GB791416A - Improvements in or relating to the production of substituted tetrahydrooxazines - Google Patents

Abstract

The invention comprises 2 - (3 - hydroxyphenyl)- and 2-(4-methoxyphenyl)-tetrahydro-oxazine, and a process for the preparation of tetrahydro-oxazines of the general formula <FORM:0791416/IV (b)/1> wherein R1 represents an aryl group which may contain a hydroxy or alkoxy substituent, R2 represents hydrogen or an alkyl or aryl group, and R3 represents an alkyl, aryl or aralkyl group, by heating a compound of the general formula <FORM:0791416/IV (b)/2> wherein R1, R2 and R3 have the above significance, in a high-boiling, water immiscible solvent in the presence of a catalytic amount of a mineral acid or a mineral acid salt of said compound to split off water to form a 5,6-dihydro-oxazine of the general formula <FORM:0791416/IV (b)/3> wherein R1, R2 and R3 have the above signi ficance, and the 5,6-dihydro-oxazine or a salt thereof with an inorganic or organic acid is then hydrogenated to form the desired tetrahydrooxazine or a salt thereof respectively. A suitable salt of the 5,6-dihydro-oxazine is the bioxalate salt. The water split out during the formation of the 5,6-dihydro-oxazine may be removed by azeotropic distillation, e.g. by using anisole or xylene as the reaction solvent. The above process is preferably applied to compounds in which R1 represents a phenyl group which may be substituted by a hydroxy group or an alkoxy group containing from 1 to 5 carbon atoms, R2 represents hydrogen or a phenyl or lower alkyl group and R3 represents a phenyl, benzyl or lower alkyl group. In the case of 4-benzyl-tetrahydro-oxazine prepared by the above process, further hydrogenation splits off the 4-benzyl group to form a tetrahydro-oxazine of the general formula <FORM:0791416/IV (b)/4> wherein R1 and R2 have the above significance. In the examples: (1) 2-phenyl-2-hydroxy-3,4-dimethyl-tetrahydro-oxazine is refluxed in anisole containing a small amount of hydrochloric acid to form 2-phenyl-3,4-dimethyl-5,6-dihydro-oxazine, oxalic acid is added to form the bioxalate salt which is hydrogenated in the presence of a palladium catalyst to form 2-phenyl-3,4-dimethyl-tetrahydro-oxazine bioxalate from which the free base is obtained by the addition of alkali; the hydrochloride of the free base is also mentioned; (2) by the method of (1) 2 - phenyl - 3 - methyl - 4 - benzyl - 5,6 - oxazine and the bioxalate thereof and 2-phenyl-3-methyl-4-benzyltetrahydro-oxazine and the bioxalate and hydrochloride thereof are prepared; 2 - phenyl - 3 - methyl - tetrahydro - oxazine is obtained by hydrogenating 2 - phenyl - 3 - methyl - 4 - benzyltetrahydro - oxazine in the presence of a palladium catalyst; (3) by the method of (1) using xylene as the solvent 2 - (3 - benzyloxyphenyl) - 4 - benzyl - 5,6 - dihydro - oxazine and the bioxalate salt thereof are prepared, the bioxalate salt is hydrogenated in the presence of a palladium catalyst and 2-(3-hydroxyphenyl)-tetrahydro-oxazine is then precipitated by the addition of alkali; (4) 2-(4-methoxyphenyl)-4-benzyl-5,6-dihydro - oxazine and 2 - (4 - methoxyphenyl) - tetrahydro-oxazine are prepared by the method of (1). Starting compounds. 2 - Phenyl - 2 - hydroxy-3,4-dimethyl-tetrahydro-oxazine and 2-phenyl-2-hydroxy - 3 - methyl - 4 - benzyltetrahydro - oxazine are prepared by reacting a -bromo-propiophenone with N-methyl-ethanolamine and N-benzyl - ethanolamine respectively. Specifications 705,543 and 773,780 are referred to.ALSO:Therapeutic compositions in the form of injectable solutions, tablets, drops or suppositories contain as the active ingredient 2-(3-hydroxyphenyl) - tetrahydro - oxazine or 2-(4-methoxyphenyl) - tetrahydro - oxazine. Specifications 705,543 and 773,780, [both in Group IV (b)], are referred to.