The method of obtaining the sodium salt of 6-[3-(2-chlorophenyl)-5 - methylisoxazol-4-carbamido]-penitsillanovoy acid

 

(57) Abstract:

The invention relates to a method for producing a sodium salt of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamido] - penitsillanovoy acid (cloxacillin) is a highly effective antibiotic. The method is performed by the synthesis of cloxacillin by acylation Na-salt of 6-aminopenicillanic acid in aqueous-acetone medium with the acid chloride of 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid while maintaining the pH environment in the range of 6.0 to 9.5 pH, separation of cloxacillin in the form of acid from the resulting solution by bringing the pH of the medium to be 2.5-3.5 pH, dissolution of hydrated paste of cloxacillin - acid in butanol adding to the suspension a solution of sodium hydroxide, crystallization of the product during distillation, water-butanole azeotrope from the reaction mass under vacuum followed by filtration and drying, the sodium salt of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamido] - penitsillanovoy acid (cloxacillin) under vacuum. The inventive method enables the production of a product with the release of 85-91% of theory, calculated on a 6-APK. The product produced as a result of the claimed method, is a white crystalline at 430 nm, due to the presence of light-absorbing impurities (the derivative penitsillanovoy acid) is 0,02-0,04 (in a cell with a layer thickness of 10 mm). The technical result - simplifying the process and reducing raw material costs. table 1.

The present invention relates to the production of highly antibiotic - sodium salt of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamido]-penitsillanovoy acid (cloxacillin).

Known methods for producing sodium salt of cloxacillin interaction trimethylsilyl derivatives of 6-aminopenicillanic acid or a salt thereof with 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonylchloride in the environment of an organic solvent, followed by hydrolysis of the resulting trimethylsilyl derivative of cloxacillin and selection of the target product from the organic layer by the action of alkaline salts of sodium. As cilleruelo agent is used trimethylchlorosilane [U.S. patent 4182709] or N-trimethylsilylacetamide [U.S. patent 4181656]. Significant disadvantages of the above methods are the multi-stage process, the use of expensive raw materials (N-trimethylsilylacetamide or trimethylchlorosilane), the possibility of contamination of the target present method to the technical essence and the achieved result is a way for U.S. patent 4912211, in accordance with which the synthesis of cloxacillin is carried out in aqueous-acetone medium by the interaction of sodium salt of 6-aminopenicillanic acid with 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonylchloride. From the solution obtained after removal of methylene chloride and adjusting the pH values of up to 2.5 pH cloxacillin in the form of the acid is extracted with methylene chloride. Methylenchloride layer washed with water, then the product is transferred to the aqueous layer while bringing the pH of the medium to pH 7, the layers separated, the aqueous layer was treated with activated carbon and subjected to lyophilization. The resulting product is dissolved in absolute ethanol, the solution filtered. Crystallization of cloxacillin is carried out by heating the resulting solution to the 30oC and then cooling to 10oC. After filtering, washing the precipitate on the filter and drying under vacuum to obtain the sodium salt of cloxacillin monohydrate with a purity of 96.2% and output 90,9%.

The main disadvantages of the method on the prototype are the complexity of the technological process, the use of an expensive operation lyophilization of the solution, using one process, acetone, methylene chloride, Atenea in the production of the sodium salt of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamido]-penitsillanovoy acid (cloxacillin).

This goal is achieved by carrying out synthesis of cloxacillin by acylation Na-salt of 6-aminopenicillanic acid in aqueous-acetone medium with the acid chloride of 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid while maintaining the pH environment in the range of 6.0 to 9.5 pH, separation of cloxacillin in the form of acid from the resulting solution by bringing the pH of the medium to be 2.5-3.5 pH, dissolution of hydrated paste of cloxacillin - acid in butanol adding to the suspension a solution of sodium hydroxide, crystallization of the product during distillation, water-butanole azeotrope from the reaction mass under vacuum followed by filtration and drying, the sodium salt of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamido]-penitsillanovoy acid (cloxacillin) under vacuum.

Distinctive features of the claimed method are:

maintaining the value of pH of the environment in the process of acylation in the range of 6.0 to 9.5 pH,

- deposition of cloxacillin in the form of acid from the reaction mass after the process of acylation in communicating the value of water pH level between 2.5 and 3.5 pH,

- dissolution of cloxacillin acid in water-butanol is[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamido] -penitsillanovoy acid (cloxacillin) in the process of distillation under vacuum of the water-butanole azeotropic mixture to achieve mass fraction of water in the reaction mass values are not more than 3.5%.

The combination of the above distinguishing features achieve a positive result in the claimed method for the account identified in the process of developing the following factors:

- Acylation of sodium salt of 6-aminopenicillanic acid almost quantitatively without significant formation of by-products while maintaining the value of water pH level in the range of 6.0 to 9.5 pH. When carrying out the acylation with the value of pH below 6.0 pH significantly decreases the reaction rate, and when the value of pH above 9.5 pH increases the rate of hydrolysis of the acid chloride of 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid, which reduces the yield of the target product and the contamination of his 3-(2-chlorophenyl)-5-methylisoxazol-4-carboxylic acid. Maintaining the value of water pH level in the range of 6.0 to 9.5 pH in the process of acylation is achieved by simultaneously metering in a solution of sodium salt of 6-aminopenicillanic carboxylic acid 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid and sodium hydroxide solution.

