Tazobactam synthesis method

A technology for tazobactam and a synthesis method is applied in the synthesis field of β-lactamase inhibitor tazobactam, can solve the problems of low total yield, danger and explosion, and achieves simple operation, easy industrial production, The effect of mild reaction conditions

Active Publication Date: 2011-04-20
YIYUAN XINQUAN CHEM
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

The advantage of this process is that penicillin G potassium salt is much cheaper than 6-aminopenicillanic acid. The disadvantage is that it uses dangerous and explosive substances and generates six-membered cycloisomerization by-products in the nucleophilic substitution reaction. low overall yield

Method used

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  • Tazobactam synthesis method

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Experimental program
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Effect test

Embodiment 1

[0058] (1) Add CH to a 1000mL three-necked bottle 2 Cl 2 300mL and 1.5mol.L -1 h 2 SO 4 100mL, stirred and cooled to 0°C, then added 36.5g (0.228mol) of bromine, 0.33g of hexadecyltrimethylammonium bromide and 10.5g (0.152mol) of sodium nitrite into the reaction liquid, and continued stirring to dissolve Then add 33g (0.152mol) of 6-APA in batches, and after stirring for 1h at 0-5°C, add 1mol.L -1 NaHSO 3 Until the solution is tested with KI-starch test paper and does not change color. Then let the layers stand, and the water layer was washed with 100mL CH 2 Cl 2 After two extractions, the organic layers were combined, followed by water, 7% NaHCO 3 Aqueous solution, saturated sodium chloride aqueous solution washing, the obtained CH containing 6,6-dibromopenicillanic acid 2 Cl 2 The solution was directly used in the next reaction.

[0059] (2) Add the CH of 6,6-dibromopenicillanic acid in a 1000mL three-necked bottle 2 Cl 2 Solution (about 400ml), after cooling ...

Embodiment 2

[0066] (1) Add CH to a 1000mL three-necked bottle 2 Cl 2 300mL and 1.5mol.L -1 h 2 SO 4 100mL, stirred and cooled to 0°C, then added 73g (0.456mol) of bromine, 1.65g of dodecyltriethylammonium bromide and 10.5g (0.152mol) of sodium nitrite into the reaction liquid, and kept stirring, after dissolving Add 33g (0.152mol) of 6-APA in batches, and after stirring for 1h at 0-5°C, add 1mol.L -1 NaHSO 3 Until the solution is tested with KI-starch test paper and does not change color. Then let the layers stand, and the water layer was washed with 100mL CH 2 Cl 2 After two extractions, the organic layers were combined, followed by water, 7% NaHCO 3 Aqueous solution, saturated sodium chloride aqueous solution washing, the obtained CH containing 6,6-dibromopenicillanic acid 2 Cl 2 The solution was directly used in the next reaction.

[0067] (2) Add the CH of 6,6-dibromopenicillanic acid in a 1000mL three-necked bottle 2 Cl 2 Solution (about 400ml), after cooling down to 5...

Embodiment 3

[0074] (1) Add CH to a 1000mL three-necked bottle 2 Cl 2 300mL and 1.5mol.L -1 h 2 SO 4 100mL, stirred and cooled to 0°C, then added 122g (0.762mol) of bromine, 2.2g of dodecyltrimethylammonium bromide and 35g (0.508mol) of sodium nitrite into the reaction solution, and kept stirring, dissolved and divided Add 55g (0.254mol) of 6-APA in batches, and after stirring for 1h at 0-5°C, add 1mol.L -1 NaHSO 3 Until the solution is tested with KI-starch test paper and does not change color. Then let the layers stand, and the water layer was washed with 100mL CH 2 Cl 2 After two extractions, the organic layers were combined, followed by water, 7% NaHCO 3 Aqueous solution, saturated sodium chloride aqueous solution washing, the obtained CH containing 6,6-dibromopenicillanic acid 2 Cl 2 The solution was directly used in the next reaction.

[0075] (2) Add the CH of 6,6-dibromopenicillanic acid in a 1000mL three-necked bottle 2 Cl 2 Solution (about 400ml), after cooling to ...

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Abstract

The invention relates to a tazobactam synthesis method which comprises the steps of: with 6-APA(Amino Penicillanic Acid) as raw material, preparing a key intermediate 6,6-dihydro penam sulphoxide acid diphenylcarbinol ester through successive reactions of esterification, oxidation, reduetive debromination and the like without separation; then, reacting with 2-triphenyl silicon-1,2,3-triazole; introducing a triazole ring; and finally obtaining the final product of tazobactam through potassium permanganate oxidation and metacresol deprotection. The tazobactam synthesis method is mainly characterized in that a phase transfer catalyst is introduced in the first step, therefore, the reaction rate and the product purity are improved; since an environment-friendly hydrogen peroxide-cobalt acetate catalytic oxidation system is adopted in the third step, the characteristics of good reaction selectivity, high yield, catalyst recyclability and the like are achieved; a method for synthesizing 2 alpha-methyl-2 beta-(1,2,3- triazole-1- radical) methyl penam-3 alpha-carboxylic acid diphenylcarbinol ester by using 2-triphenyl silicon-1,2,3-triazole is adopted in the fifth step, and the tazobactamsynthesis method is simple and convenient to operate, is safe and reliable, shortens the reaction route and improves the total yield. Compared with the traditional process, the tazobactam synthesis method greatly reduces the production cost and the environment pollution and has greater implementation value and economic benefits.

Description

technical field [0001] The invention relates to a method for synthesizing beta-lactamase inhibitor tazobactam. Background technique [0002] Tazobactam, chemical name (2S, 3S, 5R)-3-methyl-7-oxo-3-(1H-1,2,3,-triazolylmethyl]-4-thia-1 -Azabicyclo[32.0]heptane-2-carboxylic acid-4,4-dioxide.It is a β-lactamase inhibitor developed by Japan's Dapeng Pharmaceutical Company, which has low toxicity, good stability, and enzyme inhibition It has strong activity and other characteristics, and it has achieved extremely effective synergistic effects when combined with ampicillin, amoxicillin, piperacillin and other antibiotics. It is an important pharmaceutical intermediate. [0003] According to the different starting materials, there are three main synthetic routes of tazobactam. [0004] Taniguchi, M., etc. (EP 0331146, 1989) etc. used penicillane-3α carboxylate diphenylmethyl ester-1β-oxide as raw material through ring opening, chloromethylation, azidation, potassium permanganate o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/87C07D499/08
CPCY02P20/584
Inventor 鲜树雍高峰张立明翟风陈坤李学平李祥伟
Owner YIYUAN XINQUAN CHEM
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