CN102286001A - Method for preparing ceftezole sodium - Google Patents

Abstract

The invention discloses a preparation method of ceftezole sodium, which belongs to the field of medicinal chemistry. The method uses 1H-tetrazolium acetic acid and 2-mercapto-1,3,4-thiadiazole as raw materials to generate 1H-tetrazolium acetic acid-1 under the catalysis of p-toluenesulfonic acid or dicyclohexylcarbodiimide , 3,4-thiadiazole-2-thioester (active ester), and then the active ester and 7-aminocephalosporanic acid under the action of a quaternary ammonium phase transfer catalyst to synthesize ceftezoleic acid, and then Generate sodium salt, further recrystallization and purification to obtain high-purity ceftezole sodium. The preparation process is simple and easy, the atom utilization rate is high, the product quality is good, and the demand for industrial production can be met.

Description

The preparation method of ceftezole sodium

technical field

The invention belongs to the field of medicinal chemistry and relates to a synthesis method of ceftezole sodium medicine.

Background technique

Ceftezole sodium, the English name is Ceftezole Sodium, the molecular weight is 461.9963, the molecular formula is C ₁₃ H ₁₁ N ₈ NaO ₄ S ₃ , the chemical name is (6R,7R)-3-{[(1,3,4-thiadiazole -2-yl)thio]methyl}-7-[(1H-tetrazol-1-yl)acetamido]-8-oxo-5-thia-1-azabicyclo[4,2,0 ] Oct-2-ene-2-carboxylic acid sodium salt. Its structural formula is as follows:

Ceftezole sodium is the first generation of semi-synthetic cephalosporin antibiotics for injection. The mechanism of action is to inhibit the synthesis of bacterial cell walls to achieve antibacterial activity. It is sensitive to Gram-positive bacteria, especially Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumococcus, Streptococcus viridans, Staphylococcus epidermidis, Bacillus diphtheriae and Bacillus anthracis. It has good effect on some Gram-negative bacteria such as Haemophilus, Escherichia coli, Klebsiella, Proteus mirabilis, etc., and has good effect on Shigella, Salmonella, Citrobacter, and some indole-positive Proteus Also has antibacterial effect. Clinically, it is mainly used for infections caused by sensitive bacteria such as pneumonia, bronchitis, sepsis, peritonitis, urinary tract infection and infections caused by post-operative or trauma.

Ceftezole Sodium was developed by Japan Fujisawa Co., Ltd., and was listed under the trade name "Falomesin" in 1978. It entered the Chinese market in 1995, and its clinical usage is increasing day by day. Improving its synthetic process line and reducing production costs will be beneficial to industrial production.

A kind of synthetic method of ceftezole sodium has been reported in "New Drug Synthesis Handbook" (published by Chemical Industry Press, August, 2003), with 7-ACA as starting material, and 1H-tetrazolium acetic acid in The reaction under the effect of dicyclohexylcarbodiimide (DCC) generates 7-amino acylate, and then reacts with 2-mercapto-1,3,4-thiadiazole to produce ceftezole acid. This method is relatively simple, but always The yield is low, only 18.3%.

Patent application CN101229129A discloses a method similar to the above, but requires the ratio of raw material 1H-tetrazolium acetic acid to DCC and 7-ACA to be 1.4-1.7:1-1.3:1, and the amount of raw materials is relatively large. , ethyl acetate, and triethylamine are solvents, and the acylation yield is only 72.8%, and the total yield improves to some extent, and is 55.0%.

Patent application CN1803803A discloses a method for preparing the 3-position intermediate of ceftezole, reacting in a solvent complex with 7-ACA and 2-mercapto-1,3,4-thiadiazole, the The solvent complex is a complex of acetonitrile, formic acid and boron trifluoride. The method uses expensive and highly polluting boron trifluoride, which raises the production cost and increases the difficulty of treating the three wastes.

Patent application JP 56053684A discloses that the amino acylate of 7-ACA is used as a raw material to generate thioether with 2-mercaptobenzimidazole, and then replace the thioether hydrocarbon group with 2-mercapto-1,3,4-thiadiazole The reaction produces ceftezole. The method introduces the reaction of generating thioether with 2-mercaptobenzimidazole, which increases the reaction steps and increases the production cost.

Patent application CN101544659A discloses a method for preparing ceftezole, using boric acid as a catalyst, and reacting 7-ACA with 2-mercapto-1,3,4-thiadiazole in water to obtain 3 - position intermediate, but a large amount of 2-mercapto-1,3,4-thiadiazole and boric acid are used, and then reacted with 1H-tetrazolium acetyl chloride to prepare ceftezole acid, the acylation yield is low, and the total The yield was 38%.

Patent application CN101735250A discloses a method for preparing ceftezole sodium, that is, tetrazoleacetic acid and 2-mercapto-1,3,4-thiadiazole are condensed to form tetrazoleacetic acid-1,3,4-thiadiazole -2-thioester reacts with 7-aminocephalosporanic acid to generate ceftezole sodium, which uses expensive reagent chlorine in the synthesis of tetrazoleacetic acid-1,3,4-thiadiazole-2-thioester Isopropyl formate and N-methylpiperidine used nitrogen in the reaction of 7-aminocephalosporanic acid to generate ceftezole sodium, which increased production costs.

