The method of obtaining the sodium salt of 6-(3-phenyl-5-methylisoxazol - 4-carbamido)-penitsillanovoy acid

 

The invention relates to a method for producing a sodium salt of 6-(3-phenyl-5-methylisoxazol-4-carbamido)-penitsillanovoy acid (oxacillin) by acylation Na-salt of 6-aminopenicillanic acid, acid chloride 3-phenyl-5-methylisoxazol-4-carboxylic acid in aqueous-acetone medium while maintaining the value of water pH level in the range of pH 6.0 to 9.5, followed by separation of the target product from the reaction mass, characterized in that the separation of the sodium salt of 6-(3-phenyl-5-methylisoxazol-4-carbamido)-penitsillanovoy acid is carried out by dilution of the reaction mixture of aliphatic alcohol to reduce the concentration of water in it to the level of 8.0 to 15.0%, the separation of sodium chloride from aqueous-alcoholic solution of sodium salt of oxacillin and crystallization of the desired product during distillation, water-alcohol azeotrope before reaching the water concentration in the reaction mass is not more than 8%. The technical result is an improvement of the method. 2 C.p. f-crystals, 1 table.

The present invention relates to the production of highly antibiotic - sodium salt of 6-(3-phenyl-5-methylisoxazol-4-carbamido)-penitsillanovoy acid (sodium salt oxacillin).

Known for the way the floor is rbonillavid in aqueous-acetone medium in the presence of an alkaline agent, followed by separation of the target product extraction oxacillin in the form of acid butyl acetate when the value of pH of the environment 2-3 pH and precipitation of the sodium salt oxacillin of butylacetate extract the action of sodium salts of carboxylic acids, for example, sodium acetate (ed. St. USSR 343978, C 07 D 499/72, 1972).

A significant drawback of the method according to ed. St. 343978 the USSR is the formation of derivatives of penitsillanovoy acid in the translation process of oxacillin in the form of acid and, consequently, a high concentration of light-absorbing at a wavelength of 335 nm impurities (optical density of a 1% solution in a cuvette of 1.0 mm at the wavelength reaches a value of 0.7-1.0) and low yield (not more than 87%).

Closest to the claimed method according to technical essence and the achieved result is the method according to the patent of the Russian Federation 2043355, C 07 D 499/16, 1991, under which the receipt of the sodium salt of 6-(3-phenyl-5-methylisoxazol-4-carbamido)-penitsillanovoy acid is carried out by acylation of sodium salt of 6-aminopenicillanic acid, acid chloride 3-phenyl-5-methylisoxazole-4-carboxylic acid when the value of pH 6,5-9,0 pH and temperature 6-15oWith in aqueous-acetone medium or in an aqueous medium in the presence of nonionic sorbent as a catalyst, for example, a macroporous copolymer of styrene with divinylbenzene, and the selection of the target product is carried out by treating the reaction mixture with a solution of chloride or sodium acetate at 25-35

The main disadvantages of the method on the prototype are the formation of a large amount of troublesome and difficult delaborated waste water-salt mother liquor, and the difficulty of obtaining sterile substance in the processing cycle of selection of the target product from the reaction mass.

The inventive method is directed at elimination of the discharge of water-salt waste in the environment and simplify the process of obtaining a sterile substance sodium salt of 6-(3-phenyl-5-methylisoxazol-4-carbamido)-penitsillanovoy acid (oxacillin).

This goal is achieved by acylation Na-salt of 6-aminopenicillanic acid in aqueous-acetone medium with the acid chloride of 3-phenyl-5-methylisoxazol-4-carboxylic acid while maintaining the pH environment in the range of 6.0 to 9.5 pH, dilution of the reaction mass isopropyl or butyl alcohol to reduce the concentration of the water level to 8,0-15,0%, the separation of sodium chloride from aqueous-alcoholic solution of sodium salt of oxacillin and crystallization of the desired product during distillation, water-alcohol azeotrope before reaching the water concentration in the reaction mass is not more than 6%.

Distinctive features of the claimed method I is the acid chloride of 3-phenyl-5-methylisoxazol-4-carboxylic acid, aliphatic alcohol.

- Separation of sodium chloride from aqueous-alcoholic solution of sodium salt oxacillin when the water concentration in the reaction mass 8,0-15,0%.

- Crystallization of the desired product during distillation, water-alcohol azeotrope before reaching the water concentration in the reaction mass is not more than 6%.

- Use as aliphatic alcohol is isopropyl or butyl alcohol.

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: - the Dilution of the reaction mass obtained after acylation of Na-salt of 6-aminopenicillanic acid, acid chloride 3-phenyl-5-methylisoxazol-4-carboxylic acid, aliphatic alcohol to achieve the concentration of water in the reaction mass 8,0-15,0% provides separation of sodium chloride from aqueous-alcoholic solution of sodium salt of oxacillin. When the sodium chloride precipitates and is separated from the solution by filtration (when used as the aliphatic alcohol is isopropanol) or forms a water-salt layer and is separated from the solution of the target product in the process of separation of the layers.

- Poured sodium and does not lead to the separation of precipitated sodium salt oxacillin. At higher concentration of water in the reaction mass in solution remains a significant concentration of sodium chloride, which then leads to contamination of the target product chlorides. Upon dilution of the reaction mixture with an alcohol to obtain the concentration of water is less than 8.0% may be allocated to precipitate sodium salt oxacillin, which reduces the yield of the target product.

- Reduce the water concentration to no more than 6% during distillation, water-alcohol azeotrope provides almost quantitative yield by crystallization oxacillin sodium salt of the alcohol and water solution.

