RU2487871C1 - Method of producing sodium salt 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2h-1-benzopyran-2-one - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing a sodium salt 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one, a warfarin preparation base, from 4-hydroxy-coumarin and benzalacetone in water while boiling in the presence of a heterogeneous catalyst which is a solid polymer with an amine that is chemically attached to its surface, wherein the catalyst is taken in amount of 5-30 wt % of the 4-hydroxy-coumarin used.

EFFECT: method considerably simplifies the technology due to easier extraction of the end product and its purification and enables to obtain a product of high purity with sufficiently high output.

3 cl, 2 tbl, 18 ex

Description

The invention relates to chemical technology, in particular, to a method for producing 4-hydroxy-3- (3-oxo-1-phenylbutyl) -2H-1-benzopyran-2-one sodium salt, the basis of the drug warfarin.

Warfarin is an anticoagulant that acts on the synthesis of blood coagulation factors by inhibiting vitamin K epoxy reductase and thus inhibiting the regeneration of vitamin K.

A report on the production of a number of new 3-substituted 4-hydroxycoumarin preparations with anticoagulant properties was first published in the United States in 1944 (M.A. Stahmann, M. Ikawa, K.P. Link Journal of the American Chemical Society 66,902, 1944). These new drugs had the following general formula:

where R is an alkyl, phenyl or oxyphenyl group;

R ₁ is an alkyl, phenyl or substituted phenyl group.

In accordance with this work, warfarin, in which R is methyl, R ₁ is phenyl, was obtained by reacting 4-hydroxycoumarin with benzalacetone in three times the amount of pyridine (relative to 4-hydroxycoumarin) at its boil, under reflux. The process was carried out for 24 hours. After cooling, the reaction mass was mixed with a five-fold volume of water, acidified with hydrochloric acid to pH 2. The precipitate was filtered off, purified by recrystallization in ethanol, and a product was obtained with a melting point of about 161 ° С (literary 158.9-161.2 ° С, OHS Database. 1994. Occupation Health Services, Inc. 1994 (June) MSDS for Warfarin. OHS Inc., Secaucus, NJ.) In 40% yield.

In US patent No. 2427578, 1947, the same authors, pyridine in this process was replaced by water and the selection of the product was carried out from water-acetone mixtures. As a result, the duration of the process was reduced to 12 hours, and the yield increased to 48%.

The disadvantages of these technologies are the low product yield and the long process time.

In work (M. Seidman, DN Robertson, KPLink Journal of the American Chemical Society 72.5193.1950), dioxane was used as a solvent and the first catalyst was piperidine, as a result, the product yield increased to 67%, and the duration of the process reduced to 9 hours.

The presence of a catalyst led to a sharp increase in the yield of the product and to a significant reduction in the duration of the process, but still these parameters remained unsatisfactory.

In UK patent No. 715846, 1952 (prototype), a series of amine catalysts were proposed for the process — pyridine, aniline, triethylamine, tributylamine, triethanolamine, piperidine, diethylamine, diethanolamine, monoethanolamine and ammonia.

The process of obtaining warfarin using these catalysts was carried out in boiling water, under reflux with vigorous stirring, while the reaction time was reduced to 2-5 hours. Received technical warfarin containing a large number of impurities and necessarily, among them, the used homogeneous catalyst.

A complex, multi-stage procedure was used to purify the product from impurities and the catalyst, including boiling the product powder in benzene under reflux and separating the product from benzene by filtration. Dissolving the obtained precipitate in an aqueous alkaline solution and washing the solution three times with carbon tetrachloride (each time with the separation of the aqueous and organic layers). Then, precipitation of warfarin with concentrated hydrochloric acid was carried out, filtration and washing of the product precipitate on the filter from carbon tetrachloride with water, and the product was dried.

The described method provides the yield of the target product 42-90%. The content of catalysts in the reaction mass varied from 0.5 to 50% molar of the loaded 4-hydroxycoumarin, but the best results were obtained at their concentrations up to 5% molar. Thus, the results achieved in this patent are certainly high, however, the introduction of homogeneous catalysts in the reaction mass leads to additional contamination of the product and complicates its purification, which is a disadvantage of this method.

