RU2458059C1 - Method of producing n-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidine-sulphone)-n'-isonicotinoyl hydrazide - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidine-sulphone)-N'-isonicotinoyl hydrazide - an immunostimulant which has an effect on all parts of the immune system, is active with respect to mycobacteria and is used in treating diseases on the background of secondary immunodeficiency conditions: tuberculosis, leprosy, clamidiosis, herpetic infection, by reacting 6-methyluracil-5-sulphochloride with isonicotinic acid hydrazide,m characterised by that the solvent used is an aliphatic alcohol: ethyl, isopropyl and methyl alcohol.

EFFECT: method reduces process hazard, reduces material consumption, reduces labour input, prevents formation of liquid organic wastes and improved environmental friendliness of the process.

Description

The present invention relates to the field of chemistry of biologically active drugs with antimycobacterial, immunostimulating, antiviral and anabolic activity.

N- (6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinesulfone) -№-isonicotinoylhydrazide (preparation I), due to its wide spectrum of action, finds application in medical practice for the treatment of and prevention of secondary immunodeficiencies in case of infectious and somatic pathology, mycobacterial and viral infections (tuberculosis, leprosy, viral pneumonia, etc.).

A known method of producing drug I according to the patent of the Russian Federation: RU No. 2235723, which consists in the interaction of 6-methyluracil-5-sulfochloride with isonicotinic acid hydrazide in anhydrous ethyl acetate in the presence of dioxane as an activator of the reaction of the formation of drug I with a molar ratio of reactants 1: 1, 5: 2.5, respectively. The process was carried out at a temperature of 50 ... 75 ° C for at least 6 hours, followed by treatment of the condensation product with an aqueous 10% solution of dimethylformamide at pH 6 of the solution and recrystallization of preparation I from high-boiling aprotic solvents:

dimethylformamide, dimethyl sulfoxide, dimethylacetamide, etc. The total yield of pharmaceutically pure preparation I with a basic substance content of at least 99.0% was 38% of theory.

The main disadvantages of this method is the low yield of the target product and the use of deficient dioxane as a solvent.

In addition, a known method for producing drug I, proposed in patent RU No. 2404977. Preparation I was carried out by reacting equimolecular amounts of 6-methyluracil-5-sulfochloride with isonicotinic acid hydrazide in γ-butyrolactone medium at a temperature of 90 ... 100 ° С. The reaction of the formation of the hydrochloride of drug I was completed within 2 hours. The distinguished intermediate product, the solvent complex with the hydrochloride of preparation I, was purified in an aqueous ammonia solution. Purified preparation I was isolated from an aqueous ammonia solution when it was acidified to a pH of not more than 4.5.

The total yield of pharmacopeia drug I, according to the patent, was 80% of theory.

This method is the closest analogue of the proposed method of obtaining drug I.

Despite certain advantages compared with the previous method (RU No. 2235723) for the preparation of drug I, this method (RU No. 2404977) had disadvantages that impeded its introduction into production:

- the use of expensive and highly toxic γ-butyrolactone;

- the need to highlight a highly toxic intermediate solvent complex with the hydrochloride of preparation I;

- the formation in the process of synthesis of non-regenerable liquid waste-uterine solvent from the operation of condensation of 6-methyluracil-5-sulfochloride with isonicotinic acid hydrazide.

The present invention is to develop a method for producing N- (6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinesulfone) -N'-isonicotinoyl hydrazide, which eliminates the use of dangerous highly toxic solvents, to increase the manufacturability of the method, reduce the amount of waste generated, reduce the cost of raw materials, labor and the cost of the drug I.

The expected technical result is achieved due to the use of 6-methyluracil-5-sulfochloride with isonicotinic acid hydrazide as the medium for the interaction and the formation of the preparation I of ethyl, isopropyl, and methyl aliphatic monohydric alcohols widely used in the synthesis of medications.

It was shown that during the interaction of 6-methyluracil-5-sulfochloride with isonicotinic acid hydrazide in an alcoholic medium, the effect of clumping and sticking of intermediate preparation I hydrochloride on the reactor walls is not observed, which inevitably occurs when aprotic solvents, ethylapetat and γ-, are used as reaction medium butyrolactone.

The use of alcohols as a reaction medium makes it possible to exclude the intermediate operation of separating the hydrochloride of preparation I from the reactor using the method of distillation (evaporation) of the spent solvent from the reaction mixture and subsequent dissolution of the condensation product in an aqueous solution of ammonia.

It is proposed to purify the aqueous-ammonia solution of preparation I with activated carbon in the same reactor in which the interaction of 6-methyluracil-5-sulfochloride with isonicotinic acid hydrazide is carried out. The selection of drug I is carried out by neutralizing the purified aqueous ammonia solution to a pH of not more than 4.5. The isolated preparation I is washed in a 1% aqueous solution of acetic acid and dried at 100 ... 110 ° C to a constant weight of the sample. The yield of drug I was 75 ... 81.5%, depending on the alcohol used.

