Patent GB-1513954-A (GB)
Title: Pyrrolidine derivatives
IPC: C07D207/16
Filed: 1975-05-16
Abstract: 1513954 Pyrrolidine derivatives ERSQUIBB & SONS Inc 16 May 1975 [15 Aug 1974] 20911/75 Heading C2C Novel compounds of the formula wherein R and R 1  each is H, -(CH 2 ) 6 COOH, -(CH 2 ) 6 COO-, C 1-7  alkyl or -(CH 2 ) 6 COO- benzyl; and R 2  is H, -COO(CH 2 ) 5 CH 3 , -CONH(CH 2 ) 5 CH 3  or with the proviso that at least one of R and R 1  is H and R 1  and R 2  are not both H, and acid addition salts thereof, may be prepared by (1) removing a t-butoxycarbonyl or benzyloxycarbonyl group at R, (2) reducing a corresponding pyrrolidone, (3) introducing an R group using RI; (4) converting an ester to a free acid, (5) esterifying a free acid. Various intermediates of the Formula I wherein R is hydrogen, t-butoxycarbonyl, benzyloxy carbonyl; R 1  is 2- or 3-COO(CH 2 ) 5 CH 3 , 2-CH : CHCHOH(CH 2 ) 4 CH 3 , 2- or 3-carboxy, 2- or 3-(CH 2 ) 6 COO-benzyl,   3-CH : CH(CH 2 ) 5 CH 3 , 2- or 3-hydroxymethyl, 2- or 3-formyl, 2-CONH(CH 2 ) 5 CH 3  and R 2  is hydrogen, 2-, 3- or 4-carboxy or t-butoxycarbonyl may be prepared by (1) conversion of an ester to a free acid, (2) esterification of an acid, (3) formation of an amide group, (4) reduction of a carboxy group to hydroxymethyl, (5) oxidation of hydroxymethyl to formyl, (6) conversion of a formyl group to  (7) reduction of a keto group to a hydroxy group, (8) introduction of a substituent at R, (9) reduction of a pyrrolidone to a pyrrolidine, (10) conversion of a formyl group to (11) reduction of a 1-benzyl group to 1-unsubstituted pyrrolidine. Intermediate 2-pyrrolidones substituted by 5 - octyl; 4 - t - butoxycarbonyl - 5 - (CH 2 ) 6 COO- benzyl, 3 - t - butoxycarbonyl - 4 - (CH 2 ) 6 COO- benzyl are prepared by a cyclization process. 2-Octylpyrrolidine is prepared, as an illustration of a generally applicable reaction, by cyclizing methyl 4-oxododecanoate with ammonium bromide in the presence of sodium cyanoborohydride to yield 5-octyl-2-pyrrolidone which is reduced to the required compound. Similarly 3-octylpyrrolidine is prepared, as an illustration, by reducing 1-(t-butyloxycarbonyl)- 3-pyrrolidine carboxylic acid to 1-(t-butoxycarbonyl)-3-pyrrolidine methanol, which is oxidized to 1 - (t - butoxycarbonyl) - 3 - pyrrolidine carboxaldehyde, which is heptyltriphenyl phosphonium iodide and sodium methoxide yields 1 - (t - butoxycarbonyl) - 3 - (1 - octenyl)- pyrrolidine which yields the required compound on hydrogenation and treatment with trifluoroacetic acid. 3 - Ethoxycarbonylmethyl - decanedioic acid 10 - benzyl ester - 1 - t - butyl ester is prepared by reaction of benzyl 7-formylheptanoate with t-butyl bromoacetate in the presence of zinc to form 3 - hydroxydecane dioic acid 10 - benzyl ester-1-t-butyl ester which is oxidized to 3-oxodecanedioic acid 10-benzyl ester-1-t-butyl ester which yields the required compound on reaction with ethyl bromoacetate and zinc. 2 - (Methoxycarbonyl) - 3 - formyldecanedioic acid 10 - benzyl ester - 1 - t - butyl ester is prepared by reacting the pyrrolidine enamine of benzyl 8-formyl octanoate with 1-t-butyl-2- bromo-3-methylmalonate. 3 - (Methoxycarbonylmethyl) - 2 - oxodecanedioic acid 10-benzyl ester-1-t-butyl ester is prepared by reacting 1-t-butyl-2-oxo-5-methyl glutarate with 1 - benzyl - 7 - iodoheptanoate in the presence of sodium hydride. 1 - t - Butyl - 2 - bromo - 3 - methylmalonate is prepared by bromination of 1-methyl-3-tbutyl malonate. Benzyl 7-iodoheptanoate is prepared by reducing benzyl hydrogen pimelate to benzyl 7- hydroxy heptanoate followed by esterification to the tosylate, which gives the required compound on reaction with sodium iodide. Benzyl 7 - formlyheptanoate is prepared by reducing benzyl hydrogen sebacate to benzyl 8-hydroxy octanoate which is oxidized to the required compound. 1 - t - Butyl - 2 - oxo - 5 - methylglutarate is prepared by reacting 1-methylglutarate with aqueous pyridoxal hydrochloride/cupric chloride followed by esterification using isobutylene/ acid. Pharmaceutical compositions of the compounds I with the usual excipients inhibit prostaglandin dehydrogenase and potentiate prostaglandin activity when administered parenterally. The composition may also contain a prostaglandin.