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Preparation method of 2 beta-triazole methyl penicillanic acid diphenyl methyl ester, tazobactam intermediate and tazobactam

A technology for triazole methyl penicillic acid diphenylmethyl and tazobactam is applied in the field of preparation of tazobactam, can solve problems such as low yield, shorten reaction steps and improve reaction yield , improve the effect of selectivity

Active Publication Date: 2021-11-19
ASYMCHEM LAB TIANJIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The main purpose of the present invention is to provide a kind of preparation method of 2β-triazole methyl penicillanic acid diphenylmethyl ester, tazobactam intermediate and tazobactam, to solve the problem of synthesizing other methods in the prior art. The method of Zobactam has the problem of low yield

Method used

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  • Preparation method of 2 beta-triazole methyl penicillanic acid diphenyl methyl ester, tazobactam intermediate and tazobactam
  • Preparation method of 2 beta-triazole methyl penicillanic acid diphenyl methyl ester, tazobactam intermediate and tazobactam
  • Preparation method of 2 beta-triazole methyl penicillanic acid diphenyl methyl ester, tazobactam intermediate and tazobactam

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preparation example Construction

[0039] In a typical implementation of the present application, a method for preparing 2β-triazolemethyl penicillanic acid diphenylmethyl ester is provided, the preparation method comprising: comprising a disulfide ring-opening compound, 1, The reaction raw materials of 2,3-triazole and the first oxidant are reacted in the first solvent to obtain a product system including 2β-triazole methyl penicillanic acid diphenylmethyl ester, wherein the disulfide ring-opening compound The structural formula is , the structural formula of 2β-triazolemethyl penicillanic acid diphenylmethyl ester is .

[0040] Under the action of the first oxidant, 1,2,3-triazole is used to directly close the ring of the disulfide ring-opening compound, avoiding the chlorinated intermediate with poor stability, and successfully realizing the direct conversion of the disulfide ring-opening compound to the key Efficient and highly selective synthesis of the intermediate 2β-triazolemethylpenicillanic acid b...

Embodiment 1

[0070] In the first step, the disulfide ring-opening compound 2 is prepared in the following route:

[0071]

[0072] At room temperature, add toluene (975 mL) into a four-neck flask equipped with a water separator, and then add 2-mercaptobenzothiazole (28.92 g, 172.90 mmol, 1.02 eq) and penicillane sulfoxide to the system in sequence Diphenylmethyl ester 1 (65 g, 169.51 mmol, 1.0 eq), then the system was heated up to 120 °C and refluxed to separate water for 2 hours. After the reaction of the raw materials was completed, the system was rapidly cooled to room temperature. The HPLC purity of the product was 96%, and the external standard yield of the system was 95%, and then concentrated under reduced pressure at a temperature of 30-40 °C until there was no distillate, which was directly used in the next reaction.

[0073] In the second step, prepare 2β-triazole methyl penicillanic acid diphenylmethyl ester 3 with the following route:

[0074]

[0075] At room temperatur...

Embodiment 2

[0086] The difference between Example 2 and Example 1 is that in the second step of the reaction, the amount of 1,2,3-triazole added is 8.0 eq, and finally 2β-triazole methyl penicillanic acid diphenylmethyl ester is obtained 3. Further, obtain tazobactam.

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Abstract

The invention provides a preparation method of 2 beta-triazole methyl penicillanic acid diphenyl methyl ester, a tazobactam intermediate and tazobactam. The preparation method comprises the steps that reaction raw materials including a disulfide ring-opening compound, 1, 2, 3-triazole and a first oxidizing agent react in a first solvent, a product system including 2 beta-triazole methyl penicillanic acid diphenyl methyl ester is obtained, the structural formula of the disulfide ring-opening compound is shown in the specification, and the structural formula of 2 beta-triazole methyl penicillanic acid diphenyl methyl ester is shown in the specification. Under the action of a first oxidizing agent, 1, 2, 3-triazole is used for direct ring closing of the disulfide ring-opening compound, and efficient and high-selectivity synthesis from the disulfide ring-opening compound to the key intermediate 2 beta-triazole methyl penicillanic acid diphenyl methyl ester is successfully realized. Furthermore, the 2 beta-triazole methyl penicillanic acid diphenyl methyl ester is used as a key intermediate for synthesizing the tazobactam, so that the yield of the tazobactam is increased, and the cost is reduced.

Description

technical field [0001] The present invention relates to the technical field of preparation of tazobactam, in particular to the preparation of a kind of 2β-triazole methyl penicillanic acid diphenylmethyl ester, tazobactam intermediate and tazobactam method. Background technique [0002] Clinical studies have shown that with the widespread use of antibiotics, pathogens are increasingly resistant to antibiotics, and the clinical efficacy of antibiotics is far less than before. In order to solve the problem of drug resistance, BLA inhibitors represented by tazobactam have done a lot of research on drug resistance and made great breakthroughs. The drug has the characteristics of low toxicity, good stability, and strong enzyme inhibitory activity. Its enzyme inhibitory activity is ten times stronger than that of sulbactam, and its stability is better than that of clavulanic acid. The in vivo and in vitro experiments of this drug combined with ampicillin, amoxicillin, piperacill...

Claims

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Application Information

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IPC IPC(8): C07D499/87C07D417/12C07D499/04C07D499/06
CPCC07D499/87C07D417/12C07D499/04C07D499/06C07B2200/07
Inventor 洪浩肖毅熊正常王学智王成栋
Owner ASYMCHEM LAB TIANJIN