BG61649B1 - Method of obtaining 7-aminothiazole methoxyiminoacetamidocefalosporine acids and their salts - Google Patents

Abstract

The invention refers to a method of obtaining 7-aminothiazolemethoxyiminoacetamodo-3-R-cefalosporine acids, in which R ismethyl, acetoxymethyl or 1-methyl-1,2,3,4-tetrazole-5-thiomethylgroup. The pharmaceutically acceptable acid salts are antibiotics,applicable in medicinal practice. According to the method, thecompounds are synthesized and isolated through the addition of lowalcohol to the reaction medium in which they have been obtained.The method is one-phase at minimum energy consumption and is easyto reproduce in industrial conditions.

Description

(57) The invention relates to the preparation of 7-aminothiazolmethoxyiminoacetamido-3-N-cephalosporic acids, where R is methyl, acetoxymethyl or 1-methyl-1,2,3,4-tetrazol-5-thiomethyl group, and their pharmaceutically acceptable salts , which are antibiotics used in medical practice. The method is single-phase, is implemented with minimal energy costs and is easily reproducible in industrial conditions. The synthesis and isolation of the compounds is accomplished by the addition of lower alcohol to the reaction medium in which they are obtained.

claims (54) METHOD FOR PREPARATION OF 7-AMINOTIAZOLMETOXYMINOACETAMIDOCEPHALOSPORINIC ACIDS AND THEIR SALTS

The invention relates to a process for the preparation of 7-aminothiazolmethoxyiminoacetamidocephalosporic acids and their salts, which is useful in the pharmaceutical industry.

The pharmaceutically acceptable salts of 7aminothiazolmethoxyiminoacetamidocephalosporic acids of the general formula:

COOH in which R is a methyl, acetoxymethyl or 1-methyl-1,2,3,4-tetrazol-5-thiomethyl group are known as antibiotics for use in medical practice.

A method is known for the preparation of 7aminothiazolmethoxyiminoacetamidocephalosporic acids, in which the corresponding 7 amino-3-k-cephalosporic acid, in the structure of which R has the above meanings, is fused to a dimethylformamide solvate of 1- [α-syn-methoxyamino] -aminothiazol-4-yl) -acetyl] -benzthiazole-3-oxide in a water-organic solvent medium in the presence of an inorganic base. After condensation, the organic solvent is removed by evaporation, cooled to 0-5 ° C, acidified to pH-4.0 with mineral acid, filtered, saturated with sodium chloride and the corresponding 7-aminothiazolmethoxyiminoacetamido-3-precipitated. -Cephalosporic acids by acidification again with mineral acid. In some cases, precipitation is also carried out in the presence in the aqueous phase of an organic solvent, which is further added (1).

There is also a method in which 7-amino3-β-cephalosporic acids are silylated with N, O-bis (trimethylsilyl) acetamide, condensed with 2- (2-aminothiazol-4-yl) 2-mercaptobenzthiazole or 2-pyridyl ester -sup-methoxyiminoacetic acid in dichloromethane medium, the obtained compounds are hydrolyzed with alkalized water on cooling, the organic phase is separated, and the aqueous phase is extracted with a mixture of organic solvents in an acidic medium, the organic phase is evaporated and the resulting 7-aminotoxinosinothiazolinosinothiazoline se sus endirat in an organic solvent and are separated by filtering / 2 /.

The crystalline physiologically tolerated sodium salts of 7-aminothiazolmethoxymethoiminoacetamidocephalosporic acids are obtained by dissolving the corresponding acids in methyl alcohol, ethyl acetate or other organic solvent by the addition of sodium salt of 2-ethyltracaric acid, acetic acid, The corresponding salt of the corresponding cephalosporic acid is precipitated with a suitable organic solvent, for example ethyl or i-propyl alcohol. There is also a method of preparing crystalline sodium salts of 7-aminothiazolmethoxyiminoacetamidocephalosporic acids from their non-crystalline sodium salts, the latter being dissolved and precipitated in methyl or ethyl alcohol by changing the temperature conditions (3, 4).

