SETT ATT FRAMSTELLA BETA-METYLEN-ALFA-OXO-KARBOXYLSYRAESTRAR

摘要

1423741 Cephem compounds ROUSSEL-UCLAF 1 Jan 1973 [31 Dee 1971 (5) 7 Sept 1972] 114/73 Heading C2C Novel 7-tritylamino-cephem compounds of Formula (X) wherein A 1 is C 2 -C 5 alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 heterocyclyl and R1 2 is the residue of an ester grouping, are prepared according to the following reaction scheme in which the reactions and intermediate compounds are as follows: (Ia) A 2-halo-2,3-epoxybutanoate (III) in which A 2 is methyl or A 1 as defined above and Hal is Cl or Br, is dehydrohalogenated to give a 2-oxo-but-3-enoate (IV). (Ib) A #-amino-propenoate (XIII) wherein Z is a cyclic imido group which may be substituted, a benzoylamino group or a thiobenzoylamino group, and R11 2 is C 1 -C 10 alkyl or C 7 -C 15 aralkyl, is reacted with H 2 S in the presence of an acid HX where X is halogen, sulphate or sulphonate, to give a corresponding thioaminal (V). (2) The butenoate (IV) is condensed with the thiominal (V) in the presence of tert amine to give either a 2-substituted - methyl - 4 - hydroxy - 1,3 - thiazane (VI) or a 2-substituted methyl-2,3-dihydro-1,3- thiazine (VI1), according to the reaction conditions. (3) The thiazane (VI) or the thiazine (VI1) is then treated with hydrazine or hydrogenolysed, followed by acid hydrolysis, to give a corresponding 2 - aminomethyl - 2,3 - dihydro- 1,3-thiazine (VII). Alternatively, when Z in the compound (VI) or (VI1) is benzoylamino or thiobenzoylamino, the compound may be alkylated to the corresponding 2-(α-alkoxybenzylaminomethyl) derivative which is then subjected to acid hydrolysis and dehydration to give the required compound (VII). (4) The compound (VII) is selectively saponified to a corresponding 2-(α-amino-α-carboxy)methyl-2,3- dihydro-1,3-thiazine (VIII), which is then tritylated to a 2-(α-tritylamino-α-carboxy)methyl- 2,3-dihydro-1,3-thiazine (IX). (5) The compound (IX) is cyclized by treatment with a lactamisation agent (e.g. a carbodiimide) to give the cephem compound (X). The 7-tritylamino-cephem compounds (X) may be subjected to mild acid hydrolysis to give 7-amino-cephem carboxylic esters of Formula (XI), or to more severe acid hydrolysis to give the corresponding 7 - amino - cephem - carboxylic acids (XI1), these esters and acids being novel compounds when A 1 is not an ethyl group.