UA106558U - Process for the preparation of 6-methyluracil-5-sulfochloride - Google Patents

Abstract

The method of obtaining 6-methyluracil-5-sulfochloride involves the interaction of 6-methyluracil with chlorosulfonic acid in a molar ratio of 1: 3. The sulfochlorination reaction is carried out in an inert organic solvent medium at the boiling point of the solvent within 60-80C, followed by distillation of the solvent and isolation of the target product by known methods.

Description

The useful model belongs to the synthesis and technology of obtaining b-methyluracil-5-sulfochloride (MUSC) - an important starting product for the synthesis of dyes, medical drugs such as sulfonamides (antiviral drugs), sulfonylureas (glycemic drugs), for the synthesis of herbicides, germicides. The method of synthesis consists in the interaction of methyl uracil with chlorosulfonic acid in the medium of an inert organic solvent of aliphatic polyhalogen derivatives, such as: methylene chloride, trichloromethane, tetrachloromethane, dichloroethane. To carry out the process, chlorosulfonic acid is dissolved in an organic solvent, and methyluracil is added to the obtained solution in small portions at room temperature and intensive stirring. At the same time, the temperature rises to 40-45 degrees.

Leave to stand for 1.5-2 hours, then heat to the boiling point of the solvent and leave to stand until the release of hydrogen chloride stops and the original methyluracil is absent.

The solvent, which is used in subsequent syntheses, is distilled off, and the target product is isolated by known methods, pouring the reaction mass on ice.

A known method of synthesis of b-methyluracil-5-sulfochloride by the interaction of b-methyluracil with a mixture of chlorosulfonic acid and thionyl chloride at a temperature of 75 C for 8 hours.

The target product was isolated during the decomposition of the reaction mass in a mixture of ice and water. The output of the IAS was 72 95 of the theoretical, t.pl. 235 "С (AS USSR 226620, published on 16.09.81). The disadvantages of this method include a rather low yield of the final product, a significant consumption of chlorosulfonic acid and thionyl chloride, 2.7 mol of chlorosulfonic acid and 1.6 moles of thionyl chloride, as well as the difficulty of regulating the process due to the presence of an induction period in the sulfochlorination reaction and the possibility of a sudden release of gases, a sharp increase in temperature, which creates a danger to the process and the formation of by-products (RF Patent 2087471). The presence of DMF and thionyl chloride in the reaction mass leads to the formation of aromatic and heterocyclic compounds (Zandmeyer reaction), which leads to contamination of the target product.

There is a known method of synthesis of MUC by the interaction of methyluracil with an excess of chlorosulfonic acid and subsequent treatment of the reaction product with phosphorus trichloride in the presence of dimethylformamide (DMF) as a catalyst. Ratio of reagents: Methyluracil: chlorosulfonic acid: phosphorus trichloride - 1.0:2.7: 2.2.

The disadvantage of this method is the complexity of the technological process.

Methyluracil is added in portions to chlorosulfonic acid, maintaining the temperature of the reaction mass within the range of no higher than 40 "С, since the reaction is quite exothermic. Then during

3 min. the temperature is raised to 80 "C and allowed to stand for an hour. Then the reaction mass is cooled to 40-45 "C, DMF is added as a catalyst, and phosphorus trichloride is added in portions over the course of 2 hours. After that, the temperature of the reaction mixture is raised to 60-63 "C and allowed to stand for another hour. Then the mass is cooled to 0-5 C and diluted with ethyl alcohol, maintaining the temperature at 0-10 C and stirred for another hour. At the same time, ethanol can easily react with an excess of chlorosulfonic acid and phosphorus trichloride, forming a number of by-products, which negatively affects the quality of MUS, including the methyluracil formylation product.

The purpose of the useful model is to expand the raw material base for the production of sulfonamide drugs, sulfonylurea derivatives as glycemic drugs, simplify the technological process by conducting the sulfochlorination reaction in an environment of inert organic solvents, reduce the cost of the initial components of the methyluracil sulfochlorination process, and, as a result, reduce the cost of medical preparations based on it.

The problem is solved by the fact that the original methyluracil is sulfochlorinated with chlorosulfonic acid in an environment of inert organic solvents with a boiling temperature close to the temperature of the sulfochlorination process. The most suitable solvents in this process are chloroform (b.p. 61-62,795), tetrachloromethane (b.p. 77"C), dichloroethane (b.p. 83-84 C). The use of the mentioned solvents makes it possible to avoid overheating of the reaction mass due to the exothermic reaction of sulfochlorination.As a result, the formation of by-products is avoided, as well as a sharp increase in temperature in the reaction mass due to the exothermic reaction of sulfochlorination.

