阅读说明：本技术 一种头孢曲松钠的制备方法 (Preparation method of ceftriaxone sodium ) 是由 于永宏 林琳 张义 赵春雷 于 2020-04-09 设计创作，主要内容包括：本发明提供了一种头孢曲松钠的制备方法,其特征在于：采用7-ACA与三嗪酸经缩合反应后得到7-ACT,采用有机碱催化剂将7-ACT成盐,然后7-ACT胍盐再与氨噻肟乙酸酸酐进行缩合反应形成头孢曲松酸,用配制好的钠盐水溶液萃取得到头孢曲松钠固体。本发明的合成方法,将7-ACT胍盐与氨噻肟乙酸酐缩合中间没有毒性较大巯基苯并噻唑副产物。(The invention provides a preparation method of ceftriaxone sodium, which is characterized by comprising the following steps: the method comprises the steps of carrying out condensation reaction on 7-ACA and triazinic acid to obtain 7-ACT, salifying the 7-ACT by using an organic base catalyst, carrying out condensation reaction on 7-ACT guanidine salt and aminothiaximetic acid anhydride to form ceftriaxone acid, and extracting by using a prepared sodium salt aqueous solution to obtain ceftriaxone sodium solid. According to the synthesis method, 7-ACT guanidine salt and aminothiazoly loximate acetic anhydride are condensed without mercaptobenzothiazole by-products with high toxicity.)

1. A preparation method of ceftriaxone sodium is characterized in that: the method comprises the steps of carrying out condensation reaction on 7-ACA and triazinic acid to obtain 7-ACT, salifying the 7-ACT by using an organic base catalyst, carrying out condensation reaction on 7-ACT guanidine salt and aminothiaximetic acid anhydride to form ceftriaxone acid, and extracting by using a prepared sodium salt aqueous solution to obtain ceftriaxone sodium solid.

2. The process for preparing ceftriaxone sodium according to claim 1, wherein:

the reaction method for salifying 7-ACT by using the organic base catalyst comprises the following steps: slowly adding organic base into an organic solvent of 7-ACT at the temperature of below-5 ℃ to prepare 7-ACT guanidine salt;

wherein the mol ratio of the organic base to the 7-ACT is 0.8-2: 1.

3. the process for preparing ceftriaxone sodium according to claim 1, wherein:

the condensation reaction method of the 7-ACT guanidine salt and the aminothiazoly loximate anhydride or acyl chloride activator comprises the following steps: reacting 7-ACT guanidine salt with aminothiazoly loximate anhydride or acyl chloride activator at the temperature of below 10 ℃ for 0.5 to 2 hours;

wherein, the mol ratio of the 7-ACT guanidine salt to the ammonia-thiophene oxime acetic anhydride or acyl chloride activating substance is 0.8-2: 1.

4. the process for preparing ceftriaxone sodium according to claim 1, wherein:

the structure of the aminothiazoly loximate anhydride is shown below:

5. the process for preparing ceftriaxone sodium according to claim 4, wherein:

the compound 1 shown in the following structure and a chlorinating agent are subjected to an anhydride forming reaction to obtain a product;

wherein the structure of the compound 1 is shown as follows:

l is a leaving group.

6. The process for preparing ceftriaxone sodium according to claim 5, wherein:

the specific preparation method of the aminothiazoly loximate anhydride comprises the following steps: cooling the solution of the compound 1 to a temperature below-10 ℃, adding an alkaline agent, controlling the temperature of a reaction system to be below-40 ℃, adding a chlorinating agent, and reacting for 0.5-2 hours;

wherein the mol ratio of the compound 1 to the chlorinating agent is 1-2: 1-2;

the molar ratio of the alkaline agent to the compound 1 is 1-2: 1.

7. the process for preparing ceftriaxone sodium according to claim 1, wherein:

the product of the anhydride-forming reaction of a compound 1 and a compound 2 shown in the following structures is adopted as the aminothiazoly loximate anhydride;

wherein the structure of the compound 1 is shown as follows:

the structure of compound 2 is shown below:

the L₁And L₂Are groups that can react with each other to form an anhydride.

8. The process for preparing ceftriaxone sodium according to claim 7, wherein:

the L₁Is hydroxy, halogen, sulfonyl, ester group;

the L₂Hydroxyl, halogen, sulfonyl and ester.

9. The process for preparing ceftriaxone sodium according to claim 7, wherein:

the specific preparation method of the aminothiazoly loximate anhydride comprises the following steps: cooling the solution of the compound 1 or the compound 2 to a temperature below-10 ℃, adding an alkaline agent, cooling the reaction system to a temperature below-40 ℃, adding the compound 2 or the compound 1, and reacting for 0.5-2 hours;

wherein the molar ratio of the compound 1 to the compound 2 is 1-2: 1-2;

the molar ratio of the alkaline agent to the compound 1 is 1-2: 1.

