Crystal form of 6, 7-dihydro-6-mercapto-5H-pyrazolo[1,2-alpha][1,2,4] triazoliumchloride and preparation method thereof

A chloride, 2-a technology, applied in organic chemistry and other directions, can solve the problems of high equipment requirements, complicated operation, long production cycle, etc., and achieve the effects of high crystal purity, simple operation and low cost

Active Publication Date: 2010-06-16
石药集团中诺药业(石家庄)有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The above-mentioned patents and documents mainly adopt column purification for the preparation of 6,7-dihydro-6-mercapto-5H-pyrazol[1,2-a][1,2,4]triazole ylide chloride, and the operation It is cumbersome,

Method used

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  • Crystal form of 6, 7-dihydro-6-mercapto-5H-pyrazolo[1,2-alpha][1,2,4] triazoliumchloride and preparation method thereof
  • Crystal form of 6, 7-dihydro-6-mercapto-5H-pyrazolo[1,2-alpha][1,2,4] triazoliumchloride and preparation method thereof
  • Crystal form of 6, 7-dihydro-6-mercapto-5H-pyrazolo[1,2-alpha][1,2,4] triazoliumchloride and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0038] Example 1

[0039] Dissolve 200 g of 6,7-dihydro-6-mercapto-5H-pyrazole[1,2-α][1,2,4]triazole ylide and 150 mL of methanol, and add 1500 mL of acetone under stirring. Cool in an ice-water bath, continue to stir until a large amount of solid precipitates, keep for 5h, filter with suction, and dry to obtain white crystals 165.1g, mp 124~126°C, HPLC purity 97.6%. The obtained crystals are analyzed by powder X-ray diffraction. The results are shown in the table. 1. The powder X-ray diffraction spectrum of the obtained crystal is attached figure 1 .

[0040] Table 1

[0041] d value

Example Embodiment

[0042] Example 2

[0043] Dissolve 200 g of crude 6,7-dihydro-6-mercapto-5H-pyrazole [1,2-α][1,2,4]triazole ylide chloride in 150 mL of methanol, and then add the isopropyl alcohol dropwise with stirring 900 mL of propanol, continue to stir until a large amount of solid precipitates, cool in an ice-water bath, keep for 5 hours, filter with suction, and dry to obtain 155.7 g of white crystals. mp 126~128℃, HPLC purity 98.0%, powder X-ray diffraction analysis of the obtained crystals, the results are shown in Table 2, and the obtained crystal powder X-ray diffraction spectrum is shown in the attached figure 2 .

[0044] Table 2

[0045] d value

[0046] d value

Example Embodiment

[0047] Example 3

[0048] Dissolve 200 g of 6,7-dihydro-6-mercapto-5H-pyrazole[1,2-α][1,2,4]triazole ylide chloride in 150 mL of methanol, and add ethyl acetate dropwise with stirring 250mL, 250mL of isopropyl ether, cooling in an ice-water bath, continue to stir until a large amount of solids precipitate, keep for 5h, suction filtration, and dry to obtain white crystals 162.4g, mp126~128℃, HPLC purity 98.2%, the obtained crystals are subjected to powder X-ray Diffraction analysis, the results are shown in Table 3, and the powder X-ray diffraction spectrum of the obtained crystal is shown in the attachment image 3 .

[0049] table 3

[0050] d value

[0051] d value

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Abstract

The invention relates to a crystal form of 6, 7-dihydro-6-mercapto-5H-pyrazolo [1,2-alpha][1,2,4] triazoliumchloride and a preparation method thereof. The 6, 7-dihydro-6-mercapto-5H-pyrazolo [1,2-alpha][1,2,4] triazoliumchloride is a key intermediate for synthesizing the carbapenem antibiotic biapenem. The crystal form of 6,7-dihydro-6-mercapto-5H-pyrazolo[1,2-alpha][1,2,4] triazoliumchloride is characterized in that the X-ray diffraction spectrum of powder of the crystal form is represented by an angle of 2theta, and has peaks at 27.487+/-0.2 and 26.707+/-0.2, the intensity of the peak is 100% when 2theta is 27.487+/-0.2, and the ratio of intensity of the peak I/I0 is no less than 60% when 2theta is 26.707+/-0.2. The 6, 7-dihydro-6-mercapto-5H-pyrazolo[1,2-alpha][1,2,4] triazoliumchloride is prepared by the recrystallization method which abandons the column chromatography and has high efficiency and low cost and is more suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a crystal form of 6,7-dihydro-6-mercapto-5H-pyrazol[1,2-a][1,2,4]triazole ylide chloride and its preparation method. Background technique [0002] 6,7-Dihydro-6-mercapto-5H-pyrazol[1,2-a][1,2,4]triazolium chloride is a key intermediate in the synthesis of biapenem, and its structural formula is as follows picture: [0003] [0004] The chemical name of biapenem is 6-[[(4R,5S,6S)-2-carboxy-6-((1R)-1-hydroxyethyl)-4-methyl-7-oxo-1-nitrogen Heterobicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-prarazolone[1,2-a][1,2,4]triaza- The 4-inner salt is a 1β-methyl carbapenem antibiotic, and its structural formula is as follows: [0005] [0006] Biapenem was developed by Lederle Corporation of Japan and Cyamide Corporation of the United States, and was jointly listed in Japan by Lederle Corporation of Japan and Meiji Corporation of Japan in March 2002. Biapenem i...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D477/20
Inventor 史颖谢振刚于秀芹李坤谢赞
Owner 石药集团中诺药业(石家庄)有限公司
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