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Synthesis method of abiraterone

A technology of abiraterone and synthetic methods, applied in the production of steroids, bulk chemicals, organic chemistry, etc., can solve the problems of high risk and toxicity, high price, and many by-products, and achieve quantity and content control, Inexpensive, easy-to-operate effects

Active Publication Date: 2015-05-20
BRIGHTGENE PHARMA
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Problems solved by technology

[0009] The purpose of the present invention is to provide a new method for synthesizing abiraterone, to solve the problem that there are many by-products in the process of synthesizing abiraterone, the use of dangerous and toxic hydrazine hydrate, and the use of expensive palladium catalysts and borane The problem

Method used

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  • Synthesis method of abiraterone
  • Synthesis method of abiraterone
  • Synthesis method of abiraterone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040] step 1:

[0041] Dissolve 2.32g of compound 1 (dehydroepiandrosterone) in 50ml of anhydrous THF, add 0.22g of sodium hydride at room temperature, stir for 30 minutes, slowly inject 2.5ml of iodomethane (2.28g / ml), and then heat to Stir at 40°C for 2.5 hours, cool the reaction solution to room temperature, add 150ml of water to the reaction solution, extract with ethyl acetate (3×50ml), combine the organic layers, dry over anhydrous magnesium sulfate, filter the magnesium sulfate, evaporate solvent to obtain 2.13 g of crude compound 2-1 ((3β)-methoxydehydroepiandrosterone), with a yield of 88.4%.

[0042] 1 H-NMR (400 MHz, CDCl 3 ) δ =0.88 (s, 3H), 0.96-1.05 (m, 1H), 1.03 (s, 3H), 1.04-1.14 (m, 1H), 1.28-1.32 (m, 2H), 1.45-1.56 (m, 4H) , 1.62-1.71 (m, 3H), 1.81-1.90 (m, 3H), 1.91-1.98 (m, 1H), 2.06-2.14 (m, 2H), 2.21-2.36 (m, 2H), 2.43-2.49 ( dd, J =15.2, 8.0 Hz, 1H), 3.15 (s, 3H), 3.18-3.19 (m, 1H), 5.39 (d, J =2.0Hz, 1H)

[0043] Step 2:

[0044] ...

Embodiment 2

[0053]

[0054] step 1:

[0055] Dissolve 2.35g of compound 1 in 30ml of anhydrous THF, add 0.24g of sodium hydride at room temperature, stir for 30 minutes, dissolve 1.12g of MEMCl in 15ml of anhydrous THF, and slowly add it dropwise to the reaction solution. Above 0°C, stir for 1 hour, after rising to room temperature, add 150ml of water to the reaction solution, extract with ethyl acetate (3×50ml), combine the organic layers, dry over anhydrous magnesium sulfate, filter out anhydrous magnesium sulfate, The solvent was evaporated to obtain 2.88 g of crude product of compound 2-2 ((3β)-methoxyethoxymethoxy-17-(3-pyridyl)-androst-5-en-17-ol), yield 93.9 %.

[0056] 1 H-NMR (400 MHz, CDCl 3 ) δ =0.89 (s, 3H), 0.94-1.04 (m, 1H), 1.03 (s, 3H), 1.06-1.14 (m, 1H), 1.27-1.31 (m, 2H), 1.46-1.56 (m, 4H) , 1.64-1.74 (m, 3H), 1.80-1.90 (m, 3H), 1.92-1.98 (m, 1H), 2.03-2.12 (m, 2H), 2.22-2.36 (m, 2H), 2.43-2.48 ( dd, J =15.2, 8.0 Hz, 1H), 3.20 (s, 3H), 3.25-3.26 (m, 1H), 3.28-...

Embodiment 3

[0066]

[0067] step 1:

[0068] Dissolve 2.54g of compound 1 in 30ml of pyridine, then slowly drop into 1.91g of TMSCl (trimethylchlorosilane), stir at room temperature for 3 hours, add 60ml of water to the reaction solution, and then use ethyl acetate (3×50ml ) to extract the aqueous layer, combine the organic layers, wash the organic layer with 50ml of water and 50ml of saturated brine, and add anhydrous magnesium sulfate to dry overnight to obtain 2.86g of compound 2-3 ((3β)-trimethylsilyloxy de Hydrogen epiandrosterone) crude product, yield 90.0%.

[0069] 1 H-NMR (400 MHz, CDCl 3 ) δ =0.31 (s, 9H), 0.95 (s, 3H), 0.95-1.05 (m, 1H), 1.05 (s, 3H), 1.07-1.15 (m, 1H), 1.29-1.32 (m, 2H), 1.48 -1.57 (m, 4H), 1.67-1.76 (m, 3H), 1.85-1.99 (m, 4H), 2.05-2.17 (m, 2H), 2.28-2.39 (m, 2H), 2.45-2.51 (m, 1H), 3.25-3.26(m, 1H), 5.32(d, J =2.0Hz, 1H)

[0070] Step 2:

[0071] First, dissolve 0.43g of isopropylmagnesium chloride in 15ml of anhydrous THF, cool to 0°C in a low-t...

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Abstract

The invention relates to a synthesis method of abiraterone. The synthesis method comprises the following steps of with dehydroepiandrosterone as a raw material, carrying out ether formation protection on hydroxyl by using a protecting group to obtain a compound; next, subjecting the compound, 3-bromopyridine and a Grignard reagent to reaction to obtain 3 beta-substituted oxo-17-(3-pyridyl)-androst-5-ene-17-ol; and heating the 3 beta-substituted oxo-17-(3-pyridyl)-androst-5-ene-17-ol, acid or a dehydrant and the like in an organic solvent, dehydrating, and then, removing the protecting group of the hydroxyl to obtain the abiraterone. The method provided by the invention has the advantages of simplicity and easiness in operation, adoption of low-toxicity raw materials and particular suitability for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing Abiraterone. Background technique [0002] Prostate cancer is one of the most common solid cancers in Western countries and is the second leading cause of cancer-related death in men after lung cancer. [0003] The 3β-hydroxyacetylated derivative of Abiraterone, Abiraterone acetate, is an oral drug. The US FDA approved the combination of Abiraterone acetate and prednisone (steroids) on April 29, 2011. For the treatment of patients with advanced (metastatic) resistant prostate cancer. Abiraterone acetate is a drug that targets microchrome P45017A1 (CYP17A1), which plays an important role in the production of testosterone. The drug works by reducing the production of this hormone that stimulates cancer cells to keep growing. Because abiraterone acetate has broad commercial prospects, more and more people pay attention to it. [0004] There are mainly...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J43/00C07J1/00
CPCY02P20/55
Inventor 刘平袁建栋
Owner BRIGHTGENE PHARMA
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