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Preparation method for tazobactam

A tazobactam and triazole-based technology, which is applied in the field of preparation of tazobactam, can solve the problems of high probability of six-membered ring by-products, restrictions on industrial scale production, difficulty in nucleophilic substitution, etc., and achieve process stability , easy operation and improved yield

Inactive Publication Date: 2014-09-10
JIANGXI HUABANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Since the sulfur atom in compound (4) has more lone pairs of electrons, it can promote the departure of halogen atoms (Cl, Br, I). The 1H attack of nuclear ions, the generated carbocations are prone to rearrangement, and the probability of forming six-membered ring by-products is high. If the sulfur atom is oxidized to sulfone, the sulfur atom has no lone pair of electrons to provide, although it can increase its stability, but At the same time, it has a passivation effect on the departure of halogen atoms (Cl, Br, I), making it difficult for nucleophilic substitution to occur. At the same time, expensive heavy metal raw materials such as mercury salts and silver salts are used, which are costly and pollute the environment. Greatly restricts industrial scale production

Method used

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  • Preparation method for tazobactam
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  • Preparation method for tazobactam

Examples

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Effect test

example 1

[0040] Example 1: Preparation of 3-methyl-[2-oxo-4-(2-benzothiazoledithio)-1-azetidinyl]-3-butene diphenylmethyl ester (compound 3)

[0041] Using diphenylmethyl penicillanic acid sulfoxide (compound 2) as the raw material, referring to the preparation method in the literature (Synthesis, 2005, 3, 442-446), crystallized with acetone to obtain a light yellow solid powder with a yield of 95%.

example 2

[0042]Example 2: Preparation of 2β-bromomethyl-2α-methyl-penicillanic acid benzhydryl ester (compound 4)

[0043] The solid matter (compound 3) 26g (0.05mol) that obtains in the example 1 is dissolved in the 300mL methylene chloride, is cooled to below 0 ℃, adds 33.5g (0.075mol) copper bromide anhydrous, after adding, in 0 ~ Stir and react at 5°C for 10-12 hours, take a sample TLC to detect the disappearance of the raw material point, filter, rinse the filter cake with 50mL dichloromethane, and wash the filtrate with 200mL water, 200mL saturated sodium bicarbonate, and 200mL water respectively to obtain 2β-bromomethyl The dichloromethane solution of 2α-methyl-penicillanic acid diphenylmethyl ester (compound 4) was directly used in the next reaction.

example 3

[0044] Example 3: Preparation of 2β-bromomethyl-2α-methyl-penicillanic acid benzhydryl ester-1β-oxide (compound 5)

[0045] Add 30 mL of methanol to the 2β-bromomethyl-2α-methyl-penicillanic acid diphenylmethyl ester (compound 4) dichloromethane solution obtained in Example 2, cool down to below -5°C, add dropwise 30 mL of 50% hydrogen peroxide / The sodium tungstate mixture was dropped in about 30 minutes, and the temperature was controlled at 0~5°C for 4 hours, and then the temperature was raised to 10~15°C for 4~6 hours, and the raw material (compound 4) disappeared by sampling TLC. Add 200mL water, stirred for 5 minutes, allowed to stand and separate layers, and the dichloromethane liquid layer was washed with 200mL 5% sodium bicarbonate aqueous solution to obtain 2β-bromomethyl-2α-methyl-penicillanic acid diphenylmethyl ester- The dichloromethane solution of 1β-oxide (compound 5) was directly used in the next reaction.

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Abstract

The invention discloses a preparation method for tazobactam. The preparation method comprises the following steps: with benzhydryl s-oxopenicillanate as a raw material, successively carrying out thermal cracking, bromination, catalytic oxidation and a reaction with 1H-1,2,3-triazole under the action of an anion resin carrier so as to obtain an important intermediate 2beta-(1H-1,2,3-triazolyl)-2alpha-methyl-benzhydryl penicillanate-1beta-oxide; and carrying out potassium permanganate oxidation and then protective group removal under the action of meta-cresol so as to obtain the target product tazobactam. The invention is characterized in that a sulfur atom is subjected to monooxidation so as to improve compound stability, then a nucleophilic substitution reaction with 1H-1,2,3-triazole is carried out so as to effectively control the possibility of ring enlargement during introduction of a triazole ring, and total yield is increased to 68%. The preparation method has the advantages of stable process, simple and convenient operation, easy separation and purification of the reaction product, a small amount of waste gas, waste water and industrial residues, high yield and suitability for clean, industrial and large-scale production.

Description

technical field [0001] The invention relates to a preparation method of tazobactam. Background technique [0002] Tazobactam (tazobactam) is a new penicillane sulfone β-lactamase inhibitor developed by Dapeng Pharmaceutical Company of Japan. [0003] Chemical name: [2S-(2α,2β,5α)]-3-methyl-7-oxo-3-(1H-1,2,3-triazole-1-methyl)-4-thia- 1-Azabicyclo-[3,2,0]-heptane-2-carboxylic acid-4,4-dioxide. [0004] Structural formula: [0005] [0006] It was first prepared from 6-aminopenicillanic acid (6-APA) by Hall T.W et al. Its structure is to add a triazole ring on the basis of sulbactam to improve the enzyme inhibitory effect. It is currently the The β-lactamase inhibitor with the best clinical effect has the characteristics of high stability, low activity, low toxicity and strong enzyme inhibitory activity. In 1992, the compound drug tazobactam / piperacillin (1:8) of tazobactam was first launched in France for the treatment of various bacterial infections. [0007] Accordi...

Claims

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Application Information

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IPC IPC(8): C07D499/87C07D499/08
CPCY02P20/55C07D499/87C07D499/08
Inventor 刘毅陈喜谢国云
Owner JIANGXI HUABANG PHARMA
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