10. the process for preparing ceftriaxone sodium according to claim 1, wherein:

the molar ratio of the sodium salt to the 7-ACT is 1.5-2.5: 1.

Technical Field

The invention relates to the field of organic synthesis, in particular to a preparation method of an antibacterial drug ceftriaxone sodium.

Background

Ceftriaxone sodium is chemically known as sodium (6R,7R) -3- [ [ (1,2,5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [ [ (2-amino-4-thiazolyl) methoxyiminoacetyl ] amino ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate and has the following structural formula:

ceftriaxone sodium is a long-acting antibiotic drug in third-generation cephalosporins, has bactericidal effects on a plurality of gram-positive bacteria, gram-negative bacteria and anaerobic bacteria, and is highly stable to most β -lactamase produced by bacteria, so that the antibacterial effect of ceftriaxone sodium is enhanced.

At present, the technology of the variety is mainly that 7-aminocephalosporanic acid (7-ACA) and triazine acid (TTZ) are subjected to three-position condensation under the action of acetonitrile and boron trifluoride complex thereof to generate (6R,7R) -7-amino-3- [ [ 6-carboxyl-2-methyl-5-oxo-2, 5-dihydro-1, 2, 4-triazine-3-yl sulfur ] methyl ] -3-cephem-4-carboxylic acid (7-ACT), then the obtained product and 2-methoxyimino-2- (2-amino-4-thiazolyl) - (z) -thioacetic acid phenylhydrazine thiazole ester are condensed into ceftriaxone acid in solvents such as dichloromethane or tetrahydrofuran/water and the like, and then sodium acetate solution is added for salt formation, and (4) dropwise adding solvents such as acetone and the like for crystallization, and performing centrifugal separation to obtain completely dried ceftriaxone sodium solid.

In the process, as 7-ACT and 2-methoxyimino-2- (2-amino-4-thiazolyl) - (z) -thioacetic acid phenylhydrazine thiazole ester are condensed (AE-active ester), a certain genotoxicity 2-mercaptobenzothiazole byproduct is generated, so that certain hidden danger is brought to the quality safety of medicines, a large amount of solid waste is generated, the environment-friendly treatment cost is increased, and the requirements of the modern low-carbon environment-friendly green synthesis process are not met.

Disclosure of Invention

The invention aims to overcome the defects in the technology, avoid the generation of a 2-mercaptobenzothiazole by-product, omit the procedure of synthesizing AE-active ester by using the aminothiazoly loximate and the 2-mercaptobenzothiazole, simplify the process and reduce the generation and discharge of a plurality of wastes.

In order to achieve the purpose, the invention provides a preparation method of ceftriaxone sodium, which is characterized by comprising the following steps: the method comprises the steps of carrying out condensation reaction on 7-ACA and triazinic acid to obtain 7-ACT, salifying the 7-ACT by using an organic base catalyst, carrying out condensation reaction on 7-ACT guanidine salt and aminothiaximetic acid anhydride to form ceftriaxone acid, and extracting by using a prepared sodium salt aqueous solution to obtain ceftriaxone sodium solid.

The 7-ACT is a traditional preparation method, namely acetonitrile is used as a solvent, boron trifluoride/acetonitrile complex is subjected to catalytic reaction, and ammonia water is used for adjusting pH and crystallizing after hydrolysis to obtain the product.

7-the preparation method of the ceftriaxone sodium is further characterized by comprising the following steps:

the reaction method for salifying 7-ACT by using the organic base catalyst comprises the following steps: slowly adding organic base into an organic solvent of 7-ACT at the temperature of below-5 ℃ to prepare 7-ACT guanidine salt;

wherein the mol ratio of the organic base to the 7-ACT is 0.8-2: 1, preferably the molar ratio of organic base to 7-ACT is 1-1.4: 1.

the above process can be carried out in a similar organic solvent such as dichloromethane, chloroform, carbon tetrachloride, 2-methyltetrahydrofuran, etc. The weight ratio of the solvent to the 7-ACT is 2-100: 1, preferably, the weight ratio of solvent to 7-ACT is 4-10: 1. the dissolution process is preferably carried out at a temperature of-20 to-5 ℃.

The dropping speed of the organic alkali agent is generally 0.2 to 1 hour, and the organic alkali can be selected from tetramethylguanidine, sulfanylguanidine or an organic alkali agent having a similar structure.

The preparation method of the ceftriaxone sodium is further characterized by comprising the following steps:

the condensation reaction method of the 7-ACT guanidine salt and the aminothiazoly loximate anhydride or acyl chloride activator comprises the following steps: reacting 7-ACT guanidine salt with an aminothiazoly loximate anhydride or acyl chloride activator at a temperature below 10 deg.C (preferably-40-10 deg.C) for 0.5-2 hours;

wherein, the mol ratio of the 7-ACT guanidine salt to the ammonia-thiophene oxime acetic anhydride or acyl chloride activating substance is 0.8-2: 1.

the process is preferably carried out in an anhydrous solvent.

