A kind of synthetic method of cefixime

A technology of cefixime and synthetic method, which is applied in the field of chemical pharmacy, can solve problems such as difficult removal, and achieve the effects of easy removal, reduced loss, and improved color and quality

Active Publication Date: 2016-08-17
ZHEJIANG APELOA TOSPO PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

5-Methyl-1,3,4-thiadiazole active ester, 5-phenyl-1,3,4-oxadiazole active ester and benzothiazole active ester are solid, and the residues in the product are not easy to remove. 5-Methyl-1,3,4-thiadiazole active ester, 5-phenyl-1,3,4-oxadiazole active ester and benzothiazole active ester are carcinogenic

Method used

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  • A kind of synthetic method of cefixime
  • A kind of synthetic method of cefixime
  • A kind of synthetic method of cefixime

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] (1) Add 150g MICA (0.579mol) into a 2000mL four-necked reaction flask, then add 400ml dichloromethane, 0.2g triethylenediethylamine (CAS: 280-57-9) and 107.3g tri-n-butylamine ( 0.579mol), stirring and cooling down to -5°C, and controlling the temperature of the material. Add 132 g (0.7 mol) of diethylphosphoryl thiochloride dropwise. After the addition is complete, keep the temperature at 0° C. to 5° C. and react for 2 to 3 hours. The temperature was controlled at 20° C., P=-0.95 MPa, and the dichloromethane solvent was distilled off under reduced pressure and low temperature to obtain 200 g of cefixime side-chain parathion active ester in a light orange oily form, with a yield of 84%.

[0079](2) Add 900 mL of tetrahydrofuran and stir to dissolve the orange-yellow cefixime side-chain parathion active ester obtained in step (1), add 80 g of 7-AVCA (0.353 mol), and add 0.7 g of sodium bisulfite. Add 100 mL of aqueous sodium hydroxide solution (prepared with 18.4 g of N...

Embodiment 2

[0086] According to (1) step in the above-mentioned embodiment 1, the orange-yellow cefixime side-chain acid phosphine active ester was obtained, and 900mL tetrahydrofuran was added to stir and dissolve, 80g 7-AVCA (0.353) was added, and 100mL aqueous sodium hydroxide solution (NaOH 18.4 g+700mL water), maintain the temperature at 5-10°C, and keep the reaction for 6 hours. After the reaction was completed, 800 mL of ethyl acetate was added, stirred for 30 minutes, allowed to stand for 60 minutes, and separated into layers; the lower aqueous layer was collected. Add 400 mL of ethyl acetate to the aqueous layer and extract once more. Stir for 20 minutes. Let stand for 60 minutes, and separate layers; the lower aqueous phase is collected into a hydrolysis bottle.

[0087] Cool the water phase to 0°C, add the mixed alkali solution (pre-prepared mixed alkali solution: add 34.5g NaOH and 24.5g sodium bicarbonate to 180mL purified water, stir to dissolve and pre-cool to 0°C-5°C, se...

Embodiment 3

[0089] The orange-yellow cefixime side chain acid phosphion active ester that (1) step makes in the above-mentioned example 1, add 900mL tetrahydrofuran and stir to dissolve, add 80g 7-AVCA (0.353), dropwise add 100mL sodium hydroxide aqueous solution (NaOH 18.4g +700mL water to prepare), maintain the temperature at 5-10°C, and keep the reaction for 6 hours. At the end of the reaction, 800 mL of butyl acetate was added, stirred for 30 minutes, allowed to stand for 60 minutes, and separated into layers; the lower aqueous layer was collected. Add 400 mL of butyl acetate to the aqueous layer and extract once more. Stir for 20 minutes. Let stand for 60 minutes, and separate layers; the lower aqueous phase is collected into a hydrolysis bottle.

[0090] (3) Cool the water phase to 0°C, add the mixed alkali solution (pre-prepared mixed alkali solution: add 34.5g NaOH and 24.5g sodium bicarbonate to 180mL purified water, stir to dissolve and pre-cool to 0°C ~ 5°C, set aside ), the...

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Abstract

The invention discloses a method for synthesizing cefixime. The method comprises the following steps: (1) carrying out an amidation reaction between MICA ((Z)-2-(methoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetic acid) sulfur-phosphorous active ester and 7-AVCA to obtain cefixime methyl ester, wherein the structure of the MICA sulfur-phosphorous active ester is as shown in the formula (II); (2) hydrolyzing the cefixime methyl ester to obtain cefixime. According to the synthesizing method, a new MICA active ester, namely (z)-2-(2-amino-4-thiazolyl)-methoxycarbonyl methylene imino-acetic acid-diethyl phosphoryl active ester, is adopted, a byproduct diethyl phosphate has small toxicity; and the diethyl phosphate is liquid and can be easily removed, the method is simple in steps and is high in yield.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a method for synthesizing antibiotics. Background technique [0002] Cefixime, whose structure is shown in formula (I), generally contains three crystal waters in the product, and is a third-generation oral cephalosporin, which plays a bactericidal effect by inhibiting the synthesis of bacterial cell walls, and is stable to most β-lactamases. Many strains producing penicillinase and cephalosporinase are still sensitive to this product. Cefixime is effective against Gram-positive cocci such as pneumococcus and Streptococcus pyogenes in vitro and in vivo, Gram-negative bacilli such as influenza bacilli (including enzyme-producing strains), Moraxella catarrhalis (including enzyme-producing strains), large intestine Bacillus, Proteus mirabilis, and Neisseria gonorrhoeae (including enzyme-producing strains) all have good antibacterial effects. Cefixime in vitro against S...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/22C07D501/04C07D501/12
CPCC07D501/04C07D501/12C07D501/22
Inventor 厉昆任红阳马向红陈治葛政亮陈亮
Owner ZHEJIANG APELOA TOSPO PHARMA
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