GB1594271A - Penicillin and cephalosporin-1-a-sulphoxides and processes therefore - Google Patents

Description

(54) PENICILLIN AND CEPHALOSPORIN-l-a- SULFOXIDES AND PROCESSES THEREFORE (71) We, CONNLAB HOLDINGS LIMITED, a Canadian Company of 7575 Trans Canada Highway, St. Laurent, Quebec, H4T 1V6, 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 relates to a convenient high yield process for the preparation of penicillin-l-a-suffoxides, 1, and cephalosporin-l-a-sulfoxides, 2.

wherein RCO and R3CO each represent an amino protecting group and may be the same or different, R1 is a carboxy protecting group and R2 is H, Cl, Br, I, -OCH3, -OCOCH3, -OCOH, N3, NO3, CN or phenylamino, and the compounds of formulae I and 2 in which RCO, R3CO, R1 and R2 are as defined above except that R may also be hydrogen, and to the compounds per se.

The compounds of formula 2 have broad-spectrum antibacterial activity and the compounds of formula I are useful intermediates for the synthesis of modified penicillins and cephalosporins.

The penicillins and cephalosporins in which the substituent at C6 or C7, respectively, is an amide functionality or the free amino group, on oxidation with a variety of oxidising agents, give the corresponding 1p- (or S)-sulfoxide as the major, if not the exclusive isomer. This reaction is well known to the art, and the stereospecifity of this oxidation to produce the IX-sulfoxide (by attack at the hindered face of the molecule) has been explained as due to steric approach control in which the hydrogen of the amide(-CONH-) or amine moiety exerts a powerful directing influence on the reaction by hydrogen bonding with the oxidant. Barton et al, J. Am. Chem. Soc., 91, 1529 (1969) found that the use of iodobenzene dichloride as the oxidant resulted in a two-step reaction and in this case produced both the 1ss-(or S-)sulfoxide and the 1α-(or R-)sulfoxide in a ratio of about 1:1. Chromatography was necessary to separate the products. Subsequently, D. O. Spry has shown that mixtures containing varying ratios of l, B-(or S) and la-(or R)sulfoxides are also obtained by treating various penam and cepham derivatives with ozone, see J. Org. Chem. 37, 793 (1972).

In accordance with the suggested directing influence of the C6 or C7 amide or amine functionality, those compounds in which the substituent in the C6 or C7 position does not contain any -NH- protons, on oxidation produce the 1 a-(or R-) sulfoxide almost exclusively. Thus, the 6-phthalimido-penicillins, see D. O. Spry, cited above, the cephalosporin "Schiffs bases", and the cephalosporin 7isocyanates, on oxidation produce the la-(or R-)sulfoxides, as the almost exclusive products and the cephalosporin la-(or R-)sulfoxides, were found to possess broadspectrum antibacterial activities, see de Koning et al., "Recent Advances in the Chemistry of s-Lactam Antibiotics", J. Elks, Ed., The Chemical Society, London 1977. Chapter 17. The isomeric lp-(or S-)sulfoxides on the other hand have either greatly reduced antibacterial activities, see "Cephalosporins and Penicillins", E. H.

Flynn, Ed., Academic Press New York and London 1972, p. 577, or have been reported in British Patent 1,442,993 as being completely devoid of such activities.

A A number of 2-(substituted methyl)-2-methylpenicillins in which the methyl substituent is, for example, Cl, Br, or acetoxy are known, see e.g. Kamiya et al, Tetrahedron Letters 1973, 3001 and Tanida et al., Tetrahedron Letters 1975, 3303.

These compounds have been made by a variety of methods preferentially starting from penicillin sulfoxides and in almost every instance the major, if not the exclusive products from these reactions were the 2p-(substituted methyl) isomers rather than the 2a(substituted methyl) isomers. The nature of the C6-substituent (whether amide or phthalimido) had little effect on the product isomer ratio on most of these reactions. However, it should be noted that Tanida et al. cited above obtained the 2a-chloromethylpenam as the major product and the 2, chloromethylpenam as the minor product in the chlorinative rearrangement of 6 phthalimidopenicillin- 1 a-sulfoxide.

The oxidation of 2-(substituted methyl)-2-methylpenams has not been as thoroughly studied. The available data and out work seem to indicate that the same directive influences are present in these compounds as reported for the corresponding unsubstituted penam derivatives, e.g. by Cooper et al, J. Am. Chem.

Soc. 91, 1528 (1969). Thus, oxidation of the 6-amido-2p-(substituted methyl)-2methylpenams by most oxidizing agents produces the 6-amido-2p-(substituted methyl)-2-methylpenam- 1 p-sulfoxides as the major, if not the exclusive product; while oxidation of the 6-phthalimido-2p-(substituted methyl)-2-methylpenams produces the 6-phthalimido-2p-(substituted methyl)-2-methylpenam- 1 a-sulfoxides, see e.g. D. N. McGregor, Recent Developments in the Chemistry of Penicillins, in "Fortschritte der Chemie Organischer Naturstoffe" 31, 1 (1974).

Certain 6-diacylamidopenicillins have been made by converting a 6amidopenicillin to the corresponding 6-chloroimine using phosphorus pentachloride and a suitable amine such as pyridine or N,N-dimethylaniline, and said 6-chloroimine upon treatment with the salt of an acid under appropriate conditions, is converted to the corresponding 6-diacylamidopenicillin. Said lastnamed compound is easily hydrolysed, one acyl group being extruded, to obtain the corresponding 6-aminopenicillin, in which the acyl group originally present in the starting material has been replaced by another acyl group. This process has been utilised for the conversion of a commercially available penicillin such as penicillin G or V, to the commercial semisynthetic penicillins such as ampicillin or amoxycillin, without going through the usual synthetic intermediate 6aminopenicillanic acid (6-APA), see e.g. Busko-Oszczapowicz et al., Reczniki Chemii 45, 111 (1971), Chem. Abs. 75, 5784s (1971); Abe et al., U.S. Patent 3,668,200, June 6, 1972, Chem, Abs. 77, 88493m (1972): German Offenlegungsschrift 2,016,892, published Oct. 22, 1970; and German Offenlegungsschrift 2,063,985, published July 22, 1971, Chem. Abs. 75, 118310c (1971). The same procedure has also been used with certain cephalosporins to obtain the corresponding 7-diacylamidocephalosporin derivatives. These lastnamed compounds have also been prepared by treating a 7-amidocephalosporin with an acyl halide in a suitable solvent in the presence of a hydrogen halide acceptor such as bis-(trimethylsilyi)acetamide (BSA) or a molecular sieve, see e.g.

British Patent 1,438,422 published June 9, 1976; Weinstock et al., Tetrahedron Letters 1975, 3979; and Japan. Kokai 74-45092, Chem. Abs. 81, 120663n (1974).

According to the present invention there is provided a process for preparing Denicilllin lo-sulfoxides and cephalosporin la-sulfoxides of the formulae I and 2

wherein RCO and R3CO are the same or different and are selected from aminoprotecting groups commonly used in the penicillin and cephalosporin art in which R and R3 are selected from C1-C4 alkyl, cyanomethyl, thienylmethyl, furylmethyl, tetrazolylmethyl, phenylmethyl, phenoxymethyl, phenoxyisopropyl, R4O-, R4S- or R4R6N- wherein R4 is lower alkyl, phenyl, phenylloweralkyl or trichloroethyl, R6 is hydrogen or is the same as R4; a-hydroxybenzyl, a-aminobenzyl or benzyl-acarboxylic acid wherein the a-hydroxy, a-amino or a-carboxylic acid moieties are optionally protected by an easily removable group, R1 is a carboxy protecting group selected from lower alkyl, 2,2,2-trichloroethyl, benzyl, p-nitrophenyl, pmethoxybenzyl, benzhydryl, fluorenyl, phenacyl, methoxymethyl, phenoxymethyl, benzyloxymethyl or trimethylsilyl, and R2 is selected from hydrogen, chloro, bromo, iodo, methoxy, acetoxy, formyloxy, azido, nitro, cyano, and phenylamino, which comprises treating a compound of the formulae 3 or 4.

in solution in a solvent selected from halogenated hydrocarbons containing 1 or 2 carbon atoms and from 2-4 atoms of chlorine or bromine and monocyclic aromatic hydrocarbons containing from 6-8 carbon atoms with an oxidizing agent selected from peracids, hydrogen peroxide, sodium metaperiodate, iodobenzene dichloride, metachloroperbenzoic acid, and ozone, and isolating the corresponding compound of formula I or 2.

(As used herein in relation to an alkyl group, the term "lower" signifies that such group contains 1 to 4 carbon atoms).

It will be evident to those skilled in the art that the nature of the RCO and the R3CO groups is not critical of the process of this invention and that the RCO and R3CO groups may be any of the amino protecting group well known in the penicillin and cephalosporin antibiotic literature. The RCO and R3CO groups can also be any of the amino protecting groups commonly used in peptide synthesis, and particularly an acyl group. More specifically, R and R3 represent C1-C4 alkyl, cyanomethyl, thienylmethyl, furylmethyl, tetrazolylmethyl, phenylmethyl, phenoxymethyl, phenoxyisopropyl, R4O-, R4S- or R4R6N- wherein R4 is lower alkyl, phenyl, phenylloweralkyl, or trichloroethyl, R5 is hydrogen or is the same as R4; a-hydroxybenzyl, a-aminobenzyl or benzyl-a-carboxylic acid wherein the a- hydroxy, a-amino or a-carboxylic acid moieties may be optionally protected by an easily removable group. Numerous other amino protecting groups which are useful in the RCO and R3CO positions are known from the Prior Art, for example those disclosed in Kamiya et al. U.S. Patent 4,009,159 issued Feb. 22, 1977, columns 5 and 6.

