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Preparation method of high-purity biapenem

A biapenem, high-purity technology, applied in the field of preparation of pharmaceutical compounds, can solve the problems of reduced purity, difficult separation, difficult recovery, etc., and achieve the effects of reducing the generation of impurities, small reaction volume, and high production efficiency

Inactive Publication Date: 2015-08-12
JIANGSU TASLY DIYI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the price of the aprotic capital punishment organic solvent is relatively high, and it is difficult to separate after being miscible with water, and it is not easy to recycle; no buffer or acid-binding agent is used, and the hydrogen ions generated during the reaction process cannot be neutralized, so that the reaction mixture is soluble in water. Afterwards, it is acidic, but Biapenem has poor stability in acidic solution (Journal of Pharmaceutical and Biomedical Analysis49(2009) 937–944), it is easy to open the ring, produce dimers, increase impurities, and reduce purity. Only reach more than 98%

Method used

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  • Preparation method of high-purity biapenem

Examples

Experimental program
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Effect test

Embodiment 1

[0043] 6-[[(4R,5S,6S)-2-[(4-nitrobenzyloxy)carbonyl]-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 Preparation of azol-4-ium chloride (compound of formula VII)

[0044] (4R,5R,6S)-3-(Diphenoxyphosphonooxy)-6-((R)-1-hydroxyethyl)-4-methyl-7-carbonyl-1-azabicyclo [3.2.0] p-nitrobenzyl hept-2-ene-2-carboxylate (compound of formula V) 50.0g, 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a Add 18.6g of [1,2,4]triazol-4-ium chloride (compound of formula VI), 23.7g of N,N-dimethylformamide and 11.7g of triethylamine into 400g of acetonitrile, stir and blow nitrogen Protected, stirred at -10 to -15°C for 10 hours, filtered, and dried to give 6-[[(4R,5S,6S)-2-[(4-nitrobenzyloxy)carbonyl]-6-[(1R)- 1-Hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyridine Azolo[1,2-a][1,2,4]triazol-4-ium chloride (compound of formula VII) 36.7g, yield 83.7%, purity 98.6%.

Embodiment 2

[0046] 6-[[(4R,5S,6S)-2-[(4-nitrobenzyloxy)carbonyl]-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 Preparation of azol-4-ium chloride (compound of formula VII)

[0047] (4R,5R,6S)-3-(Diphenoxyphosphonooxy)-6-((R)-1-hydroxyethyl)-4-methyl-7-carbonyl-1-azabicyclo [3.2.0] p-nitrobenzyl hept-2-ene-2-carboxylate (compound of formula V) 50.0g, 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a ][1,2,4]Triazol-4-ium chloride (compound of formula VI) 19.2g, N,N-dimethylformamide 23.7g and triethylamine 11.7g were added to 400g of acetonitrile, stirred, nitrogen gas Protected, stirred at -10 to -15°C for 10 hours, filtered, and dried to give 6-[[(4R,5S,6S)-2-[(4-nitrobenzyloxy)carbonyl]-6-[(1R)- 1-Hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyridine Azolo[1,2-a][1,2,4]triazol-4-ium chloride (compound of formula VII) 39.1g, yield 89.1%, purity 99.0%.

Embodiment 3

[0049] 6-[[(4R,5S,6S)-2-[(4-nitrobenzyloxy)carbonyl]-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 Preparation of azol-4-ium chloride (compound of formula VII)

[0050] (4R,5R,6S)-3-(Diphenoxyphosphonooxy)-6-((R)-1-hydroxyethyl)-4-methyl-7-carbonyl-1-azabicyclo [3.2.0] p-nitrobenzyl hept-2-ene-2-carboxylate (compound of formula V) 400.0g, 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a Add 154.8g of [1,2,4]triazol-4-ium chloride (compound of formula VI), 129.6g of N,N-dimethylformamide and 93.6g of triethylamine into 3200g of acetonitrile, stir, and blow nitrogen Protected, stirred at -10 to -15°C for 8 hours, filtered, and dried to obtain 6-[[(4R,5S,6S)-2-[(4-nitrobenzyloxy)carbonyl]-6-[(1R)- 1-Hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyridine Azolo[1,2-a][1,2,4]triazol-4-ium chloride (compound of formula VII) 320.3g, yield 91.2%, purity 98.9%.

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Abstract

The invention relates to a preparation method of high-purity biapenem, which includes the steps of: (A) carrying out a condensation reaction with a compound represented as the formula V and a compound represented as the formula VI in an acetonitrile solvent in the presence of a less amount of N,N-dimethylformamide and an organic alkali to obtain a compound represented as the formula VII; (B) carrying out a catalytic hydrogenation to the reaction product in the step (A) in a mixed solution composed of an alcohol solvent and a non-proton polarity organic solvent in the presence of a catalyst and an organic alkali to remove a carboxylic acid protective group in the compound represented as the formula VII; and (C) filtering a reaction mixed solution to obtain a filter cake, adding the filter cake in water with stirring to obtain a filtrate, mixing the filtrates, adding an organic solvent under stirring, performing precipitation crystallization, and filtering and drying a product to obtain the biapenem.

Description

Technical field: [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to a preparation method of high-purity biapenem. Background technique: [0002] Biapenem, chemical name 6-[[(4R,5S,6S)-2-carboxy-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]triazole- 4-onium internal salt is a 1β-methyl carbapenem antibiotic with a broad antibacterial spectrum. It is more stable to renal dehydropeptidase DHP-I than meropenem, and does not need to be combined with DHP-I inhibitors or renal urine cell inhibition It is widely used clinically in acute and chronic infections caused by Gram-negative aerobic bacteria, Gram-positive aerobic bacteria and anaerobic bacteria. Its activity is similar to that of alipenem, and it has good curative effect on plastic surgery infection, gynecological infection and ear, nose and throat infection, and has been listed in many countries around...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/06
CPCY02P20/55C07D519/06
Inventor 徐学宇孟巍郁达熹王国成
Owner JIANGSU TASLY DIYI PHARMA CO LTD
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