GB1604755A - Penicillanic acid ester 1-oxides - Google Patents

Description

(54) PENICILLANIC ACID ESTER l-OXIDES (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

in which RA2 forms together with the carbonyl grouping -C(=OH a protected carboxyl group and a process for their manufacture.

The new compounds may be prepared as described further below under stage 1.1.

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 p- lactam ring and having antibiotic properties.

Since the discovery of penicillin, numerous bicyclic thia-aza compounds having a p-lactam structure have become known. A survey of earlier works reveals E. H. Flynn, "Cephalosporins and Penicillifis", 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 > 77, and P. G. Sammes, Chem. Rev. 1976, Vol. 76, No. 1, 113-155. At the symposium "Recent Advances in the Chemistry of p-lactam Antibiotics" from 28th to 30th June, 1976, held in Cambridge, England, 6 - 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 positions have also become known, for example 3 - carboxy - 2,2dimethylpenam (J. P. Clayton, J. Chem. Soc., 1969, 2123) and 3 - methyl - 4 carboxy - 3 - cephem (K. Kiihlein, 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 unknown.

The problem underlying the present invention is to produce intermediates for the synthesis of bicyclic thia-aza compounds containing a p-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 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

and may systematically be called 7 - oxo - 4 - thia - 1 - azabicyclo[3,2,01 - hept 2 - ene. For the sake of simplicity it is referred to hereinafter as "2-penem", wherein the following numbering derived from penam and customary in penicillin chemistry shall be used:

The 2-penem ring system has an asymmetrically substituted carbon atom in the 5-position, and corresponding compounds, according to the Cahn-Ingold-Prelog designation, occur in the (5R)-confilguration.

The compounds of the present invention may be used as intermediates for the preparation of 2-penem-3-carboxylic acid compounds of the formula

in which R1 represents hydrogen, an organic radical bonded by a carbon atom to the ring carbon atom, or an etherified mercapto group, and R2 represents hydroxy or a radical RA forming together with the carbonyl grouping (=O) a protected carboxyl group, I-oxides thereof, as well as salts of such compounds having salt-forming groups which have valuable pharmacological properties. These compounds, processes for the ir manufacture and pharmaceutical preparations containing them are described and claimed in copending application 18282/78, Serial No. 1604751.

A protected carboxyl group of the formula (=OHRA2 is primarily an esterified carboxyl group in which RA2 represents a hydroxy group etherified by an 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 heterocyclic aliphatic radicals, preferably having up to 18 carbon atoms.

An etherified hydroxy group RA2 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 functionally modified carboxyl group, such as into another esterified carboxyl group or into a hydrazinocarbonyl group. Such a group R2 is, for example, 2-halorower alkoxy, in which the halogen preferably has an atomic weight of more than 19, for example 2,2,2-trichloroethoxy or 2-iodoethoxy, also 2-chloroethoxy or 2 bromoethoxy which may readily be converted into 2-iodoethoxy, or 2-lower alkylsulphonyl-lower alkoxy, for example, 2-methyl-sulphonylethoxy. The group RA2 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 unsaturated aliphatic hydrocarbon radical, such as lower alkenyl, for example 1-lower alkenyl, such as vinyl, by a carbocyclic aryl group having electron-donating substituents, or by a heterocyclic group of aromatic character having oxygen or sulphur as ring member. Examples of such groups R2 are tert.-lower alkoxy, for example tert.-butoxy or tert.-pentoxy; optionally substituted diphenylmethoxy, 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 5-position), primarily 3- or 4-methoxybenzyloxy or 3,4dimethoxybenzyloxy; or, 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 substituted in the I-position by lower alkyl, such as methyl, (lower alkoxy)carbonyl, such as methoxycarbonyl, (lower alkyl)carbonyl, such as methylcarbonyl, aralkylcarbonyl, such as benzylcarbonyl, or arylcarbonyl, such as benzoyl. Thus R2 represents, for example, acetonyloxy, phenacyloxy, 2,4-dioxo-3pentoxy, 1 - methoxycarbonyl - 2 - oxopropoxy or I - ethoxycarbonyl - 2 oxopropoxy. The group RA 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 2-cyanoethoxy or 2 - cyano - 2 - phenylethoxy. R2 is alternatively a 2 (S1XS2S3)-silylethoxy group, in which each of the substituents Si, S2 and S3 independently of one another represents an optionally substituted hydrocarbon radical and the individual radicals may be linked by a single C-C bond. A hydrocarbon radical Si, S2, S3 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 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 phenylethyl. Radicals RA of this kind to be singled out are 2-trilower alkylsilylethoxy, such as 2-trimethylsilylethoxy or 2 - (dibutylmethylsilyl) ethoxy, and 2 - triarylsilylethoxy, such as 2 - triphenylsilylethoxy.

