GB1326531A - Cephalosporin compounds - Google Patents

Abstract

1326531 Cephalosporins GLAXO LABORATORIES Ltd 6 Aug 1970 [26 Aug 1969 23 Jan 1970 26 March 1970 10 July 1970] 42502/69 3463/70 14980/70 and 33698/70 Heading C2A Novel cephalosporin 1-sulphoxides of Formula IV or V wherein R<SP>1</SP> is a protected amino group, R<SP>2</SP> is hydrogen or a carboxyl-blocking group, X is Cl, Br or I and Z is H or Br are prepared by brominating a corresponding 3-methyl cephalosporin 1-sulphoxide and in the case of compounds of Formula IV optionally converting the 3-bromomethyl group to a 3-chloromethyl or 3-iodomethyl group. R<SP>1</SP> is preferably an acylamido group containing 1-20 carbon atoms, numerous such groups being listed. R<SP>2</SP> may be the residue of an ester-forming alcohol or phenol R<SP>2</SP>OH, the group-COOR<SP>2</SP> preferably being t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl or a silyloxycarbonyl group. The bromination is preferably effected in an inert solvent using bromine itself, 1,3,5-tribromo- 1,2,4-triazole or an N-bromoamide or bromoimide, e.g. N-bromoacetamide, N-bromosuccinimide, N-bromophthalimide, N-bromocaprolactam or a 1,3-dibromo-5,5-dialkylhydantoin. The bromination reaction is initiated by a freeradical initiator such as an azo compound or a peroxide, or by irradiation by ultra-violet or visible light or γ-radiation. Small amounts (e.g. 5% by volume) of water and weak bases, e.g. NaHCO 3 , Na 2 CO 3 , CaCO 3 or sodium acetate, are preferably added to the reaction medium to assist the initiation and improve the yield. The reaction may be conducted under an inert atmosphere. Conversion to 3-chloromethyl or 3-iodomethyl compounds is by reaction of the 3-bromo compound with an alkali metal chloride or iodide, suitably in a solvent such as acetone or dimethyl-formamide. The compounds of Formula V are by-products and are preferably subjected to Zn/acid reduction to re-form the 3-methyl starting material and then re-cycled to give further yields of the compounds of Formula IV. Antibiotically active known cephalosporins of formula VIII and salts thereof, wherein R<SP>10</SP>CO is an acyl group and Y is the residue of a nucleophile, are prepared by subjecting a compound of Formula IV to the following procedures in any order: (a) reduction of the 1-sulphinyl group to the corresponding sulphide; (b) reaction with a nucleophile to displace the group X by a nucleophilic group; (c) removal of the group R<SP>2</SP> to give the 4-carboxyl compound which may optionally be converted to a salt; (d) if required, N-deacylating to give the 7-amino compound and reacylating to introduce R<SP>10</SP>, when this differs from the group R<SP>1</SP>. Reaction (a) may be effected by converting the sulphoxide to the corresponding acyloxy- or alkyloxy-sulphonium salt by reaction with acyl chloride and reducing the salt with sodium dithionite or potassium iodide, or else by treating the sulphoxide with PCl 3 or PBr 3 in a solvent. The nucleophilic displacement (b) is carried out in a solvent which may be the nucleophile itself, at pH 5-8 preferably in the presence of an acid acceptor e.g. triethylamine, and especially in the case of oxygen nucleophiles, in the presence of a salt of Hg, Ag or Au. Many nucleophilic substances are listed, grouped into nitrogen-, sulphur-, carbon- and oxygen-nucleophiles. The de-esterification (c) and N-acyl group replacement (d) are carried out by conventional procedures appropriate to the nature of the groups R<SP>1</SP>, R<SP>10</SP> and R<SP>2</SP>. The 3 - methyl cephalosporin 1 - sulphoxide starting materials are prepared by oxidizing a compound of Formula III wherein R<SP>1</SP> and R<SP>2</SP> are as defined above and the dotted line indicates that the compound may be a #<SP>2</SP> or #<SP>3</SP> cephem compound or a mixture thereof. The oxidation is effected preferably below 10‹ C. in an organic solvent with metaperiodic acid, peracetic acid, permonophthalic acid or m-chloroperbenzoic acid in an amount such as to provide one atom of active oxygen per atom of dihydrothiazine sulphur.