The R1 group may be hydrogen or a carboxy protecting group, for example lower alkyl, 2,2,2-trichloroethyl, benzyl, p-nitrophenyl, p-methoxybenzyl, benzhydryl, fluorenyl, phenacyl, methoxymethyl, phenoxymethyl, benzyloxymethyl or trimethylsilyl. Numerous other carboxy protecting groups which are useful in the R1 position are known from the Prior Art, for example those disclosed in Kamiya et al. U.S. Patent 4,009,159 cited above, columns 7 and 8.

The starting materials for the process of this invention, viz., the diacylamido-2 (substituted methyl)-2-methylpenams 3 and the diacylamido-3-(substituted methyl)-cephems 4 in which RCO, R3CO, R1, and R2 are as defined above are prepared as follows.

When it is desired to obtain the diacylamido-2-(substituted methyl)-2methylpenams, 3, an acylamido-2-(substituted methyl)-2-methylpenam of formula 3 in which R3CO represents hydrogen and RCO, R1 and R2 are as defined above is treated with a chlorinating agent in the presence of an organic base to obtain the corresponding chloroimine which is then treated with the salt of an acid of the formula R3COO-M+ in which M+ represents a suitable cation, to yield the corresponding diacylamido-2-(substituted methyl)-2-methylpenam of formula 3 in which RCO, R3CO, R1 and R2 are as defined above. This process is analogous to that described for the preparation of diacylamido-2,2-dimethylpenams, for example by Busko-Oszczapowicz et al., in U.S. Patent 3,668,200, and in German Offenlegungsschrift 2,063,985 and 2,016,892, all cited above.

Alternatively, an acylamido-2,2-dimethylpenam of formula 3 in which R3CO and R2 represent hydrogen and RCO and R1 are as defined above is acylated in the same manner as described above to give the corresponding diacylamido-2,2dimethlypenam of formula 3 in which RCO and R3CO both represent acyl groups as defined above, R2 is hydrogen, and R1 is as defined above. Said last-named compound is treated with an oxidising agent such as metachloroperbenzoic acid or ozone to yield the corresponding la-sulfoxide of formula I in which RCO, R3CO, and R1 are as defined above and R2 is hydrogen. Said last-named compound is heated in the presence of a suitable mercaptan, for example 2mercaptobenzothiazole to yield the corresponding diacylamido-unsym-azetidinone disulfide which upon treatment with a halogenating agent gives the corresponding compound of formula 3 in which RCO, R3CO, and R1 are as defined above and R2 is the corresponding halogen. This alternative is analogous to the process described by Kamiya et al., in Tetrahedron Letters 1973, 3001 cited above.

When it is desired to obtain the diacylamido-3-(substituted methyl)-cephems 4, the appropriate acylamido-3-(substituted methyl)-cephem of formula 4 in which R3CO is hydrogen and RCO, R1 and R2 are as defined above is treated with a chlorinating agent in the presence of a base to give the corresponding chloroimine which is in turn reacted with the salt of an acid of the formula R3COO-M+ in which M+ represent a suitable cation, to yield the corresponding diacylamido-3 (substituted methyl)-cephem 4. Alternatively, an acylamido-3-(substituted methyl)cephem of formula 4 in which RCO, R', and R2 are as defined above and R3CO is hydrogen is treated with an acyl halide, preferably an acyl chloride or bromide of the formula R3COCI or R3COBr in the presence of a hydrogen halide acceptor such as bis-(trimethylsilyl)-acetamide (BSA) or of a molecular sieve, to yield the corresponding compound of formula 4 in which RCO, R3CO, R1 and R2 are as defined above.

The above diacylamidopenams of formula 3 and the diacylamidocephems of formula 4 are treated with an oxidising agent such as metachloroperbenzoic acid.

When the reaction is carried out in solution in one of the solvents normally employed for this type of reaction, viz., in a halogenated hydrocarbon such as chloroform or methylene chloride, a mixture of the corresponding sulfoxides is obtained in which the corresponding la-sulfoxide is the major constituent which can be isolated by crystallization, and the corresponding l-sulfoxide is the minor constituent. However, when the above oxidation with metachloroperbenzoic acid is carried out in an aromatic hydrocarbon solvent such as benzene, toluene, or xylene, preferably in benzene, it ~ has been found surprisingly that the corresponding diacylamidopenam la-sulfoxides I and the corresponding diacylamidocephem la-sulfoxides 2 are obtained almost exclusively.

The diacylamido la-sulfoxides of formulae I or 2 are easily converted into other compounds by means of processes known per se. For example, the compound of formula 2 in which RCO and R3CO are both phenylacetyl, R1 is benzhydryl, and R2 is hydrogen is transformed into the corresponding mono-acylated compound of formula 2 in which R3CO is hydrogen, by treatment with formic acid, to yield the corresponding cephalosporin; la-sulfoxide of formula 2 in which RCO is phenylacetyl, R3CO, R1, and R2 are all hydrogen and which is useful as a broadspectrum antibacterial agent. A large number of such cephalosporin la-sulfoxides has been found to possess broad spectrum antibacterial activities, see de Koning et al, cited above. Moreover, we have also found that certain diacylamido compounds of formula 2 in which R1 and R2 are hydrogen have useful broad-spectrum antibacterial activities.

The diacylamido la-sulfoxides of formula 1 are equally conveniently transformed into the corresponding monoacylamido la-sulfoxides, and the compounds of formula 1 in which RCO is as defined above the R3CO, R1 and R2 are all hydrogen have broad-spectrum antibacterial activities, see British Patent 1,442,993 cited above. Moreover, the compounds of formula I are useful as intermediates in the synthesis of commercially important antibiotics, as follows.

Using a procedure analogous to that described by Kukolja et al., in J. Am.

Chem. Soc. 98, 5040 (1976), a compound of formula 1 in which RCO, R3CO, and R1 are as defined above and R2 is hydogen, or the corresponding compound of formula I prepared therefrom in which R3CO is hydrogen, is heated in solution in carbon tetrachloride with N-chlorosuccinimide to give the corresponding sulfinyl chloride which, upon treatment with SnCl4, gives the corresponding 3exomethylenecepham la-sulfoxide which is treated with PBr, to yield the corresDondinp 3-exomethvleneceDham. Alternatively and using a procedure analogous to that described by kukolja et al, in J. Org. Chem, 41, 2276 (1976), a compound of formula I in which RCO, R3CO, and R1 are as defined above and R2 is chlorine is heated in solution in benzene with 2mercaptobenzothiazole to obtain the corresponding 4-(2'-benzothiazolyldithio)-3 RCO-3-R3CO - 1 - [1' -(R' -oxycarbonyl)- 2' -chloromethylprop -2' -enyl]- azetidin - 2 - one. Said last-named compound is heated with potassium iodide, to yield the corresponding 3-exomethylenecepham. That last-named compound is a key intermediate in the synthesis of various 3-substituted cephalosporin antibiotics, as shown in some of the references cited by Kukolja et al. in the papers cited above.

For example, the 3-exomethylenecepham obtained above is treated with ozone to give the corresponding 3-hydroxycephem, which is in turn treated with phosphorus pentachloride to yield the corresponding 3-chlorocephem derivative. Removal of the amino-protecting groups RCO and R3CO in the conventional manner and replacement by the phenylglycyl moiety, followed by removal of the carboxyprotecting group R1, gives the commercially important antibiotic Cefaclor, see Drugs of the Future, Vol. II, No. 6, p.368.(1977).

The processes for preparing penicillin-l-sulfoxides from commercially available starting materials described in the Prior Art cited above are known to yield mixtures of la- and lp-sulfoxides which usually have to be separated by the laborious method of column chromatography. Moreover, the yields of the desired la-sulfoxides are usually not satisfactory, except when using a 6phthalimidopenicillins as starting material. however, the 6-phthalimidopenicillins are made from 6-APA which is in turn obtained from penicillin G or V via the 6chloroimine. This adds to the number of stages in the overall process, lowering the overall yield and increasing the total cost. Moreover, the 6-phthalimido-penicillins or 7-phthalimidocephalosporins are biologically inactive. Hence in cases where a phthalimido compound is employed it is necessary in the final stages to remove the phthalimido group and replace it by a more suitable amide moiety. There is at present no known convenient high-yield process for the removal of the phthalimido group. The usual process employs hydrazine or similar compounds which also cleave the p-lactam ring. As a result, the overall process employing a phthalimido group is inefficient and relatively expensive.

It is a particular advantage of the process of this invention that it provides the desired la-sulfoxides of formulae 1 and 2 in excellent yields and without having to use laborious separation methods such as column chromatography. In addition, the process of this invention offers the possibility of carrying out an "acyl switch", i.e. the acyl group RCO initially present in the starting material may be removed selectively without affecting the acyl group R3CO, similar to the procedures disclosed for certain penicillin derivatives e.g. in U.S. Patent 3,668,200 and in German Offenlegungsschrift 2,016,892, both cited above, or the procedure disclosed for certain cephalosporin derivatives e.g. in British Patent 1,438,422, also cited above. In this manner a comparatively undesirable acyl group, e.g. RCO, i.e., an acyl group which imparts for example a low degree of antibacterial activity or a low degree of antibiotic selectively or a low degree of stability to the final product, may be removed and replaced by a more desirable acyl group, e.g. R3CO, which will give a more active, a more selective, or a more stable final product. Such an "acyl switch" may be effected without adding any extra steps to the overall process for preparing certain penicillin or cephalosporin antibiotics when using the compounds of formulae I or 2 as intermediates.

