Patent GB-1185987-A (GB)
Title: Morpholine Derivatives and Process for their Production
IPC: C07D265/30
Filed: 1967-03-15
Abstract: 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 R<SP>1</SP> represents a hydrogen atom, or both R<SP>1</SP> together represent a methylene group, R<SP>11</SP> 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 R<SP>1</SP> represents hydrogen, and R<SP>11</SP>, X, Y and Am have the meanings above, or both R<SP>1</SP> represents a methylene group, X represents C 1-5  alkanoyloxy or C 1-4  alkanoylamino while, simultaneously Y represents hydrogen and R<SP>11</SP> 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 R<SP>1</SP> represents an arylmethyl or diarylmethyl group or both R<SP>1</SP> together represent a methylene group, and R<SP>11</SP> 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 R<SP>11</SP> and possibly as R<SP>1</SP> 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.