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Method for preparing biapenem

A biapenem and aprotic technology, which is applied in the field of synthesis of pharmaceutical compounds, can solve the problems of increasing the cost of recycling solvents, slowing down production progress, and being unfavorable for industrial scale production, so as to facilitate large-scale production, improve production capacity, easy separation effect

Active Publication Date: 2010-07-07
SICHUAN KELUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, a large amount of organic solvents also increases the cost of solvent recovery, slows down the production progress, and is not conducive to industrial scale production

Method used

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  • Method for preparing biapenem
  • Method for preparing biapenem
  • Method for preparing biapenem

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 6-[[(4R,5S,6S)-2-(4-nitrobenzyloxycarbonyl)-6-[(R)-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 Add 30g (57.5mmol) of azolium chloride salt, add 80ml of N,N-dimethylformamide, stir to dissolve, add 8g (5%) of platinum carbon, and control the hydrogen pressure at 8Kg / cm 2 , reacted at 30°C for 2.5h, added the reaction mixture to 700ml of water, filtered, added 2500ml of ethanol to the filtrate, stirred for 1h, filtered, washed the solid with 2×30ml of ethanol, dried under reduced pressure to obtain 15.3g of white solid of biapenem (43.7 mmol), yield 72.9%.

[0033] Elemental analysis: theoretical value C: 51.42; H: 5.18; N: 15.99

[0034] Test value C: 51.48; H: 5.27; N: 15.87

[0035] IR(KBr)cm -1 : 3345.2, 3124.2, 1750.7, 1601.0, 1563.5

[0036] 1 HNMR (D 2 O, internal standard TMS): δ1.23 (3H, d, J = 7.2Hz); 1.28 (3H, d, J = 6.4Hz); 3.36-3.40 (1H, m); 3.51 (1H, dd, J = 6.0Hz, 2.8Hz); 4.23-4.30(2...

Embodiment 2

[0038] 6-[[(4R,5S,6S)-2-(4-nitrobenzyloxycarbonyl)-6-[(R)-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 Add 30g (57.5mmol) of azolium chloride salt, add 110ml of N-methylpyrrolidone, stir to dissolve, add 3g of platinum dioxide, and control the hydrogen pressure to 4Kg / cm 2 , reacted at 35°C for 4h, added the reaction mixture to 800ml of water, filtered, added 1600ml of acetone to the filtrate, stirred for 1h, filtered, washed the solid with 2×30ml of acetone, dried under reduced pressure to obtain 16g (45.7mmol) of biapenem as a white solid , yield 76.2%.

Embodiment 3

[0040] 6-[[(4R,5S,6S)-2-(4-methoxybenzyloxycarbonyl)-6-[(R)-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] Triazolium chloride salt 30g (59.2mmol), add N,N-dimethylacetamide 90ml, stir to dissolve, add palladium carbon (5%) 8g, control hydrogen pressure 6Kg / cm 2 , react at room temperature for 3h, add the reaction mixture to 900ml of water, filter, add 2500ml of tert-butanol to the filtrate, stir for 1h, filter, wash the solid with 2×30ml of tert-butanol, and dry under reduced pressure to obtain 15.9g of white solid Biapenem (45.4 mmol), yield 75.7%.

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Abstract

The invention discloses a method for preparing biapenem, which is applicable to industrialization. The method comprises the following steps: performing a hydrogenation reaction on aprotic polar organic solvent serving as the solvent for a catalytic hydrogenation reaction and H2 in the presence of a catalyst; removing the protective group of a compound in a formula (II); and collecting the biapenem in reaction mixture. By using the method, the usage amount of reaction solvent is small, and the production capability of a pressure reaction still is greatly improved. Moreover, the reaction condition is mild; the operation is simple; and the biapenem can directly be precipitated from water and the organic solvent by using the solubility of the product without buffer, purification of ion exchange resin, concentration of mass aqueous solution or low temperature freezing crystallization, so that the separation and purification operation processes of the product are simplified, and the reaction yield is improved; and the obtained product has high purity, and the method is applicable to industrial and large-scale production.

Description

technical field [0001] The present invention relates to a synthesis method of a pharmaceutical compound, in particular to a preparation method of biapenem. Background technique [0002] Biapenem, chemical name 6-[[(4R,5S,6S)-2-carboxy-6-[(R)-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 inner salt is a 1β-methyl carbapenem antibiotic, which is widely used in acute and chronic infections caused by Gram-negative aerobic bacteria, Gram-positive aerobic bacteria and anaerobic bacteria. The activity of gram-negative bacteria is better than that of imipenem, and the activity of gram-positive bacteria is similar to that of imipenem. It has good curative effect on plastic surgery infection, gynecological infection and ear, nose and throat infection. countries listed. [0003] In the literature, the synthesis of biapenem is obtained by removing the protective group from the compound with general formula ...

Claims

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Application Information

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IPC IPC(8): C07D519/06C07D477/20A61P31/04
CPCY02P20/55
Inventor 张超罗美明祝华军李明验梁隆程志鹏
Owner SICHUAN KELUN PHARMA CO LTD
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