CN107964558B - Preparation method of cefotiam hydrochloride impurity destetrazolium cefotiam - Google Patents

Abstract

The inventionDiscloses a preparation method of cefotiam hydrochloride impurity 3-methyl cefotiam hydrochloride, which adds POCl into an organic solvent₃And DMF, adding aminothiazole acetate for reaction, adding a mixed solvent for crystallization after 12-24 hours, growing crystals, filtering and washing; adding 7-ADCA into the mixed solution, adding organic base to adjust the pH value, adding aminothiazole acetyl chloride when 7-DACA is dissolved, adding an organic solvent when the residue is less than 1.0%, standing for phase separation, collecting a water phase, adding acetone and concentrated hydrochloric acid, growing crystals, filtering, washing and drying to obtain the 3-methyl cefotiam hydrochloride. The method solves the bottleneck problem in the research and development process of cefotiam hydrochloride, changes the product form of impurities, improves the product stability, obtains the impurity reference substance with high purity and stable property, fills the blank of the preparation process of the impurity reference substance, effectively shortens the synthesis steps, achieves the yield of 115 percent, reduces the cost to about 600 yuan/KG, and reduces the synthesis cost of the impurities.

Description

Preparation method of cefotiam hydrochloride impurity destetrazolium cefotiam

Technical Field

The invention relates to biological and medical raw materials and intermediates, in particular to a synthesis and preparation method of critical known impurity, namely, destetrazolium cefotiam in the quality research of cefotiam hydrochloride.

Background

Because the related substances of the medicine have relevance with the adverse reaction of the medicine, the tracing to the impurities of the medicine is particularly important, and can be effectively combined with clinic to confirm whether the adverse reaction is related to specific impurities, meanwhile, the related substance research is the most critical part in the research and development process of the bulk drugs and the preparations, relates to the whole process of the medicine development and research, is the key point of medicine quality research, quality control and safety control, and the national requirements for the impurity research of the medicine are gradually improved and are in international connection. At present, the impurity research of domestic medicines is mostly researched by adopting an area normalization method or a self-contrast method, the method cannot meet the attribution classification, qualitative and quantitative control of impurities and is gradually not accepted by the country, and the quality research carried out by an external standard method solves the problems and is increasingly emphasized. The key to solve the problems is to obtain an impurity reference substance, and the current research and development situation is that the synthesis of the impurity reference substance is not regarded, so that the acquisition of the impurity reference substance becomes a bottleneck problem in the process of drug research and development, and the problem cannot be effectively solved, so that the preparation cost of the impurity is extremely high. In the process of researching and developing cefotiam hydrochloride, the cefotiam tetrazole is found to be a main degradation product in the stability process of the cefotiam hydrochloride, and the research on the cefotiam tetrazole is a key point for the research and development success or failure of the cefotiam hydrochloride variety.

The invention content is as follows:

the invention provides a preparation method of cefotiam hydrochloride impurity, namely, destetrazolium cefotiam, so as to obtain a destetrazolium cefotiam product with high purity and stable property under conventional conditions.

The invention provides a method for preparing tetrazole-free cefotiam by a chemical synthesis means, which comprises the following reaction equation of a synthesis route:

in order to realize the purpose of the invention, the preparation method of the tetrazole-free cefotiam comprises the following steps:

a. preparation of aminothiazole acetyl chloride

Sequentially adding POCl3 and DMF (dimethyl formamide) into an organic solvent system at the temperature of-10 ℃, adding aminothiazole acetic acid hydrochloride to react when the temperature is controlled to-5 ℃, adding a mixed solvent consisting of an organic solvent and acetonitrile to crystallize when the reaction is carried out for 12-24 hours, growing crystals for 5 hours, filtering, washing the filtered crystals with the mixed solvent, filling nitrogen into the prepared aminothiazole acetyl chloride wet product, and storing at the temperature of-5 ℃ for later use;

b. preparation of 7-aminothiazole acetamido cephalosporanic acid

Sequentially adding 7-ACA and a protective agent into an organic solvent system, controlling the temperature to be 10-40 ℃, reacting for 3-6 hours, and then adding aminothiazole acetyl chloride in batches;

