47,1.41,1.36 and 1,32 (61-1, 4s, CH3),1.2 and 1.4 (31-1, 2t, CH2CH3). km,,x 257 (e = 3705) and 302 (F- = 3815).

EXAMPLE 20 cis andtrans 6-0 -Hydroxy- 1 -ethyl)-2-methoxymethylpenem-3-carboxylic Acid, Sodium Salts To a solution of 2-meth oxym ethyl pen u m-3-ca rboxyl ic acid (see Preparation 6; 116 mg, 0.55 mmoles) in 45 THF (10 ml) was added diisopropylamine (0.08 ml, 0.57 mmoles) atO'and n-butyl lithium (0.75 ml, 1.20 mmoles) at -780. After stirring 2 min at -78o freshly distilled acetaldehyde (0.5 ml) was added and stirring was continued for 10 min. The reaction mixture was quenched with a saturated ammonium chloride solution 0 0 ml) and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (0.1 N, 18 ml) and extracted with ethyl acetate (3 x 20 ml). Concentration of the dried ethyl acetate phases left an oil (53 mg) which was converted to a mixture of the sodium salts of the title compounds described in Example 33. 50 White amorphous hygroscopic powder (21 mg). 6 (ppm, D20): 5.7-5.85 (1 H, m, H-5, cis and trans) 3.38 (3H, 2s, OCH3),1.22 and 0.92 (31-1, 2d, CH3). vc-0 1770,1600 cm-1.

EXAMPLE 21 cis and trans 6-Acetyl-2-methylpenem-3-caraboxylic Acid, Sodium Salts 0 11 (Y = -C-CH3; X = -CH3) 60 To a solution of 2-methylpenem-3-carboxylic acid (100 mg, 0.54 mmoles) in THIF (10 ml) was added diisopropylamine (0.08 ml, 0.57 mmoles at 0'and n-butyl lithium (0.75 ml, 1.20 mmoles) at -78'. After stirring for 2 min at -78', ethyl acetate (1 ml) was added and stirring was continued for 10 min. The reaction mixture was quenched with a saturated ammonium chloride solution (10 ml) and washed with ethyl acetate.65 36 GB 2 042 515 A The aqueous layer was carefully acidified at O'With 0.1N hydrochloric acid and extracted rapidly with ethyl acetate (3 X 20 mi) Concentration of the dried extracts left an oil (36 mg) which was converted to the title compounds as described in Example 33. & (ppm, D20): 5.90-6.10 (1 H, 2d, J = 4, J = 2, H-5),3.8 (1 H, m, H-6 cis and trans, 2.34 and 2.27 (3H, 2s, CH3), 2.12 and 2.0 (3H, 2s, CH3).

EXAMPLE 22

The following compounds may be prepared according to the general procedures of Examples 3-5 and 17-21.

N / 0 - CO 2 z X -CH 3 -Cif 3 -CII 3 -Cl.. 3 -CH 3 _C2 if 5 -c 2 1! 5 _C2 11 5 ---COS -c 6 H 5 c 6 H 5 X n1 X 0 -Cif 2 OCH 3 -CP. 2 OCE 3 -CH 2 OCH 3 -CA 2 LICII 3 -C!I'SCH 1 3 CII 3\ /0 CH 2_ c \"i Y OH 1 -cil-c 6 F. 4-OCE3- 011 1 -Cli-nau 0 11 -C0 -CH2 Of! 011 1 -CflcF 3 -SCH 3 OU 1 -C-CH 3 CI 11 -C-Cli, 011 1 -Cl]-CH 3 -C(Cll 3)2 0 11 -C-Cp. 3 Y CH 1 -Cil - CII 3 011 1 -c (CH 3) 2 OK 1 -C-0 0 0 -C-CH 0 11 -C-0 OH 1 -clic4, OH 1 -C(CH 3) 2 2 K Na ila Na ia K N.

N a K lia K Na pla i4a :c 36 37 GB 2 042 515 A 37 EXAMPLE 23 The following compounds may be prepared according to the general procedure of Example 3 Y I- I 5. n ', / c 5 CO 2 % X Y z 10 OH -H -CACII 3 Na X Y z -11 cH -CA-0 K 011 IN 011 Na 20 0!1 -cl-CF 3 Na -H -C!! 2 0.. N a 25 -H 0 R -C-CF 3 Na -H -H ---1 ---1 -sell 3 OH t 35 -CHCH 3 Na !1 7 -CIL-0 K 0 K 40 __1 -C-elf 3 Na -D 011 1 -CH-CH 3 Va 7!! -C. 2 00 -CH-CH 3 l,' a 45 0 If - C.4 2 00 -Cli-0 K OH 1 - C.4 2 00 -elf (CH 3)2 K 50 EXAMPLE 24 2-(4-Phthalimido- 1 -butyl)penem-3-carboxylic Acid 0 021' C0 SA. H 25 0 2 38 GB 2 042 515 A To a solution of triethylamine hydrosulfide, previously prepared by bubbling H2S gas through a methylene chloride (200 m]) solution of triethylamine (8.8 mi, 63.7 mmoles), was added dropwise a methylene chloride (75 mi) solution of 1 (Gabriel Ber. 41,2010) (10.65 g, 40.2 mmoles), at OOC over a 30 min period. The mixture was stirred at O'C for 15 min and 2 h at room temperature. The Organic solution was diluted with methylene chloride (125 mO and washed with 1 N HCl (2 x 15 mi), water (2 X 15mi) and brine. It was dried over M9S04 and the solvent was flashed down to give 10.5 g (100%) of 2 as a white solid. m.p.: 93-94C n.m.r. (CDC]3) 6 7. 5 - 8 (4H, m), 4.47 (1 H, broad s), 3.5 - 3.9 (2H, m), 2.5 - 2.9 (2H, m), 1.4 - 1.9 (4H, m). Anal. Calc'd for C13H13NO3S; C, 59.29; H, 4.97: N, 5. 32; S, 12.17. Found: C, 58.92; H, 58.92; H, 4.91, N, 5.42; S, 12.31.

*"c I 0.

N'i H 3 0 - dE]N'H 1 10 i A suspension of 2 (3.04 g, 11.6 mmoles) in a solution of M sodium bicarbonate (11.6 mi) was stirred at room temperature under nitrogen for 15 min. To it was added 3 (1.5 g, 11.6 mmoles) and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water and extracted with methylene chloride. The organic phase was dried and evaporated in vacuo to give 3.82 g of solid 4; m.p.: 95-96'C; i.r. (CHC13) 1775,1710 cm-1. n.m.r. 6 7.8 (4H, d, J = 2Hz), 7.05 (1 H, broad s), 5.25 (1 H, dd, Jci, 5Hz, Jt,',,' = 3Hz), 3.5 3.0 (2H, m), 1.5 - 2.0 (4H, m) Anal. Cale'd for: C16HUN204S: C, 57.62: H, 4. 85; N, 8.43; S, 9.64. Found C, 57.43; H, 4.82; N, 8.44; S, 9.71.

38 0 C.4C02C]1 -CO H 2 0 30 6 0 NO i 8, 0-1 0 35 02CI2-N02 A benzene solution (30 mi) of 4 (3.0 g, 9.04 mmoles) and p-nitrobenzyl glyoxalate (2.22 g, 9.8 mmoles) was 40 refluxed under a Dean-Stark condenser filled with 3A molecular sievesfor 21 h. Evaporation of the solvent afforded 5.4 g of 5 as an oil (100%). i.e. (neat) 3200 - 3600,1770,1710, 1525 cm-1 n.m.r. (CDC13) 8 8.21 (2H, d J = 9Hz), 7.75 (4H, d J = 2Hz), 7.52 (2H, d, J = 9Hz, 5.52 (1 H, broad s), 5.32 (3H, 2s), 4.55 (1 H, broad s), 3.5 3.7 (2H, m), 3.45 (1 H, dd Jgem = 15Hz, J,i = 5Hz) 3.02 (1 H, dd, Jg,, = 15Hz, Jtrans = 3Hz), 2.4 - 2.9 (2H, m), 1.4 - 2.0 (4H, m) 45 0 4 r" 0cl C0 2C"2 C0 2CH2-@_% 50 A 6 Azetidinone glyoxalate 5 (4.9 g, 9.05 mmoies) was treated at O'C with thionyl chloride (15 ml) at O'C for 0.5 h and at room temperature for 1 h. The excess of thionyl chloride was codistilled with benzene in vacuo to afford 6as a yellow syrup (5.0 g, 100%) n.m.r. (CDCL3) 6 8.2 (2H, d, J = 9Hz), 7.72 (4H, broads), 7.60 (2H, d, J 55 = 9Hz), 6.1 (1 H, broad s), 5.50 - 5.85 (1 H, m), 5.32 (2H, 2s), 3.4 - 4. 0 (2H, m), 3.1 - 3.3 (1 H, m), 2.8 - 3.05 (1 H, m), 2.50 - 2,85 (2H, m), 1.5 - 1.9 (4H, m).

0 0 - 'S' 1( 101 F71 'g',.)r--- d' "-ycl G f 3 C'2C'I-()-NO 2 C0 2 CH 2-&:02 i 7 39 GB 2 042 515 A 39 A solution of 6(21.69,38.8 mmoles) in tetrahydrofuran (85 mi, distilled over LAH) was treated with triphenyl phosphine(10.2g 38.8 mmoles) and 2.6- lutidine(5.0 mi,42.9 mmoles) for 18 hat 4WC. The mixture was diluted with bezene-ether 1: 1 (30 ml), washed with water, 1 N HCI, saturated Nal-IC03, brine and dried over M9S04. Evaporation of the solvent afforded a dark brown oil. It was passed through a silica gel (700 g) column (benzene-ether) to give 16.0 g (53%) of 7 as a thick oil. NIVIR (CIDC13) 6 8.2 (2H, d, J = 9Hz), 7..8 (8H, cl, J = 2Hz), 7.52 (16H, broad s), 5.2 (1 H, broad s) 4.78 (1 H, 2s), 4.30 4.52 (1 H, m), 3.5 - 3.8 (2H, m), 2.8 - 3.5 (2H, m), 2.1 - 2.9 (4H, m), 15- 1.9 (41-1, m) Q 0 N 0 10 CO 2 CH 2' -o)-'0 C02CK2_@ '4()2 7 9 A solution of phsophorane 7 (5.0 9, 6.4 m moles) in toluene (35 mi) was refluxed for 3 h. Evaporation of the solvent gave a residue which was passed through a silica gel (100 g) colum n. Elution with benzene followed by ether gave 600 mg of the ester 8 as oil i.r. (neat 1790,1710, 1520 cm1 n.m.r. (CIDC13) 8 8.22 (2H, d, J = 9Hz), 7.82 (4H, d, J = 2Hz), 7.65 (2H, d, J = 9Hz), 5.69 (1 H, dd, Jci = 4Hz,---Itrans= 2Hz), 5.35 (2H, 2s), 4.12 (1 H, dd, Jgem = 16Hz, Jcis = 4Hz), 3.50 (1 H, dd, Jgem = 16Hz, Jtrans = 2Hz), 3.1 - 3.8 (2H, m), 2.5 - 3.0 (2H, m). 1.4 - 2.0 20 (41-1, m).

0 0' 0 CO 2:'12 0 a 2 e)2H 25 -g- 8 i Atwo phase mixture made of ester 8 (196 mg, 0.39 mmole) in ether (2 mi), tetrahydrofuran (4 mi) and sodium bicarbonate)32 mg, 0.39 mmoles) in water (2 mi) was hydrogenated on 30% of Palladium on Diatomaceous earth (190 mg) in a Parr shaker at 40 p.s.i. H2. After 4.5 h it was filtered over celite pad and the pad was washed with water and tetra hydrofu ran. The filtrate and washings were combined and the organic phase was separated. The aqueous solution was washed with ether, acidified with 1 N hydr9chloric acid (3 X 0.4 mi) and extracted (after each acid portion added) with ethyl acetate (4 X 2 mi). The organic extracts were 35 washed with brine, dried over M9S04 and the solvent was removed by evaporation to afford the acid 9,67 mg (47%), as a yellow solid. i.r. (nujol) 1775,1705,1690 cm-1. n.m.r. (DMSO) 6 7.92 (4H, s), 5.71 (1 H, dd, J,i - 4Hz,---Itrans= 2Hz), 3.90 (1 H, dd, Jgem = 16 Hz, J,,j, = 4Hz), 3.47 (1 H, dd, Jgem = 16 Hz, Jtrans = 2Hz), 3.3 - 4.3 (3H, m), 2.7 - 3.05 2H, m), 1.5 - 2.0 (41-1, m).

EXAMPLE 25 Sodium 2-(Acetonylmethyl oxime)-penem-3-carboxylate o,jL 3 2 45 c C11 Ci SCOC:11 -C4 50 0 i 2 Ketal 1(2.0 g, 4.54 mmoles) was treated at Wwith 95%TFA (20 cc) for 15 min. The mixture was diluted with brine and extracted with methylene chloride (4 x 30 cc). The methylene chloride extracts were washed with water-brine (3 times) and brine, and dried over M9S04 (1.44 g, 80%). 8 (ppm, CDC13) 8.27 (2H, d, J = 9, Hm 60 aromatic), 8.60 (2H, d, J = 9, Ho aromatic), 5.70 - 5.25 (m, CH2-PNB, H-C-0, H-4, GB 2 042 515 A Cc \ rrj c =C H OH 4.75 (1 H, bs, OH),3.76 (center of ABq, CH2-CO),3.47 (part of a dd,J3- 4cis 5, H-3),3.05 (2H, 2dd,Jg,n, = 15, J3-4trans = 3, H-3),2.30,2.28 (1. 67H, 2s,CH3),1.98 (1.33 H, s, CH3)VC=0 (CHC13) 1780,11755,VN02 1525.

3 CO 2PN13 - -:" d 3 2 3 dlcc)CH O-T-ICH CO 2 PUB 2 3 15 A methylene chloride (50 cc) solution of ketone 2 (1.44 g, 3.63 mmoles) was treated at 0' under nitrogen atmosphere with methoxy amine hydrochloride (334 mg, 1.1. eq).

Triethyl amine (367 mg, 0.51 cc, 1 eq) was then added dropwise to the mixture. ltwas then stirred at room temperature for 18 h. The reaction mixture was diluted with methylene chloride, washed with water-brine (2 20 times), brine and dried over M9S04 (1.52 g, 98%). 6 (ppm, CDC13) 8.12 (2H, cl, J=8, Hm aromatic), 8.40 (2H, d, J = 8 Ho aromatic), 5.50-5.05 (4H, m, CH2-PNB, H-4, H-C-0), 3.80-3.60 (m, OCH3, part of H-3 cis, part of OH), 3.55-270 (m, part of H-3 cis, H-3 trans, CH2CO, Part of OH), 1.97,11.90,1. 88 (314, 3s, CH3) VC=0 (CHC13) 1770, 1750,1690.

f tOCII. 3 25 SCOCH -!-C., ci; 2 3 01i 2 E f,' r 't." Cl C32pr. co,?,:z- 2 4 30 A cold (- 1 WC) THF (20 cc, distilled over LAH) solution of azetidinone 3 (1.52 g, 3.57 mmoles) was treated dropwise with pyridine (325 mg, 0.332 cc, 4.10 mmoles 1.15 eq) and thionyl chloride (488 mg, 0.299 cc, 4.10 mmoles, 1.15 eq) under nitrogen atmosphere. The mixture was stirred for 15 min at -150. The solid was filtered off and washed with benzene. The resulting solution was evaporated down. The residue was taken upon benzene and treated with charcoal (1.2 g, 76%) 6 (ppm, CDC13) 8.23 (2H, d, Hm aromatic), 7.80 (2H, cl, Ho aromatic), 6.12,6.08 (1 H, 2s, H-C-CI), 5. 75 - 5.55 (1 H, m, H-4), 5.40,530 (2H, 2s, CH2-PNB), 3.95 3.80 (3H, 3s, OCH3L3.80 - 2.95 (4H, m, 21-1-3, CH2-CO), 2.00 - 1.85 (3H, 4s, CH3).VC=0 (CHC13) 1790,1765 (shoulder), 1700, VN02 1530.

11 p- - 14---ZCH 3 N c: 1 1-ocm SCO 112-C-C113 SCOC.1 -C-CH 3 --- 2 cl 0 'Err.

COYNB 45 A THF (20 cc, distilled over LAH) solution of chloroazetidinone 4 (1.2 g, 2.70 mmoles) was treated with triphenyl phosphine (1.06 g, 4.05 mmoles 1.5 eq) and 2,6-lutidine (318 mg, 0.346 cc, 2.97 mmoies, 1.1 eq). The mixture was stirred for 4 days at room temperature under nitrogen atmosphere. It was diluted with ethyl acetate, washed with 2% aqueous HCl, H20.2% aqueous Nal-IC03, water and brine. The solution was then dried over M9S04 and the solvent was evaporated. Crude 5was purified on silica gel (10 times by weight) column (ethyl acetate, 770 mg, 45%).

vc=O(CHC13)1755,1695,Y1630-1610,VNO2 1525.

1 3 C02 ? '52 it 50..

tg;- H 3 SCOCH 2-C-CP 3 J1 9. cc" 1 CH 2-C- c13 T.1------E.

0 :27" I 41 GB 2 042 515 A 41 Phosphorane 5 (700 mg, 1.05 mmole) was refluxed in toluene for 4.5 h. Toluene evaporation afforded a residue which was passed through a silica gel (1: 15 ratio) column (4% ether-benzene). It gave 6 as a crystalline material (251 mg, 62%, m.p. 116-125). Anal. caic'd for C17H17N306S: C, 52. 17; H, 4.38; N, 10.74. 5 Found: C, 51.15; H, 4.18; N, 10.33. 8 (ppm, CDC13) 7.70 (2H, cl, Hm aromatic), 7.12 (2H, cl, Ho aromatic) 5.00 (2H, s, CH2PN13), 4.85 (1 H, m, H-5), 3.75 - 2.70 (7H, m, CH30, CH2, H-6),1.77,1. 72,1.65 (3H, s, CH3). vc=o (CHC[3) 1787, 1742, 1705, YN02 1530. U.V. (EtOH) krnax 318 (e = 8420) 262 (E = 12,539).

dfTll- CH2-C-CH 3 C02"S 2 i Ch 2-'-: 4 3 0 '2 4' A mixture of ester 6 (151 mg, 0.386 mmole) in THF (20 cc) ether (40 cc) and NaHCO3 (32 mg, 0.381 mmole) in water (20 cc) was shaken in a Parr hydrogenator for 3 h at 35 p.s.i. H2, using 30% Pcl on celite (200 mg) as catalyst. The catalyst was filtered off and washed with water and ether. The resulting aqueous mixture was washed with ether (3 x 60 cc) and lyophilized (32 mg, 30%). 6(ppm, DIVISO) 5.50 (m, H-5),3.75 (s, OCH3),037 20 (s, CH3). YC=0 (nujol mull) 1770,1600,1400. U. V. (H20) rnax 300 (F- = 2, 800) 255 (c = 2,400).

EXAMPLE 26

The following 2-penem compounds may be prepared by acylation of 1 -(pnitrobenzyloxycabonyimethyitriphenyl-phosphoranyl)-4-(silver mercaptidyi)2-azetidinone with the approp- 25 riate acylating agent followed by cyclization and deblocking steps. The general reaction scheme is shown below:

0 0 SCOP.

--- or 30 IMC P 0 0---, r 3 2. RCOC1j - - P03 C02 P1W co,ptlB S 6 R CO 2 ': " "':3 c '1 1-71 - / p CO 2' forvariationl: useRC02H + iBuCOC1 forvariation2: useHCI + PC15 + RC02H li 2 /301 Pd/diatomaceous earth Acylating Agent Method Product 50 OCH20CONH-(CH2)47CO2H 2-(4-Aminobutyi)penem-3- carboxylic acid CH3 55 OCH20CONH-CH-CO2H 2-(1-Aminoethyl)penem-3 (both D and L) carboxylic acid CH2CH3 60 1 OCH20CONH-CH-CO2H 2-(1-Aminopropyi)penem-3 (both D and L) caboxylic acid 142 GB 2 042 515 A 42 CH3 1 CH-CH3 1 OCH20CONH-CH-CO2H 1 2-(1-Amino-2-methylpropyi) (both D and L) penem-3-carboxyli.c acid _ 0 1 OCH20CONH-CH-CO2H 1 2-(1-Aminobenzyi)penem-3- 10 (both D and L) carboxylic acid CH20 1 OCH20CONH-CH-CO2H 2-(1-Amino-2-phenylethyi)- 15 (both D and L) penem-3-carboxylic acid CH20CH20-NOz-p 1 OCH20CONH-CH-CO2H 1 2-(1 -Amino-2-hydr-oxyethyi)- 20 (both D and Q penem-3-carboxylic acid CH2CO2CH20-NOz-p 1 OCH20CONH-CH-CO2H 1 2-0 -Amino-2-caboxyethyl)- 25 (both D and L) penem-3-carboxylic acid CH2CONH2 1 OCH20CONH-CH-CO2H 1 2-(1-Amino-2-carbamoylethyi)- 30 (both D and Q penem-3-carboxylic acid CH2CH2SCH3 1 OCH20CONH-CH-CO2H 1 2-0 -Amino-3-methylthio pro pyl). 35 (both D and Q penem-3-carboxylic acid (CH2)4NI-ICO2CH20 i OCH20CONH-CH-CO2H 1 2-(1,5-Diaminopentyi)penem- 40 (both D and L) 3-carboxylic acid CH3 1 OCH20CONCH2CO2H 2-[(Methylami no) methyl] penem45 3-carboxylic acid CH3 OCH20CONCH2CH2CO2H 2-[M ethyl am i no)ethyllpenem-3-carboxylic acid Acylating Agent Method Product CH3 55 OCH20CONCH2CH2CH2CO2H 2-[3-(Methylamino)propyll- penem-3-carboxylic acid CH3 60 1 OCH20CONCH2CH2CH2CH2CO2H 2-[4-(methylamino)butyll penem-3-carboxylic acid 43 C2H5 1 OCH20CONCH2CO2H C.B 2 042 515 A 43 1 2-[(Ethylamino)methyllpenem3-carboxylic acid C2H5 1 - OCH20CONCH2CH2CO2H 2-[2-(Rhyl am i no)ethyll penem- 3-carboxylic acid C2H5 1 OCH20CONCH2CH2CH2CO2H 1 C2Hs 1 OCH20CONCH2CH2CH2CH2CO2H 0 1 OCH20CONCH2CO2H 0 OCH20CONCH2CH2CO2H 1 1 2-[3-(ethylamino)propyllpenem-3-carboxylic acid 2-[4-Ethylamino)butyllpenem-3-carboxylic acid 2-[(Phenyla m i no)m ethyl)penem-3-carboxylic acid 2-[2-(Phenylamino)ethyllpenem-3-carboxylic acid 0 1 OCH20CONCH2CH2CH2CO2H 2-[3-(Phenylamino)propyll penem-3-carboxylic acid 0 35 1 OCH20CONCH2CH2CH2CH2CO2H 2-[4-(Phenylamino)butyll penem-3-carboxylic acid CH3CONHCH2CO2H 2-[(Acetylamino)methyll- 40 penem-3-carboxylic acid CH3CONHCH2CH2CO2H 2-[2-(Acetylamino)ethyll penem-3-carboxylic acid 45 CH3CONHCH2CH2CH2CO2H 2-[3-(Acetylamino)propyll penem-3-carboxylic acid Acylating Agent Method Product 50 CH3CONHCH2CH2CH2CH2CO2H 1 2-[4-(Acetylamino)butyll penem-3-carboxylic acid C6H5CONHCH2CO2H 1 2-[(Benzoylamno)methyllpenem-3-carboxylic acid C6H5CONHCH2CH2CO2H 1 2-[2-Benzoylamino)ethyll penem-3-carboxylic acid 60 C6H5CONHCH2CH2CH2CO2H 1 2-[3-(Benzoylamino)propyi penem-3-carboxylic acid C6H5CONHCH2CH2CH2CH2CO2H 1 2-[4-Benzoylamino)butyll penem-3-carboxylic acid 65 44 GB 2 042 515 A OCH20CONHCH2CONHCH2CO2H 1 44 OCH20CONHCH2CONHCH2CH2CO2H 1 OCH20CONHCH2CONHCH2CH2CH2CO2H 1 2-[(Glycinamido)methyllpenem-3-carboxylic acid 2-[2-(Glycinamido)ethyllpenem-3-carboxylic acid 2-[3-(Glycinamido)propyllpenem-3-carboxylic acid OCH20CONHCH2CONI-ICH2CH2C1-12- 1 2-[4-(Glycinamido)butyll- 10 CH2CO2H penem-3-carboxylic acid H2NCONHCH2CO2H 2-(Ureidomethyi)penem-3 carboxylic acid 15 H2NCONHCH2CH2CO2H 2-(2-Ureidoethyi)penem-3 carboxylic acid H2NCONHCH2CH2CH2CO2H 1 2-(3-Ureidopropyi)penem-3 carboxylic acid H2NCONHCH2CH2CH2CH2CO2H 1 2-(4-Ureidobutyi)penem-3 carboxylic acid Acylating Agent Method Product 25 CH3NHCONHCH2CO2H 2-[(Methylcarbamoylamino) methyl] penem-3-caboxylic acid CH3NHCONHCH2CH2CO2H 2-[2-(Methylearbamoylamino)- 30 methyl] penem-3-carboxyl ic acid CH3NHCONHCH2CH2CH2CO2H 2-[3-(Methylearbamoylamino propyllpenem-3-carboxylic acid 35 CH3NHCONHCH2CH2CH2CH2CO2H 1 2-[4-(Methycarbamoylamino) butyllpenem-3-carboxylic acid ONHCONHCH2CO2H 1 2-[(Phenylcarbamoylamino) methyl] penem-3-ca rboxyl ic acid 40 ONHCONHCH2CH2CO2H 2-[2-Ph enylca rba m oyl amino) ethyl) penem-3-ca rboxyl ic acid x ONHCONHCH2CH2CH2CO2H 2-[3-(Phenylcarbamoylamino)propyllpenem-3-carboxylic aid ONHCONHCH2CH2CH2CH2CO2H 1 2-[4-(Phenylcarbamoylamino) butyllpenem-3-carboxylic acid 50 CH3CONHCONHCH2CO2H 1 2-[(Acetylcarbamoylamino) methyl] penem-3-carboxyl ic acid CH3CONHCONHCH2CH2CO2H 1 2-[2-(Acetylcarbamoylamino) ethyl] pen em-3-ca rboxyl ic acid CH3CONHCONHCH2CH2CH2CO2H 1 2-[3-(Acetylcarbamoylamino) propyllpenem-3-carboxylic acid CH3CONHCONHCH2CH2CH2CH2CO2H 1 2-[4-Acetylcarbamoylamino)butyllpenem-3-carboxylic acid OCONHCONHCH2CO2H 1 2-[(Benzoylcarbamoylamino) methyl] penem-3-ca rboxyl ic acid (CH3)3Si(CH2)20CONHCONHCH2CH2CH2CH2CO2H CH3S2CNHCH2CO2H 1 GB 2 042 515 A 45 Acylating Agent Method Product OCONHCONHCH2CH2CO2H 2-[2-(Benzoylcarbamoylamino ethyl] penem-3-carboxylic acid OCONHCONHCH2CH2CH2CO2H 1 2-[3-(Benzoylcarbamoylamino) propyi)penem-3-carboxylic acid OCONHCONHCH2CH2CH2CH2CO2H 1 2-[4-(Benzoylcabamoylamino) butyll-penem-3-carboxylic acid 10 CH30CONHCONHCH2CO2H 1 2-[(Carbomethoxycarbamoy] amino) methyl] penem-3 carboxylic acid CH30CONHCONHCH2CH2CO2H 1 CH30CONHCONHCH2CH2CH2CO2H 1 2-[2-(Carbomethoxycarbamoyiamino)ethyllpenem-3.carboxylic acid 2-[3-(Carbomethoxycarbamoyl amino)propyllpenem-3carboxylic acid CH30CONHCONHCH2CH2CH2CH2CO2H 1 2-[4-(Carbomethoxycarbamoyi amino)butyi)penem-3- 25 carboxylic acid (CH3)3Si(CH2)20CONHCONCH2CO2H 2-[(2-trimethyisilylethyloxy carbonylcarbamoylamino) methyl] penem-3-carboxyl ic acid 30 (CH3)3Si(CH2)20CONHCONHCH2- 2-[2-(2-tri m ethylsi lyl ethyl CH2CO2H oxycarbonylcabamoyiamino) ethyl] pen em-3-ca rboxyl ic acid 35 (CH3)3Si(CH2)20CONHCONHCH2- 2-[3-(2-tri m ethylsi ly] ethyl CH2CH2CO2H oxycarbonylcarbamoylamino) propyllpenem-3-carboxylic acid Acylating Agent Method Product 40 2-[4-(2-Trimethyisilylethyioxycarbonylearbamoylamino)butyllpenem-3carboxyli c acid 2-[(Methyithiothiocarbonylamino)methyi]penem-3carboxylic acid CH3S2CNHCH2CH2CO2H 2-[2-(Methyithiothiocarbonyiamino)ethyllpenem-3 carboxylic acid CH3S2CNHCH2CH2CH2CO2H 1 2-[3-(Methyithiothiocarbonyiamino)propyllpenem-3carboxylic acid CH3S2CNHCH2CH2CH2CH2CO2H 1 2-[4-Methylthiothiocarbonyl amino)butyl)penem-3 carboxylic acid 60 CH3S02NHCH2CO2H 1 2-[(Methanesuifonylamino)methyl] penem-3-ca rboxyl ic acid 46 GB 2 042 515 A 46 CH3S02NHCH2CH2CO2H 2-[2-(Methanesuifqnylamino)ethyl] penem-3-ca rboxyl ic acid CH3S02NHCH2CH2CH2CO2H 2-[3-(Methanesuifonylamino)- 5 propyllpenem-3-carboxylic acid CH3S02NHCH2CH2CH2CH2CO2H 1 2-[4-(Methanesuifonylamino) butyllpenem-3-carboxylic 10 - acid OS02NHCH2CO2H 2-[(Benzenesuifonylamino) methyl] penem-3-carboxyl ic acid 15 Acylating Agent Method Product S 11 20 H3CNHCNHCH2CH2CO2H 1 2-[2-(N-Methyithiocarbamoyl amino)ethyllpenem-3 carboxylic acid S 25 11 H3CNHCNHCH2CH2CH2CO2H 1 S 11 H3CNHCNHCH2CH2CH2CH2CO2H 1 S 2-[3-(N-Methyithiocarbamoyia mi no) propyl 1 penem-3carboxylic acid 2-[4-N-Methyithiocarbamoyl amino)butyllpenem-3carboxylic acid Ii ONHCNHCH2CO2H 2-[N-Phenylthiocarbamoy]am i no) methyl] penem- 3carboxylic acid S 11 ONHCNHCH2CH2CO2H 1 2-[2-(N-Phenyithiocarbamoyiamino)ethyllpenem-3 carboxylic acid 45 S l ONHCNHCH2CH2CH2CO2H 1 2-[3-N-Phenyithiocarbamoy]- amino)propyllpenem-3- 50 carboxylic acid S il - ONHCNHCH2CH2CH2CH2CO2H 1 2-[4-(N-Phenylthiocarbamoyiamino)butyllpenem-3 carboxylic acid -1r-NliCH 2 CO 2 It tio ' it -0 'N 1 2-[(Guanylamino)methyll- penem-3-carboxyic acid 60 CH CO \=CII H 2 2 2 1 2-[2-(Guanylamino)ethyll- penem-3-carboxylic acid 65 1 11 47 GB 2 042 515 A 47 2 2CH2 21' 2-[3-(Guanylamino)propyll- 1 CH co do, 10 penem-3-carboxylic acid Acylating Agent Method Product 5 11 NHCH 2 CH 2 C11 2 CH 2 co H 1. 1 2 ll, 1 2-[4-(Guanylamino)butyil penem-3-carboxylic acid 10 -0 0 i---CH 2 CO 2 H 1 2-[(Acetimidoylamino)methyi)w penem-3-carboxylic acid 15 -CH2CH2CO2H 2-[2-(Acetimidoylamiho)ethyll penem-3-carboxylic acid 20 -CH2CH2CH2CO2H 2-[3-(Acetimidoylamino)propyi) penem-3-carboxylic acid -CH2CH2CH2CH2CO2H 1 2-[4-(Acetimidoylamino)butyll penem-3-carboxylic acid 25 0 N - h 1 2-[(Formimidoylamino)methyll- C.4 2 penem-3-carboxylic acid 30 -CH2CH2CO2H 1 2-[2-(Formimidoylamino)ethyll penem-3-carboxylic acid -CH2CH2CH2CO2H 1 2-[3-(Formimidoylamino)propyll35 penem-3-carboxylic acid -CH2CH2CH2CH2CO2H 1 2-[4-(Formimidoylamino)butyllpenem-3-carboxylic acid 02NCH2CO2H 2-[(Hyd roxyam ino) methyll penem-3-carboxylic acid 02NCHACH2CO2H 2-[2-(Hydroxyamino)ethyll penem-3-carboxylic acid 45 02NCH2CH2CH2CH2CO2H 2-[4-(Hydroxyamino)butyll penem-3-carboxylic acid Acylating Agent Method Product 50 1 OCH3 - i (CH3)3Si(CH2)20CON-CH2CO2H 1 2-[(Methoxyamino)methyll penem-3-carboxylic acid 55 OCH3 1 (CH3)3Si(CH2)20CON-CH2CH2CO2H 1 2-[2-(Methoxyamino)ethyll penem-3-carboxylic acid 60 OCH3 1 (CH3)3Si(CH2)20CONCH2CH2CH2CO2H 1 2-[3-(Methoxyamino)propyll penem-3-carboxylic acid 65 48 GB 2042515 A (CH3)3Si(CH2)20CONCH2CH2CH2CH2C(1H ' 1 48 2-[4-(methoxyamino)butyllpenem-3-carboxylic acid NI-12 5 1 (CH3)3Si(CH2)20CONCH2CO2H 2 2-[(Hydrazino)methyllpenem- 3-carboxylic acid NH2 10 1 (CH3)3Si(CH2)20CONCH2CH2CO2H 2 2-[2-(Hydrazino)ethyllpenem3-carboxylic acid NH2 15 1 (CH36Si(CH2)20CONCH2CH2CH2CO2H 2 2-[3-(Hydrazino)propyllpenem 3-carboxylic acid NH2 20 1 (CH3)3Si(CH2)20CONCH2CH2CH2CH2CO2H 2 2-[4-(Hydrazino)butyllpenem N(C1-13)2 3-carboxylic acid 25 1 (CH3)3Si(CH2)20CONCH2CO2H 2 2-[2,2-Dimethyihydrazino) N(C1-13)2 methyl] penem-3-carboxylic acid 30 1 (CH3)3S!(CH2)20CONCH2CH2CO2H 2- 2-[2-(2,2-Dimethyihydrazino) N(CH3)2 ethyl] penem-3-carboxyi ic acid 35 i (CH3)3Si(CH2)20CONCH2CH2CH2CO2H 2 2-[3-(2,2-Dimethyihydrazino) propyllpenem-3-carboxylic acid 4n N(C1-13)2 1 (CH3)3Si(CH2)20CONCH2CH2CH2CH2CO2H 2 2-[4-(2,2-Dimethyihydrazino)- use tri methyl silylethyl instead of PNB in azetidinone butyllpenem-3- carboxylic acid 45 intermediate and deblock with F- Acylating Agent Method Product so CH3CONHNHCH2CO2H 2 2-[(2-Acetyihydrazino)methyll penem-3-carboxylic aid CH3CONHNHCH2CH2CO2H 2 2-[2-(2- Acetylhydrazino) ethyl penem-3-carboxylic acid 55 CH3CONHNHCH2CH2CH2CO2H 2 2-[3.-(2-Acetyihydrazino) propyllpenem-3-carboxylic acid CH3CONHNHCH2CH2CH2CH2CO2H 2 2-[4-(2-Acetylhydrazino)- 60 butyllpenem-3-carboxylic acid (CH3)2NCH2CO2H 2 2-[(Dimethylamino)methyll penem-3-carboxylic acid 49 GB 2 042 515 A 49 (CH3)2NCH2CH2CO2H 2 2-[2-(Dimethylamino)ethyll penem-3-carb'oxylic acid (CH3)2NCH2CH2CH2CO2H 2 2-[3-(Dimethylamino)propyll penem-3-carboxylic acid 5 (CH3)2NCH2CH2CH2CH2CO2H 2 2-[4-(Dimethylamino)butyll penem-3-carboxylic acid CH3 10 CH3C0 1 NCH2CO2H 1 2-[(N-Methylacetamido)methyll penem-3-carboxylic acid CH3 15 CH3C0 1 NCH2CH2CO2H 1 2-[2-(N-Methylacetamido)ethyll CH3 penem-3-carboxylic acid 1 CH3CONCH2CH2CH2CO2H 1 2-[3-(n-Methylaceta m ido) pro pyl 20 penem-3-carboxylic acid CH3 CH3C0 1 NCH2CH2CH2CH2CO2H 1 2-[4-(N-Methylacetamido)butyl 25 penem-3-carboxylic acid Acylating Agent Method Product 0 CH CO H 1 2-[(Phtha 1 i m ido) methyl] penem- 30 2 2 3-carboxylic acid 0 35]-cif CH CO 2 1 2-[2-(Phthalimido)ethyllpenem-3-carboxylic acid 0 CH H 1 2-[3-(Phthalimido)propyll- 40 2C:112C02 P-C'2 penem-3-carboxylic acid 0 -Cillcit C!! CH cc h 2-[4-(Phthaiimido)butyll- 45 2 2 2 2 penem-3-carboxylic acid OCH20CONHCH2CH2OCH2CO2H 1 2-Am i noeth oxy)m ethyl 1penem-3-carboxylic acid OCH20CONHCH2CH2SCH2CO2H 1 2-[(2-Am i noethylth io)m ethyl] penem-3-carboxylic acid 55 C02CH20 1 OCH20CONHCH2CH2NCH2CO2H 1 2-[(2-Aminoethylamino)methyll penem-3-carboxylic acid 60 CH3 1 OCH20CONHCH2CH2NCH2CO2H 2 2-[N-(2-Aminoethyl)-N- methylaminol methyl penem-3 carboxylic acid 65 GB 2 042 515 A 50 1SCII 2 WONH-G-li,Co,It 2-(p-Aminobenzyi)penem-3- carboxylic acid CH 2 CO 2 H 5 OCIf 2 0CONli: 2-(o-Aminobenzyi)penem-3- carboxylic acid 10 OCH 20CONHJ/ -0.4 2-(p-Aminophenyi)penem-3caboxylic acid CO 2 - 15 OCH 2 C>CON]i2-(m-Aminophenyi)penem-3 carboxylic acid Acylating Agent Method Product CO 2 H 2-(o-Aminophenyi)penem-3- OCH 2 0CONH carboxylic acid 25 OCH 2 0CONHCH 2 _WC0,1 2-[p-(Am i nom ethyl) phenyl]penem-3-carboxylic acid cl 2 11 OCH 0CONNU 5, 2 2-[m-(Amino methyl) phenyl] penem-3-carboxylic acid CO 2 JC!i CCOMICII- 2-[o-(Ami nomethyl) phenyl]penem-3-carboxylic acid EXAMPLE 27 The 2-penem products listed below as the triethylamine salts are treated with (CH3)3N.SO3 in CH2C12 solution at C Addition of sodium 2-ethyfhexanoate in 1-butanol to the reaction solution results in precipitation of the indicated products as disodium salts.

Starting Material Product 5 [--f- 50 0 0 CO 2N (C 2 H 5)3 55 Exp. A n = 1 A. n=l Exp. B n = 2 B. n=2 Exp. C n = 3 C. n=3 60 Exp. D n = 4 D. n=4 v 51 GB 2 042 515 A 51 EXAMPLE 28

The following 2-penem products maybe prepared from the indicated starting materials by the procedure --S 0 0 5 C.M 2),,N (C.4 CH 1 /1 (CH2) 2 4 (Ca 3)3 1 3 2 CO,PN3 C02 MB 5 10 H 2 /Pd (CH 2) n"4CH3) 3 [i E) tt 0 CO 2 G Starting Material Exp. A n = 1 Exp. B n = 2 Exp. C n = 3 Product (Cli,),,N (CH 3 CO,PNB Exp. D n = 4 (D (CR 2) n tl (CII 3)3 CO 2 0 A. n=l B. n=2 C. n=3 D. n=4 EXAMPLE 29 The following 2-penem products may be prepared from the indicated starting materials by the procedure SAg SCO(C.4) cl Cl (CH nCOCI 2 n 35 -t" F, P03 "v p ' 3 C02 PNB CO 2 P1:8 40 S (CII (C'i,) 2' nC1 :1 Nal 0 P. ' 11 COPNB C02 pt4B 45 deblocking deblocking (CII 2) J1 (C112) -N 50 CO 211 Starting Material Product -S 1/ 55 2 n 2 cc),p.j3 0 \ co,e Exp. A n = 1 A. n=l 60 Exp. B n = 2 Exp. C n = 3 Exp. D n = 4 D. n=4 65 52 GB 2 042 515 A 52 EXAMPLE 30 The following 2-penern products may be prepared from the indicated starting materials by the procedure F-7 5 0 0 0 0 SC- (C11 2)-C-R TFA SC-(C112),-C-R H OH 0 0 Y CO 2Z CO 2 z 10 0 H 2 NB R 1 sc- (elf 2)m-C-R OH Y 15 C02Z it B 1, SC- (C" 2)M-C-R 20 SOC1 2 1. 3 21 E Cl 2.. 1 - Y C02Z 25 S tin - 11 - (elf 2),-C-R F CO 2 30 -C-R 35 0 CV1 m 0-2 Z -(CH2)2Si(CH36 40 R = H, CH3 B = -O(CH2)2Si(CH3)3 Starting Material Product 0 F-] GH 45 0 p 5 5-C tCH) -,:-R.1 Oil 2 m (CH 2),,-C-11 co,it CO 2 PN B 50 Exp. A R= H,m =0 A. R= H,m =0 Exp. B R = H,m = 1 B. R= H,M= 1 55 Expl. C R = H,m =2 C. R = H,m =2 Exp. D R = CH3r M = C) D. R = C H 3, M = 0 Exp. E R = CH3, M = 1 E. R = CH3, m = 1 60 Expi. F R = CH3,m =2 F. R = CH3, m = 2.

Substitution in the above procedure of H2NOCH3 forthe H2NO(CH2)2Si(CH3)3 used therein results in formation of the following products. 1 65 53 GB 2 042 515 A 53 NOCH PN 1 3 (C4 2),,-C-R CO 2.4 5 Exp. A m=O, R=H Exp. B M=1, R=H Exp. C m=2, R=H 10 Exp. D M=O, R=CH3 Exp. E M=1, R=CH3 15 Exp. F m=2, R=CH3 Substitution in the above procedure of (CH3)3Si-(CH2)20CONHNH2 for the E12NO(CH2)2Si(CH36 used therein results in formation of the following products.

(CH,)M-C CO 2 H NNH U 2 25 Exp. A m=O, R=H Exp. B m=l, R=H Exp. C m=2, R=H 30 Exp. D M=O, R=CH3 Exp. E m=l, R=CH3 35 Exp. F m=2, R=CH3 Substitution in the above procedure of (CH3)2NNH2 for the H2NO(CH2)2Si(CH3)3 used therein results in formation of the following products:

MN (CH) 40 j 3 2 (CH,)MC-R C02a Exp. A M=O, R=H 45 Exp. B m=l, R=H Exp. C m=2, R=H 50 Exp. D M=O, R=CH3 Exp. E - m=l, R=CH3 Exp. F m=2, R=CH3 55 Substitution in the above procedure of 54 GB 2 042 515 A 54 0 1 (CH3)3Si(CH2)20CON-NH2 for the H2NO(C1-112)2Si(CH36 used therein results in formation of the following products:

Exp. A Exp. B Exp. C Exp. D Exp. E Exp. F EXAMPLE31 - 5 M10 11 )M- (CH C-R 2 CO,H m=9, R=H m=l, R=H m=2, R=H m=O, R=CH3 m=l, R=CH3 m=2, R=CH3 SAS 0 1 C:02p;3 1 2 C:'2n - C1COCH 2CH2C 1 ii 2 Iii A solution of/ (1.1 g, 1.6 mmole) and 11 (0.16 mL 1.6 mmole) in methylene chloride (30 ml) was cooled in an ice bath and treated dropwise with 1 M solution of pyridine in methylene chloride (1.7 mi, 1.7 mmole). The resulting reaction mixture was stirred at room temperature for 1 h and then filtered over celite and washed with methylene chloride. The filtrate and washings were combined and washed successively with 1 N HCI (5 mi), water (5 mi), 1 M NaHC03 (5 mi) and brine, and then dried (M9S04) and evaporated in vacuo to give 111 900 mg (87%) as an amorphous solid. It was used in the next step withoutfurther purification. IR (CHC13) 1755,1690cm-1.NMR(CDC13)68.22(2H,d,J=9Hz),7.55(15H,m),6.72(2H,d,J=9Hz),5. 7(1 H,m),5.0(2H, 40 2s), 3.55 (21-1, 2s), 2.8 (4H, m).

'-it 2C J-f-- PO 3 Y C0J43 ill 1 ' (>--0)3p -- IV 3 '112 ""- --- 0 If P.3 C027"' v A mixture of 111 (1.3 g, 2 mmoles) and 1V (0.65 mi, 3 mmoles) was heated at WC for 4 h. The reaction mixture was diluted with methylene chloride (10 mi) and washed with water (2 x 5 ml). Organic layer was dried (M9S04) and evaporated in vacuo to give V, 1.4 g (90%), as an amorphous solid. It was used in the next step without further purification. M (CHC13) 1755,1690 cm-1 NW(MC13) 68. 25 (2H, cl, J=9 Hz), 7.55 (15 H, m), 6.8 (21-1, cl, J =9 Hz), 5.7 (1 H, m), 5.1 (2H, 2s), 4.72 (21-1, dq J=1 2 Hz, J=6 Hz), 2.6 (4H,m), 1.4 (6H, s), 1.28 (61-1, S).

s'-t (0 2 0 03 C!2p"M v 11 1S L-<) 2 0 C0 2P" v 1 GB 2 042 515 A 55 A solution of V (1.6 g, 2.06 mmoles) in toluene (60 mi) was heated under reflux for 5 h.

