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Synthetic method of tazobactam diphenylmethyl ester

A technology for the synthesis of zobactam diphenylmethyl ester and its synthesis method, which is applied in the field of synthesis of tazobactam diphenylmethyl ester, can solve the problems of unfavorable industrial production, large amount of triazole consumption, difficult recovery, etc., and achieve high recovery rate , reduce reaction time, shorten the effect of reaction time

Pending Publication Date: 2022-04-05
YIYUAN XINQUAN CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this route has short reaction steps, the consumption of triazole is large, the recovery is difficult, the yield is low, and the cost is high, which is not conducive to industrial production

Method used

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  • Synthetic method of tazobactam diphenylmethyl ester
  • Synthetic method of tazobactam diphenylmethyl ester
  • Synthetic method of tazobactam diphenylmethyl ester

Examples

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preparation example Construction

[0041] (1) Preparation of nano silicon dioxide

[0042] Prepare a mixture of n-pentanol (35ml) and sodium dodecylbenzenesulfonate (35g), add cyclohexane (165ml) and ultrasonically shake evenly, then transfer to water (10ml) and stir at room temperature for 30min, and finally add orthosilicic acid Ethyl esters continue to react. Centrifuge, wash with ethanol, and dry in vacuum at 100° C. for 2 hours to obtain nano-silica.

[0043] (2) Preparation of 1,2-bis(4-pyridinethio)ethane

[0044] 4-bromopyridine hydrochloride (1g), 1,2-ethanedithiol (0.3ml), sodium hydroxide (0.3g) were added to DMF (10ml) and reacted at 80°C for 24h; after the reaction, the 10ml of water and 10ml of ethyl acetate were added to the reaction solution and filtered, the filtrate was extracted and layered to obtain an aqueous phase and an organic phase, and then the aqueous phase was concentrated under reduced pressure, and finally the obtained concentrate was recrystallized with methanol. 1,2-Bis(4-pyri...

Embodiment 1

[0050] (1) Preparation of 2β-azidomethylpenicillanic acid diphenylmethyl ester

[0051] Add 0.01mol of nano-loaded Cu ionic liquid catalyst and 0.02mol of sodium ascorbate to polyethylene glycol-400 / water (1:1, 200mL) and stir for 15min, then add 42g (0.1mol) of 2β-chloromethyl Penicillium Diphenylmethyl alkanoate, 7.8g (0.12mol) NaN 3 and 7g (0.1mol) propiolic acid were added to the reaction system, stirred at room temperature for 2.5h, after the reaction was completed, 200mL ethyl acetate was added, centrifuged, the obtained catalyst was washed with acetone and water and dried for repeated use The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, recrystallized from ethanol to obtain 40.9g of 2β-azidomethylpenicillanic acid diphenylmethyl ester, yield 90.4% [with 2β-chloro Diphenylmethyl penicillanic acid is calculated, yield=dry product weight / (2β-chloromethyl penicillanic acid diphenylmethyl ester mass×1...

Embodiment 2

[0055] (1) Preparation of 2β-azidomethylpenicillanic acid diphenylmethyl ester

[0056] Add 0.03 mol of nano-loaded Cu ionic liquid catalyst and 0.03 mol of sodium ascorbate into polyethylene glycol-400 / water (1.5:1, 200 mL) and stir for 20 min, then add 42 g (0.1 mol) of 2β-chloromethyl Penicillium Diphenylmethyl alkanoate, 8.5g (0.13mol) NaN 3 and 10.5g (0.15mol) propiolic acid were added to the reaction system, stirred at room temperature for 3h, after the reaction was completed, 200mL ethyl acetate was added, centrifuged, the obtained catalyst was washed with acetone and water and dried for repeated use The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, recrystallized from ethanol to obtain 41.2g of 2β-azidomethylpenicillanic acid diphenylmethyl ester, yield 91.09% [with 2β-chloro Diphenylmethyl penicillanic acid is calculated, yield=dry product weight / (2β-chloromethyl penicillanic acid diphenylmethyl...

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of tazobactam diphenylmethyl ester. 2 beta-chloromethyl penicillanic acid diphenyl methyl ester, propiolic acid and sodium azide are used as raw materials, under the catalysis of a catalyst, a one-pot reaction is adopted, and 2 beta-azido methyl penicillanic acid diphenyl methyl ester is obtained; and oxidizing with potassium permanganate to obtain the product. Compared with a traditional 6-APA route, azidation and cyclization addition are combined into one-step reaction, a one-pot method is adopted for experiment, the reaction time is shortened, and the reaction steps are simplified; by introducing the nano Cu-loaded ionic liquid catalyst as a novel catalyst, the reaction time is shortened, the reaction yield is improved, and the catalyst is high in recovery rate and can be repeatedly used, so that the production cost is greatly reduced; the propiolic acid is adopted as the raw material, acetylene is avoided, the reaction safety can be improved, the reaction condition is mild, the reaction yield is improved, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, in particular to a method for synthesizing tazobactam diphenylmethyl ester. Background technique [0002] Tazobactam was developed by Dapeng Pharmaceutical Company of Japan. It is a spectrally efficient β-lactamase inhibitor with the characteristics of small toxic and side effects, good stability and high inhibitory activity. [0003] According to literature reports, the current synthesis methods of tazobactam can be divided into: penicillin G salt method, sulbactam method and 6-APA method according to the different starting materials. Among them, the most widely used one is 6-APA as the starting raw material, which has undergone bromination, oxidation, esterification, reduction, thermal cracking, chloromethylation, azidation, double oxidation, cycloaddition, and desorption. Protection and other steps to obtain tazobactam, wherein tazobactam diphenylmethyl ester is a product obt...

Claims

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Application Information

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IPC IPC(8): C07D499/04C07D499/87B01J31/02
Inventor 张立明李朝云常明珠马祥云张雯婷
Owner YIYUAN XINQUAN CHEM
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