In the process of evaporation (distillation) of the solvent from the reaction mass after the formation of the hydrochloride of preparation I, a practically pure solvent (alcohol) is released with a yield of up to 70% of the 6-methyluracil-5-sulfochloride taken from the condensation reaction with isonicotinic acid hydrazide. It is shown that the stripping solvent can be reused in the preparation of preparation I without additional purification and drying.

The proposed method for producing drug I allows:

- eliminate the need to use expensive and highly toxic γ-butyrolactone;

eliminate the need for operations of isolation and filtering of an intermediate product - the hydrochloride of drug I;

- to reduce the danger and the complexity of the production process by combining the stages from the preparation of the hydrochloride of preparation I to purification in aqueous ammonia solution in the same reaction volume;

- return to the process up to 70% of the solvent used as the medium;

- eliminate the formation of liquid organic waste;

- reduce raw material costs by using available alcohols as a reaction medium instead of γ-butyrolactone and solvent regeneration.

Below are examples of the proposed method for producing the preparation I and the prototype method according to patent RU No. 2404977.

Prototype Example

56.2 g (0.25 mol) of 6-methyluracil-5-sulfonyl chloride and 34.3 g (0.25 mol) of isonicotinic acid hydrazide are dosed simultaneously with stirring to 350 ml of γ-butyrolactone at a temperature of 70 ... 80 ° C in within an hour.

The reaction mixture is heated to 100 ° C and give a 2-hour exposure at 95 ... 100 ° C. The reaction mixture after cooling is cooled to 50 ° C and the crystalline product is filtered off from the mother liquor, washed on a vacuum filter twice with 30 ml of acetone, and dried on a vacuum filter.

The isolated product is placed in 500 ml of distilled water. The suspension is heated to 75 ° C. with stirring and an aqueous ammonia solution is dosed thereto under a layer of liquid mass until a pH of 7 is reached in the reaction medium. A half-hour exposure is given at 75 ... 80 ° C and acetic acid is dosed to the reaction mass until a pH of 4.5 is reached.

The suspension in the reactor with vigorous stirring is cooled to 50 ° C, and the crystalline product on the vacuum filter is filtered from the mother liquor, washed twice with hot (40 ... 50 ° C) distilled water of 50 ml each, and dried on a vacuum filter.

The wet product (“20% water) from the vacuum filter is placed in 1 liter of distilled water and the suspension is heated to 75 ° C with stirring.

To the heated reaction mass, 70 ml of a 25% solution of ammonia are poured under the suspension layer, a 15-minute exposure at 75 ... 80 ° C is given.

If the crystalline product is not completely dissolved, an additional amount of an aqueous solution of ammonia is dosed until the product is completely dissolved.

4 g of activated carbon are added to the solution at 75 ... 80 ° C with stirring, a 15-minute exposure at 75 ... 80 ° C is given. Activated carbon is filtered off from the hot solution on a vacuum filter.

To the solution with vigorous stirring and a temperature of 75 ... 80 ° C, dose for 30 minutes 70 ml of acetic acid to achieve a pH of 4.5. The suspension with intensive stirring is cooled to 40 ° C, and the crystalline fraction is filtered off from the mother liquor, washed on the filter twice with 100 ml of hot (50 ... 60 ° C) distilled water.

The wet product is dried at atmospheric pressure and a temperature of 100 ... 110 ° C to constant weight. The yield of dried N- (6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinesulfone) -N'-isonicotinoyl hydrazide was 65.9 g, 80% of theory, mp. 255 ° C (decomp.).

- Found,%: C - 40.71; H 3.34; N, 21.4; S - 9.78.

C ₁₁ H ₁₁ O ₅ N ₅ S.

Calculated,%: C - 40.61; H - 3.38; N, 21.54; S - 9.85,

Example 1 (the inventive method).

34.3 g (0.25 mol) of isonicotinic acid hydrazide are charged with 450 ml of 96% ethanol with stirring at a temperature of 15 ... 25 ° C. The suspension is heated to 40 ° C and 56.2 g (0.25 mol) of 6-methyluracil-5-sulfochloride are metered in portions over the course of an hour through the reactor nozzle and the mixture is allowed to stand for an hour at 40 ... 50 ° C. The reactor is connected to a reflux condenser to condense the solvent vapor and return it to the reaction mass. The suspension in the reactor after an hour exposure is heated to 75 ... 77 ° C and give a two-hour exposure.

