CS259633B1 - Process for the preparation of 7-hydroxy-4-methylcumarin - Google Patents

Abstract

Method for producing 7-hydroxy-4-methylcoumarin by reacting resorcinol with ethyl acetoacetate in a mixture of concentrated sulfuric acid with ethanol or acetic acid.

Description

The invention relates to a process for the production of pure 7-hydroxy-4-methylcoumarin, which is known in the literature under the generic name hymecromone. 7-Hydroxy-4-methylcoumarin shows significant spasmolytic effects on the bile ducts in animals and humans, is rapidly absorbed after oral administration and has a rapid onset of action. It is an active ingredient of choleretically active drugs, especially used in the treatment of biliary tract spasms. Thus, the preparation of 7-hydroxy-4-methylcoumarin in the purity required for pharmaceutical use is of considerable importance to the pharmaceutical industry.

The preparation of 7-hydroxy-4-methylcoumarin by condensation of resorcin with ethyl acetate in concentrated sulfuric acid was already described in 1883 by H. v. Pechmann and C. Duisberg [Chem. Ber. 16, 2 119 (1883) 1 in a general work on the preparation of coumarin derivatives. A practically identical procedure was developed by A. Russel and J. R. Frye [Org. Synthesis, Coll. Vol. III., 282 (1955)). A solution of 2 moles of resorcin in 2 moles of ethyl acetate is added dropwise under cooling to 10 ° C. After allowing the reaction mixture to stand at room temperature for 12 to 24 hours, 7-hydroxy-4-methylcoumarin is isolated by pouring the reaction mixture into excess crushed ice and suctioning off the precipitated solid. It is purified by transfer to an aqueous solution in the form of its sodium salt, acidification of the solution and suction. The product thus purified is crystallized from 95% aqueous ethanol and has a melting point of 185 ° C. Sulfuric acid used in technically unsuitable large amounts for the reaction of resorcin with ethyl acetoacetate was successfully replaced by J. Koo (Chem. Ind. 1955, 445) with polyphosphoric acid. Apparently the same goal was pursued by S.S. Israelstam and E. Barris (Chem. Ind. 1958, 1430), who catalysed the condensation of resorcin with ethyl acetate in a small amount of sulfuric or polyphosphoric acid. The use of acidic ion exchangers in this condensation has been described by E.V.O. John and S.S. Israelstam [J. Org. Chem. 26, 240 (1961). The use of other condensing agents, phosphoric chloride, phosphonyl chloride, phosphorus pentoxide, aluminum chloride, zinc chloride, bromine, iodine and the like has been described by V. M. Thakor and A. B. Acharya [J. Indian Chem. Soc. 48, 499 (1971)].

After laboratory testing of virtually all the described processes for the preparation of 7-hydroxy-4-methylcoumarin, it has been found that the yields reported in the literature relate to a product of a purity unsuitable for pharmaceutical use. From an economic point of view, undoubtedly the most preferred condensing agent for the reaction of resorcin with ethyl acetate is concentrated sulfuric acid. By reproducing the cited procedures in which the initially used large amount of concentrated sulfuric acid (1000 ml per 1 mol of resorcin) was reduced to a catalytic amount, it was found that the reduction in the amount of conc. In this case, the yield of 7-hydroxy-4-methylcoumarin is reduced and condensation must be carried out at an elevated temperature of 70 to 120 ^{° C.}

These drawbacks are solved by the process underlying the present invention wherein part of the conc. the sulfuric acid used in the condensation of resorcin with ethyl acetate is replaced by a suitable water-miscible solvent, preferably ethanol or acetic acid. Use of conc. sulfuric acid with ethanol or acetic acid to carry out the reaction of resorcin with ethyl acetate, besides significantly reducing the amount of conc. sulfuric acid also reduces the viscosity of the reaction mixture and thereby facilitates its processing, carrying out the reaction at 0 to 50 ° C for 1 to 7 hours and, last but not least, easier suction of the crystalline product precipitated after dilution with water, aqueous ethanol or dilute acetic acid. The product can be purified by conventional crystallization. According to the invention, the reaction of resorcin with ethyl acetate is carried out either by adding dropwise a solution of 1 mole of resorcin in 1 mole of ethyl acetate to a stirred mixture of 100 to 200 ml conc. sulfuric acid with 50 to 200 ml of ethanol or acetic acid at a temperature of 0 to 50 ° C, or a solution of 1 mole of resorcin in 1 mole of ethyl acetate is added dropwise with stirring to 100 to 200 ml of conc. sulfuric acid, and in both cases, the reaction mixture is stirred at 0 to 50 ° C for 1 to 7 hours. After crystallization, the crystallized product is purified by crystallization, for example from methanol or from about 70% acetic acid. The product thus prepared has a purity sufficient for pharmaceutical use.