when the 7-ACA residue is less than or equal to 2.0%, sequentially adding a mixed solution consisting of an organic solvent and purified water, adjusting the pH value to 6.2-7.8, standing for phase separation, then adding ethyl acetate into the collected water phase, adjusting the pH value to 1.5-4.0, growing crystals, filtering, washing and drying to obtain 7-aminothiazole acetamido cephalosporanic acid with the water content of less than or equal to 2.0%;

c. preparation of tolylfluzam

Adding the 7-aminothiazole acetamido cephalosporanic acid into a purified water system, controlling the temperature to 25-35 ℃, adjusting the pH value to 7.0-8.0 for dissolution, adding cephalosporin C deacetylase, then keeping the temperature to 25-35 ℃, adjusting the pH value to 7.3-7.7, filtering to remove the cephalosporin C deacetylase after the pH value is kept stable, combining water phases after washing an enzyme filter cake, adjusting the pH value to 3.0-4.0, cooling to 0-15 ℃, then growing crystals, filtering, washing, and drying until the water content is less than 1.5%, thus obtaining the product, namely the tetrazole cefotiam; the organic solvent adopts chloroform, dichloromethane or ethyl acetate; the protective agent adopts BSA, hexamethyldisilane amine or trimethylchlorosilane; the weight ratio of the organic solvent to the aminothiazole acetic acid hydrochloride is 3: 1-8: 1; the molar ratio of the POCl3 to the aminothiazole acetic acid hydrochloride is 1.5: 1-2.2: 1; the weight ratio of the organic solvent to the 7-ACA is 5: 1; the molar ratio of the protective agent to the 7-ACA is 1.1: 1-1.5: 1; the volume ratio of the organic solvent to the acetonitrile in the mixed solvent is 2: 1-4: 1; the volume ratio of the organic solvent to the purified water in the mixed solution is 2: 1-4: 1.

The invention achieves the technical progress that:

1. the invention solves the bottleneck problem in the research and development process of cefotiam hydrochloride, fills the blank of the preparation process of the impurity reference substance, and obtains the impurity reference substance with high purity of 98 percent and stable property.

2. Because the wet aminothiazole acetyl chloride is adopted for feeding, the energy consumption of a dried product is saved, the damage to the aminothiazole acetyl chloride in the drying process is avoided, the usage amount of the aminothiazole acetate hydrochloride serving as a raw material is reduced by 5-10%, the cost is reduced, the product purity of the intermediate 1 is improved by 2%, and the intermediate purity reaches 96%.

3. The cephalosporin C deacetylase is applied to the process of the invention, so that the reaction condition is mild, the reaction condition is easy to control, the decomposition of the product is reduced, and a high-quality intermediate product is obtained.

Drawings

FIG. 1 is a MS diagram of tolyltriazole cefotiam.

FIG. 2 shows the synthesis of tolyltriazole cefotiam¹HNMR map.

FIG. 3 shows the preparation of tolyltriazole cefotiam¹³A CNMR map.

Detailed Description

Example 1:

a. synthesis of aminothiazole acetyl chloride

Adding 90mL of chloroform into 1000mL of dry and clean four-mouth bottle, sequentially adding 36 g of POCl3 and 13 g of DMF (dimethyl formamide) when the temperature is reduced to 0-10 ℃, stirring for 30 minutes, slowly adding 23 g of aminothiazole acetic acid hydrochloride when the temperature is controlled to 0-5 ℃ for reaction, adding a mixed solvent (50 mL of chloroform +25mL of acetonitrile) pre-cooled to 5 ℃ after 24 hours of reaction, growing crystals for 5 hours, filtering, washing a filter cake with the mixed solvent (60 mL of chloroform +30mL of acetonitrile) pre-cooled to 0 ℃ to obtain an aminothiazole acetyl chloride wet product with the wet weight of about 22g, dividing the wet product into 8 equal parts, respectively bagging, filling nitrogen, and storing at the low temperature of 0-5 ℃ for later use;

b. synthesis of 7-aminothiazole acetamido cephalosporanic acid

Adding 320ml of chloroform and 27g of 7-ACA into a 1L dry four-neck flask in sequence, stirring for 5 minutes, then adding 38g of protective agent trimethylchlorosilane at a controlled temperature of 25-30 ℃, keeping the temperature at 25-30 ℃ after the addition for reaction for 3 hours, then adding 22g of aminothiazole acetyl chloride wet product at a temperature of 25-30 ℃ for eight times every 10 minutes, stirring for 10 minutes after the addition is finished, and finishing the reaction when the 7-ACA residue is detected to be less than or equal to 2.0% by sampling;

