BG62696B1 - Method for the preparation of clindamycin phosphate - Google Patents

Abstract

The clindamicin phosphate is an ester of clindamycin finding application in medicine for the treatment of intraabdominal anaerobic and respiratory infections caused by streptococcus, staphylococcus and pneumococcus. By the method clindamycin phosphate is produced with high yields and purity by phosphorylation of clindamycin acotonide in organic medium with in situ produced phosphorylation reagent containing trisimidazolidonphosphate. The mixture is washed in water, is evaporated to oil and is subjected to deprotection successively in a mixture of acetic acid and water and after that in water medium at pH 1.4-4.0 and heating until the production of aqueous solution of clindamycin phospate. The active substance is settled in the presence of ammonia as an alkaliearth salt, and after filtration and drying is treated in aqueous solution in succession in strongly cross-linked cathionide and anionide. The aqueous solution is evaporated and the finished product is subjected to crystallization from organic solvent, is filtrated and dried. 4 claims, 1 figure

Description

Technical field

The invention relates to a method for the preparation of clindamycin phosphate, which is used in the pharmaceutical industry.

Clindamycin is a potent antibiotic that is used in serious intra-abdominal anaerobic infections and in serious respiratory infections caused by streptococci, staphylococci and pneumococci.

Clindamycin phosphate ester (clindamycin phosphate) is hydrolyzed rapidly in blood plasma to clindamycin, which is why it has the same biological action and use as clindamycin hydrochloride. The advantage of clindamycin phosphate is that it is administered parenterally, thereby avoiding the gastrointestinal side effects characteristic of oral clindamycin. Clindamycin phosphate can be successfully and topically applied as a solution, gel and the like.

BACKGROUND OF THE INVENTION

A method of producing clindamycin phosphate is known in which the hydroxyl groups at the 3 and 4 sites in the clindamycin hydrochloride molecule are protected by condensation with aromatic aldehyde to give 3,4-arylide clindamycin, after which the 2-hydroxyl group is acylated with phosphorus oxychloride and the protection of the 3,4-hydroxyl groups is withdrawn (US 3487068).

This method produces significant amounts of by-products due to the trifunctionality of the acylating agent-phosphorus oxychloride used. Moreover, the yield is low (30%).

Methods for preparing clindamycin phosphate from clindamycin acetonide are known. The latter is obtained by condensation of clindamycin base with 2,2-dimethoxypropane (US 4849515 and US 5182374) or of clindamycin hydrochloride solvate with 2,2-diethoxypropane (BG 61652).

A method is known in which clindamycin acetonide is acylated with phosphorus oxychloride competitively in the presence of benzyl alcohol to produce clindamycin-2-phosphoryl benzylate, which is subjected to catalytic hydrogenation with hydrogen to remove the benzylate group (US 48495).

The disadvantage of this method is the need to work with explosive and fire hazardous hydrogen.

A method is known in which clindamycin acetonide is acylated in pyridine medium with bis- (2,2,2-trichloroethyl) phosphorochloride, avoiding the trifunctionality of phosphorus oxychloride. The resulting clindamycin 2-phosphorochloridate is treated with zinc powder in acetic acid to remove trichloroethyl residues, and then the isopropylidene protection is removed in a mixture of acetic acid and sulfuric acid - 0.5 N.

This method uses the inaccessible acylating reagent and zinc dust.

SUMMARY OF THE INVENTION

In the process for the preparation of clindamycin phosphate according to the invention, a solution of clindamycin acetonide base in organic solvent is slowly added to a crystalline suspension of tris-imidazolidophosphate obtained in situ by mixing imidazole with phosphorus oxychloride in an organic solvent medium. distillation using a Dean-Stark suffix. The mixture was stirred at 20 to 35 ° C, then washed three times with water and the organic solvent was evaporated to an oil. The oily residue is initially deprotected with a mixture of acetic acid and water at a temperature of 50 to 90 ° C, then the acetic acid is removed in vacuo and the treatment is continued in aqueous medium at pH 1.4 to 4.0, at a temperature of 80 to 100 ° C. The solution thus treated is brought to a concentration of 3 to 10% and to it is added 0.1-2.5% ammonia and 1.05-1.5 M / mol of alkaline earth sludge dissolved in water. The solution was cooled to 0 to 10 ° C, which crystallized the alkaline earth salt of clindamycin phosphate, which was filtered, washed with ice water and dried. The dried salt is treated in a solvent, for example water or a mixture of water and alcohol, with continuous stirring, in succession with strongly crosslinked cationite and strongly crosslinked anionite. The aqueous solution was evaporated to dryness in vacuo, and the dry residue was dissolved in an organic solvent, with or without the addition of water, the solution was cooled to crystallize on clindamycin phosphate, which was filtered and dried.

