Verfahren zur Herstellung von neuen Morpholinderivaten

摘要

1,185,987. Morpholine derivatives. J. R. GEIGY A.G. 15 March, 1967 [16 March, 1966], No. 12107/67. Heading C2C. The invention comprises a process for preparing morpholine derivatives of the Formula (II) wherein each R1 represents a hydrogen atom, or both R1 together represent a methylene group, R11 represents a hydrogen atom, X represents hydrogen, hydroxyl, amino, C 1-5 alkanoyloxy, or C 1-4 alkanoylamino, while simultaneously Y represents hydrogen, or X and Y together represents the ozo group, and Am represents an amino, C 1-4 alkylamino or di-(C 1-4 alkyl)amino, a polymethyleneimino group having 5-8 ring members or a morpholine group as well as their pharmaceutically acceptable acid addition salts, and the novel compounds of the above Formula (II) in which each R1 represents hydrogen, and R11, X, Y and Am have the meanings above, or both R1 represents a methylene group, X represents C 1-5 alkanoyloxy or C 1-4 alkanoylamino while, simultaneously Y represents hydrogen and R11 and Am have the meanings given above and the pharmaceutically acceptable acid addition salt. The said process consists of treating a compound of Formula (II) above wherein each R1 represents an arylmethyl or diarylmethyl group or both R1 together represent a methylene group, and R11 represents an arylmethyl or diarylmethyl group, or an acid addition salt thereof, with catalytically activated hydrogen until the amount required to split off the arylmethyl or diarylmethyl radicals present as R11 and possibly as R1 has been taken up and, if desired, converting the product into a pharmaceutically acceptable acid addition salt. d,l - cis (diequat.) - N - Methyl - 4 - benzyl - 6 - (3,4 - dibenzyloxyphenyl) - 2 - morpholine propionamide (A) is obtained by the sequence: α - aminomethyl - 3,4 - dibenzyloxybenzyl alcohol#3,4 - dibenzyloxy - α - (benzylideneaminomethyl) - benzyl alcohol#3,4 - dibenzyloxy - α - (benzylaminomethyl)- benzyl alcohol #ethyl 5 - [N - benzyl - N - (3,4 - dibenzyloxy- # - hydroxyphenethyl)amino]- 4 - hydroxy - valerate#ethyl d,l - cis (diequat.) - 4 - benzyl - 6 - (3,4 - dibenzyloxyphenyl) - 2 - morpholine propionate# A. d,l - cis (diequat.) - 4 - Benzyl - 6 - (3,4 - dibenzyloxy - phenyl) - 2 - morpholine lactamide (B) is prepared by the sequence: 3,4-dibenzyloxy - α - (benzylaminomethyl) - benzyl alcohol #4 - [N - benzyl - N - (3,4 - dibenzyloxy - # - hydroxy - phenethyl) amino] - 3 - hydroxy - butyraldehyde diethyl acetal#d,l-cis (diequat.)-4cbenzyl - 6 - (3,4 - dibenzyloxyphenyl) - 2 - morpholine acetaldehyde diethyl acetal#d,l-cis (diequat.) - 4 - benzyl - 6 - (3,4 - dibenzyloxyphenyl) - 2 - morpholine acetaldehyde# corresponding acetaldehyde cyanohydrin#corresponding lactic acid ethyl ester#(B). d,l-cis(diequat.) - 4 - Benzyl - 6 - (3,4 - dibenzyloxy phenyl)-2-morpholine pyruvic acid is made by oxidizing Compound B above with activated manganese dioxide. Ethyl 4,5-epoxyvalerate is prepared by reacting ethyl allylacetate with perbenzoic acid. d,l - cis (diequat.) - N - Methyl - 4 - benzyl - 6 - (3,4 - dibenzyloxyphenyl) - 2 - morpholine alanine amide (C) is obtained by the sequence: d,l-cis (diequat.) - 4 - benzyl - 6 - (3,4 - dibenzyloxyphenyl) - 2 - morpholine acetaldehyde cyanohydrin#d,l - cis (diequat.) - a - amino - 4 - benzyl - 6 - (3,4 - dibenzyloxyphenyl) - 2 - morpholine propionitrile#d.l - cis (diequat.) - 4 - benzyl - 6 - (3,4 - dibenzyloxyphenyl) - 2 - morpholine alanine ethyl ester#. d,l - cis (diequat.) - 4 - Benzyl - 6 - (3,4 - methylenedioxyphenyl) - 2 - morpholine lactamide (D) is obtained by the sequence: α- aminomethyl - 3,4 - methylenedioxybenzyl alcohol#3,4 - methylenedioxy- α - (benzylideneaminomethyl) - benzyl alcohol#3,4 - methylenedioxy - α- (benzylaminomethyl) - benzyl alcohol#4 - [N - benzyl - N - (3,4 - methylenedioxy - # - - hydroxyphenethyl)amine]- 3 - hydroxybutyraldehyde diethyl acetal#d,lcis (diequat.) - 4 - benzyl - 6 - (3,4 - methylenedioxy - phenyl) - 2 - morpholine acetaldehyde diethyl acetal # corresponding aldehyde #cyanohydrin#corresponding lactic acid ethyl ester #D. d,l - cis (diequat.) - α - acetoxy - 4 - benzyl - 6 - (3,4 - methylenedioxyphenyl)- 2 - morpholine propionamido is made by reacting acetic anhydride with Compound D above. d,l - cis (diequat.) - 4 - benzyl - 6 - (2,3 - dibenzyloxyphenyl) - 2 - morpholine lactamide (E) is obtained by the sequence: 2,3-dibenzyloxymandelonitrile#α - aminomethyl - 2,3 - dibenzyloxybenzyl alcohol#2,3 - dibenzyloxy- α - (benzylideneaminomethyl) - benzyl alcohol# 2,3 - dibenzyloxy - α - (benzylaminomethyl)benzyl alcohol#4 . [N - benzyl - N - (2,3 - dibenzyloxy - # - hydroxyphenethyl)amino] - 3 - hydroxybutyraldehyde diethyl acetal#d,l - cis (diequat.) - 4 - benzyl - 6 - (2,3 - benzyloxyphenyl) - 2 - morpholine acetaldehyde diethyl acetal# aldehyde# cyanohydrin# corresponding lactic acid ethyl ester#E.