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Preparation method of 2β-azidomethylpenicillanic acid diphenylmethyl ester, tazobactam intermediate and tazobactam

A technology of diphenylmethyl azidomethylpenicillanic acid and tazobactam, which is applied in the field of preparation of medicines, can solve the problems of high cost and low yield, and achieve increased yield, improved conversion rate, shortened The effect of the reaction step

Active Publication Date: 2022-02-22
ASYMCHEM LAB TIANJIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The main purpose of the present invention is to provide a kind of preparation method of 2β-azidomethylpenicillanic acid diphenylmethyl ester, tazobactam intermediate and tazobactam, to solve the problem of synthesizing tazobactam in the prior art. The method of Batan has the problems of low yield and high cost

Method used

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  • Preparation method of 2β-azidomethylpenicillanic acid diphenylmethyl ester, tazobactam intermediate and tazobactam
  • Preparation method of 2β-azidomethylpenicillanic acid diphenylmethyl ester, tazobactam intermediate and tazobactam
  • Preparation method of 2β-azidomethylpenicillanic acid diphenylmethyl ester, tazobactam intermediate and tazobactam

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preparation example Construction

[0028] In a typical implementation of the present application, a preparation method of 2β-azidomethylpenicillanic acid diphenylmethyl ester is provided, the preparation method comprising: comprising a disulfide ring-opening compound, an azide source , The reaction raw material of oxidizing agent carries out free radical reaction in solvent, obtains the product system that comprises 2β-azidomethyl penicillanic acid diphenylmethyl ester, wherein, the structural formula of disulfide ring-opening compound is , the oxidizing agent causes the azide source to generate azide radicals.

[0029] The oxidant causes the azide source to generate azide radicals, and the carbon-carbon double bond of the disulfide ring-opening compound undergoes free radical addition through the azide radical, and then intramolecular free radical substitution successfully realizes the direct conversion of the disulfide ring-opening compound to Efficient and highly selective synthesis of benzhydryl 2β-azidome...

Embodiment 1

[0052]

[0053] Dissolve disulfide compound 2 (10 g, 18.77 mmol) in THF (70 mL) at room temperature and stir to clarify, then add PhI(OAc) 2 solid (4.84 g, 15.02 mmol, 0.8 eq), the system was cooled to 5 °C, and then slowly added TMS-N 3 (2.38 g, 20.65 mmol, 1.1 eq) and tetrahydrofuran (30 mL) mixed solution, the temperature of the process control system was 5 ℃. After dropping, the system was kept at this temperature and stirred for 6 hours. After the reaction of the raw materials was completed, the system was reddish-brown turbid. After filtering to remove the bithiazole by-product, the filtrate was quenched with 10wt% sodium thiosulfate aqueous solution, and dichloromethane (50 mL) was added. Separation, organic phase detection HPLC external standard, system external standard yield 85%, intermediate 4 (2β-azidomethyl penicillanic acid diphenylmethyl ester) product HPLC purity 95%, temperature control 30~40 °C, concentrated under reduced pressure until no distillate was ...

Embodiment 2

[0066] Dissolve disulfide ring-opening compound 2 (10 g, 18.77 mmol) in acetonitrile (150 mL) and stir to clarify at room temperature, then add 10 mL of sodium azide aqueous solution (2.24 g, 37.54 mmol, 2 eq) and 10 mL of zinc chloride Aqueous solution (512 mg, 3.75 mmol, 0.2 eq), the system was cooled to 0 °C, stirred for 30 min, and then a mixed solution of ceric ammonium nitrate (20.58 g, 37.54 mmol, 2 eq) and water (30 mL) was slowly added dropwise to the system, The temperature of the process control system was 0 °C, and there were gassing and exothermic phenomena during the reaction. After dripping, the system was kept at this temperature and stirred for 60 minutes. The reaction of the raw materials was completed. The system was red and turbid. After filtering to remove the bithiazole by-product, the filtrate was quenched with 10% aqueous sodium thiosulfate solution, and dichloromethane (50 mL) was added to carry out the reaction. Separation, organic phase detection HPL...

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Abstract

The invention provides a preparation method of 2β-azidomethylpenicillanic acid diphenylmethyl ester, an intermediate of tazobactam and tazobactam. The preparation method comprises: performing a free radical reaction in a solvent on the reaction raw materials including a disulfide ring-opening compound, an azide source, and an oxidizing agent to obtain a product system including 2β-azidomethylpenicillanic acid diphenylmethyl ester, and the oxidizing agent Make the azide source generate azide free radicals. The free radical addition of the carbon-carbon double bond of the disulfide ring-opening compound by the azide radical, followed by intramolecular free radical substitution successfully achieved the direct conversion of the disulfide ring-opening compound to 2β-azidomethylpenicillanic acid di Efficient and highly selective synthesis of benzyl esters, thereby significantly improving its yield and reducing production costs. Further, 2β-azidomethylpenicillanic acid diphenylmethyl ester is used as a key intermediate in the synthesis of tazobactam, which improves the yield of tazobactam and reduces the cost.

Description

technical field [0001] The invention relates to the technical field of preparation of medicines, in particular to a preparation method of 2β-azidomethylpenicillanic acid diphenylmethyl ester, a tazobactam intermediate and tazobactam. Background technique [0002] Tazobactam, chemical name: 3-methyl-7-oxo-3-(1H-1,2,3,-triazole-1-methylene)-4-thia-1- Azabicyclo[3.2.0]heptane-2-carboxylic acid-4,4-dioxide is a new penicillane sulfone β-lactamase inhibitor developed by Dapeng Pharmaceutical Company of Japan. Tazobactam is currently recognized as the most promising β-lactamase inhibitor with the broadest antibacterial spectrum, the best resistance, the best clinical application effect. Tazobactam has a strong curative effect on abdominal cavity, respiratory tract, urinary tract and skin tissue infections, and also has obvious therapeutic effects on pediatrics, burns and blood diseases. Its structure is to add a triazole ring on the basis of sulbactam to improve the enzyme inhib...

Claims

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Application Information

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