after the reaction is finished, adding a mixed solution consisting of 60ml of chloroform and 40ml of purified water in sequence, adjusting the pH value to 7.0-7.5 by using a saturated sodium bicarbonate solution, standing for 10-15 minutes, performing phase separation, collecting a water phase, adding 20ml of ethyl acetate into the water phase, adjusting the pH value to 3.8 by using 4M hydrochloric acid, stirring, performing crystal growth for 30 minutes, adjusting the pH value to 1.8-2.5 by using 4M hydrochloric acid within 35-40 minutes, performing crystal growth for 2 hours, filtering, draining, washing a filter cake by using 304ml of purified water, drying the filter cake at 45 ℃ in a vacuum drying box for 3-5 hours, sampling and detecting that the water content is less than or equal to 2.0% to obtain 7-aminothiazole acetamido cephalosporanic acid, wherein the yield is 110%, and the purity is more than or equal to 96.0%;

c. synthesis of tolylfluzamide

Adding 440mL of purified water and 30 g of 7-aminothiazole acetamido cephalosporanic acid into a 1L four-mouth bottle, controlling the temperature to 25-35 ℃, dropwise adding 3M ammonia water to adjust the pH value to 7.3-7.7, dissolving and clearing, then adding 30 g of cephalosporin C deacetylase, finely adjusting by using 3M ammonia water and keeping the pH value to 7.3-7.7 when the temperature is kept to 25-30 ℃, and finishing the reaction when the pH value is 7.6 and is kept stable for 3 minutes; and then filtering to remove cephalosporin C deacetylase, washing the enzyme filter cake with 80mL of purified water, then combining the water phases, adjusting the pH to 3.0-3.5 with 4M hydrochloric acid, cooling to 5-10 ℃, growing the crystals for 30 minutes, filtering, washing with 100mL of purified water, crystallizing twice, and thus obtaining the cefotiam tetrazolium wet product, wherein the wet product is dried in vacuum at 35 ℃ until the moisture is less than 1.5%, the yield is about 65%, and the purity is more than or equal to 98.0%. The structure of the product is confirmed and shown in the attached figures 1-3.

Example 2: the difference between this example and example 1 is that dichloromethane is used as the organic solvent, BSA is used as the protective agent, and the charge ratio is different.

Adding 70mL of dichloro into 1000mL of dry and clean four-mouth bottle, sequentially adding 39 g of POCl3 and 13 g of DMF (dimethyl formamide) when the temperature is reduced to-5 ℃, stirring for 30 minutes, slowly adding 23 g of aminothiazole acetic acid hydrochloride when the temperature is controlled to 0-5 ℃ for reaction, adding a mixed solvent (40 mL of dichloro +25mL of acetonitrile) pre-cooled to 5 ℃ after 24 hours of reaction, growing crystals for 5 hours, filtering, washing a filter cake with the mixed solvent (60 mL of dichloro +40mL of acetonitrile) pre-cooled to 0 ℃ to obtain an aminothiazole acetyl chloride wet product with the wet weight of about 22g, dividing the wet product into 8 equal parts, respectively bagging, filling nitrogen, and storing at-5-0 ℃ for later use;

b. synthesis of 7-aminothiazole acetamido cephalosporanic acid

Adding 390ml of dichloromethane and 27g of 7-ACA into a 1L dry four-neck flask in sequence, stirring for 5 minutes, then adding 32g of BSA (BSA) as a protective agent at a temperature of 25-30 ℃, keeping the temperature at 25-30 ℃ for reacting for 4 hours, then adding the 22g of aminothiazole acetyl chloride wet product at a temperature of 25-30 ℃ for eight times every 10 minutes, stirring for 10 minutes after adding, and sampling to obtain 7-ACA residue which is less than or equal to 2.0 percent, and finishing the reaction;

