CS276904B6 - Process for preparing crystalline 3,5,6-tri-0-benzyl-alpha-d-glucofuranose - Google Patents

Abstract

Preparation of crystalline 3,5,6-tri-O-benzyl- -of-D-glucofuranose for pharmaceutical and others purposes from 1,2-O-isopropylidene-3,5,6-tri-O- -benzyl-α-D-glucofuranose purified by molecular distillation. Pure substance hydrolysis is carried out in an acid medium acetic acid in the presence of phosphoric acid at elevated temperature for 8.5 to 9 hours. The product was extracted into toluene and precipitated gasoline, crystallizes at reduced temperature and isolates. The product is cleaned recrystallization by dissolving in toluene and re-precipitation with gasoline.

Description

. The invention relates to a process for the preparation of crystalline 3,5,6-tri-O-benzyl-D-glucofuranose, which is used for pharmaceutical purposes, for example for the preparation of the venotonic agent Tribenoside, but also for other purposes wherever high purity is required. of this chemical.

The preparation of 3,5,6-tri-O-benzyl-D-glucofuranose by acid hydrolysis of 1,2-O-isopropylidene-3,5,6-tri-O-benzyl-Z-D-glucofuranose is already known. However, it is difficult to obtain a pure product, since after completion of the hydrolysis and concentration of the solution, 3,5,6-tri-O-benzyl-β-D-glucofuranose results in the form of a viscous high-boiling oil which is very difficult to purify. It contains, on the one hand, a small amount of unreacted 1,2-O-isopropylidene-3,5,6-tri-O-benzyl-oxyl D-glucofuranose, as well as dehydrating impurities from the preparation of this substance (mono- and dibenzyl derivatives) or dibenzyl ether phenyltolylmethane. In addition, 3,5,6-tri-O-benzyl-α-D-glucofuranose in the form of an oil is unsuitable for further use due to its color.

We have found that the course of the hydrolysis is strongly influenced by the purity of the starting 1,2-O-isopropylidene-3,5,6-tri-O-benzyl-α-D-glucofuranose, in particular it depends on the complete removal of the above-mentioned impurities. If this requirement is not met, after hydrolysis, 3,5,6-tri-O-benzyl- and C-D-glucofuranose is obtained in the form of a yellow-brown oil of difficult-to-define composition and difficult to purify by conventional physicochemical methods. This oily preparation cannot then be practically brought to crystallization, and if so, its quality is debatable and the yield is low (about 40%).

The difficulties have been overcome by the process according to the invention, the principle of which is that 1,2-O-isopropylidene-3,5,6-trisole is used to prepare 3,5,6-tri-Obenzyl-O-D-glucofuranose. O-benzyl-α-D-glucofuranose, treated by short-path distillation apparatus. The treatment of crude 1,2-O-isopropylidene-3,5,6-tri-O-benzyl-β-D-glucofuranose consists in the complete removal of all impurities preventing the crystallization of 3,5,6-tri-O-benzyl- o-D-glucofuranose after hydrolysis. This can be achieved in two ways. If 1,2-O-isopropylidene-3,5,6-tri-O-benzyl-ob-D-glucofuranose contains more volatile components, removal of these substances is achieved by distillation as a front fraction. In the case of higher contents of mono- and dibenzylated derivatives, a subsequent distillation of 1,2-O-isopropylidene-3,5,6-tri-O-benzyl-β-D-glucofuranose is carried out. The distillation can advantageously be carried out on a short-path distillation apparatus with a scraped filter.

The resulting brownish, yellowish honey substance is distilled in the case of distillation and is dissolved in acetic acid. The hydrolysis is catalyzed by a mineral acid (hydrochloric acid or preferably phosphoric acid) at an elevated temperature of 60 to 80 ° C for 8.5 to 9 hours. After cooling to room temperature, the reaction mixture is poured into water and extracted into a high-boiling organic solvent, preferably toluene, and after neutralizing the mixture, this solvent is distilled off to a predetermined weight of the residue. A precisely calculated amount of a low-boiling organic solvent such as petroleum ether or, preferably, gasoline is added thereto at room temperature. After crystallization for three hours at room temperature and subsequent crystallization for 16 hours at -10 DEG C. to -6 DEG C., crystalline 3,5,6-tri-O-benzyl-ob-D-glucofuranose is obtained, which is dried at room temperature in free air, or preferably in a vacuum.

