CS197175B1 - Process for the purification of 3-methoxy-6-sulphanil-amidopyridazine - Google Patents

Description

The invention relates to a method of purifying 3-methoxy-6-sulfanilamidopyridazine, an important, clinically used, long-acting chemotherapeutic. By known methods, a yellowish substance is obtained, while there is still a greater demand for pure white on the world markets.

All known methods of producing 3-methoza-6-sulfanilanidopyridazine are based on 3,

6-dichloropyridazine. According to the first group of methods for producing 3,6-dihloropyridazine, the sulfanilamide is melted to 3-chloro-6-sulfanilamidopyridine (U.S. Pat. No. 2,712,011), which is then methoxylated with sodium methylene (U.S. Pat. No. 2,712.012). In the second and third group of reactions, the starting 3,6-dihloropyrididine is converted in an autoclave by treatment with ammonia to 3-chloro-6-aminopyridazine, which can either be methoxylated and the resulting 3-methoxy-6-aminopyridazine condensed with β p -cetylsulfahil chloride to 3- Ethoxy-6-acetylsulfanilamidopyridazine, which by desacetylation affords the title compound (British Pat. No. 836.150, Belgian Pat. No. 559.039, Japanese Pat. No. 3583 ('61), German Pat. No. 1,088.061, Soviet pst. 8). 146.313), or condensed with p-aostylpulfanil chloride to 3-chloro-6-acetylsulfanilamidopyridszine, from which the title compound is obtained by methoxylation with sodium or potassium methylate in methanol (NSR Pat. No. 1,103,935, J.Am.Chsm.Soc. 80,

980, 1958, Czechosl. U.S. Pat. Nos. 100,573 and 100,774, French Pat. No. 1,315,022, Chem.

197 175

Bull. (Tokyo) 10, 595, 1962, Japanese Pat. δ. 13.824 ('61).

The methods described provide 3- ' -ethoxy-6-sulfanilamidopyridazine in the sodium or potassium salt in the methanolic solution. The desired compound can be isolated in a number of ways, for example by neutralizing the methoxylation product with methanolic acid, distilling off the methanol, dissolving the residue in ammonia water and filtering the solution with activated carbon and precipitating the desired compound with dilute acetic acid from the filtrate. Nos. 100,573 and 100,774, French Pat. Nos. 1,315,022). According to German Pat. No. 1,088,061 and after saponification

The 3-methoxy-6-acetylsulfanilamidopyridazine was neutralized with acetic acid and hydrochloric acid to give a yellow product. According to J.Am.Chem.Soc. 80, 980, 1958, the methoxylation product is acidified with acetic acid, concentrated, filtered and recrystallized from methanol. Similarly, and according to US Pat. The residue is dissolved in dilute sodium hydroxide solution, the product is precipitated with acetic acid and the crude 3-methoxy-6-sulfanilamidopyridazine is recrystallized from water. According to Japanese Pat, No. 13,824 (6L), the methoxylation product is concentrated without acidification, the residue is dissolved in water with acetic acid, the desired product precipitates and recrystallized from methanol. According to German Pat. No. 1,119,870, Acta polon. pharm. 17 355, 1960 and Roczniki Chem, 34, 299, 1960, the methoxylation product is concentrated, the obtained 3-methoxy-6-sulfanilamidopyridazine sodium salt is recrystallized from water, dried and decomposed in anhydrous methanol with acetic acid.

The disadvantages of these processes are their complexity and, in many cases, the use of organic solvents, which, in the end, does not lead to a pure white product.

The deficiencies of the prior art have been eliminated by the purification of 3-methoxy-6-aulfanilamidopyridazine prepared by methoxyacetyl 3-chloro-6-sulfanilamidopyridazine with sodium methylate in methanol according to the invention, which comprises removing the reaction mixture after distillation by distillation. under reduced pressure of 1330 to 9330 Pa at 60-80 ° C methanol, the residue of 3-methoxy-6-aulfanilamidopyridazine sodium salt is dissolved at 50-80 ° C in aqueous sodium hydroxide solution to a final alkalinity of 2.5 to 3, 0mol / liter, after the addition of a reducing agent, and preferably sodium bisulfite, the precipitated sodium salt precipitates with cooling of the treated solution.

The 3-methoxy-6-sulfanilamidopyridazine is isolated by filtration and purified by washing with a saturated aqueous solution of sodium chloride, and then the purified and isolated sodium aoli is liberated in the aqueous medium by acidification, preferably with ootic acid.

In the process according to the invention, it is expedient to firstly remove methanol from the reaction mixture after methoxylation, preferably by distillation under reduced pressure, a second time after the addition of water, which may optionally be repeated. The paste in the form of a pasty mass of the sodium salt of 3-methoxy-6-sulfanilamidopyridazine is then dissolved at a slightly elevated temperature in a 10-15% sodium hydroxide solution. The resulting solution is treated with sodium bisulfite in an amount of 1 to 3% by weight. (based on the final product), whereby unwanted ballasts, in particular colored ones, are reduced. The sodium salt of 3-methoxy-6-sulfanilamidopyridazine is then quantitatively crystallized in very pure form from the treated solution by slow cooling to 0-25 ° C. The salt is coarse crystalline, with proper weight ratio conditions, easy to aspirate, and washed efficiently with saturated sodium chloride solution at 0-5 ° C, which does not dissolve the sodium salt.

