GB1604758A - 2-azetidinyl-2-oxoacetic acid ester derivatives - Google Patents

Description

PATENT SPECIFICATION ( 11) 1 604 758

0 ( 21) Application No 2021/81 ( 22) Filed 8 May 1978 ( 62) Divided out of No1604751 ( 19) ( 44) Complete Specification published 16 Dec 1981 n ( 51) INT CL 3 C 07 D 205/08 ( 52) Index at acceptance C 2 C 1310 200 215 247 250 251 25 Y 30 Y 351 352 355 366 368 390 556 AA QZ ( 72) Inventors JACQUES GOSTELI IVAN ERNEST and ROBERT BURNS WOODWARD ( 54) 2-AZETIDINYL-2-OXOACETIC ACID ESTER DERIVATIVES ( 71) We, CIBA-GEIGY AG, a Swiss body corporate, of Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-

The present invention provides compounds of the formula 5 Z' II a R 1 (XII) 0 Lr o-e-l in which Z' represents oxygen, sulphur or a methylidene group optionally carrying an organic substituent y, R, represents hydrogen, an organic radical bonded by a carbon atom to the 10 group -C(=Z')-, or an etherified mercapto group, and R 2 together with the carbonyl group -C(=O) represents a protected carboxyl group, and processes for their manufacture.

The new compounds may be prepared as described further below under stage 1 5 15 The compounds are intermediates useful in the synthesis of new bicyclic thiaaza compounds containing a p-lactam ring unsubstituted in the 3-position of the /3lactam ring and having antibiotic properties.

Since the discovery of penicillin, numerous bicycle thia-aza compounds having a /-lactam structures have become known A survey of earlier works reveals E H 20 Flynn, "Cephalosporins and Penicillins", Academic Press, New York and London, 1972 Very recent developments are described by J Cs Jaszberenyi et al, Progr.

Med Chem, Vol 12,1975, 395-477, and P G Sammes, Chem Rev 1976, Vol 76, No 1, 113-155 A the symposium "Recent Advances in the Chemistry of/ plactam Antibiotics" from 28th to 30th June, 1976, held in Cambridge, England, 6 25 acylamino 2 penem 3 carboxylic acid compounds having an antibiotic action and containing the novel 2-penem ring system were described by R B. Woodward.

Apart from the usual penam and cephem compounds carrying an acylamino group in the 6 or 7-position, such compounds that are unsubstituted in these 30 positions have also become known, for example 3 carboxy 2,2 dimethylpenam (J P Clayton, J Chem Soc, 1969, 2123) and 3 methyl 4 carboxy 3 cephem (K Kfihlein, Liebigs Ann, 1974, page 369 and D Bormann, ibid, page 1391) None of these compounds, however, has any substantial antibiotic activity 2-penem compounds that are unsubstituted in the 6-position are so far 35 unknown.

2 1,604,758 2 The problem underlying the present invention is to produce intermediates for the synthesis of bicyclic thia-aza compounds containing a /-lactam ring that possess the 2-penem ring system unsubstituted in the 6-position and that are active against normal and against resistant bacteria.

The manufacture according to the invention of the new intermediate products 5 open up new fields in which research into other commercially valuable compounds can be carried out.

The ring system of the compounds which can be produced with the intermediates of the present invention has the formula 3 10 0 l 7 1 and may systematically be called 7 oxa 4 thia 1 azabicyclol 3,2,0 l hept 2 ene For the sake of simplicity it is referred to hereinafter as " 2penem", wherein the following numbering derived from penam and customary in penicillin chemistry shall be used:

H 1 2 15 o 4 \ The 2-penem ring system has an asymmetrically substituted carbon atom in the 5-position, and corresponding compounds, according to the Cahn-IngoldPrelog designation, may occur in the ( 5 R)-configuration.

The compounds of the present invention may be used as intermediates for the preparation of 2 penem 3 carboxylic acid compounds of the formula 20 __ |,-1 (Ia) O=C -R 2 in which R, represents hydrogen, an organic radical bonded by a carbon atom to the ring carbon atom, or an etherified mercapto group, and R 2 represents hydroxy or a radical RA forming together with the carbonyl 25 grouping -C(=O) a protected carboxyl group, 1-oxides thereof, as well as salts of such compounds having salt-forming groups which have valuable pharmacological properties These compounds, processes for their manufacture and pharmaceutical preparations containing them are described and claimed in copending application 18282/78 Serial No 1604751 30 An organic radical R, bonded by a carbon atom to the group -C(=Z') is primarily an aliphatic hydrocarbon radical unsubstituted or substituted by one or more functional groups or an optionally substituted cycloaliphatic, cycloaliphaticaliphatic, aromatic or araliphatic hydrocarbon radical having up to 18, preferably up to 10, carbon atoms, especially optionally substituted lower alkyl, optionally 35 functionally modified carboxyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl, naphthyl or phenyl-lower alkyl Examples of substituents of such radicals are optionally functionally modified, such as optionally etherified or esterified, hydroxy or mercapto groups, for example hydroxy, lower alkoxy, for example methoxy or ethoxy, lower alkanoyloxy, for example acetoxy or propionyloxy, 40 A halogen, for example chlorine or bromine, or lower alkylthio, for example methylthio or tert -butylthio, or optionally functionally modified carboxyl groups, such as carboxyl, lower alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl carbamoyl or cyano; also nitro; or amino optionally mono or disubstituted, such as by lower alkyl, for example methyl or ethyl, or optionally 5 disubstituted by lower alkylene, for example 1,4-butylene or 1,5pentylene, or protected, such as acylated.

A lower alkyl radical R 1 contains up to 7, especially up to 4, carbon atoms, and is, inter alia, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl or pentyl.

Substituted lower alkyl is, primarily, substituted methyl, or ethyl or propyl that are 10 substituted in the 1 or especially in the co-position, such as hydroxymethyl or hydroxyethyl; lower alkoxymethyl or lower alkoxyethyl, for example, methoxymethyl or methoxyethyl; lower alkanoyloxymethyl or lower alkanoyloxyethyl, for example acetoxymethyl, propionyloxymethyl or acetoxyethyl; halomethyl or haloethyl, for example chloromethyl or bromomethyl 15 or chloroethyl or bromoethyl; lower alkylthiomethyl or lower alkylthioethyl, such as methylthiomethyl, tert -butylthiomethyl, methylthioethyl or methylthiopropyl; lower alkoxycarbonylmethyl or (lower alkoxy)carbonylethyl, for example methoxycarbonylmethyl, ethoxycarbonylmethyl or methoxycarbonylethyl; cyanomethyl or cyanoethyl; or aminomethyl, aminoethyl or aminopropyl that are 20 optionally protected, for example by a semi-ester of carbonic acid, such as by tert butoxycarbonyl, benzyloxycarbony orp-nitrobenzyloxycarbonyl, or acylated, such as by optionally substituted acetyl, for example phenoxyacetyl.

An optionally functionally modified carboxyl group R 1 is a free carboxyl group or one of the for example esterified or amidated carboxyl groups mentioned under 25 the groups -C(=O) R, such as (lower alkoxy)carbonyl, for example methoxy-, ethoxy or tert -butoxycarbonyl; aryl (lower alkoxy)carbonyl, such as benzyloxy-, p-nitrobenzyloxy or diphenylmethoxycarbonyl; aryloxycarbonyl, such as phenoxycarbonyl optionally substituted for example by halogen, such as chlorine, by lower alkoxy, such as methoxy, or by nitro, such as phenoxycarbonyl, o, m or 30 p chlorophenoxycarbonyl, pentachlorophenoxycarbonyl, o, m or pmethoxyphenoxycarbonyl or p nitrophenoxycarbonyl; aminocarbonyl or aminocarbonyl mono or disubstituted by, for example, lower alkyl, for example methyl or ethyl.

A cycloalkyl radical R, has, for example, 3 to 7 carbon atoms and is, for 35 example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, whereas a cycloalkyllower alkyl radical R 1 contains, for example, 4 to 7 carbon atoms and is, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

A phenyl or naphthyl radical R, for example a 1 or 2-naphthyl radical, or a 40 phenyl-lower alkyl radical R, for example a benzyl or I or 2-phenylethyl radical, may be substituted, preferably in the aromatic radical, for example by lower alkyl such as methyl or ethyl, by lower alkoxy, such as methoxy, or by halogen, such as fluorine or chlorine, further by nitro, amino or substituted amino, such as di-lower alkylamino, for example dimethylamino 45 The radical R, may alternatively be a heterocyclic or heterocyclicaiphatic radical, preferably of aromatic character, bonded by a carbon atom, for example such a radical having 5 or 6 ring members and nitrogen, oxygen or sulphur as hetero atoms, such as pyridyl, for example 2-, 3 or 4-pyridyl, thienyl, for example 2so thienyl, or furyl, for example 2-furyl, or a corresponding pyridyl-, thienyl or furyl 50 lower alkyl, especially -methyl, radical.

