RU2201419C2 - Method of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamino]-penicillanic acid sodium salt preparing - Google Patents

Abstract

FIELD: antibiotics, chemical technology. SUBSTANCE: invention relates to method of preparing 6-[3-(2-chloro-phenyl)-5-methylisoxazol-4- carbamino] -penicillanic acid sodium salt that is highly effective antibiotic. Method is carried out by synthesis of cloxacillin by acylation of 6-aminopenicillanic acid Na-salt in aqueous-acetone medium with 3-(2- chlorophenyl)-5-methylisoxazol-4-carboxylic acid chloroanhydride at maintenance of medium hydrogen index in the range pH 6.0-9.5, isolation of cloxacillin as acid form from the obtained solution by reduction of pH value to 2.5-3.5, dissolving cloxacillin hydrated paste in butanol in addition of sodium hydroxide solution to suspension followed by crystallization of product in the process of distillation of aqueous-butanol azeotrope from reaction mass under vacuum and the following filtration and drying 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamino]-penicillanic acid sodium salt (cloxacillin) under vacuum. The claimed method provides the possibility to obtain product with the yield 85-91% of theoretical value as measured for 6- aminopenicillanic acid. The preparation prepared by the claimed method is white crystalline powder with specific rotation 168,5^° (1% solution in freshly boiled water). Optical density of 1% solution in water at 430 nm due to the presence of light-absorbing impurities (by derivatives of penicillenic acid) is 0.02-0.04 (in cell with layer thickness 10 mm). EFFECT: improved method of preparing, simplified technological process, reduced raw consumptions. 1 tbl, 11 ex

Description

 The present invention relates to the production of a highly effective antibiotic - the sodium salt of 6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carbamino] penicillanic acid (cloxacillin).

 Known methods for producing cloxacillin sodium salt by reacting trimethylsilyl derivatives of 6-aminopenicillanic acid or its salt with 3- (2-chlorophenyl) -5-methylisoxazolyl-4-carbonyl chloride in an organic solvent, followed by hydrolysis of the resulting trimethylsilyl derivative of the cloxacillin product layer and isolating the celloxacillin product and the action of alkaline sodium salts. As the silylating agent, trimethylchlorosilane [US patent 4182709] or N-trimethylsilylacetamide [US patent 4181656] is used. Significant disadvantages of these methods are the multi-stage process, the use of expensive raw materials (N-trimethylsilylacetamide or trimethichlorosilane), the possibility of contamination of the target product with organic amines used as proton acceptors.

The closest to the claimed method according to the technical essence and the achieved result is the method according to US patent 4912211, in accordance with which the synthesis of cloxacillin is carried out in an aqueous acetone medium in the interaction of the sodium salt of 6-aminopenicillanic acid with 3- (2-chlorophenyl) -5-methylisoxazolyl- 4-carbonyl chloride. From the resulting solution, after removal of methylene chloride and adjusting the pH to 2.5, cloxacillin in the form of an acid is extracted with methylene chloride. The methylene chloride layer is washed with water, then the product is transferred to the aqueous layer when the pH of the medium is adjusted to pH 7, the layers are separated, the aqueous layer is treated with activated carbon and lyophilized. The resulting product is dissolved in absolute ethanol, the solution is filtered. Cloxacillin crystallization is carried out as a result of heating the resulting solution to 30 ^° C and then cooling to 10 ^° C. After filtration, washing of the filter cake and drying under vacuum, sodium cloxacillin monohydrate is obtained with a purity of 96.2% and a yield of 90.9%.

 The main disadvantages of the prototype method are the complexity of the process, the use of the expensive operation of lyophilization of the solution, the use of acetone, methylene chloride and ethanol in one technological process.

 The inventive method is aimed at reducing raw materials costs and simplifying the process in the production of sodium salt of 6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carbamino] -penicillanic acid (cloxacillin).