The quality and purity of the product can be increased by subsequent recrystallization, in which the substance is dissolved in a calculated amount of a high-boiling organic solvent, eg toluene, and precipitated with a precisely determined volume of petroleum ether or petrol. Further processing is already identical to the crystallization described above.

In the literature, crystalline 3,5,6-tri-O-benzyl-D-glucofuranose is described as a white waxy substance with a melting point of 63-65 ° C. When dissolved in ethanol, it gives a clear colorless solution, sometimes slightly opalescent.

The process for the preparation of 3,5,6-tri-O-benzyl-α-D-glucofuranose according to the invention is illustrated by the examples.

Example 1 125.0 g of concentrated crude 1,2-O-isopropylidene-3,5,6-tri-Obenzyl- <00-D-glucofuranose are subjected to molecular distillation on a TMO 50 short-path distillation apparatus under the following conditions: heating temperature medium 188 to 190 ° C, pressure 7 to 15 Pa. The distillate collected during distillation is purified 1,2-O-isopropylidene-3,5,6-tri-O-benzyl-α-D-glucofuranose.

Yield 100 g (80%).

Dissolve these 100 g of substances in 350.0 ml of acetic acid in a three-necked flask equipped with a stirrer, thermometer and reflux condenser, add 150.0 ml of water and 12.0 ml of phosphoric acid. The resulting emulsion is heated to 60-80 ° C and stirred for 8.5-9 hours at this temperature. After cooling to room temperature, the mixture is poured into 500.0 ml of water and the precipitated oily product is extracted into 400.0 ml and 200.0 ml of toluene. The combined toluene extracts are extracted successively with 400.0 ml of water, 100.0 ml of saturated sodium bicarbonate solution and finally 2x200.0 ml of water. Toluene was then distilled off under reduced pressure at 50 ° C to a total residue weight of 420.0 g. The concentrated solution was warmed to room temperature and 760.0 ml of gasoline was added portionwise with stirring. After seeding, the solution is allowed to crystallize freely for 2 to 3 hours at room temperature. The crystallization is completed by standing at -10 ° C to -6 ° C for 16 hours. The product is filtered off with suction while still cold, washed twice with 60.0 ml of ice-cold petrol and dried in free air or in vacuo at room temperature. 64.9 g (70.7%) of crystalline 3,5,6-tri-O-benzyl-06-D-glucofuranose are obtained. Toluene and gasoline are recovered from the mother liquors and washings by distillation.

Example 2

Recrystallization of 3,5,6-tri-O-benzyl-D-glucofuranose is carried out as follows: 55.0 g of the crystalline substance are dissolved in 220.0 ml of toluene with stirring at room temperature. To the clear toluene solution was added 400.0 mL of gasoline with stirring. After seeding, the solution is allowed to crystallize freely for 2 hours at room temperature and the crystallization is completed by standing at -10 ° C to -6 ° C for at least 16 hours. The cold product is then filtered off with suction, washed twice with 60.0 ml of ice-cold petrol and dried in free air or under vacuum at room temperature to constant weight. 52.0 g (94.5%) of chromatographically pure are obtained

3,5,6-tri-O-benzyl-D-glucofuranose. Toluene and gasoline are recovered from the mother liquors and washings by distillation.

Claims (1)

PATENT CLAIMS Process for the preparation of crystalline 3,5,6-tri-O-benzyl-α-D-glucofuranose for pharmaceutical purposes by reaction from 1,2-O-isopropylidene-3,5,6-tri-O-benzyl-06-D-glucofuranose characterized in that the 1,2-O-isopropylidene-3,5,6-tri-O-benzyne-N-D-glucofuranose is first purified by molecular distillation, then subjected to hydrolysis in acetic acid and in the presence of phosphoric acid at 60-80 ° C for 8.5-9 hours, the product is extracted into toluene, precipitated with gasoline, crystallized at -10-6 ° C and crystalline 3,5,6-tri-O- benzyl-D-glucofuranose is isolated, after which the product obtained is optionally recrystallized from toluene and gasoline and crystallized at -10 to -6 ° C. End of document