An etherified mercapto group R 1 is etherified by an aliphatic hydrocarbon radical unsubstituted or substituted by one or more functional groups or is an optionally substituted cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical having up to 18, preferably up to 10, carbon atoms, 55 and is especially optionally substituted lower alkylthio, lower alkenylthio, cycloalkylthio, cycloalkyl-lower alkylthio, phenylthio or phenyl lower alkylthio.

Substituents of such radicals are, for example, optionally functionally modified, such as optionally etherified or esterified, hydroxy or mercapto, for example hydroxy, lower alkoxy, for example methoxy or ethoxy, lower alkanoyloxy, for 60 example acetoxy or propionyloxy, halogen, for example chlorine or bromine, or lower alkylthio, for example methylthio; or optionally functionally modified carboxyl groups, such as carboxyl, (lower alkoxy)carbonyl, for example methoxycarbonyl or ethoxycarbonyl, carbamoyl or cyano; also nitro; or amino optionally mono or di substituted such as by lower alkyl, for example methyl or 65 1,604,758 ethyl, or by acyl, such as lower alkanoyl, for example acetyl: or amino optionally di-substituted by lower alkylene, for example by 1,4 butylene or 1,5 pentylene.

A lower alkylthio radical R 1 contains up to 7, especially up to 4, carbon atoms.

and is, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio.

isobutylthio, tert -butylthio or pentylthio Substituted lower alkylthio R, is 5 primarily, substituted methylthio, ethylthio or propylthio, the substituents standing in the 1-, 2 or 3-position, such as methoxymethylthio ethoxymethylthio.

methoxyethylthio or methoxypropylthio; (lower alkanoyl)oxymethylthio, (lower alkanoyl)oxyethylthio or (lower alkanoyl)oxypropylthio, such as acetoxymethylthio, acetoxyethylthio or acetoxypropylthio; halomethylthio 10 haloethylthio or halopropylthio, for example chloroethylthio or bromoethylthio, or chloropropylthio or bromopropylthio; (lower alkoxy)carbonylmethylthio or (lower alkoxy)carbonylethylthio, for example methoxycarbonylethylthio:

cyanomethylthio; cyanoethylthio; or optionally protected, for example acetylated, aminomethylthio, aminoethylthio or aminopropylthio 15 A lower alkenylthio radical R 1 contains 2 to 7, especially 2 to 4, carbon atoms and is especially 1-lower alkenylthio, for example, vinylthio, I propenylthio, 1 butenylthio or 1 pentenylthio or also 2-lower alkenylthio, for example allylthio.

Substituted lower alkenylthio R, is, primarily, substituted in the 2position, wherein the substituents that chiefly come into consideration are lower alkoxy, lower 20 alkanoyloxy and optionally protected amino Thus R 1 is, for example, 2methoxyvinylthio, 2-acetoxyvinylthio, 2 acetylaminovinylthio or correspondingly substituted 1 propenylthio.

A cycloalkylthio group R, has, for example 3 to 7 carbons atoms, and is, for example, cyclopropylthio, cyclobutylthio, cyclopentylthio or cyclohexylthio 25 A cycloalkyl lower alkylthio radical R 1 has, for example 4 to 7 carbon atoms and is, for example, cyclopropylmethylthio, cyclobutylmethylthio, cyclopentylmethylthio or cyclohexylmethylthio.

A phenylthio radical R 1 or a phenyl-lower alkylthio radical R, for example benzyl or 1 or 2 phenylethylthio radical, may be substituted, preferably in the 30 aromatic radical, for example by lower alkyl, such as methyl or ethyl, by lower alkoxy, such as methoxy, by halogen, such as fluorine or chlorine, or by nitro or amino.

A protected carboxyl group of the formula -C(=O)-RA is primarily an esterified carboxyl group in which R^ represents a hydroxy group etherified by an 35 organic radical or an organic silyl or stannyl group Organic radicals, also as substituents in organic silyl or stannyl groups, are aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, especially optionally substituted hydrocarbon radicals of these kinds, and heterocyclic or heterocyclicaliphatic radicals, preferably having up to 18 carbon atoms 40 An etherified hydroxy group R forms together with the carbonyl grouping an esterified carboxyl group that can preferably be readily split, for example by reduction, such as by hydrogenolysis, or by solvolysis, such as acid hydrolysis or, especially, basic or neutral hydrolysis, oxidatively, or under physiological conditions, or an esterified carboxyl group that is readily convertible into another 45 functionally modified carboxyl group, such as into another esterified carboxyl group or into a hydrazinocarbonyl group Such a group RA is, for example, 2 halo lower alkoxy, in which the halogen preferably has an atomic weight of more than 19, for example 2,2,2 trichloroethoxy or 2 iodoethoxy, also 2chloroethoxy or 2 bromoethoxy which may readily be converted into 2 50 iodoethoxy or 2 lower alkylsulphonyl-lower alkoxy, for example, 2methylsulphonylethoxy The group RA is furthermore a methoxy group polysubstituted by optionally substituted hydrocarbon radicals, especially saturated aliphatic or aromatic hydrocarbon radicals, such as lower alkyl, for example methyl, and/or phenyl, or is a methoxy group monosubstituted by an 55 unsaturated aliphatic hydrocarbon radical, such as lower alkenyl, for example 1lower alkenyl, such as vinyl, by a carbocyclic aryl group having electrondonating substituents, or by a heterocyclic group of aromatic character having oxygen or sulphur as ring member Examples of such groups R are tert lower alkoxy, for example tert butoxy or tert pentoxy; optionally substituted diphenylmethoxy, 60 for example diphenylmethoxy or 4,4 ' dimethoxydiphenylmethoxy; lower alkenyloxy, especially 2 lower alkenyloxy, for example allyloxy; lower alkoxyphenyl lower alkoxy, for example lower alkoxybenzyloxy, such as methoxybenzyloxy (in which methoxy is, primarily, in the 3-, 4 and/or 5position), primarily, 3 or 4 methoxybenzyloxy or 3,4 dimethoxybenzyloxy; or 65 1,604,758 above all, nitrobenzyloxy, for example, 4 nitrobenzyloxy, 2 nitrobenzyloxy or 4,5 dimethoxy 2 nitrobenzyloxy; or furfuryloxy, such as 2 furfuryloxy The group RA is furthermore a 2 oxoethoxy group that is optionally substituted in the 2-position by lower alkyl, such as methyl, by lower alkoxy, such as methoxy or ethoxy, by aralkyl, such as benzyl, or by aryl, such as phenyl, and is optionally 5 substituted in the 1-position by lower alkyl, such as methyl, lower alkoxycarbonyl, such as methoxycarbonyl, lower alkylcarbonyl, such as methylcarbonyl, aralkylcarbonyl, such as benzylcarbonyl, or arylcarbonyl, such as benzoyl Thus RA represents, for example, acetonyloxy, phenacyloxy, 2,4 dioxo 3 pentoxy, I methoxycarbonyl 2 oxopropoxy or I ethoxy carbonyl 2 oxopropoxy 10 The group R is alternatively a 2 cyanoethoxy group that is optionally substituted in the 1 and/or in the 2 position, for example by lower alkyl, such as methyl, or by aryl, such as optionally substituted phenyl, and represents, for example 2cyanoethoxy or 2 cyano 2 phenylethoxy RA is alternatively a 2-(S,)( 52)( 53)515 silylethoxy group, in which each of the substituents 51, 52 and 53 independently of 15 one another represents an optionally substituted hydrocarbon radical and the individual radicals may be linked by a single C-C bond A hydrocarbon radical S, 52, 53 is, for example, an alkyl radical, a cycloalkyl radical or an aryl radical, preferably such a radical having a maximum of 12 carbon atoms, wherein such alkyl, cycloalkyl or aryl radical may be substituted by another such radical or by 20 lower alkoxy, such as methoxy, or by halogen, such as fluorine or chlorine; and is especially alkyl having up to 7, preferably up to 4, carbon atoms, such as methyl, ethyl, propyl or butyl; cycloalkyl having up to 7 carbon atoms, such as cyclopropyl or cyclohexyl; cycloalkylalkyl, such as cyclopentylmethyl; aryl having up to 10 carbon atoms, such as phenyl, tolyl or xylyl; or aryl-lower alkyl, such as benzyl or 25 phenylethyl Radicals RA of this kind to be singled out are 2-tri-lower alkylsilylethoxy, such as 2-trimethylsilylethoxy or 2-(dibutylmethylsilyl) -ethoxy, and 2 triarylsilylethoxy, such as 2 triphenylsilylethoxy.

