FORFARANDE FOR FRAMSTELLNING AV 3-HALOGENCEFALOSPORINER

摘要

1458293 3-Halocephalosporins ELI LILLY & CO 22 Feb 1974 [23 Feb 1973] 8096/74 Heading C2C The invention comprises compounds of formula wherein R is hydrogen or an acyl group R1CO, where R1 is (i) C 1 -C 6 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 cyanoalkyl, phenyl, methylphenyl, hydroxyphenyl, halophenyl, nitrophenyl, aminophenyl, methoxyphenyl, 5 - amino - 5- carboxybutyl, or a 5 - substituted - amino - 5- carboxybutyl ester group where A is diphenylmethyl, p-nitrobenzyl, pmethoxybenzyl, benzyl, t - butyl or 2,2,2- trichloroethyl, and A1 is C 2 -C 4 alkanoyl, C 2 -C 4 haloalkanoyl, benzoyl, halobenzoyl, 2,4 - dinitrophenyl, or phthaloyl; (ii) where a and a1 independently are hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, nitro, amino or carboxy; Z is O or S; and m is 0 or 1; (iii) PCH(Q) where P is 2-thienyl, 3-thienyl, phenyl or a substituted phenyl group a(a1)C 6 H 3 where a and a1 are as defined above, Q is hydroxy, formyloxy, acetoxy, carboxy, or sulpho; (iv) PC(:NOY) where P has the same meaning as defined above and Y is hydrogen, methyl or acetyl; (v) R11CH 2 where R11 is 2-thienyl, 3-thienyl, 2-furyl, 2- oxazolyl, 2-thiazolyl, or 1-tetrazolyl; (vi) where a, a1, Z and m have the same meanings as defined above; R 1 is hydrogen, benzyl, pmethoxybenzyl, p-nitrobenzyl, diphenylmethyl, 2,2,2 - trichloroethyl, t - butyl, or a pharmaceutically acceptable ester radical (C 1-4 alkyl) CO 2 CH 2 and X is fluoro, chloro, or bromo; and when R 1 is hydrogen the non-toxic pharmaceutically acceptable salts thereof. These compounds may be prepared by (1) hydrogenolysis of nitrobenzyl esters to give the acids, (2) N-acylation, or conversely N-deacylation, (3) halogenating the 3-position in the 3-hydroxy or 3-methylsulphonyloxy cephem analogues, (4) (in case vi) reducing with H 2 (Raney Ni) the analogues where R1 is 3-(aryl, aryloxy or arylthio)methyl - 1,2,4 - oxadiazolin - 5 - on - 4 - yl methyl. Starting materials otherwise prepared (by N - deacetylation) are the analogous 7 - amino- 3-methylenecepham compounds. Therapeutic compositions for parenteral administration comprise compounds of the above formula, in which R is acyl and R 1 is H or (C 1-4 alkanoyloxy)methyl, which are active against both gram-positive and gram-negative organisms.