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Preparation method of bicalutamide intermediate

A technology for bicalutamide and intermediates, which is applied in the field of preparation of anti-androgen drugs bicalutamide intermediates, can solve high problems, can spontaneously ignite in humid air, and is released when heated or in contact with moisture and acids. Heat and hydrogen, the quality of finished products is difficult to guarantee, and it is difficult to industrialize production, etc., to achieve the effect of low cost, good product quality and low price

Inactive Publication Date: 2010-11-24
HANGZHOU MINSHENG PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in the condensation with p-fluorothiophenol, sodium hydrogen hydrogen, an expensive reagent, is used, which has high chemical reactivity and can spontaneously ignite in moist air; when heated or in contact with moisture and acids, heat and hydrogen are released, causing combustion and Explosion; it can react strongly with oxidants, causing combustion or explosion; when it encounters moisture and water, it will form hydroxide, which is very corrosive
Therefore, the reaction conditions are very harsh. When adding reagents, it is required to be at 0°C, and it needs to be carried out under the protection of nitrogen. The reaction solvent tetrahydrofuran needs to be dehydrated. The reaction yield is low, it is difficult to realize industrial production, and the quality of the finished product is difficult to guarantee.

Method used

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  • Preparation method of bicalutamide intermediate
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  • Preparation method of bicalutamide intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0021] The preparation of embodiment 1, 4'-cyano-3-[(4-fluorophenyl) sulfur]-2-hydroxyl-2-methyl-3'-(trifluoromethyl)propionanilide

[0022] In the reaction vessel, add 20ml of dimethylformamide, 1,2-epoxy-2-methyl-N-[4'-cyano-3'-(trifluoromethyl)phenyl]propionamide 5g, four 0.10g of butyl ammonium bromide, 2g of potassium carbonate, stirring and dissolving, adding 2.8g of p-fluorothiophenol, slowly heating to 50-60°C for 16 hours, cooling to room temperature, adding 100ml of water, extracting with diethyl ether twice, anhydrous Na 2 SO 4 dry. The solvent was recovered to obtain 7.7 g of solid. Recrystallized from petroleum ether to obtain 6.7g, m.p 115-117°C, yield 91%.

Embodiment 2

[0023] Embodiment 2, the preparation of 4'-cyano-3-[(4-fluorophenyl)sulfur]-2-hydroxyl-2-methyl-3'-(trifluoromethyl)propionanilide

[0024] Add 20ml of dimethylformamide, 1,2-epoxy-2-methyl-N-[4'-cyano-3'-(trifluoromethyl)phenyl]propionamide 5g, carbonic acid Potassium 2.5g, stirred and dissolved, added 2.8g of p-fluorothiophenol, slowly heated to 50-60°C and reacted for 16 hours, and the remaining treatment methods were the same as in Example 1 to obtain 6.8g of solid, m.p115-116°C, yield 92.2 %.

Embodiment 3

[0025] Example 3, (R)-(-)4'-cyano-3-[(4-fluorophenyl)sulfanyl]-2-carbonyl-2-methyl-3'-(trifluoromethyl) Preparation of Propionanilide

[0026] Add 40ml of dimethylformamide to the reactor, (R)-(-)3-bromo-2-hydroxyl-2-methyl-N-[4-cyano-3-(trifluoromethylphenyl) ] Propionamide 12.7g, salt of wormwood 3g, stir and dissolve and add p-fluorothiophenol 4.9g, stir slowly and heat to 50~60 ℃ and react for 16 hours, all the other treatment methods are the same as embodiment 1, get solid 13.2g, m.p 93~ 96°C, yield 92%.

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Abstract

The invention provides a preparation method of bicalutamide intermediate shown in the formula (II) and the method is more reasonable and more suitable for industrial production. The method comprises the following steps: adding compound (I), potassium carbonate and p-fluorophenol in reaction solvent, stirring while slowly heating the mixture to reaction temperature 30-80 DEG C, reacting for 12-18 hours, extracting, and purifying. The method of the invention is performed under mild conditions, the reagent potassium carbonate is accessible, the price is cheap and the method does not have burning and blast hazards, and the use security is high. Agents are added at room temperature without the protection of nitrogen, the reaction solvent does not need special treatment, the reaction yield is more than 75%, the raw material cost is greatly reduced and the method is more suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of an antiandrogen drug bicalutamide intermediate. Background technique [0002] Bicalutamide, chemical name (±)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2 -Hydroxyl-2-methylpropionamide, its structural formula is as follows: [0003] [0004] Bicalutamide is an anti-androgen drug developed by Zeneca for the combined treatment of advanced prostate cancer, and its trade name is Casodex. It is a non-steroidal anti-androgen drug recorded in the 32nd edition of the United States Pharmacopoeia with definite curative effect, strong specificity of action, effective oral administration, convenient administration, good tolerance, and a long half-life. It is currently the only oral One-time (50mg / tablet) drug for treating prostate cancer. [0005] At present, there are two kinds of preparation techniques that are more suitable for practical use reported in literature at home and abroad...

Claims

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Application Information

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IPC IPC(8): C07C323/60C07C319/14
Inventor 李艳芹庄胜利倪旭晖
Owner HANGZHOU MINSHENG PHARM CO LTD
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