In accordance with the process of this invention, the compounds of formulae I and 2 may, according to preferred procedures, be prepared as follows.

A diacylamidopenam derivative of formula 3 or a diacylamidocephem derivative of formula 4 in which RCO, R3CO, R1 and R2 are as defined in the first instance is treated in solution in a halogenated hydrocarbon containing I or 2 carbon atoms and from 2--4 atoms of chlorine or bromine, or in a monocyclic aromatic hydrocarbon solvent containing from 6-8 carbon atoms such as benzene, toluene, or xylene with an oxidising agent such as a peracid, hydrogen peroxide, sodium metaperiodate, iodobenzene dichloride, metachloroperbenzoic acid, or ozone, with the last-named being useful only in the case of the diacylamidopenam derivatives of formula 3. Benzene as the solvent and metachloroperbenzoic acid as the oxidant are the preferred agents for the above reaction. The reaction is carried out at temperatures in the range of 0"--30"C, preferably at about 20"C, for periods of time of from 1060 minutes, preferably for 2030 minutes, using substantially one molar equivalent of the oxidising agent, preferably metachloroperbenzoic acid, per mole of diacylamidopenam derivative 3 or of diacylamidocephem derivative 4. Washing the reaction mixture with aqueous sodium bisulfite, then with aqueous sodium bicarbonate and with brine followed by drying and evaporation of the solvent gives mixtures of the corresponding Ia- and lp-sulfoxides when using a halogenated hydrocarbon solvent as defined above, and said mixtures are separated by crystallization or by column chromatography.

However, when using an aromatic hydrocarbon solvent as defined above, we have found surprisingly that only the corresponding diacylamidopenam la-sulfoxides of formula I and the corresponding diacylamidocephem la-sulfoxides of formula 2, respectively, are obtained. Said last-named compounds may be used for further reactions in the state of purity in which they are obtained as described above, or they may be purified by crystallization or by column chromatography.

The stereochemistry of the above compounds of formulae I and 2 as being l cw- sulfoxides has been established by their respective nmr spectra. Moreover, the stereochemistry of the diacylamidopenam la-sulfoxides of formula I in which R2 is other than hydrogen has also been pnequivocally established by their conversion to allylic compounds upon thermolysis in the presence of a mercaptan such as 2mercaptobenzothiazole, by their conversion to allylic sulfinyl chlorides or sulfinyl bromides upon treatment with N-chlorosuccinimide or N-bromosuccinimide by using procedures which are known per se, and by their conversion to allylic thiol esters upon treatment with trimethyl phosphite.

The diacylamidopenam derivatives of formula 3 and the diacylamidocephem derivatives of formula 4 are obtained from the corresponding monoacylamidopenam or -cephem derivatives, i.e., the compounds of formulae 3 and 4, respectively, in which R3CO is hydrogen, by treating the latter with phosphorus pentachloride in the presence of an organic base as hydrogen halide acceptor, to obtain the corresponding chloroimine. The reaction is preferably carried out with cooling in an ice bath, using slightly more than one molar equivalent of PCl5 and 4-5 molar equivalents of the organic base, preferably pyridine, per mole of monoacylamido-penam or -cephem derivative. Washing the reaction mixture with cold aqueous sodium bicarbonate, brine, water, aqueous cupric sulfate, brine or water, followed by drying and evaporation of the solvent gives the corresponding chloroimine which is dissolved in an aromatic hydrocarbon such as benzene or toluene and stirred at 30--700C, preferably at about SO"C, for 1--24 hours with the salt of an acid of the formula R3COO-M+ in which M+ is a suitable cation, for example Na+. Washing the reaction mixture with aqueous bicarbonate, drying, and evaporating the solvent gives the corresponding diacylamido-penam or -cephem derivative of formulae 3 or 4, respectively. The procedure is analogous to that described e.g. by Busko-Oszczapowicz et al, in U.S. Patent 3,668,200, and in German Offenlegungsschrift 2,063,985, all cited above.

Alternatively, the compounds of formula 3 in which R2 is a halogen and RCO, R3CO, and R1 are as defined above may also be obtained by a modification of the method described by Kamiya et al. in Tetrahedron Letters 1973, 3001 cited above, as follows. A monoacylamidopenam derivative of formula 3 in which R3CO and R2 are hydrogen and RCO and R1 are as defined above is acylated in the manner described above to give the corresponding diacylamidopenam derivative of formula 3 in which R2 is hydrogen and RCO, R3CO, and R1 are as defined above.

Said last-named compound is treated with an oxidizing agent as defined above, preferably metachloroperbenzoic acid, under the same conditions as described above, to obtain the corresponding diacylamidopenam la-sulfoxide of formula I in which RCO, R3CO, and R1 are as defined above and R2 is hydrogen. Heating of the above compound in solution in an aromatic hydrocarbon solvent, preferably toluene, with a suitable mercaptan, preferably 2-mercaptobenzothiazole, for 2-7 hours, preferably for about 4 hours, gives the corresponding diacylamido-unsvm azetidinone disulfide. Said last-named compound is treated with a halogenating agent, such as bromine or chlorine in solution in a halogenated hydrocarbon, preferably methylene dichloride, to obtain the corresponding 2P- bromomethylpenam or 2p-chloromethylpenam derivatives, respectively, i.e. the compounds of formula 3 in which RCO, R3CO, and R1 are as defined above and R2 is chlorine or bromine, respectively.

As another alternative, the diacylamidocephem derivatives of formula 4 are also obtained by treating a monoacylamido-cephem derivative of formula 4 in which R3CO is hydrogen and RCO, R1, and R2 are as defined above in solution in a solvent with an acyl halide of the formula R3COX in which X is chlorine or bromine in the presence of a hydrogen halide acceptor such as bis-(trimethylsilyl) acetamide (BSA) or of a molecular sieve in a manner analogous to the procedure described by Weinstock et al. cited above. Preferred conditions include the use of a halogenated hydrocarbon solvent as defined above, e.g. 1,2-dichloroethane; using 3-4 molar equivalents of the acid halide of the formula R3COX per mole of mono acylamidocephem derivative; using finely powdered molecular sieve 4A (Baker Analyzed Chemicals), about 4 parts by weight per part of monoacylamidocephem derivative and heating the reaction mixture under nitrogen to 50--800C, preferably to 60-650C, for periods of time of from one to several days, preferably for about 5 days. Cooling to room temperature, filtering, stirring the filtrate at about 0 C with a large excess of saturated aqueous sodium bicarbonate, extracting with a water immiscible solvent, preferably ethyl acetate, and evaporation of the solvent gives the corresponding diacylamidocephem derivative of formula 4 which may be purified by chromatography on a column of si monoacylamidopenam derivatives, by reacting a corresponding compound in which R2 is e.g. chlorine or bromine with a suitable nucleophile, e.g. sodium methoxide, sodium azide, silver nitrate, sodium cyanide, or aniline; in this manner the corresponding monoacylamidocephem derivatives in which R2 is methoxy, azido, nitro, cyano, or phenylamino are obtained, respectively.

The compounds of formulae I and 2 obtained as described above, quite apart from being capable of undergoing the reactions described above as proof of their stereochemistry as 1 a-sulfoxides, are also capable of being transformed into related compounds by procedures known per se.

For example, the compound of formula 2 in which RCO and R3CO are both phenylacetyl, R1 is benzhydryl, and R2 is hydrogen is treated with benzylamine in toluene solution at room temperature to give the corresonding monophenylacetyl derivative of formula 2 in which RCO and R1 are as defined immediately above and R3CO and R2 are both hydrogen; said last-named compound upon treatment with concentrated, e.g. 97% formic acid at room temperature gives the corresponding free acid, i.e. the compound of formula 2 in which RCO is phenylacetyl and R3CO, R1, and R2 are all hydrogen.

Similarly, the compound of formula 2 in which RCO and R3CO are both phenylacetyl, R1 is benzhydryl, and R2 is hydrogen is treated with trifluoracetic acid at room temperature to give the corresponding free acid of formula 2 in which RCO and R3CO are both phenylacetyl and R1 and R2 are both hydrogen.

Again similarly, the compound of formula 2 in which RCO and R3CO are both phenylacetyl, R1 is methyl, and R2 is hydrogen is treated with benzylamine in benzene solution at room temperature, to give the corresponding monophenylacetyl compound of formula 2 in which RCO, R1, and R2 are as defined immediately above and R3CO is hydrogen.

It is well known that concentrated acids at room temperature will remove a carboxy-protecting group such as a benzhydryl ester group from certain cephem derivatives in the manner illustrated above. However, we have found surprisingly that concentrated, e.g. 97% formic acid used at room temperature will also remove one acyl groups from a diacylamidocephem la-sulfoxide of formula 2. For example, the compound of formula 2 in which RCO and R3CO are both phenylacetyl, R1 is benzhydryl, and R2 is hydrogen yields, upon treatment with 97% formic acid at room temperature, a mixture of the corresponding diacylamido free acid, i.e. the compound of formula 2 in which RCO and R3CO are both phenylacetyl and R1 and R2 are both hydrogen, and the corresponding monoacylamido free acid, i.e. the compound of formula 2 in which RCO is phenylacetyl and R3CO, R1, and R2 are all hydrogen.