RA may alternatively be 2-oxa or 2 thia cycloalkoxy or -cycloalkenyloxy having 5-7 ring members, such as 2 tetrahydrofuryloxy, 2 30 tetrahydropyranyloxy or 2,3 dihydro 2 pyranyloxy or a corresponding thia group, or R forms together with the -C(=O) grouping an activated ester group and is, for example, nitrophenoxy, for example 4-nitrophenoxy or 2,4dinitrophenoxy, or polyhalophenoxy, for example pentachlorophenoxy RA may, however, alternatively be an unbranched lower alkoxy, for example methoxy or 35 ethoxy.

An organic silyloxy or organic stannyloxy group R is especially a silyloxy or stannyloxy group substituted by 1 to 3 optionally substituted hydrocarbon radicals, preferably having up to 18 carbon atoms It contains as substituents preferably aliphatic hydrocarbon radicals optionally substituted by one or more functional 40 groups, for example by lower alkoxy, such as methoxy, or by halogen, such as chlorine; or optionally substituted, for example by lower alkoxy, such as methoxy, or by halogen, such as chlorine, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals Examples are lower alkyl, halogen-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl Thus, R 2 represents primarily tri-lower alkylsilyloxy, 45 for example trimethylsilyloxy, halo-lower alkoxy-lower alkyl-silyloxy, for example, chloromethoxymethylsilyloxy, or tri-lower alkylstannyloxy, for example tri N butylstannyloxy.

The group R 2 may alternatively be an etherified hydroxy group that together with the carbonyl grouping -C(=O) forms an esterified carboxyl group that can 50 be split under physiological conditions, primarily an acyloxymethoxy group, in which acyl represents, for example, the radical or an organic carboxylic acid, primarily an optionally substituted lower alkanecarboxylic acid, or in which acyloxymethyl forms the radical of a lactone Hydroxy groups etherified in this manner are lower alkanoyloxymethoxy, for example acetoxymethoxy or 55 pivaloyloxymethoxy, amino-lower alkanoyloxymethoxy, especially a amino lower alkanoyloxymethyl, for example glycyloxymethoxy, L valyloxymethoxy, L leucyloxymethoxy, and also phthalidyloxy In other ester groups -C(=O)RA 2 that can be physiologically split, RA is a 2-aminoethoxy group, in which amino is substituted by two lower alkyl groups or by alkylene optionally containing an oxa 60 group, and represents, for example 2 dimethylaminoethoxy, 2 diethylaminoethoxy or 2 (I morpholino) ethoxy.

A radical R' forming with a -C(=O)-grouping an optionally substituted hydrazinocarbonyl group is, for example, hydrazino or 2-lower alkylhydrazino, for example 2-methylhydrazino 65 1,604,758 Preferred groups RA are those that can be converted into a free hydroxy group under neutral, basic or physiological conditions.

Z' is oxygen, sulphur or alternatively, especially when R, is hydrogen, a methylidene group optionally substituted by an organic substituent Y, which group can be converted by oxidation into an oxo group Z A substituent Y of this 5 methylidene group is an organic radical, for example one of the organic radicals mentioned under R, such as one of the mentioned, lower alkyl groups unsubstituted or substituted by one or more functional groups or optionally substituted cycloalkyl, cycloalkyl lower alkyl, phenyl or phenyl-lower alkyl radicals, and especially one of the functionally modified, such as esterified, 10 carboxyl groups Esterification with an optically active alcohol such as 1menthol is included This methylidene group preferably carries one of the substituents mentioned The 2-methoxycarbonylmethylidene and the 2 ( 1) menthyloxycarbonylmethylidene group Z' are singled out.

The invention provides especially intermediates of the formula XII, in which 15 R, represents hydrogen; a lower alkyl optionally substituted by etherified or esterified hydroxy or mercapto, such as lower alkoxy, lower alkanoyloxy or lower alkylthio, by functionally modified carboxyl, such as lower alkoxycarbonyl, or by optionally substituted, for example acylated, amino; or represents phenyllower alkyl or phenyl optionally substituted by lower alkyl, lower alkoxy, halogen, nitro, 20 amino or di-lower alkylamino; an aromatic heterocyclic radical, or an etherified mercapto group, such as lower alkylthio; and R 4 represents a hydroxy group etherified by an organic radical or an organic silyl or stannyl group, that can be split under basic or neutral conditions, or physiologically; or represents an optionally substituted hydrazino group R^ 25 Preferably, R 1 represents hydrogen; alkyl having up to 7 carbon atoms, for example methyl, isopropyl or pentyl; lower alkoxy-lower alkyl, in which the term "lower" in each case denotes up to 4 carbon atoms, for example methoxymethyl; lower alkanoyloxy-lower alkyl, in which the term "lower" in each case denotes up to 4 carbon atoms, for example acetoxymethyl; lower alkylthio-lower 30 alkyl, in which the term "lower" in each case denotes up to 4 carbon atoms, for example methylthiomethyl or tert -butylthiomethyl; (lower alkoxy)carbonyllower alkyl, in which the term "lower" in each case denotes up to 4 carbon atoms, such as (lower alkoxy)carbonylmethyl or (lower alkoxy)carbonylethyl, for example methoxycarbonylethyl; amino-lower alkyl, in 35 which the term "lower" denotes up to 4 carbon atoms and in which the amino group is optionally acylated by a semi-ester of carbonic acid or by a substituted acetyl group, for example aminomethyl, aminoethyl or aminopropyl, or the corresponding aminomethyl, aminoethyl or aminopropyl N-acylated by benzyloxycarbonyl, p-nitrobenzyloxycarbonyl or phenoxyacetyl; or phenyl 40 optionally substituted by lower alkyl, halogen, nitro, amino or di-lower alkylamino, for example phenyl or dimethylaminophenyl; phenyl-lower alkyl, for example benzyl; an aromatic heterocyclyl radical containing 5 or 6 ring members with a nitrogen, an oxygen or a sulphur atom as hetero atom, for example pyridyl, furyl or thienyl; or lower alkylthio, for example ethylthio; and RA primarily represents an 45 etherified hydroxy group that can be split under basic or neutral conditions or physiologically, such as optionally a-polybranched lower alkoxy, for example tert butyloxy, 2 substituted 2 oxoethoxy, for example acetonyloxy, or phenacyloxy, 2 cyanoethoxy, 2 (SX 52 X 53) silylethoxy, in which each of S, 52 and 53 represents lower alkyl, such as methyl, or phenyl, such as 2 trimethylsilylethoxy 50 or 2 triphenylsilylethoxy, I phenyl lower alkoxy having 1-3 phenyl radicals optionally substituted by lower alkoxy and/or nitro, for example 4 methoxybenzyloxy, 4 nitrobenzyloxy, 2 nitro 4,5 dimethoxybenzyloxy, diphenylmethoxy, 4,4 ' dimethoxydiphenylmethoxy or trityloxy, lower alkanoyloxymethoxy, for example acetoxymethoxy or pivaloyloxymethoxy, a 55 amino lower alkanoyloxymethoxy, for example glycyloxymethoxy, 2phthalidyloxy, pentachlorophenoxy, also tri-lower alkylsilyloxy, for example trimethylsilyloxy, and lower alkenyloxy, especially 2-lower alkenyloxy, for example allyloxy.

Especially, R, represents hydrogen, alkyl having up to 5 carbon atoms, such as 60 methyl, isopropyl, or pentyl; alkoxy-alkyl having up to 4 carbon atoms, for example methoxy methyl; or alkanoyloxy alkyl having up to 4 carbon atoms, for example, acetoxymethyl; alkylthio-alkyl having up to 5 carbon atoms, for example, methylthiomethyl or tert butylthiomethyl; alkoxycarbonyl alkyl having up to 5 carbon atoms, for example 2 methoxycarbonylethyl; amino lower alkyl such as 65 PEfi L, w:,/;.

