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Method for preparing cefixime side chain active ester

A technology of cefixime side chain acid and active ester, applied in the preparation of 2--2-methoxycarbonylmethoxyimino-mercaptobenzothiazolyl ester, the field of cefixime side chain acid active ester, capable of Solve problems such as unfavorable actual production and increased production costs, and achieve the effects of low cost, shortened reaction cycle, and reduced production costs

Active Publication Date: 2012-07-25
SHANDONG JINCHENG KERUI CHEMICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the process uses triphenylphosphine raw material, which increases the production cost, which is not conducive to the application in actual production.

Method used

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  • Method for preparing cefixime side chain active ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Add 200kg of dichloromethane into the dry reaction kettle, start stirring, add 25.9kg (100mol) of cefixime side chain acid and 40.4kg (121mol) of DM, cool down to 10°C, and add 11.1kg (115mol) of triethyl ether at one time Amine and 0.4kg (5mol) pyridine, after stirring for 30min, 22.4kg (135mol) triethyl phosphite was added dropwise within 2.5h at room temperature, then reacted at room temperature for 2.0h, cooled to -10°C and filtered with 20kg The filter cake was washed with acetonitrile and dried in vacuo to obtain 35.7 kg of orange powdery solid cefixime side chain acid active ester with a yield of 87.6% (based on cefixime side chain acid) and a content greater than 98.5%.

Embodiment 2

[0018] Add 380kg of dichloromethane into the dry reaction kettle, start stirring, add 25.9kg (100mol) of cefixime side chain acid and 46.6kg (140mol) of DM, cool down to -5°C, and add 24.1kg (130mol) of three n-Butylamine, after stirring for 30min, add 24.9kg (150mol) triethyl phosphite dropwise within 1.0h at room temperature, then react at room temperature for 4.0h, cool down to -10°C, filter by rejection, and wash with 20kg of dichloromethane The filter cake was vacuum-dried to obtain 11.3 kg of orange powdery solid cefixime side-chain acid active ester, with a yield of 27.6% (calculated as cefixime side-chain acid), and a content greater than 98.5%.

Embodiment 3

[0020] Add 130kg of toluene to the dry reaction kettle, start stirring, add 25.9kg (100mol) of cefixime side chain acid and 33.3kg (100mol) of DM, control the temperature at 30°C, and add 10.1kg (100mol) of triethylamine at one time and 1.0kg (10mol) lutidine, after stirring for 30min, add 18.3kg (110mol) triethyl phosphite dropwise within 4.0h at 30°C, then react at 30°C for 2.0h, and cool down to -10°C , filter by rejection, and wash the filter cake with 20kg toluene, get 32.0kg orange-yellow powdery solid cefixime side chain acid active ester after vacuum drying, yield 78.4% (in terms of cefixime side chain acid), and content is greater than 98.5% .

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Abstract

The invention discloses a method for preparing (Z)-2-(tert-Methoxycarbonyl Methoxyimino)-2-(2-Aminothiazol-4-yl)Acetic Acid active ester, which includes that: in an organic solvent system and at -10 DEG C to 50 DEG C, 1.0mol of (Z)-2-(tert-Methoxycarbonyl Methoxyimino)-2-(2-Aminothiazol-4-yl)Acetic Acid (MICA Acid) and 1.0mol to 1.4mol of rubber accelerator DM (MBTS) are mixed; then 1.0mol to 1.3mol of organic amine and 0mol to 0.1mol of pyridinium derivative as a catalyst are added in; 1.1mol to 1.5 mol of phosphonic acid triethyl ester is dripped in within 1h to 8h at -10 DEG C to 50 DEG C;and the temperature is preserved for 1h to 6h, then the (Z)-2-(tert-Methoxycarbonyl Methoxyimino)-2-(2-Aminothiazol-4-yl)Acetic Acid active ester is obtained. The method adopts cheaper raw materials and a phase transfer catalysis technique; thus shortening reaction period, reducing production cost and having super high industrial application value.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to cefixime side chain acid active ester, i.e. (Z)-2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxyimine The preparation method of base-mercaptobenzothiazolate. Background technique [0002] (Z)-2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxyimino-mercaptobenzothiazole ester (referred to as cefixime side chain acid active ester) is a third-generation oral cephalosporin The main raw material of cefixime. Cefixime (cefixime) is the third-generation oral cephalosporin, which was first developed and listed by Fujisawa Pharmaceutical Co., Ltd. in Japan. Its trade name was Cefspan. It was approved by the US FDA in 1987. It has surpassed cefuroxime axetil to become the oral cephalosporin with the largest market share. Cefixime is characterized by broad spectrum resistance, strong antibacterial effect, long duration of effective concentration, stability to β-lacta...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/40C07D501/22
Inventor 张学波刘刚侯乐伟孙滨孙智源王润涛
Owner SHANDONG JINCHENG KERUI CHEMICAL CO LTD
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