The objective of the invention is the development of a method of obtaining the target product, simplifying the process technology and at the same time providing a high purity product.

The problem is solved by carrying out the process of condensation of 4-hydroxycoumarin with benzalacetone in the presence of a heterogeneous catalyst in the amount of 5-35% of the load of 4-hydroxycoumarin, which is a polymer or copolymer (polystyrene, divinylbenzene, polyacrylate, etc.) with amines chemically fixed on its surface.

When the amount of catalyst is less than 5%, it is not possible to achieve a high yield, and when its amount is more than 35%, there is no further increase in yield.

The heterogeneous catalyst does not contaminate the product due to its insolubility and can be separated from the reaction mass by ordinary filtration and reused after washing it with water. Moreover, the product is purified due to the adsorption of impurities introduced with the raw material and generated during the process on the surface of the heterogeneous catalyst. As a result, there is no need for the benzene purification stage of the product used in the prototype.

A heterogeneous catalyst obtained by special synthesis can be used by reacting halogen-containing polymers with amines in the presence of alkali or without it, or ready-made industrial anion-exchange resins in which various amines or quaternary ammonium bases are active components can be used.

The second option is clearly preferable to the first. It allows you to choose the right catalyst by choosing from ready-made anion-exchange resins available on the market.

The following examples illustrate the invention.

Example 1. Comparative prototype.

50 g (0.304 mol) of 4-hydroxycoumarin (melting point 212-214 ° C), 50 g (0.342 mol) of benzalacetone (crystallization temperature 37-38 ° C) were charged into a two-necked 1-liter flask equipped with a reflux condenser and stirrer. 350 ml of water and 3.4 ml (0.024 mol) of triethylamine (exchange capacity 7.1 mEq / cm ³ ). The mixture was heated to boiling, with stirring, and refluxed for 2 hours, the appearance of a white precipitate was observed. Boiling was continued for another hour, increasing the intensity of mixing.

Then the reaction mixture was cooled to room temperature, the precipitate was separated by filtration, washed with cold water and dried in air. Then it was suspended in 200 ml of benzene, refluxed with stirring for 30-45 minutes, cooled, filtered, washed with cold benzene and again dried in air.

The dried mass was dissolved at room temperature in 400 ml of a 5% sodium hydroxide solution (the residual benzene was removed from the surface) and the solution was washed three times with carbon tetrachloride according to the following scheme: first time 200 ml, second time 100 ml and third time 100 ml. The washed alkaline solution was neutralized with concentrated hydrochloric acid to pH 1-3. The precipitate was filtered off, washed with water and dried. A white crystalline product was obtained with a melting point of 159-160.3 ° C.

The yield of a technical product is 85%, calculated on 4-hydroxycoumarin.

Example 2

50.1 g of 4-hydroxycoumarin (with a 5% excess, which is necessary to prevent the formation of impurities from benzalacetone), 44 g of benzalacetone, 3.5 ml of AN -31 (5% by weight relative to 4-hydroxycoumarin) and 350 ml of water. Anionite AN-31 is a copolymer of styrene and divinylbenzene with grafted secondary and tertiary amino groups of the aliphatic series. Its exchange capacity is 2.6 mEq / cm ³ .

The contents of the flask were heated to a boil with the stirrer turned on and the extract was allowed to stand for 3 hours. The solid product began to precipitate an hour after the start of boiling.

The flask was cooled to room temperature and a solution of sodium hydroxide (14 g of sodium hydroxide in 50 ml of water) was added to it, the whole product was dissolved and transferred into sodium salt. The catalyst was separated by filtration. The alkaline solution was washed with 250 ml of methylene chloride, the aqueous layer was separated on a separatory funnel and poured into 1000-1500 ml of water containing 18 g of concentrated sulfuric acid. The precipitated technical product (already white) was separated on the filter, washed with water and dried. The yield of a technical product is 92%. Melting point 160.7-161.2 ° C.

Examples 3-5

The process was carried out as in example 2, but the catalyst used was Purolite CTA-190 anion exchange resin, which is a macroporous copolymer of styrene with divinylbenzene, with an active component containing 90% tertiary amine and 10% quaternary ammonium base (exchange capacity 1.3 mEq / cm ³ ).