1,604,758 7 1,604,758 7 aminomethyl, 2 aminoethyl or 3 aminopropyl, optionally N-acylated by benzyloxycarbonyl, p nitrobenzyloxy-carbonyl or by phenoxyacetyl; phenyl optionally substituted by dimethylamino; benzyl; pyridyl, for example 2-, 4 or especially 3 pyridyl; furyl, for example 3-furyl or especially 2-furyl; or thienyl, for example 3 or especially 2-thienyl; or lower alkylthio having up to 4 carbon atoms, 5 for example, ethylthio; and RA primarily represents hydroxy, the above-mentioned etherified hydroxy groups that can be split under basic or neutral conditions or physiologically, especially p-nitrobenzyloxy or acetonyloxy, More especially, R, represents hydrogen, methyl, pentyl, acetoxymethyl, 10 tert butylthiomethyl, 2 methoxycarbonylethyl, 2 aminoethyl, 3aminopropyl, phenoxyacetylaminomethyl, 3 ( 2 phenoxyacetylamino) propyl, phenyl, 3 dimethylaminophenyl, benzyl, 2 furyl, 3 pyridyl or ethylthio.

Thus, R 1 is especially one of the preferred, optionally substituted hydrocarbon radicals, wherein functional groups are usually present in the protected form, 15 amino, for example, in acylated form or alternatively in the form of the nitro or azido group, and RA preferably represents an etherified hydroxy group forming together with the -C(=O) grouping an esterified carboxyl group that can readily be split, especially under mild conditions, wherein functional groups that are optionally present in a carboxyl protective group RA may be protected in a manner 20 known per se, for example as indicated above A group RA is inter alia lower alkoxy, especially a-polybranched lower alkoxy, for example methoxy or tert butyloxy; lower alkenyloxy, especially 2-lower alkenyloxy, for example allyloxy; or 2-halolower alkoxy, for example 2,2,2 trichloroethoxy, 2 bromoethoxy, or 2iodoethoxy; 2-lower alkylsulphonyl lower alkoxy, for example 2 25 methylsulphonylethoxy; or an optionally substituted, such as lower alkoxy, for example methoxy or nitro-containing 1-phenyl-lower alkoxy group, such as diphenylmethoxy or benzyloxy optionally substituted, for example as mentioned, for example benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4 ' dimethoxydiphenylmethoxy; pentachlorophenoxy; acetonyloxy; 2 30 cyanoethoxy; a 2-(S,)( 52)( 53) silylethoxy group, such as 2 trimethylsilylethoxy, 2 (dibutylmethylsilyl) ethoxy or 2 triphenylsilylethoxy; also an organic silyloxy or stannyloxy group, such as tri lower alkylsilyloxy, for example trimethylsilyloxy; or one of the mentioned etherified hydroxy groups that can be split physiologically 35 The preparation of compounds of the formula XII and their conversion into compounds of the formula Ia may be carried out, for example, according to the following reaction schemes:

1,604,758 Reaction scheme 1 o 1 ' H Stage 1 1 Stage 1 3 0 N> ii (vi\ (I I) o C 3 d '-2 C 3 (x) tage J 4 0 =C-R 2 (VIII) Stage 1 2 S-S-R 0 oCH C O=C-R 2 (Ix) |Stage 1 4 a II 9 S-C-R, o 1 CH 3 Stage 1 3 a O=C-R 2 (XI) Zt H S-C-R 0 CH 2 1 0 K CEI 2 CH C 0 =C-RA CH 3 2 3 (Xa) Stage 1 5 Z' II 11 S-C-R 1 0 N (XII) O =C-R 2 Stage 1 6 Z' II H S-C-R 1 o O r (I Va) "CH 1,604,758 Reaction Scheme 2 Z' 0 11 I S C VN IV,.

stage 2 1 ZE CI -C-C < stage 2 2 IICR / S C R 1 0 \ c H CE A 0 = C -R 2 stage 2 3 Z 1 H II IS-C-R 1 L-11 -N K Co x t A O = C R 2 I Ia stage 2 4 > H A C C-R 1 0,c//' I C=C-K 2 In the compounds of the formulae VII to XII, RA preferably represents lower alkoxy, especially methoxy.

Details of stages 1 6, 2 1, 2 2, 2 3 and 2 4 and of the optional subsequent reactions including conversion of compounds of the formula Ia into their salts or into 1-oxides thereof, are described in copending application 18282/78 Serial No.

1604751. In stage 1 1, an oxide of a penicillanic acid compound of the formula

VIII is obtained by oxidising a penicillanic acid compound of the formula VII in the Iposition The oxidation is carried out in a manner known per se with suitable oxidising agents, such as hydrogen peroxide or inorganic or organic peracids.

Suitable inorganic peracids are, for example, periodic or persulphuric acid.

Suitable organic peracids are, for example, percarboxylic acids, such as performic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, 3chloroperbenzoic acid or monoperphthalic acid, or persulphonic acids, for example p-toluenepersulphonic acid The peracids may also be produced in situ from hydrogen peroxide and the corresponding acids The oxidation is carried out under mild conditions, for example at temperatures of-50 to + 1001, preferably at -10 to + 400, in an inert solvent.

Starting compounds of the formula VII are known or can be produced according to known processes For example, they may be obtained by hydrogenation of potassium 6 a bromopenicillanic acid and subsequent H CH -X I a O=-C -R 2 VI R 1 esterification of the carboxyl group lE Evrard, M Claesen and H Vanderhaege, Nature 201, 1124 ( 1964)l or by hydrogenation of 6,6 dibromopenicillanic acid esters, for example the methyl ester lJ P Clayton, J Chem Soc (C), 2123 ( 1969)l.

Stage 1 2 A 3-methylenebutyric acid compound of the formula IX is obtained by 5 treating a 1-oxide of a penicillanic acid compound of the formula VIII with a mercapto compound R -SH.

In the mercapto compound R -SH and in the reaction product of the formula IX, R is an optionally substituted aromatic heterocyclic radical having up to 15, preferably up to 9, carbon atoms, and at least one ring nitrogen atom, and 10 optionally a further ring hetero atom, such as oxygen or sulphur, which radical is bonded to the thio group -S by one of its ring carbon atoms that is bonded to a ring nitrogen atom by a double bond Radicals of this type are monocyclic or bicyclic and may be substituted, for example by lower alkyl, such as methyl or ethyl, lower alkoxy, such as methoxy or ethoxy, halogen, such as fluorine or 15 chlorine, or aryl, such as phenyl.

Radicals R of this type are, for example, monocyclic five-membered thiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclic radicals of aromatic character, especially monocyclic five-membered diazacyclic, oxazacyclic and thiazacyclic radicals of aromatic character, and/or primarily the corresponding 20 benzdiazacyclic, benzoxazecyclic or benzthiazacyclic radicals, in which the heterocyclic part is five-membered and has an aromatic character, wherein in R radicals a substitutable ring nitrogen atom may be substituted, for example by lower alkyl Representative of such R groups are I methylimidazol 2 yl, 1, 3 thiazol 2 yl, 1,3,4 thiadiazol 2 yl, 1,3,4,5 thiatriazol 2 yl, 1,3 25 oxazol 2 yl, 1,3,4 oxadiazol 2 yl, 1,3,4,5oxatriazol 2 yl, 2 quinolyl, I methylbenzimidazol 2 yl, benzoxazol 2 yl and especially benzthiazol 2 yl.

The reaction is carried out in an inert solvent, such as an aliphatic or aromatic hydrocarbon, for example benzene or toluene, while warming up to the reflux 30 temperature of the solvent used.

Stage 1 3 A 3-methylcrotonic acid compound of the formula X is obtained by isomerising a 3-methylenebutyric acid compound of the formula IX by treating with a suitable basic agent 35 Suitable basic agents are, for example, organic nitrogen bases such as tertiary amines, for example tri-lower alkyl amines such as triethylamine or Hfinig base, or inorganic bases, which are used in an inert solvent, such as an optionally halogenated hydrocarbon, for example methylene chloride, at room temperature or optionally slightly reduced or elevated temperature 40 Stage 1 4 A thio compound of the formula XI is obtained by treating a compound of the formula X with a suitable reducing agent and simultaneously or subsequently reacting with an acylation derivative of a carboxylic acid of the formula R 1C(=Z)-OH, or, when Z' represents a methylidene group optionally substituted by 45 Y, reacting with an alkyne of the formula R 1-C=C-Y, in which Y' is a hydrogen atom or an organic substituent Y and, if desired, converting a group R, in a compound so obtained into a different group R, and/or, if desired, converting an optionally substituted methylidene group Z' into an oxo group Z.