after the reaction is finished, adding a mixed solution consisting of 80ml of dichloromethane and 40ml of purified water in sequence, adjusting the pH to 7.0-7.5 by using a saturated sodium bicarbonate solution, standing for 10-15 minutes, performing phase separation, collecting a water phase, adding 20ml of ethyl acetate into the water phase, adjusting the pH to 3.8 by using 4M hydrochloric acid, stirring, performing crystal growth for 30 minutes, adjusting the pH to 1.8-2.5 by using 4M hydrochloric acid within 35-40 minutes, performing crystal growth for 2 hours, filtering, draining, washing a filter cake by using 304ml of purified water, drying the filter cake at 45 ℃ in a vacuum drying box for 3-5 hours, sampling and detecting that the water content is less than or equal to 2.0% to obtain 7-aminothiazole acetamido cephalosporanic acid, wherein the yield is 115%, and the purity is more than or equal to 96.0%;

c. synthesis of tolylfluzamide

Adding 540mL of purified water and 30 g of 7-aminothiazole acetamido cephalosporanic acid into a 1L four-mouth bottle, controlling the temperature to 25-35 ℃, dropwise adding 3M ammonia water to adjust the pH value to 7.3-7.7, dissolving and clearing, then adding 30 g of cephalosporin C deacetylase, finely adjusting by using 3M ammonia water and keeping the pH value to 7.3-7.7 when the temperature is kept to 25-30 ℃, and finishing the reaction after the pH value is 7.6 and is kept stable for 3 minutes; and then filtering to remove cephalosporin C deacetylase, washing the enzyme filter cake with 80mL of purified water, then combining the water phases, adjusting the pH to 3.0-3.5 with 4M hydrochloric acid, cooling to 5-10 ℃, growing the crystals for 30 minutes, filtering, washing with 100mL of purified water, crystallizing twice, and thus obtaining the cefotiam tetrazolium wet product, wherein the wet product is dried in vacuum at 35 ℃ until the moisture is less than 1.5%, the yield is about 65%, and the purity is more than or equal to 98.0%.

Example 3: this example is different from example 1 in that ethyl acetate is used as the organic solvent and hexamethyldisilazane is used as the protecting agent.

Adding 120mL of ethyl acetate into 1000mL of dry and clean four-mouth bottle, sequentially adding 42 g of POCl3 and 13 g of DMF (dimethyl formamide) when the temperature is reduced to-10-0 ℃, stirring for 30 minutes, slowly adding 23 g of aminothiazole acetic acid hydrochloride when the temperature is controlled to 0-5 ℃ for reaction, adding a mixed solvent (80 mL of ethyl acetate +25mL of acetonitrile) pre-cooled to 5 ℃ after 24 hours of reaction, growing crystals for 5 hours, filtering, washing a filter cake with the mixed solvent (100 mL of ethyl acetate +30mL of acetonitrile) pre-cooled to 0 ℃ to obtain an aminothiazole acetyl chloride wet product with the wet weight of about 22g, dividing the wet product into 8 equal parts, respectively bagging, filling nitrogen, and storing at-2 ℃ for later use;

b. synthesis of 7-aminothiazole acetamido cephalosporanic acid

Sequentially adding 480ml of ethyl acetate and 27g of 7-ACA into a 1L dry four-neck flask, stirring for 5 minutes, then adding 44g of protective agent hexamethyldisilazane at a controlled temperature of 25-30 ℃, keeping the temperature at 25-30 ℃ after the addition, reacting for 5 hours, then adding the 22g aminothiazole acetyl chloride wet product every 10 minutes at a temperature of 25-30 ℃, stirring for 10 minutes after the addition, and finishing the reaction when the sampling detects that 7-ACA residue is less than or equal to 2.0%;

after the reaction is finished, adding a mixed solution consisting of 80ml of ethyl acetate and 40ml of purified water in sequence, adjusting the pH to 7.0-7.5 by using a saturated sodium bicarbonate solution, standing for 10-15 minutes, performing phase separation, collecting a water phase, then adding 20ml of ethyl acetate into the water phase, adjusting the pH to 3.8 by using 4M hydrochloric acid, stirring, performing crystal growth for 30 minutes, adjusting the pH to 1.8-2.5 by using 4M hydrochloric acid within 35-40 minutes, performing crystal growth for 2 hours, filtering, drying, washing a filter cake by using 304ml of purified water, drying the filter cake at 45 ℃ in a vacuum drying oven for 3-5 hours, sampling and detecting that the water content is less than or equal to 2.0% to obtain 7-aminothiazole acetamido cephalosporanic acid, wherein the yield is 107%, and the purity is more than or equal to 96.0%;

