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Preparation method of biapenem bulk drug

A technology for biapenem and raw materials, applied in the field of preparation of biapenem raw materials, which can solve the problems of difficult control of product particle size, increased production costs, uneven particle size distribution, etc., to facilitate industrial packaging and storage , easy to control, uniform particle size distribution

Active Publication Date: 2020-11-03
SHENZHEN HAIBIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the product prepared by the above method has large crystal particles and poor water solubility, and further mechanical crushing is required to obtain the biapenem API with good water solubility, short reconstitution time and suitable for medical use
However, additional mechanical pulverization steps will lead to inevitable product loss and increase production costs; moreover, in the mechanical pulverization process, the particle size of the product is difficult to control, which may lead to too fine particles of the product, or uneven particle size distribution, Can not fundamentally solve the problem of poor water solubility

Method used

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  • Preparation method of biapenem bulk drug
  • Preparation method of biapenem bulk drug
  • Preparation method of biapenem bulk drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Example 1 Preparation of Crude Biapenem

[0086]

[0087] Add 10kg of biapenem intermediate (II), 89kg of tetrahydrofuran, and 200kg of purified water into the hydrogenation kettle, stir and dissolve, add 60kg of ethyl acetate, 4kg of 2,6-lutidine, and 3kg of 7.5% Pd / C. 1.0~1.2MPa, hydrogenation reaction at 30~35°C for 2 hours, stop the reaction, filter, wash the filter cake with 20kg purified water, separate the phases, transfer the water phase to the crystallization kettle, cool down to 2~7°C, add 356kg tetrahydrofuran, control Adding speed, the dropwise addition is completed in 1 hour, keep warm at 2-7°C, grow crystals for 2 hours, filter, wash the filter cake with 10kg of tetrahydrofuran, and dry in vacuum to obtain 5.02kg of crude biapenem, with a yield of 75%, by HPLC normalization method The detection purity is: 96.3%, the impurity A is 0.59%, and the impurity B is 0.27%.

Embodiment 2

[0089] Add 450 g of purified water to the reaction flask, control the temperature to 20°C, and add 10 g of the crude biapenem obtained in Example 1 under stirring, stir to dissolve, control the temperature to 20°C, add 1 g of activated carbon, stir for 10 minutes, and filter out activated carbon, the filtrate was cooled to 5°C, and set aside;

[0090] Add 382.5ml of acetone and 67.5ml of ethanol to the reaction flask, cool down to 10°C, add dropwise 18ml of the above-mentioned filtrate under stirring, stir for 60 minutes, add the rest of the above-mentioned filtrate dropwise, control the rate of addition, and complete the dropwise addition in 1 hour. Stir at 15°C for 30 minutes, cool down to 7°C, continue to stir for 1.5 hours, filter, wash the filter cake with 20g of acetone, and dry it under vacuum at 40-50°C to obtain 9.48g of biapenem raw material, with a yield of 94.8%, HPLC The purity is 99.77%, the impurity A is 0.1%, the impurity B is 0.01%, and the particle size distr...

Embodiment 3

[0095] Add 450 g of purified water to the reaction flask, control the temperature to 30°C, and add 10 g of the crude biapenem obtained in Example 1 under stirring, stir to dissolve, control the temperature to 30°C, add 1 g of activated carbon, stir for 10 minutes, and filter out activated carbon, the filtrate was cooled to 10°C, and set aside;

[0096] Add 382.5ml of acetone and 67.5ml of ethanol to the reaction flask, cool down to 15°C, add dropwise 18ml of the above-mentioned filtrate under stirring, stir for 60 minutes, add the rest of the above-mentioned filtrate dropwise, control the rate of addition, and complete the dropwise addition in 1.5 hours. Stir at 20°C for 30 minutes, cool down to 12°C, continue to stir for 1.5 hours, filter, wash the filter cake with 20g of ethanol, and dry it under vacuum at 40-50°C to obtain 9.45g of biapenem raw material with a yield of 94.5%, HPLC The purity is 99.73%, the impurity A is 0.11%, the impurity B is 0.01%, and the particle size ...

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Abstract

The invention provides a biapenem bulk drug preparation method, which comprises: 1) dissolving a biapenem crude product in water at a certain dissolving temperature T1 to prepare a biapenem crude product aqueous solution; (2) controlling the temperature of the biapenem crude product aqueous solution obtained in the step (1) to be T1 or T2, adding activated carbon with stirring for decolorization,filtering the liquid, and cooling the filtrate to T3 for later use; 3) dropwise adding the filtrate obtained in the step 2) into a mixed solvent of acetone and ethanol, which is cooled to T4 in advance, and crystallizing the filtrate; 4) growing crystal; and 5) separating, washing and drying the crystals separated out in the step 4) to obtain the biapenem bulk drug.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a preparation method of a biapenem bulk drug. 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-pyrazol[1,2-a][1,2 ,4] Triazol-4-ium inner salt is a carbapenem antibiotic with broad antibacterial spectrum and strong antibacterial activity. Compared with other marketed carbapenems, biapenem has almost zero nephrotoxicity, can be administered alone, has no central nervous system toxicity, and does not induce seizures. It is widely used in clinical practice Acute and chronic infections caused by sensitive gram-negative aerobic bacteria, gram-positive aerobic bacteria and anaerobic bacteria. The specific chemical structural formula of biapenem is shown in formula (I): [0003] [0004] The stability of biapenem and the solubility of its reconstitut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/06A61P31/04
CPCC07D519/06A61P31/04
Inventor 罗文军林楠棋王东胡金军汪小华郑春莲欧军周月广黄锦钿龙利松
Owner SHENZHEN HAIBIN PHARMA
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