- Cloxacillin is in the form of acid is excreted almost quantitatively be the 2,5-3,5 pH. In communicating the value of water pH level to a value below 2.5 pH increases the rate of hydrolysis of the target product, which reduces the yield of the target product and the contamination of its products of hydrolysis, in communicating the value of water pH level to a value of more than 3.5 pH increased loss of the target product from the mother liquor.

- Crystallization of sodium salt of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamido] -penitsillanovoy acid (cloxacillin) of the water-butanole solution is carried out with high yield in the process of distillation under vacuum of the water-butanole azeotropic mixture to achieve mass fraction of water in the reaction mass values are not more than 3.5%. When exceeding the concentration of water in the reaction mass of 3.5% observed a sharp increase in the solubility of the target product from the mother liquor and consequently decrease its output.

Example 1

To a suspension of 40.0 g (38,4 g in terms of 100% substance) 6-aminopenicillanic acid in 240 ml of distilled water, cooled to a temperature of 2oWith, poured a 15% solution of sodium hydroxide to dissolve the precipitate, which occurs when the value of the water pH level of 7.5-8.5 pH. To receive emesto) of acid chloride of 3-(2-chlorophenyl)-5-methylisoxazol-4-carboxylic acid in 35 ml of acetone. At the same time in the reaction mass is metered 15% solution of sodium hydroxide in an amount to provide maintenance of pH of the medium in the range of 7.5-8.5 pH. Reaction mass is stirred for 15-30 minutes at a temperature of 10-15oTo achieve a constant pH environment in the range of 6.0 to 9.5 pH.

In obtained after acylation solution give 6 g of activated carbon, the reaction mass is stirred for 10-15 minutes, filtered on a Buechner funnel, coal on the filter is washed with 30 ml of distilled water, wash water added to the main filtrate.

To the obtained filtrate, cooled to a temperature of 0-5oC, under stirring in a thin stream, add 10% solution of hydrochloric acid until the value of pH of the environment 2,9-3,1 pH. The resulting suspension of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamido] - penitsillanovoy acid (cloxacillin) is stirred for 20-30 minutes and filtered on a Buechner funnel. The residue on the funnel is washed with distilled water until the value of pH in the wash water of 4.5-5.0 pH and wring out the excess moisture.

The wet precipitate is suspended in 350 ml bout what I'm up to complete dissolution of the precipitate of cloxacillin, which is observed when the value of pH of the medium pH of 6.8. The resulting solution is filtered and transferred to the installation for the distillation of water-butanone mixture under vacuum. The distillation of the water-butanone mixture is conducted at a residual pressure of 30-40 mm RT. tbsp. at a temperature in pairs from the 20oWith the beginning of the 35oWith the end of the distillation process. The Stripping end when reaching a concentration of water in the VAT residue of 1.5%.

After the process of distillation, the resulting suspension of sodium salt of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamido] - penitsillanovoy acid is cooled under stirring to a temperature of 8-10oC and maintained at this temperature of 2.0-2.5 hours. Then the suspension is filtered on a Buechner funnel, the precipitate is washed with twice 50 ml of butanol, squeezed and dried under vacuum at a temperature not exceeding 40oTo achieve a constant weight.

Get to 78.1 g of the monohydrate of sodium salt of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamido] - penitsillanovoy acid with a basic substance content of 99.5%, which corresponds to the output 90,7% of theory, calculated on a 6-aminopenicillanic acid.

The resulting product is characterized by the following indicators.

The drug not only is Oronogo indicator pH of 6.7, specific rotation - 168,5((1% solution in svejeprokipachena water). The optical density of a 1% solution in water at 430 nm due to the presence of light-absorbing impurities (the derivative penitsillanovoy 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-methylisoxazol-4-carbamido] - penitsillanovoy acid in examples 2-8 are carried out in accordance with the description of example 1, but with the process parameters, boundary and incredible values with respect to is given in the formula of the invention.

The results of the synthesis are presented in the table.

The method of obtaining the sodium salt of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamido] -penitsillanovoy acid (cloxacillin) by acylation Na-salt of 6-aminopenicillanic acid, acid chloride 3-(2-chlorophenyl)-5-methylisoxazol-4-carboxylic acid in aqueous-acetone medium, followed by separation of the target product from the reaction mass, characterized in that the acylation of 6-aminopenicillanic acid is carried out while maintaining the value of water pH level in the range of 6.0 to 9.5 pH, and the selection of sodium salt of 6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carbamido] -podno-butanole environment adding sodium hydroxide, distillation of the resulting solution of water-butanone mixture to achieve mass fraction of water in the reaction mass values are not more than 3.5%, followed by filtering, washing and drying of the target product.

 

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-< / BR>
Known methods for producing ampicillin by acylation of 6-aminopenicillanic acid (6-AIC) phenylglycine derivative, activated at the carboxyl group (galogenangidridy or mixed anhydride) in aqueous organic solution upon cooling [1, 2, 3]

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