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

An organic silyloxy or organic stannyloxy group RA2 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 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 RA2 represents primarily tri-lower alkylsilyloxy, for example, trimethylsilyloxy, halo-lower alkoxy-lower alkylsilyloxy, for example, chloromethoxymethylsilyloxy, or tri-lower alkylstannyloxy, for example, tri-n butylstannyloxy.

The group RA2 may alternatively be an etherified hydroxy group that together with the carbonyl grouping -C(=O forms an esterified carboxyl group that can be split under physiological conditions, primarily an acyloxymethoxy group, in which acyl represents, for example, the radical of an organic carboxylic acid, primarily an optionally substituted (lower alkane)carboxylic acid, or in which acyloxymethyl forms the radical of a lactone. Hydroxy groups etherified in this manner are (lower alkanoyl)oxymethoxy, for example acetoxymethoxy or pivaloyloxymethoxy; aminolower alkanoyl)oxymethoxy, especially a - amino (lower alkanoyl)oxymethyl, for example glycyloxymethoxy, L-valyloxymethoxy, Lleucyloxymethoxy, and also phthalidyloxy. In other ester groups C(=ORA2 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 group, and represents, for example 2-dimethylaminoethoxy, 2-diethylaminoethoxy or 2 - (I - morpholino) - ethoxy.

A radical A2 forming with a (O)grouping an optionally substituted hydrazinocarbonyl group is, for example, hydrazino or 2-lower alkylhydrazino, for example 2-methylhydrazino.

Preferred groups RA2 are those that can be converted into a free hydroxy group under neutral, basic or physiological conditions.

The invention provides especially intermediates of the formula VIII in which RA2 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 RA2. Preferably RA2 represents an 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-(S,KS,XS,)-silylethoxy, in which each of S" S2 and S3 represents lower alkyl such as methyl, or phenyl, such as 2-trimethylsilylethoxy or 2-trihenylsilylethoxy, I-phenyl-lower alkoxy having 1--3 phenyl radicals optionally substituted by lower alkoxy and/or nitro, for example 4methoxybenzyloxy, 4-nitrobenzyloxy, 2-nitro-4,5-dimethoxybenzyloxy, diphenylmethoxy, 4,4'-dimethoxydiphenylmethoxy or trityloxy, (lower alkanoyl)oxymethoxy, for example acetoxymethoxy or pivalolyoxymethoxy, aamino-lower alkanoloxymetoxy, for example glycyloxymethoxy, 2phthalidyloxy, pentaclorophenoxy, also tri-lower alkylsilyloxy, for example trilnethylsilyloxy, and lower alkenyloxy, especially 2-lower alkenyloxy, for example allyloxy.

Especially, RA2 represents the above-mentioned etherified hydroxy groups that can be split under basic or neutral conditions or physiologically, especially pnitrobenzyloxy or acetonyloxy.

