Patent GB-1368234-A (GB)
Title: Thiosubstituted szetidinones and other antibiotic precursors
IPC: C07D499/00
Filed: 1970-11-03
Abstract: 1368234 Thio - substituted azetidinones GLAXO LABORATORIES Ltd 30 July 1971 [3 Nov 1970] 52286/70 Heading C2C The invention comprises compounds of the Formula (IX) wherein R<SP>1</SP> is an amino or blocked amino group, R<SP>2</SP> is a hydrogen atom or a group of formula (wherein R m  is a hydrogen atom, an esterified or etherified hydroxyl group, an acylamino group, a carboxyl group or an esterified carboxyl group) and R<SP>4</SP> is an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbyl group or an aliphatic or araliphatic acyl group in which the aliphatic or araliphatic portion is a C 1-6  alkyl group or a monocyclic aralkyl containing a C 1-6  alkyl group except that R<SP>4</SP> is not an optionally substituted isopropyl, or isopropenyl group when R<SP>2</SP> is hydrogen and R<SP>2</SP> is not a group (VI) in which R m  is a carboxyl or esterified carboxyl group when R<SP>4</SP> is an unsubstituted alkyl, aralkyl or alkenyl group; and also compounds of the Formula (A) and salts and esters thereof, which exhibit antibiotic activity. Compounds of the Formula (IV) (wherein R<SP>2</SP> a  is a hydrogen atom or an aliphatic, araliphatic or aromatic group and R<SP>4</SP> is an aliphatic, araliphatic, cycloaliphatic, or aromatic hydrocarbyl group or an acyl group or R<SP>2</SP> a  and R<SP>4</SP> together form a divalent, optionally substituted hydrocarbyl group) are obtained by subjecting the -S-S- bond of a disulphide of Formula (II) (wherein R<SP>2</SP> is a hydrogen atom or an aliphatic, araliphatic or aromatic group and R<SP>3</SP> is an optionally substituted aliphatic, araliphatic, cycloaliphatic or aromatic group containing 1 to 20 carbon atoms or a group of the Formula (III)) to reductive cleavage in the presence of an S- etherifying or S-esterifying reagent to introduce R<SP>4</SP>, e.g. R<SP>4</SP>X, where X is a halogen atom or aromatic or aliphatic sulphonyloxy group. The S-etherifying or S-esterifying reagent may be a group R<SP>2</SP> in the compound (II) which carries a reactive ester group which cyclizes with the sulphur atom. The reductive cleavage of the -S-S- bond may be effected by reducing agents or electrolysis, whereby electrons areintroduced, or by a thiophilic sulphur-containing nucleophile. Suitable reactants include trivalent phospeorus compounds, HI, hydride reducing agents, e.g. alkali metal borohydrides, thiols, hydrogen sulphide, thiophosphates, thioamides, thiosulphates, sulphates, sulphinates, thiocyanates or thioglycollates. Compounds of the Formula IV may also be obtained by reacting a compound of Formula I (where R is the residue of an acyl group RCO- having 1 to 21 carbon atoms) with an S-etherifying or S-esterifying reagent, preferably in the presence of a thallium triacylate or a weak base having a pKa of less than 10 (in water at 25‹ C.) e.g. urea. Compounds of Formula (IV) may also be obtained by subjecting the -S-S- bond of Formula (II) to oxidative cleavage (e.g. with bromine or iodine) in the presence of an unsaturated aliphatic or cycloaliphatic hydrocarbon.