Patent GB-1140754-A (GB)
Title: 3,4-difluorophenyl compounds
Inventor: DANILEWICZ JOHN CHRISTOPHER
IPC: C07C49/807
Filed: 1966-09-21
Abstract: 1,140,754. Difluorophenyl oximes and amines. PFIZER Ltd. 21 Sept., 1967 [21 Sept., 1966; 26 Jan., 1967], Nos. 42071/66 and 3854/67. Heading C2C. The invention comprises compounds of the formula where X is -CO- or -CH(OH)-, R is C 1-4  alkyl, and either Y<SP>1</SP> is H and Y<SP>2</SP> is NH 2 , or Y<SP>1</SP>Y<SP>2</SP> is =N-OH and the pharmaceutically acceptable acid addition salts of the compounds in which Y<SP>1</SP> is H and Y<SP>2</SP> is NH 2 . Compounds in which X is -CO- and Y<SP>1</SP>Y<SP>2</SP> is =N-OH are obtained by nitrosating a 3<SP>1</SP>,4<SP>1</SP>-difluoro C 2-5  alkyl phenone using, for example, an alkyl nitrite and hydrogen halide, nitrous acid, nitrosyl chloride or diphenylnitrosamine. A compound in which X is -CH(OH)- and Y<SP>1</SP>Y<SP>2</SP> is =N-OH or Y<SP>1</SP> is H and Y<SP>2</SP> is NH 2  can be obtained by reducing the corresponding compounds in which X is -CO- with an alkali metal borohydride or a mixture of an aluminium alkoxide and the corresponding alcohol. Compounds in which X is -CO- or -CH(OH)- and Y<SP>1</SP> is H and Y<SP>2</SP> is NH 2  are obtained from the corresponding compounds in which Y<SP>1</SP>Y<SP>2</SP> is =N-OH by reaction of the oxime with hydrogen in the presence of a catalyst, e.g. palladium, at a temperature of, for example, 10-60‹ C. for 2-24 hours. Compounds in which X is -CO-, Y<SP>1</SP> is H and Y<SP>2</SP> is NH 3  may also be made by (a) reaction of odifiuorobenzene with an N-di-substituted α- amino-acid chloride in the presence of a Friedel- Crafts catalyst, followed by removal of the N- substituents; (b) reaction of 3,4-difluorophenyl magnesium bromide with an N-disubstituted α-aminonitrile and subsequent removal of N- substituents; (c) reaction of a 3<SP>1</SP>,4<SP>1</SP>-difluoro C 2-5  alkylphenone with Br 2  to form the 2- bromo-ketone, reacting this with an N-disubstituted amine then removing N-substituents; (d) reacting a fluorinated ketone as in (c) with hydroxylamine yielding the oxime which is reacted with p-toluene sulphonyl chloride and subjecting the tosyl derivative to the Neber re-arrangement. Compounds where X is -CH(OH)-, Y<SP>1</SP> is H and Y<SP>2</SP> is NH 2  are also made by (e) reduction of the fluorinated oxime where X is -CO- and Y<SP>1</SP>Y<SP>2</SP> is = N-OH using LiAlH 4 ; (f) reaction of 3,4-difluorobenzaldehyde with Zn and the ethyl ester of an α-bromo-acid, conversion to the hydrazide, treatment with nitrous acid and Curtius rearrangement. Products of (e) and (f) are erythro isomers. A threo isomer is obtained by reducing a N-disubstituted aminoalkyl-3,4- difluorophenone with LiAlH 4  then removing N- substituents. 3,4-Difluoropropiophenone is obtained by reacting o-difluorobenzene with propionyl chloride. 3,4-Difluorobutyrophenone is obtained from odifluorobenzene and butyric anhydride. 1 - (3,4 - Difluorophenyl) - propane - 1,2- dione is obtained by hydrolysis of anti-3<SP>1</SP>,4<SP>1</SP>- difluoro-2-oximinopropiophenone with sulphuric acid. 2 - Bromo - 3<SP>1</SP>4<SP>1</SP> - difluoropropiophenone is obtained from 3,4<SP>1</SP>-difluoropropiophenone and Br 2  in glacial acetic acid. 2 - Dibenzylamino - 3<SP>1</SP>,4<SP>1</SP>- difluoropropiophenone is obtained by reacting the above compound with dibenzylamine. Pharmaceutical compositions, useful as antihypertensive agents comprise a compound of Formula (1) together with a pharmaceutical carrier in forms suitable for oral or parenteral administration.