The disadvantages of the known methods are the low rate of silylation and the low solubility of the resulting silylated 7-amino-3-Cephalosporic acids, necessitating operation in dilute reaction media; the need to maintain certain temperature regimes, the use of acids and bases in the preparation process, and in particular for the extraction isolation of the respective cephalosporic acids, which adversely affects their labile β-lactam ring; the multi-stage isolation results in a complicated equipment scheme, increased production costs and reduced yield of the target products.

It is an object of the invention to provide a process for the preparation of pharmaceutically acceptable sodium salts of 7-aminothiazolmethoxyiminoacetamidocephalosporic acids at high purity and yield of 7-aminothiazolmethoxyiminoacetamido-3-K-cephalosporinic acidic acid costs.

The problem is solved by a method in which 7-amino-3'-cephalosporic acids, where R has the above meanings, is silylated in dichloromethane with a mixture of Ν, с -bis (trimethylsilyl) acetamide and trimethylchlorosilane, preferably in a mole ratio 1: 0.05 - (- 0.3, 2- (2-aminothiazol-4-yl) -2-5-methoxyiminoacetic acid 2-mercaptobenzthiazole ester is added, after completion of the process condensation is added to the reaction medium alcohol, e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl or i-butyl, wherein the resulting products are hydrated they are lysed and precipitated, and the crystallized 7-aminothiazolmethoxyiminoacetamido-3-R-cephalosporin acids are filtered off, washed with the corresponding lower alcohol and dried. -Ethylacetic acid and the corresponding pharmaceutically acceptable sodium salts are precipitated by the addition of i-propyl alcohol, filtered and dried.

Advantages of the process according to the invention are the use of substances that increase the speed of the silylation process and increase the solubility of the silylated products obtained in the organic solvent, allowing operation in higher concentration and yield media; the exothermic condensation process as well as the hydrolysis reaction conditions required for the process allow the reaction to proceed without the need for external temperature influences, i. no energy consumption; the process of isolating

The 7-aminothiazolmethoxyiminoacetamidocephalosporin compounds of the reaction mixture guarantee the high purity and yield of the acids obtained and their pharmaceutically acceptable salts.

The method according to the invention is illustrated by the following examples:

Example 1. To 4.8 I dichloromethane was added 322 g (1.5 mol) of 7-aminodesacetoxycephalosporic acid, 407 g (2 mol) of N, bis- (trimethylsilyl) acetamide and 22 g (0.2 mol) of trimethylchlorosilane. The reaction mixture was stirred for one hour. 542 g of 2- (2-aminothiazole- 2-mercaptobenzthiazolyl ester) was added.

4-yl) -2-tup-methoxyiminoacetic acid. The end of the condensation process is monitored by TLC.

After the condensation was completed, dichloromethane N, O-bis (trimethylsilyl) -7- [2- (2-amino-4-thiazolyl) -2-synmethoxyiminoacetamido] -3-desacetoxycephalosporin acid, obtained in dichloromethane, was added 4.8 l ethyl alcohol . The crystallized product was filtered off, washed with ethyl alcohol and dried in vacuo.

483 g of 7- [2- (2-amino-4-thiazolyl) -2- [beta] -methoxyaminoacetamido] -3-desacetoxycephalosporic acid are obtained;

Quantity 98.2% (HPLC-HPLC calculated on dry matter);

NMR Spectrum (Bruker WM 250 spectrometer at 250.13 MHz, DMSO-d ₆ solvent, TMS standard):

9.64d, 1H, NH, J = 7.7; 6.74s, 1H, H-ar .; 5.6ldd, 1H,> 7.7 in 3.8, H-7; 5.03d, 1H, > 3.8, H-6; 3,82s, 3H, CH ₃ O; 3.50d at 3.27d, 2H, > 18.3, CH ₂ S; 1,97s, 3H, CH _3.