The solvent was evaporated in vacuo and the residual oil was chromatographed on silica gel column (30 g). Elution with benzene followed by ether removed first upolar material and then ethyl acetate gave V1, 620 mg (62%) as a white solid, m.p.: 83-4'C from ether.

IR (CHC13) 1790,1710 em-' NMR: (CIDC13) 6 8.2 (2H, cl, J =9 Hz), 7.6 (2H, cl, J=9 Hz) 7,5 (2H, s) 5.65 (1 H, dd, 5 ---Itrans= 4 Hz, Jcis = 2 Hz), 5.22 (2H, 2s), 4.75 (2H, dq J= 12 Hz, J =6 Hz), 3.85 (1 H, dd, Jgem 15 Hz, Jtrans = 4 Hz), 3.5 (1 H, dd, Jgem 15 Hz, J.

i = 2 Hz), 2.8-3.3 (2H, m), 1.4 (6H, s), 1.28 (6H, s).

2 - - - ---------- P.:y 10 C0 2P""' V1 Vil C0211 To a solution of V1 (200 mg, 0.4 mmole) in tetrahydrofuran (8 mi) and ether (4 mi) was added sodium bicarbonate (34 mg, 0.4 mmole) water (4 m]) and 30% Pd/Celite (200 mg) followed by hydrogenation 2h at40 15 p.s.i. The mixture was filtered and layers were separated. The aqueous phase, after washing with methylene chloride (2 x 5 mO, was cooled with ice, acidified with 1 N HCl (1 mO, and extraced with chlorofrom (5 x 5 mi). Organic extracts were dried (M9SO4) and evaporated in vacuo to give V11, 76 mg (52%), as an oil.]R (CHC13) 1790,1710 em. NMR (CDC13) 6 9.5 (1 H, ws), 5.65 (1 H, dd,---Itrans= 4 Hz, Jci = 2 Hz), 4.72 (2H, dq J= 12 Hz, J=6 Hz), 4.2-5.1 (2H, m), 3.44.1 (2H, m), 23-3.4 (2H, m), 1.35 (6H, s), 1.25 (6H, s).

EXAMPLE 32

S --,,W C025 25 9 9 3 CIC(CH 2)3p0C2fS)2 30 cc,i V3 rS 3p C2H5) 2 p 3 3 C02---' To a cooled (ice bath) mixture of 1 (1.324 g, 2 mmolesi) and 2 (0.54 g, 2. 2 mmoles, crude) in CH2C12 (15 M0 was added dropwise 1 M solution pyridine/CH2C12 (2.2 mi, 2.2 mmoles). The mixture was stirred at r.t. for 1 h and filtered over celite. The filtrate was washed successively with 0. 5N HCI, H20,0.5 M NaHC03 and brine. It was dried (M9S04) and filtered over celite charcoal to give after evaporation of dryness 0.9 g of an oil. The oil 40 was chromatographed on Si02 (10% H20) and eluted with ethylacetateto give 0.5 g of 3.(32.8%). NIVIR 6 (ppm, CDC13) 7.0-8.4 (m, 19H), 4.8-5.8 (3H, m), 4.1 (4H, q), 3.34.2, (2H, m) 2.7 (2H, m), 1.9 (2H, m), 1.3 (6H, t).

0 0 F- W ' 3 45 C0 2P'1B 7T_ 5 0 2p'S i 50 3 (0.4 g, 0.52 mmole) in toluene (35 mi) was refluxed for 4 h and evaporated to dryness to give an oil which contained 3,4 and 1)2P0. This was chromatographed on Si02 (10% H20) and eluted with EtOAc to give 0.1 g of pure 4, followed by 0.15 g of 3 and 4. NMR 6 (ppm, CDC13). 8.3 (2H, d), 7.67 (2H, d), 5.7 (H, q), 5.33 (2H, d), 4.2(4H,q),3.83 (H,q),3.4(H,q)2.9(2H,m), 1.9(2H,m) 1.3(6H,t). IR (neat) 1790cm-1 (P-Iactam) 1710cm-1 55 (ester).

PIR - gGEt) 2 i (OEC:N C3 a 2 56 GB 2 042 515 A 56 A mixture of 4 (0.1 g, 0.207 mmole), 30% Pd/celite (0.1 g) and NaHC03 (17 mg, 0.207 mmole) in THF (10 mi), ether (5 m]) and Water (5 mO was hydrogenated at an initial pressure of 40 psi for 2 h. ltwas filtered over celite and the layers separated. Basic aqueous layer was washed well with ethylacetate and acidified with 1 NHCI. It was extracted with CH2C12 and dried (M9S04). The CH2C12 solution was evaporated to give 48 mg of 5 5 (66.5%). IR spectrum 6 1790 (P-Iactam) 6 1700 0 11 (-C-OH).

EXAMPLE33

9 ' 0,1 2 C, 2' 9 __c:; + (14e01 3;' -J- G5, 5 Na 2 20 A mixture of 1 (1.07 9,1.66 mmole) and 2 (0.42 9,3 mmoles) in CH2CL2 (3 mi) was heated at 80'for 5 h. The crude oil was chromatographed on Si02 (3% H20) and eluted with ether, eth e r-ethyl acetate (1: 1) and ethyl 25 acetate: 5% ROH to give 1.0 g of 3 (82%). The oil crystallized on standing, M.P. (ether) 138-40'. NIVIR 6 (ppm, CDC13) 8.2 (2H, d) 7.0-8.0 (17H, m), 4.6-5.5 (3H, m), 3.8 (3H, s), 3.6 (3H, s), 1.5-3.5 (6H, m).

2 0 30 i 3 (0.5 g, 0.69 mmole) in toluene (30 ml) was refluxed for 4 h. It was evaporated to dryness, chromatographed on Si02(3% H20) and eluted with Et20: EtOAc (1:1)foliowed byEtOAc: 10% E10Hto give 35 0.18gof4(58%).NMR6(ppm,CDCL3),8.25(2H,d),7.6(2H,d),5.65(H,q),5.3(2H,d),3. 8(3 H,s)3.6(3H,s), 2.7-3.6 (2H, m), 15-2.5 (4H, m).

40 1 45 a mixture of 4 (50 mg, 0.112 mmol), NaHC03 (9.125 mg) and 30% Pd/celite (50 mg) in THF (5 ml), Et20 (2.5 ml) and water (2.5 ml) was hydrogenated at an initial pressue of 40 psi (for 2 h). It was filtered over celite, and 50 the layers separated. The basic aqueous layer was washed well with EtOAc and Iyophilized under high vacuum to give 28 mg of 5.(75.9%) (hygroscopic). IR (KBr) 1770 cm-1 (P- lactam), 1610 cm-1 (-COO-).

EXAMPLE 34 (1W,5R,6R) and (l'S,5S, 6S)6-(1 -Hydroxy1.ethyl)-2-methylpenem3- caboxylic Acid (isomerD) (illustrates 55 most preferred process of introducing 6-substitutent in mid-synthesis 60 K A. Preparation of 4-Tritylthio-2-azetidinone Intermediates 1. 1(Trimethylsilyl)-4-tritylthio-2-azetidinone 57 0 3 GB 2 042 515 A 57 SCO 3 i Ef, :1, 5 1 (M ) 3 A solution of 4-trityithio-2-azetidi none (345 mg, 1 mmole), 1,1,1,3,3,3,- hexamethyidisilazane (80 mg, 0.5 mmole) and chlorotrimethylsilane (55 mg, 0.5 mmole) in dichloromethane (20 mi) was heated under reflux for 18 h. Concentration of the reaction mixture left virtually pure title compound. 8 (ppm, WC13): 7.32 (15H, m, aromatics), 4.22 (1 H, dd, H-4), 2.67 (1 H, dd, J = 4.1, J = 16, H-3), 2.22 (1 H, dd, J = 2.2, J = 16, H-3), 0.3 (91- 1, 10 s, CH3).

2. 1-(t-Butyldimethylsilyl)-4-tritylthio-2-azetidinone SC:4. 3 Jil.

C:,3 -H of:,C 3 fl- CH 3 C ':H 313 Triethylamine (1.62 mi, 11.6 mmoles) was added dropwise in 5 min to a cooled (0') and stirred solution of 4-tritylthio-2-azetidinone (3.5 g, 10.1 mmoles) and chloro-tbutyidimethyisilane (1.68 g, 12.7 mmoles) in DIVIF 20 (35 ml). The reaction mixture was stirred at room temperature for 18 h, diluted with water (250 mi) and ether (200 mi). The organic phase was washed with water (3 X 50 ml), dried and concentrated to leave an oil (4.33 g). Crystallization from pentane gave a total of 4.1 g (89%) of the title compound as a white solid, m.p. 113-40.

6 (ppm, WC13): 7.45 (15H, m, aromatics), 4.2 (1 H, dd, H-4), 2.63 (1 H, dd, J = 4, J = 16, H-3),2.13 (1 H, dd, J = 2, J = 16, H-3),1.0 (91-1, s, t-Bu), 0.35 (6H, s, Me). vc=o 1735 cm-1. Anal. Calc'd for C281-133NOSSi: C, 73.15; H, 7.24; N, 3.05; S, 6.97%. Found: C, 73.27; H, 7.32; N, 2.97; S 6.94%.

3. 1-Methoxymethyl-4-tritylthio-2-azetidinone 51-1 3 0 J- N', H A solution of 4-tritylthio-2-azetidinone (1.38 g, 4.0 mmoles) in THF (10 mi) was added to a well stirred 35 suspension of sodium hydride (200 mg of commercial 50%,4A mmoles, washed with pentane) in THF (10 ml) maintained at -15'. Methanol (12 drops) was added and the mixture was stirred at -15'for 0.5 h.

Methoxymethyl bromide (0.58 g, 4.6 mmoles) was added and the mixture was stirred for 2h, diluted with ether washed with water and brine, dried and concentrated to leave an oil (1.72 g). Crystallization from pentane gave a white solid (1.41 9) m.p. 72-76 6 (ppm, CDC13): 7.3 (15H, m, aromatics), 4.4 (31-1, m, NCH20 and 40 H-4), 3.22 (31-1, s, CH3), 2.76 (21-1, m, H-3).

4. 1-(Methoxyethoxymethyl)-4-tritylthio-2-azetidinone To a suspension of tetrabutylammonium bromide (322 mg, 1 mmole) and potassium hydroxide (85%,70 mg, 1.1 mmole) in dichloromethane (10 mi) cooled to 50 was added with vigorous stirring 4-tritylthio-2azetidinone (345 mg, 1 mmole) and m ethoxyethoxym ethyl chloride (187 mg, 1.5 mmole). The mixture was stirred at room temperature for 2 h, the solvent was evaporated and the residue partitioned between water and ethyl acetate. The dried organic phase was concentrated to leave a viscous oil (415 mg). Purification by column chromatography on silica gel eluting with ether (5%)-dichloromethane gave the title compound (206 mg, 48%) as an oil. 6 (ppm, CDC13): 7.30 (15H, m, aromatics), 4.57 (21-1, AB quartet, N-CH20),4.46 (1 H, dd, H-4),3.50 (41-1, s, OCH2CH20),320 (31- 1, s, CH3),235 (21-1, m, H-3).

5. 1-(2-Tetrahydropyranyl)-4-tritylthio-2-azetidinone C3 , Er, ', -, 'r% 1 C r-, "i 58 GB 2 042 515 A n-Butyl lithium (1.6M, 1.6 mi, 2.56 mmoles) was added dropwise to a solution of 4-trity[thio-2-azetidi none (863 mg, 2.5 mmoles) in THF maintained at -78'. After stirring for 15 min, 2-chlorotetrahydropyran (560 mg, 4.7 mmoles) was added and the reaction mixture was allowed to come to room temperature in 1.5 h. The reaction solution was diluted with ethylacetate, washed with brine, dried and concentrated to leave an oil (635 mg). Column chromatography on silica gel eiuting with dichloromethane-ether gave a mixture of the isomeric title compounds contaminated with a little starting material. 6 (ppm, C13C13): 7.28 (15H, m, aromatics), 4.4 (H, dd, H-4),2.9-2.2 (2H, m, H-3),M-3.2 and 2.2-0.7 (tetrahydropyranyl).

B. Preparation of3-(1'1-Hydroxy-l-ethyl)-1-methoxymethyl-4-tritylthio-2azetidinones 10 sc 58 a) WS,3SAR and 1'R,3R,4S)isomer (isomer Q A solution of lithium diisopropyl amide was prepared in THF (5 mi) at - 78'C from n-butyl lithium (1.6M, 1.0 mi, 1.6 mmol) and diisopropylamine (0.25 mi, 1.84 mmol). After 30 mina solution of 1-methoxymethyl-4 tritylth io-2-azetid in one (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% HCI and extracted with ethyl acetate (5 x 20 mi). The combined organic phases 20 were washed with brine, dried and concentrated to leave an oil which crystallized upon trituration with ether:

440 mg, 80%, mp 188.5-9'C; 1 Hmr (CDCI,3, M.3- (15H, m, aromatics), 4.37 (2H, ABq, N-CH20),432 (1 H, cl, J=2, H-4), 3.17 (3H, s, OCH3), 3.32-2.70 (2H, m, H-3 nd H-5), and 1. 12 ppm (3H, d, J=7, CH3); Anal. calcd for C26H27 N 03S: C 72.02, H 6.28, N 3.23, S 7.39; fo u n d: C 71.99, H 6.02, N 3.2 1, S 7.40%.

b) (1S,3S,4R and 1W,3R,4S) and (1W,3S,4R and 1S,3R,4S) (isomers C and B).

A solution of lithium diisopropyl amide (0.482 mmol) is prepared at -780C in dry ether (3 mi) from butyl lithium 0.191 mi 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 (411 and 4S) 1-methoxymethyi-4-trityithio-2azetidinone (0.171 g, 0.439 mmol) in a 30 mixture of dry ether (1 ml) and dry THF (1 mi) was added dropwise and the resulting clear solution was stirred at -78'C for 15 min. A solution of tetrabutyl ammonium fluoride (0,96 mi 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 -78'C, the reaction mixture was quenched with freshly distilled acetaldehyde (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 35 chloride and extracting with ethyl acetate (2 x 25 ml). The combined 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 10 g of silica gel A mixture of benzene and ethyl acetate (M) gave 0.106 g (62% 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 g, 17%) was 40 identical to the above isomer (isomer C): mp 188.5-189'C (Ether-dichloromethane); The alcohol with low Rf (0.030 g, 16%) (isomer B), was obtained as an oil which crystallized with difficulty from hexanes: mp 94-950C. ir (CH2C12) Ym,,x: 3600 (OH), 1760 cm-1 (C=O); 'Hmr (CDC13) 6:6A-7.5 (15H, m, aromatics), 4.2 (2H, center of ABq, J=1 1.5, CH20-CHA4.28 (1 H, d, J=2.0,4-H), 3.65 (1 H, center of a broad sextet, H-1% 3.3 (1H, dd, J3,4trans 45 = 2.5,J3,1'= 5.5, H3),115 (3H, s, O-CH3),1.55 (1H, broads, CH-1% 1.05 (3H, d, J=6.5, H-2'); Anal. calcd for C26H27NO3S: 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%.

C. Preparation oftrans3-Acetyl-l-methoxymethyl-4tritylthio-2-azetidinone 0 ' - >C:

LDA ci 3 50 3 Lithium diisopropylamide was prepared under nitrogen atmosphere at -78'C in the usual manner from 55 diisopropylamine (0.34 mi, 2.4 mmol) and n-butyl lithium (1.1 mi of a 2. 2M solution in hexane, 2.4mmol) in THF (3 mi). A solution of 1-methoxymethyi-4-tritylthio-2-azetidinone (0. 78 g, 2 mmol) in THF (3 mi) was added dropwise and, after stirring at -78'C for 20 min, ethylacetate (0. 53 9, 6 mmol) was added in one portion and stirring continued for 0.75 h at -78'C. 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 benzene. The pertinent fractions were concentrated to give the title material as a coloriess oil (0.32 g, 37%); 'Hmr (CDC13) 6: 73-6.8 (15H, aromatics), 4.85 (1 H, d, J=2, H-4),4.5 (2H, s, N-CH2-0),3.9 (1 H, d, J=2, H-3),122 (3H, s, CH.) and 2.0 ppm (3H, s, CH3); irv,a>,: 1770, 1710 cm-1.

59 GB 2 042 515 A 59 D. Preparation oftrans3-Acetyl-l-(t-butyldimethylsilyl)-4-tritylthio-2- azetidinone 0 C 3 LOA SC41 3 00L EtOAc 3 NN t-B t" it-i!u "312 -(CH 3)2 5 Diisopropyl lithium amide was prepared in the usual manner from diisopropylamine (0.18 mi, 1.24 mmol) and n-butyl-lithium (0.78 mi of a 1. 6M solution in hexane, 1.24 mmol) in THF (8 m]). A solution of 1-(t-butyl d i methylsi]yi)-4-trityith io-2-azetid i none (0.46 g, 1 mmol) in THF (8 ml) was added dropwise at -78'C. After a 5 min stirring period, ethyl acetate (1 mi) was added in one portion and the mixture was stirred 3 h at -78'C. The mixture was acidified with cold hydrochloric acid (0.5N) to pH 6 and extracted with ethyl acetate (2 x 20 mi) ' The combined organic phases were dried and concentrated to give an oil (0.5 g) which crystallized from pentane: 200 mg iotal, 40%; mp 1224C; ir Yniax: 1750,1710 cm-l; 11-1mr (CDC13) 6: 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, CH3),0.92 (9H, s, Bu and 0.3 ppm (6H, s, CH3).

E. Preparation oftrans-l-(t-Butyldimethylsilyl)-3-formyl-4-tritylthio-2azetidinone 5"3 3 "f, S' C" 3) 20 To a cooled (-78'C) solution of diisopropylamine (0.34 m], 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-butyidimethyisiiyi)-4-trityithio-2-azetidinone (1.0 g, 2.18 mmmol) in tetrahydrofuran (5 m]) was added dropwise and stirring was maintained for 30 min. Ethyl formate (0.8 m], 9.9 mmol) was added and the cooled solution was stirred for 10 min. The 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 (M9S04), evaporated and crystallized from pentane to give 810 mg (76%) of formate as a white solid mp 1320C; ir (CI-IC13)VIIX: 1760,1715cm-1; 'Hmr(CDC13)8: 9.0 (1H,d,J=1.25 Hz),730 (15H, m),4.7 (1H,d,J=1.5Hz) and 3.5ppm(1H,t,J=1.5Hz). 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 A c) ethyl formate was stirred at room temperature with K2C03, then distilled over P205 d) n-BuLi was titrated with 1N hydrochloric acid F. Preparation of 1-(t-Butyldimethylsilyl)3-(1'1-hydroxy-l-ethyl)-4tritylthio-2-azetidinone s. (4 isomers).

Z11 7: 3 C! -c -t3 tb, "S 45 12 2 n-Butyllithium (1.6M, 3.4 mi, 5.44 mmol) was added in 5 min to a solution of diisopropylamine (0.847 mI, 6.23 mmol) in THF (30 mi) maintained at -780C. After 0.5 h a solution of 1-(t-butyidimethyisiiyl)4-trity[thio-2- azetidinone (2.0 g, 4.4 mmol) in THF (20 mi) was added; after 15 min acetaidehyde (10 mi) was added in one portion; after another 15 min water (100 mi) was added. The mixture was acidified (pH 5-6) with dilute hydrochloric acid and extracted with ethyl acetate (3 x 30 mi). The organic phases were washed with brine, dried and concentrated to leave an oil which was found to consist to a mixture of four isomers by tic (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 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 -78'C, the relative proportions of A,13,C, and D were: 12.9,30.5,38.2 and 18.4%. In ether, when the reaction was allowed to come to 20'C 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 60 changed to: 19.2,19.7,30.1 and 31%. IsomerA: This isomer possesses a cis-stereochemistry at C3-C4. it is a racemic mixture composed of the (1's, 3R, 4R) and the V11, 3S, 4S) enantiomers. Compounds later derived from compound A are referred to as 1somer A". They consist of an enantiomeric mixture and possess the same configuration at CV,C3 and C4. 65 Compounds derived from compound A, through a reaction that proceeds with inversion of configuration, GB 2 042 515 A will be referred to as 1somer W if the inversion takes place at C,, and as "isomer W for the inversion, at C3 mp 1152-WC; 'Hmr(CDC13) 6: 8.0-6.8 (15H, m, aromatics), 4.30 (1 H, d,J=5.5, H-4),3.78 (1 H, m, H-1'),3.10 (1 H, dd,J=5.5,J=10, H-30.22 (3H, d,J=6.5, CH3),0.95 (9H,s, Bu),027 (6H,2s, CH3).Anal, calcd for: C301-137NO2Si: C 71.52, H 7.40, N 2.78, S 6.36%. found: C 71.28, H 7.41, N 2.48, S 6.19%.

Isomer& This isomer posseses atrans-stereochemistry at C3-C4. It is a racemix mixture comosed of the WF1,3SAR) and the WS,3RAS) enantiomers. Compounds with the same configuration at C,,, C3 and C4 are referred to as 1somer W; ir (CHC13) Vmax: 1745 cm-1 (C=O); mp 158-9'C; 'Hmr (C13C13) 6: 7.60-7.10 (15H, m, aromatics), 4.02 (1 H, cl, J=0.8 H-4),3.32 OH, dd, J=3.0, J=0.8, H-3),3.55-3.15 (1 H, m, H-1% 0.88 (12H, CH3, andt-Bu),0.16(6H,s,CH3); IsomerC.. This isomer possesses a trans-stereochemistry at C3-C4. It is a racemate formed of the WS,3SAR) and the WMIRAS) enantiomers. Compounds with the same configuration at C,,, C3 and C4 are referred to as "Isomer C-. mp 134-WC; 11-1mr (CDC13) 6: 7.60-7.10 (15 H, m, aromatics), 4.32 (1 H, d, J=1.8, H-4),3.02(1H,dd,J=2.7,J=1.8,H-3),3.0-2.5(1H,dq,J=2.7,J=6,H-1'),1.02(3H,d, J=6,CH3),0.95(9H,s, 15 t-BU), 0.27 (6H, s, CH3); ir (CHC13) Vmax: 1735 cm-1 (C=O).

IsomerD: This isomer possesses a cis-stereochemistry at C3-C4. It is a racemate composed of the WIR,31RAR) and the WS,3SAS) enantiomers. Compounds with the same configuration at C,,, C3 and C4 are referred to as---IsomerW'. mp 171-2'C; Hmr (CDC13): 7.80-6.90 (15H, m, aromatics), 4.70 (11H, d, J=4.5, H-4), 3.02(1H,dd,J=4.5,J=0.5,H-3),2. 39(1H,dq,J=0.5,J=6.5,Hl'),1.0(3H,d,J=6.5,CH3),0.97(9H,s,t-Bu), 0.32 (6H, si, CH3). Anal. calcd for C301-137NO2SSi: C71.52, H 7.40, N 2.78, S 6.36%. found: C 71.27, H 7.43, N 2.51, S 6.31 %.

IM' OH scl 2 trans isomers A solution of trans 3-acetylA -(t-butyl di methyl-si lyl)-4-tritylth io-2- azetidi none (1.0 g, 2 mmol) in THF (30 ml) was added dropwise, under a nitrogen atmosphere, to a cooled (0') and stirred suspension of sodium borohydride (0.38 g, 10 mmol) in THF (120 ml). 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 (M). 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 119-121'C; 84%.

- 10 c j 0 \ C'!3 t-3.

Isomer B Asuspension of cuprous iodide (4.789,15 mmol) in ether(50 mi) was cooled to WC and treated underN2, 45 with a 1.9 M solution of methyl lithium (26 mi, 50 mmol).The brown solution was stirred atO'Cfor10 min andthen cooledto -60'Candtreated dropwise with the trans 1-1(t-butyl dimethylsilyl)-3-formyl-4-trityithio- 2-azetidinone (2.43g, 5.0 mmol) in a mixture oftetra-hydrofuran (10 mi)lether(40 mi). Stirring was continued for 3 h. The solution was warmed up to -40'C 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 50 ammonium chloride (3 x 5 mi) and then brine and dried over sodium sulfate. Filtration and evaporation gave alcohol, isomer B, which crystallized from warm pentane to yield 1.6 9 (65%), mp 160-YC; ir (CHC13) Ymax:

1730 cm-l; 11-1mr (CDC13) 6: 7.32 (15H, m), 4.05 (1 H, s), 3.4 (1 H, d, J=31-IZ, 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) tetrahydrofu ran and ether were distilled over L.A.H.

b) methyl lithium was titrated with 1 N hydrochloric acid c) copper(]) iodide was purified by continuous extraction with anhydrous tetrahydrofuran in a Soxhiet extractor for 18 h, then dried under vacuum in a dessicator- W205) for 18 h.

1 61 d) '' --SC3 0 14,SM2 tN ' tau 011 '3 3 c,, 1 tau Methylmagnesium iodide (0.1 ml,O.1 mmol) was added dropwise to a cooled (OOC) and stirred solution of trans 1-(t-butyl-di methylsi lyl)-3-fo rmyl- 4-tritylth io-2-azetidi none (25 mg, 0.05 mmol) in THF (2 ml). The solution was stirred 1.5 h at O'C, poured onto an ammonium chloride solution, acidified with a hydrochloric acid solution (1N) 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 (1S,3S,4R and 11R,3R,4S) 1-(t-Butyldimethylsilyl)-3-(1trimethyl-silyloxy-l'-ethyl)-415 trityfthio-2-azetidinone (isomer Q OM --,C 3 0 -b 1 C63 GB 2 042 515 A 61 A solution of (1'S,3S,4R and 1'R,3R,4S)1-(t-butyldimethylsilyl)-3- (l'hydroxy-l'-ethyl)-4-tritylthio-2azetidinone (15 mg, 0.3 mmol) and azidotrimethylsilane (35 mg, 0.30 mmol) in dry THF (6_ml) was stirred at room temperature until disappearance of the starting material (15 min). Purification of the reaction mixture by column chromatography (silica gel, CH2Cl2) gave the desired compound as a white solid (128 mg, 74%) mp 144-46'C, 'Hmr (CDC13) 6: 7.10-7.60 (15H, m, aromatics), 4.30 (11-1, d, J=1.5, H-4),2.25-2.89 (21-1, m, H-3, 25 H-l'), 0.82-1.07 (12H, m, t-Bu, H-2'), 0.27 (61-1, s, CH3),-0-10 (9H, s, 0-Si(CH3)3; ir (CHC13) vmax: 1736 cm-1 (C=O). I G. Preparation of (1S,3R,4R and 1W,3S,4S) 1'(t-Butyldimethylsilyl)-3-(1'1. methoxymethoxy ether- l-ethyl)- 4-tritylthio-2-azetidinone (isomerA).

0:

I.J.

c.. 1, i 1p32 L-BU ri20CH3 Sco -si 1 t-B.

n-Butyllithium (ca 12.5 mi of 1.6M solution in hexane, 20 mmol; just enough to obtain a permanent pink coloration) was added dropwise to a solution of (VS, 3R, 4R and VIR,3S, 4S) 1 -(t-B utyidi methyl si lyl)-3-(V hydroxy-l'-ethyl)-4-trityithio-2-azetidinone (isomer A) (10.1 g, 20 mmol) in THF (100 mi) maintained at -78'.

After a 15 min stirring period a solution of b ro mom ethoxym ethyl ether (2 mi, 24 mmol) in THF (30 mi) was added dropwise. The mixture was stirred 1 h at -78'and 2 h at room temperature and poured into an 40 ammonium chloride solution (200 mi). Extraction with ethyl acetate (3 x 200 mi), washing with brine, drying with sodium suffate and concentration gave the crude title compound which was purified by chromatogra phy on silica gel eluting with increasing amounts of ether in benzene (10. 4 g 95%). 11-1mr (CDC13) 6: 7.1-7.5 (1 5H, m, aromatics), 4.47 (1 H, d, H-4),4.23 (21-1, ABq, J=7, O-CH2-0), 11-3.4 (21-1, rn, H-3 et WV) 3.23 (31-1, s, O-CH30.37 (31-1, d,J=6.5,CH3),0.97 (9H,s, Bu) and 0.25 ppm (6H, 2s, CH3).

H. Preparation of (l'S,3S,4R and 1W,3R,4S) 1-(t-Butyldimethylsilyl)-3-(1formyloxy-l'-ethyl)-4-tritylthio-2azetidinone (isomer Q 0 51,4_ - 0 3 n 4A solution of WS,3S,41R and VIR,31R,4S) 1 -(t-butyidimethyisiiyi)-3-(1'hydroxy-l'-ethyi)-4-tritylthio-2- azetidi none (isomer c) (50 mg, 0. 1 mmol), p-bromobenzenesu Ifonylch loride (100 mg, 0.4 m mol) and 55 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 (M9S04) and evaporated. The title compound was purified by column chromatography. 'Hmr (CDC13) 6: 7.80 (1 H, s, CHO), 7.20-7.66 (15H, m, aromatics), 3.90-4.36 OH, rn, H-1'),4.07 (1H, d,J=2, H-4),122 (11-1, broads, H-3),1. 18(3H,d,J=6.5, H-2% 1.0 (9H,s,t-Bu), 60 0.31 (6H, s, di-CH3).

62 GB 2 042 515 A 62 1. Preparation of (M,3S,4R and l'S,3R,4S) 1'(t-Butyldimethylsilyl)-3-1. acetoxy-l-ethyl-4-tritylthio-2azetidinone (Isomer B) ST d + 1 0Ac A'20 Tr p y,jde G U15 4_ A solution of (VR,3S,4S and VS 3R 4S) 1 -(t-butyidimthyisiiyl)-3-(1'hydroxy-l'-ethyi)-4-tritylthio-2- azetidinone (13.85 g, 27.5 mmol) in pyridine (75 mi) acetic anhydride (50 m[) (prepared atO') was stirred at room temperature for 40 h. The reagents were evaporated off (the last traces being removed azeotropically with toluene 3 times) leaving a nearly white solid. Crude derivative was crystallized from an ether-petroleum ether mixture to give pure title compound (97.5%). 11-1mr (CDC13 6: 7.64-7.03 (15H, m, H aromatic), 4.60 (1 H, m,J=6,H-1'),3.92(1H,d,J=2,H-4),3.55(1H,dd,J=2,J=6,H3),1.79(3H,s,CH3CO),0.98 (3H,d,J=6,CH3), 0.88(9H,s,t-butyi),0.12(6H,s,CH3);ir(CHC13)Vmiax:1775,1740crn-1(C=O) J. Preparation of 1-(t-Butyldimethylsilyl)-3-(1'paranitrobenzyldioxvcarbonyl)- 1 -ethyl)-4-tritylthio-2azetidinone. (4 isomers) 2 ---IsomerC- n-Butyl lithium (8.8 m 1 of 1.6 M solution in hexane, 14 mmol; just enough to obtain a permanent pink coloration) was added dropwise to a solution of 1somer W of 1-(tbutyidimethyisiiyl)-3-(1'-hydroxy-l'- 25 ethyi)-4-trityithio-2-azetidinone (6.55 g, 13 mmol) in THF (70 mi) maintained at -780C. After a 15 min stirring period a solution of paranitrobenzyl chloroformate (3.2 g, 14.8 mmol) in THF (30 mi) was added dropwise.

The mixture was stirred 1 h at -78'C and poured into an ammonium chloride solution (100 mi). Extraction with ethyl acetate (3 x 100 mi) washing with brine, drying and concentration left 11 g of crude material. The pure title compound was obtained by chromatography on silica gel (220 g) eluting with increasing amounts 30 of ether in benzene. 93%, mp 118-9'C (ether); 'Hmr (CDC13) 6: 8.35-7 (19H, m, aromatics), 5.12 (2H, s, benzyl), 4.08(1H,d,J=1.8,H-4),4-3.5(1H,dq,J=6.5,J=2,H-1'),3.10(1H,dd,J=2,J=1.8,H3),1.2(3H,d,J=6.5,CH3), 1.0 (9H, s, Bu) and 0.30 ppm (6H, 2s, CH3); ir (CHC13) 6max 1745 cm-1 (C=O); AnaL calcd for C:38H42N206SiS: C 66.83, H 6.20, N 4.10, S 4.69; found: C 66.90, H 6.26, N 4.11, S 4.59.

---1somerB-The -Isomer W' of 1 -(t-butyidimethylsiiyl)-3-(1'-hydroxy-l'ethyi(-4-tritylthio-2-azetidinone, treated as described above gave pure 1somer W' of 1 -(t- butyidimethyisiiyi)-3-(1' paranitrobenzyidioxycarbonyl-l'-ethyl)-4-trityithio-2-azetidinone as a foam, 95%. 11-1mr (CDC13) 6: 8.32-6.90 (1 9H, m, aromatics), 5.1 (2H, s, benzyO, 4.65-4.20 (1 H, m, H-1'), 3.97 (1 H, d, J = 1.5, H-4),3.58 (1 H, dd, J= 1.5, J=5.8, H-3),1.1 (3H, d, CH3), 0.7 (9H, s; Bu and 0.2 ppm (6H, s, CH3); ir (film) vmax: 1755,1740 cm-1 C=O.

---1somerA---The1somer A'of 1 -(t-butyl d i m ethylsi lyl-3-(V-hyd roxyl'-ethyi)-4-trityith io-2-azetid i none, tre ated as described above gave pure 'Isomer X' of 1-(t-butyidimethylsilyl-3(1'-paranitrobenzyidioxycarbony]- 1'-ethyi)-4-tritylthio-2-azetidi none as an oil. 95% 'Hmr (CDC13) 6: 83-6. 7 (19H,'m, aromatics), 4.95 2H, ABq, benzyi). 4.53 (1 H, p, J=7.5, J=7.5, WV_ 4.31 (1 H, d, J=6, H-4),332 (1 H, dd, J=6, J=7.5, H-3),1.44 (3H, d, J=6.5),0.95 (9H, s, tBu) and 0.2 ppm (6H, 2s, CH3).

---IsomerD- Likewise 'Isomer W of 1-(t-butyidimethyisiiyi-3-(1'-hydroxyl'-ethyi)-4-trityithio-2-azetidinone, gave pure 'Isomer W' of 1-(t-butyidimethyisilyi)-3-(1'paranitrobenzyidioxycarbonyl-l'-ethyi)-4-trit ylthio-2- azetidinone, 90%. 'Hmr (CDC13) 6: 83-6.7 (19H, m, aromatics), 5.20 (2H, ABq, benzyi),4.72 (1H, d,J=5, H-4), 3.50 (1 H, dq, J=6.5, J=0.5, H-1% 2.85 (1 H, dd, J=0.5, J=5, H-3),1.03 (3H, d, J=6.5, CH3), 1.0 (9H, s, t-Bu) and 0.35 ppm (6H, s, CH3); mp 130-20C. Anal. calcd for C 66.83, H 6.20, N 4. 10, S 4.70; found: c 66.56, H 6.28, N 3.96, S 4.89.

K. Preparation of (l'S,3S,4R and 1W,3R,4S) 1-(t-Butyldimethylsilyl)-3(1'1-methane-sulfonyloxy-l.ethyl)-4- 55 tritylthio-2-azetidinone (Isomer Q J I.' 'MY 2 3 3)2 A solution of (VS,3S,4R and 1'R,3R,4S)-1-(t-butyidimethyisilyl)-3-(1'hydroxy-l'-ethyi)-4-trityithio-2- azetidinone (Isomer C) (2.0 g, 4 mmol) in dichloromethane (80 ml) was treated at 5'C, with methanesulfonyl chloride (0.99 g, 8.6 mmol) and triethylamine (0.87 g 8.6 mmol). After stirring at that temperature for 1 h under N2, the solution was washed with brine, dried (MgSO) and evaporated to dryness. After crystallization 65 63 GB 2 042 515 A 63 from ether-pet-ether, 1.9 g (81.9%) of mesylate was obtained. mp 120-220C, 11-1mr (CDC13) 6: 7.13-7.61 (15H, m, aromatics), 4.50 (1 H, d, J=2, H-4), 3.62 (1 H, del, J=6.5,2, H-1% 2.96 (1 H, dd,J=2,2, H-3),2.84 (3H, s, methanesulfonyl), 1.22 (3H, cl, J=6.5, H-2'), 0.99 (9H, s, Si-t-Bu) and 0. 30 ppm (6H, s, Si-(C1-13)2); iryrnEi. (CHC13):1746 (C=O), 1343 and 1180 em-' (S02).

L. Preparation of (1R,3S,4R and l'S,3R,4S) 1-(t-Butyldimethylsilyl)-3(1'methane-sulfonyloxy- l.ethyl)-4tritylthio-2-azetidinone (Isomer 8) OH 0 0 SC't- JIN, A solution of WIR,3SAR and VS,3MS) 1-(t-butyidimethyisiiyi)-3-(1'-hydroxy- l'-ethyl)-4-trityithio-2azetidinone (Isomer B) (5.03 g, 10 mmol), methanesulfonylchloride (2.52 9, 22.0 mmol) and triethylamine (2.23 g, 22.0 mmol) in CH2C12 (200 mi) was stirred at 5'C 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 9,93%) mp 127-31'C. 11-1mr (C13C13) 6: 7.20-7.63 (15H, m, aromatics), 4.51 (1 H, del, J=5.0-6.2, H-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 (3H, s, -CH30.01 (3H, d, J=6.2, H-2'), 0.90 (9H, s, t-Bu), 0.12 (6H, s, -CH3); ir (CHC13) vmax: 1745 em-' (C=O).

M. Preparation (l'S,3S,4R and 1W,3R.4S) 3-(1'-p-Bromobenzenesulfonyloxyl'.ethyl)-1-(tbutyldimethylsilyl)-4-tritylthio-2-azetidinone (Isomer Q OH OSO 2 ---0 3 3 0 A solution of (l'S,3S,4R and VIR,31R,4S) 1-(t-butyidimethyisiiyl)-3-(1'- hydroxy-l'-ethyi)-4-trityithio-2azetidinone (Isomer C) (2.5 g, 5 mmol) in dry THF (100 mi) was cooled to 78T and treated with 2.52M butyllithium/hexane (2.38 mi, 6 mmol). After 3-4 min p- bromobenzenesuifonylchloride (1.53 9,6 mmol) dissolved in THF was added dropwise. The solution was stirred at -78'C for 3 h and then allowed to come to room temperature. Then the solvent was evaporated and the desired product purified by column chromatography (silica gel, CH2C12) (3.36 9,94.6%) mp 142-44C; 'Hmr(CDC13) 67.68 (4H, s, benzenefulsonyl), 7.28-7.60 (15H, m, aromatics), 4.59 (1H, d, J=l, H-4), 3.68 (1H, del, J=6.2, H-1'), 2.99 (1H, dd,J=1.8, 2.0, H-3),1.18 (3H, d, J=6.2, H-2'), 1.08 (9H, s, t-Bu), 0.40 and 0.38 (6H, 2S, -CH3); ir (CHC13) vmax: 1749 em (C=O).

N. Preparation of (l'S,3R,4R and 1W,3S,4S) 3-(1'-Methoxymethyl- l-ethyl)4-tritylthio-2-azetidinone (isom- erA).

OCH2DCH3 OCH2OCH3 sc 3 Q l -51 fl"C 1 '1'2 fl 1 t [!U 45 A cold OC) HIVIPA-1-120 (116 mi-13 mi) solution of lsomerA of 1 -(t-butyl d i methyl 1 si lyl)-3-(V- methoxym ethyl'-ethyi)-4-trityith i o-2-azetid i none (119, 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 was then poured into cold water (1.3 t) and dried. The title compound recrystallized from ethyl acetate-hexanes (7.2 g, 83%) as a white 50 solid mp 173-1740C. 11-1mr (CDC13) 6: 7.10-7.(15H, m, aromatics), 4.85 (2H, ABq, J=7.4, O-CH2-0),4.53 (1H, cl, J=5.2,H-4),4.42(1H,s,N-H),4.15(1H,m,H-1'),3.5(1H,m,H-3),3.47(3H,s,O-CH3), 1.5 (3H,d,J=6,CH3)-ir (KBr) Vmax: 3400-3500 (N-H) and 1760 em-' (C=O).

0. Preparation of (1S,3S,4R and 1W,3R,4S) 3-(1-Methoxymethyloxy-l'ethyl)4-tritylthio-2-azetidinone 55 (Isomer Q ON lX, ( OCH 2 OCP. 3 J. STr BIC1120CH, si + NaN3 dE -1 H 11 60 A cold (dry ice-acetone bath) solution of (VS,3S,411 and VIR,31R,4S) 1-(t- butyidimethyisiiyi)-3-(1 -'-hydroxy-l'- ethyl)-4-tritylthio-2-azetidinone (5.03 g, 10 mmol) in THF (50 mi, distilled over LAH) was treated dropwise with a 1.6M solution of n-butyl lithium in hexane (13.0 mi) until a pink coloration persisted. ATHF (20 mi) solution of bromomethyl methylether (1.49 g, 0.97 mi, 1.19 mmol) was added dropwise. The mixture was 65 64 GB 2 042 515 A 64 stirred at -780C for 30 min and for a 3 h period at O'C. It was poured in an ice cold ammonium chloride solution and extracted with ether. The ether extracts were combined, washed with water, dried (M9S04) and concentrated to give crude (VS,3S,4R and VR,3R,4S) 1-(tbutyidimethyisiiyi)-3-(1'-methoxy-methyloxy-l'ethyl)-4-trityithio-2-azetidi none (5.83 g, 100%) which was deprotected as described below:

A cold (ice bath) solution of the above derivative (5.83 g, 10 mmol) in HIVIPA-H20 (90 mi-1 0 m]) was treated 5 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 (M9S04) to give the title compound (3.0 g, 69.3%), mp 172-2.5 (ethyl acetate-hexane); ir (CHC13) vn,,,: 3400 (N-H) and 1760 cm-1 (C=O); 11-1mr (CDC13) 6: 7.67-7,12 (15 H, m, H aromatics), 4.63 (2H, center of ABq, J=6, O-CH2-0),4.49 (1 H, s, WHO, 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, CH3 and H-3) and 1.30 ppm (3H, cl, J=6, CH3) P P. Preparation of (1W,3SAR and l'S,3R,4S) 3-(1'Formyloxy- 1 -ethyl)-4- tritylthio-2-azetidinone (Isomer 8) OS10,013 OCHO 15 1 ' S c03 3 0 'It A solution of WS,3SAR and 1'R,3R,4S) 3-(1'-p-bromo-benzenesuifonyloxy-l'- ethyi)-1-(t-butyidimethyisiiyi)4-trityithio-2-azetidinone (Isomer C) in DMF (3 mi) was heated at WC for 48 hand then at 100'C for 4 h. The reaction mixture was then diluted with H20 and extracted with ether. The ethereal extracts were washed with brine, dried (M9S04) 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; 11-1mr (CDC13) 8: 8.07 (1H,s,CHO),7.24-7.56 (15H, m, aromatics), 5.23 (1H, dq,J=6.4,7, H-1'),4. 38(1H,dmJ=2.4, H-4),4.25(1H,s, 25 NH), 3.20 (1 H, dd, J=7, 2.4, H-3),1.43 (3H, d, J=6.4, H-2'); ir (CHC13) vniax: 3400 (NH), 1765 W=OL 1725 cm-1 (C=O).

Q. Preparation of (1W,3S,4R and l'S,3R,4S) 3-(1.Acetoxy- l.ethyl)-4tritylthio-2-azetidinone (isomerB) ST N.N3 CAZ 1J. 1-1 Pure derivative (1'R,3S,4R and VS,313,4S) 1-(t-butyl-dimethylsilyl)-3-(l'acetoxy-l'-ethyl)-4-tritylthio-2- 35 azetidinone (5.77 g, 10.47 mmol) was dissolved in warm HMPT-water (60 ml, 10 ml). The solution was cooled down at room temperature and NaN3 (1.2 g was added in. It was stirred for 45 min (reaction progression was followed by t1c) and poured slowly in stirred cold water (800 ml). The mixture was stirred for 20 more min.

The crystalline material was collected and washed with water. It was redissolved in CH2CI2, washed with water (twice) and brine and dried over MgS04. Solvent evaporation left a foam which crystallized out fromether-petroleum ether (4.90 g, 96.5%, mp 143-44.5'C).

ir (CH2CI2)Vmax: 3395 (N-H), 1772,1738 cm-1 (C=O). 'Hmr (CDC13) 8: 7.9-6. 8 (15H, m, H aromatic), 5.12 (11-1, center of dq, J=6.5,7.5, H-l'), 4.33 (1 H, d, J=2.8, H-4),4.20 (1 H, bs, N-H), 3.17 (1H, ddd, J3-1,=7.5, J34=2.8, J3-NH=1, H-3), 2.1 (3H, s, CH3CO), 1.35 (3H, d, J-6.5, CH3)- R. Preparation of 3-(1.Hydroxy- 1 -ethyl)-4-tritylthio-2-azetidinone. Mixture of four isomers) CH sct 3 L -- ' C. ' se 3 J (CH 3)l Ac 20 ne _+ Lc, "--'-N(Ft), 0A.

