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Improved method for the crystallization of intermediates of carbapenem antibiotics

一种结晶析出、结晶的技术，应用在氮杂环丁酮化合物领域，能够解决过滤时间延长、品质差、结晶稳定性差等问题，达到提高操作性和稳定性、控制结晶粒径分布、过滤性良好的效果

Inactive Publication Date: 2009-05-13
KANEKA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] Like this, there is following problem in existing crystallization method: (1) quality can not satisfy requirement fully, (2) filterability when obtaining crystallization is poor, and when producing on industrial scale, filtration time prolongs, and productivity is low, and quality is poor, (3) Crystals obtained under severe conditions have poor stability and are problematic in long-term storage

Method used

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  • Improved method for the crystallization of intermediates of carbapenem antibiotics
  • Improved method for the crystallization of intermediates of carbapenem antibiotics
  • Improved method for the crystallization of intermediates of carbapenem antibiotics

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preparation example Construction

[0036] Regarding the preparation of seed crystals in the system of the present invention, it can be generated naturally, or can be carried out through concentration gradients, temperature gradients, external stimuli, and the like. As the preparation method in the system, it can be mentioned that by mixing the good solvent solution of the compound (1) and the hydrocarbon solvent, the method of precipitating the compound (1) can also be used. The method of precipitating the compound (1) from the hydrocarbon solvent may also be a method of precipitating the compound (1) by adding a good solvent solution of the compound (1) to the hydrocarbon solvent at one time, continuously or in portions. In addition, a method of precipitating the compound (1) may be performed by performing operations such as concentration, temperature rise, and cooling on a good solvent solution of the compound (1). In addition, these methods can also be combined.

[0037] When mixing with a hydrocarbon solve...

Embodiment

[0057] Hereinafter, the present invention will be further described by way of examples, comparative examples, and reference examples, but the present invention is not limited thereto.

reference example 1

[0059] Preparation of (4R,5R,6S)-1-aza-3-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxobicyclo- [3.2.0] Good solvent solution of p-nitrobenzyl hept-2-ene-2-carboxylate (1)

[0060]

[0061]Under nitrogen atmosphere, 21.6g (3S, 4R)-3-[(R)-1-hydroxyethyl]-4-[(R)-1-methyl-3-diazo-3- (p-Nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone in 500mL of dichloromethane solution, add 20mL of dichloromethane solution dissolved with 135mg rhodium octanoate, and react at 40°C 6 hours. Then, the reaction liquid was cooled to -15° C., and 16.4 g of diphenyl chlorophosphate (diphenyl chlorophosphate) was added at the same temperature. Then, 9.5 g of N,N-diisopropylethylamine and 140 mg of N,N-dimethyl-4-aminopyridine were dissolved in 110 mL of dichloropyridine dropwise over 30 minutes at -15°C. Methane solution, reacted for 30 minutes. Subsequently, while keeping the reaction liquid below 10° C., 216 mL of 0.3 N aqueous hydrochloric acid solution and 216 mL of 5% sodium...

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Abstract

The present invention relates to an azetidinone compound extremely useful as a common intermediate for the synthesis of 1beta-methylcarbapenem compounds. The present invention provides a crystallization method to obtain a crystal which has a higher quality and a higher stability than a conventional crystal and is excellent in filterability at the time of recovering crystal; an azetidinone compound having a low content of impurity; and an azetidinone compound which has a controlled particle size distribution of crystals and improved handleability and stability. The crystallization is carried out by adding a hydrocarbon solvent to a solution in which an azetidinone compound extremely useful as a common intermediate for the synthesis of 1beta-methylcarbapenem compounds is dissolved in the presence of a seed crystal in an amount of 200% by weight or less based on the weight of the azetidinone compound. According to the method, the crystal having a high quality and a high stability and excellent filterability at the time of recovering the crystal can be obtained.

Description

technical field [0001] The present invention relates to an improved crystallization method of an azetidinone compound, a high-purity azetidinone compound with less impurity content, and an azetidinone compound with controllable crystal particle size distribution and improved operability and stability , the azetidinone compound is extremely useful as a co-synthetic intermediate of the 1-β-methylcarbapenem compound. Background technique [0002] The 1-β-methylcarbapenem compound (1-methilcalvapenem) exhibits good antibacterial activity against a wide range of pathogenic bacteria, and is one of the most concerned antibacterial agents because of its stability in living organisms. Azetidinone compounds (Azetidinone) represented by the general formula (1) are known as useful intermediates for synthesizing the aforementioned 1-β-methylcarbapenem compounds (Patent Documents 1, 2, and 3). [0003] [0004] Regarding the compound represented by the above formula (1) (hereinafter r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/09C07D477/00
CPCC07D477/18C07F9/65611C07F9/09C07D477/00
Inventor 西野敬太古贺照义深江正文上田恭义
Owner KANEKA CORP
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