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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  • 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 hi

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

Examples

Experimental program
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Example Embodiment

[0046]Example 1

[0047]Measure 800ml of ammonium chloride solution (10%), adjust the pH to 8.5 with ammonia, measure 750ml of the prepared ammonium chloride-ammonia inorganic buffer solution and heat to 50℃, add 15g crude imipenem, stir to dissolve, Add 4.5 g of activated carbon, and after the temperature drops to 5-10°C, keep the temperature at 5-10°C and stir for 30 minutes, and filter the filtrate. Transfer the filtrate to a crystallization kettle, add 600ml of acetone, maintain 0~5℃ for 30min, add 1400ml of acetone dropwise, after the crystals are precipitated, add dropwise, maintain 0~5℃ for 2 hours, stir and crystallize, and filter with suction. 12.80 g of white-like imipenem monohydrate was obtained by vacuum drying. The refined yield is 85.33%, which is detected by HPLC (see attachedfigure 2 ): 99.40%, impurity II content 0.0018% (peak time 19.7min).

Example Embodiment

[0048]Example 2

[0049]Measure 800ml of ammonium chloride solution (20%), adjust the pH to 7.1 with ammonia, measure 600ml of prepared ammonium chloride-ammonia inorganic buffer solution and heat to 50℃, add 15g crude imipenem, stir to dissolve, Add 4.5 g of activated carbon, and after the temperature drops to 5-10°C, keep the temperature at 5-10°C, stir for 30min, and filter to obtain the filtrate. Transfer the filtrate to a crystallization kettle, add 480ml of acetone, maintain 0~5℃ for 30min, add 1200ml of acetone dropwise, after the crystals are precipitated, add dropwise, maintain 0~5℃ for 2 hours, stir and crystallize, and filter with suction. 12.72 g of white-like imipenem monohydrate was obtained by vacuum drying. The refined yield is 84.80%, and it is detected by HPLC (refer to the attachedfigure 2 ): 99.39%, impurity II content 0.0021%.

Example Embodiment

[0050]Example 3

[0051]Measure 800ml of ammonium chloride solution (1%), adjust the pH to 9 with ammonia, measure 600ml of prepared ammonium chloride-ammonia inorganic buffer solution and heat to 50℃, add 7.5g crude imipenem, stir to dissolve , Add 2.3g of activated carbon, after the temperature drops to 5-10℃, keep 5-10℃, stir for 30min, filter to obtain the filtrate. Transfer the filtrate to a crystallization kettle, add 480ml of acetone, maintain 0~5℃ for 30min, add 1200ml of acetone dropwise, after the crystals are precipitated, add dropwise, maintain 0~5℃ for 2 hours, stir and crystallize, and filter with suction. After vacuum drying, 6.38 g of white-like imipenem monohydrate was obtained. The refining yield is 85.06%, detected by HPLC (refer to attachmentfigure 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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