3 A solution of lithium diisopropyl amide' (0.74 mmol) was prepared at -78C in dry tetrahydrofuran (5 ml) from diisopropyl amine (0.103 ml, 0.74 mmol) and BuLi (0.29 ml of a 2.52 Min hexane). After 30 min at -78'C, a solution of the (R and S) 1 -trimethylsilyi-4-tritylthio-2- azetidinone (0.292 g, 6.99 mmol) in dry tetrahydrofurane (2 ml) was added dropwise. After 5 min, excess of freshly distilled acetaldehyde (0.2 ml) was added all at once. After 20 min at -78'C, tlc indicated comp!ete disappearance of starting materials and 60 the reaction mixture was quenched by adding to a saturated solution of ammonium chloride. Extraction with ethyl acetate (2 X 25 ml) followd by washing of the combined organic phases with saturated NH4CI, 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 C6H6:EtOAc, 6:4) gave a mixture of alcohols (0.215 g, 80%). This mixture ('Hmr) cannot be separated either by hpic or bytlc.

i GB 2 042 515 A 65 wAcetylation Acetylation of an aliquot of the mixture (0.065 g) with excess acetic anhydride 0.0 ml) and pyridine (1.4 ml) gave a mixture of acetates. hpIc 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-Butyldimethylsilyl derivatives The mixture of alcohols (0.121 g,0.34mmol) was treated with t-butyl dimethy[chlorosilane(0.117g,0.776 mmol) and triethyl amine (0.10 ml, 7.14 mmol) in dry dimethy1formamicle (1 ml) 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 gave an oil (0. 716 g) which contains 4 components by HPLC. a= 3.7%; b = 60.6%; c = 31.1%; d= 4.6% (the identity of each one has not been established)4 NOTE:

'Butyl lithium and lithium hexamethyl disilazane were ineffective 2 Order of increasing polarity 3 Acetylation of the product derived from 1-t-butyidimethylsilyi-4- trityithio-2-azetidinone gave the following ratio:

d = 29.5%; c = 24.1 %; b = 33.8%; a = 12.6% 4 Reaction of a mixture of alcohols derived from (R and S) 1 -(t-butyl d i methylsi lyl)-4-tritylth io-2-azetidi none 20 gave the following proportions: a = 5.2%; b = 41.3%; c = 48%; d= 4.6% S. Preparation of (l'S,3S,4R and 1W,3R,4S) 3-(1 -Benzoxyl-ethyl)-4- tritylthio-2-azetidinone (Isomer 8) MW J 1- 1 'S':03 -,S ch 3 25 0 N'_11 A solution of (1'R,3S,4R and VS,3R,4S) 3-(V-meth a nesu Ifo nyl oxy- V- ethyl)-4-tritylth io-2-azetid i none (Isomer C) (035 mg, 2 mmol) and sodium benzoate (432 mg, 3 mmol) in 10% H20-DMF (10 mi) was heated at90'Cfor 30 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 CN-CH2C12) gave the title compound as a white solid (108 mg, 23.2%) mp 158'C. 'Hmr (CDC[3) 6: 7.03-8.25 (20H, m, aromatics), 5.32 (1 H, dq, J=6.1, 9, H-1'), 4.40 (1 H, cl, J=2.5, H-4),430 (1 H, s, N-H),3.40(1H,dd,J=9,2.5,H-3),1.50(3H,d,J=6.1,H-2');ir(CHC13)Y,,,.:3400(NH), 1765(C-0),1715cm-1 35 (C=O).

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

^ ' ma.5c, 5m S. /.M 2 %tsu -1, 'f" SC,3 ---IsomerC a) A solution of 'Isomer C- of 1-(t-butyidimethyi-siiyl)-3-(1'paranitrobenzyidioxycarbonyi-l'-ethyi)-4- trity[thio-2-azetid i none (1.3 g) in a mixture of TFA (5 mi), water (5 mi), dichloromethane (20 mi) and methanol (30 mO was stirred for 2 days at room temperature. The solution was diluted with water and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with sodium bicarbonate and water, dried and concentrated to leave an oil. Crystallization from ether gave the pure title compound (902 mg), mp78-80'C; 'Hmr(CDC13):8.25-6.75 (19H, m, aromatics), 5.21 (2H,s, benzyl) 5.05 (1H, m, H-114.40 (Ms, N-WA.27 (1H, d,J=2.8, H-4),3.37 0H, dd,J=5.3,2.8, H-3) and 1.37 ppm (3H, cl,J=6.5, CH3); ir (CHC]3) Yr,,a>,: 3390 (N-H), 1765 and 1745 (shoulder) (C=O, and 1525 cm-1 (N02).

b) A cold WC) HIVIPT-1-120 (90 m[ - 19 mi) solution of 'Isomer W of 1-(t-butyldimethylsiiyl)-3-(1' paranitrobenzyidioxy-carboxy-l'-ethyi)-4-tritylthio-2-azetidi none (9.119, 13.3 mmol) was treated with 55 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 (1) and extracted with ether (5 x 200 mi). The ether fractions were combined and washed with water (5 x 200 mO brine and dried over 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.

---1somerB "Isomer W' of 3-(Y-pa ran itrobenzyl dioxyca rbo nyi-l'-ethyi)-4-trityith io-2-azetidi none was prepared as described above for the 1somer W, 92%; mp 155.5-6'C (ether); 11-1mr (CDC13) 6: 8.25-6.80 (19H, m, aromatics), 5.20 (2H, s, benzyi), 4.95 (1 H, m, H-1'), 4.35 (1 H, cl, J=2. 9, H-4), 4.17 (1 H, s, N-H), 3.20 (1 H, dd, H=10.8,J=2.9, H-3) and 1.40 ppm (3H,d,J=7.5,CH3); ir(CHC13)Vniax: 3480, 3390 (N-H), 1772,1750 (C=O), 66 GB 2 042 515 A 66 and 1525cm-1 (N02).AnaL calcd for C32H28N206S; 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.

so ---1somerA - 1somer X' of 3-W-pa ran itrobenzyidioxyca rbo nyi-l'-ethyl)-4-trityithio- 2-azetidi none was prepared as described above for the '1somer W; mp 205- 60C. 1 Hmr (CDC13) 8: 8.2-6.7 (1 9H, m, aromatics), 5.22 (2H, ABq, benzyi), 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),165 (1 H, dd, J=6.5,12, JN-Hl, H-3) and 1.52 ppm (3H, d, J =7.5).

"IsomerD- 1somer W of 3-(V-pa ranitrobenzyid ioxyca rbo nyi-l'-ethyi)-4-trityithio- 2-azetidi none was prepared as described above for "Isomer W; 'Hmr (CDC13) 6: 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),142 (1 H, J=5.5,3, H- 3 and 1.5 ppm (3H, d, J=6.5, CH3). Q value for H-3 taken after D20. exchange).

U. Preparation of (1W,3S,4R and 1S,3RAS) 3-(1'-methanesulfonyloxy-l. ethyl)-4-tritylthio-2-azetidinone OsomerB) 0, 11 20 A solution of WR,3S,41R and VS,31R,4S) 1-(t-butyidimethyisilyi)-3-(1'methanesuifonyloxy-l'-ethyi)-4- trithylthio-2-azetidinone. (isomer B) (4.95 g, 8.5 mmol) and sodium azide (1.11 g, 17.0 mmol) in 10% H20-HMPA (60 m[) was stirred at room temperature for 30 min. Then the solution was diluted with water (250 25 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 g, 83.8%). mp 130-31C. 'Hmr (C13C13) 6: 7.20-7.62 (15H, m, aromatics), 4.97 (1 H, dq, J =6.4,6.1, H- 1% 4.56 (1 H, d, J=2.8, H-4),4.22 (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) vm,,: 3195 (n-H), 1768 ern (C=O).

V. Preparation of (l'S,3S,4R and 1W,3R,4S) 3-(1.methanesulfonyloxy-l. ethyl)-4-tritylthio-2-azetidinone. (Isomer Q -1r sc 3 'S':03 35 p fCH3)2 "H A solution of (VR,3S,4R and VS,3R,4S) 1 -(t-butyidimethyisilyl)-3-(1'methanesuifonyloxy-l'-ethyi)-4- trityithio-2-azetidinone (isomer C) (2.85 g; 4.9 mmol) in 10% aqueous HWA(25 mi) was treated with sodium 40 azide (0.65 g, 10 mmol) and stirred at 25'C for 0.5 h. By diluting the 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 evaporated. Trituration in ether gave the title compound as white crystals mp 155-60OC; 1.80 g; 78.6%; 1 Hmr (CDC[3) 6: 7.43 (15H, m, aromatic), 5.02 (1 H, dq, J =6.9, 4.9, H-1% 4.55 (1 H, s, N-H),4.95(1H,d,J=3,H-4),3.33(1H,dd,J=4.9,3,H-3),1.51(3H,d,J=6.9,H-2'); irvmax:3395(N-H),1768 em-' (C=O); AnaL calcd for C25H25NO4S. C64.22, H 5.39, N 3.00; found: C 63.93, H 5.39, N 3.24%.

W. Preparation of (l'S,3S,4R and 1W,3R,4S) 3-(1'.PBromobenzenesulfonyloxy-l.ethyl)-4-tritylthio-2azetidinone (Isomer 0 05, 2 'Br OS0 2 B 3 50 4 C, t, A solution of WS,3S,4R and 1S,3R,4S) 3-(1'-p-bromobenzenesuifoxyloxy-l'- ethyi)-1-(t-butyidimethyisilyi)4-tritylth io-2-azetidi none (isomer C) (1.42 g, 2 mmol) and sodium benzoate (0.865 g 6 mmol) in 10% H20-HMPA (40 mO was stirred at room temperature for 1 h. Then the solution was diluted with H20 (100 MO and extracted with ether. The ether extracts were washed with brine, dried (M9S04) and evaporated. The crude crystalline title compound was triturated in a small volume of ether and collected by filtration (0.92 g, 60 77%) mp 125-260C. 'Hmr (C13C13) 6: 7. 80 (4H, s, benzenesuifonyi),7.30-7.65 (15H, m, aromatics), 5.13 (1H, dq, 60 J=6.5,4.0,H-1'),4.50(1H,d,J=2.9,H-4),4.40(1H,s,N-H),3.40(1H,dd,J=4.0,2. 9,H-3),1.50(3H,d,J=6.5, H-2'); ir (CHC13) vn,,,.: 3400 em-' (N-H), 1770 em-' (C=O).

67 GB 2 042 515 A 67 X. Preparation of (l'S,3S,4R and 1W,3R,4S) 3-(1 -Hydroxy- 1 -ethyl)-4- tritylthio-2-azetidinone (Isomer 8) 2 Br 3 - OH CO 3 a / -V^,C 0 ic 0 5 To a warm solution of (1'R,3S,4R and VS,3R,4S) 3-(1'-p- bromobenzenesulfonyloxy-l'-ethyi)-1-(tbutylclimethylsi lyi)-4-trityith io- 2-azetid in one (Isomer C) in HMPA (5 mi) was added dropwise 1 mi of H20. The reaction mixture was kept at 900C for 20 h, then diluted with ether 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% CH3MCH2C12). A white solid was obtained (122 mg, 44.5%) rrip 187-189C which was found to be identical to a sample of the title compound prepared by another method.

Y. Preparation of3-(1'-Hydroxy-l-ethyl)-4-tritylthio-2-azetidinone 03 S C Z 17 r sc 3 0 '-,, Both isomers, (VS,3S,41R and VIR,31R,4S) 3-(V-hyd roxy-l'-ethyi)-4- trityith i o-2-azetidi none (Isomer C) and (VS,3S,411 and V13,311,4S) 3-(1'-hydroxy-l'-ethyi)-4-trityithio-2- azetidinone (Isomer B) were prepared by the same method. For example, a solution of (VR,3S,41R and VS,311,4S) 1-(t- butyidimethyisiiyi)-3-(1'-hydroxy-l'ethyl)-4-tritylth 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 mIJI was stirred 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 134-35'C. 'Hmr (CDC13) 6: 7.12-7.56 (1 5H, m, aromatics), 4.48 (1 H, s, N-H), 4.28 (1 H, d, J =2.8, H-4), 2. 94 (1 H, dq, J=6.5,6.2, H-1'), 3.06 (1 H, dd, J=6.2, 2.8, H-3), 2.18 (1 H, s, -OH), 1.30 (3H, cl, J =6.5, H-2'); ir (CHQ3) vrn,,x- 3400 (n-H), 1760 cm-1 (C=O).

Similarly (VR,3S,411 and VS,31R,4S) 1-(t-butyidimethyisilyi)-3-(1'hydroxy-l'-ethyi)-4-trityithio-2-azetidinone 30 (Isomer B) mp 190-92'C.'Hmr (CDC13) 6: 7.10-7.55 (15H, m, aromatics), 4. 45 (IH, cl, J=2.5, H-4),4.28 (1H, s, NH), 4.10 (1H, dq, J=6.4,53, H-1'), 3.08 (1H, dd, J=5.3,2.5g, H-3),1.50 (1H, s, -OH), 1.30 (3H, cl, J=6.4, H-2'); ir (CHC13) v,a,,: 3400 (N-H), 1760 cm-1 (C=O) Z. Preparation of WS,3S,4R and 1R,3R,4S) 3-(1-Methoxymethyl-l.ethyl)-1- (paranitrobenzyl2".hydroxy 35 2"1-acetate)-4-tritylthio-2-azetidinones (IsomerA) OCR 2 OCH 3 OC"20CH3 t 3 C -1. OH H 40 CO 2p A mixture of Isomer A of 3-(1'-rn eth oxymethyl-l'-ethyi)-4-trityith io-2- azetid i none (7.5 g, 17.3 mmol), paranitrobenzyi glyoxylate hydrate (4.7 g, 20.8 mmol) and toluene (300 ml) was heated under reflux for 1 h in a Dean and Stark apparatus filled with 3A molecular sieves. The solution was cooled in ice and triethylamine (0.24 m], 1.7 mmol) was added dropwise. The mixture was stirred for 1 h, washed with diluted hydrochloric 45 acid, sodium bicarbonate and brine, dried and concentrated to give the title compound as a foam (10.5 g, 94%). 11-1mr (CDC13) 6: 8.25-6.84 (19H, m, aromatics), 5.24 (2H, s, benzyis), 4.67-4.83 (3H, m, O-CH2 and H-4), 4.34-4.55 (1 H, m, H-21, 4.02 (1 H, m, HAT 3.54 (1 H, m, H-3),3.40 (3H, s, O-CH30.38 (3H, cl, J=6.5, CH3); ir (KBr) v ax: 3360 (OH), 1770 (C=0 of P-lactam), 1735 (C=0 of ester) and 1605 cm-1 (aromatics).

AA. Preparation of (l'S,3S,4R and 1W,3R,4S) 3-(1-Methoxymethoxy-l-ethyl)1-(paranitrobenzyl2'. hydroxy-2'-acetate)-4-tritylthio-2-azetidinone (Isomer Q mi 2 OCH 3 CHO M1 lon! 3 -- 02p'" 'i - C E:.- 55 2 A solution of hydrated paranitrobenzyl glyoxylate (1.73 g 7.11 mmol) was refluxed in toluene (90 mi) using a Dean Stark condenser filled with 3A molecular sieves fora 2 h period. To the boiling solution was added WS,3S,41R and VR,31R,4S) 3-(1'-methoxymethyloxy-l'-ethyi)-4-tritylthio-2- azetidinone (3.0 g, 6.93 mmol) and 60 the mixture was refluxed for 2 h more. The mixture was cooled to room temperature, triethyl amine (70 mg, 97[ti, 0.69 mmol) was added and it was stirred for 2 h. The reaction mixture was diluted with ether, washed with 1% aqueous HCl, water, 1% aqueous NaHC03, Water and brine, dried (M9S04) and concentrated to give the title compound (4.60 g, 100%); ir (CHC13) VM,,: 3530-3100 (O-H), 1765, 1750 (C=O) and 1525 cm-1 (N02); 'Hmr(CDC13) 6: 8.22,8.18 (2H, 2d,J=8, Hm aromatics), 7.67-7.0 (17H, m, H- aromatics) 5.3 (2H, bs, CH2-PN13), 65 68 GB 2 042 515 A 68 5.30-5.02 (m, H-2"), 4.89-4.52 (m, H-l'and 0-H), 4.63,4.59 (1 H, 2d, J=2, H-4),4.33,4.30(2H, 2 center of 2 ABq, J=7, J=7, O-CH2-0),4A-3.67 (1 H, rn, HA'), 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 (1W,3S,4R and 1S,3R,4S) 3-(1'-Acetoxy-l'.ethyl)- 1(paranitrobenzyl-2'.hydroxy-2'. 5 acetate)-4-tritylthio-2-azetidinone OAC STr 0 PNO 0 NB TEA 10 CO PNB 2 ---1somerB- A solution of hydrated p-nitrobenzyl glyoxylate (triturated with ether) (1.82 g, 30 mol) was refluxed in benzene through a Dean Stark condenser filled with 3A molecular sieves for 2 h. To that was added azetidinone (VR,3S,41R and VS,3R,4S) 3-(1'-acetoxy-l'-ethyi)-4-trityithio- 2-azetidinone (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) Vmax: 3520 (OH), 1775, 1745 em-' (C=O); 'Hmr (C13C13) 6: 8.2,8.18 (2H, 2d,J=8, Ho aromatic), 7.80-6.90 (17H, rn, H-aromatic), 5. 28,5.17 (2H, 24, C1-12-PN13,4.89 (0.67H, d, J=7, CHO), 4.80 (center of rn, H-1'), 4.38 (0.33 H, 2d, J=8.8, CHO), 4.22 (D.33H, d, 43=2.5, H-4),4.09 (0.67H, d, H4-3=2.1, H-4),3.65 (D.67H, dd, J3-1-5.8, J3-4=2.1, H-3),3.47 (0.33H, dd, J3-1-5.5 J34=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, CH3CD), 1.10, 1.06 (3H, 2d, J=5.8, 6.3,CH3) CC. Preparation of3-(1-Paranitrobenzyldioxycarbonyl-l-ethyl)-1- (paranitrobenzyl2'-hydroxy -2'acetate)4-tritylthio-2-azetidinone (4 isomers).

1 v A X0 2 Pril-1 OCO 2 FNB s- S 03 3 30 0 7 C02P.KB ---IsomerC A mixture of 1sorner W of 3-(1'-paranitrobenzyidioxycarbonyi-l'-ethyi)-4trityithio-2-azetidinone (1.70 g, 0.3 mmol), paranitrobenzyl glyoxylate hydrate (815 mg, 3.6 mmol) and toluene (50 mi) was heated under 35 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 brine, dried and concentrated to give the title compound (2.1 g) 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 at2": 'Hmr (CDC13) 6: 8.25-6.80 (23H, m, aromatics), 5. 30 and 3.12 (4H, 2s, benzyls), 4.65 40 (1H,d,J=9,H-2"),4.45(1H,d,J=2.5,H-4),4.45-4.10(1H,m,H-1'),3.50(1H,d,J=9, 2"-0 H),3.28(1H,dd, J=2.5,J=2.5, H-3) and 1.23 ppm (3H,d,J=6.5,CH3); ir(CHC13)vma,,: 3530to3200 (D-H), 1765,1750 (C=O) and 1525 em (N 02). More polar isomer at C-2-: 'H mr (CDC13) 6: 8.25-6.85 (23H, rn, aromatics), 5.25 and 5.08 (4H,2s,benzyis),5.05(1H,d,J=7,H-2"),4.35(1H,d,J=2.5,H-4),4.40-4.05(1H,m,H1'),3.42(1H,J=7, 2"-OH),3.33(1H,dd,J=2.5,2.5,H-3),1.23(3H,d,J=6.5,CH3);ir(CHC13)vna,>, :352Oto 3200(0-H),1755(C=O) 45 and 1525 em-' (N02).

---1somerB A mixture of hydrated paranitrobenzyigiyoxylate(l.74 g, 7.66 mmol) and (VR,3S,4R and VS,3R,4S) 3-(V-pa ran itrobenzyl d i oxyca rbonyiV-ethyl)-4-tritylth i o-2-azeti di none (3.63 g, 6.38 mmol) was refluxed in 50 toluene (70 mi) on a Dean Stark condenser filled with 3A molecular sieves for 3h. The solution was cooled down to room temperature and triethyl amine (64.5 mg, 89 mI, 0.639 mmol) was added. It was then stirred for 4 h, diluted with ether and washed with 2% aqueous HCI, water, 2% aqueous NaHCO3, 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. Lesspolar epimerat2-: ir (CHC13) vma.: 3500 (O-H), 1772,1750 (C=O) 55 1525 em-' (N02); 11-1mr (CDC13) 6: 8.30-8.0 and 7.65-6.80, (23H, rn, aromatics), 5.27 and 5.13 (4H, 2s, benzyis), 4.71 (1 H, rn, J=6.5,6.5, H-1'), 4.28 (1 H, d, J=2.2, H-4),4.23 (1 H, d, J=8.6, H-2"), 3.50 (1 H, dd, J=2.2,6.5, H-3), 3.28 (1 H, d, J=8.7, 0-H) and 1.18 ppm (3H, d, J=6.5, CH3). More polar epimer: ir (CHC13) vrna,,: 3480 (O-H) 1772,1750 (C=O) and 1525 cm-l(N02); 11-1mr (CDC13) 6: 8.35-6.90 (23H, rn, aromatics), 5.15 (4H, benzyis), 4.72 (1H,d,J=7.5,H-2"0),4.90-4.50(1H,m,J=6.5,6.5,H-1'),4.10(1H,d,J=2,H-4),3. 68(1H,dd,J=2,6.5,H-3), 60 3.28(1H, d,J=6.5,0-H) and 1.15 ppm (3H,d,J=6.5,CH3).

A 69 ib 1 10 GB 2 042 515 A 69 -"IsomerA" The 1somer X' of 3-(1'-paranitrobenzyidioxycarbonyi-l'-ethyi)-4- trityithio-2-azetidinone likewise gave a mixture of 1somer X' of 3-(1'paranitrobenzyidioxycarbonyi-l'-ethyi)-1-(paranitrobenzyI 2"-hydroxy2"acetate)-4-trityithio-2-azetidinones. 11-1mr (CDC13) 6: 83-6.7 (23H, m, aromatics), 5.17 (2H, benzyis), 5.0 (1H, m, 5 H-1'), 4.9 and 4.8 (1H, 2d, J=6, H-4, two epimers), 4.32 and 3.96 (1 H, 2s, H-2", two epimers), 3.68 (1H, dd, J=6, 6, H-3) and 1.47 ppm (3H, 2d, J=6.5, CH,3, two epimers).

"IsomerD" The "Isomer W of 3-W-pa ran itrobenzyl d ioxyca rbo nyi-l'-ethyi)-4- trityithio-2-azetidi none likewise gave a mixture of 1somer W' of 3-(1'paranitrobenzyidioxycarbonyi-l'-ethyi)-1-(paranitrobenzyl 2"-hydroxy2"acetate)-4-trityithio-2-azetidinones. 'Hmr (CDC13) 6: 8.30-6.60 (23H, m, aromatics), 5.20 (4H, m, benzyis), 4.83 (1 H, 2d, J=5, H-4),5.50-4.30 (2H, m, H-l'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, CH,9).

DD. Preparation of (l'S,3S,4R and 1W,3R,4S) 3-(1'-Methanesulfonyloxy-l'. ethyl)- 1-(paranitrobenzyl2'hydroxy-2-acetate)--4-tritylthio-2-azetidinone (isome Q (epimers at C2-).

am. OMS CO sc'3 3H a Y. 2 20 A solution of paranitrobenzyigiyoxylate 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 VR,3R,4S) 3-(1'-methanesuifonyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (16.62 g, 35.5 mmol) and the reflux maintained for an additional 0.5 h. Then the reaction mixture was cooled to room temperature, treated with 25 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. 'Hmr (C13C13) 6: 8.12 (2H, d, J=9, Hm aromatic), 7.28 (17H, part of d, Ho aromatic, trityl), 5.28 (2H, s, -CH2- PNB), 4.88 (0.5 H, s, H-11---),4.62 (1.5H, m, H-2" and H-4),4.00 (2H, m, H-1', -OH), 3.15 (1 H, m, H-3), 2.73 (3H, s, mesylate and 1.30 ppm (3H, d, J=6 Hz, H-2'); irvm,,x: 3520 (O-H), 1775 (C=O), and 1765 cm-1 (C=O).

EE. Preparation of (l'S,3R,4R and 1W,3S,4S) 3-(Methoxymethyl- 1'-ethyl)-1(paranitrobenzyl2"chloro-2'acetate)--4-tritylthio-2-azetidinone (IsomerA) C111 2 OCH 3 0C11 20CH ' 3 111 5-,3 -1 SC3 35 1:

jj "., a, ' cl cc 2 Ca2P' Pyridine (1.1 m[, 14.2 mmol) was added dropwise to a solution of Isomer A of 3-(1'-methoxymethyl-l' ethyl)- 1 -(pa ran itro benzyi-2"-hyd roxy-2"-acetate)-4-trityith io-2- azetid in one (7 g, 10.9 m m o 1) in TH F (350 m J) 40 cooled to -1 5'C. Immediately after thionyl chloride (1.0 mi, 14.0 mmol) was added dropwIse and the mixture was stirred at -1 5'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 to title compound as an oil (6.5 g, 90%), 11-1mr (CDC13) 6:

6.65-8.35 (19H, m, aromatics), 5.24 (2H, s, benzyl), 3.43 (3H, s, OCH3) and 1.42 ppm (3H, d, J=6, CH3).

FF. Preparation of (1'S,3S,4R and 1'R,3R,4S) 3-(l-ethoxymethyloxy-lethyl)l-(paranitrobenzyl2'-chloro2"-acetate)--4-tritylthio-2-azetidinone (Isomer C) "CH Cai, CCH2OCH3 j ', CC1 2 A -1 50 111-1-1 -- 0-111 cl C02p,s CO 2 PN3 A cold (ice-MeOH bath) THF (60 m], distilled over LAH) solution of (VS,3S, 4R and VR,313,4S) 3-(1'-methoxym ethyl oxy- V-ethyl)- 1 -pa ran itro benzyl 2"-hyd roxy-2"- acetate)-4-tritylth io-2-azetid i none (4.25 55 g, 6.62 mmol) was treated dropwise with pyridine (0.696 mi, 8.61 mmol) and thionyl chloride (0.530 mi, 8.61 mmol). The mixture was stirred for 30 min at -1 5T. 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) Vmax: 1770 (C=O) and 1525 cm-1 60 (N02);'Hmr(CDC13)6:8.15,8.12(2H,2d,H-aromatics),7.70-7.00(17H,m,Haromatics),5.62,5.02(1H,2s, H-2"),5.27(2H,s,CH2-PNB),4.7(1H,d,H-4),4.7-3.7(m,O-CH2-0,H-1'),3.5-2.8(m, H-3),3.12,3.08(3H,2s, O-CH3), and 1.30-0.96 ppm (3H, m, CH3).

GB 2 042 515 A GG. Preparation of (1W,3S,4R and l'S,3R,4S) 3-(1.Acetoxy-l'.ethyl)- 1(paranitrobenzyl2,-chloro2"acetate)-4-tritylthio-2-azetidinone SOCI, STr Tr STr Pyridine 5 C02"B 2 ---1somerB ATHF (distilled over LAH) solution of (VR,3S,4R and VS,313,4S) 3-(1'- acetoxy-l'-ethyi)-1-(paranitrobenzyi2"-hydroxy-2"-acetate)-4-trityith io-2-azetidi none (from 10.88 g of N-H) was treated at -WC (ice-methanol bath) under nitrogen atmosphere with pyridine (2.19 g, 2.24 mi, 27.7 mmol) and thionyl chloride (3.3 g, 2.02 m[, 27.7 mmol) and thionyl chloride (3.3 g, 2.02 mi, 27.7 mmol). The mixture was stirred for20 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 (CH2C12) Vmax: 1780, 1740 em-' (C=O) 11-1mr (C13C13 6: 8.17, 15 8.21 (2H, 2d, J=8, He aromatic) 7.76-6.88 (17H, m, H-aromatic), 5.31, 5. 16,512,433 (3H, 4s, CH2-PNB, CHQ, 5.12-4.55 (1 H, m, H-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 1.07 (3H, J=6.5, CH3).

HH. 3-(1 -Paranitrobenzyldioxycarbonyl- 1 l-ethyl)- 1-(paranitrobenzyl2'. chloro-2".acetate)-4-tritylthio-2- 20 azetidinone (mixture of epimers at C2").

OCO 2 PNO OCO 2 MB 3 3 -NI - _1 1,-SC cl 0 "r ' C1M 25 C02 M 2 7somer C Pyridine (58 mg, 0.73 mmol) was added dropwise to a solution of "Isomer W of 3-(V- pa ran itrobenzyl d ioxyca rbo nyi-l'-ethyl)- 1-(paranitrobenzyl 2"- hyd roxy-2"-acetate)-3-trityith i o-2-azeti d in ones (470mg,0.6mmol; mixture of epimers at W") in THF (15 mi) cooled to -15"C. Immediately after thionyl chloride (86.5 mg, 0.73 mmol) was added dropwise and the mixture was stirred at -150C 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%. 11-1mr (CDC13) 6: 8.7-6.8 (23H, m, aromatic), 5.53 (1 H, s, H-21, 5.30 and 5.17 (4H, 2s, benzyis), 4.52 (1 H, d, J=2, H- 4),4.20-3.70 (1 H, m, H-1'), 3.31 (1 H, dd, 35 H-3),1.27 and 1.21 ppm (3H, 2d, J=6.5); ir (CHC13) Vmax: 1780,1750 (C=O) and 1525 em-' (N02).

---1somerB 1somer W' of 3-(1 -paranitrobenzyidioxycarbonyi-l'-ethyi)-1 (paranitrobenzyi 2"-chloro-2"-acetate)-4- tritylthio-2-azetidinones (mixture of C-T' epimers) was prepared as described above for the 1somer W in quantitative yield. 'Hmr (C13C13) 6: 8.25-6.90 (23H, m, aromatics), 5.40- 5.0 (4H, 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 (3H, 2d, J=6.5, CH3); ir (CHC13) V Max: 1780,1750 W=O), and 1525 em-' (N02).

45"IsomerA - 1somer X' of 3-(1'-paranitrobenzyidioxycarbonyl-l'-ethyl)-1'(paranitrobenzyI 2"-chloro-2"-acetate)-4- tritylthio-2-azetidinones (mixture of C-2" epimers). 'Hmr (CDC13) 6: 8.30- 6.80 (23H, m, aromatics), 5.45-4.80 (1 H, m, H-1'), 5.18 and 5.21 (4H, 2s, benzyis), 4.87 (1 H, 2d, H-4),4.22 and 3.87 (1 H, 2s. H-2"), 4.05-3.40 (1H, m, H-3),1.57 and 1.50 ppm (3H, 2d, CH3).

---1somerD 1somer W of 3-(1 "-paranitrobenzyidioxycarbonyl-l'-ethyi-l'(paranitrobenzyI 2"-chloro-2"acetate)-4- tritylthio-2-azetidinones (mixture of C-T' epimers). 11-1mr (CDC13) 6: 8. 30-6.70 (23H, m, aromatics) 5.32-5.10 (4H, m, benzyis), 5.48 and 5.30 (1 H, 2s, H-2"), 4.82 (1 H, d, J=5, H-4), 5.30-520 (1 H, m, H-1'), 3.15 (1H, m, H-3), 1.40 and 1.30 ppm (3H, 2d, J=6.5, CH3): ir (CHC13) Ymax: 1780,1750 (C=O) and 1525 em-' (N02) 11. Preparation of (l'S,3S,4R and 1W,3R,4S) 3-(1.Methanesulfonyloxy-l- ethyl)-1-(paranitrobenzyl2'. chloro-2'.acetate(-4-tritylthio-2azetidinone (isomer Q (ppimers at C2-).

4 10.

V, 60 C,3 0 To a cold soludion (50C) of (VS,3S,4R and VR,3R,4S) 3-(1'methanesuifonyloxy-l'-ethyl)-1-(paranitrobenzyI 2"-hydroxy-2"-acetate-4-tritylthio-2-azetidi none (24.0 g, 35.5 mmol) in dry tetrahydrofuran (350 mi) was 65 71 added pyridine (3.659,46.2 m mol) and thionyl chloride (5.5 g, 46.2 mmol) dropwise. After stirring for 45 min, ether (100 mi) was added to precipitate the hydrochloride salt which was filtered off. The filtrate was evaporated and the residue redissolved in benzene (200 m]) and treated with charcoal. Evaporation of the solvent left a nearly white foam which was used as such in the next step. 'Hmr (CDC13) 6: 8.18 (2H, cl, J=9, Hm aromatic), 7.72 (17H, m, part of d.Ho aromatic, trityl), 5.57 and 5,12 (1 H, s, H-2"), 5.28 (2H, s, -CH2PNB), 4.73 (1 H, 2d, H-4),3.21 (1 H, 2dq, H-3), 2.78 (3H, 2s, mesylate and 1.21 ppm (3H, 2d, H-6H2; H-2'); ir vn,, x 1779 cm-1 (C=O) JJ. Preparation of (1S,3R,4R and 1W,3S,4S) 3-(1-Methoxymethoxy- l-ethyl)1-(paranitrobenzyl2"10 triphenylphosphoranylidene-2"-acetate)-4tritylthio-2-azetidinone(IsomerA) OCII2OCH3 0C112"3 3 3 C, c'.,C ",0 c ' ' r B 2PNi' C02" GB 2 042 515 A 71 A mixture of Isomer A of 3-(1'-methoxymethoxy-l'-ethyl)-1(paranitrobenzyi-2"-chloro-2"-acetate)-4trity[thio-2-azetidinone(6.6g,10mmol),triphenylphosphine(3.3g,12.5mmol),2, 6-1 utidine(l.3ml,l1 mmol) and dioxane (140 mi) was heated under reflux for 2 days. The solution was diluted with ether, washed with dilute acid (5% HQ, 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 20 the pertinent fractions left the title compound as a foam (1.4 g, 13.7%) ir (KBr) vm,,x: 1750 (C=O) and 1660-1650 cm-1 (C=C, aromatics).

KK. Preparation of (l'S,3S,4R and 1W,3R,4S) 3-(1-Methoxymethyloxy-lethyl)-1-(paranitrobenzyl2'.

triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone (Isomer Q Adioxane (100 mi, distilled over LAH) solution of (VS,3S,4R and V13,3R, 4S) 3-(methoxymethyloxy-l'ethyi)-1-(paranitrobenzyi-2"-chloro-2"-acetate)-4-trityithio-2azetidinone(4.86g,6.62mmol),triphenylphos- phine (2.60 g, 9.93 mmol) and 2,6Autidine (770 mg, 0.837 mi, 7.20 mmol) was heated under reflux for 4 hand kept in a hot bath (1OWC) for 16 h. The mixture was diluted with ether, washed with 1% aqueous HCI, water, 10% aqueous Nal-IC03, water and brine and dried (M9S04). The solution was concentrated and the residue 35 filtered through a silica gel (65 g) column (5%, 10% and 20% etherbenzene) to give the title compound (2.8 9, 48%). ir (CHC13) Vi-nax: 1795 (C=O), 1620 and 1605 (phosphorane) and 1515 cm-1 (N02).

Z.CH2OCH3 CZ:110CH 3 STr STr Er - - "I.C2"i13,P-118 LL. WR,3S,4R and l'S,3R,4S) 3-(1'-Acetaxy-l'-ethyl)-1-(paranitrobenzyl-2"triphenylphosphoranylidene40 2"1.acetate)-4-tritylthio-2-azetidinone (IsomerB) AC -A.

1 j ' j-. r D 3? '1 ' ST r - ii: c 1 2. rlil 1 Yv.:C2 PS3 45 A dioxane (100 mI, freshly distilled over LAH) solution of crude (VR,3S, 4R and VS,3R,4S) 3-(V-acetoxy-V- ethyl)-1-(paranitrobenzyl 2"-ch loro-2"-acetate)-4-trityithio-2-azetidi none was treated with 2,6Autidine (2.97 g, 3.23 mi, 27.72 mmol) and triphenyl phosphine (9.91 g, 37.8 mmol). The mixture was refluxed (oil bath 1309 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-IC03,H20 and brine. 50 Drying and solvent evaporation left the title compound as a solid which was triturated with ether and collected by filtration (14.6 g, 65.9%); ir (CH2C12)Vmax: 1750 (C=O) and 1620,1610 cm-1 (phosphorane).

MM. 3-(1-Paranitrobenzyldioxycarbonyl-l-ethyl)-1-(paranitrobenzyl-2'tripheny lphosphoranylidine-2'- aceta te)-4-tritylthio-2-azetidin one )C02'!'B OCO 2 M 3 1 3 -'T 5 eel 4 Y_ P" 3 0 2 CCY'" 60 Isomer 8 A mixture of (VR,3S,413 and VS,313,4S) 3-(1'-paranitrobenzyidioxycarbonyl-l'-ethyi)-1-(paranitrobenzyl- 2"-ch 1 oro-2"-acetate)-4-trityith ioazeti d i none (isomer B) (4.96 g, 6. 22 mmol, mixture of epimers at C-2"), triphenyl phosphine (2.47 g, 9.42 mmol) and 2.6-lutidine (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 65 72 GB 2 042 515 A 72 with 5% aqueous HCI, water, 10% aqueous Nal-11C03, 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%), mp 189-190' (ether); ir (CHC13) Yrriax: 1750 (C=O), 1620,1605 (phosphorane) and 1522 em (N02).

Isomer C Isomer C of 3-(1'-paranitrobenzyidioxycarbonyi-l'-ethyi)-1(paranitrobenzyi-2"triphenyiphosphoranylidene-2"-acetate)-4-trityithio-2azetidinone was prepared as described above for isomer B. ir (CHC13) Vmax: 1750 (C=O), 1610,1620 (phosphorane) and 1520 cm-1 (N02); 11-1mr (CDC13) 8: 10 8.6=6.7 (H, aromatics), 5.22 and 4.95 (benzyis), 4.70 (H-4), 2.6 (H-3),1.19 and 1.07 ppm (CH3).

IsomerD A mixture of Isomer D of 3-(1'-p-nitrobenzyidioxycarbonyi-l'-ethyi)-1-(p- nitrobenzyI 2"-chloro-2"-acetate)- 4-trityithio-2-azetidinone (4.598 g, 4.45 mmol; purity 77%, mixture of epimers at C-2"), trip henyl phosphi ne (1.425 g, 5.44 mmol; Aldrich) and 2,6-lutidine (0.63 mi, 580 mg, 5.40 mmol; Anachemia) in dioxane (65 mi; distilled from LAH) was heated at gentle reflux under N2for 41 h, monitoring the reaction bytic (benzene: ether=3: 1). The dark reaction mixture was cooled, diluted with ROAc and washed successively with 0.1 NHCI, water, 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 (Si02, 88 g; eluent 10-25% ether in benzene), yielding 1.108 g (1.08 mmole, yield 24.3%) of the title compound as a yellowish foam: 11-1mr 20 (CDC13) 6: 1.08 (d, J=61-1z, V-CH3; ir (neat) vna>,: 1745 cm-l(s, C=O).

NN. Preparation of (l'S,3S,4R and 1W,3R,4S) 3-(1 -Methanesulfonyloxy- lethyl)-1-(pananitrobenzyl2'triphenylphosphomaylidene-2'-acetate)4tritylthio-2-azetidinone (isomer Q 25 3 A solution of (1'S,3S,4R and 1'13,313,4S) 3-(l'-methanesulfonyloxy-l'- ethyl)-1 -(paranitrobenzyl 2"-chloro2"-acetate)-4-tritylthio-2- azetidinone (24.7 g, 35.5 mmol), triphenylphosphine (11.2 g, 42.7 mmol) and 2.6-lutidine (4.2 g, 39.1 mmol) in dry dioxane (350 ml) was refluxed under nitrogen for 19 h. The solvent was evaporated and the crude product redissolved in ethyl acetate andwashed successively with dilute HCI, NaHC03 and brine. Purification was completed by chromatography on a silica gel column (8.5 x 12 cm). 35 Elution with 10% ether- dichloromethane (1.5,0 and then ether (1.5 flgave the purified phosphorane; 12.36 g 35 (40%). 1Hmr (CDC13) 6: 2.53 and 2.93 ppm (3H, 2s, mesylate); ir (CHC13) vmax: 1749 and 1620 cm-1 (C=O) 00. Preparation of (1W,3S,4R and 1'S,3R,4S) 3-(1.Hydroxy-i-ethyl)-1(paranitrobenzyl-2'triphenylphosphoranylidene-2'-acetate) -4-tritylthio-2azetidinone (Isomer B).

'Ac 1H 40 It, ' STr P tz.ca 3 0 3 C02p:M C02p" A solution of phosphorane WR,3S,4R and VS,3RAS) 3-(1'-acetoxy-l'-ethyi)-1 -(paranitrobenzy] 2"triphenyl phosphoranyl idene-2"-acetate)-4-tritylthio-2-azetidi none (4. 43 g, 5.00 mmol) in methanol (10 mi) THF (60 mi) was trearted at room temperature with 1% aqueous NaOH (1 eq, 200 mg in 20 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, H20 and brine. Solvent evaporation afforded a residue which was crystallized from benzene-ether (3.7 g, 87.7%) mp 169.5-170.5'C. ir (CH2C12) Vmax: 1745 (C=O) and 1620 cm-1 (phosphorane) Heating the mixture increased the reaction rate.

PP. Preparation of (11S,3S,4R and 1'R, 3R,4S) Silver 3-(1.methoxymethyl1'1-ethyl)- 1-(paranitrobenzyl 55 2"-triphenylphosphoranylidene-2'-acetate)-2-azetidinone-4-thiolate (IsomerA) r4H2OCH3 'C420CH1 SA9 3 / PO 3 C02PM3 60 Silver 3-(V-meth oxym ethyl- V-ethyl)- 1 -(pa ran itro benzyi-2"-tri phenyl phospho ra nyl idene-2"-acetate)-3tritylth io-2-azetid in one (isomer A), was prepared as described elsewhere forthe isomer C of the pa ran itrobenzyidioxyca rbonyl derivative. Yield 50%. ir (neat) Yr,,,,: 1745 cm-1 (C=O).

73 GB 2 042 515 A 73 QQ. Preparation of (l'S,3SAR and 1W,3R,4S) Silver 2-(1 -methoxymethyloxy- 1.ethyl)- 1-(paranitrobenzyl 2'.triphenylphosphoranylidene-2'.acetate)-2-azetidinone 4-thiolate (Isomer Q.

OCH OCH 3 OCH2OCH3 SAg ST, A9N03 5 0 -11" 3 3 CO2P.4B C02p" (VS,3S,4R and VR,31R,4S) 3-(1'-methoxymethyloxy-l'-ethyl)-1- (paranitrobenzyI 2"tri phenyl phosphora nyl idene-2"-acetate)-4-trityith io-2-azetidi none (887 mg, 1.0 mmol) was first dissolved in hot (40OC) 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 hat 23'C, 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 (CHC]3) vmax: 1745 (C=O), 1605 (phosphorane) and 1520 em-' (N02).

RR. Preparation of Silver 3-(1 -paranitrobenzyldioxycarbonyl- 1.ethyl)- 1(paranitrobenzyl2"triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4thiolate.

OCO 2 phla p 2 0 3 p 03 -5 " 3 20 0 Y. 2 1.. R-r 2.

"IsomerB (VR,3S,41R and VS,31R,4S) 3-(1'-paranitrobenzyicarbonyidioxy-l'-ethyl)-1- (paranitrobenzyi-2"triphenylphosphoranylidene-2"-acetate)-4-trithio-2-azetidinone (1.02 g, 1 mmol) was first dissolved in 25 CH2C12 (3m1) and diluted with hot (55'C) MeOH (20 mi). The hot solution was treated firstwith pyridine (120 mi, 117 mg, 1.48 mmol) and a hot (55'C) 0.15M methanolic solution of silver nitrate (8 m], 1.2 mmol). The mixture was stirred at room temperaturefor 15 min, then at WC for 2 h. It was then concentrated to a 10% solution on the rotary evaporator (no bath). The mercaptide was filtered and washed twice with cold (-15"C) methanol and three times with ether. (917 mg, 100%). ir (Nujol mull) Ymax: 1745 (C=O), 1600 (phosphorane) 30 and 1517 em-' (N02).

---IsomerC Silver 3-(1'-paranitrobenzyidioxycarbonyi-l'-ethyi)-1 -(paranitrobenzyl 2"-triphenylphosphoranylidene-2"triphenylphorphoranylidene-2"-acetate)-2-azetidinone-4-thiolate, 1somer W, was prepared as described 35 above for the 'Isomer W'; ir (nujol) vmax: 1745 (C=O) and 1600 em-, (phosphorane).

---1somerD A solution of Isomer D of 3-(1'-p-nitrobenzyicarbonyidioxy-l'-ethy-)-1-(p- nitrobenzyI 2,'- tri phenyl phosphoranylidene-2"-acetate)-4-trityithio-2-azetidi none (145 mg, 0.142 mmol) was prepared by 40 first dissolving it in CH2C12 (5 ml), removing the CH2C12 at W-600 and adding hot MeOH (4 mi). To the above solution was added a hot solution of A9N03 in MeOH (0.15 M, 1.14 mi, 0.17 mmol, 1.2 eq), followed by pyridine (14 [ti, 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 00. The mercaptide was collected by filtration and washed with ice-cold MeOH and ether, yielding 99 mg (0.11 mmol, 78%) of the title compound as a brownish solid: ir (nujol) vrx: 1750 em-' (s, C=O).

SS. Preparation of (1W,3S,4R and l'S,3RAS) Silver 3-(1'1.hydroxy- 1 '1. ethyl)- 1-(paranitrobenzyl-2"triphenylphosphoranylidene-2'-acetate)-2azetidinone-4-thiolate (Isomer Bi OR OR 50 Ag:M 3 1J. - -1.11 Y p 3 C5USU M3 C02P.13 V1 2'RB A solution of W13,3SAR and VS,313,4S) 3-(1'-hydroxy-l'-ethyi)-1 - (paranitrobenzyl-2"triphenyl phosphoranyl idene-2"-acetate)-4-tritylthio- 2-azetidi none (1 g, 1.19 mmol) in Me01-1 (10 m 1), was treated with pyridine (124 RI, 11.3 mg, 1.53 mmol) and at 100C with a 0.15M solution of silver nitrate in Me01-1 (15 mi, 2.25 mmol -or until no more precipitation of the silver mercaptide occurred). The mixture was stirred for 1 hand concentrated on the rotary evaporator (no bath) to approximatively 10% concentration.

The solvent was filtered off. The cake was washed once with MeOH and 3 times with ether, and pumped under high vacuum (954 mg, 100%). ir (Nujol mull) v,,,>,: 3500-3400 (OM), 1752 (C=O) 1595 (phosphorane) and 1525 em-' (N02). The crystalline material was first dissolved in CH2C12.

