CS239762B1 - Process for the preparation of methylimine 1-hydroxycyclopentyl- (2-chlorophenyl) ketone hydrochloride - Google Patents

Abstract

methylimine hydrochloride 1-hydroxycyclopentyl-/2-chlorophenyl/-ketone is a key intermediate for the preparation of 2-(2-chlorophenyl/.-2-methylaminocyclohexanone hydrochloride. , ■ This substance is used in pharmacy under the generic name Ketamine in injectable form as an ultra-short narcotic. Methylimine hydrochloride 1-hydroxycyclopentyl-/J-chlorophenyl/-ketone is prepared by reacting 1-hydroxycyclopentyl-/2- -chlorophenyl/-ketone dissolved in lower alcohols, preferably in methanol, with gaseous methylamine under the catalysis of methylamine hydrochloride at a temperature of 20 to 60 °C. The substance is then diluted with benzene, filtered, distilled off with benzene, diluted with acetone, acidified with ethereal hydrogen chloride solution, isolated by crystallization in a yield of about 60% th.

Description

Methylimine hydrochloride 1-hydroxycyclopentyl- (2-chlorophenyl) -ketone is a key intermediate of the synthesis of 2- (2-chlorophenyl) -2-methylaminocyclohexanone hydrochloride. This substance, under the generic name Ketamine, is used in pharmacy as an injection as an ultra-short narcotic.

Methylimin-i-hydroxycyclopentyl- (2-chlorophenyl) ketone is prepared according to the patents of Parke-David: Stevens C. L. US Pat. 3254124 (1966), U.S. Pat. 3394182 (1968), Belg. U.S. Pat. 634208 (1962), by reacting 1-bromocyclopentyl- (2-chlorophenyl) ketone with liquid methylamine.

A disadvantage of the process disclosed in the US patents is that special technical equipment for reactions at temperatures of -20 to -40 ° C is required for operational implementation. This fact limits the implementation capacity of the production equipment.

The technical disadvantages of this process are eliminated by the novel process of the present invention, which consists in reacting 1-hydroxycyclopentyl- (2-chlorophenyl) ketone, which is an intermediate of the synthesis, in a solution of lower alcohols, preferably methanol with methvlamine gas. , for catalyzing methylamine hydrochloride.

The reaction temperature is between 20 and 60 ° C. The reaction temperature begins at 20 ° C, then rises to 60 ° C and then begins to fall again. After adding 7 moles of methylamine per mole of 1-hydroxycyclopentyl- (2-chlorophenyl) ketone, methanol is distilled off, replaced with benzene, the benzene solution is filtered, the filtrate is concentrated in vacuo, replaced with acetone and the desired compound is obtained by acidifying the acetone solution with ethereal hydrogen chloride. in the form of a beige crystalline substance ·

The yield of the reaction, calculated on the starting 1-hydroxycyclopentyl- (2-chlorophenyl) ketone, is about 60% th. The material thus prepared is suitable for further processing into the hydrochloride of 2- (2-chlorophenyl) -2-methylaminocyclohexanone without further purification.

EXAMPLE 1-Hydroxycyclopentyl-2 (chlorophenyl) ketone (318 g) was dissolved in 300 ml of methanol, 15 ml of ethereal hydrogen chloride solution was added, and methylamine gas was passed from the steel bottle with stirring.

The temperature of the reaction mixture rises spontaneously until it reaches about 55 ° C. Methylamine gas is then added while stirring the solution until a total of 314 g of gas is introduced. The addition was discontinued and the reaction mixture was allowed to stand for 16 hours.

Methanol is distilled off from the reaction mixture in vacuo, the mixture is diluted with 300 ml of benzene, the benzene solution is filtered through a Seitz filter on which a layer of 30 g of ostacol is deposited and the benzene filtrate is distilled off under vacuum.

The residual oil is dissolved in 480 ml of acetone and, without cooling, the reaction mixture is acidified to pH 1 with ethereal hydrogen chloride with stirring. During acidification, a crystalline substance precipitates from the solution. The mixture was allowed to cool in the refrigerator for 16 hours, then filtered and washed with acetone on the filter.

The yield of crystalline substance is 242 g, i.e. 62.3% of th. The substance is chromatographically uniform and capable of further processing.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of 1-hydroxycyclopentyl- (2-chlorophenyl) ketone methylimine hydrochloride, characterized in that the 1-hydroxycyclopentyl- (2-chlorophenyl) ketone dissolved in lower alcohols, preferably methanol, is reacted with methylamine gas under catalysis methylamine hydrochloride, at a reaction temperature of 20 to 60 ° C, after which the product is isolated after distillation of the alcohol, dilution with benzene, filtration of the benzene solution, distillation of benzene, dilution with acetone and acidification with ethereal hydrogen chloride to pH 1.