Methanol, ethanol, i-propanol, n-propanol, acetonitrile, butanol, acetone or mixtures thereof, with or without the addition of water, are used as the organic solvent to crystallize the dry residue obtained after evaporation of the aqueous solution.

The advantages of the process according to the invention lie in the production of clindamycin phosphate in high yield and purity using available reagents and a simplified flow chart.

Examples of carrying out the invention

The invention is illustrated by the following example.

Example I. 1.1. Preparation of the calcium salt of clindamycin-2-phosphate.

A. Clindamycin acetonide base solution

Dissolve 60 g of clindamycin acetonide hydrochloride (790 pg / mg, 112 mmol) in a mixture of 300 ml of chloroform and 18 ml of triethylamine and dry the solution by azeotropic distillation using a Dean-Stark extension.

B. Phosphorylating reagent

To the cooled suspension of 86 g of imidazole in 450 ml of chloroform was added dropwise 17 ml of phosphorus oxychloride. The mixture was stirred at 0 ° C for 30 min and at room temperature for 2 h. A crystalline suspension containing trisimidazolidophosphate was obtained.

A solution was added to the cooled phosphorylation reagent for 1 h. The mixture was stirred for 1 h at 0 ° C and at room temperature for 4 h. The solution was washed three times with 30 ml of water each and the chloroform was evaporated to an oily consistency. 800 ml of water was added and the pH was adjusted to 3.0 with hydrochloric acid. The solution was concentrated in vacuo at 90 ° C to 400 ml, 90 ml of 25% ammonia and 400 ml of water were added, then the calcium salt was precipitated with a solution of 18 g of calcium dichloride in 200 ml of water. After cooling to + 4 ° C, the crystals were filtered, washed with ice and dried to give 69.9 g of the calcium salt of clindamycin phosphate in a purity of 630 pg / mg / 103.6 mmol, yield 92.5 %. Melting point: + 210 ° C (decomposition).

1.3. Preparation of clindamycin phosphate

To a suspension of 200 ml of AMBERUT 200 cation exchange resin in 700 ml of water was added 56 g of calcium salt of clindamycin phosphate (630 pg / mg, 83 mmol) and the mixture was stirred for 1 h. The polymer is filtered and washed with water. To the total solution (1500 ml) was added portionwise anion exchange resin DOWEX 1X16 to pH 4.3. The polymer was filtered, washed with water and the combined aqueous solution was evaporated to dryness in vacuo. To the residue was added 200 ml of methanol, the mixture was stirred for 4 hours at room temperature and at -10 ° C for 8 hours. The product was filtered and dried at 90 ° C for 5 h.

40.25 g of clindamycin phosphate are obtained with a purity of 822 mg / pg / 77.9 mmol; yield: 93.8%. In the accompanying FIG. 1 shows the chromatograms of HPLC, respectively, of a standard substance clindamycin phosphate with a biological activity of 799 mg / ml and of crystalline clindamycin phosphate according to the invention with a biological activity of 822 mg / ml.

The product meets the requirements of USP-23.

Claims (4)

Claims A method for producing clindamycin phosphate by phosphorylating clindamycin acetonide in an organic medium, followed by deprotection, characterized in that the phosphorylation of clindamycin acetonide is carried out at a temperature of from 20 to 35 ° C, with continuous stirring, with phosphorylation -imidazolididophosphate obtained in situ by mixing imidazole and phosphorous oxychloride in an organic solvent medium, after which the solution is washed three times with water, evaporated to an oil, and deprotection is carried out in the processing of the obtained oil initially with a mixture of water / acetic acid at a temperature of 50 to 90 ° C, and after evaporation of the acetic acid in vacuo, in aqueous medium at pH 1.4 to 4.0 and a temperature of 80 to 100 ° C, then the aqueous the solution is brought to a concentration of 3 to 10% and precipitated with 1.05-1.5 M / moI water-soluble alkaline earth salt in the presence of 0.1-2.5% ammonia at a temperature of 0 to 10 ° C, at which the alkaline earth salt of clindamycin phosphate is filtered, washed with ice water, dried and treated in a solvent with continuous stirring, successively with strongly crosslinked cationite and strongly crosslinked anionite, 5 the solution is evaporated to a dry residue, which crystallized from an organic solvent, then filtered and dried. A method for producing clindamycin phosphate according to claim 1, characterized in that the calcium salt is used as the alkaline earth salt for crystallization of clindamycin phosphate after deprotection. Method for the preparation of clindamycin phosphate according to claims 1 and 2, characterized in that water is used as the solvent in the treatment with the highly crosslinked cationite and the strongly crosslinked anionite. Method for the preparation of clindamycin phosphate according to claims 1, 2 and 3, characterized in that methanol, ethanol, i-propanol, n is used as an organic solvent for crystallization of the dry residue obtained after treatment with cation exchanger and anionite. -propanol, acetonitrile, butanol, acetone or mixtures thereof, with or without the addition of water.