SYNTHESIS OF (+)- AND (-)-1-(5,5-DIPHENYLTETRAHYDROFURAN-3-YL)-N,N-DIMETHYLMETHYLAMINE, (+)-AND (-)-1-(2,2-DIPHENYLTETRAHYDROFURAN-3-YL)-N,N-DIMETHYLMETHYLAMINE AND (+)- AND (-)-1-(2,2-DIPHENYLTETRAHYDROFURAN-3-YL)-N-METHYLMETHYLAMINE

摘要

The present invention relates to (+)- and (-)-1-(5,5-diphenyltetrahydrofuran-3-yl)-N,N-dimethyl-methylamine [(+)1] and [(-)1] respectively, including the pharmaceutically acceptable salts thereof. The new derivatives can be prepared by the reaction of 5,5-diphenyltetrahydrofuran-2(3H)-one [(4)] by introduction of an aldehyde group in an α-position, reduction to form the prechiral 3-(hydroxymethyl)-1,1-diphenylobutanediol-1,4 [(6)], chemoenzymatic desymmetrization by using Amano Lipase PS30, tosylation, intramolecular nucleophilic attack, hydrolysis, reaction with trifluoromethanesulfonic anhydride and substitution by dimethylamine to provide (+)-1-(5,5-diphenyltetrahydrofuran-3-yl)-N,N-dimethyl-methylamine [(+)1]. Protection of the chemoenzymatic desymmetrization product with tert-butyldimethylsilylchloride, hydrolysis, tosylation, intramolecular nucleophilic attack, removal of the tert-butyldimethylsilyl group, reaction with trifluoromethanesulfonic anhydride and substitution by dimethylamine provides (-)-1-(5,5-diphenyltetrahydrofuran-3-yl)-N,N-dimethyl-methylamine [(-)1]. The invention also relates to (+)- and (-)-1-(2,2-diphenyltetrahydrofuran-3-yl)-N,N-dimethyl-methylamine [(+)2] and [(-)2] respectively, and (+)- and (-)-1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methyl-methylamine [(+)3] and [(-)3] respectively, including the pharmaceutically acceptable salts thereof. The new derivatives can be prepared either by the treatment of 5-oxo-2,2-diphenyltetrahydrofuran-3-carboxylic acid [(13)] with LiAlH4, cyclization under acidic conditions of the produced triol [(14)], treatment with 1S-(-)- or 1R-(+)-camphanyl chloride, recrystallization, hydrolysis, treatment with trifluoromethanesulfonic anhydride and substitution by dimethylamine or methylamine, or by the treatment of racemic 1-(2,2-diphenyltetrahydrofuran-3-yl)-N,N-dimethyl-methylamine [(2)] with R-(-)- or (S)-(+)-mandelic acid and acetic acid, recrystallization and treatment with a base. The products of the invention exhibit neuroprotective, anti-epileptic and anti-depressive properties and may be employed as therapeutic agents.