Suitable reducing agents are, for example, hydride reducing agents such as 50 alkali metal borohydrides, for example sodium borohydride, or also zinc in the presence of a carboxylic acid, for example a carboxylic acid of the formula R C(=Z)-OH The hydride reducing agents are usually used in the presence of suitable solvents, such as dimethylformamide The hydride reduction is preferably carried out in dimethylformamide with sodium borohydride at temperatures of 55 -50 to -10 , preferably at approximately -20 , whereupon at the same temperature the acylating agent and optionally a tertiary base such as pyridine, are added The reduction with zinc and a carboxylic acid is optionally carried out in a solvent, for which the carboxylic acid, if liquid, can itself be used, at temperatures of-10 to + 50 , preferably at 0 to room temperature The acylating agent can be 60 added to the reduction mixture from the beginning or when reduction is complete and optionally after evaporating off the carboxylic acid used and/or the solvent.

1.604,758 Suitable acylating agents are especially anhydrides of the carboxylic acids mentioned, such as symmetric anhydrides, for example acetic anhydride, or mixed anhydrides, preferably those with halogen hydracids, that is the corresponding carboxylic acid halides, for example the chlorides and bromides, such as acetyl bromide For example, a compound of the formula X may be converted with zinc 5 in a mixture of acetic acid and acetic anhydride at 00 to 200 into a compound of the formula XI, in which R, is methyl Owing to the reduced risk of racemisation, the zinc/carboxylic acid reduction is preferred The alkyne can also be added to the reduction solution from the beginning or when reduction is complete The addition of the 4 mercaptoazetidin 2 one, produced as an intermediate product in the 10 reduction, to the triple bond of the alkyne takes place spontaneously at the reduction temperature.

Stage 1 3 a A thio compound of the formula XI is also obtained by isomerising a compound of the formula Xa in accordance with the reaction conditions of stage 15 1.3 by treating with a suitable basic agent, if desired converting a group R, in a compound obtained into a different group R 1, and/or, if desired, converting an optionally substituted methylidene group Z' into an oxo group Z.

Stage 1 4 a A compound of the formula Xa is obtained by treating a 3-methylenebutyric 20 acid compound of the formula IX in accordance with the reaction conditions of stage 1 4 with a suitable reducing agent, and simultaneously or subsequently reacting with an acylating derivative of a carboxylic acid of the formula R 1C(=Z)-OH, or, when Z' represents a methylidene group optionally substituted by Y, with an alkyne of the formula R -C-C-Y', in which Y' is a hydrogen atom or 25 an organic substituent Y, and, if desired, converting a group R, in a compound obtained into a different group R, and/or, if desired, converting an optionally substituted methylidene group Z' into an oxo group Z.

Stage 1 5 A 2-oxoacetic acid compound of the formula XII is obtained by ozonising a 30 compound of the formula XI and splitting the ozonide formed to the oxo group by means of reduction, and if desired converting a group R, in a compound obtained into a different group R 1 and/or, if desired, converting an optionally substituted methylidene group Z' into an oxo group Z.

The ozonisation is usually carried out with an ozone/oxygen mixture in an inert 35 solvent, such as a lower alkanol, for example methanol or ethanol, a lower alkanone, for example acetone, an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, for example a halogen-lower alkane, such as methylene chloride or carbon tetrachloride, or in a solvent mixture, including an aqueous mixture, preferably while cooling, for example at temperatures of -90 to 0 40 An ozonide obtained as intermediate product is, usually without having to be isolated, split reductively to form a compound of the formula XII, wherein catalytically activated hydrogen, for example hydrogen in the presence of a heavy metal hydrogenating catalyst, such as a nickel catalyst or palladium catalyst, preferably on a suitable carrier material, such as calcium carbonate or 45 carbon, is used; or chemical reducing agents, such as reducing heavy metals, including heavy metal alloys or amalgams, for example zinc, in the presence of a hydrogen donor such as an acid, for example acetic acid, or of an alcohol, for example a lower alkanol, are used; or reducing inorganic salts, such as alkali metal iodides, for example sodium iodide, or alkali metal bisulphites, for example, 50 sodium bisulphite, in the presence of a hydrogen donor, such as an acid, for example acetic acid, or water, are used; or reducing organic compounds such as formic acid are used It is also possible to use as reducing agents compounds that may readily be converted into corresponding epoxy compounds or oxides wherein the epoxide formation can take place on account of a C,C-double bond and the 55 oxide formation on account of an oxide-forming hetero atom, such as a sulphur, phosphorus or nitrogen atom Compounds of this type are, for example, suitably substituted ethylene compounds (which are converted into ethylene oxide compounds in the reaction), such as tetracyanoethylene, in particular suitable sulphide compounds (which in the reaction are converted into sulphoxide 60 compounds), such as di-lower alkyl sulphides, especially dimethyl sulphide, suitable organic phosphorus compounds, such as a phosphine, which may contain 1 1 1 1 1,604,758 optionally substituted aliphatic or aromatic hydrocarbon radicals as substituents (and which in the reaction is converted into a phosphine oxide), such as tri-lower alkylphosphines, for example tri N butylphosphine, or triarylphosphines, for example triphenylphosphine, or phosphites, which contain optionally substituted aliphatic hydrocarbon radicals as substituents (and in the reaction are converted 5 into phosphoric acid triesters), such as tri-lower alkyl phosphites, usually in the form of corresponding alcohol adduct compounds, such as trimethyl phosphite, or phosphorous acid triamides, which contain optionally substituted aliphatic ydrocarbon radicals as substituents such as hexa-lower alkyl phosphorous acid triamides, for example hexamethyl phosphorous acid triamide, the latter preferably 10 in the form of a methanol adduct, or suitable nitrogen basis (which in the reaction are converted into the corresponding N-oxides), such as heterocyclic nitrogen bases of aromatic character, for example bases of the pyridine type and especially pyridine itself The splitting of the usually unisolated ozonide is normally carried out under the conditions used for its manufacture, that is to say, in the presence of 15 a suitable solvent or solvent mixture, and while cooling or heating gently, wherein preferably temperatures of-10 C to + 25 C are used and the reaction usually terminates at room temperature.

The compounds of the invention may also be prepared by using an intermediate in the above-described process as starting material and carrying out 20 the remaining process steps The process of the invention also includes embodiments in which the process is interrupted at any stage and then resumed:

furthermore, starting compounds may be used in the form of derivatives or may be formed in situ, optionally under the conditions of their subsequent reaction.

In the process according to the invention, and in additional steps to be carried 25 out where applicable and where necessary, if required free functional groups that do not participate in the reaction are temporarily protected in a manner known per se: for example, free amino groups are temporarily protected, for example by acylation, tritylation or silylation; free hydroxy groups, for example by etherification or esterification; and free carboxyl groups or sulpho groups, for 30 example by esterification, inclusive of silylation: and can, if desired, be released individually or jointly in a manner known per se after the reaction For example, amino, hydroxy, mercapto, carboxyl or sulpho groups present in a starting material, may be protected, for example in the form of acylamino groups, such as those mentioned above, for example the 2,2,2-trichloroethoxycarbonylamino group, 2 35 bromoethoxycarbonylamino group, 4 methoxybenzyloxycarbonylamino group, or tert butyloxycarbonylamino group, or in the form of aryl or aryl-lower alkylthioamino groups, for example the 2-nitrophenylthioamino group or arylsulphonylamino group, for example the 4 methylphenylsulphonylamino group, in the form of 1-lower alkoxycarbonyl 2 propylideneamino groups or of the o 40 nitrophenoxyacetylamino group, or of acyloxy groups, such as those mentioned above, for example the tert -butyloxycarbonyloxy group 2,2,2 trichloroethoxycarbonyloxy group, 2 bromoethoxycarbonyloxy group or p nitrobenzyloxycarbonyloxy group, or corresponding acylmercapto groups, or in the form of esterified carboxy groups, such as those mentioned above, for example the 45 diphenylmethoxycarbonyl group, p nitrobenzyloxycarbonyl group, acetonyloxycarbonyl group of 2 cyanoethoxycarbonyl group, or of substituted sulpho groups, such as the above-mentioned lower alkylsulpho groups, for example the methylsulpho group, and when the reaction is complete may be released, optionally after converting the protective group For example, a 2,2,2 trichloro 50 ethoxycarbonylamino group or 2 iodoethoxycarbonylamino group or alternatively a p-nitrobenzyloxycarbonylamino group may be split by treating with suitable reducing agents, such as zinc in the presence of aqueous acetic acid or hydrogen in the presence of a palladium catalyst; a diphenylmethoxycarbonylamino group or tert butylcarbonylamino group may be split by treating 55 with formic acid or trifluoroacetic acid; an aryl or aryl-lower alkylthioamino group may be split by treating with a nucleophilic reagent such as sulphorous acid; an arylsulphonylamino group may be split by means of electrolytic reduction: a Ilower alkoxycarbonyl 2 propylideneamino group by treating with aqueous mineral acid, and a tert butyloxycarbonyloxy group by treating with formic or 60 trifluoroacetic acid or a 2,2,2 trichloroethoxycarbonyloxy group or pnitrobenzyloxycarbonyloxy group may be split by treating with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, or with hydrogen in the presence of a palladium catalyst; and a diphenylmethoxycarbonyl group may be split by treating with formic or trifluoroacetic acid or by hydrogenolysis; an 65 1,604,758 acetonyloxy or cyanoethoxycarbonyl group may be split by treating with bases, such as sodium bicarbonate or 1,5-diazabicyclol 5,4,0 Olundec 5 ene, and a substituted sulpho group by treating with an alkali metal halide; the splitting may, if desired, in each case be carred out in stages.

