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Technical synthesis method of (S)-2-benzothiazolyl (Z)-2-(2-aminothiazole-4-yl)-2-methoxycarbonylmethoxyiminothioacetate

A technology of cefixime side chain acid and chain active ester, which is applied in the direction of organic chemistry, can solve the problems of affecting the environment, complex synthesis process of cefixime side chain active ester, and many residues, so as to achieve less environmental pollution and less residue , the effect of simple route steps

Pending Publication Date: 2019-01-29
珠海市格特生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, the synthesis process of the existing cefixime side chain active ester is relatively complicated, and there are many residues after the preparation is completed, which affects the environment

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Add 400mL of dichloromethane to the dry reaction vessel as a basis, and then add 40g (0.12mol) of accelerator DM, 31.5g (0.12mol) of triphenylphosphine and 10mL of triethylamine at one time, and stir evenly at room temperature After 2 hours, add 30g (0.1mol) of cefixime side chain acid in batches within 2 hours. After the addition, continue to stir evenly at room temperature for 6 hours. After the reaction is completed, place the reaction solution at 0°C. Place the reaction mixture in a freezer at -15°C overnight for 4 hours, filter it with a filter cake while it is cold, and wash the filter cake with a little cold dichloromethane and cold ether. After the vacuum drying treatment, a nearly white crystalline powder is obtained, which is a side chain active ester of cefixime, with a yield of 68.7% and a content of more than 98%.

Embodiment 2

[0017] Add 500mL of dichloromethane to the dry reaction vessel as a basis, then add 80g (0.22mol) of the accelerator DM, 70g (0.22mol) of triphenylphosphine and 20mL of triethylamine in one go, and stir evenly at room temperature for 2.5 In 2.5 hours, add 60g (0.2mol) of cefixime side chain acid in batches within 2.5 hours. After the addition, continue to stir evenly at room temperature for 6.5 hours. After the reaction is completed, place the reaction solution in a refrigerator at 0°C Place the reaction mixture in a freezer at -15°C for 4.2 hours. Filter it with a filter cake while it is cold, and wash the filter cake with a little cold dichloromethane and cold ether. After vacuum drying treatment, a nearly white crystalline powder is obtained, which is a side chain active ester of cefixime, with a yield of 65.2% and a content of more than 98%.

Embodiment 3

[0019] Add 800mL of dichloromethane to the dry reaction vessel as the basis, and then add 120g (0.32mol) of the accelerator DM, 90g (0.3mol) of triphenylphosphine and 40mL of triethylamine at a time, and control the temperature at 28℃ , Stir evenly for 3 hours, add 140g (0.3mol) of cefixime side chain acid in batches within 3 hours, continue to stir evenly for 7.5 hours after the addition, and place the reaction solution at 0℃ after the completion of the reaction. Place the reaction mixture in the freezer at -15°C overnight for 4.7 hours, filter it with a filter cake while it is cold, and wash the filter cake with a little cold dichloromethane and cold ether. After the vacuum drying treatment, a nearly white crystalline powder is obtained, which is a side chain active ester of cefixime, with a yield of 78.4% and a content of more than 98%.

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PUM

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Abstract

The invention discloses a technical synthesis method of(S)-2-benzothiazolyl (Z)-2-(2-aminothiazole-4-yl)-2-methoxycarbonylmethoxyiminothioacetate. The technical synthesis method comprises the following steps: A, adding 0.12-0.42 mol of an accelerant DM, 0.12-0.42 mol of triphenylphosphine and quantitative triethylamine into a reaction solvent based on quantitative dichloromethane, and uniformly carrying out stirring at room temperature for 2-4 hours; B, adding 0.1-0.4 mol of (Z)-2-(methoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetic acid in batches within 2-4 hours, and continuing to carryout stirring at room temperature for 6-8 hours after the addition is completed; C, after the reaction is completed, placing the reaction liquid in a refrigerator at 0 DEG C overnight, and then putting the obtained reaction mixture into a refrigerating cabinet with a temperature of-15 DEG C for standing for 4-5 hours, then carrying out filtering while the reaction liquid is cold to obtain a filter cake, and washing the filter cake with a little cold dichloromethane and cold diethyl ether; and D, carrying out vacuum drying treatment at a temperature lower than 50 DEG C to obtain near-white crystalline powder, which is the(S)-2-benzothiazolyl (Z)-2-(2-aminothiazole-4-yl)-2-methoxycarbonylmethoxyiminothioacetate. The synthesis method disclosed by the invention is simple in steps, few in residues and small in environmental pollution.

Description

Technical field [0001] The invention relates to the technical field of pharmaceutical intermediates, in particular to a process synthesis method of cefixime side chain active ester. Background technique [0002] (Z)-2-(2-Aminothiazol-4-yl)-2-methoxycarbonylmethoxyimino-mercaptobenzothiazole ester (abbreviated as cefixime side chain acid active ester) is the third-generation oral cephalosporin The main raw material of cefixime, cefixime is the third-generation oral cephalosporin. It was first developed and marketed by Fujisawa Pharmaceutical Co., Ltd. under the trade name Cefspan. It was approved by the US FDA in 1987 and was approved in 1998. In developed European markets, cefixime has surpassed cefuroxime axetil to become the oral cephalosporin with the largest market share. [0003] However, the existing synthetic process of cefixime side chain active ester is complicated, and there are more residues after the preparation, which affects the environment. Summary of the invention...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/74
CPCC07D277/74
Inventor 石文燕
Owner 珠海市格特生物科技有限公司