CS247445B1 - Process for producing 3- (7-theophyllyl) -1- (N-methyl-N-2- hydroxyethyl) amino-2-propanol nicotinate - Google Patents

Abstract

The essence of the process is the preparation of an alkaline salt of theophylline using a solution obtained by dissolving solid sodium or potassium hydroxide in lower aliphatic alcohols or in mixtures of these alcohols with toluene or xylene and subsequent processing of the salt thus formed in a known manner, i.e. by alkylation with 1-(N-methyl-N-2-hydroxyethyl)- -amino-3-chloro-2-propanol and conversion of the resulting product to a nicotinate salt. The invention can be used in the production of nicotinate 3-(7-theophyllyl)-1-(N-methyl-N-2-hydroxyethyl)amino-2-propanol or derivatives of this compound.

Description

The invention relates to a process for the preparation of nicotinate 3- (7-theophyllyl) -1- (N-methyl-N-2-hydroxyethyl) amino-2-propanol (generic name xantinol nicotinate).

This medicine is used as a medicine in diseases related to insufficient peripheral blood circulation.

The present process advantageous for industrial use is based on the alkylation of the theophylline alkali salt with 1- (N-methyl-N-2-hydroxyethyl) amino-3-chloro-2-propanol and the conversion of the resulting intermediate to a nicotinate salt, i.e. to xantinol nicotinate. . Lower aliphatic alcohols are used as the reaction medium (US Patent 2,924,598 (1960), DB Patent 1,102,750 (1961)). An increase in yields was achieved by a production process in a mixture of a lower aliphatic alcohol and toluene or xylene (AO No. 182 386 (1980)). The latter also reduced contamination of the crude product with sodium chloride. A common feature of the above procedures was that theophylline sodium was prepared using an aqueous sodium hydroxide solution.

The essence of the new preparation process is to substantially reduce the presence of water in the reaction, which is due to the fact that the sodium or potassium salt of theophylline is obtained by a solution prepared from solid sodium or potassium hydroxide in a mixture of methanol or ethanol with toluene or xylene. alkylation with 1- (N-methyl-N-2-hydroxyethyl) amino-3-chloro-2-propanol and converting the resulting intermediate to the nicotinate salt. Solid sodium hydroxide or potassium hydroxide can also be dissolved in methanol or ethanol and toluene or xylene added subsequently.

Thus, the main advantage of the new process is to reduce the formation of side reactions and to obtain a product of high purity, since it has now been found that the presence of water in the reaction contributes to the increased formation of by-products.

The crude products can be purified by simple crystallization from aqueous alcohols in high yield, the purity of the crude products is so high that the mother liquors and washings from the previous crystallization can be reused for crystallization after eventually replenishing with solvents to their desired amount and composition. The crystallization losses are thus minimized since these lyes are saturated with xanthine nicotinate from the previous operation.

The resulting higher effect of the new process is to increase the yield of the end product, which results in economically reduced raw material costs. The possible re-use of the crystallization mixture brings an additional effect in reducing the amount of waste which would require additional treatment and disposal.

Examples

Example 1

110.0 ml of methanol and 120.0 ml of toluene are introduced into the flask and 10.3 g of solid sodium hydroxide are added with stirring. After stirring for about 25 minutes, the sodium hydroxide dissolves to form two layers of liquid phase or emulsion. 45.6 g of theophylline are added to the reaction mixture at 45 ° C with stirring.

The contents of the flask are heated to boiling and 47.1 g of 1- (N-methyl-N-2-hydroxyethyl) amino-3-chloro-2-propanol are added dropwise at 65-68 ° C over three hours and the reaction mixture is stirred three hours at 65-68 ° C. After cooling to 20 ° C, the precipitated sodium chloride is filtered off with suction and washed with 15.0 ml of methanol-toluene.

The filtrate is heated to 55 ° C and 30.8 g of nicotinic acid are added with stirring. Temperature

It is raised to 76 ° C and after 45 minutes of boiling, the suspension is allowed to cool for two hours and then cooled to 3 ° C. After stirring at 3 ° C for 1 hour, the product is filtered off with suction and washed twice

27.0 ml of methanol.

The crude product obtained is recrystallized from 90% aqueous methanol.

97.9 g (89.1%) of the pharmacopoeial nicotinate of 3- (7-theophyllyl) -1- (N-methyl-N-2-hydroxyethyl) amino-2-propanol of m.p. 183.0-184.5 ° C.

Example 2

The crude product obtained according to the method of Example 1 is recrystallized from the mother liquors and washings after crystallization of the previous batch of crude 3- (7-theophyllyl) -1-1H-methyl-N-2-hydroxyethyl) amino-2-propanol nicotinate after adding methanol to the required volume.

100.6 g (91.5%) of the pharmacopoeial nicotinate of 3- (7-theophyllyl) -1- (N-methyl-N-2-hydroxyethyl) amino-2-propanol, m.p. 182.5-184.0 ° C.

Example 3

To the flask was charged 90.0 mL of ethanol, 140.0 mL of toluene, and while stirring, 17.0 g of solid 85% potassium hydroxide was added and dissolved with stirring.

The further procedure for the preparation of crude 3- (7-theophyllyl) -1- (N-methyl-N-2-hydroxyethyl) amino-2-propanol nicotinate is identical to Example 1 except that the isolated potassium chloride is washed with ethanol-toluene. and the crude product is washed 4 times with 20.0 ml of ethanol.

The crude product obtained is recrystallized from 90% aqueous methanol.

97.7 g (88.9%) of the pharmacopoeial nicotinate of 3- (7-theophyllyl) -1- (N-methyl-N-2-hydroxyethyl) amino-2-propanol, m.p. 183.0-185.0 ° C.

Claims (2)

A process for the preparation of 3- (7-theophyllyl) -1- (N-methyl-N-2-hydroxyethyl) amino-2-propanol nicotinate by alkylation of the sodium or potassium salt of theophylline 1- (N-methyl-N-2-hydroxyethyl) amino-3-chloro-2-propanol followed by conversion of the base to a nicotinate salt, characterized in that the solid sodium or potassium hydroxide is dissolved in a lower aliphatic alcohol having 1 to 2 carbons or in a mixture of these alcohols with toluene and / or xylene and adding theophylline to form the sodium or potassium salt of theophylline which is further processed in a manner known per se to the nicotinate salt of 3- (7-theophyllyl) -1- (N-methyl-N-2-hydroxyethyl) amino-2-propanol. 2. Process according to claim 1, characterized in that the crystallization of crude 3- (7-theophyllyl) -1- (N-methyl-N-2-hydroxyethyl) amino-2-propanol nicotinate is carried out from aqueous aliphatic alcohols having a carbon number of 1. to 4 using mother liquors and / or washings from the previous crystallization of crude 3- (7-theophyllyl) -1- (N-methyl-N-2-hydroxyethyl) amino-2-propanol, optionally after addition to the required amount and composition.