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Preparation method of high-purity abiraterone acetate

A technology of abiraterone acetate and dehydroepiandrosterone acetate, which is applied in the field of preparation of abiraterone acetate and intermediates, can solve the difficulty of post-processing and production operations, the high price of trifluoromethanesulfonic acid, and unsuitability for industrialization No bad smell, low cost, easy to operate, etc.

Active Publication Date: 2013-07-10
LIANYUNGANG RUNZHONG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this salt-forming method avoids column purification, when the methanesulfonic acid of CN101044155 is salified, it forms a thick suspension, which is difficult to filter, and the filter cake obtained by filtering is sticky and easily retains impurities, with a purity of about 89%. The purity is not high, and it obviously contains impurities such as pigmented substances, raw materials, and hydrolyzed abiraterone
The trifluoromethanesulfonic acid used in CN102030798 is expensive, easy to produce acid mist, also has strong corrosion, serious corrosion to equipment, difficult post-processing and production operations, serious air pollution, so it is not suitable for large-scale industrial production

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] The preparation of embodiment 1 compound (IV) and abiraterone acetate crude product

[0046] (1) Preparation of compound (IV)

[0047]

[0048] N 2 Under protection, after cooling 1.5L of dichloromethane to -10~-5°C, add 150g of dehydroepiandrosterone (III) acetate, 7.5g of dimethylaminopyridine (DMAP), 200g of Na 2 CO 3 . Add Tf slowly 2 O 180g, 1 ~ 1.5h drop, continue to react for 2 ~ 3h. Add 1.5 L of ice water to quench, separate the liquids, extract the aqueous phase with dichloromethane (0.5 L), combine the organic phases, wash 4 times with 1.5 L of water, dry over anhydrous sodium sulfate, and concentrate to obtain about 203 g of a purple-black oily compound ( IV), yield 96.6%.

[0049] (2) Preparation of Abiraterone Acetate Crude Product

[0050]

[0051] Formula IV compound (203g), THF (1.5L), Pd(PPh 3 ) 2 Cl 2 (2.7g), diethyl-(3-pyridine)borane (72g) and 2M Na 2 CO 3 (0.75L). Heat to an external temperature of 80°C, and react for 4 to 5 hours...

Embodiment 2～7

[0059] Embodiment 2~7: the preparation of compound (IV) and abiraterone acetate crude product

[0060] Use each material and consumption in Table 1 to obtain compound (IV) according to the method of embodiment 1 (1), then obtain the crude product of abiraterone acetate with reference to the method of embodiment 1 (2), wherein the consumption of each material can be adjusted appropriately according to the situation , the results are shown in Table 1.

[0061] Table 1:

[0062]

Embodiment 8

[0063] The preparation method of embodiment 8 high-purity abiraterone acetate

[0064]

[0065] Prepare the crude product of abiraterone acetate according to Example 1, take 100 g of the crude product of abiraterone acetate prepared in Example 1, add 400 ml of methanol, add 100 ml of 10% NaOH aqueous solution under stirring, stir for 4 hours, filter, and add 500 ml of dichloride to the filter cake Methane was heated to dissolve, washed twice with 200ml of water, dichloromethane was concentrated, and dried under reduced pressure at 50°C for 4h to obtain 78.5g of (II) as a solid.

[0066]

[0067] At room temperature, add 78.5g (II), 500ml of dichloromethane, and 35g of triethylamine, and slowly add acetyl chloride (the molar ratio of compound (II) is 4 equivalents) dropwise under stirring, and the dropwise addition is completed within 1 hour. The reaction was continued for 5 h. After the reaction was completed, 200 ml of water was added to wash 3 times. The organic phase ...

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Abstract

The invention relates to a preparation method of high-purity abiraterone acetate. The preparation method comprises that dehydroepiandrosterone acetate and trifluoromethanesulfonic anhydride undergo a sulfonylation reaction in the presence of an inorganic base. The preparation method obviously improves the yield of abiraterone acetate, greatly reduces by-products, has a low cost and no odor or strong smell, can be operated easily and is especially suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of a medicine preparation method, in particular to a preparation method of abiraterone acetate and an intermediate. Background technique [0002] Abiraterone acetate is a key enzyme in androgen synthesis, 17α-hydroxylase-C17, 20-lyase (also known as steroid 17α-monooxygenase inhibitor or human cytochrome P450 17α ) is a potent and selective oral inhibitor for the treatment of prostate cancer. On April 28, 2011, the FDA approved abiraterone acetate in combination with prednisone for the treatment of metastatic castration-resistant prostate cancer in patients previously treated with docetaxel chemotherapy. The chemical name of Abiraterone acetate is (3β)-17-(3-pyridyl)-androst-5,16-dien-3-ol acetate, and its structural formula is as follows: [0003] [0004] The synthetic method of abiraterone acetate has prior art disclosure (WO9320097, WO9509178, J.Med.Chem, 1995, Vo38 (13), 2463-2471, Org.Prep.Proced....

Claims

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Application Information

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IPC IPC(8): C07J31/00C07J43/00
CPCC07J43/003
Inventor 郭猛王华张喜全
Owner LIANYUNGANG RUNZHONG PHARMA CO LTD
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