CS218384B1 - Process for preparing 2,5-dihydroxybenzenesulfonic acid calcium salt - Google Patents

Abstract

The invention relates to a method for producing the calcium salt of 2,5-dihydroxybenzenesulfonic acid, a clinically used intravenous drug, by reacting benzoquinone with sodium or potassium bisulfite in an aqueous ethanol environment, by decomposing the obtained sodium or potassium salt of 2,5-dihydroxybenzenesulfonic acid in an alcoholic solution with gaseous hydrogen chloride and neutralizing the crude acid with calcium carbonate, oxide or hydroxide and crystallization of the crude calcium salt from water, with the addition of decolorizing agents, e.g. sodium dithionate.

Description

The present invention relates to a process for the production of a 2,5-dihydroxybenzenesulfonic acid calcium salt, a clinically used venopharmaceutical, by reacting benzoquinone with sodium or potassium disulphite in aqueous ethanol, decomposing the obtained sodium or potassium salt of 2,5-dihydroxybenzenesulfonic acid in an alcoholic solution with hydrogen chloride gas, and neutralization of the crude acid with carbonate, oxide or calcium hydroxide; and crystallization of the crude calcium salt from water with the addition of decolorizing agents such as sodium dithionate.

The invention relates to a process for the production of 2,5-dihydroxybenzenesulfonic acid calcium clinically used as a venopharmaceutical (cirrhosis, hypertension, arteriosclerosis, diffuse bleeding, postoperative capillary bleeding, etc.) under various trade names.

The processes known to date for the preparation of 2,5-dihydroxybenzenesulfonic acid salts can be roughly divided into two groups. The first group includes substitution reactions, the second group addition reactions.

The first group is known to react 2,5-dichlorobenzenesulfonic acid with sodium hydroxide at 200 ° C (DRP No. 284 533; C. 1915, 11, 168). The same group includes the preparation of 2,5-dihydroxybenzenesulfonic acid free acid by heating 1 part of hydroquinone and 8 parts of a mixture of concentrated and fuming sulfuric acid at 50 ° C (Seyda, Chem. Ber. 16, 688, 693; Hesse, J. Liebigs Ann. Chem. 114, 301).

The second group is considerably more numerous and essentially comprises the addition of hydrogen sulphites (ammonium, potassium, sodium and calcium) to the quinone.

The preparation of the ammonium salts of 2,5-dihydroxybenzenesulfonic acid is described in French Pat. No. 6163 (Chem. Abstr. 71, 128 752 c). The reaction is carried out at 0 ° C by dropwise addition of a saturated solution of ammonium hydrogen sulphite to an alcoholic quinone solution and the product is isolated from the concentrated solution.

The preparation of 2,5-dihydroxybenzenesulfonic acid calcium is described in French Pat. No. 77,958. It is operated in an ether-water environment with a saturated solution of calcium hydrogen sulphite at a temperature of -5 to 5 ° C. The reaction of quinone with sodium sulfite is based on an analogous principle (Pinnow, J. prakt. Chem. 89, 541; Dodgson, J. Chem. Soc. 105, 2441).

The process from hydroquinone and sodium sulfite in the presence of oxygen is somewhat modified (oxygen preferably oxidizes hydroquinone to quinone) (Pinnow, C. 1912, 11.1601; 1914, 1102). A number of analogous or modified procedures are also protected (US Patent Nos. 112 261, 140 525, 114 162 and

188 142).

The first group manufacturing processes, which are based on substitution (electrophilic, nucleophilic) reactions, are disadvantageous in that they either operate at high temperatures or in autoclaves, or handle aggressive chemicals such as fuming sulfuric acid, etc. The isolation and cleaning of final substances. The production equipment is expensive and wears out relatively quickly.

The second group of manufacturing processes, which is based on the addition reactions of hydrogen sulphites to quinone, is operationally viable and does not require complex equipment. Despite these indisputable advantages, these processes are burdened with some shortcomings which lead to lower yields, deteriorated quality and thus difficult cleaning and isolation of pure substances. As has been found experimentally, the small amounts of sulphites which are present in the hydrogen sulphites used in each case are disturbed by these reactions. The addition is then not unambiguous and there is always a side reduction reaction in which the hydroquinone is formed. In addition, another undesirable by-product, 2,5-dihydroxy-1,4-benzenedisulfonic acid, is also formed in these reactions.

As has been found, even more difficulties are encountered with the preparation of a pure calcium hydrogen sulphite solution. The solutions can only be prepared in a largely diluted state (about 8% by weight), and insoluble calcium sulfite is also gradually precipitated under these circumstances. Conversely, in the presence of excess free sulfur dioxide, quinone to hydroquinone is also reduced. For these reasons, the direct preparation of the 2,5-dihydroxybenzenesulfonic acid calcium salt by the addition of calcium hydrogen sulfite to the quinone is disadvantageous.

