RU2203278C2 - Method of synthesis of 5-chloro-4-amino-2,1,3-benzo- thiadiazole - Google Patents

Abstract

FIELD: organic chemistry, chemical technology. SUBSTANCE: invention relates to method of synthesis of 5-chloro-4-amino-2,1,3-benzothiadiazole by reduction of 5-chloro-4-nitro-2,1,3-benzothiadiazole with pickled iron taken in the amount 2.3-2.5 mole per 1 mole of 5-chloro-4-nitro-2,1,3-benzothiadiazole at temperature 75-80 C in isopropyl alcohol medium. Reaction mixture is treated with alkaline agent aqueous solution, formed iron slime is separation by filtration and isopropanol solution is cleared with activated carbon and diluted with water followed by filtration and drying the isolated product. Method provides increase of yield of 5-chloro-4-amino-2,1,3-benzothiadiazole. EFFECT: simplified method, increased yield. 2 ex

Description

 The present invention relates to organic chemistry, in particular to the production of 5-chloro-4-amino-2,1,3-benzothiadiazole, which is the starting material for the synthesis of the drug tizanidine.

 The preparation of 5-chloro-4-amino-2,1,3-benzothiadiazole by reduction of 5-chlorop-4-nitro-2,1,3-benzothiadiazole has been described (B.G. Pecin, A.M. Khaletsky. ZhOKh, 1957, t. 27, 9, p. 2599).

 The recovery is carried out with iron chips taken in excess of the stoichiometric amount, pickled with boiling water with the addition of a small amount of acetic acid, with a gradual loading of the nitro compound into the mixture of chips with water at the boiling temperature of the mass. The amount of iron shavings taken is 13.5 moles per 1 mole of nitro compound, with a stoichiometric amount of 2.25 moles per 1 mole of nitro compound.

After loading the nitro compound, the reaction mixture is boiled for 5 minutes and the mixture of iron sludge and the resulting product is filtered off. The target product is recovered from this mixture by repeated treatment of the precipitate with ether. The extract was evaporated to dryness and the product was obtained in 75.7% yield, based on the starting nitro compound. The resulting product is purified by recrystallization from water to achieve a melting point of 92.0 ^o C.

 The disadvantage of the described method is, first of all, the need to limit the duration of recovery, which with its small size (5 min) makes it difficult to successfully conduct the process.

 This is due to the fact that the benzothiazole cycle is unstable to the action of the indicated reducing agent and decomposes with the formation of substituted 1,2-phenylenediamine and hydrogen sulfide (L.S. Efros, R.M. Levin. ZhOKh, 1955, v. 25, 1, p. 199 ), resulting in reduced yield and quality of the target product.

 In addition, a non-technological method is to isolate the resulting product, associated with repeated extraction with ether and significant costs of this solvent, which is a very fire and explosive substance.

 The isolated product does not have a sufficient degree of purity, and its purification by recrystallization is required, which leads to additional product losses and a decrease in yield.

 The objective of the invention was the development of such a method of recovery of 2-chloro-4-nitro-2,1,3-benzothiadiazole, which would simplify the process and ensure high yield and purity of the target product.

This problem is solved by carrying out the recovery process by treating the starting compound with pickled iron powder, taken in an amount of 2.3-2.5 mol per 1 mol of nitro compound, in isopropyl alcohol at 78-80 ^o C. The resulting reaction mixture is treated with an aqueous solution of an alkaline agent, the resulting iron sludge is separated by filtration, and the isopropanol solution is diluted with water, followed by filtration and drying of the separated product.

When carrying out the recovery process below 75 ^o With the product partially precipitates, increasing the process temperature above 80 ^o With technologically impractical. The duration of the recovery process under these conditions is 40-60 minutes

 The limitation of iron loading close to the stoichiometric amount (2.3-2.5 mol per 1 mol of the starting compound) excludes the possibility of re-reduction of the nitro product and, accordingly, the requirement to limit the duration of the process, which, as a result, ensures a high yield and quality of the target product.

The product yield is at least 86%, based on the initial nitro compound, the melting point of the dry product is 91.5-92.0 ^o C.

In accordance with the source of information (V.G. Pesin, A.M. Khaletsky. ZhOKh, 1957, v. 27, 9, p. 2599), the melting point of the recrystallized product is 92.0 ^o C. According to TLC and GLC, extraneous impurities substances in the product are not detected.

Example 1
12.2 g (0.2188 mol) of iron powder and 1.7 g of glacial acetic acid are charged into 35 cm ^{3 of} water and the mixture is boiled for 30 minutes.

A suspension of 19.0 g (0.0876 mol) of 5-chloro-4-nitro-2,1,3-benzothiadiazole in 84 cm is added to the resulting mixture with stirring and boiling under reflux (temperature in the mass of 75-80 ^o C) ³ isopropyl alcohol. After the suspension is added, the mass is mixed at a temperature of 75-80 ^{° C. for} 40-60 minutes, controlling the completeness of the conversion of the nitro compound by the potentiometric method.

When complete conversion of the nitro compounds is achieved, a 20% sodium carbonate solution is added to the resulting mixture until a pH of 9.1-9.3 is reached and mixed for 5 minutes. Add 80 cm ^{3 of} isopropyl alcohol and filter the resulting mixture from iron sludge, which is washed on a filter with 120 cm ^{3 of} isopropyl alcohol.

 4 g of activated carbon are added to the filtrate and the mixture is boiled for 1 hour.

The coal sludge is filtered off and washed with 50 cm ^{3 of} isopropyl alcohol.

275 cm ^{3 of} water are added to the clarified solution with stirring and the mixture is cooled to 0-5 ^° C. The precipitate formed is filtered off and washed with 150 cm ^{3 of} water. Dry the product at 40-50 ^o C under reduced pressure to constant weight.

Obtain 14.0 g of a dry product with a melting point of 91.5-92.0 ^o C. the Yield of the product is 87% of theoretical, based on the original nitro compound.

Example 2
The process is carried out as in example 1. Instead of a sodium carbonate solution, a 20% sodium hydroxide solution is used.

A product is obtained with a melting point of 91.5-92.0 ^{° C.} and a yield of 86%.

 Thus, the proposed method for producing 5-chloro-4-amino-2,1,3-benzothiadiazole differs from the prototype in the simplicity and manufacturability of the processes of recovery and isolation of the product, a sufficiently high yield and high degree of purity of the isolated product, reduction of iron costs and, accordingly, the amount of waste iron sludge, excluding the use of fire and explosion hazard solvent.

Claims (1)

The method of obtaining 5-chloro-4-amino-2,1,3-benzothiadiazole by reduction of 5-chloro-4-nitro-2,1,3-benzothiadiazole with etched iron, followed by isolation of the target product from the reaction mixture, characterized in that the recovery process 5-chloro-4-nitro-2,1,3-benzothiadiazole is carried out with iron powder taken in an amount of 2.3-2.5 mol per 1 mol of 5-chloro-4-nitro-2,1,3-benzothiadiazole, with 75-80 ^o C in a isopropyl alcohol, and the reaction mixture was treated with an aqueous solution of an alkali agent, an iron slurry is formed is separated by filtration, and isoprene anolny solution is clarified with charcoal and diluted with water, followed by filtration and drying of the isolated product.