A kind of crystal form of carbapenem antibacterial drug and preparation method thereof

A technology of antibacterial drugs and carbapenems, applied in the field of new crystal forms of drugs, can solve the problems of poor crystal form stability, complicated process, and high cost

Active Publication Date: 2015-11-25
SHANDONG FREDA PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] The purpose of the present invention is to overcome the technical problems of poor stability of the existing crystal form, high cost, complicated process and difficulty in industrial production, without the need for a special intermediate crystal form, and to provide a new type of doripenem crystal with excellent stability. In the new crystal form In the diffraction pattern of powder X-ray diffraction, there are characteristic absorption peaks at diffraction angles 2θ=15.20, 16.06, 16.83, 19.40, 21.29, 23.68, 24.08, 24.70, 26.28, 28.43, 29.17, 34.35

Method used

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  • A kind of crystal form of carbapenem antibacterial drug and preparation method thereof
  • A kind of crystal form of carbapenem antibacterial drug and preparation method thereof
  • A kind of crystal form of carbapenem antibacterial drug and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0043]Add 10g of doripenem into 200ml of 80% isopropanol aqueous solution, stir and cool down to 0-5°C, add 20% NaOH aqueous solution dropwise, adjust pH=10, dissolve the solid, filter with suction, adjust the filtrate with 10% dilute hydrochloric acid pH = 5, solids precipitated, stirred and crystallized at 0-5°C for 3-4 hours, filtered with suction, washed the filter cake with cold 80% isopropanol aqueous solution, dried under reduced pressure (gauge pressure not less than 0.095MPa) at 50°C for 24 hours, 8.5 g of the new crystal form of doripenem was obtained.

[0044] The powder X-ray diffraction spectrum of gained crystal sees figure 1 , where there are main peaks at diffraction angles 2θ=15.19, 16.05, 16.84, 19.35, 21.23, 24.08, 26.27, 28.42, 29.14, 34.34.

Embodiment 2

[0046] Add 10g of doripenem to 100ml of 80% ethanol aqueous solution, stir to cool down to 0-5°C, add dropwise 20% KOH aqueous solution, adjust pH=9, dissolve solid, filter with suction, and adjust the filtrate to pH=9 with 10% dilute sulfuric acid 5. Solid precipitation, stirring and crystallizing at 0-5°C for 3-4h, suction filtration, washing the filter cake with cold 80% ethanol aqueous solution, drying under reduced pressure (gauge pressure not less than 0.095MPa) at 50°C for 24h to obtain a new crystal form Dolipenem 7.9g.

[0047] The powder X-ray diffraction spectrum of gained crystal sees figure 2 , where there are main peaks at diffraction angles 2θ=15.19, 16.05, 16.84, 19.31, 21.26, 24.07, 26.27, 28.42, 29.14, 34.34.

Embodiment 3

[0049] Add 10g of doripenem into 150ml of 80% acetone aqueous solution, stir to cool down to 0-5°C, add dropwise 20% sodium carbonate aqueous solution, adjust pH=10, dissolve solid, suction filter, and adjust pH of filtrate with 10% dilute hydrochloric acid =4.5, solid precipitated, stirred and crystallized at 0-5°C for 3-4h, filtered with suction, washed the filter cake with cold 80% acetone aqueous solution, dried under reduced pressure (gauge pressure not less than 0.095MPa) at 50°C for 24h, and obtained new crystals Type doripenem 8.2g.

[0050] There are main peaks at diffraction angles 2θ=15.20, 16.05, 16.84, 19.41, 21.30, 23.69, 24.07, 24.69, 26.26, 28.40, 29.21, 34.38 of the obtained crystals.

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Abstract

The invention provides a novel crystal form of a carbapenem antimicrobial medicament, namely, (+)-(4R,5S,6S)-3-[[(3S,5S)-5-(aminosulfonyl)aminomethyl]-3-pyrrolidine]sulfur]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic[3,2,0]heptyl-2-ene-2-carboxylic acid-hydrate (doripenem). The X-ray powder diffraction pattern of the crystal powder shows main peaks when 2theta is equal to 15.20 degrees, 16.06 degrees, 16.83 degrees, 19.40 degrees, 21.29 degrees, 23.68 degrees, 24.08 degrees, 24.70 degrees, 26.28 degrees, 28.43 degrees, 29.17 degrees and 34.35 degrees. The novel crystal form has the advantages of easiness in preparation and industrial production, low cost, high solubility and high stability.

Description

technical field [0001] The invention relates to a new crystal form of a drug, in particular to a carbapenem antibacterial drug (+)-(4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)amino ]methyl]-3-pyrrolidine]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]heptyl- New crystalline form of 2-ene-2-carboxylic acid monohydrate (doripenem) and process for its preparation. Background technique [0002] Doripenem (S-4661) is a broad-spectrum carbapenem antibiotic developed by Shionogi Company in Japan. -1 stability and other advantages. Its chemical name is (+)-(4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)amino]methyl]-3-pyrrolidine]sulfur]-6 -[(1R)-1-Hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid monohydrate, the structural formula is as follows Formula (I) shown. [0003] [0004] Chinese patents CN200510021270.1 and CN92111069.3 describe the preparation of its amorphous powder. Due to the relatively poor stability of the amorphous pow...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D477/20C07D477/02
CPCC07D477/02C07D477/20
Inventor 郑德强刘文涛毋立华王长斌孙利民索栋李帅任文杰郭新艳张玲凌沛学
Owner SHANDONG FREDA PHARMA GRP CO LTD
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