The diacylamidocephem la-sulfoxides of formula 2 have useful antibacterial activities against a representative number of gram-positive and gram-negative microorganisms, including both penicillin-sensitive and penicillin-resistant strains of Staphylococcus aureus. Similar activities have also been found for certain monoacylamidocephem la-sulfoxides, e.g. for the compound of formula 2 in which RCO is phenylacetyl, and R3CO, R', and R2 are all hydrogen. The starting material of formula 4 in which RCO is phenylacetyl and R3CO, R1, and R2 are all hydrogen has also been found to possess similar activities, although of a lower order.

The following formulae and Examples I to 5 and 11 to 17 illustrate this invention. Examples 6 to 10 illustrate the use of the compounds of the invention.

EXAMPLE I Trichloroethyl 6-di-(phenylacetyl)amino-2,2-dimethylpenam-3-carboxylate A mixture of the trichloroethyl ester of penicillin G (11.392 g., 24.5 mmole), and pyridine (8.2 ml., 100 mmole) in benzene (60 ml) was cooled in an ice-bath, and phosphorus pentachloride (5.203 g., 25 mmole) was added in portions during a period of 30 mins. After stirring at ice temperature for 1 hr, a tlc (silica plate, ethyl acetate: benzene=3:7, one homogeneous spot) showed no starting material. The precipitate was filtered and washed with benzene. The combined filtrates were washed in sequence with ice-cold aqueous sodium bicarbonate, then brine, water, aqueous cupric sulfate and brine, and dried (Na2SO4). Filtration and concentration gave the penicillin 6-chloroimine as a brown foam (tlc still one spot). The crude product was immediately dissolved in benzene (60 ml) and sodium phenylacetate (3.871 g., 24.5 mmole) added and the mixture stirred at 500 overnight. The crude reaction mixture was washed with ice cold aqueous sodium bicarbonate, then brine. The organic layer was dried (Na2SO4), filtered and concentrated, to give the crude product as a foam. The tlc (silica plate, ethyl acetate: benzene=3:7) showed two spots, the minor one with lower Rf value identical with the original penicillin G ester. Column chromatography on a silica gel column (benzene, 20% ethyl acetate in hexane) gave the two separated products. There was thus obtained 6.905 g. (54%) of the title compound, along with 1.304 g. of the starting penicillin G ester. The nmr (CDCl3) spectrum: 61.57 (d, 6H, gem-CH3), 4.0 (s, 4H, JCH2CO), 4.62 (s, 1H, C3- H), 4.73 (q, 2H, -CH2CCl3), 5.28 (q, 2H, p-lactam C5 and C6-H), 7.1 to 7.35 (m, 10H, C6H5) is consistent with the assigned structure.

In the same manner, but using sodium or potassium phenoxyacetate, 2thienylacetate, or l-tetrazolylacetate instead of sodium phenylacetate, and using the methyl or the benzhydryl ester of penicillin G instead of the trichloroethyl ester as starting material, the following 2,2-dmethylpenam-3-carboxylates are obtained, respoectively: methyl[ 6-(phenylacetyl. phenoxyacetl)amino- methyl 6-(phenylacetyl, 2-thienylacetyl)amino-, methyl 6-(phenylacetyl, I-tetrazolylacetyl)amino-, benzhydryl 6-(phenylacetyl, phenoxyacetyl)amino-, benzhydryl 6-(phenylacetyl, 2-thienylacetyl)amino-, benshydryl 6-(phenylacetyl, I -tetrazolylacetyl)amino.

EXAMPLE 2 Trichloroethyl 6-di-(phenylacetyl)amino-2ss-chloromethyl-2α-methylpenam-3- carboxylate A solution of trichloroethyl 6-phenylacetamido-2ss-chloromethyl-2α- methylpenam-3-carboxylate (1.047 g., 2.094 mmoles), and pyridine (0.068 ml., 8.376 mmole) in benzene (20 ml) was cooled in an ice bath and phosphorus pentachloride (0.436 g., 2.1 mmole) was added. The mixture was stirred at 0 for 30 minutes, and the reaction mixture extracted with ice cold aqueous potassium bicarbonate, then brine, then aqueous cupric sulfate, and concentrated to give the crude penicillin 6chloroimine (tlc one spot) as a pale brown foam, 1.068 g. (nmr consistent with the assigned structure).

The crude product was dissolved in anhydrous toluene (10 ml) and sodium phenylacetate (0.316 g) added and the mixture stirred at 500C under nitrogen for I hr. The tIc showed two spots, the one with lower Rf value corresponding to the starting material. The reaction mixture was concentrated, the residue taken up in methylene chloride and the solution washed with ice cold aqueous potassium bicarbonate, dried (Na2SO4), filtered and concentrated to give the crude product as a pale brown foam. Chromatography (silica gel column, 2.5 ethyl acetate in methylene chloride) gave 0.236 of the starting penicillin ester and 901 mg (90%) of the title compound. The nmr (CDCl3) spectrum: S1.6 (s, 3H, C2-CH3), 3.7 (q, 2H, C2-CH2Cl), 4.0 (s, 4H, sCH2CO), 4.72 (s, 2H, CH2CCl3), 5.05 (s, 1H, C3- H), 5.1 to 5.33 (m, 2H plactam C6 and C,--H), 7.18 to 7.46 (m, 10H, C6-H5), is consistent with the assignment.

In the same manner, but using sodium or potassium phenoxyacetate, 2thienylacetate, or l-tetrazolylacetate instead of sodium phenylacetate, and using the 2ss-bromomethyl-2ss-iodomethyl-, 2pmethoxymethyl-, 2B-acetoxymethyl-, 2B- azidomethyl-, 2B-cyanomethyl-, or 2B-phenylaminomethyl analogs of the starting material, and additionally using the methyl or the benzhydryl esters thereof instead of the trichloroethyl ester, the following trichloroethyl, methyl, or benzhydryl 2a- methylpenam-3-carboxylates are obtained, respectively: 6-di-(phenylacetyl)amino-2p-bromomethyl- 6-di-(phenylacetyl)amino-2ss-iodomethyl-, 6-di-(phenylacetyl)amino-2ss-methoxymethyl-, 6-di-(phenylacetyl)amino-2ss-acetoxymethyl-, 6-di-(phenylacetyl)amino-2ss-azidomethyl-, 6-di-(phenylacetyl)amino-2ss-cyanomethyl-, 6-di-(phenylacetyl)amino-2ss-phenylaminomethyl-, 6-(phenylacetyl, phenoxyacetyl)amino-2ss-bromomethyl-, 6-(phenylacetyl, phenoxyacetyl)amino-2ss-iodomethyl-, 6-(phenylacetyl, phenoxyacetyl)amino-2ss-methoxymethyl-, 6-(phenylacetyl, phenoxyacetyl)amino-2p-acetoxymethyl-, 6-(phenylacetyl, phenoxyacetyl)amino-2p-azidomethyl-, 6-(phenylacetyl, phenoxyacetyl)amino-2p-cyanomethyl-, 6-(phenylacetyl, phenoxyacetyl)amino-2ss-phenylaminomethyl-, 6-(phenylacetyl, 2-thienylacetyl)amino-2p-bromomethyl-, 6-(phenylacetyl, 2-thienylacetyl)amino-2p-iodomethyl-, 6-(phenylacetyl, 2-thienylacetyl)amino-2P-methoxymethyl-, 6-(phenylacetyl, 2-thienylacetyl)amino-2p-acetoxymethyl-, 6-(phenylacetyl, 2-thienylacetyl)amino-2p-azidomethyl-, 6-(phenylacetyl, 2-thienylacetyl)amino-24-cyanomethyl-, 6-(phenylacetyl, 2-thienylacetyl)amino-2ss-phenylainomethyl-, 6-(phenylacetyl, 1-tetrazolylacetyl)amino-2ss-bromomethyl-, 6-(phenylacetyl, 1-tetrazolylacetyl)amino-2ss-iodomethyl-, 6-(phenylacetyl, 1-tetrazolylacetyl)amino-2ss-methoxymethyl-, 6-(phenylacetyl, 1 -tetrazolylacetyl)amino-2p-acetoxymethyl 6-(phenylacetyl, I -tetrazolylacetyl)amino-2p-azidomethyl-, 6-(phenylacetyl, I-tetrazolylacetyl)amino-2P-cyanomethyl- 6-(phenylacetyl, l-tetrazolylacetyl)amino-2P-phenylamino EXAMPLE 3 Mixture of Trichloroethyl 6-di(phenylacetyl)amino-2,2- dimethylpenam-3-carboxylate Ia- and Ip-sulfoxides m-Chloroperbenzoic acid (101 mg., of 85% purity, 0.5 mmole) was added to a stirred ice-cold solution of trichloroethyl 6-di(phenylacetyl)amino-2,2- dimethylpenam-3-carboxylate (292 mg., 0.5 mmole) in methylene dichloride (6 ml).

After 20 mins. at OOC, the tIc of the reaction mixture showed no starting material to be present. The reaction mixture was extracted sequentially with ice-cold aqueous 5% sodium bisulfite, saturated sodium bicarbonate, and brine, then dried (Na2SO4) and concentrated to give 281 mg., of the crude product as a pale yellow foam. The tIc (silica plate, ethyl acetate: benzene=3:7) and nmr (CDCl3) spectrum indicated that the product was an approximately 1:1 mixture of the Ia- and Ip-sulfoxides which was separated by silica gel column chromatography.

