Patent GB-861377-A (GB)
Title: Novel basic esters
Inventor: DOYLE PETER FRANK
Filed: 1957-01-10
Abstract: The invention comprises compounds of the formula <FORM:0861377/IV (b)/1> wherein R is an alkyl group of 1-4 carbon atoms, e.g. methyl or ethyl, R1 is an alkyl group, preferably containing 1-5 carbon atoms, e.g. methyl, ethyl or propyl, R2 is a phenyl or cyclohexyl group, n is 1 or 2 and Ph represents phenyl, and acid addition salts thereof.  It also comprises the preparation of these compounds by the following methods: (a) reacting a compound of the general formula <FORM:0861377/IV (b)/2> wherein X is chlorine or bromine with a 1-alkyl-2-hydroxymethyl (or ethyl) pyrrolidine and treating the resulting ester hydrohalide with an alkanol and alkali or with an alkali metal alkoxide, the reaction with an alkanol being preferably carried out in the presence of sodium iodide as a catalyst; (b) reacting a compound of the formula <FORM:0861377/IV (b)/3> with a 1-alkyl-2-halo-methyl (or ethyl) pyrrolidine to give the hydrohalide salt of the desired compound, which is converted to the free base by treatment with alkali and (c) treating an ester of the formula <FORM:0861377/IV (b)/4> or an acid addition salt thereof with a halogenating agent to replace the hydroxy group by a halogen atom and reacting the resulting halide with an anhydrous alkanol or alkali-metal alkoxide, and where the product is a hydrohalide salt, treating with alkali to liberate the free base.  The products may be produced in optically active forms, either by using the appropriate optical isomers of the starting materials or by resolving the racemic form of the product.  The compounds are used pharmaceutically as analgesics and anti-tussive agents.  Examples describe the preparation of 1-alkyl-pyrrolidyl-2-methyl 1-alkoxy-1,1-diphenylacetates (R2=phenyl, n=1) in which R and R1 respectively have the values CH3, CH3; CH3, C3H4n; CH3, C9H5 n; CH3, C2H5; C2H5, C2H7; C2H5, CH3; C2H7, C3H7 n and C2H5, C3H7 iso; 1-alkyl-pyrrolidyl-2-ethyl 1-alkoxy-1,1-diphenylacetates (R2=phenyl, n=2) in which R and R1 respectively have the values CH3, CH3; C2H5, CH3; CH3, C2H5 and C2H5, C2H5; and also (11-methyl-21-pyrrolidyl)-methyl 1 - phenyl - 1 - cyclohexyl - 1 - methoxyacetate; the products are isolated as the free base or as a addition salt such as a hydrochloride or hydrobromide.  1 - Halogeno - 1,1 - diphenyl - acetic esters such as the 11-methyl-, 11-ethyl-, 11-n-propyl-, 11-isopropyl- and 11-n-butyl-, pyrrolidyl-(21)-methyl esters of 1-bromo-, or 1-chloro-, 1,1-diphenyl-acetic-acid and the 11-ethyl- and 1-methyl, pyrrolidyl-(21)-ethyl esters of 1-bromo-, or 1-chloro-, 1,1-diphenylacetic-acid are obtained as intermediates in methods (a) and (c) above.  1 - Alkyl - pyrrolidyl - (2) - methyl benzilates such as the 1-methyl-, 1-ethyl- and 1-isopropyl-compounds are made by reacting diphenylchloroacetyl chloride with a 1-alkyl-2-hydroxymethyl pyrrolidine and hydrolysing the resulting 1 - alkyl - pyrrolidyl - (2) - methyl diphenylchloroacetate with water. 1 - Alkyl - 2 - hydroxymethyl pyrrolidines.  The 1-ethyl-, 1-n-propyl- and 1-n-butyl-, 2-hydroxymethyl pyrrolidines are prepared by treating 2-hydroxymethyl pyrrolidine with acetic, propionic or butyric anhydride and reducing the resulting 1-acyl-2-hydroxymethylpyrrolidine with lithium aluminium hydride. 1 - Isopropyl - 2 - hydroxymethyl pyrrolidine is made by reacting iso-propyl iodide with the potassium derivative of butyl pyroglutamate and reducing the resulting butyl-1-isopropyl pyroglutamate with lithium aluminium hydride.  1 : 1 - Diphenyl - 1 - methoxyacetic acid is made by treating a -chloro-diphenyl acetyl chloride with methanol and hydrolysing the resulting methyl ester.  1 - Methyl - 2 - chloromethyl pyrrolidine is made by the action of thionyl chloride on 1-methyl-2-hydroxymethyl pyrrolidine.  1 - Phenyl - 1 - cyclohexyl - 1 - methoxyacetic acid is obtained by treating phenylcyclohexyl chloroacetyl chloride (obtained by the action of PCl5 on phenyl cyclohexyl glycollic acid) with methanol followed by hydrolysis of the resulting methyl ester.  Specifications 815,844, 820,503 and 833,820 are referred to.