Tebipenem pivoxil industrial preparation method

A technology of tipipenem ester and tipipenem, applied in the field of medicinal chemistry, can solve the problems of instability of iodomethyl pivalate, unsuitable for industrialized production, complicated post-processing operations and the like, and achieves simple and easy post-processing operations. , the use of less solvent, the effect of high product yield

Active Publication Date: 2015-02-11
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The iodomethyl pivalate used in the method reacts at low temperature, the post-treatment operation is cumbersome, and the amount of solvent used is large, which not only increases the cost but also pollutes the environment, and the iodomethyl pivalate is unstable and expensive, so it is not suitable for industrial production

Method used

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  • Tebipenem pivoxil industrial preparation method
  • Tebipenem pivoxil industrial preparation method
  • Tebipenem pivoxil industrial preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] 18g of tipipenem, 162mL of N,N-dimethylformamide, 6.54g of potassium carbonate, and 0.45g of tetrabutylammonium bromide were reacted at 25°C for 60min, and chloroform pivalate was added dropwise at this temperature 8.93g ester, after the reaction is completed, add 320ml of water and stir for 10 minutes, add 160ml of ethyl acetate to extract, extract the water phase with 160ml of ethyl acetate once, combine ethyl acetate, wash with water, separate phases, wash the ethyl acetate phase with 640ml of water, Add 60 g of anhydrous sodium sulfate to the ethyl acetate phase, dry and decolorize with activated carbon, concentrate the filtrate, add 162 mL of isopropyl ether dropwise at 25°C, stir and crystallize, filter, and dry to obtain 17.64 g of a white solid. The HPLC detection purity was 99.87%, and the yield was 89.7%.

[0030] TBPN 1 H NMR data (CDCl 3 ): 5.989-5.978ppm (1H, d, 5.5, H-13), 5.858-5.847ppm (1H, d, 5.5, H-13), 4.436-4.390ppm (2H, m, H-22e, H-24e ), 4.232-4...

Embodiment 2

[0033] React 18g of tipipenem, 162ml of N,N-dimethylformamide, 10.92g of potassium carbonate, and 0.45g of benzyltriethylammonium chloride at 20°C for 70min, and add pivalic acid dropwise at this temperature Chloromethyl ester 17.8g, after the reaction is completed, add 320ml of water and stir for 10 minutes, add 160ml of ethyl acetate for extraction, extract the water phase with 160ml of ethyl acetate once, combine ethyl acetate, wash with water, separate phases, wash the ethyl acetate phase with 640ml of water, Add 60 g of anhydrous sodium sulfate to the ethyl acetate phase, dry and decolorize the activated carbon, concentrate the filtrate to a certain volume, add 180 mL of methyl tert-butyl ether dropwise at 20°C, stir for crystallization, filter, and dry to obtain 17.30 g of a white solid. The HPLC detection purity was 99.75%, and the yield was 88%.

Embodiment 3

[0035] React 18g of tipipenem, 162ml of N,N-dimethylformamide, 4.19g of sodium carbonate, and 0.18g of tetrabutylammonium bromide at 30°C for 50min, and add pivalate chloromethyl pivalate dropwise at this temperature 8.93g ester, after the reaction was completed, add 320ml of water and stir for 10 minutes, add 160ml of ethyl acetate to extract, extract the water phase with 160ml of ethyl acetate once, combine ethyl acetate, wash with water, separate phases, wash the ethyl acetate phase with 640ml of water, wash with ethyl acetate 60 g of anhydrous sodium sulfate was added to the ester phase, and activated carbon was dried for decolorization. The filtrate was concentrated to a certain volume, and 144 mL of n-heptane was added dropwise at 25° C., stirred for crystallization, filtered, and dried to obtain 17.36 g of a white solid. The HPLC detection purity was 99.77%, and the yield was 88.3%.

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Abstract

The invention relates to the field of medical chemistry, and specifically relates to a tebipenem pivoxil industrial preparation method. The method comprises the following steps: tebipenem, a solvent I, salt, and a phase-transfer catalyst are mixed, and a salt-forming reaction is carried out under normal temperature; chloromethylpivalate is added under a same temperature, and an esterification reaction is carried out; when the reaction is finished, extraction and concentration are carried out; a solvent II is dropped for crystallization; and filtering is carried out, such that tebipenem pivoxil is obtained. With the method, operation is simple, and complicated operations of pH regulation and repeated extraction are avoided. Post-treatment solvent dose is low, such that resource is saved, and environment pollution is reduced. Chloromethylpivalate property is stable, and normal-temperature reaction requirement is low. Product yield is high, and a maximal yield can be higher than 88%. The purity of synthesized tebipenem pivoxil can be higher than 99.7%. Without refining, the obtained tebipenem pivoxil can be used for preparing medicine preparations as a raw material medicine satisfying medical requirements, and the medicine preparation can be safely used by patients. The method is suitable for industrial productions.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new method suitable for industrialized preparation of tipipenem dextrose. Background technique [0002] Tebipenem pivoxil (I), chemical name: (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo Substitute-3-[[1-(2-thiazolin-2-yl)-3-azetidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxy Acid-2-methyl pivalate), the structural formula is: [0003] [0004] Developed by Pfizer of the United States, tipipenem ester fine granule was developed by Meiji Corporation of Japan, was approved by Japan in February 2009, and went on the market in April 2009. Tipipenem ester is the prodrug of tipipenem. After oral administration, it is hydrolyzed by esterase to release the parent drug tipipenem, which binds to bacterial penicillin-binding protein (PBP) and inhibits the synthesis of bacterial cell walls. It is currently the only Oral carbapenem antibiotics. [0005] The structural...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20
CPCC07D477/20
Inventor 赵志全白文钦郭树栋
Owner LUNAN PHARMA GROUP CORPORATION
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