Furthermore, in compounds that contain in the groups R, and RA functional 5 substituents such as free amino, hydroxy, carboxy or sulpho groups, these groups may be functionally modified by processes known per se, for example by acylation or esterification or substitution For example, an amino group may be converted into a sulphoamino group by treating with sulphur trioxide, preferably in the form of a complex with an organic base such as a tri-lower alkylamine, for example 10 triethylamine Also, the reaction mixture obtained by reacting an acid addition salt of 4-guanylsemicarbazide with sodium nitrite can be reacted with a compound of the formula II in which R 1 contains an amino group, and the amino group thus converted into a 3-guanylureido group Furthermore, compounds with aliphatically-bonded halogen, for example with an optionally substituted ar 15 bromoacetyl grouping, can be reacted with esters of phosphorous acid, such as trilower alkyl phosphite compounds, and thus be made into corresponding phosphono compounds.

In addition, in resulting compounds functional substituents in the radicals R, and RA may be converted into other functional groups: a nitro or azido group, for 20 example, may be converted into an amino group by treating with hydrogen that is catalytically activated by, for example, a palladium or platinum oxide catalyst.

In the compounds VII to XII, I Ia and I Va, a group R 1 or RA can be converted according to methods known per se into a different R 1 or RA group respectively.

Thus, in a compound having an esterified grouping of the formula -C(=O) 25 RA, this grouping can be converted into a different esterified carboxy group of this formula, for example 2 chloroethoxycarbonyl or 2 bromoethoxycarbonyl can be converted into 2 iodoethoxycarbonyl by treating with an iodine salt, such as sodium iodide, in the presence of a suitable solvent, such as acetone.

In a compound obtainable according to the invention having a protected, 30 especially an esterified, carboxyl group of the formula -C(=O) RA, the latter can be converted in a manner known per se, for example depending on the type of group RA, into the free carboxyl group This is then converted into a different group -C(=O)-R For example, a carboxyl group esterified by a suitable 2 halo lower alkyl 35 group, an arylcarbonylmethyl group or a 4 nitrobenzyl group can be converted into the free carboxyl group for example by treating with a chemical reducing agent, such as a metal, for example zinc, or a reducing metal salt, such as a chromium (II) salt, for example chromium(II) chloride, usually in the presence of a hydrogen-yielding agent, which together with the metal enables the nascent 40 hydrogen to be produced, such as an acid, chiefly acetic or formic acid, or an alcohol, wherein water is preferably added; a carboxyl group esterified by an arylcarbonylmethyl group can be converted into the free carboxyl group by treating with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide; and also a carboxyl group esterified by 4 45 nitrobenzyl can be converted into the free carboxyl group by treating with an alkali metal dithionite, for example sodium dithionite A carboxyl group esterified by a 2lower alkylsulphonyl lower alkyl group can be split and released, for example by treating with a basic agent, for example one of the nucleophilic-reacting bases mentioned further below; a carboxyl group esterified by a suitable arylmethyl 50 grouping can be split and released, for example by radiation, preferably with ultraviolet light, for example of less than 290 mu when the arylmethyl group is, for example, a benzyl radical optionally substituted in the 3-, 4 and/or 5position for example by lower alkoxy and/or nitro groups, or with longer-wave ultraviolet light, for example of above 290 mu when the arylmethyl group is, for example, a benzyl 55 radical substituted in the 2-position by a nitro group; a carboxyl group esterified by a suitably substituted methyl group, such as tert -butyl or diphenylmethyl, can be split and released, for example, by treating with a suitable acid medium, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol or anisole; and an esterified carboxyl group that can be 60 split by hydrogenolysis, for example benzyloxycarbonyl or 4nitrobenzyloxycarbonyl, can be split for example by treating with hydrogen in the presence of a noble metal, for example a palladium, catalyst In addition, a carboxyl group esterified with a lower alkenyl group, such as with 2lower alkenyl, 1,604,758 especially allyl, can be converted oxidatively, for example by treating with ozone, followed by a reducing agent, for example dimethyl sulphide, into a formylmethoxycarbonyl group, from which the carboxyl group can be released by treating with a base, such as a secondary amine, for example dimethylamine; or a 2lower alkenyloxycarbonyl group, for example allyloxycarbonyl, can be isomerised, 5 for example by treating with tris-triphenylphosphine rhodium chloride, palladiumon-carbon, or an alkali metal lower alkanolate, for example tert butylate, in dimethyl sulphoxide to form a l-lower alkenyloxycarbonyl group and this can be split hydrolytically under weakly acidic or weakly basic conditions A 2oxoethoxycarbonyl or 2 cyanoethoxycarbonyl group optionally substituted in the 10 2 position by lower alkyl or by aryl, for example the acetonyloxycarbonyl or 2 cyanoethoxycarbonyl group, can be converted under mild conditions, that is at room temperature or while cooling, by treatment with a suitable base, into the corresponding salt of this carboxyl group, from which the free carboxyl group can be obtained by acidification Suitable bases are nucleophilic-reacting metal, such 15 as alkaline earth metal, and especially alkali metal, bases, such as corresponding hydroxides, carbonates, bicarbonates, alkoxides, phenolates, mercaptides, thiophenolates or amides, for example sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium ethanolate, sodium thiophenolate, sodium amide or sodium morpholide, or corresponding lithium or potassium compounds, which are 20 used in water in aqueous or hydroxyl group-containing solvents or alternatively in polar inert solvents with subsequent treatment with water To split the 2cyanoethoxycarbonyl groups, it is also possible to use tertiary amines, such as trilower alkylamine, for example triethylamine or Hiunig base, or cyclic or bicyclic amines or imines, such as N-methylmorpholine or 1,5 diazabicyclol 5,4,0 lundec 25 ene, in an inert solvent, such as methylene chloride or tetrahydrofuran, wherein the corresponding ammonium salts of the carboxyl compound are obtained directly A substituted silylethoxycarbonyl group can be converted into the free carboxyl group by treatment with a salt of hydrofluoric acid that yields fluoride anions, such as an alkali metal fluoride, for example sodium or potassium fluoride, 30 in the presence of a macrocyclic polyether ("Crown ether"), or with a fluoride of an organic quaternary base, such as tetraalkylammonium fluoride or trialkylaryl ammonium fluoride, for example tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent, such as dimethyl sulphoxide or N,N-dimethylacetamide A pentachlorophenyloxy 35 carbonyl group can be converted into a free carboxyl group under mild conditions, for example by dilute sodium carbonate solution or sodium bicarbonate solution or by an organic base in the presence of water.

A carboxyl group protected, for example, by silylation or stannylation, can be released in the usual manner by solvolysis for example by treating with water or an 40 alcohol.

If there is more than one protected carboxyl group present in a compound obtainable in accordance with the invention, these may be converted into free carboxyl groups either jointly or selectively.

In the compound thus obtained having a free carboxyl group of the formula 45 -C(=O) OH, such a group is then converted in a manner known per se into a protected carboxyl group For example, esters are obtained, for example by treating with a suitable diazo compound, such as a diazo-lower alkane, for example diazomethane or diazobutane, or a phenyldiazo-lower alkane, for example diphenyldiazomethane, if necessary in the presence of a Lewis acid, such as, for 50 example, boron trifluoride, or by reacting with an alcohol suitable for esterification in the presence of an esterifying agent, such as a carbodiimide, for example dicyclohexylcarbodiimide, or carbonyldiimidazole, or further with an N,N'disubstituted O or S-substituted isourea or isothiourea, in which an O and Ssubstituent is, for example, lower alkyl, especially tert -butyl, phenyllower alkyl or 55 cycloalkyl and N or N'-substituents are, for example, lower alkyl, especially isopropyl, cycloalkyl or phenyl, or according to any other known and suitable method of esterification, such as reacting a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid or strong organic sulphonic acid Further, acid halides, such as acid chlorides (produced, for example, by treating with oxalyl 60 chloride), activated esters (formed, for example, with an N-hydroxy nitrogen compound, such as N-hydroxysuccinimide) or mixed anhydrides (obtained, for example, with haloformic acid lower alkyl esters, such as chloroformic acid ethyl ester or chloroformic acid isobutyl ester, or with haloacetic acid halides, such as 1,604,758 trichloroacetic acid chloride) can be converted into an esterified carboxyl group by reacting with alcohols, optionally in the presence of a base, such as pyridine.

