RU2305100C1 - Method for preparing benzylpenicillin diethylaminoethyl ester hydroiodide - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to an improved method for synthesis of benzyl-penicillin diethylaminoethyl ester hydroiodide. Method involves interaction of benzyl-penicillin alkaline salt with N-(2-chloroethyl)-diethylamine in acetonitrile or N,N-dimethylformamide medium in the presence of hydroiodic acid alkaline metal salt followed by distilling off acetonitrile or N,N-dimethylformamide under vacuum and crystallization of benzyl-penicillin diethylaminoethyl ester hydroiodide in acetone medium. The crystallization process of benzyl-penicillin diethylaminoethyl ester hydroiodide is carried out in the presence of phosphoric acid alkaline metal salts wherein a mixture of potassium dihydrogen phosphate and sodium hydrogen phosphate as phosphoric acid alkaline metal salts are used in the amount 0.5-1.0% of benzyl-penicillin alkaline salt mass charged to the esterification process reaction mass. Method provides enhancing stability of aqueous suspension prepared with using product synthesized on the basis of invention claimed.

EFFECT: improved method of synthesis.

2 cl, 2 ex

Description

The invention relates to the production of benzylpenicillin diethylaminoethyl ether hydroiodide, an antibiotic used to treat diseases caused by streptococci, staphylococci and other penicillin-sensitive microorganisms.

A known method of producing diethylaminoalkyl ethers of benzylpenicillin, in particular diethylaminoethyl ether of benzylpenicillin in the form of a free base [ES 432241] by the interaction of the potassium or sodium salt of benzylpenicillin with chloroalkyl diethylamine hydrochloride in a heterogeneous medium consisting of water and methyl ethyl tetraethyl ketone in the presence of a catalyst in the presence of methyl ethyl tetraethyl ketone. The reaction is carried out at 30-35 ° C and a pH of 6.5-7.0, achieved by dosing sodium hydroxide solution into the reaction mass. The selection of the target product in the method according to the patent ES 432241 from the phase of methyl ethyl ketone is carried out by dilution of the latter with diethyl ether, followed by distillation of the solvent under vacuum and crystallization of benzylpenicillin diethylaminoethyl ether. The method according to Spanish patent No. 432241 provides the production of benzylpenicillin diethylaminoethyl ether in the form of a free base with a basic substance content of 85%, but is not intended to produce benzylpenicillin diethylaminoethyl ether in the form of a hydroiodide.

There is also known a method for producing benzylpenicillin esters [GB 759603]. The method consists in obtaining benzylpenicillin chloride by reacting the potassium salt of benzylpenicillin with phosphorus pentachloride or thionyl chloride in chloroform medium. Then, benzylpenicillin diethylaminoethyl ester hydroiodide is obtained by introducing diethylaminoethanol, sodium iodide and diethyl ether into the reaction mixture containing benzylpenicillin chloride. The isolated technical product is purified several times by recrystallization. Get benzylpenicillin diethylaminoethyl ester hydroiodide with a melting point of 171-172 ° C, activity of about 1000 IU / mg The method according to patent GB 759603 is characterized by a multi-stage and complex technological process, as a result of which it provides the desired product with a very low yield: about 1 kg of benzylpenicillin potassium salt is required to obtain 1 kg of product.

Closest to the claimed method according to the technical essence and the achieved result is a method for producing benzylpenicillin diethylaminoethyl ether hydroiodide according to patent RU 2167162. In accordance with RU 2167162, benzylpenicillin alkylene metal salt of benzylpenicillin-hydrochloride (2-chloroethyl) -hydrochloride is synthesized in the presence of an alkaline salt of hydroiodic acid in acetonitrile or N, N-dimethylformamide, followed by isolation of the target product that from the reaction mixture by distilling off acetonitrile or N, N-dimethylformamide under vacuum and crystallization hydroiodide diethylaminoethyl ester of benzylpenicillin in acetone. The method according to RU 2167162 provides the production of benzodipenicillin diethylaminoethyl ester hydroiodide with a yield of about 70% of theory. The product obtained by the aforementioned method has an activity of 1000-1050 U / mg (theoretical activity -1058 U / mg), a melting point of 175-178 ° C, specific rotation is + 150-155 °.

