CS273928B1 - Method of 2-pyroxy-5-/4-/2-pyridinylamino/sulphonyl/phenyl/azo benzoic acid production - Google Patents

Abstract

The invention concerns a method of production of 2-hydroxy-5-[4-/(2-pyridinylamino)sulphonyl)phenyl]azo benzoic acid, an important medicament that is known as Sulfasalazine. It is used for treatment of progressive polyarthritis and above all for ulcerative colitis. It is prepared by diazotation of sulphapyridine in the generally known way and copulation of the occurring diazonium salt with excess of salicylic acid and/or its salt in an aqueous alkaline environment by separation of the occurring product from the excess salicylic acid on the basis of different pH and by further removal of incidental contamination by the action of a mixture of ethanol or methanol and dilute hydrochloric acid, possible dilute acetic acid and dilute hydrochloric acid or crystallisation from a mixture of ethanol, ethyl acetate and concentrated hydrochloric acid.

Description

The present invention relates to a process for the manufacture of an important medicament for 2-hydroxy-5 - C4 - [(2-pyridinylamino) sulfonyl] phenyl] azobenzoic acid, which is mainly known under the name sulfasalazine.

Sulfasalazine was first prepared by Askelof and his co-workers (Swedish company Aktiebolaget Pharmacia) diazotization of sulfapyridine and coupling with an alkaline salicylic acid solution. This preparation is protected by the original patent of 1946 (US Patent No. 2396 145 '(1946)) and extended by modification of this preparation by two other Swedish patents of 1951 and 1952 (Swedish Patent No. 130,524 (1951)). and Swedish Patent No. 134,110 (1952)].

A substantially different process for the preparation of sulfasalazine and its derivatives is the subject of two further patents (DT 2110 613 (1970) and DT 257 629 Swedish Patent No. 15218 (1971)), according to which the reaction of 2-aminopyridine and p-ClSO 2. N = N-C 8 H 11 (COO R) OR 1 - 3.4, (where R = Me;

R @ ¹ = Ac) to prepare a substance from which subsequent alkaline hydrolysis affords 88% sulfasalazine.

A similar procedure is protected by the Romanian patent (Rum. Patent No. 61914/1974). The preparation consists in reacting 2-aminopyridine with 4- (4-acetoxy-3-carbomethoxyphenylazo) benzenesulfochloride at 20 to 40 ° C followed by hydrolysis.

The disadvantages of these processes are that in the coupling reactions several by-products are formed which are very difficult to remove, at the expense of high losses.

Disadvantages of the process are the sulfasalazine process by diazotizing the sulfapyridine with an aqueous solution of sodium nitrite in an excess of hydrochloric acid according to the invention, characterized in that the coupling of the resulting diazonium salt is carried out with an excess of salicylic acid and / or its salt in excess aqueous sodium hydroxide and unreacted. The salicylic acid is separated from the substance by acidifying the solution to pH 4.5. Thus, on the one hand, the expensive diazonium salt is used to the maximum extent, but at the same time some impurities which are not produced under these conditions or only to a small extent are removed. Excess salicylic acid is removed by acidifying the reaction mixture to pH 4.5, leaving salicylic acid in solution.

Remaining impurities are removed from the crude product by stirring hot in a mixture of ethanol and dilute hydrochloric acid, aspirated and washed with ethanol and water. This affords pure sulfasalazine by chromatography.

The effect of pH on the course of the reaction was monitored during the coupling. Sodium bicarbonate, sodium carbonate and sodium hydroxide were tested. Using sodium bicarbonate produces a completely different product, but even sodium carbonate does not give good results. Sodium hydroxide has proven to work best. The procedure is to dissolve the salicylic acid in sodium hydroxide and gradually add the diazonium salt to maintain a pH of about 8-9. As the pH increases, the product darkens strongly. As demonstrated by chromatography, the coupling time, in contrast to the generally known couplings, is relatively short. After the coupling was complete, it was stirred at room temperature for 10 minutes and the product was precipitated with dilute hydrochloric acid and then precipitated with acetic acid to pH 4.5. After washing with water, the product is stirred in a mixture of ethanol or methanol and dilute acid / hydrochloric acid and stirred at 70 ° C for 30 minutes in a flask under reflux.