For the preparation of the calcium salt of 2,5-dihydroxybenzenesulfonic acid, two other processes (U.S. Pat. No. 140,525) are described, namely the transformation of the corresponding potassium salt of 2,5-dihydroxybenzenesulfonic acid by reaction with perchlorate and calcium chloride.

The first method, which is based on different solubilities of potassium perchlorate and calcium salt of 2,5-dihydroxybenzenesulfonic acid, is not unequivocal. As has been found, potassium perchlorate is partially transferred to the calcium salt solution of the acid, making the final product difficult to purify. Also for safety reasons (possibility of perchlorate explosion, manipulation with perchloric acid) this method is unsuitable for larger production. In addition, economic reasons also adversely affect this practice.

The second method, which uses calcium chloride to transform the potassium salt of 2,5-dihydroxybenzenesulfonic acid, is seemingly simple, but the results of the cited patent have not been verified. The reaction takes place only in part, the separation of the mixture is practically impossible.

The isolation and purification of the 2,5-dihydroxybenzenesulfonic acid salt, and in particular the calcium salt, is one of the key problems of the manufacturing process. In many of the papers cited, the relevant data are very brief or absent. However, for example, a method of purifying 2,5-dihydroxybenzenesulfonic acid calcium salt from 80% ethanol by filtering with charcoal and concentrating to a small volume is described. The same source mentions the isolation of the calcium salt of this acid by concentrating the aqueous solutions under vacuum and precipitating 1: 1 ethanol: ether (U.S. Pat. No. 140,525).

It has been experimentally verified that these purification processes are imperfect and considerably loss if the chromatographically pure substance is to be obtained.

The disadvantages and disadvantages of the known processes are eliminated by the process for the production of the 2,5-dihydroxybenzenesulfonic acid calcium salt from the benzoquinone according to the invention, which consists in the first reaction of benzoquinone with sodium or potassium bisulphite in a molar ratio of 1.0: 0.8 % aqueous ethanol at a concentration of 92.0 to 99.5% v / v, preferably 94.0 to 96.0% v / v, at a temperature of from -5 to 5 ° C, to prepare the sodium or potassium salt of 2,5- dihydroxybenzenesulfonic acid, which is isolated and then decomposed in a C 1 -C 3 alkanol, preferably methanol or ethanol, at 20-30 ° C with hydrogen chloride gas, after separation of the inorganic salt formed, the solution is evaporated to dryness and the crude acid obtained 2, The 5-dihydroxybenzenesulfonic acid is converted into the calcium salt in aqueous medium by treatment with carbonate, oxide or calcium hydroxide, which is isolated and purified by crystallization.

The reaction of benzoquinone with sodium or potassium bisulfite is conveniently carried out in a 50-fold excess of aqueous ethanol based on the weight of the starting benzoquinone.

Under these conditions, the sodium or potassium salt of 2,5-dihydroxybenzenesulfonic acid is obtained in high yield and very good quality. An appropriately selected amount of ethanol allows good results to be obtained even without concentrating the ethanolic solution, which allows perfect separation of small amounts of colored impurities that remain in the mother liquors after aspiration of the product.

The process according to the invention is furthermore important in that the disulfites used, unlike the hydrogen sulfites, do not contain sulfites and therefore the addition proceeds unambiguously. This was demonstrated by analysis of mother liquors in which only a minimum amount of by-products (hydroquinone) was detected. 2,5-Dihydroxy-1,4-benzenedisulfonic acid as a by-product has not been proven, despite the fact that an excess of disulphites has been employed due to higher yields.

In the next stage of the process according to the invention, the decomposition of the sodium or potassium salt of 2,5-dihydroxybenzenesulfonic acid with gaseous hydrochloric acid in a C 1 -C 3 alkanol is carried out at a salt to alkanol weight ratio of 1: 6 to 1: 8. up to 30 ° C), the precipitated alkali metal chlorides in the stated amount of alcohol used minimally dissolve, which facilitates their separation from the free acid solution.

This solution is further worked up by evaporating to dryness under a slight vacuum of the water pump. The residue obtained is diluted with the calculated amount of water and neutralized to pH 4.5-5.0 with carbonate or calcium hydroxide. More preferred is the use of calcium carbonate, which is added when the desired pH value is reached in about 3% excess. theory. Excess calcium carbonate retains dirt on its surface. A small amount of sodium dithionate was added to the solution to remove color. After filtration, the solution is evaporated to dryness under a water pump vacuum.

Crystallization of the crude calcium salt of 2,5-dihydroxybenzenesulfonic acid (the residue from the previous operation) is preferably carried out from an aqueous saturated solution (weight ratio of about 3: 1), again with the addition of sodium dithlonate and a mixture of ether, ethanol and acetic acid in volume ratio. 10: 4: 1, which is added after cooling the solution to a temperature of about 10 ° C in triple excess weight. After stirring, the precipitate is filtered off with suction, washed with the solvent mixture and dried to a moisture content corresponding to 1 mole of crystalline water.