The preparation method of the ceftriaxone sodium is further characterized by comprising the following steps:

the structure of the aminothiazoly loximate anhydride is shown below:

the compound 1 shown in the following structure and a chlorinating agent are subjected to anhydride forming reaction to obtain the product of the aminothiazoly loximate anhydride; wherein the structure of the compound 1 is shown as follows:

the L represents a leaving group.

The specific preparation method of the aminothiazoly loximate anhydride comprises the following steps: cooling the solution of the compound 1 to a temperature below-10 ℃ (preferably-50 to-10 ℃), adding an alkaline agent, controlling the temperature of a reaction system to be below-10 ℃, adding a chlorinating agent, and reacting for 0.5 to 2 hours;

wherein the mol ratio of the compound 1 to the chlorinating agent is 1-2: 1-2; preferably, the molar ratio of the compound 1 to the chlorinating agent is 1-1.4: 1;

the molar ratio of the alkaline agent to the compound 1 is 1-2: 1; preferably, the molar ratio of the alkaline agent to the compound 1 is 1-1.4: 1;

the reaction is preferably carried out in the environment of solvents such as dichloromethane, trichloromethane, carbon tetrachloride and the like; the weight ratio of the solvent to the 7-ACT is 2-100: 1; preferably the weight ratio of solvent to 7-ACT is 4-10: 1.

preferably, the chlorinating agent is selected from pivaloyl chloride, phosphorus oxychloride, thionyl chloride or oxalyl chloride.

Preferably, the above-mentioned alkaline agent is selected from polyamines.

Preferably, compound 1 is aminothiazoly loximate, a salt formed with an alkaline agent, and a chlorinating agent to synthesize an acid anhydride or acid chloride.

The molar ratio of the compound 1 to the 7-ACT is 1-2: 1, preferably, the molar ratio of compound 1 to 7-ACT is 1-1.4: 1.

the preparation method of the ceftriaxone sodium is further characterized by comprising the following steps: the aminothiazoly loximate anhydride is a product obtained by the anhydride-forming reaction of a compound 1 and a compound 2 shown in the following structures;

wherein the structure of the compound 1 is shown as follows:

the structure of compound 2 above is shown below:

l as described above₁And L₂Are groups that can react with each other to form an anhydride.

For example, L₁Is hydroxy, halogen, sulfonyl, ester group;

L₂hydroxyl, halogen, sulfonyl and ester.

The specific preparation method of the aminothiazoly loximate anhydride comprises the following steps: cooling the solution of the compound 1 or the compound 2 to a temperature below-10 ℃, adding an alkaline agent, cooling the reaction system to a temperature below-40 ℃, adding the compound 2 or the compound 1, and reacting for 0.5-2 hours;

wherein the molar ratio of the compound 1 to the compound 2 is 1-2: 1-2;

the molar ratio of the alkaline agent to the compound 1 is 1-2: 1.

the preparation method of the ceftriaxone sodium is further characterized by comprising the following steps: the molar ratio of the sodium salt to the 7-ACT is 1.5-2.5: 1.

the above sodium salts are generally sodium salts of organic acids;

extracting with prepared sodium salt water solution, crystallizing at 10-30 deg.C (preferably 15-25 deg.C), crystallizing with organic solvent such as acetone, centrifuging, and drying to obtain ceftriaxone sodium solid.

Wherein the weight ratio of water to 7-ACT is 2-100: 1; the weight ratio of water to 7-ACT is 4-10: 1;

the weight ratio of the organic solvent to the 7-ACT is 20-40: 1; the weight ratio of the organic solvent to the 7-ACT is 20-30: 1.

the synthetic process route of the method is as follows:

has the advantages that:

in the preferred scheme of the invention, 7-ACT dry product obtained by condensing 7-ACA and triazine acid (TTZ) is used for forming a salt solution with organic base in an anhydrous solvent, then directly condensed with an anhydride compound of aminothiazoly loximate to form ceftriaxone acid, extracted by using a sodium acetate aqueous solution for forming salt, and crystallized in a solvent to obtain ceftriaxone sodium.

The synthetic method of the invention omits the process steps of synthesizing AE-active ester with more pollutants by using the aminothiazoly loximate and DM, has simple operation, can save solvent and reduce solid waste discharge compared with the prior art.

According to the synthesis method, no mercaptobenzothiazole byproduct with high toxicity is generated in the condensation of the 7-ACT guanidine salt and the aminothiazoly loximate acetic anhydride, so that the method is beneficial to environmental protection, increases the safety of the medicine, and reduces the production cost and the expenditure of environmental protection.

The synthesis method of the invention has high conversion rate of ceftriaxone sodium, and the molar conversion rate can reach 95%.

Drawings

FIG. 1 product map of example 1;

FIG. 2 product map of example 2;

figure 3 product map of example 3.

Detailed description of the preferred embodiments