More especially, RA2 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 RA2 may be protected in a manner known per se, for example as indicated above. A group RA2 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-halo-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy; 2lower alkyl-sulphonyl-lower alkoxy, for example 2-methylsulphonylethoxy; or an optionally substituted, such as lower alkoxy-, for example methoxy- or nitrocontaining, l-phenyl-lower alkoxy group, such as diphenylmethoxy or benzyloxy optionally substituted, for example as mentioned, for example benzyloxy, 4methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4' dimethoxydiphenylmethoxy; pentachlorophenoxy; acetonyloxy; 2-cyanoethoxy; a 2HS, )(S2)(S3)-silylethoxy group, such as 2-trimethylsilylethoxy, 2 (dibutylmethylsilylkethoxy 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.

The preparation of compounds of the formula VIII and their conversion into compounds of the formula Ia may be carried out, for example, according to the following reaction schemes: Reaction scheme 1

0 a s s Stage 1.1 ) ON O=C-R2 A On (VII) (vrIr) Stage 1.2 0 S-R0 g S-S-R g < S-R 0i i -] ON a', CS3 - C Ci;rC A wR2 3 o=cPXA CR3 O=0-R2 (x) (xx) tage 1.4 Stage 1.4a Z' Z' -R1 CB3 Stage l.3a /S~c~ cg2 /a'3 cSc \ cs - c I o-c-R2 A a'3 O=C-R2 (xI) (Xa) Stage Sta4e .5 Z' Z' I( II H Stage 1.6 S-C-R < Stage 1.6 < ("ra) (xII) O=C-R2 Reaction Scheme 1

- z a g ,S - C - R1 o E IVx ,, stage 2 ZI ll - Il 45 C - R1 stage 1.2 ON stage N CS ~X CZ rsOH O s O - C - R V,' stage 3 11 it C- R1 < / stage 2.4 > stage 2.4 R1 -R C-xO -N f/ o = C1 < OCR2 ITQs In the compounds of the formulae IVa, Va, VIa and Ila in the reaction scheme 2 and in the compounds of the formulae Xa, XI, XII and IVa in the reaction scheme 1, 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. Further details are given in application 18282/78. Serial No. 1604751.

In the compounds of the formulae VII to XII, R2 preferably represents lower alkoxy, especially methoxy.

Details of stages 1.2, 1.3 1.4, 1.4a, 1.3a, 1.5, 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 1oxide thereof, are described in copending application 18282/78.

In stage 1.1, an oxide of a penicillanic acid compound of the formula VIII is obtained by oxidising a penicilanicacid compound of the formula VII in the 1position. 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 acids 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-SO0 to + 1000, 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 - 6a - bromopenicillanic acid and subsequent esterification of the carboxyl group [E. Evrard, M. Claesen and H. Vanderhaege, Nature 201, 1124 (1964)] or by hydrogenation of 6,6-dibromopenicillanic acid esters, for example the methyl ester [J. P. Clayton, J. Chem. Soc. (C), 2123 (1969)].

In the compound VIII, a group RA2 can be converted according to methods known per se into a different RA group.

Thus, in a compound having an esterified grouping of the formula C(=O RA2, 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.

Also, in a compound obtainable according to the invention having a protected, especially an esterified, carboxyl group of the formula (O)RA2, the latter can be converted in a manner known per se, for example depending on the type of group RA2, into the free carboxyl group. This is then converted into a different group -C(=O)-R2A.

For example, a carboxyl group esterified by a suitable 2-halo-lower alkyl 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(I I) salt, for example chromium(II) chloride, usually in the presence of a hydrogenyielding agent, which together with the metal enables the nascent 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 iodize; and also a carboxyl group esterified by 4-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 2-lower 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 grouping can be split and released, for example by radiation, preferably with ultra-violet light, for example of less than 290 me when the arylmethyl group is, for example, a benzyl radical optionally substituted in the 3-, 4- and/or 5-position for example by lower alkoxy and/or nitro groups or with longer-wave ultraviolet light, for example of above 290 mju when the arylmethyl group is, for example, a benzyl 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 diphenylmetbyl, can be split and released, for example, by treating with a suitable acid medium, such as formic acid or trifluoroacetic acid, optionally with the addit5.ori of:a gcleophilic compound, such as phenol or anisole; nd.an esterified:carboxyl gru̥pthat can be split by hydrogenolysis, for. ezampl ben.zyloxycarbonI 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 a kenyl group, such as with 2-lower alkenyl.