74 GB 2 042 515 A TT. Preparation of (1W,3S,4R and 1S,3S,4S) 4-Acetylthio-3-(1-p- nitrobenzyldioxycarbonyl-l.ethyl)-1-(pnitrobenzyl2"triphenylphosphoranylidene-2"-acetate)-2-azetidinone (IsomerD) 74 OCO 2 PNB 52p'" -1 CH'COCI-Pyr 1 3 CH2C12 0 N Iro 3 5 C02PN'3 CO ' PNB To a stirred solution of silver 3-(1'-paranitrobenzyl 2"-tri phenyl phosphora nylidene-2"-acetate)-2azetidinone-4-thiolate (isomer D) (85 mg, 0.095 mmol) in CH2C12 (5 m[) containing pyridine (30 [ti, = 0.37 mmol; Fisher) was added at O-WC CH:3COCI (20[ti, 0.28 mmol) and the mixture was stirred at 0-50C for 30 min. 10 The precipitate which formed was filtered and washed with CH2C12. The filtrate and washings were combined, washed successively with brine, diluted HCI, saturated Nal-IC03 and then brine, dried (Na2S04) and evaporated yielding 75 mg (0.091 mmol, crude yield 95%) of the title compound as a syrup: 1 Hmr (CDC13) 6: 2.33 (s, -SOCOCH3); ir (neat) Ymax: 1750 (P-Iactam, ester), 1695 (thioester), 1520 and 1350 cm-1 (N02).

UU. Preparation of (1W,5R,6R and l'S,5S,6S) cisp-Nitrobenzyl2-methyl-6(1'-pnitrobenzyldioxycarbonylmethyl-penem-3-carboxylate (IsomerD) OCO 2 PNE, 0 N ' 1 '1' 1 ':Y'M 3 20 C02p:B A solution of the above acetylthioazetidi none (74 mg, 0.09 mmol) in toluene (30 mi) was heated at reflux under N2 atmosphere for 7 h. After evaporation of the solvent, the residue was purified by hplc (Si02; eluent, benzene: ether=3: 1) yielding 24 mg (0.044 mmol, yield 49%) of the penem ester as a syrup. (Note: this oil could be crystallized from THF-ether or CH2C12-ether: 'Hmr (CDC13) 6: 1.40 (3H, d, J=6.5 Hz, 1'-CH3), 2.38 (3H, s, 2-CH3),4.07 (1 H, dd, J5,6=4Hz, J6.1=91-1z, 6-H), 5.05-5.30-5.34-5.59 (2H, AB type, 3-CO2CH2-Ar), 5.30 (2H, s, V-0C02-CH2-Ar), 5.1-5.6 (1 H, m, V-H), 5.68 (1 H, d, J5,6=41-1z, 5-H), 7.49-7.64-8.18-8.33 (4H, A2'B2', V- aromatic. Hs), 7.53-7.68-8.18-8.33 (4H, A2'B2', 3-aromatic Hs); ir (neat) Vriiax: 1780 (P-Iactam), 1750 (-OC02-071 0 (ester), 1520 and 1350 cm-1 (-N02).

W. Preparation of WR,5R,6R and l'S,5S,6S) Potassium and sodium 6-(1hydroxyethyl)-2-methylpenem-3carboxylate (isomer D).

OR _C'3 35 .- N-,11 ---3 - 0)__. _ C, 2p'j' A solution of the above penem ester (24 mg, 0.044 mmol) in THF (5 mi) was mixed with ether (10 m]), H20 (5 m]), phosphate buffer (1.00 mi, 0.05 molar pH 7.00: Fisher) and 30% PdCelite (50 mg, Engelhard). This mixture was hydrogenated at 35 psi for 21.5 h at room temperature. After removal of the catalyst (over Celite), the aqueous layer was separated, washed with ether and lyophilized yielding 12 mg of the title mixture of sodium and potassium salts as a white powder: 'Hmr (D20) 6: 1. 23 (3H, cl, J=6Hz, V-CH3),227 (3H, s, 2-CH3),3.85 (1 H, dd, J5,6=41-1z, J6.1=9Hz, 6-H), 4.3 (1H, m, 1'- H) and 5.65 ppm (1H, d, J5,6=41-1z, 5-H); ir (Nujoi)v,,a>,: 1755(-lactam) and 1570cm- 1 GC02E); uv (H20) Xm,,: 279 (E 2300, calcd as K-salt), 258 (E 1900, 45 calcd as K-salt). This material was identical to a sample of the title compound prepared by an aidoi condensation of acetaldehyde with the dianion of 2-methylpenem-3- carboxylic acid. ('Hmr, ir, uv) E.-.1 '25 (i,S.5P.6S "d 11R.5S.6R) Acid (isomer C) CH -1,1 3 CM Mch.d A:

Oco,pNB 0 p M 0 1 ' - C; -C 3 d' % 'Y"3 3 C02p';" C02 '" Ii 1 -p o', N 0 N /1!3 C02p:' W2H GB 2 042 515 A 75 Method 13:

OCO PNB 0C0 PNh 0C0 P1:3 CCO PNB 2 c 2 2 03 S N s i:- <4- 9'02P'NB SX. 02 PN3 N OH _12 N P, 10 C"2 PN3 C0,MB METHOD A 1) (l'S,3S,4R and 1W,3R,4S) 4-Acetylthio-3-(1'paranitrobenzyldioxycarbonyl-l'-ethyl)-1-(paranitrobenz yl 2'. triphenylphosphoranylidene-2 "acetate)-2-azetidinone (isomer Q.

OCO2P:113 SA17 '72PN' C83COC1 EC".

C5145N 20 H P63 If C0 C02PMa A co 1 d (i ce- M eO H bath) of VS,3SAR a n d V13,3 R,4S s i lver 3-(V- pa ra n itro b enzyl -d i oxyca rbo nyl -1'-ethyi)- 1 - (paranitrobenzyl 2"-tri phenyl phosp ho ranyl iden e-2"-acetate)-2- azetidi no ne-4-th iol ate (isomer C) (1.14 9, 1.30 mmol) in CH2C12 (60 m] was treated with pyridine (0.6 mi, 0.74 mmol) and dropwise with acetyl chloride (236 25 mg, 0.213 mi, 3.00 mmol). The reaction mixture was stirred for 1 hat -WC. The precipitate was filtered and washed with ether. The filtrate was washed with 2% aqueous HQ water, 2% aqueous NaHC03, water and brine and dried (M9S04). The residue upon solvent evaporation was triturated in ether (895 mg, 83.7%, mp 184-WC dec); ir (CHC13) Vmax: 1755,1695 (C=O), 1620 and 1605 em-' (phosphorane), Anal. Calcd for C42HA3011SSi: C61.38, H4.42, N 5.11,S3.90; found; C61.26, H 4.49, N4.88, S4.26.

2) (l'S,5R,6S and 1W,5S,6R) Paranitrobenzyl2-methyl6-(1'paranitrobenzyldioxycarbonyl-l'.ethyl)penem-3-carboxylate (isomer Q 0C0 2 PNB 0C0 2 P90 SA A -Cl, 3 p, "r 3 CCY'I'3 2?" A solution of WS,3S,4R and VR,3R,4S) 4-acetyithio-3-(1'- paranitrobenzyidioxyca.rbonyl-l'-ethyi)-1 (pa ran itro benzyi 2"-tri phenyl ph ospho ra nyl iden e-2"-acetate)-2azetid i none (isomer C) (855 mg, 1.04 m mol) 40 in toluene (60 mi) was heated under ref lux for 4.5 h. The residue upon concentration of the solution was passed through a silica gel (10 g) column (11% ether in benzene) to give the pure title compound (393 mg, 69.6%), mp 157-158'C (CHC13-ether); ir (CHC13) Y,,,ax: 1785,1745,1710 (C=O) and 1525 em-' (N02); 'Hmr (CDC13) 6: 8.30-7.2 (8H, m, H-aromatics) 5.46 (1 H, cl, J=1.8, H-5), 5.40- 5.0 (5H, m, z CH2-PNB and H-11% 3.95 (1H, dd,J=1.8,J=5.4, H-6),235 (3H, s, CH3) and 1.43 ppm (3H, cl, J=5.4, CH3); Anal. calcd for C24H21N301OS: 45 C 53.04, H 3.89, N 7.73; found C 52.76, H 3.86, N 7.69.

3) l'S,5R,6S and 1W,5S,6R) 6-(1-Hydroxy-l-ethyl)-2-methylpenem-3carboxylic acid (isomer Q p - 02 N2 T-S _"3 50 2 A mixture made of WS,513,6S and VR,5S,6R) paranitrobenzyl 2-methyl-6-(V- paran itro benzyid ioxyca rbonyl-l'-ethyi)-penem-3-ca rboxyl ate (206 m g, 0.379 m mol), TH F-ether-H20 (30 m 1, 55 mi, 20 mi), a 0.05 M pH 7 buffer solution (7.64 mi, 0.382 mmol) and 30% Pd on Celite (500 mg) was hydrogenated at 42 psi H2 on a Parr shakerfor 16 h. The catalyst was filtered and washed with water. The aqueous phase was washed with ether (3 times), acidified portionwise with cold 1% aqueous HQ to pH 2.5 and extracted with ethyl acetate (15 x 20 mi) between each HCl addition. The ethyl acetate extracts were combined and washed with brine (3 X 30 ml). Evaporation of the solvent and trituration of the residue with 60 ether gave the title compound (57 mg, 65.6%), ir (KBr) vrn,x: 3580-3300 (O-H), 1755 and 1660 em-' (C=O); uv (EtOH) Xn: 311 (E 6538), 262 (c 3672); 'Hmr (DMSO-d6) 6: 5.57 (1 H, cl, J=1.7, H-5),4.02 (1 H, M, HAT 3.75 (1 H, dd, J=1.7, J=3.5, H-6),2.23 (3H, s, CH3) and 1.23 ppm (3H, cl, CH3).

76 GB 2 042 515 A METHOD B 1) Silver (l'S,3S,4R and 1T,3R,4S) 1-(t-Butyldimethylsilyl)-3(1'-paranitrobenzyldioxycarbonyl-l'l-ethyl)-2azetidinone-4-thiolate (isomer Q 76 oco 2 pHs -11 i, SA9 0 J__T' -s','I2 --IBu Oco 2)3NB SC4, 3 ^-N MQ2 01 Isomer C of 1'-(t-butyidimethyisiiyi)-3-(1'-paranitrobenzyidioxycarbonyil'-ethyi)-4-tri tyithio-2-azetidinone (lg, 143 mmol) was dissolved by stirring in hot (WC) methanol (12 mi). A solution of silver nitrate (0.59 g) in methanol (12 mi) was added followed by pyridine (0.13 mi). The mixture was stirred vigorously 1 hat room temperature and 2 hat W. The solid silver mercaptide was collected by filtration and washed with ether, 352 mg (46%). ir vmax: 1735 cm-1 (C=O).

2) WS,3S,4R and 1W,3R,4S) 4-Acetylthio-l-(t-butyldimethylsilyl-3-(1'1paranitrobenzyldioxycarbonyl-l' - ethyl)-2-azetidinone (isomer Q 15 OC02PNB -,I,- --,.,SAg 0 U."S tB.

"':L-CSAe 0 rf"si _Me2 tnu To a solution of isomer C of silver 1-(t-butyl d i methyl si lyl)-3-W-pa ran itro benzy] di oxyca rbonyi-l'-ethyi)-2azetidinon e-4-thio late (880 mg) in dichloromethane (40 ml) stirred at OOC was added pyridine (0.57 mi) followed, dropwise, by acetyl chloride (0.49 mi). The mixture was stirred 0.5 h at 0', the solids removed by filtration and the filtrates diluted with ether, washed with aqueous hydrochloric acid (2%), water, sodium bicarbonate (2%) and brine, dried and concentrated to leave the title material as an oil. (610 mg). 1 Hmr (CDC13) 6: 8.2 and 7.48 (4H, 2d, aromatics), 5.40 (1 H, d, J=2.2, H-4), 5. 2 (2H, s, benzyi), 5.34.9 (1 H, m, H-1'), 3.42 (1 H, dd, J=2, H-3),2.32 (3H, s, CH30.40 (3H, d, J=6.5, C1-1,3),0.95 (9H, s, t-Bu) and 0.2 ppm (6H, CH3).

3) (I'S,3S,4R and 1W,3R,4S) 4-:cetylthio-3-(1'paranitrobenzyldioxycarbonyl-l'-ethyl)-2-azetidinone. 30 (isomer Q 0C0 PNB 1 2 SA -, i ', ,l tBU .I 17--- 0 -- -.H Isomer C of the above S-acetyl N-t-butyl-methyl-silyi-azetidinone derivative (1.4 g) was dissolved in a mixture of TFA (0.5 mi), water (0,5 mi), methanol (3 mi) and dichloromethane (2 mi) and stirred at room temperature for 48 h. The solution was diluted with water (100 mi) and extracted with dichloromethane (4 x 20 mW The combined organic extracts were washed with sodium bicarbonate (2%) and brine, dried and concentrated to leave the crude title compound as an oil. Purification was done by chromatography over silica gel (30 g) eluting with 5% ether in benzene; (650 rng). Crystallization from benzene gave a white solid. 'Hmr (C13C13) 6: 8.15 and 7.45 (4H, 2d, aromatics), 6. 18 (1 H, N-H), 5.19 (2H, s, benzyi), 5.05 (2H, m, H-4 and H-11 3.35 (1 H, dd, J =2.5, 4.5, H-3), 2.34 (3H, s, CH3) and 1.42 ppm (3H, d, J=6.5, CH3); ir vma.: 1780,1750, 1695cm-1 (C=O).

(l'S,3S,4R and 1W,3RAS) 4-A cetylthio-3-(1'-paranitrobenzyldioxycarbonyl1 -ethyl)- 1-(paranitrobenzyl 2"-hydroxy2"acetate)-2-azetidinones (epimers at C-2-). (isomer Q 0C02PNB 1 5x.

"C'2-7NB A.

1 A mixture of isomer C of 4-acetylth io-3-(1 1-pa ran itro benzyidioxyca rbonyl-l'-ethyi)-2-azetidi none (750 mg), paranitrobenzylglyoxylate hydrate (525 mg) and benzene (50 mi) was heated under reflux for 3 days over a 55 Dean and Stark apparatus filled with 3A molecular sieves. A second portion of glyoxylate (52 mg) was added and reflux was continued for 2 more days. The mixture was diluted with ether, washed with hydrochloric acid (2%), water, sodium bicarbonate (2%) and water, dried and concentrated to leave an oily residue (975 mg). Chromatography on silica gel, eluting with benzene-ether (85=1 5) gave the pure title compounds. 11-1mr (CDC13) 6: 8.25-6.75 (8H, m, aromatics), 5.30 and 5.12 (4H, 2s, benzyis), 5.05-4.70 (1 H, H-2"), 4.45-4.35 (1 H, 2d, 60 H-4),4.50-4.1 0 (1 H, m, H-1'), 3.30 (1 H, m, H-2 and 1.25 ppm (3H, 2d, CH3).

i j 77 GB 2 042 515 A 77 5) (l'S,3S,4R and 1W,3R,4S) 4-acetylthio-3-(1 -paranitrobenzyldioxy- carbonyl- 1'1-ethyl)- 1-(paranitrobenzyl 2"-triphenylphosphoranylidene-2'-acetate)2-azetidinone (isomer Q 0C0 2 puB SAC 0C0 2 pt:B SOC12 -1 f- -0 ? 3 C0 2 2P" 2P" Isomer C of 4-acetyithio-3-(1'-paranitrobenzyidioxycarbonyi-l'-ethyi)-1(paranitrobenzyI 2"hydroxy-2"- acetate)-2-azetidinone(577mg,lmmol) was dissolved in anhydrous THF (10 mi) and pyridine (95 mg, 1.2 mmol) was added to the solution. The solution was cooled to Wand thionyl chloride (143 mg, 1.2 mmol) was added slowly. The mixture was stirred 30 min at 00, diluted with a little ether and the insoluble salts removed by filtration and washed with ether. The combined filtrates were concentrated to give the crude mixture of epimers of the C-2" chloro compound. It was dissolved in THF (20 mi), triphenylphosphine (314 mg, 1.2 mmol) and 2,6-lutidine (129 mg, 1.2 mmol) were added and the solution was stirred at WC for 4 days. The 15 solids were removed by filtration, washed with benzene and the combined filtrates were concentrated to leave an oil whose spectral characteristics and tic behavious were identical to a sample of the title compound prepared by acylation of the corresponding silver thiolate. ' The desired penem product may be produced by reacting the title compound according to the method of steps 2 and 3 of Example 35 (Method A).

EXAMPLE 36 (VR,5R,6Sand VS,5S,6R) 6-(1'-Hydroxy1'-ethyl)-2-methylplenem-3- carboxylic Acid (Isomer 8) 011 25 "P.: CH 3 C02" MET4CD A OH OCO,P.NB CCO 2p- NB 0C0 2 PIM 30 :F ' 3 0 3 0 Y IB 2N C 2 p 35 SAC 02N c13, )2p:ID 3) 11 1 - 1 "Y 3 -S--- 1 -- S CR 3 2) A.' C 0 3 py i d -- 27"13 30. C02PNB 40 METHOD A 1) (1W,3S,4R and l'S,3R,4S) 4-Acethylthio-3-(1'-paranitrobenzyl- dioxycarbonyl-l-ethyl)1-(paranitrobenzyl 2"-triphenylphosphoranylidene2"1-acetate)-2-azetidinone, (isomerB) 0C0 PNB C02p';3 45) 2 SA11 XC:1 SAC 45 ,5, P03 C545N OY-3 Y C02p" C02PN3 A solution of WR,3SAR and VS,31RAS) silver 3-(1'- paranitrobenzyidioxycarbonyi-l'-ethyi) V- paranitrobenzy] 2"-tri ph e nyl p hosph o ra nyl ide n e-2"-acetate)-2- (azetid in o ne-4-th io late (isomer B) (917 mg, 1.03 mmol) in CH2C12 (20 mi) wastreated at -15'C (ice-MeOH bath)with pyridine (242 [ti, 247 mg, 3. 13 mmol) and dropwisewith acetyl chloride (142 [tl, 157 mg, 2.0 mmol). The mixture was stirred for 15 min at -WC and the solid was filtered and washed with ether. The organic solution was washed with 2% aqueous HCI, water, 2% aqueous NaHC03, water and brine and dried over M9S04. The residue upon solvent evaporation crystallized from ether (710 mg, 80%, mp 183-1185'C; ir (CHC13) vrnax 1755,1695 (C=O), 1620,1605 (phosphorane) and 1625 cm-1 (N02); 2) (1W,5R,6S and l'S,5R,6R) Paranitrobenzyl2-methyl-6-(1'paranitrobenzyldioxycarbonyl-l'-ethyl)-enem3-carboxylate. (isomer B) OCO PNB j.. 2 - SAC 1: ?4, 3 PNB is OCO PNB 2 -JS 2p' 78 GB 2 042 515 A A solution of (1'R,3S,4R and VS,31R,4S) 4-acetyithio-3-(1'paranitrobenzyidioxycarbonyi-l'-ethyi)- 1 (paranitrobenzyl 2"-tri phenyl phospho ra nyl idene-2"-acetate)-2- azetidinone. (650 mg, 0.791 mmol) was refluxed in toluene for 7h. The concentrated solution upon solvent evaporation was passed through a silica gel column (10 times its weight) and the title compound (0.5% ether- benzene to 2% ether-benzene) was obtained as a white solid; 329 mg, 77%, mp 134-1350C, (CH2C12-ether); ir (CHC13)'Vrnztx. 1785,174 ' 5,1705 (C0) and 1525 cm-1 (N02); 'Hmr (CDC13) 6: 8.20 (2H, d, Ho aromatic), 7.60 (2H, d, Hm aromatic), 5.55 (1 H, d, J=1.5, H-s), 5.54.75 (5H, m, 2CH2-PNB, H-1% 3.86 (1 H, dd, J=7.8, J=1.5, H-6),238 (3H, s, CH3) and 1.50 ppm (3H, d-J=6.3, CH3); Anal. calcd for C24H21N301OS; C 53.04, H 3.89, N 7.73, S 5.90; found: C 53.05, H 3.98, N 7.6, S 6.02.

3) WR,5R,6S and l'S,5S,6R) 6-(1'-Hydroxy- 1'-ethyl)-2-methylpenem-3carboxylic acid (isomer 8) 0C0 PNB C02PN1B J.H H 2 C CH3 2 78 1; 1 - - A mixture of (V13,5R,6S and VS,5R,6R) paranitrobenzyl 2-methyl-6-(1'paranitrobenzyidioxycarbonyi-l'- ethyl)-penem-3-ca rboxyl ate (isomer B) (65 mg, 0.12 mmol), 0.05 M pH 7 buffer solution (1.06 eq), H20-THFether (10 mi, 10 mi, 25 mi) was shaken on a Parr hydrogenator using 30% Pd on Celite (200 mg) for 16 hat 50 psi H2. The catalyst was filtered and washed with small volumes of water. The aqueous layer was 20 washed with ether (3 times), acidified portionwise with 1% cold aqueous HQ extracted with ethyl acetate between each addition of HCl, and saturated with brine and extracted thoroughly with ethyl acetate. The ethyl acetate extracts were combined, washed with brine (5 times) and dried (M9S04). Solvent evaporation afforded a solid residue which was triturated with methylene chloride (19. 4 mg, 71%). ir (nujol) vmz,>,: 3500 (O-H),1785,1672cm-l(C=O);uv(EtOH)X,,ax:260(c3450),309(E6400); 'Hmr(DMSOd6)6:5.54(1H,d, J=1.5,H-5),3.88(1H,m,H-1'),4.2-3.5(2H, bs,O-H),3.65(1H,dd,J=6.5,J=1.5,H- 6),2.28(3H,s,CH3) and 1.15 ppm (3H, d, J = 6, CH3).

METHOD B 1) WR,3S,4R and l'S,3R,4S) 4-Acetylthio-3-(1-trimethylsilyloxy-l-ethyl)-1- (paranitrobenzy12"triphenylphosphoranylidene-2'-acetate)-2-azetidinone (isomer B) JH X OT, ). SA.

TMSC1 AcCl 0 1 1, TEA 5N 3 C5N C02P.W 35 A suspension of (VR,3S,4R and VS,31R,4S) silver 3-(1'-hydroxy-l'-ethyi)- 1(paranitrobenzyl 2-triphenyl ph osp h ora nyl i den e-2"-acetate)-2- azetid in on e-4-th iol ate (505 mg, 0.715 mmol) in THF (25 m[) was cooled to -1 50C (ice-MeOH bath), treated dropwise with triethyl amine (289 mg, 398 [ti, 2.86 mmol), trimethyl chlorosilane (310 mg, 362pd, 2.85 mmol) and finally with imidazole (50 mg, 0.734 mmol), stirred for 3 h at -1 YC and at room temperature for 16 h. (ir of an aliquot showed absence of hydroxyl group). The mixture was cooled to -1 WC, diluted with CH2C12 (20 mi), treated with pyridine (226 mg, 231 gi, 2.86 mmol) and acetylchloride (168 mg, 152 pil, 2.14 mmol), stirred for 0.5 h, diluted with ether, washed with dilute aqueous HQ, water 5% aqueous NaHCO3 water and brine and dried. The solvent was removed on the rotary evaporator and the residue purified by filtration through a silica gel column (1:10 ratio, 3% to 10% ether in benzene) to give the title compound (360 mg, 84.2%) mixed with a little of the desilylated derivative (30 mg, 7.8%). ir (liquid film) Vmax: 1750,1790 (C=O) 1620 (phosphorane) and 1518 cm (N02).

2) WR,3SAR and 1'S,3R,4S) 4-Acetylthio-3-(1'-hydroxy- l-ethyl)-1(paranitrobenzyl2"!- triphenylphosphoranylidene-2'-acetate)-2-azetidinone (isomer B) OTMS ON IL:5 SAC H 31p UC 3 T. 2 1. 2"" - 5 5 A solution of (VR,3S,41R and VS,313,4S) 4-acetylth io-3-1'-tri methyl sily] oxy-l'-ethyl)-1 (paranitrobenzyl 2" tri phenyl p hosp ho ra nyl idene-2"-acetate)2-azetid in one (360 mg, 0. 504 mmol) was treated with TFA (3 drops) and stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate, washed with water, dilute aqueous NaHC03, water and brine and dried (M9S04). Solvent evaporation afforded the title compound (334 mg, 100%); ir (CHC13)Vmax 1755,1690 (C=O), 1620,1605 (phosphorane and 1520 cm-1 60 (N02).

_T 79 3) WR,5MS and 1S,5S,6R) Paranitrobenzyl2-methyl-6-(1.hydroxy-l'l-ethyl)- penem-3-carboxylate (isomerB) 0H SAC 3 2PNB GB 2 042 515 A 79 A 0 2 A solution of (1'R,3S,4R and VS,31R,4S) 4-acetyithio-3-(1'-hydroxy-l'- ethyi)-1 (paranitrobenzyl 2-triphenylphosphoranylidene-2"-acetate)-2- azetidinone (410 mg, 0.638 mmol) in toluene (40 mi) was refluxed fora 7 h period. Toluene was partially evaporated. The residue was passed through a silica gel (1 to 12 ratio) 10 column (3%,4% and 5% ether in benzene) to give the title compound (151 mg, 65%) as a white solid mp 161-161.5'C; ir (CHC13) Ymax: 3600,3500-3400 (OH), 1780,1608 (c=O) and 1525 em-' (N02); 'Hmr (CDC13) 6: 8.20 (2H, d, J=7, Ho aromatic), 7.60 (2H, cl, aromatic), 5.57 (1 H, cl, J=2, H-5), 5. 29 (2H, center of ABq, J=115, CH2-PN13), 4.2 (1 H, dq, J=7, J=6, H-1% 3. 67 (1 H, dd, J=7, J=2, H-6),233 (3H, s, CH3) and 1.33 ppm (3H, cl, J=6, CH3); AnaL caled for C16H1r^06S: C 52.74, H 4.43, N 7.69, S 8.80; found: C 52.67, H 4.41, N 7.71, S 8.96. 15 4) OW,5R56S and l'S,5S,6R) 6-(1'-Hydroxy- 1'1-ethyl)-2-methylpenem-3- carboxylic acid (isomer 8) off 3 0 C:02P"' OH H -CH 3 U i CO 20 A mixture of (V, 5R, 6S and VS, 5S, 6R) paranitrobenzyl 6-(1'-hydroxy-l'ethyi)-2-methylpenem-3carboxylate (89 mg, 0.244 mmol), THIF-H20-ether (15 m], 10 mi, 30 mi), a 0,05 M pH 7 buffer solution (5.06 mi, 0.253 mmol) and 30% Pcl on Celite (250 mg) was shaken on a Parr hydrogenatorfor15 h at45 psi H2. A 25 work-up identical to the one previously described gave title compound (32 mg, 57%).

EXAMPLE 37 (l'S,5R,6R and 1W, 5S, 6S) 6-(1'-Hydroxy- 1 -ethyl)-2methylpenem-3-carboxylic Acid (isomerA) 3 2 1) (l'S,3RAR and 1R3S,4S) 4-Acetylthio-3(1-methoxymethoxy- l-ethyl)- 1(paranitrobenzyl2"!triphenylphosphoranylidene-2'-acetate)-2-azetidinone (isomerA) OC"2"3 LjjAg Y P03 C02PN8 53AC N N,rP03 C9 2 PN8 Isomer A of 4-acetyithio-3-(1'-methoxymethoxy-l'-ethyi)-1 - (paranitrobenzyi-2"tri phenyl ph osph era nyl i den e-2"-acetate)-2- azetid in one was prepared as described elsewhere for isomer C of the paranitrobenzyl dioxycarbonyl derivative, yield 85%. ir (neat) Ymax: 1750 and 1690 em-' (C=O).

2) (l'S,3R,4S and 1W,3S,4R) 4-Acetylthio-3-(1'1-hydroxy-l-ethyl)- 1(paranitrobenzyl2,'ltriphenylphosphoranylidene-2'.acetate)-2-azetidinone, (isomerA) fCH20C113 o 3 OH -I- Od, fly- 3 10-PM.

Ac IsomerA of 4-acetyithio-3-(1'-methoxymethoxy-l'-ethyl)-1-(paranitrobenzyi2"triphenyl phospho ra nyl i dene-2"-acetate)-2-azetid i none (500 mg, 0. 68 mmol) was added to a cooled solution WC) of trifluoroacetic acid (50 mO and water (10 mO and stirred for 15 min in ice and 3 hat room temperature. The reaction mixture was concentrated, dichloromethane was added and the solution was washed with sodium bicarbonate, water, and brine, dried and concentrated to give the title compound (450 mg, 96%); ir (neat 6max: 3400 (OH), 1745 and 1690 em (C=O).

3) (l'S,5R,6R and 1W,5S,6S) Paranitrobenzyl 6-(1-hydroxy-l-ethyl)-2methylpenem-3-carboxylate (isomer 60 A).

on 5-0 0 3 0- 2 P.

ON 3 2 "B - GB 2 042 515 A Prepared as described for isomer C of the paranitrobenzyl dioxycarbonyl derivative, yield 45%,'Hmr (CIDC13) 6: 7.93 (4H,A13q, aromatics), 5.68 (1 H, d,J=4.0, H-5),5.33 (2H,ABq, benzyi),4.3 (1 H, m, H-11),18 (1 H, dd,J=4. 0,H-6),2.41(3H,s,CH3),2.31 (1 H, s,OH), and 1.42ppm (3H,d,J=6,CH3); ir(CHC13)vmax: 3100-3600 (OH), 1780 and 1710 cm -1 (C= 0).

4) (1S,5R,6R and 1W,5S,6S) 6-(1-Hydroxy- l-ethyl)2-methylpenem-3carboxylic acid (isomerA) OR ON CH 3 CH 3 CO 2PR2 CO 2R 4 i A mixture of isomer A of paranitrobenzyl 6-(1'-hydroxy-l'-ethyi)-2-methyI penem-3-carboxylate (82 mg, 0.2 mmol), palladium on Celite (30%,400 mg), THF (10 mi), ether (25 mi), water (10 m]) and buffer (0.05 M, pH=7, Fisher #SO-B-108) (4 m]) was hydrogenated on a Parr shaker at an initial hydrogen pressure of 45 psi for 4 h. The catalyst was removed by filtration on Celite and washed with water. The filtrates were washed 15 with ether and the aqueous layer was acidified in the cold hydrochloric acid (0.25 M) and extracted with ethyl acetate (5 x 10 m]). The combined organic extracted were washed with brine, dried and concentrated. The foamy solid was triturated in either to give a white solid (20 mg, 44%). ir (nujol) vmax: 3500 (OH), 1765 and 1665 cm (C=O); uv (EtOH) krnz,>,: 301 (F 5922), 260 (E 4280).

* EXAMPLE 38 MR,5R,6S and l'S,5S,6R) 2-Aminomethyl-6-(1.hydroxy- 1'1-ethyl)penem-3-carboxylicAcid (isomer 8) SR3 R: ' - 25.0 P_:- C2121f112 25 C0211 WR,3S,4R and l'S,3R,4S) 4-azidoacetylthio-3-(1.hydroxy-l-ethyl)-1(paranitrobenzyl2". triphenylphosphoranylidene2"1-acetate)-2azetidinone (isomerB) CH OR 30 ), 5;kg CICGCH fD -) T"": 1 2N 3 TEA "3 C02pn CO 2 PNB A cold (ice-MeQH bath) suspension of (VR,3S,4R and VS,3R,4S) silver 3-(1'hydroxy-l'-ethyi)-1 (paranitrobenzyl 2"-triphenyl ph osph o ra nyl iden e2"-acetate)-2-azetidi no ne-4-th io late (970 mg, 1.37 mmol, from 1 g of the corresponding trityl) in THF (40 mi) was treated dropwise with trimethylchlorosilane (0.695 mi, 595 mg, 5.48 mmol), triethyl amine (0. 765 mI, 555 mg, 5.49 mmol) and imidazole (50 mg, 0.734 mmol). The mixture was stirred under N2 for 17 h, then cooled to -1 WC (ice-MeOH bath) andazidoacetyl chloride 40 (406 mg, 3.40 mmol) was added in. It was stirred for 30 min (the reaction progression being followed by tic). 40 The solid was filtered and washed with ether. The filtrate was diluted with more ether, washed with 1% aqueous HCI, water, 1% aqueous Nal-IC03, water and brine and dried (M9S04). The residue upon solvent evaporation was taken up in moist CH2C12 (50 M0 and treated with TFA (3 drops, cleavage of TMSether being followed by tic). The methylene chloride solution was then washed with 1 % aqueous Nal-IC03, water and brine and dried (M9S04). The residue was passed through a silica gel (8 times its weight) column (benzene-ether 1:1, ether and ethylacetate. ether IIA) to give the title compound (565 mg, 69.8%); ir (film) v,,,>,: 3500-3200 (O-H), 2100 (N30755,1609 (C=O), 1620-1605 (phosphorane) and 1518cm-1 (N02).

(1W,5R,6Sand 1'S,5S,6R)paranitrobenzyl2-azidomethyl-6-(1'1-hydroxy-lethyl)-penem-3-carb oxylate 50 (isomerB) SCOCH23 T.1 3 2P'4E __:112N 3 CO 2V'.-a A solution of WR,3SAR and VS,313,4S) 4-azidoacetyithio-3-(1'-hydroxy-l'- ethyi)-1 -(paranitrobenzyl 2"- tri phenyl phosp ho ra nyl idene-2"-acetate)-2-azetid in one (500 mg, 0. 731 mmol) in toluene 100 mi was refluxed under N2 for 30 min. The solution was concentrated under vacuum and the residue was passed through a silica gel (5 g) column (3.54% ether-benzene) and yielded the title compound (193 mg, 65.1%) as a yellowish solid 11-1mr (CIDC13) 6: 8.13 (21-1, d, Ho aromatic), 7.52 (2H, d, Hm aromatic), 5.59 (1H, d,J=1.8, H-5),5.27 (2H, 60 centerofABq,J=13.5,CH2-PNB),4.50(2H,centerofABq,J=16,CH2-N3),4.15(1H,m,H1'),3.73(1H,dd, J=6.3,J=1.8, H-6),1.92 (1H, d,J=4, 0-H) and 1.33 ppm (3H,d,J=6.3CH3); ir(CHC13)v,,,,,: 2110 (N3)t 1785, 1705 (C=O) and 1520 cm (N02).

T 1 81 (1W,5R,6Sand 1S,5S,6R) 2-aminomethyl-6-(1-hydroxyl-ethyl)-penem-3- carobxylic acid (isomer 8) GB 2 042 515 A 81 3 :02" 5 A solution of (VR,5R,6S and VS,5S,6R) paranitrobenzyl 2-azidomethyi-6-(1'hydroxy-l'-ethyi)-penem-3carboxylate (25 mg, 0.062 mmol) in THF-etherwater (6 mi, 6 mi, 15 m]) was shaken on a Parr hydrogenator for 2.5 h at 40 psi H2 using 10% Pcl on carbon (100 mg). The catalyst was filtered and washed with small volumes of water. The aqueous layer was washed with ether (3 times) and lyophilized to give the title compound (11 mg,73%). 'H mr(D20)6: 5.75(1 H, d,J=2,H-5),4.30(1 H, center of rn, J=6.5,H-1%4.02(1 H, dd, J=6.5, J=2, H- 6) and 1.37 ppm (3H, cl, J=6.5, CH3); ir (nujol Mull) Vmax: 3550-2450 (O- H, N-H), 1765,(C=O), and 1600 em-' (C028); uv (H20), Xmax: 309 (c 3650), 255 (E 2815).

EXAMPLE39 (1R5R,6S and 1'S,5S,6R)-2-(4-Aminobutyl)-6-(1.hydroxy-ethyl)penem-3-carboxylic Acid (isomerB) ON P.:?- ICH 214"2 COOH 20 WR,3S,5R and l'S,3R,4S) 4-(6-azidobutanoylthia)-3-(1-hydroxyethyl)-1(paranitrobenzyl2'triphenylphosphoranylidene-2"-acetate)-2-azetidinone Q;)11 '1 SA9 Tlisci H 31C12'4COC1 - H. - - (CH 2) 4 N 25 TEA, 1.. ' c H20 5"5' "IE- AY -PP). 3 'pp"3 COOPNB - 00PNB A solution of (VIR,3S,4R and VS,21R,4S) silver 3-(1'-hydroxyethyl)-1- (paranitrobenzyl 2"triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate (3.03 g, 4.28 mmol) in dry THF (55 ml) kept 30 under a nitrogen atmosphere was cooled to -25'C and successively treated with triethylamine (2.39 mi, 17.12 m mol), trimethylch lorosi lane (2.18 m 1, 17.12 m mol) and im idazole (0. 10 g, 1.47 mmol). The reaction mixture was stirred at -25'C for 0.25 h, the cooling bath was removed, and the stirring was continued for 16 h. The reaction mixture was cooled to O'C and diluted with CH2C12 (55 mi); it was then treated successively with pyridine (0.73 mi, 9.0 mmol) and with a solution of 4-aminobutanoyl chloride (1.36 9,8.56 mmol) in CH2C12 (10 mi). The reaction mixture was stirred at O'C for 1 hand filtered through a Celite pad. The pad was washed with CH2C12 (25 m[); the filtrate and washings were combined and diluted with EtOAc (300 mi). The organic solution was washed with 1 N HCl solution, H20, saturated NaHC03 solution and H20, dried over anhydrous M9S04 and concentrated on a rotary evaporator to an orange syrup (3.83 g). The syrup was dissolved in CH2C12 (75 mi) and water (4 mi) and TFA (0.2 ml) were added; the reaction mixture was stirred at 40 23% for 1.5 h, washed with NaHC03 and H20, dried over anhydrous NC12S04 and concentrated to an orange syrup (3.4 g). Purification of the syrup was achieved by a column chromatography (silica gel G 60, 80 g; eluent: EtOAc in CH2C12 10% --- > 75%). Evaporation of the appropriate fractions gave an oil; 2.14 g, 67.7%.

Anal. calcd for C37H36N507SP: C 61.23, H 5.00, N 9.65, S 4.42; found: C 61.17, H 5.10, N 10.02, S 3.71.

(1'R,5R,6Sand 1'S,5S,6R)paranitrobenzyl2-(6-azidobutyl)-6-(1.hydroxyethyl)-penem-3-carbo xylate CH OC S?(C 2) 4 W 3 5 "2)4t43 PPh 3 Pba 50 Asolution of WIR,3SAR and VS,3RAS) 4-(6-azidobutanoylthio)-3-(1'-hydroxyl'-ethyl)-1-(paranitrobenzyi- 2"-tri phenyl ph osp h o ra nyl idene-2"-acetate)-2-azetid i none (2.04 g, 2.81 mmol) in a toluene-CH2C12 mixture (30:1,310 mi) was refluxed for 9 h under a nitrogen atmosphere (The CH2C12 was removed atthe beginning of reflux). The reaction mixture was cooled to WC and the toluene was removed in vacuo leaving an orange 55 residue which was purified by column chromatography (silica gel. 60,45 g; eluent, ether in pet. ether, 1:1 --> 9:1). The appropriate fractions were combined and concentrated to a syrup which was crystallized from an ether-pet.ether mixture, 0.443 9, mp 850C, 35.2%. Anal. caled for C191--121N5OGS: C 51.00, H 4.73, N 15.65, S 7.17; found: C 51.05, H 4.87, N 15.86, S 7.19. The fractions corresponding to unreacted starting material were cyclized as described above to give an additional quantity (0.276 mg, 21.9%) of title compound. Ymax: 60 2100 (N30770 (C-0, P-lactam) and 1705 em-' (C=O, PNB ester); uv (H20 2WC) niax: 268 (F 13757),316 (c9826). 'Hmr (CDC13) 6: 1.36 (d, JH-2"-H-1"=6.3 Hz, 3H, methyl), 1.52-1. 77 (m, 4H, H-3% 2.57-3.00 (m, 2H, H4), 3.00-3.42 (m, 2H, H-11 3.72 (dd, JH-6-H-5=1.6 Hz, JH-6-H-1,,=6.4 Hz, H-6), 4.02-4.42 (m, 1H, WV), 5.32 (ABq, Ja-b=13.6 Hz, 2H, CH2 of PNB ester), 5.60 (cl, JH-5-H-6=1.6 Hz, 1 H, H-5), 7.61 (d, JHnl-Ho=8.8 Hz, 2H, Hm of PNB ester) and 8.21 ppm (d, HHo-Hm=8.8 Hz, 2H, Ho of PNB ester).

82 GB 2 042 515 A 82 (1R5R,6S and I'SSS,6R)2-(4-aminobutyl)-6-(1'hydroxyethyl)-penem-3- carboxylic acid ON I) - (CH 2),N 0 3 DVE.Et20 H20 101 Pale ON - S (CH 2) 4NH 2 To a solution of (VR,51R,6S and VS,5S,61R) paranitrobenzy] 2-(8azidobutyi)-6-(1'-hydroxyethyi)-penem-3carboxylate (0.54 g, 1.21 mmol) in dimethoxyethane (50 m[) was added ether (50 mi), water (50 mi) and 10% Palladium on charcoal (0.54 g). The reaction mixture was hydrogenated under 45 psi of hydrogen at 2WC for 3 h. The reaction mixture was filtered over a Celite pad and the filtrate was diluted with ether. The aqueous phase was separated, washed with ether and lyophylized. The crude title compound was purified by hplc. ir (KBr) vm.x: 1760 (C=O, P-lactam) and 1565 cm-1 (C-0, carboxylate); 'Hmr (D20) 6: 1.32 (cl, JCH,-H-1,'=6.4 Hz, 3H, CH3)r 1.45-1.85 (m, 4H, HA', H- 3% 2.50-3.20 (m, 4H, H-11', H4), 3.84 (dd, JH-6-H-1,,=6.1 Hz, JH-6-H-5=1. 4 HZ, 1 H, H-6),4.00-4.45 (m, 1 H, H-1 "- and 5.62 ppm (d, JH-5-H-6=1.4 Hz, 1 H, H-5); uv (H20) Xm,,x: 260 (E 4240),302 (c 5480).

W 1 EXAMPLE 40 O-R,5R,6Sand 1"S,5S,6R)-2-(trans-3'.Amino-l.cyclobutyl)-6-(1'- hydroxy-1'.ethyl)penem-3 -carboxylic Acid(isomerB) ON DOR (1"R,3S,4Randl"S,3R,4S)4-(trans-3'-azidocyclobutanoylthio)-3-(1'-hydroxyl '-ethyl)-1-(paranitrobenzyI 25 2".triphenylphosphoranylidene-2-.acetate)-2-azetidinone 1EF-1 I;j_ COOPI.15 Cli cl R ^_.

3 f-PP.h 3 COOPNE Asolutionof WIR,3S,41Rand VS,3R,4S) silver 3-(1'-hydroxyethyi)-1- (paranitrobenzyI 2"tri phenyl p hosph o ra nyl iden e-2"-acetate)-2- azetid in o ne-4-th iol ate (1.01 g, 1.43 mmol) in dry THF (25 m]), kept under a nitrogen atmosphere, was cooled to -WC and successively treated with triethylamine (0.80 m[, 5.74 mmol) trimethylchlorosilane (0.726 mi, 5.72 mmol) and imidazole (0.10 g, 1.47 mmol). The reaction mixture was warmed to -15'C, stirred for 3 h, the cooling bath was removed and the stirring was continued for 18 h.

The reaction mixture was cooled to -1 5'C and diluted with CH2C12 (25 mi); it was then treated with pyridine (0.15 mi, 1.85 mmol) and tra ns-3-azidocyclo buta noyl ch lo ride (0.274 g, 1.72 mmol). The cooling bath was removed and the solution was stirred for 1 h and treated with pyridine (0. 15 mi, 1.85 mmol) and trans-3-azidocyclobutanoylchloride (0,274 g, 1.72 mmol). The reaction mixture was stirred at 23'C for 1 h and 40 filtered through a Celite pad. The filtrate was diluted with EtOAc (100 mf) and washed with 1 N HCl, H20, saturated Nal-IC03 solution and H20, dried over anhydrous M9S04 and concentrated on a rotary evaporator to an orange syrup (1.47 g). To a solution of the syrup in CH2C12 (50 mi) was added H20 (2 mi) and TFA (0.2 mi). The reaction mixture was stirred at 23'C for 2 h, washed with saturated Nal-IC03 solution and H20, dried over anhydrous Na2S04 and concentrated to an orange syrup (1.1 g). Purification of the syrup was achieved by column chromatography (silica gel 60,20 g; eluent EtOAc-ether 35% --- > 70%). Evaporation of the appropriate fractions gave the title compound as an oil; 0.77 g, 74.4% ir (neatyrnax: 3440 (OH), 2100 (N30755 (C=0 P-lactam), 1735 (C=O), 1680 (C=O) and 1625 cm-1 (aromatics).

(1"R,5R,6Sandl"S,5S,6R)paranitrobenzyl2-(trans-3'-azidocyclobutyl)-6-(1"lh ydroxy-l'.ethyl)penem-3- 50 carboxylate C' '....

j.1 -0 ' 0 J_.! 1 COOll!:S 0.4 1J. - ',.":3 Toluene 0 COOPN11 A solution of (V'R,3S,41R and V'S,3R,4S) 4-(trans-3'azidocyclobutanoyithio)-3-(1"-hydroxy-l"-ethyi)-l(paranitrobenzy]-2"'-tri phenyl phosphoranylidene-2"'-acetate)-2-azetidi none (2.27 9,114 mmol) in CH03 (40 mO was diluted with toluene (300 mi) and refluxed under a nitrogen atmospherefor 6 h. The first 60 mi of solution (CHC13 +toluene) were removed with a Dean-Starktrapp. The reaction mixture was cooled to 23'C 60 and the solvent was evaporated under a reduced pressure leaving an orange syrup which was purified by a silica gel column (silica gel 60,35 g, eluent, ether-benzene, 0 --- > 6%). Evaporation of the appropriate fractions gave the title compound, 0.38 g, mp 134-5'C, 27.3%. Analcalcd for C19H19N506S; C 51.24, H 4.30, N 15.73, S 7.20; found: C 50.98, H 4.20, N 15.83, S 7.10; ir (KBr) vm,,.: 2110 (N30765 C=0 P-lactam), 1690 (C=0 PNB ester), 1510(N02) and 1355cm-1 (N02); 'Hmr(CDC]3)6. 1.36 (d,JCH,-H-1,,=6. 3 Hz,3H, CH3),2.0-2.75(m,4H, 65 IL 2 liL- a% 83 GB 2 042 515 A 83 H-T, 1-1-4% 3.67 (dd,JH-6-H-51.5 Hz, JH-6-H-,,,=6.5 Hz, 1 H, H-6),3.8-4. 55 (m, 3H, HA', H-3'and H-1"-, 5.30 (ABq, Ja-b=113.6 Hz, 2H, CH2-Ph- l\102), 5.60 (d,JH-5-H-6=1.5 Hz, 1 H, H-5),7.59 (d,JHc)-H,,=8.8 Hz, 2H, H- m of PN B) and 8.20 (cl, JHrn-Ho=8.8 Hz, 2H, H-0 of PN B). uv (CHC13, 2WC) X,,a.: 266 (e 13050) and 322 plarn (F 10008). The unreacted phosphorane was recovered mixed with Ph3P-O and cyclized as described before to give an 5 additional quantity of title compound: 0.145 g, 10.4% fora total yield of 37.7%.

