Patent GB-1198973-A (GB)
Title: Pyrrolidine Compounds with an Unsaturated Substituent and Methods for their Production
Inventor: LOCKHART IAN MOYLE
IPC: C07D207/08
Filed: 1969-02-07
Abstract: 1,198,973. m - (1 - Alkenyl - 3 - alkyl - 3 - pyrrolidinyl)-phenols and derivatives thereof. PARKE DAVIS & CO. 7 Feb., 1969, No. 6880/69. Heading C2C. Novel m - (1 - alkenyl - 3 - alkyl - 3 - pyrrolidinyl)-phenols and derivatives thereof of the general formula wherein R is a C 1-5  alkyl group, R<SP>1</SP> is an alkenyl, #-chloroalkenyl or #,#-dichloroalkenyl group containing from 2 to 5 carbon atoms and R<SP>2</SP> is a hydrogen atom or a -COY group, in which Y is a C 1-6  alkyl, cyclopropyl or cyclobutyl group, and salts thereof are prepared (a) when R<SP>2</SP> is a hydrogen atom, by reaction of the corresponding m - (1 - alkenyl - 3 - alkyl - 3 - pyrrolidinyl)- phenol derivative of the above general formula wherein R<SP>2</SP> is a C 1-6  alkyl or tetrahydropyranyl group, or a salt thereof, with a reagent capable of cleaving the ether linkage; (b) when R<SP>2</SP> is a hydrogen atom, by reduction of an m-( 1-alkenoyl- 3 - alkyl - 3 - pyrrolidinyl) - phenol or derivative thereof of the general formula with a complex metal hydride under anhydrous conditions, followed by hydrolysis; or (c) when R<SP>2</SP> is a -COY group, by reaction of the corresponding m - (1 - alkenyl - 3 - alkyl - 3 - pyrrolidinyl) - phenol or derivative thereof of the first general formula above wherein R<SP>2</SP> is a hydrogen atom, or a reactive derivative thereof, with a carboxylic acid of the general formula YCOOH, or a reactive derivative thereof; followed optionally by salification. m - (1 - Alkenyl - 3 - alkyl - 3 - pyrrolidinyl)- phenol derivatives of the first general formula above wherein R<SP>2</SP> is a C 1-6  alkyl group are prepared by reaction of an m-(C 1-6  alkoxy)-benzyl cyanide with sodium amide and then a C 1-5  alkyl halide, reaction of the resulting α-C 1-5  alkyl - m - (C 1-6  alkoxy) - benzyl cyanide with sodium amide and then ethylene dichloride, cyclization with lithium aluminium hydride of the resulting 1 - chloro - 3 - (m - C 1-6  alkoxyphenyl) - 3 - cyano - 3 - (C 1-5  alkyl) - propane, followed by hydrolysis, and reaction of the resulting 3 - (C 1-5  alkyl) - 3 - (m - C 1-6  alkoxyphenyl) - pyrrolidone with a halide of the general formula X-CH 2 -R<SP>1</SP>, wherein X is a halogen atom. m - (1 - Alkenyl - 3 - alkyl - 3 - pyrrolidinyl)- phenol derivatives of the first general formula above wherein R<SP>2</SP> is a tetrahydropyranyl group are prepared by reaction of a 3-(C 1-5  alkyl)-3- (m - C 1-6  alkoxyphenyl) - pyrrolidine with acetic ahydride in acetic acid, reaction of the resulting 1 - acetyl - 3 - (C 1-5  alkyl) - 3 - (m- C 1-6  alkoxyphenyl)-pyrrolidine with an acidic reagent capable of cleaving the ether linkage, reaction of the 1-acetyl - 3 - (C 1-5  alkyl) - 3 -(mhydroxyphenyl)-pyrrolidine so produced with 2,3 - dihydropyran in the presence of a small quantity of a mineral acid, hydrolysis of the 1 - acetyl - 3 - (C 1-5  alkyl - 3 - m - (tetrahydropyran - 2 - yloxy) - phenylpyrrolidine thus formed with potassium hydroxide in aqueous ethanol and reaction of the resulting 3-(C 1-5  alkyl) - 3 - m - (tetrahydropyran - 2 - yloxy)- phenylpyrrolidine with a halide of the general formula XCH 2 R<SP>1</SP>. m - (1 - Alkenyl - 3 - alkyl - 3 - pyrrolidinyl)- phenols and derivatives thereof of the second general formula above are prepared by reaction of a 3 - (C 1-5  alkyl) - 3 - (m - C 1-6  alkoxyphenyl)-pyrrolidine with an acid chloride of the general formula ClCOR<SP>1</SP> and reaction of the resulting 1 - alkenoyl - 3 - (C 1-5  alkyl) - 3 - (m - C 1-6  alkoxyphenyl) - pyrrolidine with an acidic reagent capable of cleaving the ether linkage. m - Isopropoxybenzyl cyanide is prepared by reaction of m-hydroxybenzaldehyde with sodium borohydride and then isopropyl bromide, reaction of the resulting m-iso-propoxybenzyl alcohol with thionyl chloride and reaction of the resulting m-isopropoxybenzyl chloride with potassium cyanide. 3 - (m - Isopropoxyphenyl) - 3 - propylpyrrolidine is prepared by reaction of α-propyl-misopropoxybenzyl cyanide with sodium amide and 2-bromoacetal and treatment of the resulting 1,1 - diethoxy - 3 - m - isopropoxyphenyl - 3 - cyanohexane with palladiumon-charcoal, ethanol and sulphuric acid. Pharmaceutical compositions having analgesic and morphine-antagonist properties comprise, as active ingredient, an m-(1-alkenyl-3-alkyl-3- pyrrolidinyl)-phenol or derivative thereof of the first general formula above or a salt thereof, together with a pharmaceutical carrier, and may be administered orally or parenterally.