RU2469040C1 - Method of producing 7-[2-(2-aminothiazol-4-yl)-2(z)-methoxyimino acetamido]-3-[(1-methyl-1-pyrrolidino)methyl]-cef-3-em-4-carboxylate dihydrochloride monohydrate (cefepime dihydrochloride monohydrate) - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 7-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyimino acetamido]-3-[(1-methyl-1-pyrrolidino)methyl]-cef-3-em-4-carboxylate dihydrochloride monohydrate (cefepime dihydrochloride monohydrate) of formula (I)

The method is realised by crystallising 7-[2-(2-aminothiazol-4-yl)-2(z)-methoxyimino acetamido]-3-[(1-methyl-1-pyrrolidino)methyl]-cef-3-em-4-carboxylate dihydrochloride monohydrate from aqueous or aqueous-organic solutions thereof by adding sodium chloride to the solution in an amount which provides sodium chloride concentration in the formed solution ranging from 10.0 to 15.0%. The precipitated cefepime dihydrochloride is then filtered, washed and dried.

EFFECT: improved method of producing cefepime dihydrochloride monohydrate.

2 cl, 2 ex

Description

The present invention relates to the production of a highly effective antibiotic of the cephalosporin series -7- [2- (2-aminothiazol-4-yl) -2 (z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidino) methyl] -ceph- 3-em-4-carboxylate dihydrochloride monohydrate (cefepime dihydrochloride monohydrate) corresponding to the formula

Known commercial processes for the preparation of cefepime are based on the acylation of 7-amino-3 - [(1-methyl-1-pyrrolidino) methyl] -cef-3-em-4-carboxylate hydroiodide or hydrochloride by the syn-isomer 2- (2-aminothiazole -4-yl) -2-methoxyiminoacetyl chloride hydrochloride [EP 0533047, CA 2077780, RU 2039059] or 2- (2-aminothiazol-4-yl) -2-syn-methoxyimonoacetic acid 2-benzothiazolylthio-ester (MAEM), [EP 16 CN 101735251, CN 101337971] with the subsequent isolation of the target product from the reaction mass by diluting an aqueous or aqueous methanol solution with a large volume of acetone.

Closest to the claimed method in technical essence and the achieved result is a method of producing cefepime dihydrochloride monohydrate by the method according to patent EP 1832593. Obtaining technical dihydrochloride of cefepime monohydrate in the method according to EP 1832593 is carried out by introducing into the reaction mass containing 65 g of cefepime in the form of an internal salt of 3-fold excess hydrochloric acid and 10-fold dilution of the resulting solution with acetone. Technical cefepime monohydrate dihydrochloride is obtained with a yield of 81.0% and a purity of 84.7%.

To obtain sterile cefepime monohydrate dihydrochloride in the method according to EP 1832593, the technical product is dissolved in methanol, the solution is subjected to sterilizing filtration and cefepime is isolated by diluting the resulting solution with acetone in a ratio of 25 ml of acetone per 1 g of cefepime.

Significant disadvantages of the method according to patent EP 1832593 is the need to use large volumes of organic solvent: the amount of acetone introduced into the reaction mass exceeds 44 l per 1 kg of technical product and 25 l per 1 kg of purified cefepime. The separation of cefepime from such dilute solutions (2-3% of the target product) makes it problematic to achieve the high yield of the product declared in the method according to EP 1832593 (about 80-90%) when it is sold on an industrial scale.

The inventive method is aimed at reducing the cost of organic solvents and simplifying the process in the production of 7- [2- (2-aminothiazol-4-yl) -2 (z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidino) methyl ] -ceph-3-em-4-carboxylate dihydrochloride monohydrate (cefepime dihydrochloride monohydrate).

This object is achieved by carrying out the process of obtaining 7- [2- (2-aminothiazol-4-yl) -2 (z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidino) methyl] -cef-3-em- 4-carboxylate dihydrochloride monohydrate (cefepime dihydrochloride monohydrate) by crystallization from aqueous or aqueous-organic solutions when sodium chloride is introduced into the solution in an amount that provides a concentration of sodium chloride in the resulting solution in the range from 10.0 to 15%, filtering precipitated cefepime dihydrochloride, washing the precipitate and drying.

Used in the present method, aqueous and aqueous organic solutions of 7- [2- (2-aminothiazol-4-yl) -2 (z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidino) methyl] -ceph- 3-em-4-carboxylate is obtained by the synthesis of cefepime by known methods, mainly by the interaction of 7-amino-3 - [(1-methyl-1-pyrrolidino) methyl] -cef-3-em-4-carboxylate hydroiodide or hydrochloride with 2- 2- (2-aminothiazol-4-yl) -2-syn-methoxyimonoacetic acid benzothiazolylthioether (MAEM) or by dissolving the technical product in water.

Distinctive features of the proposed method are:

- Carrying out the crystallization process in an aqueous or aqueous-organic medium in the presence of sodium chloride,

- The amount of sodium chloride introduced into the solution is necessary to ensure the concentration of auxiliary electrolyte in the resulting solution from 10, 0 to 15%.

