阅读说明：本技术 一种避免生成头孢他啶h杂质的头孢他啶叔丁酯的工艺方法 (Process method for preventing ceftazidime tert-butyl ester from generating ceftazidime H impurities ) 是由 彭继先 郭彩云 郭彦丽 董炳站 于 2021-06-24 设计创作，主要内容包括：本发明公开了一种不含头孢他啶H杂质的头孢他啶叔丁酯的工艺方法,步骤包括：在低于10℃下,头孢他啶中间体7-APCA在碱的作用下,以T6为溶剂,与他啶活性酯直接缩合反应生成头孢他啶叔丁酯,结晶后得到的产品不含头孢他啶甲酯杂质H。本发明的主要创新在于避免了合成他啶叔丁酯常规工艺中甲醇的使用,进而避免了头孢他啶甲酯杂质H的生成。本发明具有高收率,低成本且易于工业化生产的优点。本发明以7-APCA为原料,合成头孢他啶叔丁酯的工艺简单,收率较高,摩尔收率达88%,适合工业化生产。(The invention discloses a process method of ceftazidime tert-butyl ester without ceftazidime H impurities, which comprises the following steps: at the temperature lower than 10 ℃, under the action of alkali, the ceftazidime intermediate 7-APCA takes T6 as a solvent to directly perform condensation reaction with the active ester of the ceftazidime to generate the ceftazidime tert-butyl ester, and the product obtained after crystallization does not contain ceftazidime methyl ester impurity H. The main innovation of the invention is that the use of methanol in the conventional process for synthesizing the tert-butyl ester of the ceftazidime is avoided, and further the generation of impurities H of the ceftazidime methyl ester is avoided. The method has the advantages of high yield, low cost and easy industrial production. The invention takes 7-APCA as raw material, the process for synthesizing ceftazidime tert-butyl ester is simple, the yield is high, the molar yield reaches 88%, and the invention is suitable for industrial production.)

1. A process method for avoiding generating ceftazidime tert-butyl ester of ceftazidime H impurities is characterized by comprising the following steps: the method comprises the following steps:

the method comprises the following steps: mixing 7-APCA and ceftazidime active ester according to a feeding ratio, and then adding a reaction solvent T6;

step two: cooling to below 10 deg.C, and adding organic base;

step three: controlling the temperature to react for 8-20 hours;

step four: obtaining the ceftazidime tert-butyl ester through solvent crystallization, filtration and washing procedures.

2. The process of claim 1, wherein the ceftazidime tert-butyl ester is free from impurities of ceftazidime H, and the process comprises the following steps: in the first step, the molar ratio of the 7-APCA to the ceftazidime active ester is 1: 0.9-1.2, and preferably 1: 1-1.1.

3. The process of claim 1, wherein the ceftazidime tert-butyl ester is free from impurities of ceftazidime H, and the process comprises the following steps: in the first step, the feeding mass ratio of the 7-APCA to the T6 solvent is 1: 1-4, preferably 1: 2-3.

4. The process of claim 1, wherein the ceftazidime tert-butyl ester is free from impurities of ceftazidime H, and the process comprises the following steps: in the second step, the molar ratio of the 7-APCA to the organic base is 1: 0.8-2, preferably 1: 1.4 to 1.7.

5. The process of claim 1, wherein the ceftazidime tert-butyl ester is free from impurities of ceftazidime H, and the process comprises the following steps: and in the second step, the organic base is one or a mixture of more of triethylamine, tributylamine, diethylamine and ethylenediamine.

6. The process of claim 1, wherein the ceftazidime tert-butyl ester is free from impurities of ceftazidime H, and the process comprises the following steps: in the second step, the reaction temperature is-10 ℃, and preferably-5 ℃.

7. The process of claim 1, wherein the ceftazidime tert-butyl ester is free from impurities of ceftazidime H, and the process comprises the following steps: the reaction time in the third step is preferably 10-15 hours.

8. The process of claim 1, wherein the ceftazidime tert-butyl ester is free from impurities of ceftazidime H, and the process comprises the following steps: and in the fourth step, the crystallization solvent is one or a mixture of more of acetone, dichloromethane and ethyl acetate, and the washing solvent is one or a mixture of more of acetone, dichloromethane and ethyl acetate.

9. The process of claim 1, wherein the ceftazidime tert-butyl ester is free from impurities of ceftazidime H, and the process comprises the following steps: the volume ratio of the crystallization solvent to the solvent T6 in the fourth step is as follows: 5 to 10:1, preferably 7 to 9: 1.

