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Preparation method of imipenem

A technology of imipenem and ammonium chloride, applied in the direction of organic chemistry, can solve the problem of low cost, achieve rapid dissolution, prevent unstable state, and prevent formation

Active Publication Date: 2020-12-29
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] In view of the existing method, imipenem is easy to degrade and produce impurities, impurity II cannot be effectively removed, the yield is low, the product purity is not high, and industrial production cannot be realized etc., the present invention provides a method for preparing high-purity imipenem monohydrate, which overcomes the problems that impurity II cannot be effectively removed and imipenem is easily degraded to produce impurities, and the method is simple to operate and has a high yield High, high crystal purity, low cost, suitable for industrial production

Method used

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  • Preparation method of imipenem
  • Preparation method of imipenem
  • Preparation method of imipenem

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Measure 800ml of ammonium chloride solution (10%), adjust the pH to 8.5 with ammonia water, measure 750ml of the prepared ammonium chloride-ammonia water inorganic buffer solution and heat to 50°C, add 15g of imipenem crude product, stir to dissolve, Add 4.5 g of activated carbon, and after the temperature drops to 5-10°C, keep stirring at 5-10°C for 30 minutes, and filter to obtain the filtrate. Transfer the filtrate to a crystallization kettle, add 600ml of acetone, keep stirring and crystallizing at 0-5°C for 30 minutes, after the crystals precipitate, add 1400ml of acetone dropwise, after the addition is complete, keep stirring and crystallizing at 0-5°C for 2 hours, then filter with suction. Vacuum-dried to obtain 12.80 g of off-white imipenem monohydrate. Refining yield 85.33%, HPLC detects (see attached figure 2 ): 99.40%, impurity II content 0.0018% (peak elution time 19.7min).

Embodiment 2

[0049]Measure 800ml of ammonium chloride solution (20%), adjust the pH to 7.1 with ammonia water, measure 600ml of the prepared ammonium chloride-ammonia water inorganic buffer solution and heat to 50°C, add 15g of imipenem crude product, stir to dissolve, Add 4.5 g of activated carbon, and after the temperature drops to 5-10°C, keep stirring at 5-10°C for 30 minutes, and filter to obtain the filtrate. Transfer the filtrate to a crystallization kettle, add 480ml of acetone, keep stirring and crystallizing at 0-5°C for 30 minutes, after the crystals precipitate, add 1200ml of acetone dropwise, after the addition is complete, keep stirring and crystallizing at 0-5°C for 2 hours, then filter with suction. After vacuum drying, 12.72 g of off-white imipenem monohydrate was obtained. Refining yield 84.80%, HPLC detects (referring to attached figure 2 ): 99.39%, impurity II content 0.0021%.

Embodiment 3

[0051] Measure 800ml of ammonium chloride solution (1%), adjust the pH to 9 with ammonia water, measure 600ml of the prepared ammonium chloride-ammonia water inorganic buffer solution and heat to 50°C, add 7.5g of imipenem crude product, stir to dissolve , add 2.3g of activated carbon, after the temperature drops to 5-10°C, keep stirring at 5-10°C for 30min, and filter to obtain the filtrate. Transfer the filtrate to a crystallization kettle, add 480ml of acetone, keep stirring and crystallizing at 0-5°C for 30 minutes, after the crystals precipitate, add 1200ml of acetone dropwise, after the addition is complete, keep stirring and crystallizing at 0-5°C for 2 hours, then filter with suction. Vacuum-dried to obtain 6.38 g of off-white imipenem monohydrate. Refining yield 85.06%, HPLC detects (referring to attached figure 2 ): 99.38%, impurity II content 0.0020%.

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Abstract

The invention belongs to the field of medicinal chemical synthesis, and relates to a preparation method of high-purity imipenem, which comprises the following steps: dissolving an imipenem crude product in an ammonium chloride-ammonia water inorganic buffer solution to obtain a dissolved solution; adding activated carbon into the obtained dissolving solution, and conducting cooling, stirring and filtering to obtain filtrate; and separating out the imipenem from the filtrate, and conducting filtering to obtain a pure imipenem product. According to the method, the problems that an impurity II cannot be effectively removed and imipenem is easy to degrade to generate new impurities are solved, and the method is simple to operate, high in yield, high in product purity, low in cost and suitablefor industrial production.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of high-purity imipenem monohydrate. Background technique [0002] Imipenem is a carbapenem antibacterial drug developed by Merck, and it is usually clinically used as a compound preparation with cilastatin sodium. The structural formula of imipenem is as follows (I): [0003] [0004] At present, there are two main synthetic routes of imipenem: [0005] [0006] Route 1 uses thiamycin as a starting material, and reacts directly with iminobenzyl ether hydrochloride in a buffer system to obtain imipenem. Although the reaction steps of this route are relatively simple, the control of the pH value of the reaction is relatively harsh. It requires high operation precision and is not suitable for mass production. [0007] [0008] Route 2 uses the carbapenem bicyclic core as the starting material, reacts with semi-light amine hydrochlori...

Claims

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Application Information

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IPC IPC(8): C07D477/02C07D477/20
CPCC07D477/02C07D477/20
Inventor 孟俊丽白文钦
Owner LUNAN PHARMA GROUP CORPORATION
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