The use of isopropanol or butanol are added to dilute the reaction mass provides in terms of the proposed method is sufficiently complete office solution oxacillin sodium salt from sodium chloride and organic impurities, as well as the possibility of removing from the resulting solution the most part contained in the water during distillation, water-alcohol azeotrope at a relatively low temperature (25-35oC).

Example 1 To a suspension of 40.0 g (38,4 g in terms of 100% substance) 6-aminopenicillanic acid in 120 ml of distilled water, cooled to a temperature of 2oWith, prirodnogo indicator environment of 7.5-8.5 pH. To the resulting solution at a temperature of 10-12oWith poured 25-30 ml of acetone and within 30-60 minutes, a solution of 37.5 g (in terms of 100% substance) of acid chloride of 3-phenyl-5-methylisoxazol-4-carboxylic acid in 20 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 of the solution is injected 1200-1400 ml of absolute isopropyl alcohol to achieve the concentration of water in the reaction mass 10-12% and 6 g of activated charcoal. The reaction mass is stirred for 10-15 minutes, filtered on a Buechner funnel precipitated precipitated sodium chloride and coal, the coal is washed with 30 ml isopropanol, wash water added to the main filtrate.

The resulting solution was additionally subjected to sterilizing filtration and pass on crystallization, filtration, washing and drying are carried out under conditions ensuring the sterility of the product.

The resulting solution was transferred to a unit for GTO 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 6-8%, which if necessary add in VAT residue of absolute isopropanol.

After the process of distillation, the resulting suspension of sodium salt of 6-(3-phenyl-5-methylisoxazol-4-carbamido)-penitsillanovoy acid is cooled under stirring to a temperature of 15-20oC and maintained at this temperature of 2.0-2.5 hours. Then the suspension is filtered, the precipitate washed with twice 50 ml of isopropyl alcohol, squeezed and dried under vacuum at a temperature not exceeding 40oTo achieve a constant weight.

Get to 76.7 g of the monohydrate of sodium salt of 6-(3-phenyl-5-methylisoxazol-4-carbamido)-penitsillanovoy acid with a basic substance content of 99.5%, which corresponds to a yield of 97.8% of theory, calculated on a 6-aminopenicillanic acid.

The resulting product is characterized by the following indicators.

The drug is a white, crystalline powder, 10% solution of the drug in water is colorless and has a pH value of 6.7 pH, specific rotation +200,0o(1% solution in svejeprokipachena water). The optical density of a 1% solution in water at 335 nm is the response with a layer thickness of 10 mm).

Synthesis of sodium salt of 6-(3-phenyl-5-methylisoxazol-4-carbamido)-penitsillanovoy acid shown in the table.

Example 2 To a suspension of 40.0 g (38,4 g in terms of 100% substance) 6-aminopenicillanic acid in 120 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 the resulting solution at a temperature of 10-12oWith poured 25-30 ml of acetone and within 30-60 minutes, a solution of 37.5 g (in terms of 100% substance) of acid chloride of 3-phenyl-5-methylisoxazol-4-carboxylic acid in 20 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 of the solution is injected 1400-1500 ml of butyl alcohol to achieve the concentration of water in the reaction mass 8-10% and 6 g of activated charcoal.

The reaction mass is stirred for 10-15 minutes, otfiltrovana to the main filtrate.

The resulting aqueous-alcoholic solution further subjected to sterilizing filtration and pass on crystallization, filtration, washing and drying are carried out under conditions ensuring the sterility of the product. The distillation of the water-butanole azeotrope are in conditions similar to those described in example 1 to achieve a residual concentration of water in the VAT residue 4-6%.

After the process of distillation, the resulting suspension of sodium salt of 6-(3-phenyl-5-methylisoxazol-4-carbamido)-penitsillanovoy acid is cooled under stirring to a temperature of 15-20oC and maintained at this temperature of 2.0-2.5 hours. Then the suspension is filtered, the precipitate washed with twice 50 ml of butyl alcohol, squeezed and dried under vacuum at a temperature not exceeding 40oTo achieve a constant weight.

Get 77,3 g of the monohydrate of sodium salt of 6-(3-phenyl-5-methylisoxazol-4-carbamido)-penitsillanovoy acid content of the basic substance to 99.6%, which corresponds to the output 98,4% of theory, calculated on a 6-aminopenicillanic acid.

The resulting product is characterized by the following indicators.

The drug is a white, crystalline powder, 10% solution of the drug in water is bessvatnet). The optical density of a 1% solution in water at 335 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).

Claims

1. The method of obtaining the sodium salt of 6-(3-phenyl-5-methylisoxazol-4-carbamido)-penitsillanovoy acid (oxacillin) by acylation Na-salt of 6-aminopenicillanic acid, acid chloride 3-phenyl-5-methylisoxazol-4-carboxylic acid in aqueous-acetone medium while maintaining the value of water pH level in the range of 6.0 to 9.5 pH, followed by separation of the target product from the reaction mass, characterized in that the separation of the sodium salt of 6-(3-phenyl-5-methylisoxazol-4-carbamido)-penitsillanovoy acid is carried out by dilution of the reaction mixture of aliphatic alcohol to reduce the concentration of water in it to the level of 8.0 to 15.0%, the separation of sodium chloride from aqueous-alcoholic solution of sodium salt of oxacillin and crystallization of the desired product during distillation, water-alcohol azeotrope before reaching the water concentration in the reaction mass is not more than 8%.

2. The method according to p. 1, characterized in that aliphatic alcohol use isopropyl alcohol.



 

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