Patent GB-1440380-A (GB)
Title: Pyrrolidine derivatives
IPC: C07D207/26
Filed: 1973-09-06
Abstract: 1440380 4-Pyrrolidino-butyrophenone derivatives SANDOZ Ltd 6 Sept 1973 [11 Sept 1972 21 Nov 1972] 41914/73 Heading C2C Novel 4 - pyrrolidino - butyrophenone derivatives of the general formula wherein R 1  is a hydrogen or halogen (atomic number 9-35) atom or a C 1-3  alkyl or C 1-3  alkoxy group and R 2  is a hydrogen or chlorine atom or a C 1-3  alkyl or C 1-3  alkoxy group or R 1  and R 2  together form a methylenedioxy group, R 3  is a hydrogen atom or a C 1-3  alkyl or C 1-3  alkoxy group, n is 1 or 2, R 4  is a hydroxyl, C 1-3  alkoxy, C 1-4  alkanoyloxy or (when n is 1) mono-C 1-4 -alkyl-carbamoyloxy group, R 5  is a hydrogen, fluorine or chlorine atom and A is a carbonyl, 1,3-dioxolan-2-ylidene or 1,3-dioxan- 2-ylidene group, and acid addition salts thereof are prepared (a) by reacting a pyrrolidine derivative of the general formula with a compound of the general formula wherein A<SP>1</SP> is a carbonyl group or a ketal protected derivative thereof and X is a chlorine, bromine or iodine atom or an organic sulphonic acid radical, and, if necessary, removing the protective radical from the product; (b) when R 4  is -O-Y-R 6 , wherein Y is -CO- or (when n is 1) -CO-NH- and R 6  is a C 1-4  alkyl group, by reacting the corresponding compound in which R 4  is -OH and A is A<SP>1</SP> with a compound of the general formula Y<SP>1</SP>-R 6  (IV), wherein Y<SP>1</SP> is X<SP>1</SP>-CO-, in which X<SP>1</SP> is a chlorine or bromine atom or an acid radical of a C 2-4  carboxylic acid, or, when n is 1 in the starting material, Y<SP>1</SP> may be alternatively OCN-, and, if necessary, removing the protective radical from the product; (c) when A is a carbonyl group, by oxidizing the corresponding alcohol of the general formula (d) when n is 1 and R 4  is -OR 6 , by etherifying the corresponding compound in which R 4  is -OH and A is A<SP>1</SP> (e.g. by reaction with methane sulphochloride and treatment of the resulting mesyloxymethyl derivative with an alkali metal alkanolate) and, if necessary, removing the protective radical from the product; and (e) when A is a carbonyl group, by removing the protective radical from the corresponding compound in which A is ketal-protected carbonyl group; followed optionally by salification of the product. Pyrrolidine derivatives of the Formula II wherein R 4  is -OW, in which W is -Y-R 6  or, when n is 1, R 6 , are prepared by benzylating the corresponding compound in which R 4  is -OH, reacting the resulting N-benzylpiperidine of the general formula with a compound (IV) or with an etherifying agent and debenzylating the resulting compound. Pyrrolidine derivatives of the Formula II wherein R 4  is -OR 7 , in which R 7  is a hydrogen atom or, when n is 2, a alkyl group, are prepared by reducing a pyrrolidone of the general formula wherein B is -(CH 2 ) n-1 COOR 8 , in which R 8  is a alkyl group, -(CH 2 ) 2 -OH or -(CH 2 ) 2 OR 6 , or the free acid corresponding to the said pyrrolidone wherein B is -(CH 2 ) n-1 COOR 8  (obtained by hydrolysis of the ester). Pyrrolidones of the Formula VII are prepared by catalytically hydrogenating a nitrile of the general formula Nitriles of the Formula VIII wherein B is -CH 2 COOR 8 , -(CH 2 ) 2 OH or -(CH 2 ) 2 OR 6 , are prepared by reacting an alkyl #-cyano-#- phenylpropionate of the general formula with a compound of the general formula X"-B, wherein X<SP>II</SP>is a chlorine or bromine atom, in the presence of a basic condensation agent. Alkyl # - cyano - # - phenylpropionates of the Formula (IX) are prepared by reacting an R 1 , R 2 , R 3 -substituted benzaldehyde with a malonic acid ester of the general formula CH 2 (COOR 8 ) 2  and reacting the resulting benzalmalonic acid ester of the general formula with an aqueous alkali metal cyanide. Alcohols of the Formula V are prepared by reacting a pyrrolidine derivative (II) with a compound of the general formula Pharmaceutical compositions having analgesic activity comprise, as active ingredient, a 4- pyrrolidino-butyrophenone derivative (I) or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or diluent.