EXAMPLE 4 Trichloroethyl 6-di(phenylacetyl)amino-2,2-dimethylpenam-3- carboxylate l-a-sulfoxide m-Chloroperbenzoic acid (55 mg. of 85% purity, 0.25 mmoles) was added to a well stirred solution of trichloroethyl 6-di(phenylacetyl)amino-2,2-dimethylpenam- 3-carboxylate (146 mg., 0.25 mmole) in benzene (5 ml) at room temperature. After 30 mins, the tIc showed no starting material, only one major spot, viz., the lasulfoxide, and trace amounts of the Ip-sulfoxide. The reaction mixture was stirred with aqueous 5% sodium bisulfite and extracted with benzene. The combined benzene layers were extracted in sequence with saturated sodium bicarbonate, then brine, and dried (Na2SO4). Filtration and concentration gave 114 mg. of the crude product as a pale yellow foam. The tIc and nmr (CDCl3) spectrum showed that the crude material consisted of the title compound with trace amounts of the Ipsulfoxide. It was used as such in further reactions or purified by crystallisation or column chromatography.

The reaction was repeated using 5.750 g. (9.862 mmole) of the diacylpenam, and gave after work-up 6.552 g. of the crude title compound which was purified by crystallisation and had nmr (CDCl3) #1.27 (s, 3H), 1.72 (s, 3H), 4.07 (s, 4H), 4.22 (d, 1H, J=4Hz), 4.58 (ABq, 2H, J=10Hz), 4.78 (s, 1H), 5.35 (d, 1H, J=4Hz), 7.20 (m, 10H), in accordance with the assigned structure.

In the same manner, but using as starting materials methyl 6di(phenylacetyl)amino-2,2-dimethylpenam-3-carboxylate, p-nitrobenzyl 6di(phenylacetyl)amino-2,2-dimethylpenam-3-carboxylate, methyl 6-(phenylacetyl, phenoxyacetyl)amino-2,2-dimethylpenam-3carboxylate, trichloroethyl 6-(phenylacetyl, phenoxyacetyl)amino-2,2-dimethylpenam-3carboxylate, methyl 6-di(phenoxyacetyl)amino-2,2-dimethylpenam-3-carboxylate, or trichloroethyl 6-(phenylacetyl, 2-thienylacetyl)amino-2,2-dimethylpenam-3carboxylate the following la-sulfoxides are obtained, respectivel: methyl 6-di(phenylacetyl)amino-2,2-dimethylpenam-3-carboxylate 1 a- sulfoxide, p-nitrobenzyl 6-di(phenylacetyl)amino-2,2-dimethylpenam-3-carboxylate Ia- sulfoxide, methyl 6- (phenylacetyl, phenoxyacetyl)amino-2,2-dimethylpenam-3carboxylate la-sulfoxide, trichloroethyl 6- (phenylacetyl, phenoxyacetyl)amino - 2,2 dimethylpenam-3-carboxylate 1α-sulfoxide, methyl 6 - di(phenoxyacetyl)amino - 2,2 - dimethylpenam - 3 - carboxylate 1α - sulfoxide, and trichloroethyl 6-(phenylacetyl, 2-thienylacetyl)amino - 2,2 -dimethylpenam - 3 - carboxylate Ia - sulfoxide.

EXAMPLE 5 Trichloroethyl 6-di(phenylacetyl)amino-2ss-chloromethyl-2α- methylpenam-3-carboxylate 1α-sulfoxide m-Chloroperbenzoic acid (156 mg., 85% pure, 0.77 mmole) was added to a stirred solution of trichloroethyl 6-di(phenylacetyl)amino-2p - chloromethyl - 2a - methylpenam - 3 - carboxylate (486 mg., 0.77 mmole, prepared as described in Example 2) in benzene (12 ml). After 20 mins the tIc showed no starting material and the presence of one major isomer, the Ia - sulfoxide, with trace amounts of the Ip-sulfoxide. Work-up as described in Examples 3 and 4 gave the crude product (420 mg) as a pale brown foam, sufficiently pure for further reactions. The compound was purified by a column chromatography. The nmr (CDCI) spectrum: 81. 36 (s, 3H, C2-CH3), 4.02 (s, 6H, CH2 and -CH2Cl), 4.20 [d, 5=4 c/s, I H, C5 (or C6) -H], 4.69 (q, 2H, CH2CCI3), 4.78 (s, lH, C3-H), 5.33 Id, 5=2 c/s, IH, C6-(or C5)-H], 6.91 to 7.31 (m, 10H, C6H5), is consistent with the assigned structure.

The experiment was repeated using 1.235 g., (2 mmole) of the diacylpenam, and gave 1.296 g., of the la-sulfoxide as a very light brown foam.

The stereochemistry of the sulfoxide (la- or R-sulfoxide) is also established conclusively from the exclusive formation of the allylic compounds on thermolysis in the presence of a mercaptan as shown in Example 7.

In the same manner, but using as starting materials: trichloroethyl 6 - di(phenylacetyl)amino - 2ss - bromomethyl- - 2α - methylpenam - 3 - carboxylate, trichloroethyl 6 - di(phenylacetyl)amino - 2ss - iodomethyl - 2α - methylpenam - 3 - carboxylate, trichloroethyl 6-di di(phenylacetyl)amino - 2p - acetoxymethyl- 2a - methylpenam - 3 - carboxylate, methyl 6-di di(phenylacetyl)amino - 2 - acetoxymethyl - 2a - methylpenam - 3 - carboxylate, methyl 6 - (phenylacetyl, phenoxyacetyl)amino - 2ss - acetoxymethyl - 2α - methylpenam - 3 - carboxylate, trichloroethyl 6 - (phenylacetyl, phenoxyacetyl)amino - 2ss - chloromethyl 2α - methylpenam - 3 - carboxylate, trichloroethyl 6 - (phenylacetyl, phenoxyacetyl)amino - 2ss - acetoxymethyl 2α - methylpenam - 3 - carboxylate, methyl 6-di di(phenoxyacetyl)amino - 2 - acetoxymethyl - 2a - methylpenam - 3 - carboxylate, methyl 6-di di(phenoxyacetyl)amino - 2 - chloromethyl - 2a - methylpenam - 3 - carboxylate, trichloroethyl 6 - (phenylacetyl, 2 - thienylacetyl)amino - 2ss chloromethyl - 2α - methylpenam - 3 - carboxylate, trichloroethyl 6 - (phenylacetyl, 2 - thienylacetyl)amino - 2ss - acetoxymethyl 2α - methylpenam - 3 - carboxylate, trichloroethyl 6 - (phenylacetyl, 1 - tetrazolylacetyl)amino - 2ss chloromethyl - 2α - methylpenam - 3 - carboxylate, and trichloroethyl 6 - (phenylacetyl, 1 - tetrazolylacetyl)amino - 2ss acetoxymethyl- 2a - methylpenam- 3 - carboxylate, the following la sulfoxides are obtained, respectively: trichloroethyl 6-di(phenylacetyl)amino-2ss-bromomethyl-2α - methylpenam 3 - carboxylate la-sulfoxide, trichloroethyl 6-di(phenylacetyl)amino-2ss-iodomethyl - 2α - methylpenam 3 - carboxyalte 1α - sulfoxide, trichloroethyl 6 - di(phenylacetyl)amino-2ss - acetoxymethyl - 2α - methylpenam - 3 - carboxylate 1α - sulfoxide, methyl 6-di di(phenylacetyl)amino - 2 - acetoxymethyl - 2a - methylpenam - 3 - carboxylate la-sulfoxide, methyl 6-(phenylacetyl, phenoxyacetyl)amino - 2ss - acetoxymethyl - 2α - methylpenam - 3 - carboxylate 1α - sulfoxide, trichloroethyl 6 - (phenylacetyl, phenoxyacetyl)amino - 2ss - chloromethyl 2α - methylpenam - 3 - carboxylate 1α - sulfoxide, trichloroethyl 6 - (phenylacetyl, phenoxyacetyl)amino - 2ss - acetoxymethyl 2α - methylpenam - 3 - carboxylate 1α - sulfoxide, methyl 6-di di(phenoxyacetyl)amino - 2ss - acetoxymethyl - 2α - methylpenam - 3 - carboxylate 1α - sulfoxide, methyl 6-di(phenoxyacetyl)amino - 2ss - chloromethyl - 2α - methylpenam 3 - carboxylate 1α - sulfoxide, trichloroethyl 6-(phenylacetyl, 2-thienylacetyl)amino-2ss - chloromethyl 2a - methylpenam -3-carboxylate Ia - sulfoxide, trichloroethyl 6 - (phenylacetyl, 2-thienylacetyl)amino - 2ss - acetoxymethyl 2α - methylpenam - 3 - carboxylate 1α - sulfoxide, trichloroethyl 6 - (phenylacetyl, 1-tetrazolylacetyl)amino - 2ss - chloromethyl 2α - methylpenam - 3 - carboxylate 1α - sulfoxide, and trichloroethyl 6-(phenylacetyl, 1- tetrazolylacetyl)- amino - 2p - acetoxymethyl -2a-methylpenam -3-carboxylate Ia - sulfoxide.

EXAMPLE 6 Trichloroethyl 3-di-(phenylacetyl)amino-4-(2-benzothiazolyl disulfide)-azetidinone-1-isopropenylacetate A solution of crude trichloroethyl 6 - di(phenylacetyl)-amino-2,2dimethylpenam - 3 - carboxylate 1α - sulfoxide (114 mg., 0.19 mmole) obtained from the experiment described in Example 4, and 2-mercaptobenzothiazole (33 mg., 0.19 mmole) in benzene (4 ml) was heated under reflux for 30 mins, by which time a tle indicated complete reaction had occurred. The reaction mixture was concentrated to give the crude title compound as a gum.

