阅读说明：本技术 一种制备头孢沙定母核7-amoca的新方法 (Novel method for preparing cefixime mother nucleus 7-AMOCA ) 是由 杨双兵 *** 付林 魏旭力 李桂莲 鲁亮 于 2019-12-11 设计创作，主要内容包括：本发明公开了一种制备头孢沙定母核7-AMOCA的新方法,包括如下步骤：(1)、甲基化物的制备：在搅拌的过程中,加入3-羟基头孢,N、N-二甲基甲酰胺,碳酸钾,升温后加入碳酸二甲酯搅拌至反应完毕,降温至室温,加入水与二氯甲烷搅拌均匀后,静置分层,干燥、浓缩得甲基化物；(2)、头孢沙定母核的制备：在通氮气状态下加入二氯甲烷,二溴三苯基膦、2,6-二甲基吡啶,降温后加入甲基化物、间甲酚,搅拌至反应完毕；再加入水,搅拌均匀后,静置分层,水层调PH析晶、干燥得白色头孢沙定母核7-AMOCA。本方法原料易得,将三步反应减为两步反应；避免头孢沙定母核制备中剧毒试剂硫酸二甲酯的使用,操作简单,收率提高。(The invention discloses a novel method for preparing cefradine mother nucleus 7-AMOCA, which comprises the following steps: (1) preparation of methide: adding 3-hydroxy cephalosporin, N, N-dimethylformamide and potassium carbonate in the stirring process, heating, adding dimethyl carbonate, stirring until the reaction is finished, cooling to room temperature, adding water and dichloromethane, stirring uniformly, standing for layering, drying and concentrating to obtain a methylated substance; (2) and preparing a cefixadine mother nucleus: adding dichloromethane, dibromotriphenylphosphine and 2, 6-dimethylpyridine under the condition of introducing nitrogen, cooling, adding methylate and m-cresol, and stirring until the reaction is finished; and adding water, uniformly stirring, standing for layering, adjusting the pH of a water layer, crystallizing, and drying to obtain the white cefixime mother nucleus 7-AMOCA. The method has easily obtained raw materials, and reduces the three-step reaction into the two-step reaction; avoids the use of a highly toxic reagent dimethyl sulfate in the preparation of cefixime mother nucleus, has simple operation and improves the yield.)

1. A novel method for preparing cefixime mother nucleus 7-AMOCA is characterized by comprising the following steps:

(1) preparation of methide:

adding 3-hydroxy cephalosporin, N, N-dimethylformamide and potassium carbonate in the stirring process, heating, adding dimethyl carbonate, stirring until the reaction is finished, cooling to room temperature, adding water and dichloromethane, stirring uniformly, standing for layering, drying and concentrating to obtain a methylated substance;

(2) and preparing a cefixadine mother nucleus:

adding dichloromethane, dibromotriphenylphosphine and 2, 6-dimethylpyridine under the condition of introducing nitrogen, cooling, adding methylate and m-cresol, and stirring until the reaction is finished; and adding water, uniformly stirring, standing for layering, adjusting the pH of a water layer, crystallizing, and drying to obtain the white cefixime mother nucleus 7-AMOCA.

2. The novel process for preparing cefixime mother nucleus 7-AMOCA according to claim 1, characterized in that: in the step (1), the molar ratio of the dimethyl carbonate to the 3-OH cephalosporin is 6-10: 1.

3. The novel process for preparing cefixime mother nucleus 7-AMOCA according to claim 1, characterized in that: in the step (1), the reaction temperature is 60-65 ℃.

4. The novel process for the preparation of cefixime mother nucleus 7-AMOCA according to claim 1, characterized in that: in the step (2), dichloromethane is used as a solvent, 2, 6-dimethylpyridine and dibromotriphenylphosphine are added, the reaction temperature is 5-10 ℃, the reaction time is 1h, and then a methylate is added to react for 2h at-10 to-5 ℃.

5. The novel process for the preparation of cefixime mother nucleus 7-AMOCA according to claim 1, characterized in that: in the step (2), the mol ratio of the m-cresol to the methylated compound is 18-20: 1; the reaction temperature is 8-13 ℃; the reaction time is 4-5 h.

Technical Field

The invention relates to the technical field of preparation of cephalosporin intermediates, in particular to a novel method for preparing cefixadine mother nucleus 7-AMOCA.

