Patent GB-924322-A (GB)
IPC: C07D243/28
Abstract: 924,322. Substituted benzophenones. F. HOFFMANN-LA ROCHE & CO. A.G. June 26, 1961 [June 27, 1960; Dec. 2, 1960; March 20, 1961], No. 22991/61. Class 2(3). The invention comprises compounds of the formula (wherein R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP> and R<SP>4</SP> each represents an alkyl radical, R<SP>5</SP> represents a halogen atom, the trifluoromethyl radical or an alkyl or alkylthio radical, R<SP>6</SP> and R<SP>7</SP> may each have any of the values of R<SP>5</SP> or. may each represent a cyano, nitro or alkoxy radical and the broken lines denote that R<SP>5</SP>, R<SP>6</SP> and R<SP>7</SP> are optional substituents of which at least one must be present, and the alkyl and. alkylene radicals and portions of substituents contain at most 7 carbon atoms) and acidaddition and quaternary ammonium salts thereof; and their preparation by reacting a ketone of the. formula with ammonia or the appropriate alkylamine or dialkylamine. In examples (1) 2-chloro- 5-trifluoromethyl-aniline is diazotized and converted via a zinc chloride double salt into 2-chloro- 5-trifluoromethylbenzonitrile, this with a phenyl Grignard reagent gives 2-chloro-5-trifluoromethyl-phenyl phenyl ketimine hydrochloride, this on hydrolysis gives the corresponding ketone, this with ammonia gives 2-amino-5-trifluoromethyl-phenyl phenyl ketone, this with bromoacetyl bromide gives 2- bromomethylcarbonylamino- 5- trifluoromethyl-phenyl phenyl ketone and this with ammonia gives the 2-aminomethylcarbonylamino compound; (2) 2-chloro-5-trifluoromethyl-benzonitrile is hydrolysed to 2-chloro- 5-trifluoromethyl-benzoic acid, this with thionyl chloride gives the acid chloride, this with 2-trifluoromethyl-phenyl magnesium bromide gives 2-chloro-5-trifluoromethyl-phenyl- 2-trifluoromethyl-phenyl ketone, this with ammonia gives 2-amino- 5-trifluoromethylphenyl 2-trifluoromethyl-phenyl ketone (via the sulphate thereof) and this with bromoacetyl bromide and then ammonia gives the 2-aminomethylcarbonylamino compound; (3) 2-trifluoromethylphenyl magnesium bromide and 2-methyl-4H-3,1-benzoxazinone-(4) give 2- aminophenyl 2- trifluoromethylphenyl ketone, which is then treated as in (2) to give 2-aminomethylcarbonylamino- 21-trifluoromethyl-benzophenone; and 5-chloro- 2- aminomethylcarbonylamino- 2<SP>1</SP>- trifluoromethyl-benzophenone and 6-chloro-2-aminomethylcarbonylamino-benzophenone are prepared similarly; (4) 2-chloro-benzoyl chloride and p-chloraniline give 2-amino-5-chlorophenyl 2-chloro-phenyl ketone, this with bromacetyl bromide gives 2-bromomethylcarbonylamino- 5-chloro-phenyl 2-chloro-phenyl ketone and this with ammonia gives the 2- aminomethylcarbonylamino compound; similarly are prepared the 2-aminomethylcarbonylamino derivatives of 5-chloro-2<SP>1</SP>- methyl-, 5-chloro- 2<SP>1</SP>-fluoro-, 5-bromo- 2<SP>1</SP>- fluoro-, 5-chloro-, 6-nitro-, 5-nitro-, 4-nitro- and 5-methyl-benzophenone and the hydrochlorides of some of these; (5) 2-amino-5- methyl-phenyl phenyl ketone and acetic anhydride give 2- methylcarbonylamino -5- methyl-phenyl phenyl ketone, this with potassium permanganate gives 2-methylcarbonylamino-5-carboxy-phenyl phenyl ketone, this with ethyl chlorocarbonate and ammonia gives 2- methylcarbonylamino- 5- aminocarbonyl-phenyl phenyl ketone, this is dehydrated with phosporus oxychloride to 2- methylcarbonyl-amino-5-cyano-phenyl phenyl ketone, this is hydrolysed to 2-amino-5- cyano-phenyl