(1'W,5R,6Sand 1"S,5S,6R)-2-(trans-3-amino-l-cyclobutyl(-6-(1'. hydroxyethy1)penem-3-carb oxylic acid -5 10 Pd/c 2 N3 v COOH To a solution of (VR,51R,6S and V'S,5S,6Fl) paranitrobenzyl 2-(trans-3'azidocyclobutyi)-6-(1"hyd roxyethyl)-pen em-3-ca rboxyl ate (0.33 g, 0.74 mmol) in dimethoxyethane (40 mi) was added ether (40 mi) and 10% Palladium on charcoal (0.33 g). The reaction mixture was hydrogenated under 45 psi of H2for 3 h and filtered over a Celite pad. The pad was washed with water and the filtrate and washings were combined and diluted with ether. The aqueous phase was separated, washed with ether and lyophylized, 0.20 9,95%, uv (H20, 23'C) kmax: 258 (E 2725) and 306 (E 3613). The crude material was triturated with water and the white solid was filtered and dried over P205 under high vacuum for 5 h, 84 mg, 40%; 1 Hmr (D20) 6: 1.34 (d, JH-2"-H.1,,=6.3 Hz, 3H, H-2"-, 23-2.7 (m, 4H, H-2', H-4% 3.90 (dd, JH-6-H- 5 1.5 Hz, JH-6-H-1,,=6.1 Hz, 1 H, H-6) and 5.68 (d, JH-5-H-6 1.5 Hz, 1 H, H-5); uv (H20, 23'C) km,,,<: 258 (F- 4738) and 306 (F- 6318). The f iltrate was purified by hplc, 58 mg; uv (H20, 23oC) k,a.: 257 (c 3580) and 306 (E 5033).

EXAMPLE 41

Following the general procedure of Exam pie 34 the following 2,6disubstituted penern compounds maybe 25 prepared using the indicated electrophiles.

El..Zr..hil.

CH 3 1 CH 3 CH 2 050 2 CH 3 CH 3CM2CH20502-(/ --\CH3 ON 2CH-Ci -lsr HCC-CH 2, Br Isr C 050 2 C-1n 3 OCR 25' CH OCH 2CH2CM2050217---\1\_CH 3 OCR-CHCH 2 3 t OCECC4,13r CLS, Br 1 CR 3Cl-CH3 CYCH2C 1 CH3SC1i2C1 Product F. 5 PQ C,,' 3 C021' R - CH 3- CH ICH2- CH 3C'2CP 2- CH 2"CHC 4 2- He-CCH CL OCH2CH 3 i:r o:2 -CCH2- cl, Cp. 3Ce'12- CP. 3SC:"'2_ 0 84 GB 2 042 515 A 84 clectr2phile 0-CI 0 of 30CH2 cl] 2C 1 cif SCH 2 CH 2 cl HCHO c CI'3 "2C"2_ CH! 3 SC9 2 C.4 2- 6 SOCH 2- 0 0 0 1 may be oxidi-ed to produce em 35:42aod CH3SCY 0 (omay be oxidized to produce CH 3SCH2CM1od CF. 3 5 '2-2 CH 0 0 CS) ON protected via -C-OPN!! Electrophile CH3CH2CHO A /V M 1715 cr 0 OCC 4 2C OCH2CCII2C 1 OOCH 2C H 2C 1 oc:q 2 OCH 2CH2C 0SCH2C1 O"YCM2el occm;CIA2C1 oi 2SCH2CH2C 1 0 lav he oxidized to produce ilo YSCH2CM2X 4 (D -Y be c-d-ed to produce CH3C,, -C 250314 -y be C.-'di-d to prcduce 2CH 2 ---d 050,C4.- 9 0 T-v t: - i,! 1---d to produce 'X4 2C!2- "d '5C415C2CM2D,.,y b. to prd.ce 1 ? -Y bl to pro,l,ce I'd xH 502z!i,clf - 2 2 HOCH 2OM2- Q ON I:H -0 CH 3CH-C 2 H5CH 2 CH 2- 9) 10 SH CH 3 ll:H-CH 2- CP (D 0< ON OOCH2- OCH 20CH2OOCH 2CH2- OCH 2 OCH 2CH2- CH2- 9 OCH2SCH.'- 0 0SCH2CH2 - 0 OCH2Se'l2CM2- (D OM OCH2CHO "H-CH-CHO C113CH2C02 CS 3 0 A',., c 1 C"3 C-SC2RS 0 cl -Y, C4 0z OR 0 C4 3CM2 C- 0h GB. 2 042 515 A 85 0 0 I.A 0 J.

OCC 2 CH 3 (D y te mid.zed to produce 0 so 3 H Clectroohile ri -71 "' s"C. 2CH 3 nl V.-,Cl 0 OCH.C'HCO2"3 OC=C-CHG OCIC-CO 2CH3 OCHS a cHO --y 1 Electrophile U.3,, at 71 ', -I- 1 r---- 5 ' 11 J l S Br 0 0 0 0 1-k 0 0 0 0 -, R.

a '. \1 / C),,-, 0 1 0 0 oce-c- SH I c., OH 0 @ 0 C 1 in, '1 11 11 N LIO -l I--- 111 86 GB 2 042 515 A 86 0 0 C2H50c-cl C2NS OC 0 0 1 c 2 H 5 oCH 2 Br c 2 H 5 0c, N-C-CH 2 cl NC ri.,t,nphil. R.

0 FCH ZCH2C62 CH 3 1 1-11-1 02 4-CH 2 c 1 HaR.

OCIA 2 cl S o-^- , D - 1-1 0 1 (PN8-0) 2" H 203 p c H 3 CHO Nil 2 (D 0 H 0MS N 3 0 via 1 STr __1 -1, -: 1 - 0 4 SI 0 1 - Example 59 co 2 H N H 2 "ZCH3 Also, 2L 14 P. 2 M (ed) 1 2 - l.

0 0 RL MC02PMB 0 CH 1 3 N-CO 2 PNB 3 1:. 2H -i'.

!] (CM 3) 2 -1,- CH 3 co P 2 CIP.CCCH 3.1Hcnclt 3 ---21 11 \ - cH) N -CO 0 2H 01, 11 87 GB 2 042 515 A 87 1 :tHCONMR MRCOM4R CH 3 0 0 C0214 R - H. CH,1 or WCQ 4H2 2C2H5 0 0 @ AI$.' on STr CH 3 co- ococil 3 11 0 Zr -1.--, -imco ?C2 11 5 en 3 0 co 2 9 0COCH 3 c H CQZH OH OCC:JHCII 3 0CONHCH 3 CHI 2 4 N 11 OH oms CH 3 ''s J- 5 H STr -C, S_ f 3 N -"' 0 C1,11 3 N 0 \_02 C11 N: 3 H Electrophile TZ OCH 0 NFF' R, R' - Pl. CH 3 2 CHO CD C R, R' - H, CH3 RR'N CD LM 3 ccl CF.30- 88 GB 2 042 515 A EXAMPLE 42 WS,5R,6S and 1'R,5S,6Fil) P-Trimethylsilylethyl-6(1'-acetoxy-l. ethyl)-2-methylpenem-3-carboxylate (Isomer Q OAC C02' _ 5 3-(1.hydroxy- 1 -ethyl)- 1-(p-trimethylsilylethyl 2". triphenylphosphoranylidene-2'.acetate)-4-tritylthio10 2-azetidinone STr N M Y.Ime 1 3 2 2) CH 3 CHO To a solution of diisopropylamine (185 mg, 1.84 mmol) in tetrahydrofuran (5 mi) at -78% was added n-butyl lithium (1.3 mi, 2.0 mmol) with stirring. After 5 min, a solution of 1-(p-trimethyisilylethyl 2'-tri phenyl phospho ranyl idene-2'acetate)-4-tritylth io-2-azetid i none (1.27 9,1.67 mmol) in tetrahydrofuran (15 mi) was added dropwise over 20 min with stirring. After 2 min, freshly distilled acetaidehyde (1 mi) was added and the solution was stirred for 5 min. Hydrochloric acid (12.6 mi of 0.3M) was added and the mixture 20 was allowed to warm to 230C. Water and ethyl acetate (20 m] each) were added, shaken, and separated. The organic phase was washed with water and saturated sodium chloride (20 mi each), dried and the solventwas evaporated in vacuo to give crude product, 1.37 g. The product was absorbed from methylene chloride onto 7 g of silica gel and placed (dry) on a 28 g silica gel column. The column was eluted with ether (100 m[) and then with etherlethyl acetate 1: 1 (50 mi). The first 20 mI of column fractions were discarded. The rest were combined and the solvent was evaporated in vacuo to give a product, 1.03 g. This product was absorbed from ether (680 mi) and then with ethyl acetate (200 mi). Later fractions were combined (major low Rf spot on tic) and the solvent was evaporated in vacuo to give partially purified title compound, 440 mg (33%); ir v,,,, .: 3400 (OH) and 1750 cm (p-lactam and ester); 1 Hmr (CHC13) 6: too poorly resolved to make peak assignments other than aromatics and trimethylsilyl.

Silver 3-(1'-hydroxy- 1.ethyl)- 1-(p-trimethylsilylethyl2"1triphenylphosphoranylidene-2"-acetate)2-azetidinone-4-thiolate.

CA e' 'I ' sr 3" PP1,3 CO, 88 j 1 A solution of silver nitrate (425 mg, 2.5 mmol). pyridine (79 mg, 1.0 mmol) and water (10 mi) was added to a solution of the above compound (403 mg, 0.50 mmol) in ether 0Ormi). The mixture was stirred vigorously 40 for 1 h. The precipitate was collected by filtration and washed with water and ether to give the title mercaptide 267 mg (80%). ir vnax: 3400 (OH) and 1750 cm-1 (p-lactam and ester).

4-Acetylthio-3-(1.acetoxy- 1 -ethyl)- 1-(0-trimethylsilylethyl 2'triphenYlPhosphoranylidene-2'.acetate)- 2-azetidinone OH AcClIpyridim 3 O 2 2 A solution of acetyl chloride (70 mg, 0.88 mmol) in methylene chloride (1 mi) was added dropwiseto a solution of the above silver mercaptide (267 mg, 0.40 mmol) and pyridine (70 mg, 0.88 mmol) in methylene chloride (5 mi) at O'C. The mixture was stirred at O'C for 1.5 h and then at 23'C for 15 min. The precipitate was filtered off and the solution was washed with 0.1 M hydrochloric acid and 0.1 M sodium bicarbonate (10 mi 55 each). The solvent was evaporated in vacuo to give the title compound, 153 mg (59%); irv,,,x: 3450 (OH), 1750 (p-lactam and ester) and 1690cm1 (thioester); 'Hmr(CDC13) 6: 7.5-8.2 (m, 15H, Ph),5.85 (br, 1H,H-4), 3.0-5.0 (unresolved, 4H, OCH, OCH2, H-3),2.0-2.6 (3 singlets; 6H, 0Ac, SAc), 0.91.7 (m, 5H, CH3, CH2SO and 0.20 ppm (s, 9H, SIMe3).

(l'S,5R,6S and 1'R,5S,6R) P-trimethylsilylethyl 6-(1'acetoxy- l-ethyl)-2methylpenem-3-carboxylate 60 (isomer Q 7 6 4 M SA- C, -., M3 is 89 GB 2.042 515 A 89 A solution of the above phosphorane (150 mg, 0.23 mmol) in toluene (15 m]) was heated under reflux for 2 h. The solution was mixed with 1 g of silica gel and the solvent was evaporated in vacuo. The silica was placed on a 4 g silica gel column (dry) and eluted with ether. The first 5 mi fraction (single high Rf spot on tic), on evaporation of the solvent, gave the title compound, 65 mg (76%) as a waxy solid. ir Vnlax: 1790 (P- Iactam), 1740 (ester) and 1700cm-1 (0Ac); 'Hmr(CDC13) 6: (d,J=2Hz, 1H, H- 5),5.4(m, 1H, H-1'),4.3 (m,2H,OCH2), 3.90(q,J=2Hz,4Hz,1H,H-7),2.37(s,3H,2CH3),2,11(s,3H,OAc),1.42(d,J=6.5,Hz,3H, 2'-CH3),1.1(m,2H, CH2SO and 0.05 ppm (s, 9H, SiMe3). The product was found to be a single isomer.

EXAMPLE 43 - 10 (1W,5R,6S and l'S,5S,6R) 6- 1'-Amino- 1'-ethyl)-2methylpenem-3-carboxylic Acid PROCEDUREA (1W,3S,4Rand 1'S,3R,4S)3-(1.azido-l-ethyl)-1- (paranitrobenzyl2".triphonylphosphoranyli dene-2"acetate)-4-tritylthio-2- azetidinone (isomer B) 20 L: - - _ N -7:

11 I-i, 1 '1If. 1 1. p.:6 IC!2pia Asolution of (VS.3S,4R and 1'R,3R,4S) 3-(1-methane-suffonyloxy-l'-ethyi)- 1-(paranitrobenzyI 2" 1 triphenylph.osphoranylidene-2'-acetate)-4-tritylthio-2-azetidinone (isomer C) (12.36 g, 13.4 mmol) in 10% 25 H20-HMPA (135 mi) was heated at 850C for 7 h in the presence of sodium azicle (1.75 g 27.0 mmol). The solution was thenpoured into cold water (1 e) and the reaction product which crystallized out was collected by filtration. Redissolution in dichloromethane, washing with brine and drying (M9S04) gave the azido phosphorane as a yellow foam after evaporation of the solvent; 11.5 g (98. 9%). It was used as such for the nextstepArv z,,,: (CI-IC13): 2100 (N3),1740 and 1610 cm-1 W=O).

(1W,3S,4Rand 1'S,3R,4S)4-acetylthio-3-(1-azido-l-ethyl)-1(paranitrobenzyl2'. triphenylphosphoranylidene-2'-acetate)-2-azetidinone (isomer B) rf j Z A cooled solution (5'C) of (1'R,3S,4R and VS,311,4S) 3-(1'-azido-1'- ethyl)-1 -(paranitrobenzyl 2"triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone(8.9g,10. 25 mmol)indichloromethane (30 ml) was treated with a solution of mercuric acetate (2.12 g, 6.66 mmol) in methanol (30 ml). After stirring at 5'C for 0.5 h and room temperature for 1.5 h, the solvent was evaporated and the cruclemercuric salt redissolved in dichloromethane and washed with dilute NaHC03 and brine. After drying (MgS04) the solution was cooled to YC and treated directly with pyridine (1.66 g, 21 mmol) and. dropwise with acetyl chloride (1.65 g, 21 mmol). The reaction mixture was stirred at 5oC for 1 h. The precipitated mercuric chloride 45 was filtered off and the filtrate washed successively with dilute HCI, NaHC03 and brine. Then the organic solution was saturated at 5'C with hydrogen sulfide in order to precipitate the remaining mercuric impurities as mercuric sulfide. The crude thioester obtained after evaporation of the solvent was purified on a silica gel column (8.5 x 9 cm), eluting with dichloromethane (500 ml) and 15% acetonitrile-clichloromethane: 5.1 g (74.6%); 'Hmr (CDC13) 6: 3.70 (11-1, m, H-l'), 2.98 (11-1, m, H-3),2.33 and 2.20 (31-1, 2s, acetyl), 1.28 (31-1, d,J=6.2 50 Ha, H-2'); irvm,,x: (CHC13): 2115 (N3),1758,1693 and 1620 cm-' (C=O) WR,5R,6Sand l'S,5S,6R) paranitrobenzyl 6-(1'azi.dol-ethyl)-2- methylpenem-3-carboxylate (isomer 8) N - N 1 3 ' t4C":Z:Ch 3 1 '53 0 J_ 01 1 1.. - 'LOP-17.

2 A solution of (VR,5R,6S and VS,5S,6R) 4-acetyithio-2-(1'-azido-l'-ethyi)- 1 -paranitrobenzyl 2"triphenylphosphoranylidene-2"-acetate)-2-azetidinone (5.1 g, 13.1 mmol) in toluene (100 mi) was refluxed 60 for 2 h under nitrogen. The solvent was evaporated and the reaction mixture purified by chromatography on a silica gel column (7. X 5 cm). The azido penem was eluted with dichloromethane (further elution with 10% ether-dichloromethane allowed to recover 1.82 g of unreacted phosphorane). 1.21 g (40.6%) mp 132-WC; 11-1mr (C1DC13) 6: 8.21 (21-1, cl, Hm aromatic), 7.60 (21-1, cl, Ho aromatic), 5.51 (1 H, cl, J=1.6 Hz, H-5), 5.33 (21-1, ABq,H-benzyi),3.92(1H,dq,J=8,6.4Hz,H-1'),3.67(1H,dd,J=1.6,8Hz,H-6),2. 37(3H,s,CH:3),1.46(3H,d, 65 GB 2 042 515 A J=6.4 Hz, H-2'); ir v,,.. (CDC13): 2123 (N30788 and 1712 em-' W=O).

(1W,5R,6S and l'S,5S,6R) 6-(1.amino- l.ethyl)-2-methylpenem-3-carboxylic acid (isomer B) 3 2 ' tIN2 '.,,-. CH 3 2N A solution of (VR,15F1,6S and VS,5S,61R) paranitrobenzyl 6-(1'-azido-l'- ethyi)-2-methyl penem-3-carboxylate 10 (440 mg, 1.13 mmol) in THF-ether- water (MA) (120 mi) was hydrogenated at 50 psi for 1 h in the presence of 10% Pd-C (440 mg). The catalyst was filtered off, the filtrated extracted with ether and the aqueous phase lyophilized. The crude amino acid (100 mg) was purified by hplc: 19.5 mg 'Hmr (D20) 6: 5.69 (1H, d,J=0.9 Hz, H5),3.94(2H,m,H-6,H-1'),2.28(3H,s,CH3)il.50(3H,d,J=6.4Ha,H-2'); irymax(Nujol:l767,1576cm-1 (C=O); uv (H20) X,,,a,,: 300 MR (E5326).

PROCEDUREB (1W,3S,4S and l'S,3R,4S) 3-(1.azido- 1'-ethyl)-4-tritylthio-2azetidinone (Isomer 8) 143:1 3 si (CH3) 2 k t-5u 1 A_., SC3 h _ 1 _ H A solution of (VS,3S,4R and VR,3R,4S) 1 -(t-butyidimethyisiiyi)-3-(1'methanesuifonyloxy-l'-ethyi)-4tritylthlo-2-azetidinone (isomer C) (1.75 g, 3 mmol) and sodium azide (0.39 g, 6 mmol) in 10% H20MMPA (15 mi) was heated under N2 at 750-800C for 3 h. Then the reaction mixture was diluted with ethyl acetate and washed several times with brine. The organic phase was dried (M9S04) and evaporated to leave an oil which crystallized spontaneously. Trituration in ether and filtration gave 951 mg (76.5%) of the azido compound as a white solid mp 185-90'C, dec. 'HMR (CDC13) 6: 7.23-7,78 (15H, m, aromatics), 4.43 (1 H, d, J=3, H-4),437 (1 H, s, N-H), 3.89 (1 H, dq, J;--7, 6.5, H-1% 3.16 (1 H, dd, J=7,3, H-3),1. 50 (3H, d, J=6.5, H-2'); ir Yrna. (CHC13):

3410(n-H),2123 (N3) and 1765cm-1 (C0).

(1W,3S,4R and l'S,3R,4S) 3-(1 -amino- 1.ethYI)-4-tritylthio-2-azetidinone (Isomer 8) 14 3: 3 _11 f-'s H lif V'250 3 H A suspension of (V13,3S,4R and VS,3R,4S) 3-(1'-azido-l'-ethyl)-4- trityithio-2-azetidi none (isomer B) (1.0 9, 2.41 mmol) and platinum oxide (100 mg) in ethyl acetate (100 mi) was hydrogenated for 1 h at a pressure of 50 psi. Since the reaction was incomplete, 200 mg of platinum oxide was added and the mixture hydrogenated for one additional hour. Finally, 200 mg of platinum oxide was again added and the reaction continued for 2.5 h. Total catalyst: 500 mg. Total time: 4.5 h. Then the catalyst was filtered off and the solvent evaporated. The crude amine crystallized from ether: 700 mg (80%). mp 128'-300C. 'Hmr (CDC13) 6: 7.13-7.63 (15H, m, aromatics), 4.40 (1 H, d, J=2.5, H-4),4.30 (1 H, broad, H-1), 3.30 (1 H, dq, J=5.1,63, H-1% 3.03 (1 H, dd, J=5.1,2.5, H-3),1.20 (3H,d,J=6.3, H-2') and 1.0-1.80 ppm (2H, broad, NH2).

(1W,3S,4R and l'S,3R,4S) 3-(1'p-nitrobenzyloxycarbonylamino- 1'-ethyl)-4tritylthio-2-azetidinone (Isomer 8) so P'C02 C'C 3 A solution of (V13,3S,4R and VS,31R,4S) 3-(1'-amino-l'-ethyi)-4trityithio-2-azetidinone (isomer B) (1.00 9, 2.57 mmol) in dichloromethane (100 mi) was cooled to 50C and treated with p-nitrobenzylchloroformate (0.61 g, 2.83 mmol) and pyridine (0.22 g, 2.83 mmol). After stirring at 50C for 45 min and at room temperature 55 for 2.25 h, the reaction mixture was washed with dilute HCI, brine, dried (M9S04) and finally evaporated to dryness. The crude carbamate was crystallized from ether: 1.03 g (70.5%). mp 147-50'C. 'Hmr (CDC13) 8:

7.10-8.33 (19H, m, aromatics), 5.23 (2H, s, benzyt), 5.08 (1 H, N-H), 4. 40 (1 H, s, N-H), 4.29 (1 H, d, J=2.2, H-4), 4.10 (1 H, dq, J=8,6, H-1% 3.18 (1 H, dd, J=2.2, 8, H-3) and 1.23 ppm (3H, d, J=6, H-2'); ir Ymax (CHQ3): 3395 (N-H), 1765 and 1724cm(C=O).

Q R 91 GB 2 042 515 A 91 (1'R,5R,6Sand 1'S,5S,6R)p-nitrobenzyl2-methyl6-(1'.pnitrobenzyloxycarbonylamino-l.ethyl)penem-3carboxylate (Isomer B) NHCO PU NMC02PN5 2 0 3 1 S -1fSc H -11 3 5 11 2 PNES The title product was prepared from (1'R,5R,6S and VS,5S,61R) 3-(1'-pnitrobenzyloxycarbonylamino-l'ethyl)-4-trityith i o-2-azetidi none (isomer B) bythe standard procedure; mp 108-110"C. 11-1mr (CD03) 6: 10 7. 50-8.40 (8H, m, aromatics), 5.58 (1H, d,J=1.20, H-5),5.35 (2H,ABcl, benzyl ester), 5.20 (2H, s, benzyl carbamate),4.90(1H, broad N-H),4.20(1H, dq,J=6,8,H-1'),3.80(1H,dd,J=1.2,8.0,H-6),2.40(3H,s,(CH3), 1.40 (3H, d,J=6,CH3); irvr,,,>,: 3435 (n-H), 1777 and 1717cm-1 (C=O).

The p-nitrobenzyl ester may be subjected to catalytic hydrogenation as by the procedure of Example 43 (Procedure A) to provide the corresponding carboxylic acid.

EXAMPLE 44 6-Dimethylaminomethyl-2-methylpenem-3-carboxylic Acid cz N --, &1 20 20 1-(t-butyldimethylsilyl)-3-dimethylaminomethyl-4-tritylthio-2-azetidinone (cis and trans), 0 C C4 3 SC3 Me 2" 111 M' 2 NaB H 3 CN CH 3 N. Me 0!; i, 2 \t-Bu \t-B.

To a solution of dimethylamine (18.5 mi of a 2N solution in methanol, 36. 9 mmoles) in methanol (80 mi) was added a solution of hydrochloric acid in methane (2.5 mi of a 5N solution in methanol) followed by trans 30 1-(t-butyidimethylsiiyi)-3-formyl-4-trityithio-2-azetidinone (3.0 g, 6.16 mmoles) and by sodium cVanoboro hydride (0.27 g, 4.31 mmoles). The mixture was stirred at room temperature for 3.5 h, poured onto ice-hydrochloric acid (pH=2) and made basic with sodium hydroxide (1 N NaOH,pH=9). The mixture was extracted with ether and the ether phase was washed with brine, dried and evaporated to give the title compound as a crude oil (3.0 g).

cis and trans 3-dimethylaminomethyl-4-tritylthio-2-azetidinone 4,' 111 I''SC3 N.N3.4 IN SCO 3 1 \t-Bu A solution of the above crude compound (3.0 g, 6 mmoles) in hexamethyl phosphorous triamide (HMPT, 16 m[) containing water (10%) was cooled (5o) and treated with sodium azide (0.78 g, 12 mmol). The mixture was stirred 1.5 hat room temperature, poured onto ice-water and extracted with ether (5 X 30 mi). The organic 45 phases were extracted with hydrochloric acid (1 N) and the acidic extracts washed wellwith ether to remove the HMPT. The acidic phase was made basic (1 N, NaOH) and extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated to give the title compounds as an amorphous white solid (1.5 g, 62.5% overall). The mixture of isomers was separated on a Waters Prep 500, eluting with methanol (5%), ammonia (0.2%), ethyl acetate (95%). Trans isomer: 1.0 9, m.p. 129-131'C (pentane); 6 (ppm, 50 CD03): 6.8-7.8 (15H, m, aromatics), 4.5 (1 H, N-H), 4.28 (1 H, d, J=2.5, H-4),3.35 (1 H, m, H-3). 2.75-2.1 (2H, m, H-11 2.3 (6H, s, CH3).

Cis isomer: 0.5 g, m.p. 132-3'C (ether-pentane); 6 (ppm, CDC13): 73-6.7 (15H, m, aromatics), 4.72 (1 H, N-H), 4.5 (1 H, d, J=5.3, H-4), 3.5 (1 H, m, H-3), 2.85-2.35) (2H, m, H-1'), 2. 31 (6H, s, CH3). The cis to trans ratio can be varied by changes in conditions.

cis and trans 6-dimethylaminomethyl-2-methylpenem-3-carboxylic acid The title compound was prepared from cis and trans 3-dimethylaminomethyl4-tritylthio-2-azetidinone by the procedure of Example 58.

(ppm,CDC13):5.5(lH,d,J=1.3),3.7(lH,dt,J=1.3,J=8),2.8(2H,d,J=8),2.35(6H,s), 2. 3(3H,s).

92 GB 2 042 515 A EXAMPLE 45 2-Aminoacetoxymethyl-penem-3-carboxylic Acid (via mercaptide intermediate) 92 H20C':'21H2 5 A C02'4 4-Azidoacetoxyacetylthio- 1-(paranitrobenzyl2.triphenylphosphoranylidene2-acetate)-2-azetidinone 0 ON C1COC4,N3 3 10 N 03 C6H5.4 O'EQ-3 r.2,PtIB 02p'13 A cold (ice-MeOH bath) solution of 4-hydroxyacetylthio-1 (paranitrobenzyl 2'- triphenylphosphoranylidene-2'-acetate)-2-azetidinone (586 mg, 0.954 mmol) in methylene chloride (15 m[) is was treated successively with azido acetyl chloride (240 mg, 2.01 mmol) and dropwise with pyridine (226 mg, 231 m], 3.0 mmol) in methylene chloride (10 mi); At the end of the addition tic showed disappearance of starting material. The mixture was diluted with ether, washed successively with dilute I-ICI, water, dilute aqueous sodium bicarbonate, water and brine. It was dried over sodium sulfate. Purification of the residue was performed on a silica gel (10 g) column, eluting with 20% ether in benzene, ether, and 30% ethyl acetate 20 in ether. Concentration of the pertinent fraction gave the title compound as a foam; 533 mg, 80.1%; irv,,,x:

(CI-IC13): 1763,1702 (C=O), 1625 (CP03),1522 (N02) and 2110 cm-1 (N3).

paranitrobenzyl2-azidoacetoxymethylpenem-3-carboxylate N3 25 3 N A solution of phosphorane (533 mg, 0.764 mmol) was heated under reflux in toluene (90 mi) for 0.5 h using 30 a catalytic amount of hydroquinone. The solvent was concentrated on the evaporator and the concentrated solution was passed through a silica gel (10 g) column. (benzene: ether, 48:2). It gave the title compound (236 mg, 73.7%) as an oil. This oil was found to be unstable at room temperature. It was kept at -78'C until neededAmr (CIDC13) 6: 8.21 (2H, d, Hm aromatic), 7.57 (21-1, cl, Ho aromatic), 5.68 (1 H, dd, J5-6,js=4, J5-6 trans=2, H-5)o 5.43 (2H, center of A13q, J=16, CH2-PNB), 5.39 (21-1, CH20),193 (21-1. s, CHA3),172 (part of dd, 35 J6-5,j,=4, H-6), and 3.50 ppm (11-1, dd,Jgem=17,J6-5trans=2o H-6); irymax (CI-IC13): 1795,1755,1710 (C=O), 1525(N02),2110cm-l(N3).

2-Aminoacetoxymethylpenem-3-carboxylic acid 0 0 40 "2 B 2 A mixture of above ester (219 mg, 0.522 mmol) in TH F (16 mi)-ether (30 mi) and water (16 ml) was shaken 45 on a Parr hydrogenerator for 2.25 h at 50 psi of H2 using 10% Pd/C (240 mg) as catalyst. The catalyst was filtered off and washed with water and ether. The aqueous phase was washed with ether (3 x 30 mi) and Iyophilized. The crude powder was purified on a reversed phase hplc column and gave the title compound (8 mg, 6.7%) as a white powder.'Hmr (D20) 6: 5.72 (1 H, dd, J5-6,j,=3.5, J5- 6 trans=2, H-5), 5.37 (21-1, center of ABq, J=13.5, CH2-0),3.96 (21-1, s, CH2-NH2),3.87 (1H, dd,Jgem=16.5,J6-5ci=3.5, H-6) and 3.49 Nmr (11-1, dd, Jgem=16.5,J6-5trans=2, H-6); irvrnax (nujol): 1775,1755 and 1600 cm-1 (C=O); uv (H20) Xn,,306 (E4900), 256 (E3000).

EXAMPLE46

Silver 1-(P-Trimethylsilylethyl-2'-triphenylphosphoranylidene-2'-acetate)2-azetidi none-4-thiolate SA9 0 -f. 1 -,c. 1 2CH2C1251-(:113 ' 'CH3 di-p-trimethylsilylethyl fumarate 0 cl, 'i- cl 51 tCI13) 3 1,1, C 0 pyridin. 3 3 ' 0 (C4 3) 3 0 93 GB 2 042 515 A 93 To a cold (-100C) ether (20 ml) solution of 2-trimethylsilyl ethanol (4. 73g,0.04mmol) [H. Gerlach Helv. Chim Acta 60,3039 (1977)] and pyridine (5- 66 m 1, 0.07 mol), under nitrogen, was added dropwise (15 min) fumaryl chloride (3.78 ml,0.035 mol) dissolved in ether (10 ml). 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% p- brine (1:1, 150 ml). The aqueous phase was back extracted with ether (30 ml). The ether solutions were combined, washed with brine, dried over sodium sulfate, 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 ml) as eluent to give an oil (4.855 g, 77%) which solidified on standing: mp 33-34C. Anal. calcd for C14H2804S!2: C 53.12, H 8.91; found: C 53.35, H 8.91. 'Hmr (CDC13) 8: 6.78 (2H, s, C=CH),4.26 (4H, m, CH2-0),1.03 (4H, m, CH2-S0 and 0.06 ppm (18H,s, (CH36SO; ir 10 (CHC13) Vmax: 1710 (C=O of ester), 1643 (C=C), 1267,1258,862 and 840 cm-1 (Si-C).

Trimethylsilylethylglyoxylate hydrate [CII 3) 351 1!3)3 2) (C'3 2' ll ' Cq 313 02 Asolution of di-p-tri methyl silyl ethyl furnarate (37 g, 0.117 mmol) in methylene chloride (1.1 e) was ozonized at -78'C until a blue color persisted. The excess ozone was purged with nitrogen and dimethyl sulfide (2.57 ml, 0.351 mol) was added. The solution was allowed to gradually warm to 23'C. The reaction mixture was diluted with carbon tetrachloride to 2 liters and washed with 1% aqueous solution of sodium carbonate (500 ml). The organic phase was dried over sodium sulfate, filtered on Celite and evaporated (-25'C) to dryness to give 43.9 g of the title compound (97%); ir (neat) vm,,x: 3450 (-OH), 1740 (ester, 1255, 860and840cm-'(Si-C).

1-(p-trimethylsilylethyl2'-hydroxy-2'-acetate)-4-tritylthio-2-azetidinone r__.T. ' s'.CH 0 '-s -H cc) 2 C Tr S: - , - 1 H 1 ' "C" 3) 3 0 2 Trimethylsilylethyl glyoxylate hydrate (4.000 g, 11.6 mmol) and the 4tritylthio-2-azetidinone (4.8 g, 24.96 mmol) were refluxed in benzene (25 ml) 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, 35 8.5 x 14.5 cm) and eluted with ethyl acetate: methylene chloride (M9) until the title compound started to come out (1.5,e) and then with ethylacetate: methylene chloride (1:9, 2, e). The fractions containing the title compound were combined and evaporated to dryness to give 5.415 g (89%) of the title compound. 'Hmr (CDC1 3) 6: 7.80 to 6.70 (15H, m, trityl), 5.23 and 4.90 (1 H, 2s, H-C-0), 4.50 to 4.10 (3H, m, H-3 and O-CH2),2,60 (2H, m, H-2),0.95 (2H, m,CH2-Si and 0.1 ppm (9H,s,Si-CH3); ir(CHC1:3)Vrna> ,: 3520 (-OH), 1765 (C=0 of 40 P-factam), 1740 (C=0 of ester), 1595 (C-H, aromatic), 1257,860 and 840 cm (C-Si) 1-(p-trimethylsilylethyl2'-chloro-2'-acetate)-4-tritylthio-2-azetidinone P" ST, SI ",-, (C"31 3 2 "OC12 pyridine 1 (CH 3) 3 C02 A solution of thionyl chloride (0.74 mi, 10.37 mmol) in dry THF (9 mi) was added dropwise with stirring to a solution of 1 -(P-tri methyl si lyl ethyl 2'-hyd roxy-2'-acetate)-4- trityith io-2-azetid i none (4.9 g, 9.37 m m o 1), pyridine (0.84 mi, 10.38 mmol) and dry THF (40 ml) at -WC under a nitrogen atmosphere. The mixture was stirred at -WC for 2 h. The precipitate was removed by filtration on a Celite pad and washed with benzene (50 m]). The filtrate was evaporated in vacuo at WC. 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 (100g,4.7 x 11 cm): hexane-benzene (1:1,400 ml), ether-benzene (M9,1 ie).

Evaporation of the pertinent fractions gave 4.64 g of the title compound (92%). 'Hmr (CDC13) 6: 7.30 (15H, m, aromatic H), 5.77 and 5.43 OH, 2s, CH-CO, 4.7 to 4.2 (3H, m, H-4 and CH2- 0),2.85to 2.50 (2H, m, H-3),1.15 (2H, m, CH2-Si) and 0.06 ppm (9H, s, Si-CH3); ir (neat) Vmax: 1760 (C=O), 860 and 840 cm-1 (C-Si).

601-(p-trimethylsilylethyl2'-triphenylphosphoranylidene-2'-acetate)-4trity lthio-2-azetidinone Tr N C 1 5(CH 2 3 3 0 3P P- 2,6-lutidine P- 51 (CH 3) 3 2 94 GB 2 042 515 A 94 A dioxane (20 mi) solution of the above chloroazetidinone (4.12 g, 7.568) was treated with triphenylphosphine (2.209 g, 8,424 mmol) and 2,6- 1utidine (0.98 m[, 8.424 mmol). The mixture was refluxed for 3.5 h. The cooled solution was filtered and the white solid washed with THR The filtrate was evaporated to dryness. The residue was purified on a silica gel column (200 g, 4 X 31 cm) using ethyl acetate-hexane (3:7, 1 e; 7:3, 1 e) to give the title phosphorane (4.836 9,83%). ir (film) Ym,,.: 1755 (C=O), 1615 (phosphorane), 850 and 830 cm-' (Si-C). Anal. calcd for C47H46NO3PSSi: C 73.89, H 6.07, N 1.81; found: C 72.18, H 6.08, N 1.83 Silver 1-(0-trimethylsitylethyl2'-triphenylphosphoranylidene-2'-acetate)2-azetidin one-4-thiolate ST- A9.40 4 10 CF3CC2 h c rTn 1 r ', 3 3 'B,3" "'.:h 3 2 3 1-(P-trimethylsilyiethyl 2'-triphenyl phosphoranylidene-2'-azetate)-2- azetidinone (7.64 g, 10 mmol) was dissolved in ether (60 ml). An aqueous solution of silver nitrate (0.5M, 80 ml, 40 mmol) was added followed 15 by a rapid addition (1 min) of a solution of tributylamine (3 ml, 12.58 mmol) and trifluoroacetic acid (0.154 ml, 0.2 mmol) in ether (20 ml). The mixture was mechanically stirred for 19 min. The precipitate was filtered, rinsed with ether (200 ml). Triturated in water (70 ml), filtered again and rinsed with ether (100 ml). The light brown solid was dired under vacuum (water aspirator 10 min and pump 65 min) to give the title compound (6.42 g). IR (CHCL3) 'Max: 1862 (C=O, 1630 (Phosphorane), 860 and 840 cm - 1 (SI-Q.

EXAMPLE 47 6-Formamidomethyl-2-methylpenem-3-carboxylic acid, sodium andpotassium salts H 5 25 U11 NN- Q p 2 trans 1-(t-butyldimethylsilyl)-3-methanesulfonyloxymethyl-4-tritylthio-2azetidino ne 4 30 C,^ 3 4.0 (CH 3) 2 3)2 t-Bu t-B.

Asolution of trans-l-(t-butyidimethyisiiyi)-3-hydroxymethyi-4-trityithio2-azetidinone (8.0 9,16.36 mmol) 35 in dichloromethane (50 mi) was treated at 50C with methanesulfonyl chloride (1.4 mi, 18 mmol) in dichloromethane (10 mi) and triethylamine (2.5 mi, 18 mmol). Stirring was maintained for 1 h under N2. Then the solution was washed successively with cold 1 N hydrochloric acid, 1 M sodium bicarbonate and brine, dried (M9S04) and evaporated in vacuo. The residue (mixture of hydroxy and mesylate cpd) was treated a second time as before, to give the mseylate (90 g, 97%) as an amorphous solid. It was used as such in the 40 next step without further purification. The analytical sample was recrystallized from methylene chloride mp 167-168OC; ir (neat) vma>,: 1755 cm-l; 11-1mr (C13C13) 8: 7.3 (15H, m), 4. 4 (1 H, d, J=21-1z), 3.9 (1 H, dd, J=8Hz, 4Hz), 3.2 (2H, bs), 2.8 (3H, s), 0.95 (9H, s) and 0.3 ppm (6H, s).

trans 3-methanesulfonyloxymethyl-4-tritylthio-2-azetidinone and trans-3azidomethyl)-4-tritylthio-2- 45 azetidinone SC H H 3 N SC9 M50 3 'H3 2 50 t---- A solution of trans -1-(t-butyidimethyisilyi)-3-methane-suifonyimethyl-4trityithio-2-azetidinon e (21.0 g, 37.0 mmol) in HMPA (90 mO was cooled in an ice bath and treated with sodium azide (2.7 g,41.2 mmol) in H20 (10 mi). The reaction mixture was stirred at room temperature for 1 h, diluted with ethyl acetate, washed with H20 (5 x 100 mi), dried (M9S04) and evaporated in vacuo. The trans-3- methanesuifonyloxymethyl-4tritylthio-2-azetidinone was diluted with HMPA (90 mi), treated at room temperature with sodium azide (2.7 g, 41.2 mmol) in H20 (10 mi), heated at WC for 2 h and triturated with cold water. The crude azide was diluted with benzene-ether (5: 1) and washed with water (5 x 20 m]). Evaporation of the solvent followed by crystallization from ether gave 18.0 g (77%) of azide as a white solid. The analytical sample was recrystallized from CH2C12/ether mp 174-50C; Anal. calcd for C23H2ON4OS: C 68.97, H 5.03, N 13.99; found C 68.78, H 5.00, N 60 14.16; ir (nujol) vmx: 2100,1765 cm-l: 'Hmr (CDC13) 6: 7.35 (15H, m), 4. 75 (1 H, bs), 4.4 (1 H, d J=21-1z), and 11-3.7 ppm (3H, m).

2k GB 2 042 515 A 95 trans-3-aminomethyl-4-tritylthio-2-azetidinone N,. H H se 3 3 N1. U U-' -sc 3 0,;- Ne To a solution of trans 3-azidomethyi-4-trityithio-2-azetidinone (10.0 g, 47.5 mmol) in dry methanol (500 mi) was added ammonium chloride (19.0 g) and zinc powder (1.0 g) and the suspension was stirred at room temperature for 5 h. The reaction mixture was filtered and evaporated. The residue was partitioned between 1 N hydrochloric acid and benzene. The aqueous layer was basified with 1 M sodium bicarbonate and extracted with methylene chloride. The extracts were washed with brine, dried (M9S04) and evaporated in vacuo. The crude amine crystallized from ether, 14.05 g (79%); mp 1139-9'C; Anal. caled for C231-122N20C0/4 CH2C12: C 70.56, H 5.73, N 7.08; Found: C 70.68, H 5. 94, N 7.27; ir (CHC13) vmax: 3400 and 1760 cm-l; 11-1mr (CDC13) 6: 7.35 (15H, m), 5.15 (1 H, m), 4.3 (1 H, bs), 23-3.5 (3H, m) and 1.3 ppm (2H, m).

trans 3-phthalimidomethyl-4-tritylthio-2-azetidinone H H H "" ' SC 3 2 1 5-3 H A solution of trans 3-a m i no m ethyl-4-tritylth io-2-azetid i none (13. 9 g, 37.2 mmol) and Ncarbethoxyphthalimide (8.3 g, 37.9 mmol) in benzene (200 mi) was heated under reflux for 15 h. The solvent was evaporated in vacuo and the residue crystallized from ether to give 17.4 g (93%) of the title compound; 25 mp 172-3'C; Anal. calcd for C311-124N203S: C73.78, H 4. 79, N 5.55, found: C 73.92, H 4.87, N 5.49; ir (CHC13) v,ax: 1770 and 1715 cm-l; 11-1mr (CDC13) 8: 7.8 (4H, m), 7.3 (15H, m), 4.45 (1H, d, J=2Hz), 3.34.1 (3H, m) and 3.34.6 ppm (1 H, m).

is trans 3-phthalimidomethyl- 1-(paranitrobenzyl2'-hydroxy-2'-acetate)-4tritylthio-2-azetidinone sc --, @i:.' CO A mixture of trans-3-phthalimidomethyl-4-tritylthio-2-azetidinone (17.4 9, 34.52 mmol), paranitrobenzyig- 35 Iyoxylate hydrate (9.4 g, 41.4 mmol) and triethylamine (4.8 mi, 34.5 mmol) in tetrahydrofuran (250 mi) was stirred at room temperature for 20 h. The reaction mixture was evaporated in vacuo and the residue was treated with charcoal in benzene. Evaporation of the solvent yielded the crude hydroxyglyoxylate (25 g, quantitative) as an amorphous solid. It was used in the next step without further purification. ir (CHC13) Ymax:

1770 and 1715 cm-l; 'Hmr (CDC13) 6: 8.1 (2H, cl, J=9Hz), 7.55 (3H, cl, J=9Ha), 7.3 (19H, m), 5.0-5.4 (2H, bs), 40 43-5.0 (2H, m) and 2.8-3.8 ppm (4H, m).

trans-3-phthalimidomethyl- 1-(paranitrobenzyl-2'-chloro-2'-acetate)-4tritylthio-2-azetidinone C02P%.a 0 V SCO cc, PN8 2 To a cooled (ice bath, OOC) solution of trans-3-phtha li miclomethyl-1 (paranitrobenzyl-2'-hydroxy-2- acetate)-4-tritylthio-2-azetidinone (25 g, 35 mmol) in tetrahydrofuran (150 ml) was added dropwise a 1M solution of thionyl chloride in tetrahydrofuran (46 ml, 46 mmol) followed by a 1 M solution of pyridine in tetrahydrofuran (46 ml, 46 mmol). The reaction mixture was stirred at room temperature for 20 min, diluted with pet-ether (50 ml) and filtered over a Celite/charcoal bed. The solvent was evaporated in vacuo to give the chloro azetidinone (26 g, quantitative) as an amorphous solid. It was used in the next step without further purification. ir(CHC13)Yrnix: 1775 and 1720 cm-1. 'Hmr(CDC(3) 6: 8.12 (2H, d,J=9Hz),7.60 (2H, d,J=9Hz),7.3 55 (19H, m),5.25 (2H, m),4.7-5.4(1H, m), 4.55(1H, bs) and 3.34.0 ppm (3H, m).

trans-3-phthalimidomethyl- 1-(paranitrobenzyl-2'triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2 azetidinone 0 0 Y 3 C%P" A mixture of tra ns-3-p hth & i mido m ethyM -(pa ran itro benzyl-2'-ch 1 o ro-2'-acetate)-4-trityith io-2-azeticli none 65 96 GB 2 042 515 A 96 (26 g, 35.5 mmol), tri phenyl phosph i ne (10.25 g, 39.1 mmol) and 2.6 lutidine (4.6 mi, 39.1 mmol) in dioxane (200 mi) was heated at 1 OOOC for 20 h. The reaction mixture was filtered over Celite and evaporated. The residue was chromatographed on a silica gel column (350 g) eluting with benzene to benzene/ether (1: 1) to yield the phosphorane (21 g, 62%) as a white solid. ir (CHC13) Ymax: 1750 and 1710 cm-1. 'Hmr (CDC13) 6: 7.4 5 (38H, m), 4.8-5.4 (3H, m), 4.6 (2H, m) and 3.7 ppm (1 H bs).

trans-3-phthalamidomethyl- 1-(paranitrobenzyl-2'triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2- azetidinone 4 H sc ca pa 0 9 H N C 3 C 2H 3 C02P:,3 j A cooled (ice bath) suspension of trans-3-phthalimidomethy]-1 - (paranitrobertzyi-2'triphenylphosphoranylidene-2'-acetate)-4-trityithio-2-azetidinone(18.02g, 18. 83mmoi)intetrahydrofuran 15 (30 mO, water (30 mi) and acetone (30 mO was treated dropwise with sodium suifide (4.97 g, 20.7 mmol) in acetonelwater 1:1 (30 m]) and heated to reflux for 8 h. The reaction mixture was diluted with water, acidified with 1 N hydrochloric acid and extracted with dichloromethane. The organic extracts were washed with brine and evaporated in vacuo to give 17.1 g (88%) of the title compound as an amorphous light yellow solid. It was used in the next step without further purification. ir (neat) Y,,,x: 3150-3600,1750 and 1700 cm-l; 'Hmr 20 (CDC13) 6: 7.4 (38H, m) and 33-5.5 ppm (81-1, m).

trans-3-phthalisoimidomethyl- 1-(paranitrobenzyl-2'triphenylphosphoranylidene-2'acetate)-4-tritylthio-2azetidinone on 25 ^L Y"C3 503 - 14 J:-'(1 "3 0 3 C021>i3 A solution of trans-3-phth a 1 i m ido methyl -1 -(pa ran itrobenzyl-2'- trip henyl phospho ra nyl idene-2'-acetate)-4- 30 tritylth io-2-azetid i none (17.1 g, 17.54 mmol) in dichloromethane (125 mi) was treated dropwise at room temperature with N,N'-dicyclohexylcarbodiimide (3.62 g, 17.54 mmol) in dichloromethane (30 ml). The solution was filtered over Celite and evaporated to give the title compound (18.23 g, quantitative) as an oil. It was used in the next step without further purification. ir (neat) Ymax: 2110, 1755 and 1710 cm-l; 1 Hmr (CDC13) 35 6:7.5(38H, m),4.6- 5.3 (4H, m) and 3.9 ppm (21-1, bs).

trans-3-aminomethyl- 1-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'acetate)-4-tritylthio-2azetidinone 0 4 sc: N H H 5n 40 2 0 '1 ,e" YP 3 02p!ra C,3,Pra A solution of tra ns-3-p hth a 1 isoi m i do m ethyl)-1 -(pa ran itrobenzyI-2'-tri phenyl p h osphorahyl idene-2'acetate)-4-tritylthio-2-azetidinone (5.9 g, 6.16 mmol) in tetrahydrofuran (40 mi), cooled to -20'C, was treated 45 dropwise under N2 with hydrazine (0.2 mI, 6.16 mmol) and stirring was maintained for 30 min. The reaction mixture was acidified with 1 N hydrochloric acid and washed with ether; the aqueous phase was basified with 1 M sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine, dried (M9S04) and evaporated. The residue was purified on a silica gel column (60 g) eluting with so ether to ethyl acetate to give 3.38 g (66%) of the amino phosphorane as an amorphous solid. ir (CHC13) Ymax: 50 1730,1710cm-l; 'Hmr(CDC13) 6: 6.5-8.1 (34H, m),3.8-5.3(6H, m) and 0.9-1.9 ppm (21-1, m).

trans 3-formamidomethyl- 1-(Paranitrobenzyl-2'-triphenylphosphoranylidene2'-acetate)-4-tritylthio-2azetidinone ', p, se 55 Ir j ' 1C. 3 2 "' To a cooled (ice bath) solution of trans 3-(a mi nomethyM -(pa ran itrobenzyi-2'triphenyl phosphora nyl idene-2'-acetate)-4-trityith io-2azetid i none (5.0 g, 6.04 mmol) in dichloromethane (50 m]) was added dropwise under N2 a solution of acetic formic anhydride (600 mg, 6.8 mmol) in dichloromethane (5 mi) followed by a solution of triethylamine (1 mi, 7 mmol) in dichloromethane (2 mi). Stirring was continued for 30 min. The solution was washed successively with 1 N hydrochloric acid, water, 65 1 M sodium bicarbonate and brine. The organic layer was dried (M9S04), evaporated and the residue was 97 GB 2 042 515 A - 97 chromatographed on a silica gel column (50 g). Elution with etherto ethyl acetate yielded 2.0 g (30%). of the formamide as an amorphous solid. ir (CHC13) Ymax: 1740,1685 and 1620 cm-l; 11-1mr (CDC13) 6: 6.6-8.2 (35H, m), and 25-5.3 ppm (7H, m).

trans silver 3-formamidomethyl- 1-(paranitrobenzyl-2'triphenylphosphoranylidene-2'-acetate)-2azetidinone-4-thiolate SCC 2PN2 1.