10. The process of claim 1, wherein the ceftazidime tert-butyl ester is free from impurities of ceftazidime H, and the process comprises the following steps: the crystallization time in the fourth step is 2-8 hours, preferably 3-5 hours; the crystallization temperature is-10 to 10 ℃, preferably-5 to 5 ℃.

Technical Field

The invention relates to the technical field of synthesis of biological medicines and chemical industries, in particular to a process method for avoiding generating ceftazidime tert-butyl ester of ceftazidime H impurities.

Background

The chemical name of ceftazidime is (6R,7R) -7- [ [ (2Z) -2- (2-amino-1, 3-thiazol-4-yl) -2- (1-hydroxy-2-methyl-1-oxopropan-2-yl) oxyacetamido ] amino ] -8-oxo-3- (pyridin-1-ylium-1-ylmethyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. Is a cephalosporin antibiotic product for the third generation injection.

The structure of ceftazidime impurity H is (6R,7R) -7- [ [ (2-amino-1, 3, 4-thiazol-4-yl) -2- (1-methoxy-2-methyl-1-oxoendolan-2-yl) oxyacetamido ] amino ] -8-oxo-3- (pyridin-1-ium-1-yl-methyl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid; the teratogenic effect of the impurity is 25 times that of ceftazidime and the lethal effect of the impurity is 8 times that of the ceftazidime through zebrafish embryotoxicity experiments. Therefore, the ceftazidime impurity H should be strictly controlled.

According to the structural formula analysis of ceftazidime methyl ester (H) contained in EP pharmacopoeia, the most probable impurity generated in the preparation process of ceftazidime is a trace amount of the impurity in the process link of synthesizing ceftazidime tert-butyl ester or in the raw material of ceftazidime active ester. The use of methanol as a solvent is controlled in the synthesis of ceftazidime active ester and the synthesis of ceftazidime tert-butyl ester by relevant research documents.

In the research of the ceftazidime pentahydrate, the ceftazidime H hybrid is found to be universally present in the domestic sample and has higher content. In the conventional technology for synthesizing ceftazidime reported in the literature, a cosolvent methanol is commonly added in the process of condensing 7-APCA and active ester of the ceftazidime to generate the tert-butyl ester of the ceftazidime, so that the ceftazidime H exists in a high content. The US005831085A patent reports that the side chain at position seven is condensed to the tert-butyl ester of tasidine using an acid chloride reagent without the condensation of the ceftazidime active ester. Namely, ceftazidime side chain acid and DFCCS are synthesized into acyl chloride reagent, and then the acyl chloride reagent and 7-APCA are synthesized into the tertiarybutyl ester under the condition of low temperature, the whole process requires ultralow temperature reaction, the industrial control difficulty is large, the cost is high, and the acyl chloride reagent is unstable.

The reaction mechanism and literature confirm that the main source of ceftazidime H hybrid generation is the ceftazidime methyl ester (H) hybrid synthesis through side reaction in the process of synthesizing ceftazidime tert-butyl ester or in the process of acidifying ceftazidime tert-butyl ester in formic acid/hydrochloric acid mixed solution to form ceftazidime hydrochloride due to methanol residue in the ceftazidime tert-butyl ester product. The main technique for avoiding the formation of H hetero-compound is therefore to avoid the use of methanol in the synthesis of the t-butyl ester of tadine.

Disclosure of Invention

The invention provides a process method for preparing ceftazidime tert-butyl ester, which avoids generating ceftazidime H impurities, in order to make up for the defects of the prior art.

The invention is realized by the following technical scheme: a process method for avoiding generating ceftazidime tert-butyl ester of ceftazidime H impurities is characterized by comprising the following steps: the method comprises the following steps:

the method comprises the following steps: mixing 7-APCA and ceftazidime active ester according to a feeding ratio, and then adding a reaction solvent T6;

step two: cooling to below 10 deg.C, and adding organic base;

step three: controlling the temperature to react for 8-20 hours;

step four: obtaining the ceftazidime tert-butyl ester through solvent crystallization, filtration and washing procedures.

Further, in the first step, the molar ratio of the 7-APCA to the ceftazidime active ester is 1: 0.9-1.2, preferably 1: 1-1.1

Furthermore, the feeding mass ratio of the 7-APCA to the T6 solvent in the first step is 1: 1-4, preferably 1: 2-3.

