Tebipenem pivoxil crystal and preparation method thereof

A technology of tipipenem and pivoxil, which is applied in the field of drug synthesis, can solve the problems of unstable amorphous products and difficulty in meeting medicinal requirements for crystalline products

Inactive Publication Date: 2014-03-26
高瑞耀业(北京)科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, there is no clear report in the literature on the crystal form of tipipenem pivoxil, and the amorphous product prepared is usually very unstable, and the crystalline product prepared according to the current literature is difficult to meet the medicinal requirements , especially for the detection of residual solvents, it is impossible to obtain products that are qualified for residual solvents and other indicators are also qualified by drying

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Add 10g of amorphous tipipenem pivoxil into 20ml of absolute ethanol solution, heat to 40°C, stir until completely dissolved, then cool the reaction system to 5-15°C, stir and crystallize, and crystals precipitate , continue to keep warm and stir to crystallize for 3h, filter, and dry the filter cake at 40-45°C for 8h under reduced pressure to obtain 7.6g of tebipenem pivoxate crystalline sample, yield 76.0%, HPLC 99.7%, melting point 134.1-134.8°C .

Embodiment 2

[0044] Add 10g of amorphous tipipenem pivoxil into a mixture of 30ml of absolute ethanol and 10ml of n-hexane, heat to 40°C, stir to dissolve, then cool down to 10-15°C, stir to crystallize, and crystals precipitate out Afterwards, continue to keep warm and stir to crystallize for 3 hours, filter, and dry the filter cake under reduced pressure at 40-45°C for 8 hours to obtain 7.9 g of tebipenem pivoxate crystalline samples, with a yield of 79.0%, HPLC of 99.5%, and a melting point of 133.6-134.1°C .

Embodiment 3

[0046] Add 10g of amorphous tipipenem pivoxil into 30ml of ethyl acetate, stir at 20°C to completely dissolve, then cool down to 10-15°C, stir and crystallize, after crystals are precipitated, continue to stir and crystallize for 3h, filter , and the filter cake was dried under reduced pressure at 40-45° C. for 8 hours to obtain 8.3 g of a crystalline sample of tebipenem pivate, with a yield of 83.0%, HPLC of 99.8%, and a melting point of 134.3-134.8° C.

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Abstract

The invention relates to a tebipenem pivoxil crystal shown by a formula (I) and a preparation method thereof. The invention provides a high-purity tebipenem pivoxil crystal shown by the formula (I) and a preparation method thereof. The preparation method comprises the steps of dissolving (+)-(4R,5S,6S)-6-[(1R)-1-ethoxyl]-4-methyl-7-oxo-3-[[1-(2-thiazoline-2-yl)-3-azetidinyl]sulfo]-1-azabicyclo[3.2.0]-hepta-2-alkene-2-carboxylic acid-2-methyl trimethylacetate (tebipenem pivoxil) in a single or mixed solvent of ethanol, acetonitrile, acetic ether, acetone and n-hexane at a specified temperature, and performing recrystallization and drying to prepare the high-purity tebipenem pivoxil crystal. The high-purity tebipenem pivoxil crystal is stable in crystal form, all indexes of the crystal meet requirements, and the crystal is convenient to produce and store.

Description

field of invention [0001] The invention relates to the field of drug synthesis, and relates to a (+)-(4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[ 1-(2-Thiazolin-2-yl)-3-azetidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid-2-pentapentyl A method for the preparation of crystalline acid methyl ester (tipenem pivate). Background of the invention [0002] Tebipenem Pivoxil (Tebipenem Pivoxil) was first developed by Pfizer of the United States. Tebipenem Pivoxil Fine Granules was developed by Japan Meiji Company. It was approved by Japan in February 2009 and launched in April 2009. , mainly for the treatment of ENT and upper respiratory tract infections in pediatric patients. Tipipenem pivoxate is the prodrug of tipipenem. After oral administration, it is hydrolyzed by esterase to release the parent drug tipipenem, which binds to the bacterial penicillin-binding protein (PBP) and inhibits the synthesis of bacterial cell walls. The only carbapenem antibio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/02
CPCC07D477/20C07D477/02
Inventor 张晟源
Owner 高瑞耀业(北京)科技有限公司
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