,,, 1 i'd -9 J11N A solution of trans 3-formamidomethyi-l-(paranitrobenzyi-2'triphenylphosphoranylidene-2'-acetat e)-4- tritylthio-2-azetid in one (550 mg, 0.64 mmol) in dichloromethane (10 mi) was evaporated to dryness and diluted with hot methanol (20 mi). The solution was stirred at WC and treated with a pre-heated (60'C) solution of 0.15 M silver nitrate in methanol (5.7 mi, 0.86 mmol) followed by a solution of 1.5 M pyridine in 15 methanol (0.57 mI, 0.86 mmol). The creamy solution was stirred at room temperature for 30 min, then in an ice bath for 2 h. The solid was filtered washed with cold methanol and ether, and dried to give 300 mg (65%) of the silver salt as a beige solid. It was used in the next step without further purification.

trans4-acetylthio-3-formamidomethyl-l-(paranitrobenzyl-2'triphenylphosphora nylidene-2'-acetate)-2- 20 azetidinone H p 3 CO 2 pt-B ?,4 ', P P'3 CO,PNB To a cooled (ice bath) solution of trans silver 3-formamidomethyi-l- (paranitrobenzyi-2'- tri phenyl p h osph o ra nyl i dene-2'-acetate)-2-azetid in on e-4-th io late (800 mg, 1.11 mmol) in dichloromethane (10 ml) was added dropwise under N2 a solution of 1M acetylchloride in dichloromethane (1.33 mi, 1.33 mmol) followed bya solution of 1M pyridine in dichloromethane (1.33 mi, 1. 33 mmol). The solution was stirred in a cold bath for 1 h, and was then filtered over Celite. The filtrate was washed successively with 1 N hydrochloric acid, water, 1 M sodium bicarbonate and brine and the organic layer was dried (M9S04) and evaporated. The residue was purified on a silica gel column (5,0 g) and eluted with ethyl acetate to 10% methanol in ethyl acetate to give 450 mg (62%) of the title compound: ir (CHC13) Ynlax: 1755,1685 and 1620 cm-';'Hmr(CDC13)6:8.18(2H,d,J=9Hz),7.0-8.0(20H,m),6.75(2H,d,J=9Hz),6.3(1H, m),5.5(1H,m),5,2 35 (21-1, bs), 4.9 (1 H, bs), 3.6 (1 H, m), 3.0 (1 H, m) and 2.2 ppm (31-1, two s).

paranitrobenzyl 6-formamidomethyl-2-methylpenem-3-carboxylate "3.,P.

U H 1,. ' 5 H C, 02PN2 A sol ution of trans 4-acetylthio-3-forma m idomethyM -(paranitrobenzyi- 2'-tri phenyl phosphoranylidene-2'45 acetate)-2-azetidi none (450 mg, 0. 686 m mol) in toluene (10 m 1) was heated under reflux for 12 h. Concentration and purification on a silica gel column eluting with ether to 10% methanol in ether gavel 00 mg (39%) of the penem as an amorphous solid. ir (CHC13) Vrilax: 1780 and 1690 cm-l; 11-1mr (CDC13) 6: 8.2 (21-1, d, J=9Hz), 8.2 (1 H, s), 7.6 (21-1, d, J=91-1z), 6.9 (1 H, m), 5.55 (11- 1, s), 5.35 (21-1, 2s), 3.34.1 (31-1, m) and 2.33 ppm (31-1, s).

6-formamidomethyl-2-methylpenem-3-carboxylic acidsodium andpotassium salts C11 H C"2 HL '. ' 1 ', ",S 0 t! 2 A mixture of paranitrobenzy] 6-fo rm idom ethyl -2-methyl penem-3-ca rboxyl ate (80 mg, 0.21 mmol), palladium on Celite (30%, 100 mg), tetrahydrofuran (10 mi), ether (25 mi) and 0.05 M buffer solution pH 7 (4. 46 mi, 0.223 mmol) was hydrogenated on a Parr shaker at an initial hydrogen pressure of 45 psi for 3 h.

The catalyst was removed by filtration on Celite and washed with water. The filtrate and washings were combined and the phases separated. The aqueous phase was washed with ether (3 X 15 m]) and Iyophylized. The crude solid was purified by hplc to give 18 mg of a mixture of the sodium and potassium salts.

uv (H20) k,,,x: 299 (c 4933), 259 (F- 4094); ir (nujol) vmzx: 3100-3650 and 1755 cm-l; 11-1mr (D20) 6: 8.15 (1 H, s), 5.53 (1 H, cl, J=MHz), 4.0 (1 H, m), 3.74 (21-1, d, J=51-1z), 3.25-4.25 (1 H, m) and 2.27 ppm (31-1, s).

98 GB 2 042 515 A 98 EXAMPLE 48 (PS,5R,6S, and PR,5S,68) 6-(1'-Hydroxy1'-propyl)-2- methylpenem-3-carboxylic acid, sodium salt (isomer Q J1 J trans 1-t-Butyldimethylsilyl-3-propionyl-4-tritylthio-2-azetidinones CH3C82- cr- "3 0 5 LM e2 0 __A ST ".e 2 I- Procedure:

n-BuLi (37.50 m], 1.6M/hexane, 60 mmol) was added dropwise under N2 to a cooled (dry ice-acetone bath) and stirred solution of diisopropylamine (8. 50 mi, 60 mmol) in dry THF (200 mi). The mixture was stirred in the cold and 1 -t-butyidi m ethylsiiyi-4-trityith io-2-azeticli none (22.9 g, 50 mmol) in dry THF (100 mi) was added. After 15 min, methyl propionate (40 mi, excess) was added and the reaction mixture was kept at -780C for 4 h. Then the cooling bath was removed and the internal temperature was allowed to come to O'C (-40 min). It 20 was poured over ice-HCI (pH - 6) and extracted with ether. The layers were separated and the aqueous layer was extracted with ether. The combined ether solution was washed with water and brine and dried (Na2S04). It was evaporated in vacuo to give an oil in quantitative yield. This contained a mixture of starting material and title compound. It was used as such and purified in the next step.

0 1 ir (Neat) 1710 (-C-), 1750 cm-1 (P-Iactam).

1-t-Butyldimethylsilyl-3-(1'-hydroxy- 1'-propyl)-4-tritylthio-2azetidinones N.BH 0 1 N- 4 0i-T 35 Sim 2 2 Procedure:

A solution of 1 -t-butyldimethyisiiyl-3-propionyl-4-trityfthio-2azetidinone (26 g, 50 mmol) and sodium borohydride (7.6 g, 200 mmol) in THF (400 mi) was stirred at room temperature for 18 h. It was poured onto ice-HCI (1 N) (pH 6) and extracted with ether. The acidic phase was extracted several times with ether and the 40 combined ether solution was washed with brine, dried (Na2S04) and evaporated to give an amorphous solid, 25.0 g. This crude product was chromatographed on Si02 (ACT. 1, 400 g) and eluted first with CH2C12tO give 10.8 g of 1 -t-butyid i methylsi 1yl-4-trityith io-2-azetidi none. Elution with 20% ether in CH2C12 gave 10.3 g of the title compound as a mixture of two isomeric trans alcohols. This was separated by hplc (Water Associates, System 500), and using 10% EtOAc in CH2C12 as eluent. Isomer C, white solid, 3.8 g; mp (pet. ether) 134-36'C. 45 11-1mr (C1DC13) 6: 7.1-7.8 (15H, m, STr), 4.35 (H, d), 3.1 (H, dd), 2.5 (H, m), 03-1.7 (5H, m), 0.97 (9H, s) and 0.25 ppm (6H, s). Anal. calcd for C311-139NO2SSi: C 71.91, H 7.59, N 2.71; found: C 71.51,7.60, N 2.96. Isomer B, white solid, 5.4 g; mp (pentane-pet. ether) 97-99'C. 11-1mr (CDC13) 6: 7.1-7.8 (15H, m, STr), 4.15 (H, d), 3.4 (H, dd), 3.2 (H, m), 03-1.7 (5H, m), 0.85 (9H, s) and 0. 1 ppm (6H, s). 97-99'C, 'Hmr (CDC13) 6: 7.1-7.8 (15H, rn, STr), 4.15 (H, d), 3.4 (H, dd), 3.2 (H, m), 03-1.7 (5H, m), 0.85 (9H, s) and 0. 1 ppm (6H, s). Total yield of these two alcohols (based on recovered starting material was 67.5%.

WS,3S,4R and 1'R,3R.4S) 1-t-butyldimethylsilyl-3-(1'-paranitrobenzyldioxycarbonyl-l'-propyl)-4-trit ylthio2-azetidinone (isomer Q.

is Q W 50.1 55 ST, C'C02 PNB STr 0 sim,2 Proceaure: 60 Toacooled (dry ice-acetone bath) slution of WS,3SARand VR,3R,4S) 1-tbutyidimethyisiiyi-3-(1'- hydroxy-l'-propyi)-4-tritylthio-2-azetidinone (isomer C) (3.1 g, 6 mmol) in dry THF (20 m]) was added dropwise under N2 a solution of 1.6M n- BuLi/hexane (4.88 m], 7.8 mmol) stirred at -780C for 25 min. Paranitrobenzy] chloroformate (1.56 g, 7.2 mmol) in dry THF (10 mi) was then added dropwise and the resulting mixture was stirred at -780C for 4 h. It was diluted with ether and washed with NH4C1 solution and 65 99 GB 2 042 515 A 99 brine The organic phase was dried (Na2S04) and evaporated to dryness to give 4.2 g of title compound (Quantative yield). 'Hmr (C13C13) 8: 8.2 (2H, d), 7.0-7.7 (17H, m), 5.13 (2H, s), 4.05 (H, d), 3.75 (H, dt), 3.25 (dd), 0.55-1.8 (5H, m), 0.9 (91-1, s) and 0.25 ppm (6H, d).

(PS,3S,4R and 1S,3R,4S) 3-(1'-paranitr6benzyldioxycarbonyl-l'-propyl)-4tritylthio-2-azetidinone (isomer C)' 5 0C02PNB 0CO P:1M ST 2 HMPT NN3 'S' "k- 2 lot H 20) 10 Procedure:

To a cooled (ice bath) solution of (VS,3S,4R and VR,313,4S) 1-tbutyidimethyisiiyi-3-(1'paranitrobenzyid ioxy-carbonyi-l'-propyl)-4trityithio-2-azeti di none (isomer C) (4.2 g, 6 mmol) in HIVIPT (40 m]) containing 10% H20 was added sodium azide (0.78 g, 12 mmol). The mixture was stirred at room temperature for 1 h. It was diluted with water (100mi) and extracted with benzene: pet. ether (1: 1) (4 x 15 mi). The organic phase was washed several times with water (6 X 30 m]) and brine. It was dried (Na2S04) and evaporated to dryness to give 3.5 g of a solid (quantitative yield). It was treated with pentane and filtered to give 3.4 g of a pale yellow solid. mp 84-86'C; 11-1mr (CDC13) 6: 8.2 (2H, d), 7-7.7 (17H, n), 5.2 2H, s), 4.95 (H, dt), 4.4 (N H), 4.25 (H, d), 3.4 (H, dd), 1.7 (2H, m) and 0. 95 ppm (3H, t).

(1S,3S,4R and 1T,3R,4S) 3-(1'-paranitrobenzyldioxycarbonyl-ll-propyl)-1(paranitrobenzy12"-hydroxy-2 "hydroxy-2"-acetate)-4-tritylthio2azetidinone (isomer C).

J.

TH. 25 TEA C' 2"NB Procedure:

To a solution of (VS,3S,413 and V13,313,4S) 3-(1'paranitrobenzyidioxycarbonyi-l'-propyi)-4-trityithio-2- azetidinone (isomer C) (3.2 g, 5.5 mmol) and paranitrobenzyl glyoxylate hydrate (1.362 g, 6 mmol) in dry THF 30 (50 mi) was added a catalytic amount of TEA (4 drops) and Na2S04 (to absorb H20 formed). The resulting mixture was stirred at room temperature for 6 h. It was filtered and evaporated to dryness to give 4.35 g of an amorphous solid (quantitative yield). 11-1mr (CDC13) 6 8.25 (4H, dd), 7-7. 9 (19H, m), 5.28 (2H, s), 5.1 (2H, s), 4.8 (H, d), 4.4 (H, dd), 4.1 (H, dt), 3.4 (H, m), 1.1-1.8 (2H, m) and 0.8 ppm (3H, t).

(PS,3S,4Rand M,3R,4S) 3-(1'-paranitrobenzyldioxycarbonyl-l'-propyl)-1(paranitrobenzyl2"-chloro -7acetate(-4-tritylthio-2-azetidinone (isomer Q 0-0 2 Pt.-. ST- CCO 2 PNB --- _j Py/THF j 40 VH S"C 121-P5' C) ", m 2 B CO2r:;:

Procedure:

To a cooled (ice salt bath) solution of the above glyoxylate (4.35 9, 5.5 mmol) in dry THF (30 ml) was added 1 M py/THF (7 mI, 7 mmol) followed by dropwise addition of 1 M SOCI2/THF (7 mi, 7 mmol). The resulting mixture was stirred at the above-indicated temperature for 1 h It was diluted with benzene (30 mi), stirred in the cold (ice water bath) for 30 min and filtered over Celite-charcoal. The filtrate was evaporated to dryness to give 3.8 g of an amorphous solid (85.3%); 'Hmr (CDC13) 6: 8.15 (4H, d), 6. 75-7.7 (19H, m), 5.65_(H, s), 5.2 (2H, s), 5.1 (2H, s), 4.5 (H, m), 3.85 (H, m), 3.4 (H, m), 1.25-2.0 (2H, m) and 0.9 ppm (3H, t).

(PS,3SAR and M,3RAS) 3-(1'-paranitrobenzyldioxycarbonyl- V-propyl)- 1(paranitrobenzyl 7 triphenylphosphoranylidene-2"-acetate) -4-tritylthio-2azetidinone (isomer Q oco FINB OCC) P:iF 1---)', 2 ', Y 1-11. 2 ST, lutidine 0 2"NB. 2 PNB Procedure:

To a solution of the above chloro compound (3.7 9,4.568 mmol) in dioxane (35 mi) was added 03P (1.197 g, 5 mmol) and lutidine (0.54 g, 5 mmol). The mixture was heated in an oil bath at 1OWC for 3 days. It was 60 cooled, diluted with ether and washed successively with 1 N HQ, 1 M Nal- IC03 and brine. it was dried (Na2S04) and filtered over Celite-charcoal. The filtrate was evaporated to dryness to give 3.6 g of an oil. This was chromatographed on Si02 (120 9) and eluted with benzene, benzene- etherto give 1.45 g of title compound as an amorphous solid (31%); ir (neat) vmi,,<: 1750 em-' (broad).

GB 2 042 515 A (l'S,3S,4R and M,3R,4S) 4-acetylthio-3-(1'paranitrobenzyldioxycarbonyl- 1'-propyl)1-(paranitrobenzyl 7triphenylphosphoranylidene-2"-acetate)-2- azetidinone (isomer Q OCO 2 PINB ST -02P12B SAS rco,p!;b SA CH 3 C' O'03 IPYINoll 0 '1 Y P03 IYlme", 0 3 Co,PRB 'B PRB C.2" Procedure:

To a hot solution (60'C) of the above phosphorane (1.4 9,135 mmol) in MeOH (40'm1) was added with l 0 stirring a hot so] ution of Ag N 03 (0.3 g, 1.76. m mol) i n MeOH (10 m 1) fol lowed by pyridine (0. 107 g, 0. 11 mi, 1.76 mmol). The silver mecaptide began to precipitate immediately. The mixture was stirred at room temperature for 15 min and at O'C for 2 h. It was filtered, and the solid washed well with cold MeOH and ether, 1.2 g quantitative yield); mp 11 3-11WC (d); ir (nujol) Yrn.,,: 1740-1760 em-' (broad). This solid was used as such. To a cooled (ice bath) solution of the above mercaptide (1. 2 9,135 mmol) in CH2C12 (15 mi) was added acetyl chloride (0.118 g, 0.107 mI, 1.5 mmol) in CH2CL2 (2 mi) followed by pyridine (0.119 g, 0.122 mi, is 1.5 mmol) in CH2CL2 (2 m]). The mixture was stirred at OOC for 30 min. It was filtered over Celite to remove silver salt and the filtrate was washed successively with HCI (0.5N), H20, NaHC03 (0.5 M) and brine. The CH2C12 solution was dried (M9S04) and evaporated to dryness to give 0.94 g of title compound as an amorphous solid. (83.3%) ir (neat) Ymax: 1750 em-' (broad).

(1'S,5R,6Sand 1'R,5S,6R)paranitrobenzyl6-(1'-paranitrobenzyldioxycarbonyll'-propyl)-2-met hylpenem-3carboxylate (isomer Q 1 - OCO 2 PNE 2 3 25 C02""" Procedure:

A solution of the above phosphorane (0.4 g, 1.077 mmol) in toluene (35 m]) was heated to reflux and 5 mi of toluene was distilled off. The yellow solution was refluxed for 7.5 h. It was evaporated to dryness to give 30 0.76 g of a thick oil. This was chromatographed on Si02 (ACT 1.30 9) and eluted with benzene and benzene-ether to give the title compound as a solid, 0.32 g (53.4%); mp (pentane) 160-162'C; 11-1mr (CDC13) 6:

73-8.4 (8H, m, aromatic), 5.4 (HA, 5.3 (4H, benzyis, m), 5.0 (H, dt), 4.0 (H, dd), 2.35 (6H, s), 0.8 (2H, dq) and 1.0 ppm (3H, t).

(VS,5R,6S and M,5S, 6R) 6-(1'-hydroxy- 1'-propyl)-2-methylpenem-3carboxylic acid (isomer Q), sodium salt.

OCO 2 PNB 112 /Pd-Celitc HO Cl'3 phosphate C",3 40 buffer C.

2 Procedure:

A mixture of the above ester (48 mg, 0.086 mmol) and 30% Pd-Celite (100 mg) in THF (10 mi), Et20 (20 mi), H20 (10 mi) and phosphate buffer (pH7, 2 mi) was hydrogenated at an initial pressure of 50 psi for 23 h. It was 45 filtered over Celite and the layers separated. The organic layer was washed with H20 (2 x 5 m]) and the combined water layer was washed with EtOAc (2 x 10 ml). The aqueous layer was then lyophilized to give thetitle campound as a white salt, 30 mg; ir (KBr) vi-nax: 1750 (P- Iactam), and 1600 -1650 em-' (broad, -C02-); UV Max: 258 (c 1105) and 305 (F- 1244).

so EXAMPLE49 (V&SR,6S and VS,5S,6R) 6-(1'-Hydroxy1'-propyl)-2-methylpenem- 3-carboxylic acid, sodium andpotassium salts (isomer B) CO P (FR,3S,4R and l'S,3R,4S) 1-t'-Butyldimethylsilyl-3-(1'-formyloxy-l'propyl)-4-tritylthio-2-azetidinon e (isomerB).

CH HCO 2H EtP O'BO '57r 60 STr -,j.

DMAP, "C20 5Me CH2C12 0 j 5m.

4-Dimethylaminopyridine (DMAP) was prepared according to a) H.C. Brown etal. Org. Synth. Collect. Vol. 65 A % t is 101 GB 2 042 515 A 101 5,977 (1973) and b) Helmet Vorbruggen etaL Angew. Chem. Int. Ed., 17,569, (1978).

Procedure:

To a cooled ( OOC) solution of W13,3SAR and 1'S,3R,4S) 1-tbutyidimethyisiiyi-3(1'-hydroxy-l'-propyi)-45 tritylthio-2-azetidinome (isomer B) (3.612 g, 7 mmol) in CH2C12 (50 m]) was added Et3N (4.48 mi, 35 mmol), HC02H (0.63 mi, 16.8 mmol) and DMAP (0.854 g, 7 mmol) followed by dropwise addition of acetic anhydride (7.14 g, 70 mmol). The clear yellow solution was stirred at -400C and milky mixture. It was poured onto ice-1 N HCI (pH 6) and the layers were separated. The CH2C12 solution was washed with 1 M NaHC03 and brine. It was dried (Na2S04) and evaporated to dryness to give 3.8 g of a solid residue. This was treated with pentane and filtered to give 3.7 g of a white solid (96.8%); mp 125-27C; ir (neat) vmax: 1720 0 11 M-C-) and 1750 cm-1 (P-Iactam); 'Hmr (CDC13) 8: 7.1 0 11 (H, s, H-C-) 6.8-7.7 (15H, m), 4.8 (H, m), 4.05 (H, cl, J=1.5),33 K m, J=1.5, J=70.4 (2H, m), 0.95 (9H, s), 0.8 OH, t) and 0.1 ppm (6H, s); AnaL calcd for C32H39NO3SSi: C 70.42; H 7.20; N 2.57; found: C 70.20; H 7.33, N 2.73.

(M,3S,4R and 1S,3R,4S) 3-(1'-formyloxy- 1'-propyl)-4-tritylthio-2azetidinone (isomer 8) 0C110 1) STr SIMk.' OCHO I-J1, JIMP- 10% 31 20 N,'H + N.N3 b Procedure:

To a cooled (ice bath) solution of (3.7 g, 6.77 mmol) in HMPT (40 ml) containing 10% H20 was added NaN3 (0.91 g, 14 mmol). The mixture was stirred at room temperature for 1.5 h. It was poured onto ice water (200 ml) and extracted with ether (4 x 40 ml). The ether solution was diluted with pet-ether and washed extensively with water and brine to remove HIVIPT. It was dried (Na2SO4) and evaporated to dryness to give 35 2.92 g of a thick colorless oil. (quantitative yield). 1Hmr (CDC13) 8: 8. 1 0 11 (H, H-C-,s), 7.1-7.7 (15H, m, -STr), 5.23 (H, m, J=7),438 (H, d, J=25),43 (H, -NH), 3. 35 (H, dd, J=2.5, J=7),135 (2H, m) and 1.0 ppm (3H, t).

(VR,3S,4R and VS,3R,4S) 3-(1'formyloxy-l'-ethyl)-1-(paranitrobenzyl2"hydroxy-2"-acetate)-4-tritylt hio-2- 45 azetidinone (isomer B) OC$10 OCK ST PNE GLY0MATE NITHF A. 'H.:F-."' E3 1 C32":' Procedure:

A mixture of 3-(1'-formyioxy-l'-pro pyl)-4-tritylth io-2-azetidi none (isomer B), (2.9 9,637 mmol), PNB glyoxylate (1.59 g, 7 mmol), Et3N (5 drops) and Na2S04 (anhydrous, 5.0 g) in THF (50 m]) was stirred at room temperature for 18 h. It was filtered and evaporated to dryness to give an amorphous solid in quantitative 55 yield (4.33 g); 11-1mr (CDC13) 6: 8.2 (2H, d), 7.1-7.8 (18H, m), 5.2 (2H, d). 4.9 (H, m), 4.65 and 4.3 [H, 4.65 (l/2 H,s) 4.3 (112 H, s)l, 4.24.3 (H, d, 1/2 H at 4.2,1/2 H at 4.3),3.65 (H, m), 1. 4 (2H, m) and 0.8 ppm (3H, t).

(VR,3S,4R and PS,3R,4S) 3-(1'-formyloxy- 1'-propyl)- 1-(paranitrobenzyl2"chloro-2"-acetate)-4-tritylthio-2- azetidinone (isomer B) WHO l- N v OH SOC12 /T!T C021' -43 Py/THr 01HU __j - FT 00-14 Y M 02PNB 102 GB 2 042 515 A 102 Procedure:

To a cooled (ice salt bath) solution of the above glyoxyiate (4.3 g, 6.77 mmol) and 1 M Py/THF (8 ffil, 8 mmol) in dry THF (30 mO was added dropwise 1 M SOCI2/py (8 mi, 8 mmoi). The resulting solid mixture was stirred at the above temperature 1 h. It was filtered over Celite- charcoal and the filtrate was evaporated to 5 dryness to give 4.1 g of an amorphous solid (92%). ir (neat) Yn,.x: 1720 0 0 11 11 (H-C-), 1750 (-C-OPNB) 10- and 1780 em-' (g-Iactam); 1 Hmr (CDC12) 8: 8.25 (2H, d), 7.8 0 11 (H, s, H-C-), 7-7.75 (17H, m), 5.25 (2H, d), 5.0 (H, m), 4.6 (H, s), 4.4 (H, d), 3.7 (H, m), 1.6 (2H, m) and 0.9 ppm (3H, t).

(1'R,3S,4R and l'S,3R,4S) 3-(1'-formyloxy- 1'-propyl)- 1-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"- acetate)-4-tritylthio-2-azetidinone (isomer B) 20 OCRO OCH.1 yp3 C02?" C02'>Na 25 Procedure:

A mixture of the above chloro compound (4.0 g, 6.07 MMOO 1)3P (1.834 g, 7 mmol) and lutidine (0.749 g, 7 mmol) in dioxane (40 mi) was heated at 1OWC (oil bath) for 2 days. It was cooled, diluted with ether and washed successively with cold solution of 1 N HCI, 1 M NaHC03 and brine. The organic solution was dried 30 (Na2S04) and filtered over Celite-charcoal. ltwas evaporated to dryness to give an oil which was chromatographed on Si02 (Act. 1, 200 g) and eluted with benzene and benzene-ether to give 2. 60 g of the title compound as an amorphous solid (48.45%); ir (neat) v,.. : 1720 0 35 11 (H-C-O-), and 1750-1760 em-' (-C02PN13 and P-lactam).

WR,3SAR and VS,3R,4S) 4-acetylthio-3-(1'-formyloxy-l'-propyl)-1(paranitrobenzyl2"triphenylphosphoranylidene-2"-acetate)-2-azetidinone (isomer B).

OCHO ST SA OY 3 N P03 45 Y C02PNB Procedure:

A warm solution (60OC) of 0.15 M AgNO3-CH301-1 (8.7 mi, 1.3 mmol) was added to a mixture of the above phosphorane (0.88 g, 1 mmol) and pyridine (0.103 g, 1.3 mmol) in MeOH (5 mi) warmed to WC. The mixture so was stirred at room temperature for 15 min and at O'C for 2 h. It was filtered and washed with cold MeOH to give 0.53 g of the silver mercaptide as a yellow solid (71%) which was used as such. To a cooled (ice bath) mixture of the above mercaptide (0.53 9, 0.71 mmol) and pyridine (0.079 g, 1 mmol) in CHP2 (10 mi) was added dropwise CH3COCI (0. 079 g, 1 mmol) in CH2C12 (5 m[). After stirring at O'C for 1 h, it was filtered. The filtrate was washed well with a cold solution of 0.5M HCI, 0.5M NaHC03 and brine. It was dried (Na2S04) and 55 evaporated to dryness to give 0.43 g of an oil. (63%); ir (neat) Yr,,,: 1700-1760 em-' 0 A il (broad -C and P-lactam). 60 103 GB 2 042 515 A 103 (VR,3S,4R and PS,3MS) and acetylthio-3-(1'-hydroxyV-propyl- 1- (paranitrobenzY12"triphenylphosphoranylide-2"-acetate)-2-azetidinone (isomer B) OCHO SAC SAC 5 lly 0 3 er,Pt.l. CC2PM3 Procedure:

The above formate (1.0 g, 1.45 mmol) in THF (10 mi) was treated at room temperature with HCOMe01-1 (10 1r10 mi, prepared from 2 m] concentrated HCI and diluted with MeOH to a volume of 24 m]). The mixture was kept 10 at room temperature for 0.5 h. It was basified with 1 M Nal-IC03, extracted with EtOAc solution, washed with brine and dried (Na2S04). It was evaporated to give 0.9 9 of crude title compound. This was chromatographed on Si02 and eluted with ether and ether: EtOAc (1:1) to give 0.6 g of pure title compound as an amorphous solid (62.5%); 11-1mr (CIDC13) 6: 8.25 (21-1, d), 73-8.1 (17H, m, aromatic), 5.6 (H, m), 5.2 (2H), 4.9 (H),4A (H, m), 2.3 (31-1, SAc), 1.5 (21-1, m) and 0.9 ppm (3H,t).

(PR,5R,6S and 1'S,5S,6R)paranitrobenzyl6-(1'-hydroxy-l'-propyl)-2methylpenem-3-carboxylat e (isomer 8).

08 H SAC 20 0 2 2p Procedure:

The above phosphorane (0.2 g, 0.3 mmol) in toluene (45 mi) was heated to reflux and 5 m] of toluene was 25 distilled off. The resulting solution was refluxed for 6 h. It was cooled and evaporated to dryness to give 0.2 g of an oil. This was chromatographed on Si02 and eluted with ether to give 0.1 g of title compound as a white solid. (87%); mp (pentane) 133-135'C; 'Hmr (CDC13) 6: 8.3 (21-1, d), 7.6 (21-1, d), 5.6 (H, d), 5.35 (21-1, d), 4.15 (H, m), 3.8 (H, m), 2.4 (3H, s, CH3),2.2 (H, OH), 1.7 (21-1, m) and 1.05 ppm (31-1, t).

(PR,5R,6S and VS,5S,6R) 6-1'-hydroxy- 1'-propyl)-2-methylpenem-3carboxylic acid (isomerB), mixed K and Na salts Olf 01! N4- 35 C02PI48 0 2- Procedure:

A mixture of the above ester (0.07 g, 0.185 mmol), 30% Pd-Celite (150 mg) and buffer solution (pH 7,4 mi) in THF (15 mi, Et20 (25 mi) and deionized water (15 mi was hydrogenated at an initial pressure of 48 psi for 4 40 h. It was filtered over Celite and the layers were separated. The aqueous layer was washed with ethylacetate and then Iyophilized to give 91 mg of a solid; ir (KBr) Yma.: 1780 (P- Iactam) and 1650 c61 (broad, -C021; UV H20 Xmax: 255 (E 983) and 300 (E 1092).

EXAMPLE 50 (VR,5R,6S and 1S,5S,6R) 6-(1'-Hydroxy-2'-phenylethyl)-2methylpenem-3-carboxylic acid (isomerB) 50 C02p' trans 1-(t-butyldimethylsilyl)-3-phenylacetyl-4-tritylthio-2-azetidinone 0 T, ST 51x, LDA OCH 2C02 Et 55 C 2 0 2 1 -t-Butyidimethyisiiyl-4-trityithio-2-azetidi none (18.32 9,40 mmol) in dryTHF (100 mi) wasadded dropwise under N2 to a cooled (-780C) LDA solution [prepared under N2, at -78'C from dropwise addition of 1.6 M n-BuLi (101.25 mi, 162 mmol) to diisopropyl amine (22.95 mi, 162 mmol) in dry THF (150 m[) and stirred at -78'C for 30 minj. The mixture was stirred at -7WC for 30 min and ethyl phenylacetate (15.66 g, 15.12 m] 15. 12 mi, 93.6 mmol) in dry THF (50 mi) was added and the reaction mixture was stirred at -78'C for 2 h. It was poured onto ice-1 N HCl (pH 5-6) and extracted with ether several times. The ether solution was washed with brine and dried (Na2S04). It was evaporated to dryness to give 33.7 g of a crude solid. This was dissolved in ether (10 mi) and triturated with pentane (200 mi). The solid was filtered and washed several 104 GB 2 042 515 A 104 times with pentane to give 18.3 g of a white solid (79.6%) mp 141-143. 'Hmr(CDC13) 8: 7.0 -7.6 (20H, m), 4.8 (H, d), 3.7 (H, d), 3.53 (H, s), 3. 43 (H, s) 1.5 (91-1, s) and 0.3 ppm (6H, s).

1-(t-butyldimethylsilyl-3-(l'-hydroxy-2'-phenylethyl)-4-tritylthio-2azetidi none (2 trans diastereomers).

C-Ij - 0 'Ef i qM'2 trans 1-(t-butyidimethyisiiyi)-3-phenylacetyi-4-trityithio-2-azetidinone (28.8 g, 50 mmol) and NaBH4 (0.5 g, 0.25 mole) in THF (200 mi) were stirred at room temperature for 18 h. The mixture was poured onto ice-1 N HCI and extracted with CH2C12. The CH2C12 Solution was washed with brine and dried (Na2S04). It was evaporated to give an amorphous solid (27.7 g). A portion of the solid (23.0 9) was chromatographed on Si02 and eluted with hexane: ether to give off-white solid (14.4 g) which was found to be a mixture of (VR,3S,4R and VS,3R,4S) and (VS,3S,41R and V13,31R,4S) isomers in the ratio of 1:1 (60%). 11-1mr (C13C13) 8: 7-7.7 (20H, is m), 4.37 0121-1, d), 4.18 0121-1, d), 33-3.8 (H, m), 3.45 W2H, dd), 3. 10/21-1, dd), 2.7 (21-1, m), 0.87 (9H, d) and 0.25 ppm (61-1, s).

1-(t-butyldimethylsilyl)-3-(1'-formyloxy-2'-phenylethyl)-4-tritylthio-2azet idinone c 20 1:. G 2 + To a cooled (-40'C) solution of the above mixture of alcohols (14.4 g, 24. 9 mmol) in CH2C12 (250 mi) was added Et3N (15.93 mi, 125 mmol), HC02H (2. 24 mi, 59.76 mmol) and DMAP (3.04 g, 24.9 mmol). After stirring for 5 min acetic anhydride (2.35 m[, 249 mmol) was added dropwise. The clear solution was stirred at -40'C for 15 min whereby it turned into a white cloudy mixture. It was kept at -400C for another 45 min (total time 1 h). It was poured onto ice-1 N HCI, and the layers separated. The CH2C12 solution was washed well with cold 30 1 N HC1,1-120, 1 M NaHC03 and brine. It was dried (MgS04) and evaporated to give 14.0 g of an amorphous solid. This was separated by h plc (Water Associates, System 500) to give: 1somer B" 6.0 9, mp 172-73'C and 1somer C" 6.0 g mp 188-89'C. Total yield of pure compound 12.0 g (73.2%). Isomer C: 'Hmr (CDC13) 6: 6.8-7.7 (21 H, m), 5.05 (H, dt), 4.05 (CH, d) 3.65 and 3.75 (H, two doublets), 23-2.9 (21-1, d), 0.88 (9H, s) and 0.2 ppm (61-1, s). Isomer B: 'Hmr (CDC13) 6: 7.75 (H, s), 6.9-7.5 (20H, m), 4.3 (H, dt), 3.95 (H, d), 3.37 (H, dd), 2. 95 (H, 35 s), 2.85 (H, s), 0.9 (9H, s) and 0.2 ppm (61-1, s).

3-(1'-formyloxy-2'-phenylethyl)-4-tritylthio-2-azetidinone (VR,3S,4R and VS,3R,4S enantiomers) 1r it OCIR. 40 STP STr 412 :Lr i.,E, 1.

Isomer B To a cooled (ice bath) solution of the above formate (5.9 9,9375 mmol) in HMPT containing 10% water (50 45 m]) was added NaN3 (1.3 g, 20 mmol). The mixture was stirred at room temperature for 1.5 h. It was poured onto ice water (300 mi) and extracted with ether (3 X 100 mi). The ether solution was washed well with water and brine. It was dried (Na2S04) and evaporated to give a solid residue. This was treated with petroleum ether and filtered to give 4.4 g of a white solid (92%) mp 169-710C. AnaL calcd for C311-127NO3S; C 75.43, H 5.51, N 2.84; found: C75.04,H 5.64, N 2.78. 'Hmr(CDC13) 6: 7.9 (H,s),7.1- 7.6(20H, m),5.4(H,m),46(H, NH), 50 4.2 (H, d), 3.3 (H, dd), 3.15 (H, s) and 3.0 (H, s).

3-(1'-formyloxy-2'-phenylethyl)- 1-(paranitrobenzyl2"-hydroxy-2"acetate)4-tritylthio-2-azetidinome (VR,3S,4R and PS,3R,4S enantiomers) Oci OCHO 55 OH, d 0 C02PNt, Asuspension of PNB glyoxylate (2.37 g, 10.16 mmol) in dry benzene (100 ml) was refluxed under a Dean 60 Stark apparatus (packed with molecular sieve 3A) for 2 h. Then the above N-H compound (4.2 g, 8.537 mmol) was added and refluxing continued for 1 more h. It was cooled to room temperature Et3N (0.12 ml, 0.85 mmol) was added and the mixture was stirred at room temperature for 1.5 h. It was evaporated to dryness to give the title compound in quantitative yield as a mixture of two isomeric alcohols. 'Hmr (CDC13) 8: 8.0-8.3 (2H, two doublets), 7.5 and 7.6 (H, two sing lets), 7.0-7.4 (20H, m), 5. 25 (21-1, d), 4.9 (H, OH), 4.25 and 4.35 (H, 65 GB 2 042 515 A 105 two doublets), 15-4.5 (H, m, broad), 3.1-3.3 (H, m) and 2.9 ppm (2H, m).

3-(1'-formyloxy-2'-phenylethyl)-1-(paranitrobenzyl2'-chloro-2"-acetate)-4t ritylthio-2-azetidinone WR,3SAR and VS,3RAS enantiomers) OCHO OCHO 5 ST c 1 C02P1113 cc. 2P NB To a cold (ice salt bath) solution of the above glyoxylate (6.0 g, 8.537 mmol) in dry THF (30 mi) was added a 10 1M solution of pyridine in THF (10 mi, 10 mmol) followed bythe dropwise addition of a 1M solution of thionyl chloride in THF (10 mi, V0 mmol). After 1 h atthe above temperature itwas diluted with benzene (30 m]) and stirring was continued in the cold for 30 min. It was filtered over Celite-charcoal and evaporated to dryness to give 6.0 g of an amorphous solid (98%): 11-1mr (CDC13) 6: 8.2 (2H, m), 7-7.7 (23H, m), 5.8 (H, s), 5. 25 (2H, s), 4.35 15 (H, d), 3.54.0 (H, m), 3.3 (H, m) and 2.9 ppm (2H, d).

3-(1'-formyloxy-2'-phenylethyl)- 1-(paranitrobenzyl2"triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2azetidinone (PR,3S, 4R and 1S,3R,4S enantiomers).

h OCHO ST OCHO ST 20 0 ly cl 0,4. 3 C02 M;!' cc 2PN B' A mixture of the above chloro compound (6.0 g, 8.333 MMOO, (3P (2.489 9,0. 5 mmol) and lutidine (1.0165 g, 1.1 m], 9.5 mmol) in dioxane (50 mi) was heated at 1 WC (bath temp) for 18 h. ltwas cooled and filtered 25 over Celite. The filtrate was diluted with ethyl acetate and washed with cold 1 N HCI, H20, 1 M Nal-IC03 and brine. It was dried (Na2S04) and evaporated to give 8.0 g of a crude product. This was chromatographed on Si02 and eluted with ether: hexane (1: 1) and ether to give 4.0 g of the title compound. mp (needless from ether) 235-37'C (d). (51 %); ir (film) Ymax: 1720,1750 cm-1.

4-acetylthio-3-(1'-formyloxy-2'-phenylethyl)-1-(paranitrobenzyl2"triphenylp hosphoranylidene-2"-acetate)2-azetidinone WR,3SAR and VS,3RAS enantiomers) h 01Hr, H 0C110 p ' C>CH ST, SA N - 0, ' c' 3 CO 2 1"" CC-,.;h To a refluxing solution of the above phosphorane (3.6 g, 3.8 mmol) and pyridine (0.33 g, 4.2 mmol) in CH2C12 (30 mi) and MeOH (30 mi) was added dropwise a 0.15M AgN03/Me01-1 solution (28 mi,4.2 mmol). The mixture was stirred at room temperature for 2.15 h. It was concentrated to a small volume (-10 m[), cooled 40 and filtered to give the silver mercaptide as a yellow solid (2.3 9,77%). This mercaptide and pyridine (0.277 9, 3.5 mmol) in ice-cold (CH2C12 (20 m[) was treated dropwise with CH3COC1 (0.27 g, 3.5 mmol) in CH2C12 (5 MI).

The mixture was stirred at room temperature for 3 h. It was filtered over Celite and the filtrate was washed with cold 1 N HCI, H20, 1 M Nal-IC03 and brine. It was dried (M9S04) and evaporated to dryness to give 1.0 g of an amorphous solid (89.8%).'Hmr(CDC13) 6: 8.2 (2H, d),7.0-8.0 (23H, m), 4.5-5.7 (4H, m), 2.6-3.3 (3H, m), 45 and 2.3 ppm (2H, d, SAc).

4-acetylthio-3-(1'-hydroxy-2'-phenylethyl)-1-(paranitrobenzyl2"triphenylpho sphoranylidene 2"-acetate)-2azetidinone WR,3SAR and 1S,3R,4S enantiomers).

0CP.0 p. ch 50 SA N NY 7 '^ 3 PNU CciPM:

A solution of the above phosphorane (1.8 g, 2.416 mmol) in THF (10 mi) was treated with 1 N HCI/MeOH (10 55 mi) and the mixture was stirred at room temperature for 4 h. It was concentrated to remove methanol, diluted with cold water, basified with 1 M Nal-IC03 and extracted with CHC13. The CI-IC13 solution was dried (M9S04) and evaporated to give 1.65 g of an amorphous solid. This was chromatographed on Si02 and eluted with ether; ethyl acetate to give 1.30 g of the title compound (75%). 11-1mr (CDC13) 6: 8.2 (2H, d), 6.7-8.0 (22H, m), 4.0-6.0 (5H, m), 2.5-3.5 (3H, m) and 2.2 ppm (3H, SAc).