After the end of the sulfochlorination reaction, the solvent is distilled off at normal pressure and used in subsequent syntheses. The residue, which consists of MUS, sulfuric acid and a small amount of unchanged chlorosulfonic acid, after removing the solvent, is cooled and, with intensive stirring, poured onto ice. The Ministry of Internal Affairs and Communications will be allocated with output 89-93 9b5 and etc. 252-253.5 "С (in the literature 2357) by a known method. Because the synthesis scheme can be presented in the form

N H i sn, in sn,

С я 2НСОСИ vet СХ - NVO, со, сИ о (c)

The method is illustrated by the following examples.

Example 1.

25 ml of chloroform is loaded into the apparatus with a mechanical stirrer, a contact thermometer, a reflux condenser with a calcium chloride tube and a dropper. With stirring, dissolve 10 ml (17.66 g, 0.151 mol) of freshly distilled chlorosulfonic acid. With intensive stirring, add 6.4 g to the solution in small portions. (0.051 mol) of methyluracil, pre-dried at 105-110 "C. At the same time, the temperature rises to 40-45 "C. After 20-30 min. methyluracil is completely dissolved and the reaction mass becomes homogeneous. The reaction mass is heated to the boiling point of chloroform (60-65 "С) and allowed to stand for 4-5 hours, until the release of hydrogen chloride stops and the absence of original methyluracil (by chromatography on Silufol, ethyl acetate system, H-0.88).

The contents of the flask are cooled to room temperature and carefully, with intensive stirring, poured onto 50 finely crushed ice. The precipitate of b-methyluracil-5-sulfochloride is filtered, washed 2-3 times with isopropyl alcohol (10 ml each) and dried in a vacuum desiccator over sulfuric acid (to a constant weight).

10.1 g (88.1 95 of the theoretical) was allocated. T.pl. 242-243 "C (acetic acid), 235 "C (with decomposition) (Literature).

Found, 9b: C - 26.58, 26.65; H - 2.28, 2.33; SI-15.88, 16.05; 5-14.02, 14.16. C5NhSIM2O45.

Calculated: C - 26.72; H-2.22; SI-15.81; 5-14 25.

Chloroform is separated from the filtrate, which after purification is used in the next synthesis. The aqueous part of the filtrate (55 ml) is heated to boiling, 10 g of table salt is added and left overnight. The next day, the precipitated sodium salt of methyluracilsulfonic acid is filtered, washed with water, propanol and dried. 1.15 g 10.7 95) sodium methyluracilsulfonate monohydrate was obtained.

Example 2.

25 ml of carbon tetrachloride are placed in the apparatus from example 1. With stirring, dissolve 10 ml (0.151 mol) of freshly distilled chlorosulfonic acid. Add 6.4 g (0.051 mol) of methyluracil to the solution. After the transition of methyluracil into the reaction solution

The mass is heated to boiling (77-80 C) and kept at this temperature for 4-4.5 hours. Further separation of the reaction product is carried out as in example 1.

10.6 g was obtained (92.5 95 from the theoretical). T.pl. 243-243.5 "С (acetic acid).

Example 3.

It is carried out as in example 1, taking 25 ml of dichloroethane instead of chloroform. The contents of the flask are heated to boiling (84-85 "С) and kept at this temperature for 3.5-4 hours. Further processing is carried out as in example 1. 11.0 g (96.1 95 from the theoretical) are isolated. 243-243.5 "С (from acetic acid).

Example 4.

It is carried out as in example C, taking instead of 10 ml (0.15 mol) of chlorosulfonic acid, only 6.6 ml (0.10 mol) of chlorosulfonic acid gave an exposure time of 4.5 hours. Further processing was carried out as in example 1. 8.9 g (77.6 95 from the theoretical) of МСХ was isolated from T.pl. 242-243 76. 2.4 g of sodium methyluracil sulfonate monohydrate was isolated from the filtrate by salting out.

Example 5.

Carry out as in example 3, taking 15 ml (26.5 g; 0.227 mol) of chlorosulfonic acid instead of 10 ml (0.151 mol). Further processing was carried out as in example 1. 11.1 g (97.3 95 from the theoretical) of МСХ was isolated from T.pl. 242-242.5 76.

Claims (1)

USEFUL MODEL FORMULA The method of obtaining b-methyluracil-5-sulfochloride, which includes the interaction of b-methyluracil with chlorosulfonic acid in a molar ratio of 1:3, which is characterized by the fact that the sulfochlorination reaction is carried out in the medium of an inert organic solvent at the boiling temperature of the solvent in the range of 60-80 "С followed by distillation of the solvent and isolation of the target product by known methods.