The combination of the above distinguishing features ensures the achievement of a positive result in the claimed method: the process of crystallization of cefepime dihydrochloride monohydrate is carried out without the use of large quantities of solvent from solutions concentrated on the target product.

A positive result in the claimed method is achieved due to the following identified in the development process features of crystallization of cefepime dihydrochloride:

- The equilibrium solubility of cefepime dihydrochloride in aqueous solutions of the auxiliary electrolyte decreases sharply when the concentration of sodium chloride exceeds 10.0%.

- Crystallization of cefepime dihydrochloride from aqueous solutions of sodium chloride occurs at room or low temperature in the form of a monohydrate.

- The upper limit of the concentration of sodium chloride introduced into the solution of cefepime dihydrochloride (15%), provides the possibility of complete removal of the electrolyte from the precipitated product during its filtration and washing. If the concentration of 15% of the solution volume introduced into the electrolyte solution is exceeded, the product may become contaminated with sodium chloride.

Example 1

Preparation of 7- [2- (2-aminothiazol-4-yl) -2 (z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidino) methyl] -cef-3-em-4-carboxylate dihydrochloride monohydrate (cefepime dihydrochloride monohydrate) crystallization from the reaction mass

720 ml of an aqueous acetone solution containing 52.0 g (0.108 mol) of cefepime in the form of an internal salt obtained by the synthesis of acylation of 7-amino-3 - [(1-methyl-1-pyrrolidino) methyl] -cef-3- em-4-carboxylate with 2- (2-amino-thiazol-4-yl) -2-syn-methoxyimonoacetic acid 2-benzthiazolylthioester (MAEM) is decolorized with activated carbon and filtered. Acetone is distilled off under vacuum in a filtrate at room temperature and 18-20 ml of concentrated hydrochloric acid are added with stirring until the pH of the medium reaches 1.0-1.5 pH.

In the resulting aqueous solution of cefepime in a volume of 360 ml with stirring from a dropping funnel, 400 ml of a 26% sodium chloride solution are introduced over a period of 40-60 minutes. The concentration of NaCl in the resulting solution is 14.7%.

Seed (0.1 g cefepime dihydrochloride monohydrate) was introduced into the solution and the resulting suspension was stirred at room temperature for about 3 hours. Then the product is filtered off, carefully squeezed from the mother liquor, washed with acetone on the filter and dried under vacuum. 54.2 g of cefepime dihydrochloride monohydrate are obtained with a purity of 98.5%, a yield of 92.7% in terms of cefepime contained in the reaction mixture.

Example 2

Preparation of 7- [2- (2-aminothiazol-4-yl) -2 (z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidino) methyl] -cef-3-em-4-carboxylate dihydrochloride monohydrate (cefepime dihydrochloride monohydrate) from a technical product

In a 250 ml round bottom flask, 110 ml of water suitable for the preparation of injection solutions and 50.0 g of cefepime dihydrochloride monohydrate containing 98.5% of the basic substance (0.0861 mol) are charged. The resulting solution was filtered through a filter for sterilizing filtration with a pore size of 0.22 microns. Under conditions ensuring preservation of the sterility of the reaction mixture, with the stirrer switched on at a temperature of about 15 ° C, 90 ml (108 g, 28.08 g in terms of 100% substance) of a 26% sterile sodium chloride solution are introduced through a dropping funnel. The concentration of NaCl in the resulting solution is 10.5%. The rate of introduction of the sodium chloride solution should be in the range of 40-50 ml / hour. After the appearance of a precipitate in the reaction mass, which is observed after loading 40-50% of the calculated amount of sodium chloride solution, the NaCl solution is stopped and the mixture is kept under stirring for 20-30 minutes. During this time, the formation of cefepime dihydrochloride monohydrate crystals occurs. Then, the remaining sodium chloride solution is continued in the resulting suspension. After introducing the entire calculated volume of the sodium chloride solution, the reaction mass is stirred for 30-40 minutes and, observing the requirements for maintaining the sterility of the reaction mass, the precipitate is filtered, washed with a filter of 30-50 ml of acetone and dried under vacuum at a temperature of no higher than 40 ° C. 46.3 g of sterile 7- [2- (2-aminothiazol-4-yl) -2 (z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidino) methyl] -cef-3-em are obtained. 4-carboxylate dihydrochloride monohydrate (cefepime dihydrochloride monohydrate) containing 99.8% of the basic substance. The product yield is 93.9% of theory in terms of the loaded technical cefepime.

Claims (2)

1. The method of obtaining 7- [2- (2-aminothiazol-4-yl) -2 (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidino) methyl] -cef-3-em-4- carboxylate dihydrochloride monohydrate (cefepime dihydrochloride monohydrate) by crystallizing it from aqueous or aqueous-organic solutions, filtering, washing and drying the precipitate, characterized in that the crystallization of the target product is carried out by introducing sodium chloride into the solution. 2. The method according to claim 1, characterized in that the sodium chloride is introduced into the solution in an amount providing a concentration of auxiliary electrolyte in the resulting solution from 10.0 to 15.0%.