The disadvantage of the method according to RU 2167162 is the lack of stability of the aqueous suspension of the drug. The need to ensure high stability of an aqueous suspension of benzylpenicillin diethylaminoethyl ether hydroiodide is due to the use of this form (aqueous suspension) as a dosage form. The insufficient stability of the aqueous suspension of the drug is manifested in a decrease in the pH of the medium to below 3.0 pH (normalized value is not lower than 3.5 pH) and in the formation of carbon dioxide due to partial decarbonization of the antibiotic.

The inventive method is aimed at obtaining hydroiodide diethylaminoethyl ether benzylpenicillin, characterized by high stability of its dosage form in the form of an aqueous suspension, while maintaining high technological parameters.

The problem is achieved by the synthesis of benzylpenicillin diethylaminoethyl ester hydroiodide by the interaction of the benzylpenicillin alkali metal salt with N- (2-chloroethyl) diethylamine hydrochloride in the presence of an iodide-hydrogen acid alkali metal salt in acetonitrile or N, N-dimethylformamide followed by isolation of the target product from the reaction mixture by distillation of acetonitrile or N, N-dimethylformamide under vacuum and crystallization of benzylpenicilli diethylaminoethyl ether hydroiodide in acetone in the presence of alkali metal salts of phosphoric acid. As salts of alkali metals of phosphoric acid, a mixture of potassium dihydrogen phosphate and disubstituted sodium phosphate is used in an amount of 0.5-1.0% by weight of the alkaline salt of benzylpenicillin loaded into the reaction mass of the esterification process.

Distinctive features of the claimed method are:

- The process of crystallization of the hydroiodide of benzylpenicillin diethylaminoethyl ether in the presence of alkali metal salts of phosphoric acid.

- Use as a alkali metal salt of phosphoric acid a mixture of potassium dihydrogen phosphate and disubstituted sodium phosphate in an amount of 0.5-1.0% by weight of the alkaline salt of benzylpenicillin introduced into the reaction mass of the esterification process.

The combination of the above distinguishing features ensures the achievement of positive results in the claimed method due to the following factors identified in the development process:

- Used in the synthesis of N- (2-chloroethyl) -diethylamine hydrochloride contains a small excess of hydrochloride relative to stoichiometric, which causes a decrease in the pH of the aqueous suspension of the obtained product to 3.5-4.0 pH at the time of suspension and to 2.5 -3.0 pH after 72 hours. A decrease in the hydrogen index of the aqueous suspension to below 5.0 pH leads to an increase in the rate of hydrolysis of the product with the formation of carbon dioxide and a more rapid further decrease in the hydrogen index of the medium.

- The introduction of stabilizing additives of alkali metal salts of phosphoric acid in an amount of 0.5-1.0% by weight of the alkaline salt of benzylpenicillin introduced into the reaction mass of the esterification process ensures the neutralization of excess hydrochloride, does not lead to contamination of the product with toxic substances and is not prohibited by European Drag Master file.

The inventive method provides for the production of hydroiodide diethylaminoethyl ether benzylpenicillin with a yield of about 70% of theory. Obtained by the claimed method, the product has an activity of 1000-1050 U / mg (theoretical activity - 1058 U / mg), melting point 175-178 ° C, specific rotation - + 150-155 °. The pH value of the aqueous suspension of the drug at the time of preparation is 5.5-6.5 pH, and after 72 hours 3.9-4.5 pH. For the product obtained without the use of stabilizing additives of salts of phosphoric acid (method RU 2167162), the similar parameters of the aqueous suspension are 3.4-4.0 pH and 2.8-3.4 pH, respectively.

