RU2131434C1 - Method of preparing 1,4: 3,6-dianhydro-d-sorbitol - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: 1,4: 3,6-dianhydro-D- sorbitol (sorbide or isosorbide) is semiproduct in the manufacture of medicinals based on mono- and dinitroderivatives thereof which are useful as vasodilating agent of prolonged activity in treating hypertension, stenocardia and other cardiovascular diseases. Method comprises boiling food sorbitol at 130- 50 C in xylol with water separator till water separation ceases completely in the presence of n-toluene-sulfonic acid catalyst in amount of 5.0% based on sorbitol weight. EFFECT: simplified method and increased yield of the desired high-quality product. 2 tbl

Description

 The invention relates to a technology for producing 1,4: 3,6-dianhydro-D-sorbitol (sorbide, isosorbide), which is an intermediate in the manufacture of drugs based on its mono- and dinitro derivatives, which are used as a vasodilator of prolonged action for hypertension, angina pectoris and other cardiovascular diseases.

Известны несколько способов получения изосорбида, однако они в основном имеют лишь лабораторное значение, реализация их в промышленных условиях затруднена из-за дороговизны и трудоемкости процесса.Isosorbide is obtained by dehydration of food sorbitol in the presence of acid-type catalysts according to the scheme

Several methods for producing isosorbide are known, however, they mainly have only laboratory significance; their implementation under industrial conditions is difficult due to the high cost and laboriousness of the process.

 Most noteworthy are the methods of dehydration of sorbitol in toluene or xylene in the presence of acidic catalysts [1-3]. According to these studies, the yield of isosorbide ranges from 8 to 67%. Isosorbide isolation and purification methods are complex, lengthy and multi-stage.

 Currently, isosorbide is obtained according to the improved method proposed by P. M. Kochergin and colleagues [4, 5]. This method was implemented at the Krasnouralsk chemical plant (Krasnouralsk, Yekaterinburg region) and adopted by us as a prototype.

In this method, isosorbide is obtained by boiling food sorbitol at 130-150 ^o C in xylene with a water separator until the water separation is completely stopped (about 8 hours) in the presence of p-toluenesulfonic acid, taken in an amount of 5.0% by weight of sorbitol, as a catalyst.

So, for 2.0 kg of crushed food sorbitol, 7.5 l of technical xylene and 100 g of p-toluenesulfonic acid are taken. Reaction water is collected in a water separator. At the end of the water evolution (after 8.5 h), xylene is removed from the reaction mass by distillation in vacuo or decantation, and a thick dark residue is dissolved in 10 l of water and boiled for 1.0 h with 0.5 kg of activated carbon, after which the solution is cooled to 50-60 ^o C and filtered from coal. The filtered charcoal is boiled for 1 hour with 2.0 liters of water for more complete extraction of isosorbide and filtered. From the combined almost colorless filtrates, water is distilled off in vacuum at a temperature not exceeding 75.0 ^o C. A thick residue (about 1.5 kg) of the crude isosorbide is purified by deep vacuum distillation (pressure 1.0-4.0 kPa, temperature in vapors 160 -175 ^o C).

 Isosorbide is obtained in the form of a light yellow oil, crystallizing upon standing or seeding with a yield of 68-70% of theoretical.

 The advantage of this process is that the sorbide is obtained of high quality and for subsequent processing there is no need for additional recrystallization of it from flammable solvents.

The disadvantages of the method are:
- multi-stage process;
- the use of GF as a reaction medium, which makes the process fire hazardous;
- high complexity and energy intensity;
- the use of a large amount of scarce catalyst and activated carbon (5.0 and 25.0 wt.%, respectively);
- low productivity.

 According to the authors of [4, 5] and patent [3], a decrease in the amount of catalyst to 1.0 wt.% Leads to a significant decrease in the yield of the target product and an increase in the duration of the dehydration reaction.

The aim of the present invention is
- the creation of a one-stage, high-performance, fireproof production of isosorbide;
- the exclusion of labor-intensive and energy-intensive stages;
- reduction in the consumption of raw materials;
- increase the yield of the target product while maintaining its high quality.

 This goal is achieved by combining the processes of dehydration of food sorbide and purification of the resulting isosorbide.

 Distinctive features of the method is that the dehydration process is carried out with the simultaneous isolation of the target product and reaction water from the reaction zone. The reaction is carried out in the presence of catalytic amounts of water (3-10 wt.%) And an acid catalyst (0.2-0.6 wt.% P-toluenesulfonic acid of sulfuric or orthophosphoric acid).

The process is carried out at a pressure of 1.0-4.0 kPa, which corresponds to the boiling point of the reaction mass 165-195 ^o C, but not higher than 205 ^o C, because at this temperature, partial grinding of the reaction mass already takes place, which leads to a loss in the yield of the target product. The criterion of the process is vacuum (or residual pressure), which determines the boiling point (distillation) of isosorbide, which confirms the table. 1.

 The technology of the method is as follows.

In a flask equipped with a thermometer, 75.0 g of food sorbide (in terms of 100%), 0.15-0.45 g of catalyst and 2.25-7.50 ml of water were charged. The flask was connected through a Wurz nozzle to an isosorbide receiver connected through a refrigerator-condenser to a water collector that is connected to a vacuum pump. The reaction mass was heated in a sand bath under vacuum. The boiling point of the reaction mixture was 170-195 ^o C. At this temperature, isosorbide was isolated in the form of a light yellow oil, which crystallized upon standing or when seeding. The reaction water, passing through the isosorbide collector, was condensed in a condenser refrigerator and collected in a water collector.

 According to the described technological regime, in the laboratory conditions, isosorbide samples were obtained, from which, after nitration, 2,5-dinitrate-1,4: 3,6-dianhydro-D-sorbitol was obtained in good yield, satisfying the requirements of FS 42-422-86.

 The results of the experiments are presented in table 2, from which it is seen that isosorbide is obtained with a yield of 70.6-78.1%. The quality of isosorbide was evaluated by gas-liquid chromatography. It is established that the quality of isosorbide obtained by the existing and proposed technology is identical.

Claims (1)

The method of obtaining 1.4: 3,6-dianhydro-D-sorbitol by dehydration of sorbitol in the presence of an acid catalyst at an elevated temperature, characterized in that, in order to simplify and increase the safety of the process and increase the yield of the target product, p -toluenesulfonic acid, phosphoric or sulfuric acid, taken in an amount of 0.2 - 0.6 wt.%, and the process is carried out in the presence of 3.0 - 10.0 wt.% water at a temperature of 165 - 195 ^o C and a pressure of 1.0 - 4.0 kPa (-0,96 ^o C -0,99 kgf / cm ²⁾ with simultaneous removal of water and the desired pro Ukta from the reaction zone.

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