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Preparation method of cefpodoxime proxetil

A technology of cefpodoxime axetil and active ester is applied in the field of preparation of cefpodoxime axetil, can solve the problems of high content of Δ2 isomers, cannot reach preparations, low total yield, etc., and achieves simple synthetic route and guaranteed The effect of improving safety and yield

Active Publication Date: 2016-10-26
QILU ANTIBIOTICS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Juan C. Rodriguez et al. (Rodriguez, J., C.; Hernandez, R.; Gonzalez, M.; Rodriguez, Z.; Tolon, B.; Velez, H.; Valdes, B.; Lopez, M., A; Fini, A.; An improved method for preparation of cefpodoxime proxetil. II Farmaco, 2003, 58 (5): 363-369.) reported a 7-ACA as the starting material, with AE active ester as the acylating agent The method for synthesizing cefpodoxime axetil by introducing the 7-position side chain, although the yield is higher and the steps are less, the total yield is only 36%.
In the preparation process of Chinese patent CN1387533A, the use of crown ether as a catalyst is highly toxic, and the obtained cefpodoxime axetil raw material has a relatively high content of △2 isomer
In U.S. Patent 5,498,787, Korean Patent No.99-54751, and Patent WO01 / 34611, the purity of cefpodoxime axetil obtained by the method for preparing cefpodoxime axetil is not high, and it cannot reach the limit required by the preparation standard, so it is difficult to prepare Qualified preparation
[0006] In summary, in the method for the synthesis of cefpodoxime axetil, there are problems such as low total yield of reaction, high toxicity of raw material catalyst, and low purity of cefpodoxime axetil obtained, so it is necessary to find a more efficient, environmentally friendly, industrialized Production value method to synthesize cefpodoxime axetil

Method used

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  • Preparation method of cefpodoxime proxetil

Examples

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Embodiment 1

[0035] (1) Take 220mL of trimethyl orthoformate in a round-bottomed beaker, cool to -30°C, add dropwise 500mL of a mixture of boron trifluoride ether and acetonitrile, mix at a volume ratio of 1:1, and add dropwise while stirring. After dropping within 45 minutes, continue to stir for 50 minutes, add 240g of D-7-ACA raw material, stir for 15 minutes, heat it up to 25°C in a water bath, monitor the reaction with TLC, react for 5 to 6 hours, and the reaction is basically completed;

[0036] (2) Evaporate acetonitrile, wash twice with anhydrous ether ultrasonically, pour off the ether, add 2500mL dichloromethane, stir at 25°C, then add 100mL triethylamine at 0°C, adjust the pH to 8-9, Then add 378g of AE-active ester (MAEM) in three times respectively, and each time the active ester is added, adjust the pH to 8-9 with triethylamine again, and continue to react at 0° C. for 6-7 hours. After the reaction, add 3L of water, separate the layers, collect the water layer, adjust the pH ...

Embodiment 2

[0039] (1) Take 110mL trimethyl orthoformate in a round bottom beaker, cool to -20°C, add dropwise 250mL of a mixture of boron trifluoride ether and acetonitrile, mix at a volume ratio of 1:1, and add dropwise while stirring, After dropping within 25 minutes, continue to stir for 30 minutes, add 120g of D-7-ACA raw material, stir for 15 minutes, heat it up to 25°C in a water bath, monitor the reaction with TLC, react for 3 to 4 hours, and the reaction is basically completed;

[0040] (2) Evaporate acetonitrile, wash twice with anhydrous ether ultrasonically, pour off the ether, add 1500mL dichloromethane, stir at 25°C, then add 50mL triethylamine at 5°C, adjust the pH to 8-9 , and then add 189g of AE-active ester (MAEM) three times respectively, and each time the active ester is added to adjust the pH to 8-9 with triethylamine again, and continue to react at 5°C for 4-5 hours. After the reaction, add 1.5 L of water, separate layers, collect the water layer, adjust the pH value...

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Abstract

The invention discloses a preparation method of cefpodoxime proxetil. In the method, a compound of formula II is used as an initial raw material, the intermediate compound of formula III is not separated during the process, and a crude product of cefpodoxime proxetil is synthesized by one step; and after that, a simple and easy recrystallization method is adopted for purifying the crude product of cefpodoxime proxetil to obtain cefpodoxime proxetil. In the preparation method disclosed by the invention, the yield is increased without reducing the quality, the obtained product has high purity, the synthesis path is simple, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of cefpodoxime axetil. Background technique [0002] Cefpodoxime axetil, its chemical name is: 6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)-acetamido]-3 -Methoxymethyl-8-oxo-5-thio-1-azabicyclo-[4,2,0]oct-2-ene-2-carboxylic acid isopropoxycarbonyloxyethyl ester, molecular formula C 21 h 27 N 5 o 9 S 2 , molecular weight 557.59, structural formula: [0003] [0004] Cefpodoxime axetil is an oral third-generation cephalosporin with a broad antibacterial spectrum. After entering the body, it is hydrolyzed into cefpodoxime by non-specific enzymes to play an antibacterial effect. It has a wide range of activity against Gram-positive and Gram-negative bacteria. Antibacterial spectrum, stable to β-lactamase. Currently, there is no veterinary cefpodoxime axetil, which is mainly used for human use. It is clinically suitable for the tr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/34C07D501/04
CPCC07D501/04C07D501/34
Inventor 韩文梁秀婷王海挺孟双双王甜孔梅吴连勇
Owner QILU ANTIBIOTICS PHARMA
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