 This goal is achieved by synthesizing cloxacillin by acylation of the 6-aminopenicillanic acid Na-salt in an aqueous-acetone medium with 3- (2-chlorophenyl) -5-methylisoxazolyl-4-carboxylic acid chloride while maintaining the pH of the medium in the range of 6.0-9, 5 pH, isolating cloxacillin in the form of an acid from the resulting solution by adjusting the pH of the medium to 2.5-3.5 pH, dissolving the hydrated paste of cloxacillin - acid in butanol by adding sodium hydroxide solution, crystallization to the suspension uu product during distillation water-butanol azeotrope from the reaction mixture in vacuo followed by filtration and drying the sodium salt of 6- [3- (2-chlorophenyl) -5-methylisoxazole-4-karbamino] -penitsillanovoy acid (cloxacillin) under vacuum.

Distinctive features of the claimed method are:
- maintaining the value of the hydrogen index of the medium during the acylation in the range of 6.0-9.5 pH,
- deposition of cloxacillin in the form of an acid from the reaction mass after the acylation process while adjusting the pH of the medium to 2.5-3.5 pH,
- dissolution of cloxacillin acid in a water-butanol medium with the introduction of a solution of sodium hydroxide in the reaction mass,
- crystallization of the sodium salt of 6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carbamino] -penicillanic acid (cloxacillin) during the distillation of a water-butanol azeotropic mixture under vacuum until the mass fraction of water in the reaction mass reaches a value of not more than 3.5%

The combination of the above distinguishing features ensures the achievement of a positive result in the claimed method due to the following factors identified in the development process:
- The acylation of the sodium salt of 6-aminopenicillanic acid is carried out practically quantitatively without noticeable formation of by-products while maintaining the pH of the medium in the range of 6.0-9.5 pH. During the acylation process, when the pH value is below 6.0 pH, the reaction rate is significantly reduced, and if the pH value is above 9.5 pH, the hydrolysis rate of 3- (2-chlorophenyl) -5-methylisoxazolyl-4-carboxylic acid chloride increases, which leads to a decrease in the yield of the target product and its pollution with 3- (2-chlorophenyl) -5-methylisoxazole-4-carboxylic acid. Maintaining the pH value of the medium in the range of 6.0-9.5 pH during the acylation is achieved by simultaneous dosing of 3- (2-chlorophenyl) -5-methylisoxazolyl-4-carboxylic acid acid chloride and sodium hydroxide solution in the sodium salt of 6-aminopenicillanic acid sodium.

 - Cloxacillin in the form of an acid is released almost quantitatively without the formation of appreciable amounts of by-products when the pH of the medium is adjusted to pH 2.5-3.5. When the pH of the medium is brought to a value below 2.5 pH, the hydrolysis rate of the target product increases, which leads to a decrease in the yield of the target product and its contamination with hydrolysis products; when the pH of the medium is increased to a value of more than 3.5 pH, the loss of the target product increases with mother liquor.

 - The crystallization of the sodium salt of 6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carbamino] -penicillanic acid (cloxacillin) from the aqueous-butanol solution is carried out with a high yield during the distillation of the aqueous-butanol azeotropic mixture under vacuum to achieve mass fraction of water in the reaction mass of a value of not more than 3.5%. When exceeding the concentration of water in the reaction mass of 3.5%, there is a sharp increase in the solubility of the target product with the mother liquor and, as a result, a decrease in its yield.

Example 1
To a suspension of 40.0 g (38.4 g in terms of 100% substance) of 6-aminopenicillanic acid in 240 ml of distilled water, cooled to a temperature of 2 ^{° C.} , a 15% sodium hydroxide solution is poured until the precipitate is completely dissolved, which occurs when the pH of the medium is 7.5-8.5 pH. A solution of 46.6 g (in terms of 100% substance) of 3- (2-chlorophenyl) -5-methylisoxazole-4-carboxylic acid chloride is poured into the resulting solution at a temperature of 10-12 ^o C for 30-60 minutes 35 ml of acetone. At the same time, a 15% sodium hydroxide solution is dosed into the reaction mass in an amount that ensures that the pH of the medium is maintained in the range of 7.5-8.5 pH. The reaction mass is stirred for 15-30 minutes at a temperature of 10-15 ^o C to achieve a constant pH of the medium in the range of 6.0-9.5 pH.