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, 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-cyanoethoxyearbonyl group optionally substituted in the 2-position by lower alkyl or by aryl, for example the acetonyloxycarbonyl or 2cyanoethoxycarbonyl 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 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 aniide or sodium morpholide, or corresponding lithium or potassium compounds, which are used in water in aqueous or hydroxyTgroup-containing solvents or alternatively in polar inert solvents with subsequent treatment with water. To split the 2 cyanoethoxycarbonyl groups, it is also possible to use tertiary amines, such as tri lower alkylamine, for example triethylamine or Hiinig base, or cyclic or bicyclic amines or imines, such as N-methylmorpholine or 1,5-diazabicycio[5,4,0lundec-5- 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, in the presence of a macrocyclic polyether ('Crown ether"), or with a fluoride of an organic quaternary base, such as tetraalkylammonium fluoride or trialkylarylammonium fluoride, for example tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent, such as dimethylsulphoxide or N,Ndimethylacetamide. A pentachlorophenyloxycarbonyl 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 alcohol.

In the compound thus obtained having a free carboxyl group of the formula --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 Dhenyldiazo-lower alkane, for example diphenyldiazomethane, if necessary in the presence of a Lewis acid, such as, for 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 disubstituted 0- or S-substituted isourea or isothiourea, in which an 0- and S substitutent is, for example, lower alkyl, especially tert.-butyl, phenyl-lower alkyl or 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 wtih oxalyl 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 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 QC=OFOH obtained according to the process, such a group can also be converted into an optionally substituted hydrazinocarbonyl group, by reacting preferably reactive 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 kn may be converted into other functional groups: a nitro or azido group, for 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.

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

The other new intermediate products for preparing compounds of the formula Ia, i.e. those of the formulae IVa, Va, VIa, VII and IX to XII and especially of the formula Ila, and the processes for their production are claimed in copending applications 8102015, 8102016, 8102017, 8102019, 8102020 and 8102021. Serial Nos.

1604752, 1604753, 1604754, 1604755, 1604756, 1604757 and 1604758.

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

The following Example serves to illustrate the invention temperatures are in degrees Centigrade. The following abbreviation is used: sh=shoulder.

Example Penicillanic acid methyl ester I-oxide A solution of 6.5 g of penicillanic acid methyl ester (produced by catalytic hydrogenation of 6a-bromopenicillanic acid methyl ester by means of 50/to 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,ó mchloroperbenzoic 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 residue is used in the subsequent reaction in this crude form. A sample is chromatographed over silica gel (10% H2O). 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: [a]2O=+280O+lC (c=1.005% in CHCI3)7 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, 7.818.01 (broad), 8.22 (sh), 8.30--8.36, 8.47 (sh), 9.21, 9.46, 9.88 (sh) and 9.96 p; NMR spectrum (in CDCldi00 Mc, in ppm): 1.23, 3H, s; 1.70, 3H, s; 3.34, 2H, d; 3.80, 3H, s; 4.51, 1H, s; 4.97, 1H, t.

WHAT WE CLAIM IS: 1. Process for the manufacture of compounds of the formula

in which RA forms together with the carbonyl grouping -C(=O a protected carboxyl group, characterised in that a penicillanic acid compound of the formula

is oxidised in the 1-position.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (10)