Background

Cefixime is taken as an oral cephalosporin, has broad-spectrum antibacterial activity, has bactericidal action on staphylococcus, escherichia coli, bacillus influenzae, klebsiella, and the like, is clinically used for infection of parts such as respiratory tracts, urinary tracts, skins, soft tissues, reproductive organs, and the like, and is also commonly used for otitis media. 7-AMOCA is a key mother nucleus for synthesizing cefixime, has a chemical name of (6R,7R) -7-amino-3-methoxy-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid, and has a molecular structural formula as follows:

the existing cefixime mother nucleus 7-AMOCA synthesis technical route mainly comprises 2, the route 1 is obtained by taking a 3-OH cephem compound as an initial reaction raw material and carrying out methylation and deprotection reactions, and the reaction route is as follows:

the route 2 is that 3-OH-3-cephem is used as an initial reaction raw material, reacts with diazomethane, and is subjected to deprotection to prepare a 3-methoxy-3-cephem compound; the reaction route is as follows:

route 1 dimethyl sulfate is used as a toxic raw material in the above synthesis method, and has strong irritation to eyes and upper respiratory tract and strong corrosion to skin. Inhalation can lead to necrosis of epithelial cells of the trachea and the bronchus, and puncture can lead to mediastinal diaphragm or subcutaneous emphysema; causing serious physical injury to workers operating in the workshop.

Route 2 the synthesis method uses diazomethane which belongs to explosive products, and the diazomethane is easy to explode when being heated, exposed to fire or vibrated and rubbed; the inhalation has strong stimulation effect on respiratory tract and inhibition effect on central nervous system, and can cause dyspnea and chest pain; therefore, it is not suitable for industrial production.

Disclosure of Invention

The invention provides a novel method for preparing cefradine mother nucleus 7-AMOCA, which solves the problems in the background art, avoids the use of a highly toxic reagent dimethyl sulfate in the preparation of cefradine, simplifies a process route, realizes the simultaneous performance of deamination protection and decarboxylation protection, changes a three-step method of the route 1 into a two-step method, shortens the operation time, simplifies the process route, reduces the cost and is convenient for industrial production.

The invention provides a novel method for preparing cefradine mother nucleus 7-AMOCA, which comprises the following steps:

(1) preparation of methide:

adding 3-hydroxy cephalosporin, N, N-dimethylformamide and potassium carbonate in the stirring process, heating, adding dimethyl carbonate, stirring until the reaction is finished, cooling to room temperature, adding water and dichloromethane, stirring uniformly, standing for layering, drying and concentrating to obtain a methylated substance;

(2) and preparing a cefixadine mother nucleus:

adding dichloromethane, dibromotriphenylphosphine and 2, 6-dimethylpyridine under the condition of introducing nitrogen, cooling, adding methylate and m-cresol, and stirring until the reaction is finished; adding water, stirring uniformly, standing for layering, adjusting pH of a water layer to crystallize, and drying to obtain white cefixime mother nucleus 7-AMOCA;

the chemical reaction formula of the synthetic route is as follows:

in the process of preparing 7-AMOCA from a methylated compound, dibromotriphenylphosphine is added to carry out deprotection to form immino-bromoimine, and the intermediate state is not separated; after the addition of m-cresol, deamination protection and carboxyl protection are carried out simultaneously, and the reaction mechanism is as follows:

preferably, in the step (1), the molar ratio of the dimethyl carbonate to the 3-OH cephalosporin is 6-10: 1.

Preferably, in step (1), the reaction temperature is 60 to 65 ℃.

Preferably, in the step (2), dichloromethane is used as a solvent, 2, 6-dimethylpyridine and dibromotriphenylphosphine are added, the reaction temperature is 5-10 ℃, the reaction time is 1h, and then methylate is added, and the reaction is carried out for 2h at-10 to-5 ℃.

Preferably, in the step (2), the mol ratio of the m-cresol to the methylated compound is 18-20: 1; the reaction temperature is 8-13 ℃; the reaction time is 4-5 h.

The novel method for preparing the cefradine mother nucleus 7-AMOCA has the beneficial effects that:

1. in the synthetic method, all reactants are domestic commercial products, the toxicity is low, the preparation of deamination protection intermediates is avoided, and the cost is reduced; meanwhile, the use of highly toxic dimethyl sulfate and the like is avoided.

2. The whole process has mild and controllable operation conditions, and m-cresol in deprotection can be recycled after recovery, so that the production safety is improved, and the method is suitable for industrial production.

Detailed Description

The invention is further illustrated by the following examples.