The reaction was repeated using 6.552 g. of the same starting material as above and 1.680 g. (9.861 mmole) of 2-mercaptobenzothiazole in benzene (40 ml) with heating under reflux for 1 hr. Concentration gave the crude product as a pale brown foam. Crystallization from ether gave 3.797 g. (1st crop), and 0.151 g. (2nd crop), total 3.948 g (54.6% overall from the diacylpenam) of the pure title compound, The nmr (CDCl3) spectrum # 2.26 (s, 3H, -CCH), 3.9 to 4.62 (br, m, 4H, #CH2), 4.97 (q, 2H, CH2CCl3), 5.32 to 5.47 (s, m, 3H, CHCOOCH2CCl3 and -C=CH2), 5.55 (d, 1H, ss - lactam proton), 5.92 (d, 1H, ss - lactam proton), 7.3 to 8.1 (m, 14H, aryl H) is consistent with the assigned structure.

EXAMPLE 7 Trichloroethyl 3-di-(phenylacetyl)amino-4-(2-benzothiazolyl disulfide)-azetidinone- 1 -(2'-chloromethylvinyl)acetate A sample of crude trichloroethyl 6.di(phenylacetyl)-amino - 2/3 chloromethyl - 2a - methylpenam - 3 - carboxylate la-sulfoxide (1.296 g) obtained fr6m the experiment described in Example 5 was dissolved in benzene (15 ml), 2 - mercaptobenzothiazole (334 mg. 2 mmole) added and the stirred solution heated under reflux for 30 mins, by which time a tlc indicated complete reaction.

The reaction mixture was taken to dryness, when the crude title compound (1.597 g) was obtained as a brown foam. Chromatography on a silica gel column, using 5% ether in methylene chloride, gave 786 mg. of the pure title compound (50% overall yield from the starting penicillin). The nmr (CDCl3) spectrum showed no C-CH3 signals, confirming the structure -of the starting penicillin sulfoxide as the 2/3 chloromethyl - Ia - sulfoxide. The nmr (CDCl3) spectrum a 3.7 to 4.4 (m, 6H, CH2- and -CH2Cl), 4.78 (q, 2H, CH2CCI3), 5.35 to 5.55 (m, 3H, CHCOOCH2CCl3 and -C=CH2). 5.58 to 5.7 (m, 2H, A-lactam protons), 7.15 to 7.9 (m, 14H, aryl H) is consistent with the assigned structure.

EXAMPLE 8 Trichloroethyl 3-di(phenylacetyl)aminoazetidinone-4-sulfinyl chloride-l-p-chloromethylvinylacetate N-Chlorosuccinimide (34 mg., 0.25 mmole) was added to a solution of trichloroethyl 6-di(phenylacetyl)amino-2ss-chloromethyl-2α-methylpenam - 3 carboxylate 1α - sulfoxide (see Ex. 5, 158.5 mg, 0.25 mmole) in carbon tetrachloride (5 ml) and the mixture stirred and heated in a nitrogen atmosphere under reflux for 30 mins. The reaction mixture was cooled, the succinimide removed by filtration and the filtrate concentrated to give the title compound as a yellow foam, 167 mg (100%). The nmr (CDC13) spectrum S 4.10 (s, 4H), 4.20 (s, 2H), 4.67, 4.95 (ABq, 2H, J=12Hz), 5.40, 5.60 (m, 5H), 7.20 (br, s, 10H) indicated the presence of a pure compound and was consistent with the assigned structure.

EXAMPLE 9 Trichloroethyl 3-di(phenylacetyl)aminoazetidinone-4-sulfinyl bromide-1-ss-chloromethylvinylacetate N-Bromosuceinimide (45 mg., 0.25 mmole) was added to a solution of trichloroethyl 6-di(phenylacetyl)amino-2ss-chloromethyl - 2α - methylpenam - 3 carboxylate Ia - sulfoxide (see Ex. 5, 158 mg, 0.25 mmole) in carbon tetrachloride (5 ml) and the mixture stirred and heated in a nitrogen atmosphere under reflux for 20 mins. The reaction mixture was cooled, the succinimide removed by filtration, and the filtrate concentrated to give the title compound as a yellow-brown foam, 185 mg (100%). the nmr (CDCl3) spectrum # 4.10 (s, 4H), 4.20 (s, 2H), 4.63, 4.93 ABq, 2H, J=12Hz), 5.23-5.70 (m, 4H), 5.83 (d, 1H, J=4Hz), 7.20 (br, s, 10H) indicated the presence of a pure compound and was consistent with the assigned structure.

In the same manner as described in Examples 8 and 9, but using as starting materials: trichloroethyl 6-di(phenylacetyl)amino-2ss-bromomethyl - 2α methylpenam - 3 - carboxylate 1α - sulfoxide, trichloroethyl 6 - di(phenylacetyl)amino - 2ss - acetoxymethyl - 2α - methylpenam - 3 - carboxylate 1α - sulfoxide, methyl 6-(phenylacetyl, phenoxyacetyl)amino - 2ss - chloromethyl - 2α - methylpenam - 3 - carboxylate 1α - sulfoxide, and methyl 6-(phenylacetyl, phenoxyacetyl)amino - 2ss - acetoxymethyl - 2α - methylpenam - 3 - carboxylate 1α - sulfoxide and using N-chlorosuccinimide, or N-bromosuccinimide, the following sulfinyl halides are obtained, respectively: trichloroethyl 3-di(phenylacetyl)aminoazetidinone - 4 - sulfinylchloride 1p-bromomethylvinylacetate trichloroethyl 3-di(phenylacetyl)aminoazetidinone-4-sul - 1/3 bromomethylvinylacetate, trichloroethyl 3-di(phenylacetyl)aminoazetidinone - 4 - sulfinylchloride 1ss - acetoxymethylvinylacetate, trichloroethyl 3-di - (phenylacetyl)aminoazetidinone - 4 - sulfinylbromide 1ss - acetoxymethylvinylacetate, methyl 3-(phenylacetyl, phenoxyacetyl)amino - 4 - sulfinylchloride - 1ss chloromethylvinylacetate, methyl 3 - (phenylacetyl, phenoxyacetyl)amino amino-4-sulfinylbromide-1A- chloromethylvinylacetate, methyl 3-(phenylacetyl, phenoxyacetyl)amino - 4 - sulfinylchloride - 1ss acetoxymethylvinylacetate, and methyl 3 - (phenylacetyl, phenoxyacetyl)amino - 4 - sulfinylbromide - 1ss actoxymethylvinylacetate.

EXAMPLE 10 Trichloroethyl 3-phenylacetylaminoazetidinone-4-phenylacetylthiol I-p-chloromethylvinylacetate A solution of trichloroethyl 6 - di(phenylacetyl)amino - 2ss - chloromethyl 2α - methylpenam - 3 - carboxylate 1α - sulfoxide (see Ex. 5, 634 mg., 1 mmole), and trimethyl phosphite (0.4 ml) in benzene (12 ml) was heated under reflux in a nitrogen atosphere for 1 hr, by which time the tle indicated no starting sulfoxide was present. The resulting solution was cooled to room temperature, diluted with ethyl acetate, washed with cold water and dried (Na2SO4). Evaporation. of the filtered solution gave the crude title compound which still contained trimethylphosphite. This was removed under high vacuum at 600C when a pale yellow foam (615 mg) was obtained. The crude product was purified by silica gel chromatography (5% ethyl acetate in methylene chloride), and gave the title compound as a colourless foam (206 mg., 33%). The nmr (CDCl3) spectrm # 3.53 (s, 2H), 3.68 (s, 2H), 3.98 (ABq, 2H, J=12Hz), 4.73 (ABq, 2H, J=12Hz), 5.08-5.30 (m, 4H), 5.95 (d, 1H, J=4Hz), 6.35 (d, 1H, J=8Hz), 7.30 (br, s 10H) was in agreement with the assigned structure.

EXAMPLE 11 Benzhydryl 7-di(phenylacetyl)amino-3-methylceph-3-em-4-carboxylate To a suspension of benzhydryl 7-phenylacetylamino-3-methylceph - 3 - em - 4 - carboxylate (500 mg, J=16Hz), 4.07 (s, 4H), 4.17 (d, 1H, J=4Hz), 5.15 (d, 1H, J=4Hz), 6.85 (s, 1H), 7.33 (br, s, 20H).

The title compound was also obtained as follows: To a suspension of benzhydryl 7 - phenylacetylamino - 3 - methylceph - 3 - em .4 - carboxylate (15 g, 30 mmole) in 1,2 - dichloroethane (180 ml) there was added molecular sieve 4A (finely powdered, 60 g, Baker Analyzed Chemicals) followed by phenylacetyl chloride (18 ml). The mixture was stirred under nitrogen at 60=650C for 5 days, cooled to room temperature, filtered, the solid washed with 1,2-dichloroethane, the combined filtrate and washings (containing large amounts of unreacted phenylacetyl chloride) were concentrated, taken up in acetone and stirred at ice-bath temperature with a large excess of saturated aqueous sodium bicarbonate for I hr. The mixture was extracted with ethyl acetate, the extracts dried over anhydrous sodium sulfate and evaporated to give the crude title compound which was dissolved in benzene and purified by chromatography on silica gel using 5% ethyl acetate in benzene as eluant. The pure title compound (13.517 g), identical with the compound characterized above, and 1.935 g of starting material were obtained, for an overall recovery of 84%.

