Patent GB-1327308-A (GB)
Title: Process for preparing aroyl-substituted pyrroles and product prepared thereby
IPC: C07D207/337
Filed: 1971-04-19
Abstract: 1327308 Aroyl-substituted pyrrole derivatives McNEIL LABORATORIES Inc 19 April 1971 [26 Jan 1970] 20200/71 Addition to 1195628 Heading C2C Novel compounds of the Formulµ Ia, Ib, Ie and compounds of the Formulµ Ic, Id and If wherein Ar is thienyl, 5-methyl thienyl or trifluoro methyl phenyl and when R 2  is CONHOH or CONH(CH 2 ) n -N(C 1-6  alkyl) 2  in which n is 2, 3 or 4 Ar may additionally be a phenyl optionally mono or polysubstituted with halogen, C 1-6  alkyl, C 1-6  alkoxy or methylthio; Ar 1  is phenyl optionally mono or polysubstituted with halogen, C 1-6  alkyl or C 1-6  alkoxy, Ar 2  is thienyl or 5-methyl thienyl, or phenyl optionally mono or poly-substituted with halogen, C 1-6  alkyl or alkoxy, methylthio, nitro, amino, trifluoromethyl or cyano; R and R 6  are hydrogen or C 1-6  alkyl; R 1  is hydrogen, C 1-6  alkyl or benzyl; R 2  is CN, COOH, COOC 1-6  alkyl, CONH 2 , CONH(C 1-6  alkyl), CON(C 1-6  alkyl) 2 , CONHOH or CONH(CH 2 ) n  N(C 1-6  alkyl) 2 , n is 2-4; R 3  is COOH, COO(C 1-6  alkyl), CONH 2 , CONH(C 1-6  alkyl) or CON(C 1-6  alkyl) 2 ; R 4  and R 5  are C 1-6  alkyl provided that when Ar 2  is nitro-substituted phenyl or amino-substituted phenyl, then R 6  is hydrogen may be prepared by (a) reacting a compound XXXVI wherein m is 0 or 1 with a compound ArCON- (R<SP>9</SP>)2, wherein R<SP>9</SP> is an organic radical and the N together with the two R<SP>9</SP> radicals may be cyclic in the presence of a condensing agent to produce a compound XXXVII (b) reacting a compound XXXVIII  wherein R 7  is cyano or C 1-6  alkoxycarbonyl with a compound ArCO.O.OOCF 3  in CF 3 COOH to produce a compound XXXIX (c) reacting a compound XVIII with a compound Ar, CON(R<SP>9</SP>) 2  in the presence of a condensing agent to produce a compound XX perchlorinating the 2-methyl group in XX followed by hydrolysis to a 2-carboxy group and decarboxylation in a basic solvent to give XXIII (d) reacting a compound L or LI wherein R 8  is as R 7  with Ar CO-halide in the presence of a Lewis acid to produce Ia and Ib respectively wherein R 3  is COO(C 1-6  alkyl); (e) reacting a compound XXXII with Ar 2 CO-halide in the presence of a Lewis acid (with the proviso Ar is not amino substituted phenyl) to produce a compound If wherein R 3  is COOEt; (f) decarboxylating a compound LII by heating in a suitable solvent to produce a compound If wherein R 3  is COO(C 1-6  alkyl); (g) reacting a compound LIII with Ar 1 CON(R<SP>9</SP>) 2  in the presence of a condensing agent to produce a compound Ic, wherein R 3  is COO(C 1-6 ) alkyl; and (h) interconverting the groups R 2  or R 3 , modifying substituents on Ar or introducing R and R 6  groups by known methods. Intermediates of the Formula LII wherein Ar 2  is p-chloro- or methyl-phenyl, R 4  is methyl, R 5  is methyl and ethyl and lower alkyl is ethyl may be prepared by mono-esterification of the diacid which in turn is prepared by hydrolysis of the diethyl ester which is formed by a process similar to (d) or (e). Similarly, ethyl 4-C 1-4  alkyl or 1,4-di-(C 1-4 ) alkyl substituted pyrrole-2 acetate may be prepared by decarboxylation of the 3-carboxyl compound which in turn is formed by mono-esterification of 4-C 1-4  alkyl or 1,4-di-(C 1-4 ) alkyl substituted 3-carboxyl-1- pyrrole-2-acetic acid which is formed by hydrolysis of the diethyl ester which is prepared by cyclizing diethyl acetone dicarboxylate, a chloromethyl ketone and an alkylamine. Chloromethyl ethyl ketone is formed by direct chlorination of methyl ethyl ketone when 3-chloro-2-butanone is formed as a by-product. Pharmaceutical compositions of the compounds Ia-If show anti-inflammatory activity when administered orally or parenterally with a diluent or carrier.