The obtained 3-methoxy-6-e-sulfanilamidopyridazine sodium salt is then dissolved in warm water, filtered with charcoal and, after addition of a small amount of sodium bisulfite (not more than 0.1% by weight, based on the resulting product) to the filtrate at 50 to 80 ° C by acidification with dilute acetic acid eliminates the desired compound having after isolation bt181 to 185 ° C and extinction in the UY range of 0.03 to 0.07 when compared to 4% sodium hydroxide solution. The process according to the invention yields yields of 70 to 85%, usually around 78%, based on the starting 3-chloro-6-sulfanilamidopyridazine.

In the process according to the invention, it is essential to note that in a highly alkaline environment, the product does not hydrolyze in the temperature range indicated, and that sodium hydrosulphite achieves an effective reduction of by-products, particularly colored, so that the sodium 3-methoxy-6-aulfanilamidopyridazine is quantitatively crystallized from solution. in very pure form and that the salt is insoluble in the cooled saturated sodium chloride solution. In addition, the process is characterized by the simplicity and elimination of the use of organo-organic solvents, while attaining high yields and quality, in particular the novel and enhanced technical and economic effect of the invention.

Further details Jaouich apparent from the examples that the method according to the invention serve to illustrate but not limit ^8.

Example 1

100 g of 93-9 3-chloro-6-sulfanilamidopyridazine are methoxylated in a known manner, after which the reaction mixture is evaporated to dryness on a water bath at 60 DEG C., added to 150 ml of water and again evaporated under vacuum. Then 25 ml of 40% sodium hydroxide solution and water are added to a volume of 250 ml. The total alkali of the solution is 2.6 mol / l. The resulting solution of sodium salt of 3-methoxy-6-sulfanilamidopyridazine was heated to 60 ° C, added with 5 g of sodium bisulfite and left to crystallize spontaneously overnight. The next day, after cooling to 0 ° C, the product is filtered off with suction and washed with cold saturated sodium chloride solution until the filtrate is colorless. The sodium salt obtained is then added to 700 ml of water, 5 g of activated carbon are added, the solution is heated to 50 DEG C. and stirred for 1/2 hour. The activated carbon is filtered off and washed with 100 ml of warm water, which is added to the filtrate. The combined filtrates were heated to 70 ° C. and precipitate with dilute acetic acid (1: 1) to pH 6. At the first turbidity (start of crystal formation), 0.1 g of sodium bisulfite is added and precipitation is complete. The product is suction filtered at 60 ° C and washed with 200 ml of water at 50 ° C. The yield of 3-methoxy-6-sulfanilamidopyridine is 72 g, i.e. 77.3% of theory.

m.p. 182 [deg.] C. /

Example 2

200 g of 93% 3-chloro-6-sulfanilamidopyridazine are methoxylated. in a known manner; then the reaction mixture is concentrated under vacuum to 70 ° C. 300 ml of water are added to the pellet mass and again under vacuum distillation at a temperature of up to 80 ° C.

60 ml of a 40% sodium hydroxide solution and 150 ml of water are added to the evaporators aa. The total alkalinity of the solution is 2.8 mol / l. The solution is warmed to 60 ° C, 3 g of sodium bisulfite are added and allowed to cool for 8 hours. Then, the mixture was cooled to 15 ° C and aspirated. Separate with saturated sodium chloride solution at 3 ° C until the filtrate is colorless. The 3-methoxy-6-aulfanilamidopyridazine sodium salt obtained is dissolved in 1400 ml of water, 10 g of activated carbon are added, heated to 50 ° C and stirred for 1 hour. The activated carbon is filtered off, washed with 100 ml of warm water and the washing water is added to the filtrate. The filtrate was heated to 70 ° C and diluted with acetic acid (1: 1) and precipitated

3-methoxy-6-aulfanilamidopyridazine. After separation of the first crystals a and 0.2 g of sodium bisulfite are added and the precipitation is complete at pH 6. After cooling to 55 ° C, the product is filtered off with suction and washed with drinking water at 50 ° C. The yield of 3-methoxy-6-sulfanilamidopyrididaine is 145 g, i.e. 78.6% of theory, m.p. 183 ° C.

Claims (2)

Method for purification of 3-methoxy-6-aulfanilamidopyridazine, prepared by methoxylation 3-Chloro-6-sulfanilamidopyridazine, sodium methylates in mathenol, characterized in that, after completion of methoxylaoi, the reaction mixture is freed from methanol by evaporation under reduced pressure of 1330 to 9330 Pa at 60 to 80 ° C by evaporation of 3-methoxy- sodium salt. 6-sulfanilamidopyridazine aa at 50 to 80 ° C dissolve in aqueous sodium hydroxide solution to a final alkalinity of 2.5 to 3.0 mol / l, after the addition of a reducing agent, preferably sodium bisulfite, and by cooling the treated solution the precipitated sodium salt 3 The isoxethoxy-6-aulfanimamidopyridazine is isolated by filtration and purified by washing with a saturated aqueous solution of sodium chloride, whereupon the desired compound is purified in the aqueous medium by acidification, preferably with acetic acid, from the purified and isolated sodium salt.