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A kind of recrystallization refining method of tipipenem ester

A technology of tipipenem pivoxil and a refining method, which is applied in the field of refining the raw material drug tipipenem pivoxil, can solve the problems of low recrystallization yield, slow crystallization, and long melting range of the product, and achieve recrystallization High yield, short crystallization time and short melting range

Inactive Publication Date: 2011-12-14
深圳万乐药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The experimental results of the researchers show that the crystallization is slow under this process condition, often lasting tens of hours to several days, the recrystallization yield is low, the test shows that it is about 50%, and there is a phenomenon that the melting range of the product is relatively long

Method used

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  • A kind of recrystallization refining method of tipipenem ester
  • A kind of recrystallization refining method of tipipenem ester
  • A kind of recrystallization refining method of tipipenem ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] The preparation of embodiment 1 formula (I) compound crude product

[0019] Add 70g of tipipenem tetrahydrate, 70g of TEBAC (triethylbenzyl ammonium chloride), 40g of diisopropylethylamine, and 250ml of DMF (dimethylformamide) into the 1000ml reaction bottle, stir to dissolve, Under the protection of nitrogen, 50ml of chloromethyl pivalate was added dropwise, and the temperature was kept at 45°C for 5 hours to react. After completion, the reaction solution was cooled to room temperature, 200 ml of ethyl acetate and 200 ml of water were added, the pH value was adjusted to 4.0±0.1 with 1N citric acid, the liquids were separated, the aqueous phase was washed three times with 200 ml of ethyl acetate, and the organic phase was discarded. The pH value of the aqueous phase was adjusted to 7.6 ± 0.1 with potassium carbonate solution. Extract three times with 200ml ethyl acetate, combine the organic layers, wash three times with 200ml saturated NaCl solution. The organic phase...

Embodiment 2

[0020] The recrystallization purification of embodiment 2 formula (I) compound crude product

[0021] The recrystallization method is as follows: dissolve 50 g of the crude product in acetone, add isopropyl ether dropwise, stir while adding dropwise, continue to stir and crystallize for a period of time after the dropwise addition, filter under reduced pressure to obtain a white solid, and vacuum drum the solid at 50°C Wind dry. The specific process conditions and test results are shown in the table below:

[0022] volume of acetone

volume of isopropyl ether

Crystallization temperature

Crystallization time

Rotating speed

yield

melting point

HPLC purity

50ml

50ml

0℃

5 hours

10rpm

75.3％

140～142℃

99.90％

100ml

200ml

20℃

2 hours

20rpm

82.8％

140～142℃

99.96％

100ml

300ml

20℃

0.5 hours

40rpm

76.6％

140～141℃

9...

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Abstract

The invention discloses a method for purifying tebipenem by recrystallizing. Acetone and isopropyl ether are adopted as recrystallizing solvents, the operation is simple, heating or cooling equipment is not required, crystallization is realized at room temperature, crystallization time is short, and recrystallization yield is high and over 75 percent, so that the method is suitable for industrialproduction, the recrystallized product has short melting range, high purity which is over 99.9 percent by virtue of HPLC (high performance liquid chromatography) detection, and can be used as a raw material medicament in accordance with requirements to prepare a medicinal preparation for safe administration of patients.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, and further relates to a method for refining the crude drug tipipenem pivoxil. Background technique [0002] Tipipenem pivoxate (I) is a novel oral carbapenem drug researched and developed by Wyeth Pharmaceuticals. The compound is a prodrug formed by the esterification of the C2 carboxylate of the active parent tipipenem. Tipipenem has a broad antibacterial spectrum, and it has a higher antibacterial effect than penicillin series on most clinically isolated strains (except for a small number of strains such as Enterococcus faecium (Enterococcus faecium) and Pseudomonas aeruginosa (Pseudomonas aeruginosa). Compared with other injectable carbapenem antibiotics, tipipenem also showed the same degree or stronger antibacterial effect. Especially for PRSP (penicillin-resistant Streptococcus pneumoniae), MRSP (erythromycin-resistant Streptococcus pneumoniae) and Haemophilus influenzae (Haemophilus i...

Claims

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Application Information

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IPC IPC(8): C07D477/20C07D477/02
Inventor 刘立力王先登李瑞远张广明
Owner 深圳万乐药业有限公司
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