The method for synthesizing ceftezole sodium in the prior art generally has the disadvantages of low yield, poor product color grade and high industrial production cost. The difficulty of the process has resulted in the high price of the hospital preparations, causing economic burdens to the drug users, and the use of highly polluting chemical reagents in the synthesis process has caused great damage to the environment. At present, it is urgent to improve its synthesis process to meet the needs of industrial production.

Contents of the invention

The purpose of the present invention is to provide a kind of simple and easy, environmental protection, high yield, the synthetic method of ceftezole sodium that can meet the demand of industrialized production.

To achieve the above object, the technical scheme of the present invention is as follows:

The structural formula of ceftezole sodium is shown in (I):

Its synthetic route is:

The specific steps are as follows: (1) Synthesis of 1H-tetrazolium acetic acid-1,3,4-thiadiazole-2-thioester (IV): 1H-tetrazolium acetic acid (II) and 2-mercapto-1 , 3,4-thiadiazole (Ⅲ) is dissolved in an organic solvent, and the catalyst p-toluenesulfonic acid or dicyclohexylcarbodiimide is added at a temperature of 0°C to 4°C, and after the reaction is completed, filter to obtain 1H -tetrazolium acetic acid-1,3,4-thiadiazole-2-thioester (Ⅳ); the organic solvent used is one or more mixtures of ethyl acetate, acetone, tetrahydrofuran; 1H-tetrazolium acetic acid , The molar ratio of 2-mercapto-1,3,4-thiadiazole to p-toluenesulfonic acid is 1.05～1.10:1.00:0.1. 1H-tetrazolium acetic acid, 2-mercapto-1,3,4- The molar ratio of thiadiazole to dicyclohexylcarbodiimide is 1.05-1.10:1.00:1.10.

(2) Synthesis of ceftezoleic acid (Ⅴ): Add 7-aminocephalosporanic acid and sodium acetate or sodium bicarbonate into a mixed solvent of water and ethanol, and add the prepared product in step (1) at 0°C to 5°C The obtained 1H-tetrazolium acetic acid-1,3,4-thiadiazole-2-thioester (Ⅳ), then the temperature is raised to 30°C for reaction, and then a phase transfer catalyst and an organic solvent are added, and the temperature is raised to 58°C React at 62°C; monitor the completion of the reaction by HPLC, filter, adjust the pH of the filtrate to 2.0-3.0 with acid, and filter to obtain ceftezole acid; the phase transfer catalyst is quaternary ammonium salt triethylbenzyl ammonium chloride, tetrabutyl bromide ammonium chloride, cetyltriethylammonium chloride, tetramethylammonium chloride or ferrocene quaternary ammonium salt; the organic solvent used is one or more of ethyl acetate, toluene, cyclohexane; 7 -Aminocephalosporanic acid, 1H-tetrazolium acetic acid-1,3,4-thiadiazole-2-thioester (Ⅳ), and the molar ratio of the phase transfer catalyst is 1.00:1.05～1.10:0.15; in the mixed solvent The volume ratio of water and ethanol is 1:1;

(3) Synthesis and purification of ceftezole sodium (I): add the crude product of ceftezole acid obtained in step (2) into an aqueous solution of sodium bicarbonate and isopropanol containing equimolar amounts, evaporate the solvent, stir and analyze crystals to obtain ceftezole sodium.

The mass of the solvent water is equal to the mass of ceftezole acid, and the volume ratio of water to isopropanol is 1:2, and the crystallization temperature is 0°C to 4°C.

Compared with the existing technology, the present invention has the advantages of optimizing the ratio of reactants, reducing the occurrence of side reactions and increasing the product yield. The "one pot cooking" method is adopted to simplify the operation steps, the process has high atomic economy, the organic solvent can be recycled, and the environmental pollution is reduced. It is green and environmentally friendly, the process is simple and easy, the quality of the product is high, the production cost is reduced, and it can meet the needs of industrialization. production needs.

Detailed ways

The content of the present invention is further explained or illustrated by the following examples, but the provided examples should not be construed as limiting the protection scope of the present invention.

Example 1

1. Synthesis of 1H-tetrazolium acetic acid-1,3,4-thiadiazole-2-thioester

Dissolve 134.4g (1.05mol) of 1H-tetrazoliumacetic acid and 118.0g (1.00mol) of 2-mercapto-1,3,4-thiadiazole in 1000mL tetrahydrofuran, cool down to 0°C to 4°C, and then add 17.2g (0.10mol) of p-toluenesulfonic acid in tetrahydrofuran (50mL) was kept at the temperature for 2 hours, the solvent was recovered by distillation under reduced pressure, the temperature was lowered to 0°C to 4°C, and 220.8g of 1H-tetrazoliumacetic acid-1 was obtained by filtration. , 3,4-thiadiazole-2-thioester, the yield was 96.8%.

