CN-122012663-A - Synthesis method of tazobactam diphenyl methyl ester

CN122012663ACN 122012663 ACN122012663 ACN 122012663ACN-122012663-A

Abstract

The invention provides a synthesis method of tazobactam dibenzoyl ester, which aims to solve the problems of low product yield, low safety, complicated post-treatment, serious environmental pollution and the like of the existing synthesis method. The synthesis method comprises the steps of obtaining chloromethylation products (compound A) from debrominated sulfoxide diphenyl methyl ester under the action of benzoyl chloride and quinoline, carrying out substitution reaction on the compound A and triazole to obtain a compound B, and carrying out efficient oxidation on the compound B by H 2 O 2 under the catalysis of horseradish peroxidase isozyme C to obtain tazobactam diphenyl methyl ester. The method abandons the traditional method for synthesizing the chloromethylation product (thermal cracking and diazotization reaction), can obtain the chloromethylation product in one step, has no dangerous reaction, few byproducts, high yield and high atom economy (benzoyl chloride and quinoline can be recycled), adopts an enzyme/hydrogen peroxide catalytic system in the oxidation step, has high catalytic efficiency, greatly reduces the generation of solid waste, and is environment-friendly.

Inventors

PENG FEI
ZHAO YAN
XING YANHUI
CAI CHENGWEI
ZHAO YING
E DELIN
TIAN YU
ZHOU KAI
DONG YULIANG
MA YUNBO

Assignees

山东安舜制药有限公司

Dates

Publication Date: 20260512
Application Date: 20260202

Claims (10)

1. The synthesis method of tazobactam diphenyl methyl ester is characterized by comprising the following steps: 1) The method comprises the steps of taking debrominated sulfoxide diphenyl methyl ester as a raw material, and obtaining a compound A under the action of benzoyl chloride and quinoline; 2) The compound A and 1,2, 3-triazole undergo a substitution reaction to obtain a compound B; 3) The compound B is oxidized by H 2 O 2 under the catalysis of horseradish peroxidase isozyme C to obtain tazobactam diphenyl methyl ester; 。
2. The method for synthesizing tazobactam dibenzoyl ester according to claim 1, wherein said reaction solvent used in step 1) is selected from one or more of 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methylene chloride, 1, 2-dichloroethane, benzene, toluene, xylene, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, sulfolane.
3. The method for synthesizing tazobactam dibenzoyl ester according to claim 1, wherein the reaction solvent used in the step 3) is selected from a mixed solvent of a phosphate buffer system and an organic solvent, wherein the organic solvent is selected from one or more of tetrahydrofuran, 1, 4-dioxane, acetonitrile, acetone, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and sulfolane, and the volume ratio of the organic solvent is 0% -50%.
4. The method for synthesizing tazobactam dibenzoyl ester according to claim 1, wherein in step 3), the pH value of the reaction system is controlled to be 6.0-8.0, and the reaction temperature is controlled to be 10-50 ℃.
5. The method for synthesizing tazobactam dibenzoyl ester according to claim 1, wherein in step 3), the concentration of H 2 O 2 is 30% to 50%.
6. The method for synthesizing tazobactam dibenzoate according to any one of claims 1 to 5, 1) Synthesis of Compound A Adding debrominated sulfoxide dibenzoyl ester, quinoline, benzoyl chloride and 1, 4-dioxane into a reaction vessel, carrying out reflux reaction for 4-6 h, cooling to room temperature, adding water, extracting with dichloromethane, separating liquid, washing an organic phase, concentrating, removing part of solvent to obtain a dichloromethane solution, and directly using the dichloromethane solution in the next reaction; 2) Synthesis of Compound B Adding ion exchange resin and 1,2, 3-triazole into the dichloromethane solution of the previous step, reacting for 5-10 hours at 20-30 ℃, and obtaining a compound B through post-treatment; 3) Synthesis of tazobactam dibenzoyl ester Adding a compound B and HRP C into a mixed solution of a phosphate buffer system and 1, 4-dioxane, controlling the pH value of the system to be 6.5-7.5, then dropwise adding 30% -35% hydrogen peroxide, wherein the temperature is not higher than 20 ℃ in the dropwise adding process, the dropwise adding time is 1-2 hours, and after the dropwise adding is finished, carrying out heat preservation reaction on the reaction system at 20-30 ℃ for 2-3 hours, and carrying out aftertreatment to obtain tazobactam diphenyl methyl ester.
7. The method for synthesizing tazobactam dibenzoyl ester according to claim 6, wherein the aqueous phase of step 1) is adjusted to a pH value of 8-9 with sodium bicarbonate, and the quinoline in the aqueous phase is extracted with recovered dichloromethane to recover the quinoline.
8. The method for synthesizing tazobactam dibenzoyl ester according to claim 6, wherein the aqueous phase after recovering quinoline in step 1) is adjusted to have a pH value of 2-3 with aqueous hydrochloric acid, benzoic acid is precipitated as a solid, and the solid is filtered and dried to obtain benzoic acid, and the benzoic acid reacts with a chloro reagent to obtain benzoyl chloride, thereby completing the regeneration of the benzoyl chloride.
9. The process for synthesizing tazobactam dibenzoyl ester according to claim 6, wherein the post-treatment of step 2) is that after the reaction is completed, the ion exchange resin is removed by filtration, and the reaction product is washed with a small amount of dichloromethane, the organic phases are combined, concentrated under reduced pressure, and the concentrated solution is added into n-heptane for crystallization.
10. The method for synthesizing tazobactam dibenzoyl ester according to claim 6, wherein the post-treatment in step 3) comprises adding sodium bisulphite water solution to quench excess H 2 O 2 after the reaction, adding dichloromethane, separating the solution, washing the organic phase with purified water, concentrating under reduced pressure, adding n-heptane into the concentrated solution, stirring for crystallization, filtering, and drying to obtain tazobactam dibenzoyl ester.

