Patent GB-1530157-A (GB)
Title: 3-(substituted)cephems
IPC: C07D501/20
Filed: 1975-12-04
Abstract: 1530157 Cephalosporins ELI LILLY & CO 4 Dec 1975 [10 Dec 1974] 49766/75 Heading C2C  Novel cephalosporins of the general Formula I wherein R is a group of the Formula -OR 5  wherein R 5  is hydrogen or a carboxylic acidprotecting ester-forming group; R 4  taken together with Y forms a carbon-oxygen bond; R 3  is C 1 -C 6  alkyl, vinyl, allyl, ethynyl, benzyl or phenyl; R 1  is hydrogen or an acyl group of the formula wherein R<SP>1</SP> is (a) C 1 -C 6  alkyl, C 3 -C 7  alkenyl, cyanomethyl, halomethyl, 4-amino-4-carboxybutyl, 4-protected amino-4-protected carboxybutyl; or (b) benzyloxy, 4-nitrobenzyloxy or 4- methoxybenzyloxy; or (c) the group -R<SP>11</SP> wherein R<SP>11</SP> is 1,4-cyclohexadienyl, phenyl or substituted phenyl wherein the substituents are 1-3 radicals selected from halogens, hydroxy, nitro, cyano, trifluoromethyl C 1 -C 4  alkyl, C 1 -C 4  alkoxy, carboxy, carboxymethyl, hydroxymethyl, aminomethyl and protected aminomethyl; or (d) a substituted alkyl group of the formula wherein R<SP>11</SP> is as defined above, A is O or S, and m is 0 or 1; or (e) a substituted alkyl group of the formula wherein R<SP>111</SP> is R<SP>11</SP> as defined above, 2-thienyl or 3-thienyl, W is hydroxy or protected hydroxy, carboxy or protected carboxy, amino or protected amino; or (f) a heteroarylmethyl group of the formula wherein R<SP>11 11</SP> is 2-thienyl, 3-thienyl, 2-furyl, 3- furyl, 2-thiazolyl, 5-tetrazolyl or 1-tetrazolyl; and R 2  is hydrogen or methoxy; and when R 5  is hydrogen, the pharmaceutically acceptable non-toxic salts of the acids represented thereby; are prepared, e.g. by reacting a 3-formyl-2- cephem compound of the general formula with R 3 MgX (X is Cl, Br or I) in an anhydrous ethereal solvent at -78 to -30 C., optionally oxidizing the resulting compound (I) in which Y = R 4  = H, optionally oxidizing the 3-acyl-2- cephem compound obtained to the corresponding 3-acyl-3-cephem-1-oxide, followed by reduction to the 3-acyl-3-cephem by a trivalent phosphorus compound; optionally cleaving a 7-acylamino group in a resulting compound (I) to provide the corresponding compound in which R 1  is H and optionally removing a carboxylic acid-protecting ester-forming group in a resulting compound (I) to provide the corresponding free acid (R 5  = H). Benzhydryl 7 - (2 - thienylacetamido) - 3-ethoxycarbonyl - oxycarbonyl - 2 - cephem - 4 - carboxylate is prepared by esterifying 7-(2-thienylacetamido- 3 - hydroxymethyl - 2 - cephem - 4 - carboxylic acid with diphenyldiazomethane, oxidizing the resulting benzhydryl ester with chromic acid, reacting the resulting benzhydryl 7-(2-thienylacetamido) - 3 - formyl - 2 - cephem - 4 - carboxylate with ethylene glycol and ptoluene-sulphonic acid, treating the resulting 3-(1,3-dioxolan-2- yl) derivative with N-bromosuccinimide, treating the resulting 3-(2-bromoethoxycarbonyl) derivative with NaI, reacting the resulting 3-(2- iodoethoxycarbonyl) derivative with zinc dust in acetic acid-DMF and reacting the resulting 3- carboxy derivative with ethyl chloroformate. 7 - (2 - Thienylacetamido) - 7 - methoxy - 3- acetoxymethyl - 2 - cephem - 4 - carboxylic acid is prepared by treating the corresponding 3- cephem compound with acetic anhydride in pyridine. Benzhydryl 7 - (2 - thienylacetamido) - 7- methoxy - 3 - formyl - 2 - cephem - 4 - carboxylate is prepared by hydrolysing the corresponding 3-acetoxymethyl derivative with aq. NaOH and oxidizing the resulting 3-hydroxymethyl derivative with chromic acid. Pharmaceutical compositions having antibiotic activity comprise, as active ingredient, a cephalosporin (I) of pharmaceutically acceptable non-toxic salt thereof, together with a pharmaceutically acceptable carrier.