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Synthesis method of flomoxef intermediate

A fluoxetin and intermediate technology, applied in the field of drug synthesis, can solve the problems of unfavorable environmental protection, operator safety protection, unfavorable industrial production, long steps of intermediate 1, etc., and achieve short reaction route, short route and mild reaction conditions Effect

Active Publication Date: 2022-04-12
深圳市立国药物研究有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Literature (DE2800860, JP56012395), also reported other hydrolysis, route is all long, and reagent price is expensive, and yield is lower, is unfavorable for suitability for suitability for industrialized production
[0012] Therefore, in the existing disclosed technical scheme, the synthesis of intermediate 1 has the disadvantages of long steps and low yield, and carrying out chlorination reaction with chlorine gas has been listed as one of the 18 dangerous chemical processes by the country. There are outstanding safety risks, which is not conducive to environmental protection and safety protection of operators

Method used

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  • Synthesis method of flomoxef intermediate
  • Synthesis method of flomoxef intermediate
  • Synthesis method of flomoxef intermediate

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Experimental program
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Effect test

Embodiment 1

[0034] The preparation of embodiment 1 intermediate 1

[0035] Add 40mL of selenium dioxide (87.2mg, 0.784mmol) aqueous solution to 100mL dry round bottom flask, cool to 0°C, slowly add 0.72mL tert-butyl hydroperoxide (5.88mmol) 70% aqueous solution, stir at 0°C 30 minutes. Then 10mL of dichloromethane solution containing compound 3 (1.82g, 3.92mmol) was added dropwise. After the dropwise addition was completed, the reaction was carried out at room temperature. After the reaction was complete, 1.5M aqueous sodium hydroxide solution was added to the reaction system to adjust the pH to neutral. Quench the reaction, then add 20mL of dichloromethane for extraction, separate the organic layer, dry over anhydrous magnesium sulfate, concentrate under reduced pressure to remove the dichloromethane to obtain a yellow oil, add 12mL of methanol, crystallize at 0-10°C, filter and dry , 1.44 g of the target product was obtained, the yield was 76%, and the HPLC purity was 98.51%.

[0036]...

Embodiment 2

[0037] The preparation of embodiment 2 intermediate 1

[0038] Add 30 mL of selenium dioxide (130 mg, 1.18 mmol) in dichloromethane solution to a 100 mL dry round bottom flask, cool to 0° C., slowly add 1 mL of aqueous benzoic acid peroxide (0.3 g, 6.48 mmol), and stir at 20° C. for 30 minute. Then add dropwise a dichloromethane solution containing 10mL of compound 3 (1.82g, 3.92mmol). After the dropwise addition, react at room temperature. After the reaction is complete, add 1M aqueous sodium carbonate solution to the reaction system, adjust the pH to neutral, and quench the reaction. , and then add 15mL of dichloromethane for extraction, separate the organic layer, dry over anhydrous magnesium sulfate, concentrate under reduced pressure to remove dichloromethane to obtain a yellow oil, add 15mL of ethanol, crystallize at 0-10°C, filter, and dry to obtain the target Product 1.38g, yield 73%.

Embodiment 3

[0039] The preparation of embodiment 3 intermediate 1

[0040]Add 20 mL of selenium dioxide (120 mg, 1.08 mmol) in ethyl acetate to a 100 mL dry round bottom flask, cool to 0°C, slowly add 0.5mL of acetic acid (0.2g, 3.3mmol) aqueous solution, and stir at 30°C for 30 minutes. Then add dropwise an ethyl acetate solution containing 5mL of compound 3 (0.91g, 1.96mmol). After the dropwise addition, react at room temperature. After the reaction is complete, add 1M potassium carbonate aqueous solution to the reaction system, adjust the pH to neutral, and quench the reaction. , then add 10 mL of dichloromethane for extraction, separate the organic layer, dry over anhydrous magnesium sulfate, concentrate under reduced pressure to remove the dichloromethane to obtain a yellow oil, add 7 mL of methanol / acetone (2:1), and crystallize at 0-10°C , filtered, and dried to obtain 0.66 g of the target product, with a yield of 70%.

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Abstract

The invention provides a method for preparing a flomoxef intermediate 1, which comprises the step of reacting a compound 3 with selenium dioxide in the presence of an auxiliary agent to obtain the intermediate 1. The method is mild in reaction condition, the molar yield is greater than 65%, the HPLC purity is greater than 98%, and the method has the advantages of being short in route, high in yield, environmentally friendly and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of a fluoxefem intermediate. Background technique [0002] Flomoxef sodium (Flomoxef sodium, formula I), the chemical name is (6R,7R)-7-(2-((difluoromethyl)thio)acetamido)-3-(((1-(2-hydroxy Ethyl)-1H-tetrazol-5-yl)thio)methyl)-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene - Sodium 2-formate. This product is an injection-type oxacephem broad-spectrum antibiotic developed and marketed by Shionogi Pharmaceutical Co., Ltd. in 1988. It is effective against Gram-positive cocci (except Enterococcus) and most Enterobacteriaceae bacteria, including Escherichia coli Bacteria, Klebsiella pneumoniae, Proteus, influenza bacilli, etc. have high antibacterial activity. It also has good antibacterial effect on anaerobic bacteria (including Bacteroides fragilis). Neisseria gonorrhoeae is highly sensitive to this product. It is mainly used clinically for moderate to sev...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04
Inventor 王宝邓德福刘荣威林祖聪陈剑明何菁华肖桃梅
Owner 深圳市立国药物研究有限公司
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