EXAMPLE 12 Methyl 7-di(phenylacetyl)amino-3-methylceph-3-em-4-carboxylate To a suspension of methyl 7 - phenylacetylamino - 3 - methylceph - 3 - em 4. carboxylate (3.450 g, 10 mmole) in benzene (50 ml) was added pyridine (3.5 ml, 40 mmole) and then phosphorus pentachloride (3.477 g, 16.72 mmole) in small portions over a period of 20 mins. The mixture was stirred at room temperature under nitrogen for 2.5 hrs, diluted with 30 ml of ethyl acetate, washed with ice-cold saturated aqueous sodium bicarbonate, the aqueous layer was extracted with ethyl acetate (2x30 ml), the combined organic layer and extracts, was washed with brine, ice-cold aqueous cupric sulfate (10%, then brine, dried (Na2SO4) and evaporated to yield 2.818 g of the crude imidoyl chloride. The latter was dissolved in 25 ml of dry toluene 2.38 g of sodium phenylacetate was added, and the mixture was stirred at 550-600C under nitrogen for 1 hr. The solvent was removed under reduced pressure, the residue was taken up in methylene dichloride, washed with ice-cold saturated aqueous sodium bicarbonate, and brine, dried over anhydrous sodium sulfate and evaporated, to give the crude title compound as a light yellow foam (3.534 g). The crude title compound was purified by chromatography on a silica gel colum (10% ethyl acetate in benzene) and yielded 2.346 g (51%) of pure title compound as a colorless foam with nmr (CDCl3) # 2.17 (s 3H), 2.57, 3.27 (ABq, 2H, J=15Hz), 3.73 (s, 3H), 4.07 (s, 4H), 4.17 (d, 1H, J=4Hz), 5.17 (d, 1H, J=4Hz), 7.20 (br, s, 10H).

EXAMPLE 13 Benzhydryl 7.di(phenylacetyl)amino.3.methylceph-3-em.4- carboxylate la-sulfoxide A solution of benzhydryl 7-di(phenylacetyl)amino-3-methylceph-3-em-4- carboxylate prepared as described in Example 11 (8.346 g, 13.52 mmole) in methylene dichloride (50 ml) was cooled to 0 C and metachloroperbenzoic acid (85%, 2.735 g, 13.52 mmole) was added with stirring in small portions over a period of time of 20 mins. Stirring was continued at 0 C for 30 mins., the mixture was poured into 5% aqueous sodium bisulfite, extracted with methylene dichloride (3x50 ml), the extracts washed with ice-cold saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and evaporated to yield 0.635 g of the crude title compound. Chromatography on a silica gel column using 10% and 30% acetone in hexane as eluants gave 7,667 g (90%) of the title compound as a light yellow foam with nmr (CDCl3) â 2.21 (s, 3H), 3.11, 3.87 (ABq, 2H, J=1SHz), 3.93 (br, s, 5H), 5.45 (d, 1H, J=4Hz), 6.88 (s, 1H), 7.20 (br, s, 20H).

EXAMPLE 14 Methyl 7-di(phenylacetyl)amino.3-methylceph-3-em-4-carboxylate I a-sulfoxide In a manner similar to that described in Example 13, a solution of methyl 7di(phenylacetyl)amino-3-methylceph - 3 - em - 4 - carboxylate prepared as described in Example 12 (2.225 g, 4.81 mmole) in methylene dichloride (20 ml) was cooled to 0 C and metachloroperbenzoic acid (85%, 979 mg, 4.81 mmole) was added in small portions over a period of time of five minutes. Stirring was continued at 0 C for 20 mins., the reaction mixture was poured into ice-cold 5 Ó aqueous sodium bisulfite, extracted with methylene dichloride (3x40 ml), the extracts washed with ice-cold saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and evaporated to give the title compound (2.264 g, 98% yield) as a pale brown foam which was homogeneous by tlc (single spot) and sufficiently pure for further use, and had nmr (CDCl3) # 2.23 (s, 3H), 3.13, 3.91 (ABq, 2H, J=16Hz), 3.77 (s, 3H), 3.91 (d, J=4Hz, 1H), 4.07 (s, 4H), 5.47 (d, 1H, J=4Hz), 7.13 (m, 10H).

In the same manner as described in Examples 13 and 14, but using as starting materials: p-nitrobenzyl 7-di di(phenylacetyl)amino amino-3-methylceph-3-em-4- carboxylate, trichloroethyl 7 - di(phenylacetyl)amino - 3 - acetoxymethylceph - 3 - em 4 - carboxylate, trichloroethyl 7 - (phenylacetyl, phenoxyacetyl)amino - 3 - methylceph - 3 em - 4 - carboxlate, trichloroethyl 7 - (phenylacetyl, phenoxyacetyl)amino - 3 acetoxymethylceph -3-em-4- carboxylate, trichloroethyl 7 - (phenylacetyl, 2' - thienylacetyl)amino - 3 - methylceph 3 - em - 4 - carboxylate, trichloroethyl 7- (phenylacetyl, 2' - thienylacetyl)amino - 3 acetoxymethylceph -3-em-4- carboxylate, trichloroethyl 7- (phenylacetyl, I' - tetrazolylacetyl)amino - 3 acetoxymethylcep -3-em-4- carboxylate, and the following la-sulfoxides are obtained, respectively: p - nitrobenzyl 7-di(phenylacetyl)amino-3-methylceph - 3 - em - 4 - carboxylate 1α - sulfoxide, trichloroethyl 7 - di(phenylacetyl)amino - 3 - acetoxymethylceph - 3 - em 4 - carboxylate 1α - sulfoxide, trichloroethyl 7 - (phenylacetyl, phenoxyacetyl)amino - 3 - methylceph - 3 em - 4 - carboxylate 1α - sulfoxide, trichloroethyl 7-(phenylacetyl, phenoxyacetyl)amino - 3 acetoxymethylceph -3-em-4-carboxylate la-sulfoxide, trichloroethyl 7-(phenylacetyl, 2'-thienylacetyl)amino - 3 - methylceph - 3 em - 4 - carboxylate 1α - sulfoxide, trichloroethyl 7- (phenylacetyl, 2' - thienylacetyl)amino - 3 acetoxymethyiceph -3-em-4-carboxylate Ia - sulfoxide, trichloroethyl 7-(phenylacetyl, 1'-tetrazolylacetyl)amino-3 acetoxymethylceph - 3 - em - 4 - carboxylate 1α - sulfoxide, and EXAMPLE 15 7-Phenylacetylamino-3-methylceph-3-em-4-carboxylic acid 1α - sulfoxide Benzhydryl 7-di di(phenylacetyl)amino - 3 - methylceph - 3 - em - 4- carboxylate I ,a-sulfoxide obtained as described in Example 13(1.900 g, 3 mmole) was dissolved in toluene (15 ml) and a solution of benzylamine (642 mg, 6 mmole) in toluene (5 ml) was added with stirring. A gel formed after 2-3 mins., stirring at room temperature was continued for 30 mins., the mixture was filtered, the precipitate washed thoroughly with ethyl acetate and ether. Benzhydryl 7 phenylacetylamino-3-methylceph - 3 - em - 4 - carboxylate I a-sulfoxide (1.200 g) was thus obtained as a colorless solid.

Said last-named compound was dissolved in formic acid (4 ml, 97%) and the solution was stirred at room temperature for 4 hrs. Evaporation of the solvent gave the crude title compound as an oil, and trituration with ether followed by filtration and washing with ether gave the title compound (733 mg, 70% overall yield) as a colorless solid with nmr (DMSO-d6) # 2.07 (s, 3H), 3.53 (s, 2H), 3.53, 4.07 (Abq, 2H, J=16Hz), 4.67 (d, J=4Hz, 1H), 5.50 (m, 1H), 7.27 (s, 5H), 9.10 (m, 1H).

EXAMPLE 16 7-Di(phenylacetyl)amino and 7-Phenylacetylamino-3-methylceph-3-em 4-carboxylic Acid 1α - sulfoxides A sample of benzhydryl 7-di(phenylacetyl)amino - 3 - methylceph - 3 - em 4 - carboxylate la-sulfoxide obtained as described in Example 13(1.900 g, 3 mmole) was dissolved in (8 ml), the solution was cooled to 0 C, trifluoroacetic acid (8 ml) was added, and the mixture was stirred at 0 C for 3 hrs. Evaporation of the mixture under reduced pressure gave a solid residue which was stirred with ethyl acetate, filtered, and washed with ethyl acetate to yield 7-di(phenylacetyl)amino - 3 - methylceph 3 - em - 4 - carboxylic acid la-sulfoxide (1.200 g, 80% yield) as a colourless solid with nmr (DMSO-d6) â 2.07 (s, 3H), 3.40, 3.93 (ABq, 2H, J=16Hz), 4.13 (s, 4H), 4.60 (d, 1H, J=4Hz), 6.01 (d, 1H, J=4Hz), 7.20 (br, s, 10H).

Another sample of the above starting material (215 mg, 0.34 mmole) was stirred with formic acid (97%, 4 ml) for 3 hrs, the mixture evaporated under reduced pressure to give a solid residue and the latter triturated with ether, to yield 135 mg of a mixture of the title compounds as a light gray solid.

