Preparation method of biapenem

A technology of biapenem and organic solvent, applied in the field of preparation of biapenem, can solve the problems of complex equipment, low production efficiency, water removal, etc., to improve the crystallization yield and purity, reduce equipment investment, and reduce water effect of dosage

Active Publication Date: 2013-06-19
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The shortcoming of above-mentioned three kinds of existing methods is: in order to avoid the reaction product biapenem being destroyed in the environment with strong acidity, all can add buffer salt during reaction to control the pH of reaction solution, but the existence of this buffer salt makes reaction obtained The solution containing biapenem cannot crystallize, therefore, the buffer salt must be removed by resin purification after the reaction; and a large amount of water is required for elution
[0017] Since biapenem is a heat-sensitive substance, it is unstable in water, and biapenem will be cracked when heated in water, so it is impossible to remove water by long-term heating and distillation, and only freeze-drying can be used
However, freeze-drying has disadvantages such as large investment, complex equipment, low drying rate, long time, high energy consumption, and high maintenance costs, which makes the product cost high, increases the industrial investment cost, and makes the production efficiency low.
[0018] In addition, biapenem has poor water solubility, and a large amount of water is required for recrystallization, resulting in a large amount of water used for crystallization, large crystallization loss, and low yield

Method used

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  • Preparation method of biapenem

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] 6-[(4R, 5S, 6S)-2-(4-nitrobenzyloxycarbonyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-nitrogen Heterobicyclo[3,2,0]hept-2-en-3-yl]thio-6,7-dihydro-5H-pyrazolo[1,2-α][1,2,4]tri Azol-4-ium chloride (I, R=O 2 NPhCH 2 ) 300g (0.58mol), add into 1.5L of water and 1.0L of tetrahydrofuran, stir to dissolve, add 70g of palladium carbon (10%), control hydrogenation pressure 4~5Kg / cm 2 , react at 10-20°C for 2.5 hours; filter off palladium-carbon immediately after the reaction, adjust the pH to 3.0-6.0 with 4-dimethylaminopyridine, separate the liquids, add 4.0L of acetone to the water phase, and stir at 10-20°C for 3.0 hours. Crystals were precipitated, filtered, the solid was washed with 300 ml of acetone, and dried under reduced pressure to obtain 180 g of biapenem (yield: 90%).

Embodiment 2

[0051] 6-[(4R, 5S, 6S)-2-(4-nitrobenzyloxycarbonyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-nitrogen Heterobicyclo[3,2,0]hept-2-en-3-yl]thio-6,7-dihydro-5H-pyrazolo[1,2-α][1,2,4]tri Azol-4-ium chloride (I, R=O 2 NPhCH 2 ) 600g (1.16mol), was added into 3.0L of water and 2.0L of tetrahydrofuran, stirred and dissolved, and 120g of palladium hydroxide (10%) was added, and the hydrogenation pressure was controlled at 10-15Kg / cm 2 , react at 10-15°C for 1.0 hour; after the reaction, use N-methylmorpholine to adjust the pH to 3.0-6.0, filter off the palladium hydroxide, separate the liquids, add 8.0L ethanol to the water phase, stir at 0-5°C for 0.5 hours, Crystals were precipitated, filtered, the solid was washed with 600 ml of ethanol, and dried under reduced pressure to obtain 364 g of biapenem (yield: 91.0%).

Embodiment 3

[0053] 6-[(4R, 5S, 6S)-2-(4-nitrobenzyloxycarbonyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-nitrogen Heterobicyclo[3,2,0]hept-2-en-3-yl]thio-6,7-dihydro-5H-pyrazolo[1,2-α][1,2,4]tri Azol-4-ium chloride (I, R=O 2 NPhCH 2 ) 600g (1.16mol), was added to 3.0L of water and 2.0L of tetrahydrofuran, stirred and dissolved, and 200g of platinum carbon (5%) was added, and the hydrogenation pressure was controlled to 20Kg / cm 2 , react at 25-30°C for 0.5 hours; filter the platinum carbon within 10 minutes after the end of the reaction, adjust the pH to 4.0-6.0 with N-methylpiperidine, separate the liquid, add 8.0L ethanol to the water phase, stir at 5-10°C for 2.0 After hours, crystals were precipitated, filtered, the solid was washed with 600 ml of ethanol, and dried under reduced pressure to obtain 360 g of biapenem (yield: 90%).

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Abstract

The invention discloses a preparation method of biapenem. The method comprises the following steps of: undergoing a catalytic hydrogenation reaction on a compound which is shown as a formula I and serves as a raw material and H2 in a mixed solvent of water and an organic solvent; adding an organic base immediately for regulating the pH value after the reaction; adding an organic solvent for precipitating biapenem crystals; and recrystallizing the crystals in water, organic acid and ethanol or ketone to obtain a refined biapenem product. The preparation method has the advantages of easiness for operating, no need of adjusting the pH value with a buffer salt during hydrogenation, no need of resin purification after hydrogenation, no need of special equipment, greatly-lowered water consumption, high yield and high product purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of biapenem. Background technique [0002] Carbapenem antibiotics are a new class of atypical β-lactam broad-spectrum antibiotics discovered in the 1970s and developed in the 1990s. Carbapenems have good permeability to the outer membrane of Gram-negative bacteria, and can also moderately penetrate the mucous peptide layer of the cell wall of Gram-positive bacteria. They are broad-spectrum antibacterial drugs. Carbapenem antibiotics can combine with PBP-2 and PBP-3 of Gram-negative bacteria, or combine with PBP-1 and PBP-2 of Gram-positive bacteria to show strong bactericidal activity. Carbapenem antibiotics are stable to most β-lactamases, and are also stable to extended-spectrum β-lactamases (ESBLs), and the β-lactam ring in the molecule is not easily hydrolyzed and inactivated by β-lactamases. [0003] The first marketed carbapenem antibiotic was imipenem from Merck, which was used clinically in 1985. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D519/06
CPCY02P20/55
Inventor 刘相奎袁哲东朱雪焱杨玉雷沈裕辉俞雄
Owner SHANGHAI INST OF PHARMA IND CO LTD
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