2, the synthesis of ceftezole acid

Add 227.0g (0.83mol) of 7-aminocephalosporanic acid (7-ACA) and 112.9g (0.83mol) of crystalline sodium acetate into 1500mL of water and 1500mL of ethanol, stir to dissolve, cool down to 0°C to 4°C in an ice bath, Then add the above-prepared 1H-tetrazolium acetic acid-1,3,4-thiadiazole-2-thioester at a molar ratio of 1.0:1.2, stir for 0.5h, then raise the temperature to 30°C and stir for 2h, then add three Ethylbenzyl ammonium chloride (TEBA) 28.4g (0.12mol) and 300mL ethyl acetate were further heated to 58°C to 62°C, reacted for 5h, evaporated under reduced pressure to recover the organic solvent, cooled to room temperature, and the filtrate was washed with 5% Adjust the pH to 2.0 with hydrochloric acid, stir and crystallize at 0°C to 4°C for 2h, and filter to obtain 326.7g of ceftezole acid, with a yield of 89.4%.

3. Synthesis and refining of ceftezole sodium

Add 150.0 g of ceftezoleic acid into 150 mL of an aqueous sodium bicarbonate solution containing an equimolar amount, then add 300 mL of isopropanol, stir to precipitate impurities, filter, evaporate the solvent, stir and crystallize at 0°C to 4°C, and filter. Wash with 50 mL of ice ethanol, and dry under reduced pressure at 40°C to obtain 137.9 g of ceftezole sodium, with a yield of 87.6%.

Example 2

1. Synthesis of 1H-tetrazolium acetic acid-1,3,4-thiadiazole-2-thioester

Dissolve 134.4 g (1.05 mol) of 1H-tetrazolium acetic acid and 118.0 g (1.00 mol) of 2-mercapto-1,3,4-thiadiazole in 1200 mL of ethyl acetate, lower the temperature to 0°C to 4°C, and then Then add 226.6g (1.10mol) of dicyclohexylcarbodiimide (DCC) and 500mL of ethyl acetate solution, keep the temperature for reaction for 2h, recover the solvent by distillation under reduced pressure, cool down to 0℃～4℃, and filter to obtain 213.8g of 1H-tetrazolium acetic acid-1,3,4-thiadiazole-2-thioester, yield 93.7%.

2. Synthesis of Ceftezole Acid

Same as Example 1, the phase transfer catalyst adopts tetrabutylammonium bromide; the organic solvent used is toluene.

3. Synthesis and refining of ceftezole sodium

With embodiment 1. Get Ceftezole Sodium 135.6g, yield 86.1%.

Claims (1)

1. a preparation method of Ceftezole Sodium, is characterized in that, described Ceftezole Sodium is prepared as follows: (1) Synthesis of 1H-tetrazolium acetic acid-1,3,4-thiadiazole-2-thioester: Dissolve 1H-tetrazolium acetic acid and 2-mercapto-1,3,4-thiadiazole in In an organic solvent, add the catalyst p-toluenesulfonic acid or dicyclohexylcarbodiimide at a temperature of 0°C to 4°C, and filter after the reaction to obtain 1H-tetrazolium acetic acid-1,3,4-thia Oxadiazole-2-thioester; the organic solvent used is one or more mixtures of ethyl acetate, acetone, and tetrahydrofuran; 1H-tetrazolium acetic acid, 2-mercapto-1,3,4-thiadiazole and p- The molar ratio of toluenesulfonic acid is 1.05～1.10:1.00:0.1; the molar ratio of 1H-tetrazolium acetic acid, 2-mercapto-1,3,4-thiadiazole and dicyclohexylcarbodiimide is 1.05 ~1.10:1.00:1.10; (2) Synthesis of ceftezoleic acid: Add 7-aminocephalosporanic acid and sodium acetate or sodium bicarbonate into a mixed solvent of water and ethanol, and add the 1H prepared in step (1) at 0°C to 5°C -tetrazolium acetic acid-1,3,4-thiadiazole-2-thioester, then the temperature rises to 30°C for reaction, then phase transfer catalyst and organic solvent are added, and the temperature rises to 58°C to 62°C for reaction; HPLC Monitor the completion of the reaction, filter, adjust the pH of the filtrate to 2.0-3.0 with acid, and filter to obtain ceftezole acid; the phase transfer catalyst is quaternary ammonium salt triethylbenzyl ammonium chloride, tetrabutylammonium bromide, hexadecane triethylammonium chloride, tetramethylammonium chloride or ferrocene quaternary ammonium salt; the organic solvent used is one or more of ethyl acetate, cyclohexane, toluene; 7-aminocephalosporanic acid, The molar ratio of 1H-tetrazolium acetic acid-1,3,4-thiadiazole-2-thioester to phase transfer catalyst is 1.00:1.05～1.10:0.15; (3) Synthesis and purification of ceftezole sodium: add the crude ceftezole acid obtained in step (2) into an aqueous solution containing equimolar amounts of sodium bicarbonate and isopropanol, stir, evaporate part of the solvent, and stir Crystallize and filter to obtain Ceftezole Sodium.