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Crystal ertapenem intermediate as well as preparation method and application thereof

A crystallization and crystallization technology, applied in the field of ertapenem intermediates and its preparation, to achieve the effects of improved purity, good separability, and shortened filtration time

Inactive Publication Date: 2012-10-17
ZHEJIANG HISOAR CHUANNAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] It can be seen that the prior art literature only discloses the application of the solution of the compound of formula I to prepare ertapenem sodium, or the obtained solid of the compound of formula I is amorphous
However, there is no report about the compound of formula I in crystal form

Method used

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  • Crystal ertapenem intermediate as well as preparation method and application thereof
  • Crystal ertapenem intermediate as well as preparation method and application thereof
  • Crystal ertapenem intermediate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Embodiment 1: the preparation of formula I compound crystal

[0088] (1R,5R,6S)-6-[(1R)-1-Glycolic acid]-2-[(Diphenoxyphosphoryl)oxy]-1-methylcarbapenicill-2-ene-3 - p-nitrobenzyl formate (carbapenem nucleus, compound of formula III) (36.0g, 0.0605mol) was dissolved in 300ml DMF, and the side chain of ertapenem (compound of formula IV) (26.7g, 0.0599 mol) diisopropylamine (DIPA, 9.4 g, 0.0727 mol) was added dropwise at -35°C and stirred for reaction. After the reaction is completed, add it to aqueous hydrochloric acid solution (pH=4), and filter to obtain an amorphous white or off-white solid. Then add the solid to 320ml of ethyl acetate, stir and dissolve at 0°C, wash twice with 80ml of 5% (w / w) potassium dihydrogen phosphate aqueous solution each time, separate the organic phase, and then wash it with 10g of anhydrous sodium sulfate Dry, filter with suction, and stir the filtrate (solution concentration about 0.15g / ml) at 0°C (stirring speed 80 rpm) for 5h. The p...

Embodiment 2

[0093] Embodiment 2: the preparation of formula I compound crystal

[0094] (1R,5R,6S)-6-[(1R)-1-Glycolic acid]-2-[(Diphenoxyphosphoryl)oxy]-1-methylcarbapenicill-2-ene-3 - p-nitrobenzyl formate (compound of formula III) (36.0g, 0.0605mol) was dissolved in 300ml DMF, and the side chain of ertapenem (compound of formula IV) (26.7g, 0.0599mol) was added at -35°C Diisopropylamine (9.4 g, 0.0727 mol) was added dropwise and the reaction was stirred. After the reaction is completed, add it to aqueous hydrochloric acid solution (pH=4), and filter to obtain an amorphous white or off-white solid. Then add the solid to 365ml of ethyl acetate, stir and dissolve at 5°C, wash twice with 80ml of 5% (w / w) potassium dihydrogen phosphate aqueous solution each time, separate the organic phase, and then dry it with 10g of anhydrous sodium sulfate , filtered with suction, and the filtrate (solution concentration about 0.13 g / ml) was added with 0.5 g of the crystalline compound obtained in Exa...

Embodiment 3

[0099] Embodiment 3: the preparation of formula I compound crystal

[0100](1R,5R,6S)-6-[(1R)-1-Glycolic acid]-2-[(Diphenoxyphosphoryl)oxy]-1-methylcarbapenicill-2-ene-3 - p-nitrobenzyl formate (compound of formula III) (36.0g, 0.0605mol) was dissolved in 300ml DMF, and the side chain of ertapenem (compound of formula IV) (26.7g, 0.0599mol) was added at -35°C Diisopropylamine (9.4 g, 0.0727 mol) was added dropwise and the reaction was stirred. After the reaction is completed, add it to aqueous hydrochloric acid solution (pH=4), and filter to obtain an amorphous white or off-white solid. Then add the solid to 320ml of isopropyl acetate and stir to dissolve at 10°C, wash twice with 80ml of 5% (w / w) potassium dihydrogen phosphate aqueous solution each time, separate the organic phase, and dry it with 10g of anhydrous sodium sulfate , suction filtration, and the filtrate (solution concentration about 0.15g / ml) was stirred at -10°C (stirring speed 100 rpm) for 3h. The product ...

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Abstract

The invention relates to an ertapenem intermediate crystal, as well as a preparation method and the application of the ertapenem intermediate crystal. The crystal has the characteristic values shown by diffraction angle of 2theta at the parts of 5.10+ / -0.20 degrees, 8.99+ / -0.20 degrees, 10.31+ / -0.20 degrees, 15.22+ / -0.20 degrees, 17.09+ / -0.20 degrees and 22.66+ / -0.20 degrees in X-ray powder diffraction pattern. The crystal compound shown in formula I is easy to separate, has good purity and stability and is suitable for industrial production and control.

Description

technical field [0001] The present invention relates to the technical field of medicinal chemical crystallization, in particular to a crystal form of an ertapenem intermediate represented by formula I and its preparation method and application. Background technique [0002] Ertapenem sodium (Ertapenem sodium), the structural formula is as formula II, the chemical name is (4R,5S,6S)-3-[[(3S,5S)-5-[[(3-carboxyphenyl)amino]acyl ]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene- 2-Carboxylic acid sodium salt, a new type of broad-spectrum carbapenem antibiotic developed by Merck Pharmaceutical Company of the United States, including Gram-positive and negative aerobic bacteria and anaerobic bacteria, has good antibacterial activity against most penicillinases , cephalosporinase and extended-spectrum β-lactamases are stable. [0003] [0004] The compound shown in formula I is the key intermediate for the preparation of ertapenem sodiu...

Claims

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Application Information

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IPC IPC(8): C07D477/20
Inventor 陈少亭唐鹤夏晓益艾秋香陈明龙李洪明
Owner ZHEJIANG HISOAR CHUANNAN PHARMA
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