phenyl ketone, this with bromoacetyl bromide gives 2-bromoethylcarbonylamino- 5-cyanophenyl phenyl ketone, and this with ammonia gives the 2- aminomethylcarbonylamino compound; and similarly are prepared 2- aminomethylcarbonylamino- 5- cyano- 2<SP>1</SP>- fluoro and 2<SP>1</SP>-chloro-benzophenones; (6) 1- methoxy-3-acetylamino-benzene and benzoyl chloride give 4- methylcarbonylamino- 2- methoxy-phenyl phenyl ketone and 2-methylcarbonylamino- 4-methoxyphenyl phenyl ketone, the latter is brominated to the 5- bromo-compound, this is hydrolysed to 2- amino- 5-bromo- 4-methoxyphenyl phenyl ketone, this with bromacetyl bromide gives 2- bromomethyl-carbonylamino- 5-bromo- 4 methoxy-phenyl phenyl ketone and this with ammonia gives the aminomethlycarbonylamino compound; (7) anthranilic acid and N,N-dimethylformamide in thionyl chloride give 2-dimethylcarbonylaminobenzoic acid hydrochloride, this with phosphorus pentachloride and then benzene gives on hydrolysis 2-aminophenyl phenyl ketone, this with sodium thiocyanate gives 2-amino-5-thiocyano-phenyl phenyl ketone, this with sodium hydrogen sulphite and sodium hydroxide and then dimethyl sulphate gives 2-amino-5- methylthio-phenyl phenyl ketone, this with bromacetyl bromide gives 2-bromomethylcarbonylamino- 5- methylthio-phenyl phenyl ketone and this with ammonia and then hydrogen chloride gives 2-aminomethylcarbonylamino-5-methylthio-benzophenone hydrochloride; (8) 2-amino-5-nitro-phenyl phenyl ketone and α-bromo-propionyl bromide give 2-[(1-bromoethyl)carbonylamino] -5-nitrophenyl phenyl ketone and this with ammonia gives the 1-amino-ethyl compound; (9) 2- amino-5-chloro-phenyl 2-chloro-phenyl ketone and tosyl chloride give 2-(p-toluenesulphonylamino)- 5-chlorophenyl 2-chlorophenyl ketone, this with sodium methylate gives the N-methyl derivative, this on hydrolysis gives 2-methylamino- 5-chlorophenyl- 2-chlorophenyl ketone, this with bromacetyl bromide gives 2- [methyl- (bromomethylcarhonyl) amino]- 5-chlorophenyl 2-chlorophenyl ketone, and this with ammonia gives the aminomethyl compound; (10) 2-methylaminomethylcarbonylamino- 2<SP>1</SP>,5- dichlorobenzophenone and 2-methylaminomethylcarbonylamino-5-chloro-benzophenone are prepared from the bromo compounds and methylamine; (11) 2-dimethylaminomethylcarbonylamino-21,5-dichlorobenzophenone is similarly prepared and then converted to its methobromide; (12) o-fluoro-benzoyl chloride and p-chloraniline give 2-amino-5-chloro-phenyl 2-fluoro-phenyl ketone, this with sodium methylmercaptan gives 2-amino- 5-chlorophenyl 2-methylthio-phenyl ketone, this with bromacetyl bromide gives 2-bromomethylcarbonylamino- 5- chloro-phenyl- 2- methylthiophenyl ketone and this with ammonia gives the 2-aminomethylcarbonylamino compound; and (13) 2-amino-phenyl 2-trifluoromethylphenyl ketone and sodium thiocyanate with bromine give 2-amino-5-thiocyanophenyl 2- trifluoromethylphenyl ketone, this with sodium hydrogen sulphite and sodium hydroxide and then dimethyl sulphate gives 2- amino-5-methylthio-phenyl 2-trifluoromethylphenyl ketone, this with bromacetyl bromide gives 2-bromomethylcarbonylamino-5-methylthio-phenyl 2-trifluoromethyl-phenyl ketone and this with ammonia gives the 2-aminomethylcarbonylamino compound. The benzophenones of the invention, which are stated to be of use as anticonvulsants and tranquilizers, can be made up into pharmaceutical compositions for internal administration, e.g. solutions, suspensions, capsules, tablets and suppositories.