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Preparation method of biapenem

A single technology of biapenem, applied in the field of preparation of biapenem, can solve the problems of product heavy metal exceeding standard, poor purity, difficult to remove, etc., and achieve the effect of reducing product degradation and improving product purity

Active Publication Date: 2012-10-17
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In this method, the reaction solvent contains an organic solvent, which can be complexed with palladium in the catalyst and is not easy to remove, resulting in excessive heavy metals in the product; and the product is easily degraded in the post-treatment process, and the resulting product has low yield and poor purity.

Method used

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  • Preparation method of biapenem

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Example 1 Preparation of Biapenem

[0040] 40.0 L of deionized water, 1.0 kg (1.92 mol) of biapenem intermediate 2, 0.45 L (3.84 mol) of 2,6-lutidine, and 0.5 kg of 10% palladium on carbon were sequentially added into a 100 L hydrogenation reactor. Nitrogen was replaced several times, hydrogen was replaced several times, and finally hydrogen was passed to the pressure of 1.5MPa in the kettle, the temperature was controlled at 20°C, and stirred for 1.5h. Stirring was stopped, hydrogen was discharged and replaced with nitrogen. Filter and recover the filter cake for reuse; add 160L of acetone to the filtrate, stir and crystallize at 0°C for 4h. After filtration and vacuum drying, 0.49 kg of off-white solid was obtained, the molar yield was 73.0%, the HPLC purity was 99.1%, and the heavy metal content was <10 ppm.

Embodiment 2

[0041] Example 2 Preparation of Biapenem

[0042] 40.0 L of deionized water, 1.0 kg (1.92 mol) of biapenem intermediate 2, 0.11 L (0.96 mol) of 3,5-lutidine, and 0.5 kg of 10% palladium on carbon were sequentially added into a 100 L hydrogenation reactor. Nitrogen was replaced several times, hydrogen was replaced several times, and finally hydrogen was passed to the pressure of 2.0 MPa in the kettle, the temperature was controlled at 40°C, and stirred for 3 hours. Stirring was stopped, hydrogen was discharged and replaced with nitrogen. Filter and recover the filter cake for reuse; add 160L of ethanol to the filtrate, stir and crystallize at 0°C for 2h. After filtration and vacuum drying, 0.45 kg of off-white solid was obtained, the molar yield was 67.2%, the HPLC purity was 98.2%, and the heavy metal content was <10 ppm.

Embodiment 3

[0043] Example 3 Preparation of Biapenem

[0044] 40.0 L of deionized water, 1.0 kg (1.92 mol) of biapenem intermediate 2, 1.1 L (9.6 mol) of 2,6-lutidine, and 0.5 kg of 10% palladium carbon were sequentially added into a 100 L hydrogenation reactor. Nitrogen was replaced several times, hydrogen was replaced several times, and finally hydrogen was passed to the pressure of 1.8MPa in the kettle, the temperature was controlled at -10°C, and stirred for 2 hours. Stirring was stopped, hydrogen was discharged and replaced with nitrogen. Filter and recover the filter cake for reuse; add 160L of acetone to the filtrate, stir and crystallize at 0°C for 4h. After filtration and vacuum drying, 0.47 kg of off-white solid was obtained, the molar yield was 69.8%, the HPLC purity was 98.8%, and the heavy metal content was <10 ppm.

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Abstract

The invention relates to a preparation method of biapenem as shown in the formula 1. The method comprises the following steps of: using a biapenem intermediate I as a raw material, using a single solvent--water as a reaction solvent and conducting a hydrogenated deprotection reaction in the presence of alkali and a catalyst. The single solvent water is used as a reaction solvent, thus solving the problem of dissolving the catalyst by the reaction solvent, simplifying post-treatment operational step, reducing product degradation and raising product purity. In addition, the preparation method is economical, safe and environmentally friendly, and is more suitable for industrial operation at large scale.

Description

technical field [0001] The invention belongs to the field of carbapenem antibiotics, and in particular relates to an improved preparation method of biapenem. Background technique [0002] Carbapenem antibiotics are a class of broad-spectrum antibiotics developed in the 1970s. They have strong antibacterial activity and have good antibacterial effects on aerobic and anaerobic bacteria. They are stable to β-lactamase and are especially suitable for many A variety of bacteria, especially the mixed infection of aerobic bacteria and anaerobic bacteria, and it also has a killing effect on static bacteria. In addition, because this kind of drug has fewer adverse reactions, the application time is shorter, and the drug resistance has not been significantly strengthened, it is sometimes used as the last line of defense against bacteria and plays an important role in the treatment of severe hospital infections. [0003] Biapenem, the English name is "Biapenem", the chemical name is "...

Claims

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Application Information

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IPC IPC(8): C07D519/06
CPCY02P20/55
Inventor 史颖张雅然谢赞李薇吕健
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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