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Synthesis method of cefoxitin sodium key intermediate

A technology of cefoxitin sodium and synthetic method, which is applied in the field of synthesis of key intermediates of cefoxitin sodium, and can solve the problems of low reaction yield and quality, unstable yield, unstable quality and yield of cefoxitin sodium, etc. question

Pending Publication Date: 2021-11-02
ZHEJIANG GUOBANG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Analyzing the halomethoxylation process, on the one hand, due to its strong activity, the halogenating agent is easy to deteriorate or be destroyed in the reaction, so the addition method is a fixed amount, which will lead to uncontrollable halomethoxylation reaction, and the amount of halogenating agent will not Adjusted with the reaction process, resulting in low reaction yield and quality
On the other hand, there are few researches on the haloformin oxidation process of this key intermediate in the existing literature, and the yield of this step is unstable and the quality is uncontrollable, which is reflected in the quality and yield of the final product cefoxitin sodium. Unstable, the stability of the corresponding cefoxitin sodium product

Method used

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  • Synthesis method of cefoxitin sodium key intermediate
  • Synthesis method of cefoxitin sodium key intermediate
  • Synthesis method of cefoxitin sodium key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]Add 10.0g (36.76mmol) of 7-ACA to a 250ml three-necked flask, add a mixed solvent of 100ml water and 10mlEA (ethyl acetate) under stirring, heat up to 20°C, add 8.0g sodium bicarbonate (95.24mmol), and stir until Dissolve and clarify, cool down to 0°C, add 8.0g of 2-thiopheneacetyl chloride (49.84mmol) dropwise, react for 2h until the raw material remains ≤ 1.0%, raise the temperature to 25°C, add hydrochloric acid to adjust the pH to 1.5-2.5, filter to obtain cephalosporin Thiophenoic acid wet product. Add 100ml of dichloromethane to dissolve, separate layers to remove water, lower organic layer, cool to -60 ° C, add 30% sodium methoxide methanol solution 25.0g (138.89mmol), first add 2.8g tert-butyl hypochlorite (25.79mmol, tert-butyl hypochlorite: 7-ACA≈0.7:1), then detect the residual raw materials, calculate according to a certain method, add tert-butyl hypochlorite, after the raw materials are qualified, add acetic acid, add sodium chloride solution, add dilute Hy...

Embodiment 2

[0078]Add 10.0g (36.76mmol) of 7-ACA into a 250ml three-necked flask, add 120ml of water while stirring, raise the temperature to 25°C, add 7.0g of sodium bicarbonate (83.33mmol), stir until it dissolves and becomes clear, cool down to 15°C, add dropwise 6.0g 2-thiophene acetyl chloride (37.33mmol), react for 1h until the raw material residue ≤ 1.0%, raise the temperature to 30°C, add hydrochloric acid to adjust the pH to 1.5-2.0, filter to obtain the wet product of cephalothinic acid, and then add 200ml of dichloro Dissolve methane, separate layers to remove water, lower organic layer, cool to -90°C, add 30% sodium methoxide methanol solution 40.0g (222.22mmol), first add 3.5g tert-butyl hypochlorite (32.24mmol), and then detect raw materials Residue, calculated according to a certain method, add tert-butyl hypochlorite, add acetic acid, add sodium chloride solution, add dilute hydrochloric acid to control pH1.8-2.2, let stand to separate layers, concentrate and dry the lower ...

Embodiment 3

[0080] Add 10.0g (36.76mmol) of 7-ACA into a 250ml three-necked flask, add 100ml of dichloromethane while stirring, cool down to 0°C, add 9.0g of triethylamine (88.93mmol), stir until it dissolves and becomes clear, and add 7.0g of 2- Thiophene acetyl chloride (43.61mmol), reacted for 1.5h, until the raw material remained ≤0.5%, cooled to -80°C, added 30.0g (166.67mmol) of 30% sodium methoxide methanol solution, first added 4.0g tert-butyl hypochlorite ( 36.85mmol), then detect the residual raw materials, calculate according to a certain method, add tert-butyl hypochlorite, add acetic acid, add sodium chloride solution, add dilute hydrochloric acid to control PH1.8-2.2, let stand for stratification, add carbonic acid Sodium hydrogen, adjust pH 7.5, separate layers, add 100ml EA to the water layer, adjust pH 1.8 with hydrochloric acid, separate layers, dry the EA layer with anhydrous calcium chloride, add 5.2 g (52.44 mmol) of cyclohexylamine, crystallize, filter, Rinse with ac...

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Abstract

The invention provides a synthesis method of a cefoxitin sodium key intermediate, and belongs to the technical field of heterocyclic compounds. The method comprises the following steps: by taking a cephalotin solution as a treatment object, adding organic alkali, adding a halogenating agent, carrying out halogenating methoxyl reaction, adding acetic acid and saline water, regulating acid and layering, drying an organic layer, concentrating, adding cyclohexylamine to form salt, filtering and drying to obtain a key intermediate 7-alpha methoxyl cephalothin cyclohexylamine salt According to the method, one-step synthesis of the 7-alpha methoxyl cephalothin cyclohexylamine salt is realized, subsequent main impurities of cefoxitin sodium are effectively reduced from the source, the quality and purity of the product are improved, the competitiveness of the cefoxitin product is improved, the product is stable and reliable, the yield is high, the synthesis process is greatly simplified, and the method has an industrial prospect.

Description

technical field [0001] The application relates to a synthetic method of a key intermediate of cefoxitin sodium, which belongs to the technical field of heterocyclic compounds. Background technique [0002] Cefoxitin Sodium was developed by Merck & Co. of the United States and was listed in 1974. It is a cephamycin antibiotic and is similar to cephalosporins in chemical structure, but there is methoxidation on the 7-position carbon of the cephem nucleus. The methoxidation is in "trans", which can prevent the β-lactamase from approaching the β-lactam ring, reduce the affinity of the enzyme to the drug, and protect the β-lactam ring from being destroyed. Cefoxitin has a wider and more balanced antibacterial spectrum coverage, strong activity against Gram-positive and negative, anaerobic bacteria or aerobic bacteria, and has high anti-β-lactamase properties. It is clinically used for peritonitis and other intra-abdominal, pelvic and gynecological infections, as well as sepsis, ...

Claims

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Application Information

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IPC IPC(8): C07D501/57C07D501/04C07D501/06C07C209/68C07C211/35
CPCC07D501/57C07D501/04C07D501/06C07C209/68C07C211/35C07C2601/14
Inventor 王金龙侯仲轲张宜仲阮剑王亮王超奇史锰锰摆皓文王兆刚
Owner ZHEJIANG GUOBANG PHARMA
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