Further, the molar ratio of the 7-APCA to the organic base in the second step is 1: 0.8-2, preferably 1: 1.4 to 1.7.

Further, the organic base in the second step is one or a mixture of more of triethylamine, tributylamine, diethylamine and ethylenediamine.

Further, the reaction temperature in the second step is-10 to 10 ℃, and preferably-5 to 5 ℃.

Further, the reaction time in the third step is preferably 10-15 hours.

Further, in the fourth step, the crystallization solvent is one or a mixture of more of acetone, dichloromethane and ethyl acetate, and the washing solvent is one or a mixture of more of acetone, dichloromethane and ethyl acetate.

Further, the volume ratio of the crystallization solvent to the solvent T6 in the fourth step is as follows: 5 to 10:1, preferably 7 to 9: 1.

Further, the crystallization time in the fourth step is 2-8 hours, preferably 3-5 hours; the crystallization temperature is-10 to 10 ℃, preferably-5 to 5 ℃.

The reaction formula equation of the reaction process is as follows:

compared with the prior art, the invention has the advantages that:

firstly, the ceftazidime tert-butyl ester synthesized by the method does not contain ceftazidime methyl ester impurity (H), and solvent methanol residue is avoided, so that the generation of ceftazidime H impurity can be avoided;

secondly, the invention takes 7-APCA as raw material, the process for synthesizing ceftazidime tert-butyl ester is simple, the yield is high, the molar yield reaches 88%, and the invention is suitable for industrial production.

Drawings

The invention will be further described with reference to the accompanying drawings.

Fig. 1 is a spectrum of ceftazidime tert-butyl ester in example 1 of the present invention;

fig. 2 is a spectrum of ceftazidime tert-butyl ester in example 2 of the present invention;

fig. 3 is a ceftazidime H impurity localization map of example 2 of the present invention;

fig. 4 is a ceftazidime pentahydrate spectrum of example 2 of the present invention;

fig. 5 is a graph of ceftazidime tert-butyl ester of example 3 of the present invention.

Detailed Description

The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like used in the practice of the present invention are common knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.

Example 1

Adding 7-APCA 32g, ceftazidime active ester 45g and T664 ml into a 1000ml four-mouth bottle, uniformly stirring, dropwise adding 19.8ml of triethylamine at-5-0 ℃, and finishing dropping within 10-15 min. Controlling the temperature to be-5-0 ℃ and reacting for 10-12 h. And adding 448ml of dichloromethane after the reaction is completed, crystallizing for 5h, filtering, washing with dichloromethane, and drying to obtain 49.3g of ceftazidime tert-butyl ester with the purity of 98.7%.

The characterization of the product, ceftazidime tert-butyl ester, is shown in figure 1.

Example 2

Adding 32g of 7-APCA, 50g of ceftazidime active ester and T-696 ml into a 1000ml four-mouth bottle, uniformly stirring, dropwise adding 18ml of triethylamine at 0-5 ℃, and finishing dropping within 10-15 min. Controlling the temperature to be 0-5 ℃ and reacting for 12-15 h. After the reaction is completed, 864ml of dichloromethane is added, crystallization is carried out for 5h, filtration is carried out, dichloromethane is used for washing and drying, 49.1g of ceftazidime tert-butyl ester is obtained, and the purity is 99.0%.

And finally, preparing a final product of ceftazidime pentahydrate by using the obtained ceftazidime tert-butyl ester.

The characterization of ceftazidime tert-butyl ester and ceftazidime pentahydrate products is shown in fig. 2 and fig. 4, and the impurities of the ceftazidime H are positioned, and as can be seen from fig. 3, the ceftazidime H impurities are not contained in the ceftazidime tert-butyl ester.

Example 3

Adding 7-APCA 32g, ceftazidime active ester 45g and T-664 mL into a 1000mL four-mouth bottle, uniformly stirring, dropwise adding 15mL of diethylamine at 0-5 ℃, and finishing dropping within 10-15 min. Controlling the temperature to be 0-5 ℃ and reacting for 10-12 h. After the reaction is completed, 512mL of acetone is added, crystallization is carried out for 5h, filtration is carried out, acetone is washed and dried, and 49.5g of ceftazidime tert-butyl ester with the purity of 98.5 percent is obtained.

The characterization of the product, ceftazidime tert-butyl ester, is shown in figure 5.

The present invention is not limited to the above embodiments, and variations and advantages that can be realized by those skilled in the art are included in the present invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims.