Crystal of intermediate of tebipenem pivoxil and preparation method thereof

A technology for tipipenem and intermediates, applied in the field of crystallization and preparation of pharmaceutical intermediates, can solve the problems of low purity and unfavorable industrialization, and achieve the effects of high purity, good stability and easy crystallization

Active Publication Date: 2014-03-26
SHANDONG MINGREN FURUIDA PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved by the present invention is to provide a kind of crystallization of the intermediate compound (I) of tipipenem pivoxil in order to overcome the defect that the existing tipipenem pivoxil intermediate compound (I) is not high in purity and unfavorable for industrialization. and its preparation method, the crystal of the present invention is easy to store, easy to operate, good in stability and high in purity; and its preparation method is simple and reliable, cost-saving, simple in separation, and suitable for industrial implementation

Method used

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  • Crystal of intermediate of tebipenem pivoxil and preparation method thereof
  • Crystal of intermediate of tebipenem pivoxil and preparation method thereof
  • Crystal of intermediate of tebipenem pivoxil and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 105 g of 1-(4,5-dihydro-2-thiazolyl)azetidine-3-thiol hydrochloride, [4R-[4a, 5b, 6b(R*)]]-3-di Phenylphosphoryloxy-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitro Benzyl ester (MAP) 297g was mixed in 1700ml of acetonitrile, cooled and stirred, DIEA was added dropwise at -10°C, the drop was completed, and the reaction was kept for 2h. The reaction endpoint was monitored by HPLC. Add 1000ml of water and stir for 0.5h. Suction filtration, washing with 500 ml of acetonitrile-water, and vacuum drying at 50° C. for 2 h gave 258 g of light yellow solid crystals with a yield of 99.1%. That is the A crystal form.

[0032] The obtained crystals were analyzed by X-ray diffraction test, and the test conditions were as follows: Bruker D8 ADVANCE instrument was used to measure, CuKa40Kv40mA was used as light source, step size was 0.02°, scanning speed: 8° / min, scanning range: 3°~80°, room temperature. Powder X-ray diffraction analysis re...

Embodiment 2

[0036] The solid (50g) obtained in Example 1 was added to 500ml of ethanol, heated to reflux for 30min, cooled to room temperature, stirred at -5 to 5°C for 2h, filtered with suction, washed with 50ml of cold ethanol, and dried under reduced pressure at 45°C to obtain a The white solid was 46 g, the yield was 92%, and the HPLC purity was 99.98%, which was crystal form B.

[0037] The obtained crystals were tested and analyzed by X-ray diffraction. The test conditions were as follows: Bruker D8 ADVANCE instrument was used to measure, with CuKa 40Kv40mA as the light source, step size 0.02°, scanning speed: 8° / min, scanning range: 3°~80°, room temperature . Powder X-ray diffraction analysis results are shown in Table 2 and attached figure 2 .

[0038] Table 2 Powder X-ray Diffraction Data of Type B Crystal

[0039]

[0040]

Embodiment 3

[0042] The solid (20 g) obtained in Example 1 was added to 200 ml of methanol, heated to reflux for 30 min, cooled to room temperature, stirred at -10 to 0 °C for 2 h, filtered with suction, washed with 10 ml of cold methanol, and dried under reduced pressure at 45 °C to obtain a The white solid was 15.2 g, the yield was 76%, and the HPLC purity was 99.94%, which was crystal form B.

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Abstract

The invention relates to a crystal of an intermediate of carbapenem antibiotic tebipenem pivoxil and a preparation method thereof. The crystal type of the intermediate comprises a type A crystal of the intermediate of tebipenem pivoxil and a type B crystal of the intermediate of tebipenem pivoxil, wherein in a powder X-ray diffraction pattern, the type A crystal has main peaks when the diffraction angle 2(theta) is 5.90, 8.02, 14.93, 19.30, 22.65, 22.10, 24.16, 26.50 and 26.98; the type B crystal has main peaks when the diffraction angle 2(theta) is 6.76, 8.25, 15.13, 16.35, 17.47, 21.02, 22.31, 31.31 and 32.77. The preparation method of the crystal form mainly comprises a preparation method of the type A crystal of the intermediate and a method for preparing the type B crystal through crystal transformation of the type A crystal.

Description

technical field [0001] The invention relates to a crystallization of a pharmaceutical intermediate and a preparation method thereof, in particular to a crystallization of an intermediate of tipipenem axetil and a preparation method thereof. Background technique [0002] Tipipenem pivoxate (L-084) is the first new oral carbapenem drug developed by Japan Meiji Seika Company. The compound is the active parent tipipenem C 2 It is a prodrug formed by esterification of a carboxylic acid, and after oral administration, it is hydrolyzed by esterase to release the active parent drug tipipenem. Tipipenem has a broad antibacterial spectrum. Penicillin series and cephalosporin series have stronger antibacterial properties, and compared with other injectable carbapenem antibiotics, tipipenem also shows different or stronger antibacterial effects. Especially for PRSP (penicillin-resistant Streptococcus pneumoniae), MRSP (erythromycin-resistant Streptococcus pneumoniae) and Haemophilus i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/02
CPCC07D477/02C07D477/20
Inventor 郑德强毋立华王长斌刘文涛孙利民张玲索栋李帅任文杰郭新艳凌沛学
Owner SHANDONG MINGREN FURUIDA PHARMA
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