Patent GB-1348987-A (GB)
Title: Antibiotics and processes for their production
IPC: C07F9/6547
Filed: 1970-06-16
Abstract: 1348987 Cephem compounds MERCK & CO Inc 30 April 1971 [16 June 1970 9 July 1970 30 Sept 1970 10 Dec 1970 27 Jan 1971 (3) 8 Feb 1971 11 Feb 1971 (2) 26 Feb 1971] 24507/73 24509/73 24510/73 24511/73 24512/73 24513/73 24514/73 24515/73 24516/73 24517/73 and 24518/73 Divided out of 1348984 Heading C2A The invention relates to novel cephem compounds having the general Formula (I) and the corresponding 1-sulphoxide derivatives, wherein R is H or an esterifying group; A is H, halogen, hydroxy, azido, cyano, mercapto, alkoxy, aryloxy, aralkyloxy, heterocycleoxy, arylthio, heterocyclethio, sulphamoyloxy, alkylthio, aralkylthio, acyloxy, acylthio, carbamoyloxy, thiocarbamoyloxy, N-alkylcarbamoyloxy, N,N - dialkylcarbamoyloxy, alkoxycarbonyloxy, carbamoylthio, thiocarbamoylthio, N - alkylcarbamoylthio, N,N - dialkylcarbamoylthio, alkoxycarbonylthio, amino, acylamino, alkylamino, hydroxyphenyl, isothiouronium, (cis-1À2-epoxypropyl)phosphono, alkylsulphonyloxy, heterocyclic tert. amino or quaternary ammonium; or the group -CH 2 A is replaced by a formyl group; Q is azido, amino, or R<SP>0</SP>O- or R<SP>0</SP>S- in which R‹ is a univalent hydrocarbon group; and when Q is R<SP>0</SP>O- or R<SP>0</SP>S- then R<SP>1</SP> is Cl, Br or I; and when Q is azido or amino then R<SP>1</SP> is halogen, a substituted or unsubstituted hydroxy or mercapto group, a univalent substituted or unsubstituted hydrocarbon group, a phosphono or substituted phosphono group, an amino or substituted amino (not acylamino) group, a nitro, nitroso, azido, isocyanato, isothiocyanato, hydroxyamino or cyano group, or a substituted or unsubstituted formyl or thioformyl group. The compounds (I) are prepared by one or more of the following interconversion procedures: (a) A diazocephem derivative of Formula (II) or the corresponding 1-sulphoxide, in which A and R are as defined above, is reacted (i) with halogen azide to give a compound of Formula (III) in which X is Cl, Br or I; or (ii) with a hypohalite of an alcohol or thiol to give a compound of Formula (IV) in which X‹ is oxygen or sulphur, and R‹, R, A and X are as defined above; or (iii) with a boron compound: B(R<SP>0</SP>) 3  followed by treatment with a halogen azide to give a compound of Formula (V), in which R‹, R and A are as previously defined. (b) A compound of Formula (III) above is reacted (i) with a nucleophilic reagent containing a group R (wherein R is as previously defined) and capable of displacing the 7-position halogen by said group R in said compound (III), to give a compound of Formula (VI) or (ii) with phenyl-lithium followed by CO 2  or CS 2  to give a compound of Formula (VII) in which Q<SP>1</SP> is carboxy or thiocarboxy and A and R are as defined above; or (iii) with an alkali metal azide to give a compound of Formula (VIII) which compound may be catalytically hydrogenated to give a compound of Formula (IX) (c) A compound of Formula (IV) above is reacted with alkali metal azide to give a compound of Formula X in which A, R, R‹ and X‹ are as previously defined. Typical nucleophilic reagents in reaction (b) (i) are alcohols, phenols, glycolamides, glycolic esters, silver and lithium salts of organic acids, amines, phosphites, phosphonic amido and diamido acids or esters thereof, and substituted amines and salts thereof.