Description

Synthesis method of tazobactam diphenyl methyl ester Technical Field The invention belongs to the field of medicine synthesis, and particularly relates to a synthesis method of tazobactam dibenzoyl ester. Background Tazobactam is an important beta-lactamase inhibitor developed by Japanese Roc pharmaceutical company, and has the characteristics of high stability, low toxicity, high enzyme inhibition activity and the like. The tazobactam is combined with antibiotics such as piperacillin, amoxicillin and the like, is used for treating various bacterial infections, and has wide application in the field of medicines. At present, the synthetic routes of tazobactam dibenzoyl ester include the following: 1. The common synthesis process at present comprises the steps of obtaining key intermediate debrominated sulfoxide dibenzoyl ester from 6-APA serving as a raw material through bromination, oxidation, esterification and reduction, then thermally cracking the debrominated sulfoxide dibenzoyl ester and 2-mercaptobenzothiazole, and obtaining 2 beta-chloromethyl-2 alpha-methyl-6, 6-dihydro penicillanic acid dibenzoyl ester through chlorination, and obtaining tazobactam dibenzoyl ester from the intermediate through substitution and double oxidation, wherein the reaction equation is shown as follows. The thermal cracking yield of the common synthesis process is relatively low, the 2-mercaptobenzothiazole can be converted into dimer solid waste (dibenzothiazyl disulfide) which cannot be recycled, the atom economy is poor, the chloromethylation step involves diazotization dangerous reaction, belongs to dangerous chemical reaction strictly controlled by China, the oxidation step generates a large amount of manganese salt solid waste, and high-activity substances possibly remain in the manganese salt solid waste, so that the solid waste cannot be treated by common solid waste, but is treated by dangerous waste, the post-treatment cost is high, and all factors can have adverse effects on large-scale industrial production. 2. In order to avoid the thermal cracking process, a synthesis process is reported to be adopted, wherein debrominated sulfoxide diphenyl methyl ester is directly reacted with 1-trimethylsilyl-1, 2, 3-triazole without thermal cracking ring opening (the reaction equation is shown below). The reaction steps of the route are short, but the reaction conditions are very harsh, the reaction system is strictly anhydrous, and the products need column chromatography for separation. In addition, the preparation process of the 1-trimethylsilyl-1, 2, 3-triazole is also harsh, and high temperature and high pressure are required, so that the process cannot be applied to industrial production. 3. In order to avoid the hazardous procedure of chloromethylation, the thermal cracking product is also reported to directly carry out C-N coupling reaction with silver triazole to directly obtain a substituted product (the reaction equation is shown as follows), but dibenzothiazole disulfide generated in the reaction process can be attached to the surface of silver triazole particles, so that the reaction conversion rate is lower. In addition, the easily sublimated iodine simple substance is used in the reaction, and the health of operators is damaged. Aiming at the problem of excessively high hazardous waste caused by potassium permanganate, 50% hydrogen peroxide and acetic anhydride are reported to be adopted as oxidizing agents, but from the mechanism point of view, the peracetic acid generated in situ under the condition is more dangerous and explosive, and is not suitable for industrial production. In addition, an oxidation system of 30% hydrogen peroxide and Na 2WO4 is adopted to replace potassium permanganate, but the system has the problem of incomplete oxidation, so that sulfoxide impurities are higher, and in addition, the heavy metal auxiliary agent is added to introduce the problem of heavy metal ion pollution. In conclusion, the research on tazobactam dibenzoyl ester in China at present does not obtain satisfactory results, so that the development of the tazobactam dibenzoyl ester synthesis process which is short in reaction step, simple in operation and suitable for industrial production has important significance. Disclosure of Invention The invention provides a synthesis method of tazobactam dibenzoyl ester, which aims to solve the problems of low product yield, low safety, complicated post-treatment, serious environmental pollution and the like of the existing synthesis method. The synthesis method comprises the steps of obtaining chloromethylation products (compound A) from dibromosulfoxide diphenyl methyl ester under the action of benzoyl chloride and quinoline, carrying out substitution reaction on the compound A and triazole to obtain a compound B, and carrying out efficient oxidation on the compound B by H 2O2 under the catalysis of horseradish peroxidase isozyme C (HRP C) to obtain tazobactam diphenyl methyl e