阅读说明：本技术 一种制备舒巴坦酸的方法 (Method for preparing sulbactam acid ) 是由 陈贵军 程远志 梁辉 杨旭 张晓霞 于 2020-07-20 设计创作，主要内容包括：本发明公开了一舒巴坦酸的制备方法,采用次磷酸作为重氮化反应试剂的同时次磷酸也作为还原试剂使用,做到了重氮化与还原反应一锅法,所得中间体经高锰酸钾氧化得到舒巴坦酸。本发明的产物为舒巴坦酸,废盐产生量相对传统工艺大幅降低,生产成本及反应危险系数有明显降低,具备较好的经济效益和社会价值。(The invention discloses a preparation method of sulbactam acid, which adopts hypophosphorous acid as a diazotization reaction reagent and also adopts hypophosphorous acid as a reduction reagent, so that a one-pot method of diazotization and reduction reaction is realized, and the sulbactam acid is obtained by oxidizing an obtained intermediate by potassium permanganate. The product of the invention is sulbactam acid, the production amount of waste salt is greatly reduced compared with the traditional process, the production cost and the reaction risk coefficient are obviously reduced, and the invention has better economic benefit and social value.)

1. A process for the preparation of sulbactam acid, comprising the steps of:

(1) adding hypophosphorous acid into a solvent, and adding 6-APA in batches at the temperature of 0-5 ℃; after the solid is dissolved, controlling the temperature to be-5-0 ℃, adding the sodium nitrite solid, and stirring for reaction for 30-60 min; extracting the reaction solution, and washing the extracted organic phase with pure water;

(2) adding pure water into the organic phase obtained in the step (1), cooling to-5-0 ℃, and adjusting the pH of the solution to 7.0-7.5 by using a sodium hydroxide solution; dropwise adding a solution prepared from potassium permanganate, phosphoric acid and pure water under stirring, controlling the temperature to be 0-5 ℃ in the process, carrying out heat preservation reaction for 1-2h after dropwise adding, and adjusting the pH value to be 1.5-2.5 by hydrochloric acid; and (3) layering, extracting the aqueous phase, combining organic phases, washing with pure water, and evaporating the organic phases under reduced pressure to dryness to obtain the sulbactam acid product.

2. The process for preparing sulbactam acid as claimed in claim 1, wherein hypophosphorous acid is used as the diazotizing acid and the reducing agent in step (1).

3. The process for preparing sulbactam acid according to claim 1, wherein the mass ratio of hypophosphorous acid to 6-APA in step (1) is: 1: 1.2-1.5.

4. The process for preparing sulbactam acid as claimed in claim 1, wherein the solvent in step (1) is selected from one of water and ethanol.

5. The process for preparing sulbactam acid according to claim 1, wherein the mass ratio of 6-APA to the solvent in step (1) is: 1: 5 to 10.

6. The process for preparing sulbactam acid as claimed in claim 1, wherein the reaction temperature in step (1) is-5-0 ℃.

7. The process for preparing sulbactam acid as claimed in claim 1, wherein the oxidizing agent in step (2) is potassium permanganate.

8. A process for the preparation of sulbactam acid according to claim 1, wherein step (2) comprises: the molar ratio of 6-APA to potassium permanganate is 1.2-2.5.

9. The method for preparing sulbactam acid according to claim 1, wherein the mass ratio of the phosphoric acid, the potassium permanganate and the water in the step (2) is 1:10: 60-65.

10. A process for preparing sulbactam acid as claimed in claim 1, characterized in that the extractant in step (2) is selected from one or more of ethyl acetate, dichloromethane, toluene, chloroform.

Technical Field

The invention belongs to the technical field of chemical industry, and particularly relates to a method for preparing sulbactam acid.

Background

The synthesis method of sulbactam acid has the molecular formula: c₈H₁₁NO₅S, molecular weight: 233.24.

sulbactam acid is an antibiotic intermediate, is a semisynthetic beta-lactamase inhibitor, has better antibacterial effect when being used together with beta-lactam antibiotics, and is mainly used for synthesizing sulbactam sodium.