c. synthesis of tolylfluzamide

Adding 540mL of purified water and 30 g of 7-aminothiazole acetamido cephalosporanic acid into a 1L four-mouth bottle, controlling the temperature to 25-35 ℃, dropwise adding 3M ammonia water to adjust the pH value to 7.3-7.7, dissolving and clearing, then adding 30 g of cephalosporin C deacetylase, finely adjusting by using 3M ammonia water and keeping the pH value to 7.3-7.7 when the temperature is kept to 25-30 ℃, and finishing the reaction after the pH value is 7.6 and is kept stable for 3 minutes; and then filtering to remove cephalosporin C deacetylase, washing the enzyme filter cake with 80mL of purified water, then combining the water phases, adjusting the pH to 3.0-3.5 with 4M hydrochloric acid, cooling to 5-10 ℃, growing the crystals for 30 minutes, filtering, washing with 100mL of purified water, crystallizing twice, and thus obtaining the cefotiam tetrazolium wet product, wherein the wet product is dried in vacuum at 35 ℃ until the moisture is less than 1.5%, the yield is about 65%, and the purity is more than or equal to 98.0%.

Claims (1)

1. A preparation method of cefotiam hydrochloride impurity, namely, destetrazolium cefotiam is characterized by comprising the following steps:

a. preparation of aminothiazole acetyl chloride

Sequentially adding POCl3 and DMF (dimethyl formamide) into an organic solvent system at the temperature of-10 ℃, adding aminothiazole acetic acid hydrochloride to react when the temperature is controlled to-5 ℃, adding a mixed solvent consisting of an organic solvent and acetonitrile to crystallize when the reaction is carried out for 12-24 hours, growing crystals for 5 hours, filtering, washing the filtered crystals with the mixed solvent, filling nitrogen into the prepared aminothiazole acetyl chloride wet product, and storing at the temperature of-5 ℃ for later use;

b. preparation of 7-aminothiazole acetamido cephalosporanic acid

Sequentially adding 7-ACA and a protective agent into an organic solvent system, controlling the temperature to be 10-40 ℃, reacting for 3-6 hours, and then adding aminothiazole acetyl chloride in batches;

when the 7-ACA residue is less than or equal to 2.0%, sequentially adding a mixed solution consisting of an organic solvent and purified water, adjusting the pH value to 6.2-7.8, standing for phase separation, then adding ethyl acetate into the collected water phase, adjusting the pH value to 1.5-4.0, growing crystals, filtering, washing and drying to obtain 7-aminothiazole acetamido cephalosporanic acid with the water content of less than or equal to 2.0%;

c. preparation of tolylfluzam

Adding the 7-aminothiazole acetamido cephalosporanic acid into a purified water system, controlling the temperature to 25-35 ℃, adjusting the pH value to 7.0-8.0 for dissolution, adding cephalosporin C deacetylase, then keeping the temperature to 25-35 ℃, adjusting the pH value to 7.3-7.7, filtering to remove the cephalosporin C deacetylase after the pH value is kept stable, combining water phases after washing an enzyme filter cake, adjusting the pH value to 3.0-4.0, cooling to 0-15 ℃, then growing crystals, filtering, washing, and drying until the water content is less than 1.5%, thus obtaining the product, namely the tetrazole cefotiam; the organic solvent adopts chloroform, dichloromethane or ethyl acetate; the protective agent adopts BSA, hexamethyldisilane amine or trimethylchlorosilane; the weight ratio of the organic solvent to the aminothiazole acetic acid hydrochloride is 3: 1-8: 1; the molar ratio of the POCl3 to the aminothiazole acetic acid hydrochloride is 1.5: 1-2.2: 1; the weight ratio of the organic solvent to the 7-ACA is 5: 1; the molar ratio of the protective agent to the 7-ACA is 1.1: 1-1.5: 1; the volume ratio of the organic solvent to the acetonitrile in the mixed solvent is 2: 1-4: 1; the volume ratio of the organic solvent to the purified water in the mixed solution is 2: 1-4: 1.

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