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Preparation method of tazobactam

A technology of tazobactam and zobactam diphenylmethyl ester, which is applied in the field of preparation of tazobactam, can solve the problems of increased reaction steps, dangerous production process, long reaction time, etc., and achieves reduction of reaction steps and easy industrialization Production, high yield effect

Active Publication Date: 2019-02-05
山东安信制药有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Among them, the upper triazole process is a hot spot in the synthesis of tazobactam in the near future. This route avoids the dangerous operation of high temperature and high pressure, and avoids the use of flammable and explosive reagents, but the reaction time of the upper triazole process is longer, and at the same time due to The chloride ion of 2β-chloromethyl penicillanic acid diphenylmethyl ester is easily left by the influence of the lone pair of electrons of the sulfur atom, and the stability is poor, resulting in a low yield, or the route reported in CN104031065A is through the single oxidation of the sulfur atom, Improve its stability, but increase the reaction steps (monooxidation reaction); and the upper azide process uses flammable, explosive or toxic reagents, such as sodium azide and acetylene, resulting in a more dangerous production process

Method used

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  • Preparation method of tazobactam
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  • Preparation method of tazobactam

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Embodiment 1: Preparation of 2β-chloromethylpenicillanic acid diphenylmethyl ester

[0032]

[0033] Add 110g of diphenylmethyl penicillane sulfoxide, 50g of 2-mercaptobenzothiazole, and 2000g of toluene into a 3L single-port bottle, heat up, reflux (divide water during reflux), start timing from 110°C, and reflux for 90-100 Minutes, cool down to 60-70°C, distill under reduced pressure, distill under reduced pressure until the feed liquid weight is 165g, stop distillation, cool down to 40-25°C, add 400g methylene chloride for subsequent use (thermal cracking feed liquid), in 3L five Add 120g of water, 300g of concentrated hydrochloric acid, and 500g of dichloromethane into the mouth bottle, cool down to -2~-6°C, and add the prepared thermal cracking feed solution and (21g of sodium nitrite + 150g of water) solution (dropping During the addition process, the temperature of the feed liquid is controlled to be -2~-6°C), after dripping, the temperature is controlled at -...

Embodiment 2

[0034] Embodiment 2: the preparation of double oxide

[0035] Add 500g of dichloromethane to the feed solution of compound 1 above, add 78g of potassium permanganate, cool down to 10-5°C, slowly add (50g of glacial acetic acid+370g of water+50g of industrial concentrated sulfuric acid) mixed solution, and control The temperature of the feed liquid is at 10-5°C, after the addition is completed, the temperature is controlled at 5-10°C and kept for 1-2 hours. After the heat preservation is completed, TLC detects that the basic reaction of the raw materials is complete. Slowly add 50% hydrogen peroxide dropwise until the reaction solution turns light yellow to off-white. After the drop is completed, stir for 20-30 minutes, separate the liquids, and add 500g of water and 32g of solid carbonic acid to the organic phase. The solution made of sodium hydrogen was stirred for 20-25 minutes, separated, and the organic phase was concentrated under reduced pressure at 40°C to obtain an oil...

Embodiment 3

[0036] Embodiment 3: the preparation of upper triazole i.e. tazobactam diphenylmethyl ester

[0037] In the oil after the reaction of Example 2, add 270g acetone, 320g water, 30g triazole, 90g anion resin, 20g crown ether 18-crown 6 and 20g potassium iodide, heat to reflux, keep warm for 5-8h, and keep warm. TLC detects that the basic reaction of the raw material is complete, add 650g of dichloromethane, stir for 10-15 minutes, filter, wash the filter cake with 650g of dichloromethane, and wash with 350g of water; combine the filtrate and washing liquid, add 1100g of water, stir for 10-15 minutes, and separate the liquid . The organic phase was washed by adding 500ml of purified water, and the organic phase was concentrated under reduced pressure at 40°C to obtain an oily substance, which was heated to reflux by adding 200ml of ethyl acetate, kept for 0.5h, cooled to crystallize, filtered to obtain 93.4g of off-white solid, and obtained in four steps. The yield is 69.8%, the ...

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Abstract

The invention discloses a preparation method of tazobactam. The preparation method comprises the following steps: performing double oxidization on 2beta-chloromethyl penicillanic acid diphenyl methylester by adopting a solution prepared from potassium permanganate, glacial acetic acid and concentrated sulfuric acid; then loading triazole by taking crown ether as a phase transfer catalyst and taking potassium iodide as a catalyst; then performing deprotection to obtain tazobactam. Compared with the prior art, the preparation method disclosed by the invention has the advantages that although sulfur atoms are oxidized into sulfone to lower chlorine atom activity, the use of the crown ether as the phase transfer catalyst and the potassium iodide as the catalyst compensates for the inactivation well. By adopting the method, the stability of the 2beta-chloromethyl penicillanic acid diphenyl methyl ester is improved, the reaction time is shortened, the reaction yield is improved, the operation risk is lowered, and the industrial production is facilitated.

Description

technical field [0001] The invention relates to a preparation method of tazobactam, which belongs to the technical field of medicine. Background technique [0002] Tazobactam is a new type of penicillane sulfone β-lactamase inhibitor developed by Dapeng Pharmaceutical Company in Japan. It has the characteristics of low toxicity, good stability, and broad-spectrum β-lactamase inhibitory effect. Clinically, the compound preparation of tazobactam / piperacillin (1:8) is mainly used to treat various bacterial infections. [0003] Tazobactam, molecular formula: C 10 h 12 N 4 o 5 S, molecular weight 300.29; chemical name: (2S,3S,5R)-3-methyl-7-oxo-3-(1H-l,2,3-triazol-1-ylmethyl)-4- Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide, the structural formula is as follows: [0004] [0005] There are many synthetic methods for tazobactam, and there are mainly two synthetic routes: one is the preparation of azide, oxidation, cyclization and deprotection operations, s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/08C07D499/87
CPCC07D499/08C07D499/87
Inventor 张重坤杨庆坤李卓华范松吴兆申
Owner 山东安信制药有限公司
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