GB1192223A - 0-Phenyl-2-Amino Ethanes and Derivatives - Google Patents

Abstract

1,192,223. 1 - Phenyl - 2 - amino - ethanes. BOEHRINGER INGELHEIM G.m.b.H. 23 June, 1967 [23 June, 1966; 26 Aug., 1966], No. 29217/67. Heading C2C. Novel compounds of the formula where R 1 is F, Cl or CF 3 , R 2 is H or a C 1-4 alkyl group, R 3 is C 2-5 alkyl, R 4 is H, a C 1-4 alkyl, theophyllin-(7)-ethyl, acyl, formyl, carbo-benzoxy, or carboalkoxy radical, and R 5 is Cl or C 1-3 alkyl, in the form of their racemates, pure stereoisomers, pairs of diastereoisomeric antipodes, and their physiologically acceptable acid addition salts, are obtained (a) by reacting a ketone of the formula with a compound of formula QNH 2 (where Q is H or C 1-4 alkyl) in a reducing medium, (b) by reacting a ketone of Formula II above with QNH 2 in the presence of formic acid or with a formate or N-formyl derivative of Q-NH 2 to form an N-formyl compound and then, when Q is other than H 2 , removing the formyl group by hydrolysis; (c) by reduction of compounds of the formula (where A is hydroxyl, amino or C 1-4 alkyl), (d) by reduction of a nitro-olefin of the formula (e) by reaction of a compound of the formula (where X is halogen or alkyl or arylsulphonyl) with a compound of the formula R<SP>1</SP> 4 -NH 2 (where R<SP>1</SP> 4 is H, C 1-4 alkyl or the theophyllin- (7)-ethyl group), (f) by reaction of compounds of Formula (VI) with an amine or amide having two protecting groups, whereby a protected amino group is introduced into the molecule, followed by removal of the protecting groups, (g) by Hofmann, Curtius or Schmidt degradation of compounds of the formula (where R 6 is an amino, azido or hydroxy group), (h) by elimination of the 1-halogen atom or hydroxy group from compounds of the formula (where Y is Cl, Br, I or OH), (i) by chlorination of compounds of the general formula (where R<SP>1</SP> 1 is H or R 1 , R 7 is H, acyl, or C 1-4 alkyl. Racemates may be split into optical antipodes by conventional methods, e.g. using dibenzoyltartaric acid or tartaric acid. Alternatively, optically active starting materials may be used. Pairs of diastereoisomeric antipodes may be separated by fractional crystallization. Preparation of the following intermediates is also described: p-chlorobenzaldehyde with 1-nitropropane yields 1-(p-chorophenyl)2-nitrobutene-(1) which is converted to 1-(p-chlorophenyl)-butanone-(2) and the latter is reacted with formamide to yield 1-(p-chlorophenyl)-2- formylamino - butane; 1 - (p - chlorophenyl)- butanone with hydroxylamine yields 1- (pchlorophenyl) - butanone - (2) - oxime; p - fluorobenzaldehyde with 1-nitropropane yields 1-(pfluorophenyl) - 2 - nitrobutene; p - chlorophenylbutylketone with Br 2 forms the α-bromine ketone which reacts with methylbenzylamine forming 1 - (p - chlorophenyl) - 1 - oxo - 2 - benzyl methylaminopentane isolated as the hydrochloride; reduction of the free base gives 1-(pchlorophenyl) - 1 - hydroxy - 2 - methylbenzylaminopentane as the hydrochloride which is hydrogenolysed to 1-(p-chlorophenyl)-1-hydroxy- 2-methylaminopentene then converted to 1-(pchlorophenyl - 1 - chloro - 2 - methylaminopentane; 3,4 - dichlorobenzaldehyde and 1 - nitropropane give 1-(3,4-dichlorophenyl)-2-nitrobutene which is reduced to 3,4-dichlorobenzyl ethyl ketone; diethyl malonate and p-chlorobenzyl chloride form a p-chlorobenzylmalonate which forms with ethyl bromide ethyl-p-chlorobenzyl malonate; the latter is saponified and decarboxylated to α-4-chlorobenzylbutyric acid; 1-(4- chlorophenyl) butanol is converted to the methane sulphonic acid ester and thence to 1-(4-chlorophenyl)-2-phthalimidobutane. Pharmaceutical compositions, having appetitereducing activity, comprise compounds of Formula I above together with a pharmaceutical carrier or excipient in forms suitable for oral or parenteral administration.