106 GB 2 042 515 A 106 paranitrobenzyl6-(1'-hydroxy-2'-phenylethyl)-2-methylpenem-3-carboxylate (1'&5R,6S and l'S,5S,6Renantiomers) 4.-OH H - 5Ac CO,PNB N -H3 A solution of the above phosphorane (1.2 g, 1.67 mmol) in toluene (80 mi) was heated to reflux (10 mi was distilled off to remove moisture and low boiling point solvent present) for 6 h. It was evaporated to dryness and the crude product was chromatographed on Si02. The title compound was obtained by eluting the column with ether to give 0.65 g of amorphous solid (89%). 11-1mr (CIDC13) 8: 8.2 (2H, d), 7.6 (21-1, d), 5.4 (H, d), 5. 2-5.4 (21-1, d), 4.0-4.5 (H, m), 33-4.0 (H, dd), 3.0 (21-1, d) and 2.3 ppm (3H, s).

6-(1'-hydroxy-2'-phenylethyl)-2-methylpenem-2-carboxylic acid (1W,5R,6S and VS,5S,6R enantiomers) . -5 CH 3 :0- 0.

C0 2P ? A mixture of the paranitrobenzy] ester (0.33 g, 0.75 mmol), 0.05 M Buffer solution (pH 7,17.4 mi), THF (30 20 mi), Et20 (30 m[), distilled H20 (60 mi), and 30% Pd/Celite (0.69 g) was hydrogenated at an initial pressure of psi for 24 h. It was filtered over Celite and the organic layer washed with water. The combined water layer was washed several times with EtOAc and it was Iyophilized for 18 h to give the title compound as a yellow solid salt. This was treated with a small amount of water, acidified with cold 1 N HCI and extracted well with CHC13. The CHCI.3 solution was dried (M9S04) and evaporated to give a solid residue. This was treated with 25 ether and filtered to give 30 mg of a white solid (13.2%), mp 165-167'C; ir (nujol) Ym,,: 3580 (OH, Sharp), 1660 and 1760 cm-l; uv (MeOH).mE,.: 310 (E 5490) and 254 (E 4880).

EXAMPLE 51 (4'R,5R, 6S and 4'S,5S, 6R) 6-(2',2'-Dimethyl1'13'-dioxolan-4-yl)-2- methylpenem-3-carbocxylic Acid (Isomer 30 Q 3 N.

C02M A. PREPARATION OF 35 ST 0 40 WR,3SAR and 4'S,3RAS) and WS,3SAR and 4'R,3R,4S) 1-(t-Butyidimethyisiiyi)3-(2',2'-dimethyi-l'-,3dioxolan-4'-yi)-4-trityithio-2-azetidinone (1somer W and 1somer 131 z Ethyl 0-(2-methoxy-2-propyl)glycolate'J 45 -'lEt P0C13 50 To a solution of ethyl glycolate (15.6 g, 0.150 mol; freshly distilled) and 2-methoxypropene (16.4 g, 0.216 mol; 95% pure)2) in CH2CI2 (150 ml) was added at 0-5' phosphorus oxychloride (3 drops, 35 mg, 0.23 mmol) and the mixture was stirred at 0-5'for 15 min and at room temperature for 1.5 h. This was then quenched with pyridine (30 drops), stirred 45 min and the solvent evaporated. The residue diluted with pentane (150 ml) was dried over K2CO3. After filtration, the solvent was evaporated yielding 27.89 g (0.158 mol, 100%; 94.9% pure) of the title compound as a colourless oil: 1Hmr (CC14) 6:1.25 (31-1, t, J=7Hz -CH2CH3),1.28 (61-1, s, Me2),3.12 (31-1, s, -OCH3),3.88 (21-1, s, -OCH2CO-), 4.10 (21-1, q, J=7Hz, -CH2CH3); ir (neat) vma),: 1760 and 1735 cm-1 (ester).

1) J. Meinwald eta/., Tet. Lett., 4327 (1978) 2) M.S. Newman and M.C. Vander Zwan, J. Org. Chem., 38,2910 (1973).

107 GB 2 042 515 A 107 (3S,4Rand3R,4S) 1-(t-Butyldimethylsilyl)-3-(1'-keto-2'-(2"-methoxy-2'isopropyloxy)-1'-ethy l)-4-tritylthio-2- azetidinone / ,,X 1) LDA/THP +ly 'i I.

2) To a stirred solution of dlisopropylamine (18.5 mi, 0.134 mol) in THF (400 mi; freshly distilled from LAH) at -78'C was added n-butyllithium (1. 6M in hexane, 90 mi, 0.144 mol) under N2 atmosphere. After 30 min, a solution of 1-(t-butyidimethyisiiyi) 4-trityithio-2-azetidinone (50.0 9, 0.109 mol) in THF (100 mi) was added dropwise over 10 min and the mixture was stirred for 5 min. To this pink solution was added ethyl 0-(2-methoxy- 2-pro pyi)g lyco late (23.94 g, 0.136 mol) and the mixture was stirred for 1 h. After removing the dry-ice bath saturated NH4C1 solution (200 mi) was added followed by brine (100 mi). The aqueous phase was extracted with Et20 (3 X 100 mi). The combined organic extracts were washed with brine, dried (Na2S04) and evaporated yielding 60.95 g (0.103 mol, crude yield 94.6%) of the title compound as a crude orange oil. This crude material was used in the next reaction. A pure sample was obtained by column chromatography (Si02, eluent: 2% Et20 in benzene); 'Hmr (CDC13) 8: 0.30 (6H, s, Si-CH3), 0.95 (9H, s, t-Bu), 1.12 (3H, s, CH30.15 (3H, s, CH3),115 (3H, s, OCH3), 3.57 (1 H, A of AB, Jgem=1 7Hz), 3.77 (1 H, cl, J=11.61-1z, H-3),197 (1 H, B of AB, Jgem= 17Hz), 4.83 (1 H, d, J= 1.6Hz, H-4,7.11-7.6 (15H, m, aromatic Hs); ir (neat) Ymax:

1750,1725,1710cm-1 (C=O); tic, Rf 0.53 (benzene; Et20=4:1), Rf 0.61 (hexane: EtOAc= 2:11).

(3S,4R and 3R,4S) 1-(t-Butyldimethylsilyl)-3-(1'-hydroxy-2'-methoxyisopropyloxyethyl)-4-trity lthio-2- azetidinone (mixture of epimers at CV) OCH 3 A solution of crude 1 -(t-butyldimethyisiiyl)-3-(1'-keto-2'(2"-methoxy-2"isopropyloxy)-1'-ethyl)-4 -trityithio- 2-azetidinone (60.95 g, 0.103 mol) in THF (100 mi) was diluted with abs. EtOH (350 mi) and to this solution was 30 added at O'C NaBH4 (4.88 g, 0.156 mol). The mixture was stirred at room temperature for 2 hand quenched by slow addition of brine (280 m]). The mixture was extracted with Et20 (3 X 150 ml) and the extracts were washed with brine, dried (Na2S04) and evaporated to yield a yellow residue which was redissolved in CH2C12 (500 mi). This was dried (Na2S04) again and evaporated yielding 57.1 g (0. 0966 mol, crude yield 93.8%) of the title compound as a crude yellow foam: 'Hmr (C13C14) 6: 0.17 (s, SiCH3), 0.80,0.87 (2s, Si-tBu), 1.22,1.25 (2s, 35 CH3),103 (s, OCH3),432 (d, J=21-1z, H-4),7.0-7.7 (m, aromatic Hs); ir (neat) 3460 (OH), 1745 (C=O),1595 (aromatics): Rf 0.47 and 0.42 (hexanes: ROAc=2: 1). This crude material was used in the next step without purification.

(4W,3S,4R and 4'S,3R,4S) and (4'S,3S,4R and 4'&3R,4S) 1-(tButyldimethylsilyl)-3-(2',2'-dimethyl-1'13'dioxolan-4'-yl)-4tritylthio-2azetidinone. (Isomer C and Isomer 8) 0 Tr "S 1 / A solution of (3S,4R and 4R,4S) 1 -(t-butyidimethyisiiyi)-3-(1'-hydroxy2'-methoxyisopropyloxyethyi)-4- tritylthio-2-azetidinone (mixture of diastereomers at CA' (57.1 9, 0.0966 mol; crude) in CH2C12 (500 mi) was treated at room temperature with p-toluenesulfonic acid monohydrate (200 mg) and 2,2-dimethoxypropane (20 mi) and then stirred for 1 h. It was washed with sat. Nal-IC03 and then brine, dried (Na2S04) and evaporated yielding 49.64 g (0.0888 mol, crude yield 91.9%) of a mixture of the title compounds (Isomer B and Isomer C) as yellowish foam. This was purified by HPLC (Waters 500 Silicagel; eluent, hexane:

ROAc=9: 1) and by crystallization yielding 14.28 g (25.5 mmol, 26.4%) of the title compound (Isomer C) as white crystals; mp 146-7'C (pentane); 'Hmr (M4) 6 0,27 (6H, s, Si-CH3),0. 95 (9H, s, Si-tBu), 1.15 (6H, s, di-Me),2.5-2.9(1H,m,H-4'),2.97(1H,t,J=1.8Hz,H-3),3.25-3.9(2H,m,H-5'),4. 27(1H,d,J=1.8Hz,H-4), 7.11-7.6 (15H, m, aromatic Hs); ir (nujol) Yniax: 1750 (C=O) and 1595 cm- 1 (aromatics); Rf 0.45 (hexanes:

ROAc=4:1) and 14.50 g (25.9 mmol, yield 25.9%) of the title compound (Isomer B) as white crystals: mp 144-5'C (R20-pentane); 1 Hmr (M4) 6: 0.02 (6H, s, SiMe), 0.833 (91-1, s, Si-tBu), 1.13,1.18 (6H, 2s, diMe), 2.5-2.8 (1 H, m, H4), 3.34.1 (2H, m, H-5'), 3.48 (1 H, dd, J3,4=1.51-1z, J3-4,=5.01-1z, H-3),3.93 (1 H, cl, J4-3=1.5Hz, H-4),71-7.7 (15H, m, aromatics Hs); ir(nujol)v,,a.: 1650 (C=O) and 1595cm- 1 (aromatics); Rf 0.37 (hexanes: 60 ROAc=4: 1). Anal calcd for C331-141 N03SSi: C 70.80, H 7.38, N 2.50, S 5. 73; found: (Isomer C) C 70.23, H 7.30, H 7.3 -; N 2.41, S 5.53 and (Isomer B) C 70.52, H 7.31, N 2.40, S 5.05.

108 GB 2 042 515 A 108 B. Preparation of the Penem Product (Isomer Q WR53SAR and 4's,3RAS) 3-(2', 2'-Dimethyl-l',3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone (Isomer Q STr HMPT-H20 S1 -fi To a stirred solution of WIR,3SAR and 4'S,31RAS) 1-(t-butyidimethyisiiyi)-3-(2',2-dimethyi-l',3'-dioxolan4'-yl)-4-tritylthio-2azetidinone (Isomer C) (14.3 g, 25.6 mmol) in hexamethyl phosphoric triamide (230.4 mi) was added slowly (in 20 min) at 0-5'C a solution of sodium azide (2.50 g, 38.4 mmol; 1.5 eq) in H20 (25.6 m[). 10 The mixture was stirred at room temperature for 2 h and poured into cold water (2.5 t). The white precipitate formed was collected, washed with H20 and dried yielding 11.26 g (25.3 mmol, crude yield 98.8%) of the title compound as a white solid. A pure material was obtained by crystallization from CH2C12-R20: mp 192-WC (dec.); 11-1mr (CDC13)6:1.33,1.37 (6H, 2s, di-Me), 3.27 (1 H, t, J=31-1z, H-3),3.8-4.4 (3H, m, HA'and H-5'), 4.40 (1H, d,J=3Hz, H-4),4.47 (1H, br, NH, D20 exchanged) and 7.1-7.7 ppm (15H, m, aromatic Hs); ir (nujol) Y,,,.x: 15 3220 (NH), 1760 W=0) and 1950 em-' (aromatics); Rf 0.31 (hexanes: EtOAc = 3:2).

(4'R,3S,4R and4'S,3R,4S) 3-(2'12'-Dimethyl- 1',3'-dioxolan-4-yl)- 1-(Pnitrobenzyl2"-hydroxy-2"-acetate)-4tritylthio-2-azetidinone (mixture of epimers at C-2) (Isomer Q 20 Tr 02 PN5 C, NH Et 3 N/T9F dl -1Trrl.ll CO 2 PNB A suspension of p-nitrobenzyl glyoxylate hydrate (6.57 9,28.95 mmol; 1.15 eq) in benzene (500 mi) was heated at reflux with Dean-Stark trap for 2 h. Evaporation of the solvent gave p-nitrobenzyl glyoxylate as an oil. A mixture of this oil and (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyi-l'-3'dioxolan-4'-yi)-4-tritylthio-2azetidinone (Isomer C) (11.2 g, 25.2 mmol) in THF (350 mi, distilled from LAH) was treated with triethylamine (289 mg, 2.86 mmol) at room temperature under N2 for 18 h (overnight). After evaporation of the solvent, the 30 residue diluted with CH2C12 (200 mi) was washed successively with brine containing 1 N HCI (2.9 mi) sat. NalIC03 and brine, dried (Na2S04) and evaporated after addition of Et20 (30 mi) to give 17.2 g (26.3 mmol, crude yield 100%; purity 95.8%) of the title compound as a white foam: Rf 0.40 and 0.30 (benzene: R20=3:2). Each isomer was separated by hplc (Si02, eluent, benzene: R20=3:2) and purified by crystallization from CH2C12-Et20. Isomer 1: Rf 0.40 (benzene: R20=3:2); mp 1534C; 11-1mr (CDC13) 8: 1.20 (6H, s, di-Me), 3.1 (2H, m, H-3 and OH),3.5-4.2 (3H, m, H-4' and H-5'), 4.55 (1 H, d, J=21-1z, H- 4), 5.12 (1 H, br, H-2"), 5.30 (2H, s, OCH2Ar) 35 and 7.1-8.3 ppm (19H, rn, aromatic Hs); ir (nujoi)'vrnax: 3370 (OH), 1775 (P-Iactam) and 1745cm-1 (ester); AnaL calcd for C36H34N20BS: C 66.04, H 5.23, N 4.28, found: C 65.85, H 5. 64, N 4.11. Isomer H: Rf 0.30 (benzene: R20=3:2); mp 164-5'C; 11-1mr (CDC13) 6: 1.17 (6H, s, di-Me), -3. 2 (2H, rn, H-3 and OH), 3.44.0 (3H, m, HA'and H-5'), 4.57 (1 H, d, J=2Hz, H-4), 5.23 (1 H, br, -2"), 5.27 (2H, s, -OCH2Ar), and 7.1-8.3 ppm (19H, rn, aromatic Hs); ir (nujol) vnix: 3340 (OH), 1765 (P-Iactam) and 1740 em-' (ester); Anak calcd for C36H34N2OSS: 40 C 66.04, H 5.23, N 4.28, S 4,90, found: C 66.01, H 5.34, N 4.28, S 4.75.

(4'R,3S,4R andYS,3R,4S) 3-(2',2'-Dimethyl- 1',3'-dioxolan-4'-yl)-1-(pnitrobenzyl2"-chloro-2"-acetate)-4tritylthio-2-azetidinone (mixture of epimers at C-Z9 (Isomer Q.

t, T, SOC12-?y 45 V. M C02PNB 2 so To a stirred solution of (YR,3SAR and 4'S,3R,4S) 3-(2',2'-dimethyl-l', 3'-dioxolan-4'-yi)-1-(p-nitrobenzyI 50 2"-hydroxy-2"-acetate)-4-trityithio-2-azetidinone (isomer C) (17.13 9,25. 07 mmol; mixture of epimers at C-7) in THF (250 mi) was added at -150C under N2 pyridine (2.84 mi, 35.1 mmol) and then immediately afterwards thionyl chloride (2.20 m1,30.1 mmol; Anachemia). The mixture was stirred for 20 min at -150C and then the white precipitate was filtered off. After washing with benzene, the filtrates and washings were combined and concentrated. The residue dissolved in benzene (250 mi) was treated with activated charcoal, filtered and evaporated, yielding 17.94 g (26.65 mmol, crude yield 100%; purity 94.1%) of the crude title compound as white foam: Rf 0.76 (benzene: R20=3:2); 'Hmr (CDC13) 6A.20 (6H, s, diMe), 3.17 (1 H, m, H-3),3.4-3.9 (3H, m, HA' and H-5'), 4.67, 4.72 (1 H, 2d, J =2.5 Hz, H-4), 5.30 (2H, s, OCH2Ar), 5.83 (s, H-2") and 71-8.3 ppm (19 H, m, aromatic Hs); ir (neat) vmi,.: 1770 em-' (P-Iactam and ester). This material was used in the next step without purification.

c 109 GB 2 042 515 A 109 OW,3S,4R and 4'S,3R,4S) 3-(2'12'-Dimethyl1'13'-dioxolan-4'-yl)- 1-(pnitrobenzyl2'triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2azetidinone (Isomer Q 1 10 -A C,3- STr 4, N N, cl 0v CO 2 PN5 ",- ' aT dl.x.

3 A mixture of (4'I'l,3S,4R and 4'S,3R,4S) 3-(2,2'-dimethyi-l',3'-dioxolan- 4'-yi)-1-(p-nitrobenzyI 2'-chloro-2"acetate)-4-trityithio-2-azetidi none (Isomer C) (17.87 g, 25.0 mmol; purity 94.1% mixture of epimers at C-T), triphenylphosphine (7.27 g, 27.5 mmol) and 2,6-1utidine (3.19 mi, 27.5 mmol) in dioxane (350 mi; distilled 10 from LAH) was heated at reflux under N2 for 40 h. Evaporation of the solvent in vacuo gave 29.5 g of dark oil which was purified by column chromatography (Si02 330 g; eluent 20-50% Et20 in benzene), yielding 10.5 9 of yellowish solid. This solid was rinsed with Et20 to give 7.49 g (8. 33 mmol, yield 33.3%) of the title compound as slightly yellow crystals: 11-1mr (CDCI,3) 8. 1.07 (s, di-Me) and 7.1-8.2 ppm (m, aromatic Hs); ir (nujol) 1760 cm-1 (C=O). An analytical sample was obtained by crystallization from CH2C12-Et20: MP 15 231-20C; AnaL calcd for C54H47N207PS: C 72.14, H 5.27, N 3.12, S 3.57; found: C 72.18, H 5.43, N 2.98, S 3.41; Rf 0.17 (benzene: R20=1:1).

KR,3S,4R and 4'S,3R,4S) Silver 3-(2'12'-dimethyl- 1', 3'-dioxolan-4'-yl)1-(p-nitrobenzyl 720 triphenylphosphoranylidene-2'-acetate)-2-azetidinone4-thiolate (Isomer Q C A9NO,-Pyr pl3 PCC14 CO 2 PN5 25 A solution of (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyl-l',3'-dioxolan- 4'-yi)-1 -(p-nitrobenzyl 2" tri phenyl phosp h oranyl iden e-2"-acetate)-4-tritylth io-2-azetidi none (Isomer Q (319 mg, 0.355 mmol) in CH202 (10 ml) was evaporated to yield an oily residue which was redissolved in hot methanol (8 ml; 60'). To this solution was added at 60'a hot solution of AgNO3 in MeOH (0.1 5M, 4.0 ml, 0.60 mmol) and then pyridine (29 [0, 0.36 mmol). The mixture was stirred at room temperature for 5 h and at O'C for 1 h. The precipitate was 30 collected and washed with ice-cold methanol and then cold Et20, yielding 255 mg (0.334 mmol, yield 94.1%) of the title compound as a brownish solid: ir (nujol) Vrnax: 1750 cm-1 (s, C=O).

(4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-Dimethyl- 1',3'-dioxolan-4'-yl)- 1-(pnitrobenzyl 7triphenylphosphoranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer Q C, 3CC" 1 CH2C12 40 To a solution of WIR,3S,41R and 4'S,31R,4S) silver 3-(2',2'-d i methyl -V, X-d ioxo 1 a n-4'-yl)-1 -(p-nitrobenzyl T'-tri phenyl p h osph o ra nyl id en e-2"-acetate-2-azetid in o ne-4-th i o late (Isomer C) (254 mg, 0.333 mmol) in CH2C12 (15 m[) containing pyridine (100 R], 1.24 mmol; 3.72 eq) was added at 0-5'C acetyl chloride (71 RI, 1.0 mmol; 3.0 eq). The mixture was stirred at O-WC for40 min. Afterfiltration of the precipitate over Celite the filtrate was washed successively with brine containing 1 N HCl (1.25 mi), sat. Nal-IC03 and then brine, dried 45 (Na2S04) and evaporated, yielding 200 mg of an oil which was crystallized from Et20 to give 155 mg (0.222 mmol, yield 66.7%) of the title compound as white crystals: 11-1mr (C13C13) 6:123 (s, di-Me), 2.20,233 (2s-SAc) and 7.2-8.3 ppm (m, aromatic Hs): ir (nujol) Vma>,: 1750 (P-Iactam and ester) and 1690 cm-1 (thioester). An analytical sample was obtained by crystalization from CH2C12-Et20: mp 177- 80C; AnaL calcd for C37H35N208PS: C 63.60, H 5.05, N 4.01, S 4.59; found: C 63.34, H 5.32, N 3.83, S 4,31; Rf 0.62 (EtOAc).

(4'R,5R,6S and4'S,4S,6R) p-Nitrobenzyl 6-(2'.2'-dimethyl-l'.3'-dioxolan4'-yl)-2-methylpenem-3-carboxylate (Isomer C) d"I N ro 2 PNB N 2 55) A suspension of WR,3S,4R and 4'S,3RAS) 3-(2'O-di methyl -V,X-dioxo fa n4'-y1M -(p-nitrobenzyl Z triphenylphosphoranylidene-2"-acetate)-4-acetylthio-2-azetidinone (isomer C) (443 mg, 0.634 mmol) in 60 toluene (70 mi) was heated at reflux under N2 for 6 h. Evaporation of the solvent gave white solid which was purified by column chromatography (Si02 10 g; eluent 10% C20 in benzene) yielding 247 mg (0.587 mmol, yield 92.7%) of the title compound as white solid: 'Hmr (CDC13) 6: 1.42 (6H, s, di-Me), 2.38 (3H, s, 2-CH3), 3.84.5 (41-1, m, H-6, H-4'and H-5'), 5.02-5.25-5.33-5.57 (2H, AB type, - OCH2Ar), 5.57 (1 H, d, J=1.8 Hz, H-5) and 7.52-7.67-8.12-8.27 ppm (4H, A2'132', aromatic Hs); ir (nujol) vn,: 1760 (P-Iactam) and 1700 cm-1 (ester). An 65 GB 2 042 515 A analytical sample was obtained by crystallization from CH2C12-Et20: mp 167-80C; uv (EtOH) 1: 265 (F, 14,000) and 314 mg (E 10,000); AnaL calcd for C19H2ON207S: C 54.28, H 4.79, N 6.66, S 7.63; found: C 54.15, H 4.78, N 6.54, S 7.64; Rf 0.62 (benzene-Et20=1: 1).

OW,5R,6S and 4'S,5S,6R) 6-(2,2'-Dimethyl- 1'13'-dioxolan-4'-yl)-2methylpenem3-carboxylic acid (Isomer 5 Q -1 d -Q:

)i. CH 3 C"2 PM, H 2 /Pd-C 5 'NI,.-2, H 3 A solution of W11,5R,6S and 4'S,5S,6ffi p-nitrobenzyl 6-(2',2'-dimethyil',3'-dioxolan-4-yi)-2methyipenem-3-carboxylate (Isomer Q (195 mg, 0.464 mmol) in THF (20 mi) was mixed with Et20 (20 mi), H20 (20 m]), Nal-IC03 (39 mg, 0.46 mmol) and 10% Pd-C (200 mg, Engel hard). This mixture was hydrogenated at 35 psi for 4 hat room temperature. After removal of the catalyst (over Celite), the aqueous layer was washed with EtOAc (X2), saturated with NaCI, acidified with 1 N HCI (0.47 mi) and immediately extracted with EtOAc (20 mi X 3). The extracts washed with brine were dried (Na2S04) and evaporated yielding 94 mg of yellowish solid which was rinsed with pentane to give 89 mg (0.31 mmol, yield 67%) of the title compound as yellowish solid: mp (0.31 mmol, yield 67%) of the title compound as yellowish solid: mp 132-YC; Rf 0.60 (Acetone: HOAc=5:0.7);'Hmr(CDC13)6:1.37,1.43(6H,2s,di-Me),2.36(3H,s,2CH3),3.9-4.6(4H, m,H-6, 20 H-4' and H-W) and 5.59 ppm (1 H, cl, J = 1.7 Hz, H-5); ir (nujol) vm,,,: 1760 (P-Iactam) and 1660 cm-1 (COA; uv (EtOH) Xmax: 309 (E 6300) and 263 m[t (c 3800).

EXAMPLE 52 (4S,5R,6S and 4'R,5S,6R) 6-(2',2'-Dimethyl1',3'-dioxolan-4'-YI)-2- methylpenem-3-carboxylicAcid (Isomer 25 8) tli, CH 3 WS,3S,4R and 4'R,3R,4S) 3-(2',2'-Dimethyl- 1',3'-dioxolan-4'-yl)-4tritylthio-2-azetidinone (Isomer 8) :i ' f' 5 - 0 5 1 H1..PT-H 20 11 1 1) 6 -11 of:ll The title compound was prepared as described in Example 51 for the "Siomer C- from (4'S,3S,41R and 4'R,3R,4S) 1 -(t-butyl-di methyl si lyi)- 3-(2',2'-d i methylA',X-d ioxo 1 a n-3'-yi)-4-trityithio-2-azetidi none (Isomer 40 B) (14.4g,25.8 mmol): yield 10.8g,24.3 mmoi,94.1%; mp 1550C (CH2C12-Et20); Rf 0.24(hexanes: EtOAc=2:1);Hmr(CDC13):1.37,1.40(6H,2s,diMe),3.23(1H,dd,J3-4=2.5Hz,J3-4,=5Hz,H-3),3.7-4.5(4H, rn, H-4', H-5% N-11),4.50 (11-1, d, J=2.51-1z, H-4) and 7.1-7.6 ppm (15H, m, aromatic Hs); ir(nujol) 3170 (NH) and 1745 cm-1 (C=O); AnaL calcd for C27H27NO3S: C 72. 78, H 6.11, N 3.14, S 7.20; found: C 72.16, H 6.11, N 3.14, S7.17.

so WS,3S,4R and 4'R,3R,4S) 3-(2',2'-Dimethyl- V,Y-dioxolan-4'-yl)_(p_nitrobenzyl2"-hydroxy-2'-acetate)-4tritylthio-2-azetidinone (mixture of epimers at C-7) (Isomer 8) S.HO.

2 E 0 -/- J S,, t, - r oEN 1 11 The title compound was prepared as described in Example 51 for the 1somer W from (4'S,3S,4R and 4'R,313,4S) 3-(2',2'-di methylA',X-d ioxol a n-4'-yl)-4-trityithio-2- azetidi none (Isomer B) (10.8 g, 24.3 mmol):

yield 15.8 g, 24.1 mmol, 99.3%); yellowish foam; Rf 0.29 and 0.22 (benzene: R20+1:1); 'Hmr (CIDC13) 6: 1.28, 55 1.34(2s,di-Me),3.4-4.4(m, H-3, H-4', H-W, H-2",OH),4.39,4.53 (2d,J=2Hz, H- 4),5.15,5.25 (2s, OCH2Ar) and 7.1-8.3 ppm (m, aromatic Hs); ir (neat) v,,,ax: 3440 (br, OH), 1760 W=O), 1520,1350 cm-1 (N02).

WS,3SAR and 4'&3R,4S) 3-(2',2'-Dimethyl- 1',3'-dioxolan-4'-yl)- 1-(pnitrobenzyl2"-chloro-2"-acetate)-4- tritylthio-2-azetidinone (mixture of epimers at C-Z9 (Isomer 8) STr Tr-1,r 1, -- C%PN8 SOC1,-pY, C s, THF 'Er 1 C02phla ill GB 2 042 515 A ill The title compound was prepared as described in Example 51 for the--- IsomerC- from WS,3SAR and 4'R,3R,4S) 3-(2',2'-dimethyi-l',3'-1',3'- dioxolan-4'-yi)-1-(p-nitrobenzyl 2"-hydroxy-2"-acetate)-4-trityithio- 2azetidinone (isomer B) (14.9 g, 22.8 mmol; mixture of epimers at C-T); yield 14.1 g, 20.9 mmol, 91.9%; yellowish foam; Rf 0.52 (benzene: R20=3:2); 'Hmr (CDC13) 8: 1.30,1.38 (6H, 2s, di-Me), 3.44.5 (4H, m, H-3, HA', H-5%4.57 (1H, d,J=3Hz, HA),5.13 (s, H-T), 5.27 (s, OCH2Ar) and 7.1-8. 3 ppm (19H, m, aromatic Hs); ir (neat) Yniax: 1780 em-' (P-lactam, ester).

KS,3S,4R and 4'R,3R,4S) 3-(2'-Dimethyl-l',3'-dioxolan-4'-yl)-1-(pnitrobenzyl2,,triphenylphosphoranilidene-2"-acetate)-4-tritylthio-2azetidinone (Isomer B) b., --r -1 0 _flCl C02"S PO 3_ 0 03 CO 21'NB The title compound was prepared as described in Example 51 forthe--- IsomerW from WS,3SAR and XR,3R,4S) 3-(2',2'-dimethyi-l',3'-dioxolan-4'yi)-1-(p-nitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2azetidinone (isomer B) (14.0 g, 20.8 mmol; mixture of epimers at C-T): yield 4.64 g, 5.16 mmol, 24.8%; mp 190-9WC (dec., CH2C12-C20); 'Hmr (CDC13) 8: 1.12,1. 20,1.27,1.35 (4s, di-Me) and 7.0-8.1 ppm (m, aromatic Hs); ir (CH2C12) VMax: 1750 em-' (P-lactam ester); AnaL calcd for C54H47N207PS: C 72.14, H 5.27, N 3.12, S 20 3.57; found: C 71.90, H 5.57, N 3.07, S 3.56; Rf 0.21 (benzene: Et20l: 1).

(4'$,3S,4R and 4'R,3S,4R) Silver 3-(2',2'-dimethyl- V13'-dioxolan-4'-YO1(p-nitrobenzyl2"triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4thi olate (Isomer B) bstr Y C02p4B 0 3 CO 2 ma The title compound was prepared as described in Example 51 for the 1sorner W from WS,3SAR and 4'R,3S,M) 3-(2',2'-d i m ethyl- V,X-d ioxol a n4-yl)-1 -(p-n itrobenzyl 2"-triphenyi-phosphoranylidene-2"acetate)-4- trityith io-2-azeti d i none (isomer B) (1.00 g, 1.12 mmol): yield 580 mg, 0.760 mmol, 67.8%; mp 129-135'C (dec); ir (nujol) Ym,,x: 1745 em-' (P- Iactam, ester).

(4'S,3S,4R and4'R,3R,4S) 3-(2',2'-Dimethyll',31-dioxolan-4'-yl)-1-(pnitrobenzyl2,triphenylphosphoranylidene-2"-acetate)-4-acetylthio-2azetidinone (IsomerB) t S;ks C.4 3 C0C.11Pyr.

CH C12 3 Y C02PN8 U 9.

. 1 PN2 The title compound was prepared as described in Example 51 forthe--- IsomerW from WS,3S,41R and 4'R,3RAS) silver 3-(2',2'-d i methylV,X- dioxola n-4'-yl)-1 -(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"acetate)-2-azetidinone-4-thiolate (isomer B) (2.46 g, 3.22 mmol): yield after purification by column chromat6graphy(Si0232g,eluentlO%50%EtOAcinCH2C121:1);'Hmr(CDC13)6:1.23,1.2 7,1.30(3s, di-Me), 2.22,233 (2s, SAe) and 73-8.3 ppm (m, aromatic Hs); ir (neat) vrnx 1755 (P-lactam, ester) and 1695 em-' (thioester).

(4'S,5MS and 4'R,5S,6RJ p-Nitrobenzyl 6-(2',2'-dimethyl- 1',3'-dioxolan-4yl)-2-methylpenem-3-carboxylate 50 (IsomerB) i., V-1.0 3 C02 Z) - ' -c".3. 2.

1 The title compound was prepared as described in Example for the 1sorner W from WS,3SAR and 4'R,3R,4S) 3-(2',2'-dimethyi-l',3'-dioxoian-4'-yi)-1-(p- nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)4-acetyithio-2- azetidinone (isomer B) (200 mg, 0.286 mmol): yield 64 mg, 0.15 mmol, 53%; mp 151-2'C (CH2Ci21Et20); Rf 0.67 (benzene: Et201:1); 'Hmr(CDC13)6: 1.29,1.38(6H,2s, di-Me),2.30(3H,s,2-CH3), 3.6-4.4(4H, m, H-6,HA', H-5% 5.00-5.18-5.28-5. 46(4H,ABq,-OCH2Ar), 5.47 (1H,d,J=1.5Hz, H-5) and 7.42-7.55-8.05-8.15 ppm (4H, A2'B2', aromatic Hs); ir (neat) vna,,: 1785 em-' (P-Iactam) and 1710 em-' (ester); uv (EtO H) X.. i,.: 266 (E 13,000) and 314 mg (ú 9,700); AnaL calcd C191---120N207S: C 54.28, H 4.79, N 6.66, S 7.63; found: C 54. 00, H 4.75, N 6.68, S 7.61.

1 112 GB 2 042 515 A 112 (4'S,5R,6S and 4'R,5S,6R) 6-(2,2'-Dimethyl-l',3'-dioxolan-4'-yl)-2- methylpenem-3-carboxylic acid (Isomer 8) o 5 CH H21pd-C 5 C02pll CO2R The title compound was prepared as described in Example 51 for the 1sorner C: from (4S,5R,6S and 4'R,5S,6R) p-nitrobenzy] 6-(2,2'-dimethyi-l',3'-dioxolan-4'-yi)-2methylpenem-3-carboxylate (Isomer B) (79 mg, 0.19 mmol): yield after recrystallization from CH2C12-pentane 9 mg, 0. 032 mmol, 17%, Rf 0.54 (Acetone:

HOAc=5:0.5); 11-1mr (CDC13) 6:1.35,1.44 (61-1, 2s,di-Me), 2.37 (3H,s,2CH3),3.6-4.5 (41-1, m, H-6, H4, H-W) and 5.56 ppm (1 H, brs, H-5); ir (neat) 1785 cm-1 (P-Iactam); uv (EtOH) Imax: 307 (E 4300) and 262 mli (E 3700).

EXAMPLE 53 (VR,5R,6S and VS,5S,6R) 6-(1'-Hydroxy-2'-methoxymethoxy-2'-ethyl)-2ethyl)-2-methylpenem-3-carboxyli c 15 acid (Isomer Q ?H 20 WR,3SAR and VS,3RAS) 3-(1'12'-dihydroxyethyl)- 1-(p-nitrobenzyl2"triPhenylphosphoranylidene-2"acetatei-4-acetylthio-2-azetidinone (Isomer Q TFI-F 20 25 3 p, L --f07 Y - C02"t;S C02p'; A solution of WR,3SAR and 4'S,3R,4S) 3-(2',2'-dimethyi-l',3'-dioxolan-4'- yi)-1 -(p-nitrobenzyl 7tri phenyl phosph ora nyl idene-2"-acetate)-4-acetyith io-2-azetid i none (Isomer C) (472 m g, 0.676 mmol) in 30 trifluoroacetic acid (1.0 mi) and H20 (0.1 M0 Was left at room temperature for 30 min. The mixture was added dropwise to a cold solution of NaHCO3 (2.5 g) in H20 (50 mi) and extracted with CH2C12 (20 m] x 3). The extracts washed with sat. NaHC03 and then brine were dried (Na2S04) and evaporated yielding 458 mg (0.695 mmol, crude yield 100%; purity 97.3%) of the crude title compound as yellowish foam: 11-1mr (C13C13) 6: 2.20,232 (2s, SAc) and 7.2-8.3 ppm (m, aromatic Hs); ir (neat) vmax: 3420 (OH), 1745 (P-Iactam, ester) and 35 1690 cm-1 (thioester); Rf 0.16 (EtOAc).

(1'R,3S,4R and l'S,3R,4S) 3-(1'-Hydroxy-2'-methoxymethoxy- 1'-ethyl)- 1(p-nitrobenzyl2"triphenylphosphoranylidene-2"-acetate)-4-acetyl-thio-2aze tidinone (Isomer Q OH CH 40 brCH20CH3-di"thylaniline SAC 3 CH 2':12 n V'3 PNB C02PN-F To a solution of (VR,3S,4R and VS,3R,4S) 3-(1',2'-dihydroxyethyi)-1-(p- nitrobenzyI 7 triphenylphosphoranylidene-2"-acetate)-4-acetyithio-2-azetidinone (Isomer C) (291 mg, 0.430 mmol; purity 97.3%) and bro mom ethyl m ethylether (55.2 mg, 0.442 mmol; 4 drops) in CH2C12 (8 mi) was added at O'C, N,W-dimethylaniline (58.8 mg, 0.483 mmol; 5 drops) and the mixture was stirred at room temperature for 20 h. Additional brom om ethyl methyl ether (2 drops) and N,N'- dimethylaniline (2 drops) were added and it was so stirred for another 4 h. The mixture diluted with CH2C12 was washed successively with 1 N HCI, sat. NaHCO3 and brine, dried (Na2S04) and evaporated. The crude residue was purified by hplc (Si02, eluent EtOAc) collecting (31 mg, 0.186 mmol, yield 42.2%) of the title compound as an oil: Rf 0.24 (EtOAc); 11-1mr (CIDC13) 6: 2.20,232 (2s, SAc), 3.30 (s, OCH3),4.52 (s,-OCH20-) and 7.4-8.3 ppm (m, aromatic Hs); ir (neat) vmax: 3420 (OH), T755 (br, P-lactam and ester) and 1690 cm-1 (thioester).

(1'R,5R,6Sand 1'S,5S,6R)p-Nitrobenzyl6-(1'-hydroxy-2'-methoxy-methoxy-2ethyl)-2-methylpen em-3- so carboxylate 0.

i 5 t,,! - CH 3 2"B 60 p5 A solution of (VR,3SAR and VS,31RAS) 3-(1'-hydroxy-2'-methoxymethoxy-l'- ethyl)-1 -(p-nitrobenzyl T'-tri phenyl phosphoranyl idene-2"-acetate)-4-acetyith io-2-azetid i none (Isomer C) (167 mg, 0.238 mmol) in toluene (30 mi) was heated at reflux under N2 for 8 h. Evaporation of the solvent in vacuo gave oily residue 65 113 GB 2 042 515 A 113 which was purified by hplc (Si02t eluent EtOAc) to give 68 mg (0.16 m mol, yield 67%) of the title compound as an oil: W0.61 (ROAc),0.15 (benzene: Et201:1); 'Hmr(CDC13)8:2.38(3H,s,2-CH3),3.35(1 H, br,OH), 3.40 (3H, s, OCH3),16-3.8 (21-1, m, H-2% 3.90 (1 H, dd,J6-5=2Hz,J6-,,=4Hz, H-6),4.18 (1 H, m, H-1% 4.67 (21-1, s, -OCH20-) 5.03-5.27-5.38-5.62 (2H,A13q, OCH2Ar), 5.65 (1 H, d,J=2Hz, H-5) and (7.55-7.70-8.15-8.30 ppm (41-1, A2'132', aromatic Hs); ir (neat) Ymax: 3450 (01-1), 1785 (P-Iactam), 1710 (ester) and 1520 cm-1 (N02); uv (EtOH) Ir..: 266 (e 13000) and 313 mg (c 9100); AnaL calcd for C18H20NAS: C 50.94, H 4.75, N 6.60; found: C 51.13, H 4.77, N 6.36.

W&5R, 6S and l'S,5S, 6R) 6-(1'-Hydroxy-2'-methoxymethoxy2'-ethyl)-2methylpenem-3-carboxylic acid 10 (IsomerC) PH /pd-c:

2 C02H A solution of WIR,511,6S and VS,5S,61Ft) p-nitrobenzy] 6-(1'-hydroxy-2'- methoxymethoxy-2'-ethyi)-2- methylpenem-3-carboxylate (isomer C) (51 mg, 0.12 mmol) in THF (10 m]) was mixed with Et20 (10 mi), H20 (10 mi), Nal-IC03 (10 rng, 0.12 mmol) and 10% Pd-C (50 mg; Engelhard). It was hydrogenated at room temperature at 32 psi for 3 h. After filtration of the catalyst over Celite, the aqueous layer separated was washed with Et20 (x 3) and saturated with NaCi. The aqueous phase acidified at O'C with 0.1 N HU (1.2 mi) 20 was immediately extracted with EtOAc (15mi X 3). The extracts were washed with brine, dried (Na2S04) and evaporated yielding 22 mg of yellowish solid which was rinsed with a small amount of Et20 to give 20 mg (0.069 mmol, yield 58%) of the title compound as slightly yellow solid: 'Hmr (DMSO-d6) 6: 2.28 (31-1, s, 2-CH3), 3.27 (31-1, s, OCH3),149(2H, d, J=6.2Hz, 2'-H), 3.87 (1 H, dd, J6-5=1.71- 1z, J6-1-3.3Hz, 6-H), 4.58 (21-1, s, -OCH20-) and 5.55pprn (1H,d,J=1.7 Hz, 5-H); ir(KBr)vllax: 3410(01-1), 1755 (P- Iactam) and 1655cm-1 (COA; uv 25 (EtOH) Xmax: 308 (E 6800) and 262 m[t (E 4200), mp 137-WC (dec.).

EXAMPLE 54 WS,5R,6S and M55S,6R) 6-(1'-Hydroxy-2'-methoxymethoxy-2'ethyl)-2-methylpenem-3-carboxylic acid (IsomerB) CO,H (1S,3S,4R and 1W,3R,4S) 3-(1'12'-dihydroxyethyl)-1-(pnitrobenzyl2"triphenylphosphoranylidene-2'acetate)-4-acetylthio-2-azetidinone (1.somer B) 1 CH 3 -.C HO SAC 40 3 PM, 2 CC 2P The title compound was prepared as described in Example 105 for the 1somer W from (4'S,3S,41R and 4'R,3R,4S) 3-(2',2'-di methyl -V,3'-d ioxo 1 a n-4'-yi)-1 -(p-n itro benzyl T'-tri phenyl ph ospho ra nyl id ene-2"-acetate) 4-acetyithio-2-azetidinone (isomer B) (1.03 g, 1.47 mmol): yield 970 mg, 1.47 mmol, 100%; yellowish foam: 45 11-1mr (CDC13) 6: 2.20, 2.32 (2s, -SAc) and 7.3-8.2 ppm (m, aromatic Hs); ir (neat) vmx: 3410 (OH), 1750 (P-Iactam, ester) and 1690 cm-' (thioester): Rf 0. 16 (EtOAc).

(l'S,3S,4R and 1W,3R,4S) 3-(1'-Hydroxy-2'-methoxymethoxy- 1'-ethyl)- 1-(pnitrobenzyl2"- triphenylphosphoranylidene-2"-acetate)-4-acetyl-thio-2azetidinone(IsomerB) 011 09 SAC BrCH 2 OCH 3 Idir.ethylani line 0 3 C"2C12 co,p,:..n 2 55 The title compound was prepared as described in Example for the 1somer W from (1's,3S,4R and VIR,313,4S) 3-(1',2'-dihydroxyethyi)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-acetyithio2-azetidinone (isomer B) (485 mg, 0.736 mmol): yield 205 mg, 0.292 mmol, 39.6%; oil; 111mr (CDC13) 6: 2.22, 2.33 (2s, SAc), 3.32 (s, OCH3),4.57 (s,-OCH20-) and 7.2-8.3 ppm (m, aromatic Hs ir (neat) Ym,,: 3420 (01-1), 1755 60 (P-Iactam, ester) and 1690 (thioester) Rf 0.32 (EtOAc).

*114 GB 2 042 515 A 114 (VS,5R,6Sand 1'R,5S,6R)p-Nitrobenzyl6-(11hydroxy-l'-methoxy-methoxy-2'ethyl)-2-methylpe nem-3carboxylate 3 a 0 luene-BC 2 The title compound was prepared as described in Example for the Isomer W from WS,3SAR and VIR,3R,4S) 3-(1'-hydroxy-2'-methoxymethoxy-l'-ethyi)-1- (p-nitrobenzyl 2"-triphenylphosphoranylidene-2'- acetate)-4-acetyithio-2-azetidi none (isomer B) (205 mg, 0.292 m mol) and hydroqui none (10 mg, 0.09 m mol): 10 yield 38 mg, 0.090 mmol, 31%; 152-40C; Rf 0.23 (benzene: R20=1:1); 11-1mr (CDC13) 6: 2.37 (3H, s,2-CH2U.40 (3H,s,OCH3),3.4-3.9(3H,m,H-6,H-2"),4.15(1H,m,H-1'),4.67(2H,s,-OCH20-),5. 10m5.27-5.39-5.56(2H,ABq, -OCH2Ar),5.67 (1H, d,J=1.5 Hz, H-5) and 5.55-5.16-8.15-8.27 ppm (4H, A2'B2', aromatic H3); ir(CH2C12 MUll) v,,,..: 3370 (OH), 1785 (p-lactam) and 1700 cm (ester); uv (THF-ROH=1:1) 265 (e 10400) and 314 mix (s 7800).

(IS,5R,6S and 11R,5S,6R) 6-(1'-Hydroxy-2'-methoxymethoxy-2'-ethyl)-2methylpenem-3-carboxylic acid (IsomerB) 011 011 /Pli-C 20 3 PW. C32.

The title compound was prepared as described in Example 105 for the Isomer W from (VS,513,6S and VIR,5S,613) p-nitrobenzy] 6-(1'-hydroxy-2'-methoxymethoxy-2'-ethyi)-2- methylpenem-3-carboxylate (isomer 25 B) (36 mg, 0.085 mmol): yield 7.5 mg, 0.026 mmol, 30%; yellowish crystals; 'Hmr (CDC13) 6: 2.36 (3H, s, 2-CH3L3.39 (3H, s, OCH3),16-3.9 (3H, m, H-6, H-2% 4.15 (1 H, m, H-1% 4.66 (2H, s, OCH20) and 5.67 ppm (1 H, d, J=1.4 Hz, H-5); ir (CH2C12) Ymax: 1785 (P-Iactam) and 1675 cm (C02H); uv (EtOH) kmx: 308 (E 2900) and 263 mg (e2900).

