Preparation method of biapenem

A technology of biapenem and triphenylphosphine, applied in the field of preparation of biapenem, can solve the problems of danger, inconvenience in production, easy occurrence of danger and the like, and achieve the effects of improving safety, simple operation and mild reaction conditions

Active Publication Date: 2014-10-01
SHANGHAI NEW ASIA PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The above-mentioned first and second methods all need to use hydrogen, and remove the protective group after pressurization. In actual production, the use of hydrogen for catalytic hydrogenation requires special eq

Method used

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  • Preparation method of biapenem
  • Preparation method of biapenem

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Add 150 g of 1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazole-[l,2-α][1,2,4]triazole ylide chloride to the reaction flask -6 base) sulfur]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapenem-2-ene-3-carboxylic acid allyl ester (formula III compound), add 500ml tetrahydrofuran, Add 3.0 g of triphenylphosphine and 2.8 g of tetrakis(triphenylphosphine) palladium, stir at room temperature for 2 hours, add water to dilute, wash with dichloroethane, and concentrate under reduced pressure to obtain an aqueous solution. Then adjust the solution to Ph=5.5 with O.1N HCl, then add acetone, stir and crystallize at 10°C for 2 hours, and filter to obtain 52 g of off-white powder biapenem, with a yield of 65%.

[0028] Colorless crystal, melting point 210~218°C (decomposition).

[0029] 1 HNMR (D 2 0,300MHz)d; 1.26(d,3H,J=7.3Hz),1.30(d,3H,J=6.6Hz),

[0030] 3.41 (dq, 1H, J=7.3, 9.6Hz), 3.53 (dd, 1H, J=3.0, 5.9Hz), 4.27 (dq, 1H, J=5.9, 6.6Hz), 4.31 (dd, 1H, J=3.0, 9.6Hz), 4.71-4.80(m, 2H), 4.98(m, 1H...

Embodiment 2

[0032] Add 65 g of 1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazole-[l,2-α][1,2,4]triazole ylide chloride to the reaction flask -6 base) sulfur]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapenem-2-ene-3-carboxylic acid allyl ester (compound of formula III), add 200ml ethyl acetate Add 1.3 g of triphenylphosphine and 1.2 g of tetrakis(triphenylphosphine) palladium to the ester, stir and react at room temperature for 1.5 h, add water to dilute, wash with dichloromethane, and concentrate under reduced pressure to obtain an aqueous solution. Then adjust the pH of the solution to 6.0 with O.1N HCl, then add acetone, stir and crystallize at -5°C for 3 hours, and filter to obtain 24 g of biapenem with a yield of 70%. Colorless crystal, melting point 210~218°C (decomposition).

Embodiment 3

[0034] Add 30 g of 1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazole-[l,2-α][1,2,4]triazole ylide chloride to the reaction flask -6 base) sulfur]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapenem-2-ene-3-carboxylic acid allyl ester (compound of formula I), add 200ml dichloro Add 1.3 g of triphenylphosphine and 0.5 g of tetrakis(triphenylphosphine) palladium to methane, stir and react at room temperature for 2 h, add water to dilute, wash with dichloromethane, and concentrate under reduced pressure to obtain an aqueous solution. Then adjust the solution to Ph=5.0 with O.1N HCl, then add acetone, stir and crystallize at 15°C for 2 hours, and filter to obtain 10 g of biapenem with a yield of 63%. Colorless crystal, melting point 210~218°C (decomposition).

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Abstract

The invention discloses a preparation method of biapenem. The preparation method comprises the following steps: (a) by using a compound shown in a formula III as a raw material, adding a palladium catalytic system with the weight ratio of triphenyl phosphine and tri(triphenyl phosphine) palladium of (1-3) to 1 into an organic solvent, and stirring to reaction for 1.5-2 hours at 10-50 DEG C, wherein the addition of tri(triphenyl phosphine) palladium is 1.5-2% of formula III; (b) adding water into a reaction liquid in the step (a) to dilute, washing by dichloroethane or dichloromethane, and decompressing and concentrating to obtain an aqueous solution, wherein the water phase contains biapenem; and (c) adjusting the pH of the biapenem aqueous solution obtained in the step (b) to 5-6 by an organic solvent, adding acetone or ethanol, cooling to below room temperature, stirring and carrying out crystallization for 2-3 hours to separate out biapenem crystals. In the reaction process, hydrogen is not used, and the reaction does not generate hydrogen too. The reaction condition is mild, and the production safety is greatly improved. In the reaction, buffer salt needs not to be added to control the pH of the reaction liquid, so that the preparation method is suitable for industrialized production and simple to operate.

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] Biapenem is a new type of 1β-methyl carbapenem antibiotic developed by American Cyanad Pharmaceutical...

Claims

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Application Information

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IPC IPC(8): C07D519/06
CPCC07D519/06
Inventor 崔万胜郑玉林
Owner SHANGHAI NEW ASIA PHARMA
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