New process for preparing epoxide intermediate of Bicalutamide by utilizing air oxidation

A technology of bicalutamide and epoxides, which is applied in the new technology field of epoxide intermediates for the preparation of bicalutamide by air oxidation, which can solve the high requirements for production equipment and operator protection, and the high cost of m-CPBA , peroxide explosion hazard and other issues, to achieve the effect of improved atom economy, no explosion hazard, and easy operation

Active Publication Date: 2010-09-15
宁波人健化学制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The disadvantages of high cost and environmental pollution of m-CPBA have been mentioned before; hydrogen peroxide needs to be used in the presence of alkali to obtain epoxide, otherwise it will be over-oxidized and ring-opened, and the process is not easy to control; peroxide has explosive Dangerous, also has a stro

Method used

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  • New process for preparing epoxide intermediate of Bicalutamide by utilizing air oxidation
  • New process for preparing epoxide intermediate of Bicalutamide by utilizing air oxidation
  • New process for preparing epoxide intermediate of Bicalutamide by utilizing air oxidation

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Embodiment 1

[0031] Dissolve N-(4-cyano-3-trifluoromethylphenyl)-2-methacrylamide (6.35g, 0.025mol) in the solvent ethyl acetate (80ml), add isobutyraldehyde with stirring at room temperature (5.4g, 6.8ml, 0.075mol), catalyst Fe(acac) 3 (0.05g), free radical initiator 20% peroxyacetic acid aqueous solution (0.1ml). Keep the temperature at 25-30°C and react overnight. TLC detects the disappearance of the raw materials. In order to separate the obtained product from the reaction system, water (80ml) was added, the saturated sodium bicarbonate solution was adjusted to pH=7-8, shaken, stand still for separation, and the aqueous layer was extracted with ethyl acetate (2×50ml). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain an oily substance. It was recrystallized from isopropyl ether to obtain 5.63 g of white bicalutamide epoxy compound crystals. The yield was 83.4%, and the HPLC content was 98.8%.

Embodiment 2

[0033] Dissolve N-(4-cyano-3-trifluoromethylphenyl)-2-methacrylamide (6.35g, 0.025mol) in the solvent dichloromethane (80ml), add benzaldehyde ( 6.6g, 0.075mol), catalyst Co(acac) 3 (0.05g), free radical initiator 30% aqueous hydrogen peroxide solution (0.1ml). Keep the temperature at 25-30°C and react for 20h. TLC detects the disappearance of the raw materials. In order to separate the obtained product from the reaction system, water (80ml) was added, saturated sodium bicarbonate solution was adjusted to pH=7-8, shaken, stood still to separate the layers, and the aqueous layer was extracted with dichloromethane (2×50ml). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain an oily substance. It was recrystallized from isopropyl ether to obtain 5.91 g of white bicalutamide epoxy compound crystals. The yield was 87.6%, and the HPLC content was 99.3%.

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Abstract

The invention discloses a new process for preparing an epoxide intermediate of Bicalutamide by utilizing air oxidation. The process comprises the following steps: using N-(4-cyan-3-trifluoromethylphenyl)-2-methacrylamide as the compound raw material, dissolving the N-(4-cyan-3-trifluoromethylphenyl)-2-methacrylamide in a reaction solvent, adding aldehyde, a free-radical initiator and a catalyst, and carrying out air oxidation reaction at negative 20-70 DEG C for 5-45 hours, thereby obtaining the epoxide intermediate of the Bicalutamide. The mass amount of the reaction solvent is 3-15 times of that of the compound raw material; the mol ratio of the aldehyde to the compound raw material is 0.1-4.0; the mol ratio of the free-radical initiator to the compound raw material is 0.05-5%; and the mol ratio of the catalyst to the compound raw material is 0.01-2%. The process only consumes oxygen in the air is consumed, the economical efficiency of atoms is greatly enhanced, and the cost is greatly lowered; the equipment and instruments required by the reaction are simple and easy to operate, and are convenient for after treatment; the product yield is 80-95%, the purity reaches up to 99%, and the product has good color; the process is environment-friendly, since acid generated in the reaction is recyclable, no environmental pollution is caused; and the process has the advantages of no explosion hazard and high safety, and is suitable for industrial production.

Description

Technical field [0001] The invention relates to a production process of medicinal chemistry and pharmaceutical intermediates in fine chemicals, more specifically, a new process for preparing epoxide intermediates of the antitumor drug bicalutamide by air oxidation. Background technique [0002] Bicalutamide is a new type of non-steroidal antiandrogen successfully developed by Astra Zeneca in the United Kingdom. It was first launched in the United Kingdom in 1995. my country approved the import in 1999 for the treatment of prostate cancer. This medicine has strong specificity, effective oral administration, convenient administration, good tolerability, and has a long half-life. Combined with luteinizing hormone releasing hormone, it has a unique effect on the treatment of advanced prostate cancer. With the prolongation of life expectancy, changes in dietary structure, and improved diagnosis, the incidence of prostate cancer is increasing year by year, seriously threatening men’s ...

Claims

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Application Information

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IPC IPC(8): C07D303/48C07D301/06
Inventor 顾华平鲍继胜
Owner 宁波人健化学制药有限公司
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