EXAMPLE 55 2-Benzimidoylaminomethylpenem-3-carboxylic Acid NH CH NH_ C 35 COON IC C02 A. \\-CH 1 Na ' (CCC1)2 CH2C12 1!2 1 CH 2COCI 2 2 T C 40 To a suspension of 0.38 g (0.0015 mole) of sodium 3-benzyl-1,2,4oxadiazol-5-one-4-acetate (I)' in 10 ml of methyl chloride, containing 2 drops of DMF, was added at room temperature 0.13 mi (0.0015 mole) of oxalyl chloride, causing the mixture to effervesce. The reaction mixture was stirred at room temperaturefor 1 hour.

The NaCI that had formed was removed by filtration and the filter cake was washed with several small 45 portions of methylene chloride. The solution of acid chloride (11), was used directly.

1. K. Tak6cs and K. Harsjnyi, Ber, 103,2330 (1970).

is SAg L. (n) CH 2 C1 2 IrCH CH 50 J:f, - 3 pyrid,,o > t; 2- C 3 02PNB -(III) (IV) Asolution of 1.Og (0.0015 mole) of (111) and012 mi (0.015 mole) of pyridinein 10 mi of methylene chloride under a nitrogen atmosphere was cooled to 4. The acid chloride (11) solution was added all at once to the solution of (111) and the reaction mixture was stirred at 4'for 5 minutes, then at room temperature for 1.5 hrs. A thick precipitate formed in the reaction mixture. The mixture was filtered and the filtrate diluted with methylene chloride to a volume to 70-90 mi. The organic phase was then washed successively with 70 mi of OAN hydrochloric acid, 80 mI of 1% sodium bicarbonate and 80 mi of water. The methylene chloride phase was dried over magnesium sulfate. The solvent was removed at reduced pressure and the residual oil chromatographed on Mallinckrodt SilicAR CC7 silica gel using chloroform as the eluant, giving 0.4 g (30.5%) of OV) as an oil. The infrared and nuclear magnetic resonance spectra were consistent for OV) 1 GB 2 042 515 A 115 C. ly) t CH m - J: /.2 p 1 0 2 r:: 5 (v) A solution of 0.4 g (0.00045 mole) of IV in 50 mi of toluene was heated at reflux for 4 hrs. The solvent was 5 removed at reduced pressure and the residue chromatographed on Mallinckrodt SilicAR CC-7 silica qel, using 5% ethyl acetate in methylene chloride as elUant, affording 0.15 g(66.6%) of V as an oil which solidified. The infrared and nuclear magnetic resonance spectra were consistent for V.

Anal. Calcd for C231-11BN407S: C, 55.86; H, 3.67; N, 11.33. 10 Found: C, 56.17; H, 3.76; N, 11.23.

D. (v) H S NR 2 10; Pd/C 15 A solution of 0.135 g (0.00027 mole) of V in 40 mi of tetrahydrofuran and 40 m] of anhydrous diethyl ether was added to a slurry of 10% palladium on carbon catalyst in 40 m] of water under a nitrogen atmosphere. The resultant mixture was hydrogenated in a Parr hydrogenation apparatus at room temperature at an initial hydrogen pressure of 52 psi for 3.5 hrs. Hydrogen uptake was 4.5 psi. The catalyst was removed by filtration, washing the filter pad well with water. Additional diethyl ether was added to the filtrate and the phases were 20 separated. The aqueous phase was extracted 3x with diethyl ether. The aqueous phase was then concentrated to dryness at reduced pressure. The residue was chromatographed, using the high pressure liquid chromatography technique, to afford 0.050 g (58%) of the title penem acid; decomp 156-173'. The infrared and nuclear magnetic resonance spectra were consistent for the desired product.

Anal. Calcd for C15H15N303S.1.5H20: Found:

EXAMPLE 56

2-Phenylimidoylaminomethylpenem-3-carboxylic Acid N CE Nil-C - ;C N- 2 0 C) COOH C, 52.31; H, 5.27; N, 12.20.

C,51.64; H, 4.95; N, 12.31.

Following the procedure of Example 55 but using an equimolar amount of sodium 3-pheny]-1,2,4 oxacliazol-5-one-4-acetate as the starting material in place of the sodium 3-benzyi-1,2,4-oxadiazol-5-one-4- acetate used therein, there was produced the title product.

Biological data Representative compounds of the present invention were subjected to in vitro antibiotic screening against 40 a variety of microorganisms. Samples of the indicated compounds after solution in water and dilution with Nutrient Broth were found to exhibit the following Minimum Inhibitory Concentration (MIC) in mcg./mi.

versus the indicated microorganisms as determined by overnight incubation at 37'C. by the tube dilution method.

M.I.C. in mcg/mi Organism Compound Example No. 25 Streptococcus pneumoniae 125 A9585 50 Streptococcus pyogenes >125 A9604 Staphylococcus aureus 1 55 A9537 Staph aureus +50% 8 SerumA9537 60 Staphylococcus aureus A9606 Straphylococcus aureus A1 5097 32 4 116 GB 2 042 515 A 116 Streptococcus faecalis 125 A20688 Escherichia coli 8 Al 5119 5 Escherichia coli 2 A20341 -1 Klebsiella pneumoniae 125 10 Al 5130 Klebsiella species 4 A20468 Proteus mirabilis 8 15 A9900 Proteus mirabilis 63 A9716 20 Proteus morganii 63 A15153 Proteus rettgeri 32 25 A21203 Serratia marcescens 63 A20019 30 Enterobacter cloacae 16 A9659 Enterobacter cloacae 16 A9656 35 Pseudomonas aeruginosa 125 A9843A Pseudomonas aeruginosa >125 40 A21213 Hemophilus influenzae A9833 Haemophilus influenzae A21522 Bacteroides fragilis so A20931 50 Bacteroides fragilis A20929 M.I.C. in mcg/mi Compound (Example No.) Organism 2 3 Streptococcus pneumoniae 1 1 60 A9585 Streptococcus pyogenes 2 4 A9604 117 GB 2 042 515 A 117 Staphylococcus aureus 8 2 A9537 Staph aureus +50% > 63 > 63 Serum A9537 Straphylococcus aureus 4 4 A9606 Staphylococcus aureus 8 32 10 All 5097 Streptococcus faecalis 63 125 A20688 is Escherichia coli 32 63 A1 5119 Escherichia coli 32 63 A20341-1 20 Klebsiella pneumoniae 63 125 A15130 Klebsiella species A25 >125 25 A20468 Proteus mirabilis 63 63 A9900 Proteus vulgaris A9716 63 32 Proteus morganii 63 125 A1 5153 35 Providencia Stuartii 32 63 A21205 Serratia marcescens 125 63 40 A20019 Enterobacter cloacae 125 125 A9659 45 Enterobacter cloacae >125 125 A9656 Pseudomonas aeruginosa >125 >125 A9843A 50 Pseudomonas aeruginosa >125 >125 A21213 Hemophilus influenzae 55 A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteriodes fragilis A20929 65 118 GB 2 042 515 A 118 M.I.C. in mcglmi Compound (Example No.) Organism 4 5 Streptococcus pneumoniae 1.5 5 i, A9585 Streptococcus pyogenes 4 4 A9604 10 Staphylococcus aureus 8 4 A9537 Staph aureus +50% > 63 > 63 Serum A9537 15 Staphylococcus aureus 4 9 A9606 Staphylococcus aureus 125 63 20 Al 5097 Streptococcus faecalis 125 125 A20688 25 Escherichia coli >125 63 Al 5119 Escherichia coli >125 125 A20341 -1 30 Klebsiella pneumoniae >125 63 Al 5130 Klebsiella species >125 >125 35 A20468 Proteus mirabilis 63 63 A9900 40 Proteus vulgaris 63 32 A9716 Proteus morganii 125 125 Al 5153 45 Providencia stuartii 125 32 A21205 Serratia marcescens >125 63 50 A20019 Enterobacter cloacae >125 125 A9659 55 Enterobacter cloacae >125 125 A9656 Pseudomonas aeruginosa >125 A9843A 60 Pseudomonas aeruginosa >125 A21213 119 GB 2 042 515 A 119 Hemophilus influenzae A9833 Haemophilus influenzae A21522 5 Bacteroides fragilis A20931 Bacteroides fragilis A20929 M.I.C. in meg/mi Compound (Example No.) 15 Organism 11(5) 11(6) Streptococcus pneumoniae 1 2 A9585 20 Streptococcus pyogenes 2 4 A9604 Staphylococcus aureus 4 4 A9537 25 Staph aureus +50% 32 63 Serum A9537 Staphylococcus aureus 32 125 30 A9606 Staphylococcus aureus 63 63 A1 5097 35 Streptococcus faecalis > 63 125 A20688 Escherichia coli 16 16 A1 5119 40 Escherichia coli > 63 125 A20341 -1 Klebsiella pneumoniae 63 125 45 A1 5130 Klebsiella species > 63 >125 A20468 50 Proteus mirabilis 8 16 A9900 Proteus vulgaris 63 32 A21559 55 Proteus morganii A1 5153 16 32 Proteus rettgeri 32 32 60 A21203 Serratia marcescens 32 63 A20019 GB 2 042 515 A Enterobacter cloacae 63 63 A9659 Enterobacter cloacae 63 63 A9656 5 Pseudomonas aeruginosa 16 32 A9843A Pseudomonas aeruginosa 32 >125 10 A21213 is Hemophilus influenzae A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 20 Bacteroides fragilis A20929 M.I.C. in mcg/m] Compound (Example No.) Organism 12 Streptococcus pneumoniae.016 30 A9585 Streptococcus pyogenes.06 A9604 35 Staphylococcus aureus.13 A9537 Staph aureus +50% 4 Serum A9537 40 Staphylococcus aureus 8 A9606 Staphylococcus aureus 125 45 A1 5097 Streptococcus faecalis 63 A20688 50 Escherichia coli A151 19 Escherichia coli 63 A20341 -1 55 iz Klebsiella pneumoniae 8 A1 5130 Klebsiella species >125 60 A20468 Proteus mirabilis A9900 1 121 Proteus vulgaris A9716 GB 2 042 515 A 121 Proteus morganii 1 Al 5153 5 Proteus rettgeri 2 A21203 Serratia marcescens 1 10 A20019 Enterobacter cloacae 2 A9659 15 Enterobacter cloacae 1 A9656 Pseudomonas aeruginosa 1 A9843A 20 Pseudomonas aeruginosa 125 A21213 Hemophilus influenzae 125 25 A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 35 M.I.C. in mcg/mi Compound (Example No.) Organism 32 18 24 40 Streptococcus pneumoniae.25.25.016 A9585 Streptococcus pyogenes 8 2.25 45 A9604 Staphylococcus aureus 8 4.03 A9537 50 Staph aureus +50% 32 63 63 - Serum A9537 Staphylococcus aureus 16 4 16 A9606 55 Staphylococcus aureus 63 16 >125 A1 5097 Streptococcus faecalis >125 125 16 60 A20688 Escherichia coli 63 4 63 A1 5119 122 GB 2 042 515 A 122 Escherichia coli >125 16 >125 A20341 -1 1 Klebsiella pneumoniae 125 32 >125 A1 5130 5 Klebsiella species >125 125 >125 A20468 Proteus mirabilis 63 16 32 10 A9900 Proteus vulgaris 125 16 - A9555 is Proteus morganii 125 32 32 A1 5153 Proteus rettgeri 63 32 - A21203 20 Serratia marcescens 63 32 16 A20019 Enterobacter cloacae 125 32 >125 25 A9659 Enterobacter cloacae 125 63 125 A9656 30 Pseudomonas aeruginosa 125 125 >125 A9843A Pseudomonas aeruginosa 125 125 >125 A21213 35 Hemophilus influenzae A9833 Haemophilus influenzae 40 A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 so Compound (Example No.) 50 Organism 32 18 24 Pseudomonas aeruginosa A20599 Pseudomonas aeruginosa A9925 Pseudomonas aeruginosa A20229 60 Proteus species A20543 123 GB 2 042 515 A 123 Proteus mirabilis 16 A9716 Providencia stuartii 63 A21205 5 M.I.C. in mcg/mi Compound Organism 25 10 Streptococcus pneumoniae 2 A9585 Streptococcus pyogenes 16 is A9604 Staphylococcus aureus 32 A9537 20 Staph aureus +50% > 63 Serum A9537 Staphylococcus aureus >125 A9606 25 Staphylococcus aureus >125 A1 5097 Streptococcus faecalis 125 30 A20688 Escherichia coli 63 A1 5119 35 Escherichia coli >125 A20341-1 Klebsiella pneumoniae >125 A1 5130 40 Klebsiella species A20468 >125 Proteus mirabilis 63 45 A9900 Proteus vulgaris A9716 Proteus morganii A1 5153 Proteus rettgeri A21203 55 Serratia marcescens A20019 >125 Enterobacter cloacae >125 60 A9659 Enterobacter cloacae A9656 >125 124 GB 2 042 515 A 124 Pseudonomas aeruginosa 125 A9843A Pseudonomas aeruginosa 125 A21213 5 Hemophilus influenzae A9833 Haemophilus influenzae 10 A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 M.I.C. in mcg/m] 20 Compound Organism 25 Pseudonomas aeruginosa - A20599 25 1 15 Pseudomonas aeruginosa A9925 Pseudonomas aeruginosa A20229 Proteus species A20543 Proteus mirabilis 63 A9716 Proteus mirabilis - A9555 40 M.I.C. in mcg/ml Compound (Example No.) Organism 31 45 Streptococcus pneumoniae 63 A9585 so Streptococcus pyogenes 125 50 A9604 Staphylococcus aureus 32 A9537 55 Staph aureus +50% Serum A9537 32 Staphylococcus aureus >125 A9606 60 Staphylococcus aureus A1 5097 GB 2 042 515 A 125 Streptococcus faecalis 63 A20688 Escherichia coli 63 A1 5119 5 Escherichia coli A20341 -1 63 1 Klebsiella pneumoniae A1 5130 Klebsiella species A20468 Proteus mirabilis A9900 Proteus vulgaris A9555 Proteus morganii A1 5153 32 >125 63 >125 Proteus rettgeri 125 25 A21203 Serratia marcescens 125 A20019 30 Enterobacter cloacae 125 A9659 Enterobacter cloacae 125 A9656 35 Pseudomonas aeruginosa 32 A9843A Pseudomonas aeruginosa 125 40 A21213 Hemophilus influenzae 125 A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 50 Bacteroides fragilis A20929 Organism Streptococcus pneumoniae A9585 Streptococcus pyogenes A9604 M.I.C. in mcg/mi Compound (Example No.) 33 34 06 2 126 GB 2 042 515 A 126 Staphylococcus aureus 4 A9537 Staph aureus +50% 16 63 Serum A9537 Staphylococcus aureus 125 4 A9606 Staphylococcus aureus >125 16 10 All 5097 Streptococcus faecalis 125 125 A20688 Escherichia coli 16 4 A1 5119 Escherichia coli >125 16 A20341 -1 20 Klebsiella pneumoniae 125 32 A1 5130 Klebsiella species >125 125 25 A20468 Proteus mirabilis 8 16 A9900 30 Proteus vulgaris 63 16 A9555 Proteus morganii 32 32 A1 5153 35 Proteus rettgeri 16 32 A21203 h Serratia marcescens 63 32 40 A20019 Enterobacter cloacae 125 32 A9659 45 Enterobacter cloacae 63 63 A9656 Pseudomonas aeruginosa 125 125 so A9843A 50 Pseudomonas aeruginosa 125 125 A21213 Hemophilus influenzae 55 A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 65 127 GB 2 042 515 A. 127 M.I.C. in mcg/mi Compound (Example No.) Organism 35 36 40 Streptococcus pneumoniae 32.25.004 5 A9585 32.25.008 Streptococcus pyogenes A9604 1.004 1.008 Staphylococcus aureus - -.008 A9537 >125 2.008 Staph aureus +50% -.06 Serum A9537 > 63 8.06 15 Straphylococcus aureus - -.06 A9606 >125 4.06 Staphylococcus aureus - -.06 20 A1 5097 >125 8.25 Streptococcus faecalis >125 63.5 A20688 >125 63.5 25 Escherichia coli A25 16.13 A1 5119 A25 16.25 Escherichia coli >125 16 <.25 A20341 -1 >125 - 16.13 30 Klebsiella pneumoniae >125 16 <.25 A1 5130 >125 16.5 Klebsiella species >125 16.5 35 A20468 >125 16.5 Proteus mirabilis >125 32 <.25 A9900 >125 16.25 40 Proteus vulgaris A21559 >125 16 <.25 16 Proteus morganii >125 3,2 1 A15153 >125 16 1 45 Proteus rettgeri A21203 >125 >125 16 <.25 16.5 Serratia marcescens >125 16.5 50 A20019 >125 16.5 Enterobacte cloacae >125 32 4 A9659 >125 - 2 55 Enterobacter cloacae >125 16.5 A9656 >125 -.5 Pseudonomas aeruginosa >125 >125 16 A9843A >125 - 16 60 Pseudomonas aeruginosa >125 >125 125 A21213 >125 - 63 128 GB 2 042 515 A 128 Hemophilus influenzae A9833 Haemophilus influenzae A21522 5 Bacteroides fragilis A20931 Bacteroides fragilis A20929 Organism Compound (Example No.) 37 38 39 Streptococcus pneumoniae.03.03.016 A9585 Streptococcus pyogenes.06.5.03 20 A9604 Staphylococcus aureus.5.03.06 A9537 25 Staph aureus +50% 4.25.13 Serum A9537 Staphylococcus aureus 1.25.13 A9606 30 Staphylococcus aureus 1.5.25 A1 5097 Streptococcus faecalis 2 32 4 35 A20688 Escherichia coli 2 8 2 A1 5119 40 Escherichia coli 8 8 2 A20341 -1 Klebsiella pneumoniae 8 16 4 A1 5130 45 Klebsiella species 63 32 4 A20468 -E so Proteus mirabilis 2 2 4 50 A9900 Proteusvulgaris 4 2 2 A21559 55 Proteus morganii 8 2 4 A1 5153 fl Proteus rettgeri 2 2 4 A21203 60 Serratia marcescens 8 16 4 A20019 1;k- Ii 129 GB 2 042 515 A 129 Enterobacter cloacae 8 32 4 A9659 Enterobacter cloacae 32 1 16 A9656 5 Pseudomonas aeruginosa A9843A 63 2 16 Pseudomonas aeruginosa 10 A21213 Hemophilus influenzae A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 20 Bacteroides fragilis A20929 Organism Streptococcus pneumoniae A9585 Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Staph aureus +50% Serum A9537 Staphylococcus aureus A9606 M.I.C. in mcg/mi Compound (Example No.) 43 >63 >63 >63 >32 >63 Staphylococcus aureus >63 45 A1 5097 Streptococcus faecalis >63 A20688 50 Escherichia coli >63 A1 5119 Escherichia coli >63 A20341 -1 55 Klebsiella pneumoniae >63 A1 5130 Klebsiefla species >63 60 A20468 Proteus mirabilis A9900 >63 GB 2 042 515 A Proteus vulgaris A21559 Proteus morganii A1 5153 Proteus rettgeri A21203 >63 >63 >63 Serratia marcescens >63 10 A20019 Enterobacter cloacae >63 A9659 15 Enterobacter cloacae >63 A9656 Pseudomonas aeruginosa >63 A9843A 20 Pseudomonas aeruginosa >63 A21213 Hemophilus influenzae - 25 A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 35 M.I.C. in mcg/mi Compound (Example No.) Organism 45 40 Streptococcus pneumoniae 2 A9585 0 Y.

Streptococcus pyogenes 16 45 A9604 Staphylococcus aureus 32 A9537 50 Staph aureus +50% Serum A9537 >32 Staphylococcus aureus 2 A9606 55 Staphylococcus aureus A1 5097 8 Streptococcus faecalis 63 60 A20688 Escherichia coli A1 5119 2 131 1 GB 2 042 515 A 131 Escherichia coli 32 A20341 -1 Klebsiella pneumoniae 8 Al 5130 5 Klebsiella species >63 A20468 Porteus mirabilis 4 10 A9900 Proteus vulgaris 16 A21559 15 Proteus morganii 8 A15153 Proteus rettgeri 8 A21203 20 Serratia marcescens 8 A20019 Enterobacter cloacae 8 25 A9659 Enterobacter cloacae 8 A9656 30 Pseudomonas aeruginosa 63 A9843A Pseudomonas aeruginosa >63 A21213 35 Hemophilus influenzae A9833 Haemophilus influenzae 40 A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 M.I.C. in mcg/mi 50 Organism Compound Example No.) Streptococcus pneumoniae 47 A9585 55 Streptococcus pyogenes.5 A9604 Staphylococcus aureus.5 60 A9537 Staph aureus +50% 8 Serum A9537 132 GB 2 042 515 A 132 Staphylococcus aureus A9606 Staphylococcus aureus 16 A1 5097 5 Streptococcus faecalis A20688 32 Escherichia coli >63 10 A1 5119 Escherichia coli A20341 -1 Klebsiella pneumoniae A1 5130 32 32 Klebsiella species 63 A20468 20 Proteus mirabilis 63 A9900 Proteus vulgaris 32 25 A21559 Proteus morganii 32 A1 5153 C Proteus rettgeri 63 A21203 Serratia marcescens 32 A20019 35 Enterobacter cloacae 63 A9659 63 Enterobacter cloacae >63 40 A9656 Pseudomonas aeruginosa >63 A9843A %, 45 Pseudomonas aeruginosa >63 21 A21213 Hemophilus influenzae - A9833 50 Haemophilus influenzae A21522 Bacteroides fragilis 55 A20931 Bacteroides fragilis A20929 z 133 GB 2 042 515 A 133 M.I.C. in mcg/mi Organism Compound (Example No.) 48 49 50 Streptococcus pneumoniae >125 1 32 5 A9585 Streptococcus pyogenes >125 16 32 A9604 10 Staphylococcus aureus >125 32 125 A9537 Staph aureus +50% >63 >63 >63 Serum A9537 15 Staphylococcus aureus >125 32 >125 A9606 Staphylococcus aureus >125 >125 >125 20 A1 5097 Streptococcus faecalis >125 >125 >125 A20688 25 Escherichia coli >125 A25 A25 A1 5119 Escherichia coli >125 >125 >125 A20341 -1 30 Klebsiella pneumoniae >125 >125 >125 A1 5130 Klebsiella species >125 >125 >125 35 A20468 Proteus mirabilis >125 >125 >125 A9900 40 Proteus vulgaris >125 >125 >125 A21559 Proteus morganii >125 >125 >125 A1 5153 45 Proteus rettgeri >125 >125 >125 A21203 Serratia marcescens >125 >125 >125 50 A20019 Enterobacter cloacae >125 >125 >125 A9659 55 Enterobacter cloacae >125 >125 >125 A9656 Pseudomonas aeruginosa >125 >125 >125 A9843A 60 Pseudomonas aeruginosa >125 >125 >125 A21213 134 GB 2 042 515 A 134 Hemophilus influenzae A9833 Haemophilus influenzae A21522 5 Bacteroides fragilis A20931 Bacteroides fragilis 10 A20929 M.I.C. in meg/m] Compound (Example No.) 15 Organism 51 52 53 54 Streptococcus pneumoniae 63 16 4 32 A9585 20 Streptococcus pyogenes 63 32 4 32 A9604 Staphylococcus aureus >63 63 >8 63 A9537 25 Staph aureus +50% >32 >32 >32 >32 Serum A9537 Staphylococcus aureus >63 63 63 >63 30 A9606 Staphylococcus aureus >63 63 >63 >63 A1 5097 35 Streptococcus faecalis >63 63 >63 >63 A20688 Escherichia coli >63 >63 63 63 A1 5119 40 Escherichia coil >63 >63 63 63 A20341 -1 Klebsiella pneumonia >63 >63 63 >63 45 A1 5130 Klebsiella species >63 >63 >63 >63 A20468 50 Proteus mirabilis 63 >63 >63 63 A9900 Proteusvulgaris >63 >63 >63 >63 A21559 55 Proteus morganii >63 >63 >63 >63 A1 5153 Proteus rettgeri >63 63 32 63 60 A21203 Serratia marcescens >63 >63 >63 63 A20019 GB 2 042 515 A 135 Enterobacter cloacae >63 >63 63 >63 A9659 Enterobacter cloacae >63 >63 63 63 A9656 5 Pseudomonas aeruginosa A9843A 63 63 63 63 Pseudomonas aeruginosa 63 63 63 63 1 A21213 Hemophilus influenzae A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 26 Bacteroides fragilis A20929 M.I.C. in mcg/mi Compound (Example No.) Organism 55 56 Streptococcus pneumoniae.5.25 30 A9585 Streptococcus pyogenes.5.25 A9604 35 Staphylococcus aureus.5.25 A9537 Staph aureus +50% 16 16 Serum A9537 40 Staphylococcus aureus 32 16 A9606 Q Staphylococcus aureus >63 >125 45 A1 5097 Streptococcus faecalis >63 125 A20688 Escherichia coli 63 63 A1 5119 Escherichia coli >63 >125 A20341 -1 55 Klebsiella pneumoniae >63 125 A1 5130 Klebsiella species >63 >125 60 A20468 Proteus mirabilis 63 63 A9900 136 GB 2 042 515 A 136 Proteus vulgaris 63 125 A21559 Proteus morganii 63 63 A15153 5 IA Proteus rettgeri 63 63 A21203 Serratia marcescens 63 125 10 A20019 Enterobacter cloacae >63 125 A9659 15 Enterobacer cloacae - 63 125 A9656 Pseudomonas aeruginosa 63 63 A9843A 20 Pseudomonas aeruginosa 63 125 A21213 Hemophilus influenzae - - 25 A9833 Haemophilus influenzae - A21522 Bacteroides fragilis - - 30 A20931 Bacteroides fragilis - - A20929 35 M.I.C. in mcg/mi Compound (Example No.) Organism 55 56 40 Streptococcus pneumoniae.5.25 A9585 Streptococcus pyogenes.5.25 45 A9604 > Staphylococcus aureus.5.25 so A9537 50 Staph aureus +50% 16 16 Serum A9537 Staphylococcus aureus 32 16 A9606 55 A - Staphylococcus aureus >63 >125 A1 5097 Streptococcus faecalis >63 125 60 A20688 Escherichia coli 63 63 A1 5119 137 GB 2 042 515 A 137 Escherichia coli >63 >125 A20341 -1 Klebsiella pneumoniae >63 125 A1 5130 5 Klebsiella species >63 >125 A20468 Proteus mirabilis 63 63 10 A9900 Proteus vulgaris 63 125 A21559 15 Proteus morganii 63 63 A1 5153 Proteus rettgeri 63 63 A21203 20 Serratia marcescens 63 125 A20019 Enterobacter cloacae >63 125 25 A9659 Enterobacter cloacae 63 125 A9656 30 Pseudomonas aeruginosa 63 63 A9843A Pseudomonas aeruginosa 63 125 A21213 35 Hemophilus influenzae A9833 Haemophilus influenzae 40 A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 Representative compounds of the present invention were also tested in vivo in mice and their PD50 (dose 50 of compound in mg/kg required to protect 60% of the treated mice against an otherwise lethal infection of a microorganism) values determined with respect to the test organisms shown below.

S. aureus A9537 # of infecting organisms of S.aureus # of Treatment PD5o Compound A 9537 treatments route (mg/kg/treatment) 60 Compound of EX. 40 7.8 x 105 2 IM 0.12 Compound of EX. 36 6.6 x 105 2 IM 7.7 65 138 GB 2042515 A 138 S. aureus A9537 # of infecting organisms of S.aureus #of Treatment PD50 5 Compound A9537 treatments route (mg/kg/treatment) :;Y.

Compound of Ex. 62 8.6 X 105 2 IM 1.0 10 Compound of Ex. 56 8 x 105 2 IM >5 Compound of Ex. 64 8 X 105 2 IM 0.04 15 Mouse blood levels after intramuscular administration of representative compounds of the present invention were determined and are reported in the table below.

Mouse Blood Levels in mcg/m] After intramuscular Administration of 40 m g/kg Body Weight Compound Minutes After Administration 25 20 0 45 60 90 120 Compound of Ex. 40 44.7 34.4 23.7 17.6 9.8 3.6 1 Average of 6 mice 30

Claims (1)

1. A compound having the formula:

5 35 -Tix ,>-- M 0 CO,z wherein Z is hydrogen atom or an easily removable ester protecting group; X is (a) a group of the formula (i) -ORa in which Ra is a hydrogen atom; (ii) -ORb in which Rb is a hydrogen atom, a hydroxy, optionally substituted (lower)alkyl or optionally ring-substituted phenyl or heterocyclic group, the substituents on the alkyl group being one or more of a 45 halogen atom, a hydroxy, oxo, carboxy, carb(lower)alkoxy, carbamoyl, (lower)alkyl, amino, (lower)alkylamino, di(lower)alkylamino, (lower)-alkanoylamino, or optionally substituted phenyl or heterocyclic 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)-alkyl, methanesulfonyl, oxo, (lower)alkylthio, amino, (lower)alkylamino, di(lower)-alkylamino, (lower)alkanoylamino, (lower)- alkanoyloxy, carboxy, carboxy50 (lower)alkyl,sulfoorsulfo(lower)alkyI group; or (iii)-OCOR, in which Rc is an amino, (lower)-alkylamino, di(lower)alkylamino or optionally substituted (lower)alkyl group in which the substituents are as defined under (ii); or (b) a substituted (lower)aliphatic, (lower)-cycloaliphatic or (lower)cycloaliphatic(lower)- aliphatic radical or a ring-substituted phenyl, phenyl(lower)alkyl, heterocyclic, heterocyclic (lower)alkyl or heterocycliothio55 (lower)alkyl group the substituents for the above-mentioned aliphatic, cycloaliphatic, phenyl or heterocyclic 55 groups being 1 S i m i - NRi 1:z (i)-CNR2R3orN=C-NR2R3 60 1 R, in which R, is a hydrogen atom, a (lower)alkyl or phenyl group and R2 and R3 are each independently a 65 hydrogen atom a (lower)alkyi, phenyl or benzy] group; 139 is GB 2 042 515 A 139 (ii) -ORd in which Rd is an amino, (lower)alkylamino, di(lower)alkylamino, substituted (lower)alkyl, (lower)alkenyl or optionally ring-substituted phenyl, phenyl (lower)alkyl heterocyclic or heterocyclic (lower)alkyl, the substituents on the alkyl, phenyl and heterocyclic groups being as defined under (a) (ii); ON) -O(CH2),,ORr in which n is an integer from 1 to 6 and Rr is an optionally substituted (lower)alkyl or optionally ring-substituted phenyl or heterocyclic, the substituents on the alkyl, phenyl or heterocyclic groups being as defined under (a) (ii); Ov) -OCORr' in which Rr'is an amino (lower)-alkylamino, di(lower)alkylamino or Rr group, with the proviso that Rr, may not be an unsubstituted (lower)alkyl group; M -OS03H; 0 1 (vi) OP(OW2; (Vii) -OSO2Rr in which Rr is as defined in (b) (iii); 0 T (viii) -OP(ORJ(ORr) in which R. is a (lower)alkyl group and Rris as defined in (b) (iii); OX) -S(O)nRd in which n is 0, 1 or 2 and Rd is as defined in (b) (ii) or is in the case where N114 11 25 n=0 -C-NR5R6 in which R4 is a hydrogen atom or a (lower) alkyl group and R5 and R6 are each independently a hydrogen atom or a Cower)-alkyl group, with the proviso that Rd may not be an unsubstituted phenyl group; (x) -CORf in which Rf is an amino(lower)alkyi, (lower) alkylamino(lower)aiky], cli(lower) alkylamino(lower)aikyi, -NHNH2, -NR17NR,8, NHOR19, -S-R17, -O(CH2)n-A-% or-NRRg in which R17, R18 and % 30 are (lower)alkyl groups, R19 is a hydrogen atom or a (lower)aikyl group, A is 0, S, NH or NCH3 and n and R.

are as defined in (b) (Iii) and (b) (viii); (xi) -PO(ORJ2 in which R,, is a hydrogen or a (lower) alkyl group; (xii) -NHRh in which Rh is an optionally substituted phenyl, optionally substituted heterocyciic, -CH=NH, -S03H, -OH, (lower)alkoxy, amino, (lower alkylamino, di(lower)aikylamino, -NHCOCH3,-CS2-CH3,-SO2CH3,-SO2- 151 -C-NH- S S S 11 11 11 -S02NH2,-CNH2,-CNHCH3,-C-NH- -NH-O, NH 11 50 -C-NR7R8 1 in which R7 and R8 are each independently (lower) alkyl, phenyl or phenyl (lower)aikyl, NH 55 11 -C-Rg in which R9 is (lower)alkyl, phenyl or phenyl (lower)-alkyl or 0 11 -C-Ri in which Ri is amino (lower)-alkyl, -NH2, (lower)alkylamino, di(lower)- alkylamino, GB 2 042 515 A 0 H NH-C-R,() in which R10 is (lower) alkyl or optionally substituted phenyl or heterocyclic, the phenyl and heterocyclic 5 substituents being as defined under (a) (ii), NH H NI-I-C-NH2Alower)alkoxy, or -OCH 2 -O(CHA2Si(CH3)3 group; 0 I (xiii)-S-C-Rll ii k lk c in which 1311 is a (lower)alkyl group substituted by an amino, (lower)alkylamino or di(lower) alkylamino group; (xiv) -NRjRk in which Rj is a (lower)alkyl group and Rk is a (lower)alkyl, (lower)alkoxy, heterocyclic, amino, or 0 11 -C-R, group in which Ri is as defined in (b) (A) or, when taken together with the nitrogen, Rj and Rk represent 30 providing that when Rk is an amino or -CH2CH2NH2 group, Rj is a methyl group and also providing that Rj and Rk may not both be a (lowedalkyl group; (xv) - NRj'Rk' in which Rj' is a (lower)alkoxy group and Rk'is a (lower)alkyl, heterocyclic, amino(lower)alkyl, (lower)alkylamino-(Iower)alkyl, di(lower)alkylamino(lower)-alkyI or 0 h -C-Ri group in which Ri is as defined under (b) (xii) or, when taken together with the nitrogen, Ri' and Rk' represent 45 (xvi) -N131R,R,, in which R,, R, and Rn are each independently a (lower)alkyl group or when taken together with the nitrogen, represent .. j (xvii) -N=CH-R, in which Rx is a (lower)alkyl or optionally ring- substituted phenyl or heterocyclic group, the substitutents on the phenyl or heterocyclic ring being as defined in (a) (ii); (xviii) -N=CRxRy in which Ry is a (lower)alkyl or optionally ring- substituted phenyl or heterocyclic group, the 60 phenyl and heterocyclic substituents being as defined in (a) (H), and Rx is as defined in (b) (xvii); Nix) =N-Rp in which Rp is a hydroxy, (lower)alkoxy, amino, di(lower)alkylamino or 1 11 141 GB 2 042 515 A 141 group; or NOH 11 (xx) -C-(CH2),,NR15R,6 in which n is a integerfrom 1 to 6 and 1315 and R16 are each independently a hydrogen atom or a (lower)alkyl group; and Y is a hydrogen atom or a group selected from (a) an optionally substituted (lower)aliphatic, (lower) cycloaliphatic or (lower)cycloaliphatic(lower)aliphatic group, the substituents being one or more of a hydroxy, (lower)alkoxy, optionally substituted phenyloxy, 10 optionally substituted heterocyclicoxy, optionally substituted (lower) alkylthio, optionally substituted phenylthio, optionally substituted heterocycliothio, mercapto, amino, (lower) alkylamino, di(lower)alkylamino, (lower)alkanoyloxy, (lower) alkanoylamino, optionally substituted phenyl, optionally substituted heterocyclic, carboxy, carb(lower) alkoxy, carbamoyl, N-(Iower)alkylcarbamoyl, N,Ndi(lower)alkyl- carbamoyl, halo, cyano, oxo,thioxo, -S03H, -OS03H, -S02-(Iower)alkyl, (lower)alkylsulfinyl, nitro, phospho- 15 no or 0 T -OP(ORJ (OR,) group in which R. and Rr are as defined above, the substituents on the (lower)alkylthio group being one or more of a halogen atom, a hydroxy, (lower)alkoxy, amino, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic group and the phenyl or heterocyclic substituents above being one or more of a halogen atom, a hydroxy, (lower)-alkoxy, (lower)alkyl, halo(lower)alkyl, methane-sulfonyl, (lower)alkylthio, 25 amino, (lower)alkanoylamino, (lower)alkanoyfoxy, carboxy, carboxy(lower) alkyl, sulfo or sulfo(lower)alkyl; (b) -OR, in which R. is an optionally substituted (lower) alkyl or (lower)alkanoyl group oran optionally substituted phenyl or heterocyclic group, the substituents on the alkyl and alkanoyl being one or more of a halogen atom, a hydroxy (lower)alkoxy, (lower)alkylamino, di(lower)alkylamino, amino, oxo, (lower)alka noylamino or optionally substituted phenyl or heterocyclic group and the substituents on the phenyl or heterocyclic being one or more of a halogen atom, a hydroxy, (lower)alkoxy, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, (lower)alkylthio, (lower)alkylamino, di(lower)alkylamino, amino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl group; (C) -S(O)nR., inwhich n isO, 1 or2 and R.isasdefined above; (d) a halogen atom; and (e) an optionally substituted phenyl or heterocyclic group in which the substituents are one or more of a halogen atom a hydroxy, (lower)alkoxy, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, (lower)alkylthio, amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoylamino, (lower)-alkanoyloxy, carboxy, car boxy(lower)alkyl, sulfo or sulfo(lower)alkyl group, with the proviso that when Y is a hydrogen atom then X may not be -CH20CH2CH2OCH3- 2. A compound as claimed in claim 1 wherein Y is a hydrogen atom.

3. A compound as claimed in claim 1 wherein Y is a Cl-C6 alkyl group optionally substituted by a hydroxy group.

4. A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl group 5. Acompound as claimed in anyone of claims 1 to 4wherein X is 0 (a) (CH2) 11 A inwhichnisanintegerfromlto6; (b) -(CH2)nNHOH in which n is an integer from 1 to 6; (c) -(CH2)nPO(O-Cl- C6 alkyl)2 in which n is an integer from 1 to 6; NH 11 55 (d) -CH2)nNH-C-Cl-C6 alkyl in which n is an integer from 1 to 6; NH2 1 - (e) -(CH2),,N=CH in which n is an integer from 1 to 6; 0 11 (f) -(CH2)n0C(CH2),,NR A R13 142 GB 2 042 515 A 142 in which n and m are each independently 1 or 2 and R A and RB are each independently a hydrogen atom or a (lower)alkyl group; or (g) -CH2),,NHCRl 11 NH inwhichn is an integerfrom 1 to 6 and Rois Cl-C4an alkyl, phenyl or - (CH111 group in which m is 1 or 2.

6. A compound as claimed in claim 1 as specifically defined in anyone of the foregoing specific Examples.

7. A pharmaceutical ly acceptable salt of a compound as claimed in anyone of the preceding claims.

8. A process for the preparation of a compound as claimed in anyone of the preceding claims which process comprises cyclizing a compound of the formula:

wherein G is a phenyl or (lower)aikyl group, W' is an easily removable ester group and X and Y are as defined in claim 1 in an inert organic solvent at a temperature of from just above room temperature to the reflux temperature of the solvent; removing by methods known perse the removable ester group and, optionally, other protecting groups; and if desired, optionally coverting a compound of formula 1 where Y is a hydrogen atom, to any other desired product where Y is a substituent as defined in claim 1 other than a hydrogen atom by treating the product with a corresponding electrophile in an inert solvent in the presence of a strong base.

9. A process as claimed in claim 8 wherein the cyclization is carried out at the ref lux temperature of the 30 solvent.

10. A process as claimed in claim 8 substantially as hereinbefore described.

11. A compound as claimed in claim 1 whenever prepared by a process as claimed in anyone of claims 8 to 10.

12. An intermediate compound of the formula v S 1 Ar-P (Q) 3 CO R.

- 2 E X wherein Y is as defined in claim 1, Q is a phenyl or (lower)aikyl group, W' is an easily removable ester group, X is 1 or 2 and M is Cu(11), PWII) or Hg(I1) when X is 2 or Ag(l) when X is 1.

13. An intermediate compound of the formula:

1, m' - t z -T t N p (0) 3 r CO 2 R.

so (lower)aikyl or phenyl goup and group and R2 and R3 are each independently a hydrogen atom, a (lower)alkyi, phenyl or benzyl group; (ii) -0Rd in which Rd is an amino, (lower)aikylamino, di(lower)alkylamino, substituted (lower)alkyl, (lower)alkenyl or optionally ring-substituted phenyl, phenyi(lower)aikyi, heterocyclic or heteocyclic(lower)aikyl group, the substituents on the alkyl, phenyl and heterocyclic groups being as defined under (a) (ii) in 55 claim 1; I- 9 (iii) -O(CH2)nORr in which n is an integer from 1 to 6 and Rr is optionally substituted (lower)alkyl or optionally ring-substituted phenyl or heterocyclic group; the substituents on the alkyl, phenyl or heterocyclic groups being as defined under (a) (ii) in claim 1; Ov) - OCORr'in which Rr'is an amino, (lower)-alkylamino, di(lower)alkylamino or Rr group, with the proviso 60 that Rr' may not be a unsubstituted (lower)alkyl group; A,- !i 143 GB 2 042 515 A 143 (V) -OSO3H 0 T -OP(OH)2; (Vii) -OSO2R,in which R,is as defind under (b) (iii); 0 T (viii) -OP(ORJ(ORr) in which % is a (lower)aikyl group and R, is as defined under (b) (ill); (ix) -S(O),,Rd in whichn is 0, 1 or2 and Rd is asdefined under (b) (ii) oris inthecasewhere N114 11 n=0-C-NIR5R6 in which R4 is a hydrogen atom or a (lower)aikyl group and Rr, and R6 are each independently a hydrogen 20 atom or a (lower)-alkyl group, with the proviso that Rd may not be an unsubstituted phenyl group; (x) -CORf in which Rf is an amino(lower)aikyi, (lower)aikylamino(lower)alkyi,di(lower)alkylamino(lower)aikyi, -NHNH2, -NR17NR,8, -NHOR19, -S-R17, -O(CH2)n-A-R,, or -NReRg in which R17, R18 and Re are (lower)alkyi groups, R19 is a hydrogen atom or a (lower)aikyl group, A is 0, S, NH or NCH3 and n and Rg are as defined under (b) (iii) and (b) (viii); (xi) -PO(ORJ2 in which Rw is a hydrogen atom ora (lower)aikyl group; (A) -NHRh in which Rh is an optionally substituted phenyl, optionally substituted heterocyclic, -CH=NH, -S03H, -OH, (lower)alkoxy, amino,)lower) alkylamino, di(lower)alkylamino, -NI-ICOCH3, -CS2CH3, -S02CH3, S S -S02NH2,-CNH2,-CNHCH3, NH 40 11 -C-NRA8 E in which R7 and R8 are each independently (lower)aikyi, phenyl or phenyM ower)a 1 kyi, NH 11 -C-Rg in which R9 is (lower)aikyi, phenyl or phenyl(lower)- alkyl, or - 0 H -C-Ri in which Ri is amino (lower)-alkyi,-NH2, (lower) alkylamino, di(lower)alkylamino, Mn-h \ 0 11 -NH-C-Rl() in which Rjo is (lower)alkyl or optionally substituted phenyl or heterocyclic group, the phenyl and heterocyclic substituents being defined under (a) (ii) in claim 1 r 144 GB 2 042 515 A 144 NH 11 -NH-C-NH2, (lower)aikoxy, 5 -// \ ' -OCII -/ ' _OCII 2 2 "2 or -O(CH2)2Si(CH3)3; 10 0 Ii (xiii) -S-C-Rll in which R,, is a (lower)aikyl group substituted by an amino, (lower)aikylamino ordi(lower)aikylamino is group; (xiv) -NRjRk in which Ri is a (lower)aikyl group and Rk is a (lower)alkyl, (lower)alkoxy, heterocyclic amino, or 0 20 H -C-R, group in which Ri is as defined under (b) (xii) or, when taken together with the nitrogen, Rj and Rk represent 0 25 providing that 0 when Rk is an amino or -CH2CH2NH2 group, Rj is a methyl group and also providing that Rj and Rk may not both be a (lower)alkyl group; (xv) -NRj'Rk'in which Rj'is a (lower)alkoxy group and kis a (lower)aikyi, heterocyclic, amino(lower)aikyi, (lower)alkylamino- (lower)alkyl, di(lower)aikylamino(iower)-alkyl or 0 11 -C-Ri group in which Ri is as defined under (b) (xii) or, when taken togetherwith the nitrogen, Rj' and Rk' represent (xiv) -NR113,Rn in which R,, Rm and Rn are each independently a (lower)alkyl group or when taken together with the nitrogen, represent a -,n\; \=1 15. An intermediate as claimed in claim 14 wherein Y is a hydrogen atom, an ethyl or (1-hydroxyethyl group and T is r.

K m - 1 1 0 1 55 -C-X.. J 16. An intermediate as claimed in claim 14 wherein Y is a hydrogen atom or an (x-hydroxyethyl group and Tis 0 11 -C-X in which Xis a group of theformula # 1 GB 2 042 515 A 145 0 (a) - (CH 2)n_0 in which n is an integer from 1 to 6; (b). -(CH2),NHOH in which n is an integer from 1 to 6; (c) -(CH2)nPO(O-Cl- C6 alkyl)2 in which n is an integer from 1 to 6; k k NH 11 lo (d) -(CH2)nNH-C-C-Cl-C6 alkyl in which n is an integer from 1 to 6; N[H2 1 (e) -(CH2)nN=CH in which n is anInteger from 1 to 6; 0 11 (f) -(CH2)n0C(CH2)mNR A R B inwhich nand mare each independently 1 or2 and R A and R B are each independently hydrogen or (lower)alkyl; or (g) -(CH2),,NHCR' 11 NR in which n is an integer from 1 to 6 and R c is CII-C4 alkyi, phenyl or -(CH2) --0111/ in which m is 1 or 2.

17. A pharmaceutical composition which comprises as active ingredient at least one compound as claimed in anyone of claims 1 to 6, or claim 11, or a pharmaceutically acceptable salt thereof as claimed in claim 7, together with a pharmaceutical ly acceptable diluent or carrier.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon Surrey, 1980. Published by the Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.