The patent reports that 6-APA is subjected to diazotization, bromination and oxidation to generate sulfone, and finally reduction and debromination are carried out to obtain the target product sulbactam acid, wherein the yield is 70-86%.

This method has several problems: (1) a large amount of bromine is needed in the diazotization and bromination process, so that the reaction operation danger and the difficulty in equipment material selection are increased, and the raw material cost is high due to the high price of the bromine; (2) diazotization and bromination reaction can generate a large amount of inorganic waste salt due to the post-treatment of excessive bromine; (3) because diazotization uses bromine to replace amino, and zinc powder and the like are used for reduction debromination in later period, a large amount of inorganic waste salt and reaction wastewater are generated;

Therefore, the development of a method for synthesizing sulbactam acid with less three wastes, low risk factor and low production cost is urgently needed.

Disclosure of Invention

In order to solve the technical problems, the invention provides a preparation method of sulbactam acid. The method solves the problems of large waste salt amount, high production cost and high risk coefficient in the traditional sulbactam acid synthesis process, and has the advantages of simple operation, environmental protection, high yield and low production cost.

In order to achieve the purpose, the invention is realized by the following technical scheme:

hypophosphorous acid is used as diazotization reaction acid, and meanwhile hypophosphorous acid is used as a reducing agent to carry out hydrogenation reaction, so that the yield of the target product sulbactam acid is 88-92%;

a process for the preparation of sulbactam acid comprising the steps of:

(1) adding hypophosphorous acid into a solvent, and adding 6-APA in batches at the temperature of 0-5 ℃; after the solid is dissolved, controlling the temperature to be-5-0 ℃, adding the sodium nitrite solid, and stirring for reaction for 30-60 min; extracting the reaction solution, and washing the extracted organic phase with pure water;

(2) adding pure water into the organic phase obtained in the step (1), cooling to-5-0 ℃, and adjusting the pH of the solution to 7.0-7.5 by using a sodium hydroxide solution; dropwise adding a solution prepared from potassium permanganate, phosphoric acid and pure water under stirring, controlling the temperature to be 0-5 ℃ in the process, carrying out heat preservation reaction for 1-2h after dropwise adding, and adjusting the pH value to be 1.5-2.5 by hydrochloric acid; layering, extracting the aqueous phase, combining organic phases, washing with pure water, and evaporating the organic phases under reduced pressure to dryness to obtain a sulbactam acid product;

The hypophosphorous acid in the step (1) is used as a diazotization acid and a reducing agent.

The mass ratio of the hypophosphorous acid to the 6-APA in the step (1) is 1: 1.2-1.5.

The solvent in the step (1) is one of water and ethanol.

The mole ratio of the hypophosphorous acid to the sodium nitrite in the step (1) is 1: 0.2-0.25.

The mass ratio of the 6-APA to the organic solvent in the step (1) is 1: 5 to 10.

The molar ratio of the 6-APA to the potassium permanganate in the step (2) is 1:1.2 to 2.5.

The mass ratio of the phosphoric acid, the potassium permanganate and the water in the step (2) is 1:10: 60-65.

The extractant is one of ethyl acetate, dichloromethane, toluene and chloroform.

The invention has the beneficial effects that:

(1) the synthetic method of sulbactam acid avoids the use of bromine, reduces the production operation danger and the difficulty in selecting materials of equipment, and simultaneously reduces the raw material cost and the generation of a large amount of waste salt generated by the post-treatment of excessive bromine;

(2) hypophosphorous acid is used as a diazotization reagent and a reducing agent, and the reaction is a one-pot reaction, thereby reducing the generation of mixed salt, avoiding the reduction step of zinc powder, and avoiding the generation of a large amount of inorganic waste salt and reaction wastewater

Detailed Description

The present invention will be further described with reference to specific examples so that those skilled in the art may better understand the present invention, but the present invention is not limited thereto.