The details of the process for the preparation of the 7-hydroxy-4-methylcoumarin according to the invention are given in the following non-limiting examples.

Example 1

To 100 ml of ethanol cooled to 0-10 ° C, 200 ml conc. sulfuric acid. A solution of 110.1 g of resorcin in 130.1 g of ethyl acetate, prepared by heating the mixture of the two components until complete dissolution of the resorcin (about 50 ° C), is added dropwise to the mixture under stirring and cooling to 0-10 ^° C over 1.5 hours. ) and cooling to 20 ° C. The reaction mixture was stirred at 0-10 ° C for 1 hour. Upon completion of external cooling, the temperature of the reaction mixture was raised to 20 ° C over about 30 minutes, and the mixture was stirred at this temperature for 4 hours. While stirring and cooling to about 20 ° C, a mixture of 100 ml ethanol and 320 ml distilled water was added dropwise. . After further stirring for 30 minutes, the precipitated crystalline substance is filtered off with suction, stirred with 150 ml of ethanol and after suction is washed three times with 100 ml of water. 135 g of crude 7-hydroxy-4-methylcoumarin are obtained. After crystallization twice from 1200 ml of methanol, 89 g (50.5%) of the product with a melting point of 188 ^DEG- 190 ^DEG C. are obtained. By treating the mother liquors from both crystallizations by distilling off the methanol under reduced pressure to a evaporation volume of about 100 ml. 49 g of product are obtained which, after recrystallization twice from 500 ml of methanol, yields an additional 28.2 g of pure 7-hydroxy-4-methylcoumarin, m.p. 188-190 ° C. The total yield of pure 7-hydroxy-4-methylcoumarin for pharmaceutical use is 117.2 g (66.5%).

Example 2

To 5 ml of acetic acid, 12 ml of concentrated sulfuric acid was added dropwise while stirring and cooling with water. A solution of 11.5 g of technical resorcin in 13 g of ethyl acetate, prepared by heating the mixture of both components until complete dissolution of the resorcin (about 50 ° C) and cooling to 20 ° C, was added dropwise over 2 hours with stirring. the temperature of the reaction mixture is maintained at 45-50 [deg.] C. The mixture is stirred for 1 hour at the same temperature, while stirring and cooling with water, 25 ml of distilled water are added dropwise over about 30 minutes. The precipitated product is filtered off with suction and washed with dilute acetic acid (2.5 ml of acetic acid and 10 ml of water) and 200 ml of water for one hour at 20 ^DEG C. The wet crude product (25.5 g with a water content of 38 why) is dissolved. 90 ml of 70% acetic acid, the solution is filtered hot with 0.7 g of activated carbon and the filtrate is allowed to crystallize in about 16 hours at 5 DEG C. The product is filtered off with suction, washed with 10 ml of 70% acetic acid and 150 ml of water. (distilled ). 12.6 g (71.6%) for pharmaceutical purposes usable 7-hydroxy-4-methylcoumarin hydrochloride, m.p. 188-190 ° C.

Example 3

To a solution of 110.1 g of resorcin in 130.1 g of ethyl acetate, prepared by heating the mixture of both components to about 50 ° C and cooling to 20 ° C, 100 ml of acetic acid was added and the resulting solution was added dropwise with stirring over 1.5 hours. to 200 ml conc. sulfuric acid cooled to 5 ° C. During the dropwise addition, the temperature of the reaction mixture was maintained by cooling to 5 ^° C. The reaction mixture was stirred for an additional 1 hour at 5 ° C and 3 hours at 20 ° C. While stirring and cooling to 20 ° C, 500 ml of distilled water is added dropwise to the mixture, and after stirring for 15 minutes the crystallized product is suctioned off and washed with 1000 ml of distilled water. After drying, 183 g of crude product is obtained, which is purified by crystallization from methanol or dilute acetic acid as in the previous examples or is first thoroughly stirred with 900 ml of methanol and the product obtained by suction and washing with 75 ml of methanol is recrystallized from 1300 ml of methanol. 121.5 g (68.9%) of pure 7-hydroxy-4-methylcoumarin are obtained, m.p. 188-190 ° C.

Claims (2)

přeďmeτ A process for preparing 7-hydroxy-4-methylcoumarin by reacting resorcin with ethyl acetate in the presence of sulfuric acid as a condensing agent, characterized in that the reaction is carried out in a mixture of concentrated sulfuric acid with ethanol or acetic acid. 2. A process according to claim 1, wherein the reaction medium used for the reaction of 1 mole of resorcin with 1 mole of ethyl acetate is a mixture of 100 to 200 ml conc. sulfuric acid with 50 to 200 ml of ethanol or acetic acid and the reaction is carried out at 0 to 50 ° C for 1 to 7 hours.