EXAMPLE 17 Methyl-7-Phenylacetylamino-3-methylceph-3-em-4-carboxylate la-Sulfoxide A sample omethyl 7-di(phenylacetyl)amino-3-methylceph - 3 - em - 4 carboxylate prepared as described in Example 14 (144 mg, 0.3 mmole) was dissolved in benzene (3 ml), a solution of benzylamine (40 mg, 0.37 mmole) in benzene (1 ml) was added and the mixture was stirred at room temperature over night. Methylene dichloride was added, the resulting mixture was washed with icecold 2% aqueous hydrochloric acid and brine, dried over anhydrous sodium sulfate, and evaporated to give the crude title compound as a residue. Chromatography of the latter on preparative tlc silica gel plates using ethyl acetate: benzene=l:l for development, followed by evaporation, yielded the pure title compound (40 mg, 37% yield) as a pale yellow foam with nmr (CDCl3) â 2.18 (s, 3H), 3.27, 3.93 (ABq, 2H, J=16Hz), 3.53 (s, 2H, 3.77 (s, 3H), 4.37 (d, 1H, J=4Hz), 5.15 (dd, 1H, J=4Hz, 7Hz), 7. 20 (br, s, 6H).

The following tests demonstrate the antibacterial activity of compounds according to the invention.

Tests for Antibacterial Activity The antibacterial activities of the following compounds identified by Code Nos. 150, 151, and 152 were determined: Code No. 150: 7-phenylacetylamino - 3 methylceph - 3 - em 4 - carboxylic acid; Code No. 151: 7 - di(phenylacetyl)amino - 3 - methylceph - 3 - em 4 - carboxylic acid la - sulfoxide; and Code No. 152: 7-phenylacetylamino - 3 - methylceph - 3 - em - 4 - carboxylic acid la-sulfoxide.

The antibacterial activity of each compound was determined by the agardilution assay method. The medium used was Trypticase soy agar. The test compounds were dissolved in 0.1 M sodium bicarbonate solution of 2.0 mg/ml concentration and twofold serial dilutions of freshly prepared solutions were made in the agar medium. The surface of the medium was inoculated by using a 1:100 dilution of an overnight culture of each test organism. The inoculated agar plates were incubated at 370C for 20 hrs.

The minimal inhibitory concentration (MIC) of each compound was recorded as the lowest concentration which prevented visible growth, and results are shown in the following Table 1.

TABLE I Minimal Inhibitory Conc. Sg/ml Minimal Inhibitory Conc. ug/ml Test Organisms Compound: 150 151 152 Gram-positives Sarcina lutea ATCC 9341 1.0 0.5 0.5 Staphylococcus aureus ATCC 6538* 3.12 3.12 3.12 Staphylococcus aureus BRL 1555** 6.25 3.12 6.25 Streptococcus faecalis ATCC 10541 > 100.0 100.0 100.0 Streptococcus pyogenes 0.5 0.1 0.1 Bacillus subtilis ATCC 6633 0.5 0.5 0.5 Gram-negatives Bordetella bronchiseptica ATCC 4617 > 100.0 > 100.0 > 100.0 Klebsiella pneumonia ATCC 4352 12.5 6.25 6.25 EscherichiacoliATCC8739 100.0 > 100.0 > 100.0 Pseudomonas aeruginosa ATCC 10145 100.0 > 100.0 > 100.0 Salmonella typhimurium G-46 50 6.25 6.25 * penicillin sensitive strain ** penicillin resistant strain

Claims (17)

WHAT WE CLAIM IS:

1. A process for preparing penicillin la-sulfoxides and cephalosporin la- sulfoxides of the formulae I and 2

wherein RCO and R3CO are the same or different and are selected from aminoprotecting groups commonly used in the penicillin and cephalosporin art in which R and R3 are selected from C1-C4 alkyl, cyanomethyl, thienylmethyl, furylmethyl, tetrazolylmethyl, phenylmethyl, phenoxymethyl, phenoxyisopropyl, R4O-, R4S- or R4R6N- wherein R4 is lower alkyl, phenyl, phenylloweralkyl or trichloroethyl, R5 is hydrogen or is the same as R4; a-hydroxybenzyl, a-aminobenzyl or benzyl a - carboxylic acid wherein the a - hydroxy, a - amino or a - carboxylic acid moieties are optionally protected by an easily removable group, R1 is a carboxy protecting group selected from lower alkyl, 2,2,2 - trichloroethyl, benzyl, pnitrophenyl, p-methoxybenzyl, benzhydryl, fluorenyl, phenacyl, methoxymethyl, phenoxymethyl, benzyloxymethyl or trimethylsilyl, and R2 is selected from hydrogen, chloro, bromo, iodo, methoxy, acetoxy, formyloxy, azido, nitro, cyano, and phenylamino, which comprises treating a compound of the formulae 3 or 4.

in solution in a solvent selected from halogenated hydrocarbons containing I or 2 carbon atoms and from 2-4 atoms of chlorine or bromine and monocyclic aromatic hydrocarbons containing from 6-8 carbon atoms with an oxidizing agent selected from peracids, hydrogen peroxide, sodium metaperiodate, iodobenzene dichloride, metachloroperbenzoic acid, and ozone, and isolating the corresponding compound of formula 1 or 2.

2. A process as claimed on Claim I in which the oxidizing agent is metachloroperbenzoic acid.

3. A process as claimed in Claim I in which the starting material is a compound of formula 3 in which RCO, R3CO, R1 and R2 are as defined in claim I, the solvent is a monocyclic aromatic hydrocarbon, and the oxidizing agent is metachloroperbenzoic acid.

4. A process as claimed in Claim 1 in which the treatment of the starting material of formula 3 or 4 with the oxidizing agent is carried out at a temperature within the range of 0"--30"C.

5. A process as claimed in Claim I in which substantially one molar equivalent of the oxidizing agent is used.

6. A process as claimed in Claim 1 in which trichloroethyl 6di(phenylacetyl)amino-2,2-dimethylpenam-3-carboxylate is treated in benzene solution with metachlorperbenzoic acid and trichloroethyl 6 di(phenylacetyl)amino-2,2 - dimethylpenam - 3 - carboxylate la-sulfoxide is isolated.

7. A process as claimed in Claim I in which - trichloroethyl 6 di(phenylacetyl)amino-2P-chloromethyl-2a - 3 - carboxylate is treated in benzene solution with metachloroperbenzoic acid and trichloroethyl 6di(phenylacetyl)amino-2ss-chloromethyl - 2α - methylpenam - 3 - carboxylate 1α - sulfoxide is isolate.

8. A process as claimed in Claim 1 in which benzhydryl 7 di(phenylacetyl)amino - 3 - methylceph - 3 - em - 4 - carboxylate is treated with metachloroperbenzoic acid and benzhydryl 7-di di(phenylacetyl)amino - 3 methylceph - 3 - em - 4 - carboxylate Ia - sulfoxide is isolated.

9. A process as claimed in Claim 1 in which methyl 7-di(phenylacetyl)amino-3methylceph - 3 - em - 4 - carboxylate is treated with metachloroperbenzoic acid and methyl 7 - di(phenylacetyl)amino - 3 - methylceph - 3 - em - 4 - carboxylate 1α - sulfoxide is isolated.

10. A compound of the formula I or 2

wherein RCO and R3CO are the same or different and are selected from aminoprotecting groups commonly used in the penicillin and cephalosporin are in which R and R3 are selected from C1-C4 alkyl, cyanomethyl, thienylmentyl, furylmethyl, tetrazolylmethyl, phenylmethyl, phenoxymethyl, phenoxyisopropyl, R4O-, R4S- or R4R5N-wherein R4 is lower alkyl, phenyl, phenylloweralkyi or trichloroethyl, R5 is hydrogen or is the same as R4; α-hydroxybenzyl, α-aminobenzyl or benzyl α - carboxylic acid wherein the α - amino or α - carboxylic acid moieties are optionally protected by an easily removable group, R1 is hydrogen or a carboxy protecting group selected from lower alkyl, 2,2,2 - trichloroethyl, benzyl, p-nitrophenyl, p-methoxybenzyl, benzhydryl, fluorenyl, phenacyl, methoxymethyl, phenoxymethyl, benzyloxymethyl or trimethylsilyl, and R2 is selected from hydrogen, chloro, bromo, iodo, methoxy, acetoxy, formyloxy, azido, nitro, cyano and phenylamino.

11. Trichloroethyl 6 - di(phenylacetyl)amino - 2,2 - dimethylpenam - 3 carboxylate 1α - sulfoxide, as claimed in Claim 10.

12. Trichloroacetyl 6-di(phenylacetyl)amino-2ss - chloromethyl - 2α - methylpenam - 3 - carboxylate 1α - sulfoxide, as claimed in Claim 10.

13. Benzhydryl 7 - di(phenylacetyl)amino - 3 - methylceph - 3 - em - 4 carboxylate 1α - sulfoxide, as claimed in Claim 10.

14. Methyl 7-di(phenylacetyl)amino-3-methylceph - 3 - em - 4 - carboxylate 1α - sulfoxide, as claimed in Claim 10.

15. 7 - Di-(phenylacetyl)amino - 3 - methylceph - 3 - em - 4 - carboxylic acid 1α - sulfoxide, as claimed in Claim 10.

16. A process for preparing penicillin 1α - sulfoxides and cephalosporin 1α - sulfoxides substantially as hereinbefore described and exemplified.

17. A penicillin Ia - sulfoxide or cephalosporin 1α - sulfoxide whenever prepared by a process as claimed in any one of Claims I to 9 and 16.