The process conditions and the results obtained in examples 3-5 and the following examples are shown in table 1. Example 6-8

The process was carried out as in example 2, but the catalyst used was Purolite D-5325 anion exchange resin, a copolymer of polystyrene with divinylbenzene and 2-vinylpyridine as an active component, with an exchange capacity of 1.17.

Example 9-11

The process was carried out as in example 2, but the catalyst used was the Purolite D-5324 anion exchange resin, a copolymer of polystyrene with divinylbenzene and 4-vinylpyridine as the active component, with an exchange capacity of 1.51.

Table 1. No. of examples Catalyst Name Exchange capacity, mEq / cm ³ The concentration of catalyst,% mass. from loaded 4-hydroxycoumarin Product yield,% Melting point, ° С 2 AN-31 2.6 5 92 160.7-161.2 3 Purolite STA-190 1.3 twenty 74.3 159.8-160.5 four Purolite STA-190 1.3 25 82.5 160.4-160.9 5 Purolite STA-190 1.3 thirty 78.8 160.2-160.8 6 Purolite D-5325 1.17 25 83,4 160.5-161.0 7 Purolite D-5325 1D7 thirty 86.5 160.6-161.1 8 Purolite D-5325 1D7 35 83.9 160.5-161.0 9 Purolite D-5324 1.51 twenty 88.1 160.6-161.1 10 Purolite D-5324 1.51 25 90.8 160.7-161.2 eleven Purolite D-5324 1.51 thirty 81.5 160.4-160.9

A special synthesis of a heterogeneous catalyst was carried out according to the classical scheme (Soladze K.M., Pashkov AB, Tiov B.C. Ion-exchanged high-molecular compounds, M., 1960) - by chlormethylation of a polystyrene copolymer with divinylbenzene, with its further amination with diethylamine.

The test results of the obtained catalyst are shown in example 12.

Example 12

The process was carried out as in example 2, but as a catalyst, an anion exchange resin synthesized specifically — a polystyrene-divinylbenzene copolymer aminated with diethylamine — was used. The technical product yield is 91.6%, melting point 160.6 - 161.0 ° C.

The need to use sufficiently large concentrations of anion exchangers to achieve acceptable product yields, as well as their relatively high cost, make it important to reduce the consumption of heterogeneous catalysts. It can be reduced only in one way - to use the catalyst repeatedly.

The multiple use of the Purolite D-5324 catalyst (one of the best tested) is shown in Examples 13-18.

The synthesis in these examples was carried out as in example 10, but after separation of the catalyst from the reaction mass by filtration, it was sent to the next synthesis of the product, previously washed with distilled water. The procedure was repeated until a noticeable drop in catalyst activity. The results obtained in examples 13-18 are presented in table 2.

Table 2. No. of examples Catalyst condition Product yield 10 Source catalyst 90.8 13 From the 10th example 90.1 fourteen From 13 examples 91.2 fifteen From 14 examples 89.6 16 From 15 examples 88.7 17 From 16 examples 83.5 eighteen From 17 examples 76.1

From table 2 it is seen that a sharp drop in product yield was observed already in the fifth cycle of catalyst use. In the sixth cycle, the yield reached only 76.1%.

Apparently, during the synthesis of warfarin, the amine part of the anion exchange resin undergoes irreversible oxidation, leading to a loss of catalyst activity. As a result, you can really count on 5-6 times the use of the catalyst, which corresponds to a decrease in catalyst consumption by 5-6 times.

Thus, the proposed method greatly simplifies the technology and provides a high-purity product with a sufficiently high yield.

Claims (3)

1. The method of obtaining 4-hydroxy-3- (3-oxo-1-phenylbutyl) -2H-1-benzopyran-2-one sodium salt of 4-hydroxycoumarin and benzalacetone in water, in the presence of a catalyst comprising an amine, at boiling, characterized in that a heterogeneous catalyst is used, which is a solid polymer with an amine chemically fixed on its surface, with its amount of 5-30 wt.% of the loaded 4-hydroxycoumarin. 2. The method according to claim 1, characterized in that the catalyst used is an anion exchange resin with an active component of the amine type. 3. The method according to claim 1, characterized in that the catalyst is used repeatedly.