Example 2 To 3.01 dichloromethane was added 408.3 g (1.5 mol) of 7-aminocephalosporic acid, 407 g (2 mol) of N, O-bis (trimethylsilyl) acetamide and 22 g (0.2 mol) of trimethylchlorosilane . The reaction mixture was stirred for 30 min. 525 g of 2- (2-aminothiazol-4-yl) -2-sulfoxoiminoacetic acid 2-mercaptobenzthiazolyl ester is added. The end of the condensation process is monitored by TLC.

Upon completion of the condensation, dichloromethane N, O-bis (trimethylsilyl) -7- [2- (2-amino-4-thiazolyl) -2-synmethoxyiminoacetamido] -cephalosporic acid, 3.0-i-propyl alcohol, was completed . The crystallized product was filtered off, washed with 0.3 L of i-propyl alcohol and dried in vacuo.

627 g of 7- [2- (2-amino-4-thiazolyl) -2-5-methoxyiminoacetamido] -cephalosporic acid are obtained;

98.4% quantitative content (HPLC recalculated on dry matter);

NMR spectrum (Bruker DRX 250 spectrometer, operating frequency 250.13 MHz, solvent DMSO-D ₆ , TMS standard):

9.59d, 1H, > 8.1, NH; 7.22s, 2H, NH ₂ ; 6.74s, 1H, H-ar, 5.79dd, 1H, J = 8, mp 4.8, H-7; 5.15d, 1H, > 4.8, H-6; 4.99d at 4.69d, 2H, > 12.8, CH ₂ O; 3,84s, 3H, CH ₃ O; 3.63d at 3.48d, J = 18.1, CH ₂ S; 2,03s, 3H, CH ₃ CO.

620 g of 7- [2- (2-amino-4-thiazolyl) -2-5-methoxyiminoacetamido] -cephalosporic acid were added to 6.0 l of methyl alcohol in which 202 g (1.4 mol) of sodium salt were pre-dissolved 2-ethylacetic acid. 6.0 l of i-propyl alcohol was added to the solution. The crystallized product was filtered off, washed with 0.35 l of i-propyl alcohol and dried in vacuo.

598 g of 7 [2- (2-amino-4-thiazolyl) -2-5-methoxyiminoacetamido] -cephalosporinic acid sodium salt are obtained;

98.6% quantitative content (HPLC recalculated on dry matter);

NMR spectrum (D ₂ O solvent, TSPA standard):

6.99s, 1H, H-ar; 5.82d, 1H, J = 4.7, H-7; 5.22d, 1H, J = 4.7, H-6; 4.91d in 4.74d, 2H, J = 12.2, CH ₂ O; 4.00s, 3H, CH ₃ O; 3.68d and 3.4Id, 2H, J = 17.9, CH ₂ S; 2.11s, 3H, CH ₃ CO.

Example 3. To 4.01 dichloromethane were added 544.5 g (2 mol) of 7-aminocephalosporic acid, 543 g (2.67 mol) of N, N-bisCrimethylsilyl) acetamide and 29 g (0.27 mol) of trimethylchlorosilane. The reaction mixture was stirred for 30 min. 701 g of 2- (2-aminothiazol-4-yl) -2-5-methoxyiminoacetic acid 2-mercaptobenzthiazolyl ester are added. The end of the condensation process is monitored by TLC.

After the condensation was completed, 4.01 ethyl alcohol was added to the N, N-bistrimethylsilyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -cephalosporin acid thus obtained in dichloromethane. The crystallized product was filtered off, washed with 0.45 l ethyl alcohol and dried in vacuo.

857 g of 7- [2- (2-amino-4-thiazolyl) -2-5-methoxyiminoacetamido] -cephalosporic acid are obtained;

Content quantitative 98,8% (HPLC, calculated on dry matter).

The proton NMR spectrum of a substance is identical to that of the compound obtained as in Example 2.

