Patent GB-1505345-A (GB)
Title: Cephalosporins
IPC: C07D205/09
Filed: 1974-04-10
Abstract: 1505345 3 - (Carboxybenzyl) cephalosporins derivatives BEECHAM GROUP Ltd 21 March 1975 [10 April 1974] 15805/74 Headings C2C and C2P The invention comprises 3-(carboxybenzyl)- cephalosporin derivatives of the Formula I and their salts, wherein R is A 1 -(CH 2 ) n -CH(X)-(CH 2 ) m CO-, A 2 CO-, A 1 -X 2 -(CH 2 ) n CO or a radical of the formula wherein n is 0 to 2, m is 0 to 2, A 1  is C 1-4  alkyl, C 3-6  cycloalkyl, cyclohexenyl, cyclohexadienyl, optionally substituted phenyl, thienyl or pyridyl; X is H, halogen, free or esterified carboxy, azido, tetrazolyl, hydroxy, acylamino, amino, ureido, guanidino or acylureido; A 2  is 2,6-dimethoxyphenyl, 2 - alkoxy - 1 - naphthyl, 3- aryl - 4 - or 5 - isoxazolyl or 3 - aryl - 5 - methyl- 4-isoxazolyl, X 1  is CH 2 OCH 2 , CH 2 SCH 2  or (CH 2 ) n  and X 2  is O or S, and R 1  is H or carboxy and their preparation by acylating the corresponding compound of the formula The following intermediates and starting materials are also prepared: 1-bromo-[3-p-(m- or o-) - (p - methoxybenzyloxycarbonyl)]. phenylprop-2-yne; 1-bromo-3-[3,5-di-(p-methoxybenxyloxycarbonyl)phenyl] prop - 2 - yne; 1 - (1 - benzyloxycarbonyl - 2 - methyl - 1 - propenyl) - 3 - (triphenylmethylamino) - 4 - [3 - p- (or m- or o-)-(p-methoxybenzyloxycarbonyl)- phenyl - prop - 2 - ynylthio] azetidin - 2 - one; 3 - (triphenylmethylamino) - 4 - [3 - (3,5 - di- (p - methoxybenzyloxycarbonyl) phenyl prop- 2 - ynylthio] azetidin - 2 - one; 1 - (1 - hydroxy (or chloro) - 1 - t - butoxycarbonylmethyl) - 3- (triphenylmethylamino) - 4 - [3 - p - (or m- or o-) - (p - methoxybenzyloxycarbonyl) phenyl prop - 2 - ynylthio] azetidin - 2 - one; 1 - (1- hydroxy (or chloro) - 1 - t - butoxycarbonylmethyl) - 3 - (triphenylmethylamino) - 4 - [3- (3,5 - di - (p - methoxybenzyloxycarbonyl)- phenyl prop - 2 - ynylthio] azetidin - 2 - one; t-butyl 3-[p-(or m- or o-)-(p-methoxybenzyloxycarbonyl) - benzyl] - 7# - triphenylmethylamino - 3 - cephem - 4 - carboxylate; t - butyl 3 - [3,5 - di - (p - methoxybenzyloxycarbonyl)- benzyl] - 7# - triphenylmethylamino - 3 - cephem - 4 - carboxylate; t - butyl 3 - [p - (or m- or o -) - (p - methoxybenzyloxycarbonyl)- benzyl] - 7# - amino - 3 - cephem - 4 - carboxylate; t - butyl 3 - [3,5 - di - (p - methoxybenzyloxycarbonyl) benzyl] - 7# - amino - 3 - cephem- 4-carboxylate; compounds of the Formula I above in which any free amine groups in the acyl group R are protected, R 1  is H or p-methoxybenzyloxycarbonyl and the other two carboxy groups are esterified; and 1-(1-benzyloxycarbonyl - 2 - methyl - 1 - propenyl) - 3 - triphenylmethylamino - 4 - [3 - (3,5 - di - p - methoxybenzyloxycarbonylphenyl) prop - 2 - ynylthio] azetidin-2-one. 1 - (1 - t - Butoxycarbonyl - 1 - triphenylphosphoranylidenemethyl) - 3 - triphenylmethylamino) - 4 - [3 - p - (or m - or o -) - (p - methoxybenzyloxycarbonyl) phenyl - 2 - oxopropylthio]- azetidin-2-one is prepared by reacting piperidine with 1 - (1 - t - butoxycarbonyl - 1 - triphenylphosphordnylidenemethyl) - 3 - triphenylmethylamino - 4 - [3 - p (or m - or o -) - (p - methoxybenzyloxycarbonyl) phenylprop - 2 - ynylthio] azetidin-2-one, obtained by reacting triphenylphosphine with 1-(1-chloro-1-t-butoxycarbonylmethyl) - 3 - triphenylmethylamino - 4 - [3 - p- (or m- or o-)-(p-methoxybenzyloxycarbonyl)- phenylprop - 2 - ynylthio] acetidin - 2 - one. 1 - (1 - t - Butoxycarbonyl - 1 - triphenylphosphorenylidenemethyl - 3 - triphenylmethylamino- 4 - [3 - (3,5 - di - p - methoxybenzyloxycarbonylphenyl) - 2 - oxopropylthio] azetidin - 2 - one and 1 - (1 - t - butoxycarbonyl - 1 - triphenylphosphoranylidenemethyl)- 3 - triphenylmethylamino- 4 - [3 - (3,5 - di - p - methoxybenzyloxycarbonyl)- phenylprop - 2 - ynylthio] azetidin - 2 - one are obtained in a similar manner. Pharmaceutical compositions contain the above antibiotics together with pharmaceutically acceptable carriers.