Patent GB-1003687-A (GB)
Title: Substituted amines, and processes for their production
IPC: C07C45/63
Filed: 1963-06-19
Abstract: The invention comprises compounds of the general formula <FORM:1003687/C2/1> and their acid addition salts, wherein R1 is hydrogen, methyl or ethyl; R2 is hydrogen, phenyl or X; R3 is phenoxy or R2; R4 is hydrogen, C1- 4 alkyl or C1- 4 hydroxyalkyl; X is a phenyl radical substituted by one or two tertiary C1- 4-alkyl groups and optionally by an OH group; Y is a straight or branched C1- 3 alkylene chain; m is 0 or 1, n is 1-3 whereby the group (CH2)n CHR1- possesses at most 4 carbon atoms in all and the preparation thereof (a) by introducing into an amine of the formula <FORM:1003687/C2/2> the radical <FORM:1003687/C2/3> into an amine of the formula <FORM:1003687/C2/4> the radical <FORM:1003687/C2/5> or into an amine of the formula <FORM:1003687/C2/6> the radical R4 by known substitution or addition methods; (b) by treating a compound of the formula I but which contains hydrogenolytically removable radicals or a C = N double bond or one or more non-aromatic C=C double bonds or one or more carbonyl groups, with reducing agents; (c) liberating in a compound of formula I but containing a functionally modified hydroxy or amino group, the hydroxy and/or amino group, or converting an amino group present instead of a hydroxy group, into a hydroxy group by diazotization and boiling and if desired, (d) converting a tertiary amine of the formula I (however formed) into a physiologically compatible acid addition salt by treatment with an acid, or liberating a free base from its acid addition salt. Compounds formed as racemates may be resolved into their optical isomers.  4 - Tert - butyl - 3 - hydroxy - 2,6 - dimethyl phenethylamine is prepared by hydrogenating the benzyl cyanide; 4 - tert - butyl - 3 - hydroxy - 2,6 - dimethyl - phenylacetone from the benzyl cyanide and methyl magnesium iodide; similarly is prepared 1 - (41 - tert - butyl - 31-hydroxy - 21,61 - dimethylphenyl) - butane - 2- one; N - ethyl - a  - (4 - tert, butyl - 3 - hydroxy-2,6-dimethylphenyl acetamide from the benzyl cyanide by saponifying and treating with thionyl chloride and ethylamine; N-acetyl-4-tert. butyl - 3 - hydroxy - 2,6 - dimethyl - phenethylamine by acetyling the amine; N-acetyl-3 - (31,51 - di tert butyl - 41 - hydroxyphenyl propylamine from 3,5 - di - tert butyl - 4 - hydroxybenzaldehyde and cyanoacetic acid to give the cinamnic acid nitrile followed by hydrogenation to give the amine, and acetylation; 31 - (31 - ethyl - 51 - tert - butyl - 41 - hydroxyphenyl) propylamine is prepared by reacting p - bromo - o - ethyl phenol with isobutylene to give 2 - ethyl - 4 - bromo - 6 - tertbutyl - phenol, hydrogenating this to 2 - ethyl- 6 - tert butyl - phenol converting this to 3-ethyl - 5 - tert butyl - 4 - hydroxy - benzaldehyde forming the cinnamic acid nitrile and hydrogenating this; N-benzyl-4-tert-butyl-N,2,6-trimethyl phenethylamine hydrochloride by benzylating the amine; 4 - (41 - tert. butyl - 31-hydroxy - 21,61 - dimethylphenyl) - butane - 2 - one from 4 - tert butyl - 3 - hydroxy - 2,6 - dimethyl benzyl chloride and acetoacetic ester, and similarly, 4 - (21,61 - di - tert butyl - 61-methyl phenyl - butane - 2 - one; 3 - (41 - tert butyl - 31 - hydroxy - 21,61 - dimethylphenyl) - 1 - methyl-propylamine from the above butane-2-one and ammonia with subsequent hydrogenation; N - acetyl - 4 - tert. amyl - 3 - hydroxy-2,6 - dimethyl phenylethylamine from 2,4 - dimethylphenol with trimethyl ethylene to give 2 - tert. - amyl 4,6 - dimethylphenol, chloromethylating this followed by reaction with sodium cyanide, reduction and acetylation and similarly is prepared N - acetyl - 3 - hydroxy-2,6 - dimethyl - 4 - (31 - methyl pentyl - 31) phenethylamine; N,N - diethyl - a  - (4 - tert - butyl - 3 - hydroxy - 2,6 - dimethylphenyl)-acetamide by saponifying the cyanide to form the phenylacetic acid and reaction with thionyl chloride and diethylamine; g -(3-tert-butyl-4-hydroxy - 5 - methylphenyl) - propylamine from 2-methyl - 6 - tert - butyl - phenol and N - methyl formanilide to form 3-tert-butyl-4-hydroxy-5-methyl-benzaldehyde which with cyanacetic acid gives the cinnamic acid nitrile which is reduced, similarly is prepared g -(3,5-di-tert-butyl-4-hydroxy - phenyl) propylamine; (3 - tert - butyl - 4-hydroxy - 5 - methylbenzyl) methyl - ketone by reacting 2-methyl-6-tert-butyl phenol with propionyl chloride to give the phenol ester saponifying this to 3-tert-butyl-4-hydroxy-5-methyl - propiophenone, brominating to form a  - bromo - 3 - tert - butyl - 4 - hydroxy - 5-methyl propiophenone forming the amino-ketone reducing to the amino-ethanol and reacting this with phosphorous oxychloride.  Pharmaceutical compositions comprise the compounds of formula I in admixture with a carrier and may be in a form suitable for enteral, parenteral or local administration such as tablets, dragees, solutions, suspensions, emulsions, and ointments.  The compounds show anorexic, diuretic, bacteriocidal hypotensive and spasmolytic activities. Specifications 967,594 and 980,008 are referred to.