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Synthesis method of cefixime

A synthetic method, the technology of cefixime, applied in the field of drug synthesis, can solve the problems of difficult separation of by-product sulfide, low reaction yield, and large environmental impact, and achieve easy separation, shortened reaction steps, reduced energy consumption and pollution effect

Pending Publication Date: 2022-07-29
山东普洛得邦医药有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The whole side chain needs to be introduced in at least two steps, involving two steps of separation operation, the reaction yield is not high, the reagents are expensive, the by-product sulfide is not easy to separate, and has a great impact on the environment

Method used

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  • Synthesis method of cefixime
  • Synthesis method of cefixime
  • Synthesis method of cefixime

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The preparation of embodiment 1 compound cefixime (1)

[0026] At room temperature (25°C), 4.90 g (20 mmol) of aminothiazole acetoxamic acid analog (2) and 4.20 g (20 mmol) of compound (3) were added to a 250 ml round-bottomed flask, and 100 ml of dichloromethane was added and stirred until Compound (3) was completely reacted. Compound 7-AVNA 5.00 g (22 mmol) was added to the above solution and stirring was continued at room temperature in air until the intermediate (4) was completely reacted. The reaction mixture was concentrated and purified by silica gel column chromatography to obtain 8.52 g of cefixime (1) in 94.0% yield with 99.4% HPLC purity.

[0027] 1 H NMR (600MHz, Methanol-D 4 )δ: 7.12(q, J=28.9Hz, 1H), 6.96(s, 1H), 5.56(d, J=18.0Hz, 1H), 5.88(d, J=4.7Hz, 1H), 5.32(d, J=11.4Hz, 1H), 5.21 (d, J=4.8Hz, 1H), 4.75 (s, 2H), 3.78 (d, J=17.5Hz, 1H), 3.61 (d, J=17.4Hz, 1H) . 13 C NMR (600MHz, Methanol-D 4 )δ: 174.0, 171.5, 165.3, 164.2, 150.2, 141.2, 133.4, 12...

Embodiment 2

[0028] The preparation of embodiment 2 compound cefixime (1)

[0029] At room temperature (25°C), 4.90 g (20 mmol) of aminothiazole acetoxamic acid analog (2) and 4.20 g (20 mmol) of compound (3) were added to a 250 ml round-bottomed flask, and 100 ml of tetrahydrofuran was added and stirred until the compound ( 3) Completely reacted. Compound 7-AVNA 5.00 g (22 mmol) was added to the above solution and stirring was continued at room temperature in air until the intermediate (4) was completely reacted. The reaction mixture was concentrated and purified by silica gel column chromatography to obtain 7.56 g of cefixime (1) in 83.4% yield with 99.0% HPLC purity.

Embodiment 3

[0030] The preparation of embodiment 3 compound cefixime (1)

[0031] At room temperature (25°C), 4.90 g (20 mmol) of aminothiazole acetoxamic acid analog (2) and 4.20 g (20 mmol) of compound (3) were added to a 250 ml round-bottomed flask, and 100 ml of toluene was added and stirred until the compound ( 3) Completely reacted. Compound 7-AVNA 5.00 g (22 mmol) was added to the above solution and stirring was continued at room temperature in air until the intermediate (4) was completely reacted. The reaction mixture was concentrated and purified by silica gel column chromatography to give 7.87 g of cefixime (1) in 86.8% yield with 98.9% HPLC purity.

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Abstract

The invention discloses a synthesis method of cefixime, which comprises the following steps: (1) carrying out addition reaction on a compound (2) and N-ethynyl-N, 4-dimethyl benzenesulfonamide (3) to obtain an intermediate (4); and (2) carrying out nucleophilic substitution reaction on the intermediate (4) and 7-AVNA to obtain cefixime. Compared with a traditional synthesis method, the method has the advantages of tedious steps, low reaction yield, expensive reagents, difficulty in separation of by-product sulfides and great influence on the environment. According to the invention, one-pot preparation is realized under mild conditions, reaction steps are shortened, the product yield and quality are improved, and energy consumption and pollution are reduced.

Description

technical field [0001] The invention relates to a method for synthesizing cefixime, in particular to a method for realizing the condensation of 7-AVNA and aminothiazole acetoxamic acid by utilizing a novel active intermediate, and belongs to the technical field of drug synthesis. Background technique [0002] Cefixime (English name: Cefixime), chemical name: 7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)acetamido]-8-oxygen Substituted-3-ethene-5-thia-1-azabicyclo[4,2,0]-oct-2-ene-2-carboxylic acid. Molecular weight of cefixime: 453.45; CAS registration number: 79350-37-1; structural formula is shown in formula 1: [0003] [0004] Cefixime is a new third-generation high-efficiency broad-spectrum cephalosporin antibiotic, which is the main antibiotic variety used in clinical treatment. It is suitable for the treatment of respiratory, urinary and biliary tract infections caused by sensitive bacteria. Cefixime is highly stable to β-lactamase produced by gram-negat...

Claims

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Application Information

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IPC IPC(8): C07D501/22A61P31/04
CPCC07D501/22A61P31/04
Inventor 王洪根金毅强江海波王文李金海
Owner 山东普洛得邦医药有限公司
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