In a compound having a free carboxyl group of the formula -C(=O) OH obtained according to the above method, such a group can also be converted into an optionally substituted hydrazinocarbonyl group, by reacting preferably reactive 5 functionally modified derivatives such as the above-mentioned acid halides, generally esters such as the above-mentioned activated esters, or mixed anhydrides of the corresponding acid with hydrazines.

A carboxyl group protected by an organic silyl or stannyl group can be formed in a manner known per se, for example by treating compounds having -C(=O) OH 10 or salts, such as alkali metal salts, for example sodium salts, thereof, with a suitable silylation or stannylation agent, such as one of the above-mentioned silylation or stannylation agents.

The other intermediate products for preparing compounds of the formula Ia, i e those of the formula I Va, Va, Via and VII and especially of the formula I Ia, and 15 the processes for their production are claimed in copending applications 8102015, 81.02016, 81 02017, 81 02018, 81 02019, and 81 02020 Serial Nos, 1604752, 1604753, 1604754, 1604755, 1604756 and 1604757.

Referring to the present description, organic radicals referred to as "lower", unless defined otherwise, contain up to 7, preferably up to 4, carbon atoms; acyl 20 radicals contain up to 20, preferably up to 12, and primarily up to 7, carbon atoms.

The following Examples serve to illustrate the invention; temperatures are in degrees Centigrade The following abbreviations are used: TLC=thin layer chromatogram over silica gel; sh=shoulder.

Example 1 25

Penicillanic acid methyl ester 1-oxide A solution of 6 5 g of penicillanic acid methyl ester (produced by catalytic hydrogenation of 6 a-bromopenicillanic acid methyl ester by means of 5 % palladium/barium carbonate catalyst in aqueous dioxan) in 220 ml of methylene chloride is cooled to -15 under nitrogen, a solution of 6 14 g of 18 % m 30 chloroperbenzoic acid ( 30 23 mmol) in 140 ml of methylene chloride is added dropwise and the mixture is stirred for 2 hours at the same temperature The reaction mixture is diluted with methylene chloride, washed in succession with 3 % aqueous sodium bisulphite solution and 8 % aqueous sodium bicarbonate solution, and dried over sodium sulphate The solvent is evaporated off in vacuo and the 35 residue is used in the subsequent reaction in this crude form A sample is chromatographed over silica gel ( 10 % H 20) With toluene/ethyl acetate ( 2:1) the title compound is obtained in the form of an oil, which after repeating the purification by thin layer chromatography over silica gel plates with toluene/ethyl acetate ( 1:1) has the following physico-chemical properties: 40 la 1 O =+ 280 +l (c= 1 005 % in CHCI 3); IR spectrum (in methylene chloride):

characteristic absorption bands at 3 25-3 50, 5 61, 5 72, 6 86, 7 00, 7 10 (sh), 7 21, 7.32 7 42, 7 81-8 01 (broad), 8 22 (sh), 8 30-8 36, 8 47 (sh), 9 21, 9 46, 9 88 (sh) and 9 96 1 A; NMR spectrum (in CDCI 3/100 Mc, in ppm): 1 23, 3 H, s; 1 70, 3 H, s; 3 34, 2 H, d; 3 80, 3 H, s; 4 51, 1 H, s; 4 97, 1 H, t 45 Example 2

2-l( 4 R)-4-(B enzthiazol-2-yldithio)-2-oxoazetidin l -yll-3methylenebutyric acid methyl esterA solution of 685 mg of penicillanic acid methyl ester 1-oxide and 496 mg ( 2 97 mmol) of 2-mercaptobenzthiazole in 30 ml of toluene is heated under reflux for 2 5 50 hours The solvent is distilled off in vacuo and the residue is chromatographed over g of silica gel The title compound is obtained in amorphous form by elution with toluene/ethyl acetate ( 9:1) TLC: Rf= O 47 (ethyl acetate/toluene 1:1); I R spectrum (in methylene chloride): absorption bands at 5 66, 5 75, 5 97-6 05, 6 75 (sh), 6 84, 7 03, 7 28, 7 53, 7 60 (sh), 7 65 (sh); 8 10, 8 35, 8 50, 8 89, 9 25, 9 81 and 9 93 U; 55 lal 02 =-392 + 1 (c= 0 777 % in CH C 13).

Example 3

2-l( 4 R)-4-(B enzthiazol-2-yldithio)-2-oxazetidin 1 -yll-3methylcrotonic acid methyl ester 5 ml of triethylamine are added to a solution of 12 g of 2 l( 4 R) 4 60 (benzthiazol 2 yldithio) 2 oxoazetidin 1 yll 3 methylenebutyric acid methyl ester in 500 ml of methylene chloride and the mixture is allowed to stand at i 5 1,604,758 room temperature for 90 minutes The reaction mixture is washed with 5 % aqueous citric acid solution, dried over sodium sulphate and freed of solvent in vacuo The residue is purified by chromatography over silica gel (deactivated with 10 % water) with toluene and toluene/ethyl acetate ( 19:1) and yields the title compound, which after recrystallisation from diethyl ether/pentane has a melting point of 63-66 5 TLC: Rr= O 44 (ethyl acetate/toluene 1:1); IR spectrum (in methylene chloride): characteristic absorption bands at 3 35-3 60, 5 66, 5 81, 5 87 (sh), 5 93 (sh), 6 15, 6 85, 7 04, 7 26, 7 36, 7 65 (sh), 7 73, 8 17, 8 25 (sh), 8 35 (sh), 8 90, 9 18 (sh, 9 26, 9 42 (sh), 9 81 (sh), 9 92, 10 25 and 10 95 (broad); la 12 =153 + O l (c=0 916 %, in CHCI 3) 10 Example 4

2-l( 4 R)-4-Acetylthio-2-oxoazetidin 1 -yll-3-methylcrotonic acid methyl ester a) A solution of 4 6 g of 2 l( 4 c) 4 benzthiazol 2 yldithio) 2 oxoazetidin I yll 3 methylcrotonic acid methyl ester in 120 ml of 15 dimethylformamide is cooled to -20 , a solution of 670 mg of sodium borohydride in 80 ml of dimethylformamide is added and the mixture is stirred for 10 minutes at the same temperature The temperature of the reaction mixture is increased to O for 60 minutes, then cooled again to -20 , whereupon 40 ml of freshly distilled acetyl bromide are added dropwise and the mixture is further stirred at 0 for 2 20 hours After adding 1 5 1 of benzene, the reaction mixture is washed in succession with ice water, water, 8 % aqueous sodium bicarbonate solution and water, dried over sodium sulphate and concentrated in vacuo After chromatography over silica gel (deactivated with 10 %/o water) with toluene and toluene/ethyl acetate ( 19:1), the residue yields the title compound which is slightly contaminated by the ( 4 S) 25 enantiomer Repeated chromatography and recrystallisation from diethyl ether/pentane yields the pure title compound having a melting point of 8182 ; la Il O =+ 149 + 1 (c= 0 994 %, CH C 13); TLC: R-= 0 40 (ethyl acetate/toluene 1:1); IR spectrum (in methylene chloride): absorption bands at 3 35-3 57, 5 66, 5 81, 5 89, 5 96 (sh), 6 15, 7 00, 7 07 (sh), 7 25, 7 35, 7 72, 8 15, 8 22 (sh), 8 35 (sh), 8 86, 9 15, 30 9.26, 9 42, 9 95, 10 11, 10 50 (broad) and 10 80 /.

b) The partial racemisation can be prevented by the following method of operation:

I g of zinc powder is added in portions over a period of one hour to a solution.

stirred under nitrogen and in an ice bath, of 380 mg (I mmol) of 2 l( 4 R) 4 35 (benzthiazol 2 yl dithio) 2 oxoazetidin 1 yll 3 methylcrotonic acid methyl ester in 3 ml of acetic anhydride and 5 ml of glacial acetic acid The reaction mixture is further stirred for one hour at room temperature, filtered and concentrated in vacuo The residue is taken up in methylene chloride and washed in succession with 25 % aqueous ammonium chloride solution and aqueous sodium 40 bicarbonate solution The combined aqueous phases are re-extracted with methylene chloride, all the methylene chloride phases are combined, dried with sodium sulphate and concentrated in vacuo The residue is chromatographed over g of silica gel (deactivated with 10 /% water) with toluene and toluene/ethyl acetate ( 19:1) and yields the optically pure title compound having a melting point of 45 78-80 ; la 120 =+ 149 + 1 (c= 1 007 %; in CHCI 3).