Said purification process is advantageous in that it can be used to obtain the end product usually without further purification in a prescribed purity with good yields. The essence of the purification is that sodium dithionate reduces the violet-colored chinoid structure to a pale yellow normal structure. Impurities are introduced into the solvent mixture. The acetic acid present prevents oxidation by air oxygen to the quinoid structure.

The process according to the invention guarantees good yields and product quality compared to the known processes and thus enables large-scale industrial production.

The details of the process according to the invention can be seen from the following examples, which are illustrative but not limiting.

Example 1

To a solution of 17.7 g (0.163 mol) of benzoquinone in 1147 mL of ethanol cooled to 0-2 ° C was added dropwise a solution of 24.71 g (0.13 mol) of sodium bisulfite in 48.5 mL of water over 20 minutes. . The mixture was stirred at room temperature for 1 h and then stirred at room temperature for 1 h. The precipitated product was aspirated and washed with 80 ml of ethanol. After drying at 80 ° C, 31.8 g (91.96% of theory) of 2,5-dihydroxybenzenesulfonic acid sodium salt were obtained. To the product thus obtained was added 300 ml of ethanol or methanol, and hydrogen chloride gas was passed into the suspension until saturation (about 2 hours) with gentle cooling to 20-30 ° C.

After this time, the suspension was cooled to 5 ° C and the precipitated sodium chloride was aspirated. The filtrate was evaporated to dryness under a slight water pump vacuum. To completely remove the hydrogen chloride, the residue was evaporated twice more to dryness with 30 ml of ethanol or methanol.

The residue was dissolved in 100 ml of water and 8 g (0.08 mol) of calcium carbonate was added gradually to pH 5 (excess).

. The suspension was then decolourised by the addition of 0.05 g sodium dithionate. Excess calcium carbonate was aspirated and the filtrate was evaporated to dryness under a water pump vacuum. The residue was dissolved by heating in 10 ml of water and allowed to crystallize. After cooling to 5 degrees Celsius, the precipitate was filtered off with suction and washed with 10 ml of a cooled ether / ethanol / acetic acid mixture (10: 4: 1) and dried at 80 ° C. The mother liquors were evaporated to dryness in vacuo. The residue was dissolved in hot water (5 ml) and after cooling to 5 ° C, 10 ml of the above solvent mixture was added to the precipitate. The precipitate was aspirated and washed with the same mixture. The mother liquors were treated analogously to the previous case. A total of 15 g of chromatographically pure 2,5-dihydroxyibenzenesulfonic acid calcium salt was obtained.

Example 1 a d 2

Analogous to Example 1 except that 28.9 g (0.13 mol) of potassium disulfite was used instead of sodium bisulfite. Yield 14.1 g of product of satisfactory quality.

Claims (4)

SUBJECT Process for the production of a calcium salt of 2,5-dihydroxybenzenesulfonic acid from benzoquinone, characterized in that it is first reacted with benzoquinone with sodium or potassium disulphite, in a molar ratio of 1.0: 0.8, in an aqueous ethanol medium at a concentration of 92.0 up to 99.5% by volume, preferably 94.0 to 96.0% by volume, at a temperature of from -5 to 5 degrees Celsius, prepare the sodium or potassium salt of 2,5-dihydroxybenzenesulfonic acid, which is isolated and then in the environment alkanol having 1 to 3 carbon atoms, preferably methanol or ethanol, decomposes with hydrogen chloride gas at 20-30 ° C, after separation of the inorganic salt formed, the solution is evaporated to dryness and the crude 2,5-dihydroxybenzenesulfonic acid obtained is reacted in an aqueous medium by reaction with carbonate, oxide or calcium hydroxide is converted to a calcium salt which is isolated and purified by crystallization. OF THE INVENTION 2. The process of claim 1 wherein the reaction of benzoquinone with sodium or potassium bisulfite is carried out in a 50-fold excess of aqueous ethanol based on the weight of the starting benzoquinone. 3. A process according to claim 1, wherein the decomposition of the sodium or potassium salt of 2,5-dihydroxybenzenesulfonic acid with gaseous hydrogen chloride in a C1-C3 alkanol is carried out at a salt to alkanol weight ratio of 1: 6 to 1: 8. 4. The process of claim 1, wherein the crystallization of the crude calcium salt of 2,5-dihydroxybenzenesulfonic acid is carried out from an aqueous solution saturated at 92-96 ° C, in the presence of sodium dithionate and after addition of a mixture of ether, ethanol and acetic acid. in a 10: 4: 1 volume ratio.