Example 4. To 5 l of dichloromethane was added 493 g (1.5 mol) of 7-amino-3 - [(1-methyl-

1,2,3,4-Tetrazol-5-yl) thiomethyl] -cephalosporic acid, 407 g (2 mol) N, O-bis (trimethylsilyl) acetamide and 22 g (0.2 mol) trimethylchlorosilane. The reaction mixture was stirred for 20 min. 542 g of 2- (2-aminothiazol-4-yl) -2-5-methoxyiminoacetic acid 2-mercaptobenzthiazolyl ester are added. The end of condensation is monitored by TLC.

Upon completion of the condensation so obtained in dichloromethane N, O-bis (trimethylsilyl) -7- [2- (2-amino-4-thiazolyl) -2-synmethoxyiminoacetamido] -3- [(1-methyl-1,2, 3,4 Tetrazol-5-yl) thiomethyl] -cephalosporic acid 750 ml of n-butyl alcohol are added. The crystallized product was filtered off, washed with n-butyl alcohol and dried in vacuo.

698 g of 7- [2- (2-amino-4-thiazolyl) -2-5-methoxyiminoacetamido] -3 [(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] cephalosporin are obtained acid;

97.9% quantitative content (HPLC calculated on dry matter);

Proton NMR spectrum: (DRX 250 spectrometer at 250.13 MHz, DMSO-d ₆ solvent, TMS standard):

9.61d, 1H, > 8.1, NH; 7.22s, 2H, NH ₂ ; 6.74s, 1H, H-arom .; 5.77dd, 1H, J = 8, mp 4.8, H7; 5.13d, 1H, > 4.8, H-6; 4.37 in 4.23, 2H, ABsystem, J = 13.4, CH ₂ S; 3,93s, 3H, OCH _3; 3,84s, 3H, OCH _3; 3.77 in 3.61, 2H, AB-system, J = 18, 1, CHj-2.

Example 5. Under the conditions of Example 4, d-chloromethane N, O-bis (trimethylsilyl) -7- [2- (2-amino-4-thiazolyl) -2-syn-methoxyiminoacetamido] -3- [(1-methyl) -1,2,3,4tetrazol-5-yl) thiomethyl] -cephalosporic acid was added 300 ml of methyl alcohol. The crystallized product was filtered off and dried in vacuo.

673 g of 7- [2- (2-amino-4-thiazolyl) -2-5-methoxyiminoacetamido] -3 - [(1 methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] - cephalosporic acid;

97.3% quantitative content (HPLC recalculated on dry matter);

The proton NMR spectrum of the substance is identical to that of the compound obtained as in Example 4.

Claims (3)

Claims A method for the preparation of 7-aminothiazolmethoxyiminoacetamidocephalosporic acids and their salts, including silylation of 7-amino-3-N-cephalosporic acids, wherein R is methyl, acetoxymethyl or 1-methyl-1,2,3,4-tetrazol-5 -thiomethyl group, condensation of the corresponding silylated acids with 2- (2-a.minothiazol-4-yl) -2-8-methoxyiminoacetic acid 2-mercaptobenzthiazolyl ester, hydrolysis of the condensation products obtained, isolation from the organic phase and conversion in sodium pharmaceutically acceptable salt, characterized in m is that a mixture of N, O-bis (trimethylsilyl) acetamide and trimethylchlorosilane is used as the silylating agent, and the hydrolysis and isolation are carried out in a single-phase process, with lower alcohol added after condensation to the reaction medium. A method according to claim 1, characterized in that the silylation of the 7-amino-3-N-cephalosporic acids is carried out with a mixture of D 4, O-bis (trimethylsilyl) acetamide and trimethylchlorosilane in a molar ratio of 1: 0.05-g- 0.3. The method according to claim 1, characterized in that the lower alcohol to be added for hydrolysis and isolation of the 75 aminothiazolmethoxyiminoacetamidocephalosporic acids can be methyl, ethyl, n-propyl, i-isopropyl, n-butyl or i-butyl or i-butyl .