It is dried at 60 ° C. Chromatographically pure sulfasalazine is obtained. Purification can be performed by crystallization from a mixture of ethanol, ethyl acetate and conc. hydrochloric acid, or by stirring at 90 to 95 C, ^D with dilute acetic acid and dilute hydrochloric acid.

AND.

<Sn

CS 273 928 Bl

Further details are given in the examples which do not limit the method according to the invention.

Example 1

To 4.98 g of sulfapyridine (0.02 mol) was added conc. hydrochloric acid (8 ml), water (50 ml) and beaten ice (50 g). After dissolution, the solution was cooled to 0 ° C with stirring and a solution of sodium nitrite (1.38 g; 0.02 mol) in water (10 mL) was added dropwise from the addition funnel at this temperature over 10 minutes. After the addition was complete, the solution was stirred for 10 minutes. Then add 0.1 g of urea (to remove excess nitrous acid) and mix for 10 minutes (iodine starch must not be violet).

Remove the flask from the bath and transfer it to another cooling bath. In a second 250 ml large flask, dissolve salicylic acid (3.37 g; 0.024 mol) in water (30 ml) with the addition of sodium hydroxide (5 g; 0.125 mol, oven or equivalent amount of operating sodium hydroxide solution). After dissolution, ice (20 g) is added and the solution is cooled to 0-7 ° C with stirring and the diazonium salt solution is gradually added over 10 minutes. The final pH should be 8.5 to 9.

To the solution was added 40% sodium hydroxide (3 mL) to dissolve a portion of the precipitated substance, and filtered with the addition of activated carbon (0.5 g). It is then precipitated at normal temperature with dilute hydrochloric acid (1: 1) to pH 7 and precipitated with dilute acetic acid (1: 1) to pH 4 to 4.5. The resulting orange solid was filtered off with suction and washed with water (100 ml).

Ethanol (15 mL) or methanol (15 mL), water (6.5 mL), conc. hydrochloric acid (2.5 mL) and the mixture was stirred at 50 ° C for 15 minutes. It is then gradually cooled to 30 ° C over 45 minutes. The undissolved product was filtered off with suction, washed with ethanol until a dark solution (10 ml) and water (10 ml) were added.

After drying at 60 ° C, 5.6 g (70.5%) of chromatographically pure sulfasalazine are obtained.

Example 2

The crude, dry sulfasalazine (17 g) prepared according to Example 1 was dissolved in a mixture of ethanol (80 ml), ethyl acetate (50 ml) and conc. hydrochloric acid (11 mL). Add activated carbon (0.5 g), stir for 15 minutes and filter. To the hot filtrate was added distilled water (35 mL).

After cooling to room temperature, the product is filtered off with suction. After drying at 60 ° C, 11.7 g (70%) of pure sulfasalazine are obtained.

Example 3

To the crude wet sulfasalazine obtained from 19.92 g (0.08 mol) of sulfapyridine, prepared according to Example 1, was added a solution of concentrated acetic acid (150 mL), water (20 mL) and concentrated hydrochloric acid (12 mL), and with stirring, the mixture is heated at 90-95 ° C for 15 minutes. The solution was then filtered, washed with dilute acetic acid (1: 3; 50 mL) and water (150 mL). After drying at room temperature, 16.3 g (51.25% of the starting sulfapyridine) of pure sulfasalazine of pale yellow color were obtained.

Claims (3)

SUBJECT OF THE INVENTION A process for the preparation of 2-hydroxy-5- 4 - [(2-pyridinylamino) sulfonyl] phenyl) benzobenzoic acid by diazotizing sulfapyridine with an aqueous solution of sodium nitrite in an excess of hydrochloric acid and subsequently coupling in situ with salicylic acid in a conical environment. that the coupling of the resulting diazonium salt is carried out with an excess of salicylic acid and / or its salt in a ratio of 1: 1.25 moles in an environment of excess aqueous sodium hydroxide solution and unreacted salicylic acid is separated from the substance by acidifying the solution successively with hydrochloric acid and acetic acid to pH 4.5, while remaining in solution, after aspiration, the crude sulfasalazine is freed from further impurities by treatment with a dilute solution of hydrochloric acid and ethanol or methanol. 2. The process of claim 1 wherein the crude dry sulfasalazine is crystallized from a mixture of ethanol, ethyl acetate and concentrated hydrochloric acid. 3. The process according to claim 1, wherein the crude wet sulfasalazine is freed of further impurities by treatment with dilute acetic acid and dilute hydrochloric acid.