Example 1

In a round bottom flask equipped with a stirrer and thermometer with a capacity of 250 ml, 80 ml of N, N-dimethylformamide, 5.2 g of N- (2-chloroethyl) -diethylamine (5.1 g in terms of 100% substance) are loaded, 10.8 g of sodium salt of benzylpenicillin (10.5 g in terms of 100% substance), 4.6 g of sodium iodide (4.5 g in terms of 100% substance). The reaction mixture is heated to 52-55 ° C and at this temperature is stirred for 4-4.5 hours. Then the reaction mass is cooled to a temperature of 20-25 ° C, the precipitated sodium chloride is filtered on a Buchner funnel. The precipitate was washed with 10 ml of N, N-dimethylformamide, washing with N, N-dimethylformamide was added to the main solution.

From the resulting solution of benzylpenicillin diethylaminoethyl ether hydroiodide at a residual pressure of not more than 20 mmHg and at a temperature of not more than 40 ° C, N, N-dimethylformamide is distilled off until the solvent is almost completely removed from the reaction mass.

40 ml of acetone and 0.054 g of a mixture of salts (0.5% by weight of the alkaline salt of benzylpenicillin introduced into the reaction mass of the esterification process), consisting of 0.001 g of KH ₂ PO ₄ and 0.053 g of Na ₂ HPO _4, are added to the bottom residue. The resulting suspension of benzylpenicillin diethylaminoethyl ether hydroiodide is cooled with stirring to a temperature of 5-10 ° C and maintained at this temperature and with periodic stirring for 8-10 hours.

The precipitated hydroxyide of benzylpenicillin diethylaminoethyl ether is filtered off on a Buchner funnel, washed with 10-15 ml of acetone and dried under vacuum at a temperature of 40-50 ° C. 9.8 g of benzylpenicillin diethylaminoethyl ether hydroiodide are obtained, containing 98.4% of the basic substance with a melting point of 176-176.5 ° C and a specific rotation of 156 °. The pH value of the aqueous suspension of the drug at the time of preparation is 5.8 pH, and after 72 hours, 4.3 pH.

Example 2

The process is carried out analogously to example 1. Instead of N, N-dimethylformamide take 60 ml of acetonitrile to dissolve the components of the reaction mixture and 15 ml of acetonitrile to wash the precipitate of sodium chloride. After distillation of acetonitrile, 50 ml of acetone and 0.108 g of a mixture of salts (1.0% by weight of the alkaline salt of benzylpenicillin introduced into the reaction mass of the esterification process), consisting of 0.015 g of KH ₂ PO ₄ and 0.093 g of Na ₂ HPO _4, are added to the bottom residue. 9.2 g of benzylpenicillin diethylaminoethyl ether hydroiodide are obtained with quality indicators similar to the product obtained in Example 1. The pH value of the aqueous suspension of the preparation at the time of preparation is 6.5 pH, and after 72 hours, 4.6 pH.

Claims (2)

1. A method of producing a benzylpenicillin diethylaminoethyl ester hydroiodide by reacting an alkaline salt of benzylpenicillin with N- (2-chloroethyl) diethylamine in acetonitrile or N, N-dimethylformamide in the presence of an alkali metal salt of iodide-hydrogen acid, followed by distillation of acetonitrile or N, N- dimethylformamide under vacuum and crystallization of benzylpenicillin diethylaminoethyl ether hydroiodide in acetone, characterized in that the crystallization of benzylpenicillin diethylaminoethyl ether hydroiodide crystallizes in the presence of alkali metal salts of phosphoric acid. 2. The method according to claim 2, characterized in that a mixture of potassium dihydrogen phosphate and disubstituted sodium phosphate in an amount of 0.5-1.0% by weight of the alkaline salt of benzylpenicillin loaded into the reaction mass of the esterification process is used as alkali metal salts of phosphoric acid.