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Method for preparing abiraterone acetate

A technology of alcohol acetate and catalyst, applied in the direction of steroids, organic chemistry, etc., can solve the problems of high price, high price and high cost of trifluoromethanesulfonic anhydride, achieve good application prospects, easy post-processing, and promote smooth progress Effect

Active Publication Date: 2013-01-30
ZHEJIANG SHENZHOU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] This route has the following disadvantages: (1) trifluoromethanesulfonic anhydride is expensive and toxic; (2) in the process of forming enol, it is accompanied by the elimination of 3-position acetic acid to generate 3,4-double bond
[0013] The above-mentioned two foreign synthesis routes have relatively large disadvantages. Because the (3-pyridyl)-diethylborane and triphenylphosphine palladium chloride used in the reaction are expensive, the cost is relatively high when applied to industrial production

Method used

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  • Method for preparing abiraterone acetate
  • Method for preparing abiraterone acetate
  • Method for preparing abiraterone acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the preparation of compound shown in formula 5

[0042]

[0043] Add 3 g (10.4 mmol) of compound 3β-hydroxydhydrocorticosterone (Formula 4) into a 250 ml flask, and stir to dissolve with 75 mL of dichloromethane. 2.74 g (22.5 mmol) of 4-dimethylaminopyridine (DMAP), 3.3 mL (23.7 mmol) of triethylamine, and 4.5 g (29.8 mmol) of tert-butyldimethylsilyl chloride (TBDMSCl) were slowly added in portions. Stir at 25°C for 15 hours. Extract with 100ml of dichloromethane solution, wash the organic phase with 10% ammonium chloride solution and saturated brine, and dry over anhydrous sodium sulfate. Concentration under reduced pressure, followed by recrystallization to obtain about 4.1 g of compound 5, with a yield of about 97%.

[0044] 1 H NMR (300MHz, CDCl 3 )δ0.06(s, Me 2 Si), 0.88(s, Me(18)), 1.03(s, Me(19)), 0.89(s, t-Bu), 3.49(m, H-C(3)), 5.34(b r.d, J=5 ,H-C(6));

[0045] 13 C NMR (CDCl 3 ,100MHz)δ221.2,142.2,120.4,72.6,51.8,50.3,47.6,42.8,37.2,36....

Embodiment 2

[0047] Embodiment 2: the preparation of compound shown in formula 6

[0048]

[0049]

[0050] Add 37.6g (153.0mmol) of dry cerium trichloride to a 1L flask, add 300ml of pre-cooled anhydrous tetrahydrofuran at 0°C, slowly raise the temperature to 25°C and stir for 2 hours, then cool to 0°C for later use.

[0051] In another 1L flask, 4.4g (183.6mmol) of magnesium chips, 200ml of anhydrous tetrahydrofuran, and 14.8ml (153.0mmol) of 3-bromopyridine were added, and the mixture was refluxed at 80°C for 3 hours. After cooling to 0°C, it was added to the above pre-prepared cerium trichloride solution. After stirring at 0°C for 2 hours, slowly add 4.1 g (10.2 mmol) of tetrahydrofuran solution of 3β-(tert-butyldimethyl)silyloxydorcorticosterone (Formula 5) dropwise, and react at 0°C for 4 hours, Add water to quench. Concentrate under reduced pressure to remove tetrahydrofuran, extract with chloroform, wash the organic layer with saturated brine, and dry over anhydrous sodium ...

Embodiment 3

[0055] Embodiment 3: the preparation of compound shown in formula 7

[0056]

[0057] Add 4.5g of the compound (Formula 6) prepared above into a 1L flask, dissolve it in 100mL of anhydrous dichloromethane, slowly add 58.2ml (418.3mmol) of triethylamine, 63.8ml (793.6mmol) of pyridine, Methanesulfonyl chloride 4.6ml (59.1mmol). After reacting at 25°C for 3 hours, concentrate under reduced pressure to remove pyridine, add chloroform and water to extract, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized to obtain 3.3g of compound 7, two steps The total yield is about 70%.

[0058] 1 H NMR (300MHz, CDCl 3 )δ8.62(s,H-Py),8.46(d,H-Py),7.65(d,H-Py),7.21(t,H-Py),5.99(s,H-C(16)),5.34 (b r.d, H-C(6)), 3.50(m, H-C(3)), 1.04(s, Me(18)), 1.06(s, Me(19)), 0.89(s, t-Bu), δ0 .06(s, Me 2 Si);

[0059] 13 C NMR (CDCl 3 ,100MHz)δ151.6,147.9,147.8,141.8,133.6,132.9,129.2,122.9,120.8,72.5,57....

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Abstract

The invention provides a method for preparing (3beta)-17-(3-pyridyl)-androstane-5,16-diene-3-alcohol acetate. According to the method, the traditional Grignard addition reaction is adopted, pyridine groups are introduced in the presence of a catalyst such as cerous chloride, the method is low in raw material cost, available in raw materials, economical, practical, environment-friendly, convenient and simple in post-treatment, the reaction process is easily and continuously operated, the product quality and yield can be improved, and industrial production is promoted.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing (3β)-17-(3-pyridyl)-androst-5,16-dien-3-ol acetate (abiraterone acetate) (Equation 1) new method. Background technique [0002] Abiraterone acetate is an orally effective irreversible inhibitor of CYP17 enzyme developed by Centocor Ortho, which was approved by the US FDA on April 28, 2011. Zytiga is used in combination with prednisone to treat castration-resistant prostate cancer. On July 28, 2011, Zytiga was approved by Health Canada. In men with prostate cancer, the hormone testosterone stimulates tumor growth, and drug or surgical treatment can reduce testosterone production or block the effects of testosterone. But even with low testosterone levels, prostate cancer can continue to grow. Abiraterone targets and inhibits the activity of the enzyme cytochrome P45017 A1, which regulates testosterone production, reducing testosterone produc...

Claims

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Application Information

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IPC IPC(8): C07J43/00
Inventor 李援朝杜娟娟王友富王均良王荣
Owner ZHEJIANG SHENZHOU PHARMA
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