 6 g of activated carbon are introduced into the solution obtained after acylation, the reaction mixture is stirred for 10-15 minutes, filtered on a Buchner funnel, the charcoal on the filter is washed with 30 ml of distilled water, the wash water is added to the main filtrate.

To the obtained filtrate, cooled to a temperature of 0-5 ^o C, with stirring in a thin stream add a 10% solution of hydrochloric acid to achieve a pH of 2.9-3.1 pH. The resulting suspension of 6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carbamino] - penicillanic acid (cloxacillin) is stirred for 20-30 minutes and filtered on a Buchner funnel. The precipitate on the funnel is washed with distilled water until the pH value in the wash water reaches 4.5-5.0 pH and squeezed from excess moisture.

The wet cake was suspended in 350 ml of butyl alcohol. A 15% sodium hydroxide solution is introduced into the suspension, cooled to 0-5 ^{° C.} , with a thin stream until the cloxacillin precipitate is completely dissolved, which is observed at a pH value of 6.8 pH. The resulting solution was filtered and transferred to the installation for distillation of the water-butanol mixture under vacuum. The distillation of the water-butanol mixture is carried out at a residual pressure of 30-40 mm RT. Art. at a temperature in pairs of from 20 ^o With at the beginning to 35 ^o With at the end of the distillation process. The distillation is completed when the concentration of water in the bottom residue of 1.5% is reached.

After the end of the distillation process, the resulting suspension of the sodium salt of 6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carbamino] penicillanic acid is cooled with stirring to a temperature of 8-10 ^o C and maintained at this temperature 2.0-2 5 hours. Then the suspension is filtered on a Buchner funnel, the precipitate is washed twice with 50 ml of butanol, squeezed and dried under vacuum at a temperature of not more than 40 ^o C to achieve a constant weight.

 78.1 g of monohydrate of sodium salt of 6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carbamino] -penicillanic acid are obtained with a basic substance content of 99.5%, which corresponds to a yield of 90.7% of theory in terms of on 6-aminopenicillanic acid.

 The resulting product is characterized by the following indicators.

 The preparation is a white crystalline powder, a 10% solution of the drug in water is colorless and has a pH value of 6.7 pH, specific rotation is 168.5 ((1% solution in freshly boiled water). Optical density of a 1% solution in water at 430 nm, due to the presence of light-absorbing impurities (derivatives of penicillic acid), is 0.02 (in a cell with a layer thickness of 10 mm).

Examples 2-11
Obtaining the sodium salt of 6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carbamino] - penicillanic acid in examples 2-8 is carried out in accordance with the description of example 1, but with process parameters corresponding to boundary and transcendental values in relation to given in the claims of the invention.

 The synthesis results are presented in the table.

Claims (1)

 The method of obtaining the sodium salt of 6- [3- (2-chlorophenyl) -5-methylisoxazole-4-carbamino] penicillanic acid (cloxacillin) by acylation of the 6-aminopenicillanic acid Na-salt with 3- (2-chlorophenyl) -5-methylisoxazole chloride 4-carboxylic acid in an aqueous acetone medium, followed by isolation of the target product from the reaction mixture, characterized in that the acylation of 6-aminopenicillanic acid is carried out while maintaining the pH value of the medium in the range of 6.0-9.5 pH, and the selection of sodium salt 6 - [3- (2-chlorophenyl) -5-methylisoxazole-4-carbam but] -penicillanic acid is carried out by precipitation of cloxacillin at 2.5-3.5 pH, dissolving the precipitate in a water-butanol medium with the addition of sodium hydroxide, distillation of the water-butanol mixture from the resulting solution until the mass fraction of water in the reaction mass reaches not more than 3.5%, followed by filtration, washing and drying the target product.

Images