At the end of the exposure, the reflux condenser (condenser) is replaced with a direct one, and the solvent is evaporated at atmospheric pressure to ≈10% of the volume taken for the operation, the distilled solvent is collected for reuse.

To the suspension remaining in the reactor, 500 ml of distilled water is poured, heated to 60 ... 70 ° C, and an aqueous ammonia solution (25%) is metered into the reaction mass under a liquid layer until the crystalline product is completely dissolved, give 10 min. excerpt. Temperature at a dosage of ammonia solution and exposure 60 ... 70 ° С.

To the solution, 4 g of activated carbon are loaded into the reactor and a shutter speed is given for 15 min at 70 ... 80 ° C. The hot solution is filtered off from activated carbon. Acetic acid is metered in for 30 minutes to a purified solution of the condensation product with stirring at a temperature of 60 ... 70 ° C until the pH in the reaction mass reaches no more than 4.5. Give 10 ... 15 minutes exposure and the reaction mass is cooled to 30 ° C for at least an hour.

The suspension from the reactor is poured onto a vacuum filter and the product is filtered off from the mother liquor, washed on a vacuum filter with distilled water.

The wet preparation I is washed in the reactor with 1% aqueous acetic acid at 60 ... 70 ° C, with a module of 7 obd acetic acid per 1 ppm wet preparation I, and dried at 100 ... 110 ° C to constant weight.

The yield of dried N- (6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidine-sulfone) -N'-isonicotinoyl hydrazide was 67 g (81.5%). T pl. 253 ° C (decomp.).

Found,%: C - 40.58; H - 3.25; N, 21.6; S 9.81;

C ₁₁ H ₁₁ O ₅ N ₅ S.

Calculated,%: C - 40.61; H - 3.38; N, 21.54; S - 9.85.

Example 2 (the inventive method).

34.3 g (0.25 mol) of isonicotinic acid hydrazide are dosed with stirring at a temperature of 15 ... 25 ° C in 450 ml of anhydrous isopropyl alcohol. Next, the process is carried out in modes by analogy with example 1.

The yield of drug I was 64.3 g (79%), mp. 252 ° C.

Found,%: C - 40.41; H - 3.30; N, 21.23; S - 9.78.

C ₁₁ H ₁₁ O ₅ N ₅ S.

Calculated,%: C - 40.61; H 3.38; N, 21.54; S - 9.85.

Example 3 (the inventive method).

34.3 g (0.25 mol) of isonicotinic acid hydrazide are loaded into 450 ml of absolute methyl alcohol with stirring at a temperature of 15 ... 25 ° C. The suspension in the reactor is heated to 35 ° C and 56.2 g (0.25 mol) of 6-methyluracil-5-sulfochloride are metered in portions over the course of an hour, and they are allowed to stand for an hour at 35 ... 40 ° C. The temperature of the reaction mass is raised to 63 ... 65 ° C and give a six-hour exposure.

Next, the process is carried out in modes by analogy with example 1.

The yield of drug I was 61 g (75%), mp. 253 ° C.

Found,%: C - 40.51; H - 3.15; N - 21.60; S - 9.79.

C ₁₁ H ₁₁ O ₅ N ₅ S.

Calculated,%: C - 40.61; H - 3.38; N, 21.54; S - 9.85.

Example 4 (the claimed method).

34.3 g (0.25 mol) of isonicotinic acid hydrazide are charged into 450 ml of ethanol distilled from the preparation of preparation I and the basic substance contains 92-96%.

Further, the process is carried out by analogy with example 1.

The yield of drug I was 66.7 g (81%), mp. decomp. 252 ° C.

Found,%: C - 40.80; H - 3.31; N - 21.05; S - 9.90.

C ₁₁ H ₁₁ O ₅ N ₅ S.

Calculated,%: C - 40.61; H - 3.38; N, 21.54; S - 9.85.

The molecular weight determined by mass spectral analysis for the obtained preparation I (C ₁₁ H ₁₁ O ₅ N ₅ S; 325.3) was 324.5.

Determined by titration in a solution of formic acid with perchloric acid (crystalline violet indicator), the content of the preparation I in the samples obtained by the developed method was 99.0 ... 99.3%.

Determination of the content in the samples of drug I by the biometric method using Fisher's reagent showed its practical absence (0.1 ... 0.2%.).

Claims (2)

1. The method of obtaining N- (6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidine-sulfone) -N'-isonicotinoyl hydrazide by the interaction of equimolecular amounts of 6-methyluracil-5-sulfochloride and hydrazide isonicotinic acid in a solvent medium, followed by isolation and purification of the obtained preparation, characterized in that an aliphatic monohydric alcohol is used as a solvent. 2. The method according to claim 1, characterized in that ethyl, isopropyl or methyl alcohol is used as aliphatic monohydric alcohols.