Example 5

2-l( 4 R)-4-Acetylthio-2-oxoazetidin 1 -yll-2-oxoacetic acid methyl ester 50 4 equivalents of ozone are introduced over a period of 60 minutes into a solution, cooled to -15 , of 150 mg of 2 l( 4 R) 4 acetylthio -2 oxoazetidin 1 yll 3 methylcrotonic acid methyl ester in 3 ml of methanol The reaction mixture is rinsed with nitrogen, diluted with methylene chloride and washed for 2 minutes with a 5 % aqueous sodium bisulphite solution The organic phase is dried 55 over sodium sulphate and concentrated in vacuo IR spectrum of the resulting oily title compound (in methylene chloride): characteristic bands at 3 30-3 40, 5 52, 5.70, 5 83 (sh), 5 86, 6 98, 7 08 (sh), 7 40, 7 82-8 00 (broad, sh), 8 07, 8 19, 8 30 (sh), 8.46, 8 90, 9 22, 9 52, 9 91, 10 30 and 10 73,u The product obtained can be used in the next stage without further purification 60 1,604,758

Claims (16)

WHAT WE CLAIM IS:-

1 Process for the manufacture of compounds of the formula z II H o S,-C-R 1 _ Xl (Xi I) o si CR 2 in which Z' represents oxygen, sulphur or a methylidene group optionally carrying an 5 organic substituent Y, R 1 represents hydrogen, an organic radical bonded by a carbon atom to the group -C(=Z')-, or an etherified mercapto group, and R" together with the carbonyl group -C(=O) represents a protected carboxyl group, 10 characterised in that a compound of the formula Z'I 11 ER SC-R 1 (XI) c-cs in which Z', R, and R have the meanings given above, is ozonised and the ozonide formed is split reductively to form the oxo group, and, if desired, a group R, in a compound obtained is converted into a different group R, and/or, if desired, an 15 optionally substituted methylidene group Z' is converted into an oxo group Z.

2 Process according to Claim 1, characterised in that the ozonisation is carried out with an ozone/oxygen mixture in an inert solvent, and the intermediate ozonide is split reductively by treatment with sodium bisulphite.

3 Process according to Claim I or Claim 2, characterised in that a starting 20 material is used, wherein Z' represents oxygen.

4 Process according to Claim 1, carried out substantially as described in Example

5 herein.

Process according to any one of Claims I to 4, wherein the starting material of the formula XI is prepared from any one of the compounds Xa, X, IX, VIII and 25 VII shown in reaction scheme 1 herein by a method substantially as described herein.

6 Process according to Claim 5, wherein the preparation of the starting material of the formula XI is carried out substantially as described in Examples I to 4 herein 30

7 A compound of the formula Zt II H S(XII) Tno x I ok-4 in which Z', R 1 and R 2 are as defined in Claim 1.

1,604,758

8 A compound of the formula (XII), according to Claim 7, in which R, represents hydrogen or an aliphatic, cycloaliphatlc, cycloaliphaticaliphatic aromatic or araliphatic hydrocarbon radical having up to 10 carbon atoms, which is optionally substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkylthio, carboxyl, (lower alkoxy)carbonyl, carbamoyl, cyano, nitro, amino, amino 5 mono or di-substituted by lower alkyl or disubstituted by lower alkylene, or protected amino, or R, represents a heterocyclic or heterocyclic aliphatic radical of aromatic character, bonded by a carbon atom, such a radical having 5 or 6 ring members and nitrogen, oxygen or sulphur as hetero atoms, or R, represents an etherified mercapto group which is etherified by an aliphatic, cycloaliphatic, 10 cycloaliphatic aliphatic, aromatic or araliphatic hydrocarbon radical having up to carbon atoms, which is optionally substituted by hydroxy, mercapto, lower alkoxy, lower alkanoyloxy, halogen, lower alkylthio, carboxyl, (lower alkoxy)carbonyl, carbamoyl, cyano, nitro, amino, or amino mono or disubstituted by lower alkyl or acyl, or di-substituted by lower alkylene 15

9 A compound of the formula (XII), according to Claim 7, in which R, represents hydrogen, lower alkyl, optionally functionally modified carboxyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl, naphthyl or phenyl-lower alkyl, which radicals are optionally substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, alkylthio, carboxyl, (lower alkoxy)carbonyl, carbamoyl, cyano, nitro, 20 amino, amino mono or di-substituted by lower alkyl or disubstituted by lower alkylene, or protected amino, or R, represents pyridyl, thienyl, furyl or pyridyl-, thienyl or furyl-lower alkyl, or R, represents lower alkylthio, lower alkenylthio, cycloalkylthio, cycloalkyl-lower alkylthio, phenylthio or phenyl-lower alkylthio, which radicals are optionally substituted by hydroxy, mercapto, lower alkoxy, 25 lower alkanoyloxy, halogen, lower alkylthio, carboxyl, (lower alkoxy) carbonyl, carbamoyl, cyano, nitro, amino, or amino mono or di-substituted by lower alkyl or lower alkanoyl, or di-su bstituted by lower alkylene.

A compound of the formula (XII), according to Claim 7, in which R 1 represents hydrogen, lower alkyl, lower alkyl substituted by lower alkoxy, lower 30 alkanoyloxy, lower alkylthio, (lower alkoxy)carbonyl, amino or acylated amino, or R, represents phenyl-lower alkyl, phenyl, phenyl substituted by lower alkyl, lower alkoxy, halogen, nitro, amino or di-lower alkylamino, or R 1 represents lower alkylthio.

11 A compound of the formula (XII), according to any one of Claims 7 to 10, 35 in which RA represents lower alkoxy, a-polybranched lower alkoxy, 2substituted 2oxoethoxy, 2-cyanoethoxy, 2-( 51 X 52 X 53) silylethoxy, in which each of 51, 52 and 53 represents lower alkyl or phenyl, I phenyl lower alkoxy having I 1-3 phenyl radicals optionally substituted by lower alkoxy and/or nitro, (lower alkanoyl)oxymethoxy, pentachlorophenoxy, tri-lower alkylsilyloxy, or lower 40 alkenyloxy.

12 A compound of the formula (XII), according to any one of Claims 7 to 10, in which RA represents tert -butyloxy, acetonyloxy, phenacyloxy, 2cyanoethoxy, 2 trimethylsilylethoxy, 2 triphenylsilylethoxy, 4 methoxybenzyloxy, 4 nitrobenzyloxy, 2 nitro 4,5 dimethoxybenzyloxy, diphenylmethoxy, 4,4 ' 45 dimethoxydiphenylmethoxy, trityloxy, acetoxymethoxy, pivaloyloxymethoxy, pentachlorophenoxy, trimethylsilyloxy, or allyloxy.

13 A compound of the formula (XII), according to any one of Claims 7 to 12, wherein Z' represents oxygen.

14 2 l( 4 R)4 Acetylthio 2 oxoazetidin I yll 2 oxoacetic acid 50 methyl ester.

A compound of the formula XII according to Claim 7, whenever prepared by a process according to any one of Claims 1 to 6.

16 A compound of the formula XII according to any one of Claims 7 to 15, whenever used for preparing a compound of the formula 55 I 2 ZR: (Ia) O.-CR 2 1,604,758 19 1,604,758 19 in which R, represents hydrogen, an organic radical bonded by a carbon atom to the ring carbon atom, or an etherified mercapto group, and R 2 represents hydroxy or a radical RA forming together with the carbonyl grouping -C(=O) a protected carboxyl group, 5 a l-oxide thereof, or a salt of such a compound of the formula Ia or its l-oxide having a salt-forming group.

ABEL & IMRAY, Chartered Patent Agents, Northumberland House, 303-306 High Holborn, London, WC 1 V 7 LH.

Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa 1981 Published by The Patent Office, 25 Southampton Buildings, London WC 2 A l AY, from which copies may be obtained.