**WARNING** start of CLMS field may overlap end of DESC **. may be converted into other functional groups: a nitro or azido group, for 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. Starting compounds may be used in the form of derivatives or may be formed in situ, optionally under the conditions of their subsequent reaction. The other new intermediate products for preparing compounds of the formula Ia, i.e. those of the formulae IVa, Va, VIa, VII and IX to XII and especially of the formula Ila, and the processes for their production are claimed in copending applications 8102015, 8102016, 8102017, 8102019, 8102020 and 8102021. Serial Nos. 1604752, 1604753, 1604754, 1604755, 1604756, 1604757 and 1604758. Referring to the present description, organic radicals referred to as "lower" unless defined otherwise, contain up to 7, preferably up to 4, carbon atoms; acryl radicals contain up to 20, preferably up to 12, and primarily up to 7, carbon atoms. The following Example serves to illustrate the invention temperatures are in degrees Centigrade. The following abbreviation is used: sh=shoulder. Example Penicillanic acid methyl ester I-oxide A solution of 6.5 g of penicillanic acid methyl ester (produced by catalytic hydrogenation of 6a-bromopenicillanic acid methyl ester by means of 50/to 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,ó mchloroperbenzoic 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 residue is used in the subsequent reaction in this crude form. A sample is chromatographed over silica gel (10% H2O). 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: [a]2O=+280O+lC (c=1.005% in CHCI3)7 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, 7.818.01 (broad), 8.22 (sh), 8.30--8.36, 8.47 (sh), 9.21, 9.46, 9.88 (sh) and 9.96 p; NMR spectrum (in CDCldi00 Mc, in ppm): 1.23, 3H, s; 1.70, 3H, s; 3.34, 2H, d; 3.80, 3H, s; 4.51, 1H, s; 4.97, 1H, t. WHAT WE CLAIM IS:

1. Process for the manufacture of compounds of the formula

in which RA forms together with the carbonyl grouping -C(=O a protected carboxyl group, characterised in that a penicillanic acid compound of the formula

is oxidised in the 1-position.

2. Process according to claim 1, characterised in that the oxidation is carried

out with hydrogen peroxide or an inorganic or organic peracid.

3. Process according to claim 1, characterised in that the oxidation is carried out with m-chloroperbenzoic acid.

4. Process according to claim 1, carried out substantially as described in the Example herein.

5. A compound of the formula

in which RA2 is as defined in claim 1.

6. A compound of the formula (VIII), according to claim 5, in which RA represents lower alkoxy, a-polybranched lower alkoxy, 2-substituted 2-oxoethoxy, 2-cyanoethoxy, 2 < S1XS2)(S3ksilylethoxy, in which each of S" S2 and S3 represents lower alkyl or phenyl, 1-phenyl-lower alkoxy having 1--3 phenyl radicals optionally substituted by lower alkoxy and/or nitro, (lower alkanoyl)oxymethoxy, amino (lower alkanoyl)oxymethoxy, 2-phthalidyloxy, pentachlorophenoxy, tri-lower alkylsilyloxy or lower alkenyloxy.

7. A compound of the formula (VIII), according to claim 5, in which R2 represent tert.-butyloxy, acetonyloxy, phenacyloxy, 2-cyanoethoxy, 2 trimethylsilylethoxy, 2-triphenylsilylethoxy, 4-methoxybenzyloxy, 4nitrobenzyloxy, 2 - nitro - 4,5 - dimethoxybenzyloxy, diphenylmethoxy, 4,4r dimethoxydiphenylmethoxy, trityloxy, acetoxymethoxy, pivaloyloxymethoxy, glycyloxymethoxy, 2-phthalidyloxy, pentachlorophenoxy, trimethylsilyloxy or allyloxy.

8. Penicillanic acid methyl ester oxide.

9. A compound of the formula (VIII), according to claim 5, whenever prepared by a process according to any one of claims I to 4.

10. A compound of the formula (VIII), according to any one of claims 5 to 9, whenever used for preparing a compound of the formula

in which Ri represents hydrogen, an organic radical bonded by a carbon atom to the ring carbon atom, or an etherified mercapto group, and R2 represents hydroxy or a radicla RA2 forming together with the carbonyl grouping < (=OW a protected carboxyl group, a oxide thereof, or a salt of such a compound of the formula Ia or its l-oxide having a salt-forming group.