FOERFARANDE FOER FRAMSTAELLNING AV 3-METYL- OCH 3-HYDROXI-7-AMINO-1-OXACEF-3-EM-4-OINSYRADERIVAT VILKA AER ANVAENDBARA SOMMELLANPRODUKTER VID FRAMSTAELLNING AV ANTIBIOTIKA

摘要

1510794 1-Oxacephems QUEEN'S UNIVERSITY AT KINGSTON 30 June 1975 [6 Aug 1974] 34614/74 Heading C2C Novel compounds of the formula wherein R8 is H or RCO- and R is lower alkyl Ar-CH(R4)-, Ar-X-C(R5)(R6)-, R12-O-, wherein Ar is a monovalent radical selected from wherein R 1a , R 2 and R 3 are each selected from H, Cl, Br, I, CF 3 , phenyl, lower alkyl and lower alkoxy, but only one of R 1a , R 2 and R 3 may be phenyl; R 4 is H, amino, carbobenzyoxyamino, phenyl, F, Cl, Br, I, COOH, SO 3 H and azido, OH, lower alkanoyloxy and lower alkoxy; X is -O- or -S-; R5 and R6 are H, phenyl, benzyl, phenethyl, and lower alkyl; Z1, Z2 and Z3 are lower alkyl or Ar-; R12 is CCl 3 CH 2 - or benzyl; or R8NH is phthalimido; R7 is OH; and R1 is H, lower alkyl, benzyl, benzhydryl, lower alkoxyl lower alkyl, lower alkoxybenzyl, phenacyl, trimethylsilyl, CCl 3 CH 2 -, or pivaloyloxy; or the pharmaceutically acceptable salts thereof, may be obtained as indicated in the flowsheet by cyclizing the corresponding R1 yl-2-(21- chloro - 31S - R - carbonylamino - 41 - oxo)- azetidinyl - 3 - oxo - 4 - hydroxybutanoate (XXV) either in the presence of a Lewis acid catalyst and a solvent such as dimethoxyethane or by dissolution in an amine base such as pyridine. The product (XXVI) may be converted into the free amino compound (XXVII) by known methods. In examples, unsaturated ester (XVI) (R or S-chloro epimer), is converted to (XXI) by reaction with O 3 followed by Zn dust and acetic acid (RCONA being phthalimido or trichloroethoxycarbonylamino and R1 being CH 3 ) ; halogenation of enol XXI (RCONH being phthalimido) is effected using pyrrolidone hydrotribromide, N-bromosuccinimide or molecular iodine in the presence of CaO; the brominated keto ester XXII is rearranged in benzene using saturated HBr in glacial acetic acid to form XXIII; XXIII is treated with tetramethylguanidinium formate to form XXIV; the same compound is obtained by reaction of XXII with sodium formate in anhydrous formic acid, the formate ester XXIV is treated with anhydrous methanolic HCl to form XXV; the product is reacted with SuCl 2 to form XXVI;. compound XXI (where RCONH is 31-trichloroethoxycarbonylamino and R1 is benzhydryl is similarly converted to XXVI and the protecting groups are removed in usual manner to form XXVII.