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Preparation method for biapenem condensation compound and crystalline solid thereof

A technology for crystals and compounds, which is applied to the preparation of biapenem condensate and the field of crystals, can solve problems such as unfavorable cost saving, and achieve the effect of facilitating solid-liquid separation

Active Publication Date: 2010-06-23
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] The preparation method of the biapenem condensate described in the above-mentioned patents and literatures can only achieve the expected preparation effect after the purity of the compound of formula III and formula IV used as raw materials reaches a certain requirement (for example, the purity of the compound of formula IV needs to be >98%) , on another level, the preparation of raw materials has also increased the requirements (such as multiple refinements to meet the standards), which is unfavorable for cost saving in industrial production

Method used

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  • Preparation method for biapenem condensation compound and crystalline solid thereof
  • Preparation method for biapenem condensation compound and crystalline solid thereof
  • Preparation method for biapenem condensation compound and crystalline solid thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Preparation method of biapenem condensate crystals 1

[0040] 1 kg of 6,7-dihydro-6-mercapto-5H-pyrazol[1,2-α][1,2,4]triazole ylide and (4R,5S,6S)-3-diphenyl Oxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo「3.2.0」hept-2-ene-2-carboxy Add 2.5kg of p-nitrobenzyl acid to 12L of acetonitrile, then add 5L of ethanol, stir, cool down to about 0°C, add diisopropylethylamine dropwise, react at the same temperature for 2 to 5 hours, filter, wash, After drying, 1.95 kg of light yellow biapenem condensate crystals were obtained, with an HPLC purity of 98.7%. The obtained alpenem condensate crystals were analyzed by powder X-ray diffraction, the results are shown in the attached figure 1 ,Table 1.

[0041] Table 1

[0042] d value

[0043] The obtained biapenem condensate crystals were analyzed using KBr pellets to obtain infrared absorption spectra at 3415, 3147, 2964, 1763, 1695, 1605, 1552, 1518, 1442, 1403, 1384, 1343, 1322, 1289, 1221, 1178, ...

Embodiment 2～5

[0045] Preparation method of biapenem condensate crystals 2-5

[0046] Referring to the preparation method of Example 1, the lower alcohol solvent ethanol was changed to methanol, n-propanol, isopropanol, and tert-butanol to obtain pale yellow biapenem condensate crystals. The experimental results are shown in Table 2.

[0047] Table 2 embodiment 2~5 experimental result

[0048] Example number

[0049] Powder X-ray diffraction analysis and KBr tablet infrared analysis of the obtained crystals of the condensate of biapenem showed that the crystal form of the crystals of the obtained condensate of biapenem was consistent with the crystal form of the crystals obtained in Example 1.

Embodiment 6

[0051] Preparation of biapenem

[0052]Add 1.8 kg of biapenem condensate crystals obtained by the method of the present invention into 10 L of tetrahydrofuran, 30 L of 0.3 mol / L phosphate buffer (pH5.6), stir and dissolve, add 0.3 kg of 20% palladium carbon, and control the pressure at 10 kg / L. m 2 , react at 40°C for 30 min, filter, wash the aqueous phase with 20 L of ethyl acetate × 2, add 40 L of acetone, stir at room temperature for 2 h, filter, wash the solid with acetone, and dry under reduced pressure to obtain 920 g of biapenem, HPLC purity 98.2% .

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Abstract

The invention relates to a preparation method for a biapenem condensation compound shown in a formula II and a crystalline solid thereof. Impurities in reaction raw materials can be effectively removed by adding a lower alcohol solvent in a reaction system so as to obtain the crystalline solid of the biapenem condensation compound with high purity. Because particles of the obtained crystalline solid of the biapenem condensation compound are large, the crystalline solid is beneficial to solid-liquid separation and drying, and is more suitable for industrial production.

Description

technical field [0001] The present invention relates to the synthesis of biapenem intermediates, in particular to a 6-[[(4R,5S,6S)-2-(4-nitrobenzyloxycarbonyl)-6-[(1R)-1-hydroxy Ethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyrazole The preparation method of and[1,2-a][1,2,4]triazol-4-ium chloride and its crystal. Background technique [0002] 6-[[(4R,5S,6S)-2-(4-nitrobenzyloxycarbonyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1- Azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]tri Azol-4-ium chloride (hereinafter referred to as biapenem condensate) is an important intermediate for the synthesis of 1β-methylcarbapenem antibiotic biapenem, and its structural formula is as formula II: [0003] [0004] Biapenem was developed by Lederle Corporation of Japan and Cyamide Corporation of the United States, and was jointly launched in Japan by Lederle Corporation of Japan and Meiji Corporation of Japan in March 2002. Its s...

Claims

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Application Information

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IPC IPC(8): C07D519/06A61P31/04
Inventor 史颖谢振刚李坤孙晓旺贾长河
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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