Preparation method of 2-Mercaptobenzothiazolyl (Z)-2-(2-aminothiazol-4-yl)-2-(t-butoxycarbonylmethoxyimino) acetate

A technology for cefixime side chain acid and active ester, which is applied in the field of preparation of cefixime side chain acid active ester, can solve the problems of long process flow, high pollution of three wastes and high production cost, and can shorten the process and reduce the pollution of three wastes. , the effect of simplifying the operation

Inactive Publication Date: 2017-02-08
SHANDONG JINCHENG KERUI CHEMICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the invention is to provide a preparation method of cefixime side chain acid active ester, which solves the problems of long technological process, low product yield, high

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The preparation method of cefixime side chain acid active ester is as follows:

[0031] (1) ring closure:

[0032] After oximation and alkylation of tert-butyl acetoacetate, the liquid organic matter 2-methoxyformylmethoxyimino-3-oxobutanoic acid tert-butyl ester was obtained, and then 180 mL of toluene and 31.1 g of toluene were added to 60 g of the liquid organic matter Potassium thiocyanate, add 1.3g acetyl chloride dropwise at -5-5°C, keep warm at 5°C for 1 hour, add 1.5g DMF after the reaction, the pH of the solution is 8.2, cool down to 0-5°C and add 34.5g Aniline, then 3.1g of triethylamine was added dropwise, and solids were gradually precipitated, and reacted for 2 hours at 5°C to obtain the intermediate (Z)-2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxy Iminoacetic acid, the molar conversion rate of liquid organic matter in this step is 85.5% detected by Zhongkong;

[0033] (2) Esterification:

[0034] Cool the intermediate to 5-10°C, then add 88.2g of di...

Embodiment 2

[0037] The preparation method of cefixime side chain acid active ester is as follows:

[0038] (1) ring closure:

[0039] After oximation and alkylation of tert-butyl acetoacetate, liquid organic matter 2-methoxyformylmethoxyimino-3-oxobutanoic acid tert-butyl ester was obtained, and then 1200 mL of acetonitrile and 62.4 g of acetonitrile were added to 120 g of liquid organic matter Sodium thiocyanate, add 9.3g of dichloroacetyl chloride dropwise at -5-5°C, keep warm at 5°C for 1 hour, add 4.5g of DMF after the reaction, the pH of the solution is 8.0, cool down to 0-5°C and add 86.2g of aniline, then 2.31g of DMF was added dropwise, and a solid gradually precipitated out. The reaction was carried out at 25°C for 2 hours to obtain the intermediate (Z)-2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxy Iminoacetic acid, the molar conversion rate of liquid organic matter in this step is 84.5% detected by Zhongkong;

[0040] (2) Esterification:

[0041] Lower the temperature of t...

Embodiment 3

[0044] The preparation method of cefixime side chain acid active ester is as follows:

[0045] (1) ring closure:

[0046]After oximation and alkylation of tert-butyl acetoacetate, liquid organic matter 2-methoxyformylmethoxyimino-3-oxobutanoic acid tert-butyl ester was obtained, and then 960 mL of methylene chloride was added to 160 g of liquid organic matter, 46.9g ammonium thiocyanate, add 12.8g bromoacetyl chloride dropwise at -5-5°C, keep warm at 5°C for 2 hours, add 3.5g DMF after the reaction, the pH of the solution is 8.5, cool down to 0-5°C Add 77.5g of aniline, then dropwise add 3.6g of DMAC, gradually a solid precipitates, react at 15°C for 2h, and obtain the intermediate (Z)-2-(2-aminothiazol-4-yl)-2-methoxycarbonyl Methoxyiminoacetic acid, the molar conversion rate of this step detected by Zhongkong is 85.5%;

[0047] (2) Esterification:

[0048] Cool the intermediate to 5-10°C, then add 176.4g of dibenzothiazole disulfide, 8.5g of tetraethylammonium bromide, ad...

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Abstract

The invention relates to a preparation method of 2-Mercaptobenzothiazolyl (Z)-2-(2-aminothiazol-4-yl)-2-(t-butoxycarbonylmethoxyimino) acetate and belongs to the field of medical intermediate preparation technology. According to the preparation method of 2-Mercaptobenzothiazolyl (Z)-2-(2-aminothiazol-4-yl)-2-(t-butoxycarbonylmethoxyimino) acetate, tert-Butyl 3-oxobutanoate used as a starting material undergoes oximation and hydrocarbonylation to obtain 2-methoxyformylmethoxyimino-3-oxobutyric acid tert-butylester; by using acyl halide as an activator, 2-methoxyformylmethoxyimino-3-oxobutyric acid tert-butylester undergoes an annulation reaction to obtain an intermediate (Z)-2-(2-aminothiazole-4-yl)-2-methoxycarbonylmethoxyliminoacetic acid; and the intermediate undergoes an esterification reaction to obtain 2-Mercaptobenzothiazolyl (Z)-2-(2-aminothiazol-4-yl)-2-(t-butoxycarbonylmethoxyimino) acetate. The problems of long flow, low product yield, high production cost and high pollution of ''three wastes (waste gas, waste water and industrial residue)'' in the prior art are solved. By using the acyl compound as the activator, the halogenation process with low yield and much impurity is removed, the process is shortened, and operation is simplified. Meanwhile, production cost is reduced, and the ''three wastes'' pollution is minimized. The preparation method has high industrial application value.

Description

technical field [0001] The invention relates to a preparation method of cefixime side chain acid active ester, which belongs to the technical field of preparation of pharmaceutical intermediates. Background technique [0002] (Z)-2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxyimino-mercaptobenzothiazole ester, the acid active ester of cefixime side chain 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, and it was approved by the US FDA in 1987. Kexime has surpassed cefuroxime axetil to become the oral cephalosporin with the largest market share. Cefixime is characterized by broad spectrum resistance, strong antibacterial effect, and long duration of effective concentration. It has the advantages of being stable to β-lactamase, wide distribution in the body, and high oral b...

Claims

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Application Information

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IPC IPC(8): C07D417/12
CPCC07B2200/09C07D417/12
Inventor 张强孟令栋王君伟刘建国周忠玉
Owner SHANDONG JINCHENG KERUI CHEMICAL CO LTD
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