New process of preparing bicalutamide by utilizing air for oxidizing bicalutamide thioether intermediate

A technology of carbalutamide sulfide and bicalutamide, which is applied to the preparation of organic compounds, organic chemistry, chemical instruments and methods, etc., can solve the problems of complex processing and high production costs, and achieve easy reaction, cost reduction, and reaction The effect of mild conditions

Active Publication Date: 2010-09-01
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

The post-treatment of such oxidants is also complicated during oxidation, and the production cost is relatively high

Method used

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  • New process of preparing bicalutamide by utilizing air for oxidizing bicalutamide thioether intermediate
  • New process of preparing bicalutamide by utilizing air for oxidizing bicalutamide thioether intermediate
  • New process of preparing bicalutamide by utilizing air for oxidizing bicalutamide thioether intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The bicalutamide sulfide intermediate (10.0g, 0.025mol) was dissolved in ethyl acetate (80ml), and isobutyraldehyde (7.2g, 9.1ml, 0.1mol) was added under stirring at room temperature, and the catalyst Co(acac) 3 (0.05g), free radical initiator 30%, aqueous hydrogen peroxide (0.1ml). Keep the temperature at 25-30° C., react overnight, and TLC detects that the starting material disappears. In order to separate the gained product from the reaction system, add water (80ml), and the saturated sodium sulfite solution is slowly dripped in until the reaction solution makes the starch potassium iodide test paper colorless. The layers were allowed to stand, and the layers were separated, and the aqueous layer was extracted with ethyl acetate (3×50ml). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain a white solid. Recrystallization in acetone / water gave 10.5 g of white bicalutamide crystals. The yie...

Embodiment 2

[0042] Bicalutamide sulfide intermediate (10.0g, 0.025mol) was dissolved in dichloromethane (100ml), pivalaldehyde (8.6g, 10.8ml, 0.1mol) was added under stirring at room temperature, catalyst Co(acac) 3 (0.05g), free radical initiator 30%, aqueous hydrogen peroxide (0.1ml). Keep the temperature at 25-30° C., react overnight, and TLC detects that the starting material disappears. In order to separate the gained product from the reaction system, add water (80ml), and the saturated sodium sulfite solution is slowly dripped in until the reaction solution makes the starch potassium iodide test paper colorless. Cool to 10°C, filter, and wash the filter cake with water and a little dichloromethane to obtain 10.7 g of white bicalutamide solid. The yield is 99.1%, the melting point is 191-193°C, and the HPLC content is 99%.

Embodiment 3

[0044] The bicalutamide thioether intermediate is oxidized to synthesize bicalutamide, and isobutyraldehyde (7.2g, 9.1ml, 0.1mol) is replaced with pivalaldehyde (8.6g, 10.8ml, 0.1mol), and other operations are the same as in the examples 1.

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Abstract

The invention discloses a new process of preparing bicalutamide by utilizing air for oxidizing a bicalutamide thioether intermediate, and the process comprises the following steps: taking N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylthio)-2-methyl-hydroxy-propionamide as a compound raw material, dissolving in a reaction solvent, further adding aldehyde, a free radical initiator and a catalyst, using the air for carrying out oxidation for 1-25h at the reaction temperature of -20-50 DEG C, and finally preparing the bicalutamide; the mass using quantity of the reaction solvent is 3-10 times of the mass of the compound raw material; the ratio of the molar using quantity of the aldehyde to the molar using quantity of the compound raw material is 0.1-5.0; the ratio of the molar using quantity of the free radical initiator to the molar using quantity of the compound raw material is 0.05-5%; and the ratio of the molar using quantity of the catalyst to the molar using quantity of the compound raw material is that: the metal catalyst is 0.01-1%; and the non-metal catalyst is 0.01-2%. The new process has the advantages of only consuming oxygen in the air, improving atom economy, reducing cost, not producing environmental pollution and achieving green environmental protection; the post-treatment is simple and easy to operate, and the produced acid can be recycled; a product can be obtained by direct filtration, the yield is near to 100%, the HPLC purity can be more than 99%, and the safety is high, thereby being suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation process of an antineoplastic drug bicalutamide, in particular to a new process for preparing bicalutamide by air oxidation of a bicalutamide sulfide intermediate. Background technique [0002] Bicalutamide, as a non-steroidal antiandrogen compound, can feedback-inhibit the secretion of gonadotropes from the anterior pituitary gland, which can reduce the production of androgen but has almost no androgen activity. Bicalutamide was successfully developed by British company Astra Zeneca and first launched in the UK in 1995. This drug is used to treat prostate cancer, and it is the most widely used antiandrogen drug. Prostate cancer has a high incidence worldwide and is the second leading cause of death among men. Inhibiting the level of androgen in the body is a common method for the treatment of prostate cancer. Bicalutamide has been widely used in the treatment of prostate cancer because of its strong efficacy, c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C317/46C07C315/02
Inventor 顾华平郑飞
Owner 宁波人健化学制药有限公司
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