Tebipenem crystal forms, their preparation method and application in preparation of medicines

A technology of terbipenem and crystal form, which is applied to the application field in the preparation of medicines, and can solve problems such as failure to obtain target products and the like

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

AI Technical Summary

Problems solved by technology

We operated according to the literature method, but failed to obtain the target product

Method used

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  • Tebipenem crystal forms, their preparation method and application in preparation of medicines
  • Tebipenem crystal forms, their preparation method and application in preparation of medicines
  • Tebipenem crystal forms, their preparation method and application in preparation of medicines

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0058] Preparation Example 1 Preparation of Crude Tybipenem

[0059] 20.0 L of deionized water, 1.0 Kg (2.01 mol) of tibipenem intermediate 3, 0.8 L (6.87 mol) of 2,6-lutidine, and 0.5 kg of 10% palladium on carbon were sequentially added into a 50 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 20°C, and stirred for 4.5h. Stirring was stopped, hydrogen was discharged and replaced with nitrogen. Filter and recover the filter cake for reuse; add 80 L of acetone to the filtrate, stir and crystallize at 0°C for 2 hours. Filtration and vacuum drying yielded 0.56 Kg of tibipenem off-white solid with a molar yield of 75.7%, an HPLC purity of 98.9%, and a heavy metal content of <10 ppm.

[0060]

preparation example 2

[0061] Preparation Example 2 Preparation of Crude Tybipenem

[0062] 16.0L of deionized water, 1.0Kg (2.01mol) of Tibipenem intermediate 3, 160mL of THF, 0.58L (5.02mol) of 2,6-lutidine, 0.4 Kg. 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 15°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 48L of acetone to the filtrate, stir and crystallize at 5°C for 3h. Filtration and vacuum drying yielded 0.60 Kg of an off-white solid with a molar yield of 81.1%, an HPLC purity of 98.6%, and a heavy metal content of <10 ppm.

Embodiment 1

[0063] Example 1 Preparation of Tybipenem Form I

[0064] The raw material of tibipenem sodium sterile powder was prepared by recrystallization test in a clean area. Dissolve 2 kg of the crude tibipenem prepared by the above method in 80 L of water for injection, then add 40 g of activated carbon, and stir for 10 min. After filtration, a light yellow clear liquid was obtained, and 160 L of acetone was added dropwise at 5°C, and stirred for 1 h. After filtration and vacuum drying, 1.81kg of white solid was obtained, the yield was 90.5%, the HPLC purity was 99.3%, and the heavy metal content was figure 1 shown.

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Abstract

The invention relates to two Tebipenem crystal forms, their preparation method and an application in the preparation of medicines. The Tebipenem crystal forms obtained in the invention has advantages of good stability, good color (white in color), high purity and low heavy metal residue, and is more suitable for storage and development as a bulk drug.

Description

technical field [0001] The invention belongs to the field of carbapenem antibiotics, and specifically relates to two tibipenem crystal forms I and II, a preparation method thereof and an application in preparation of medicines. 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. [...

Claims

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Application Information

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IPC IPC(8): C07D477/20C07D477/06A61K31/427A61K9/20A61K9/48A61K9/14A61P31/04
CPCC07D477/06C07D477/20A61P31/04
Inventor史颖张雅然底辉锋张志宝陈玉洁李园园白敏陈素锐
OwnerCSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD