Synthetic method of abiraterone acetate and intermediate thereof

A technology of abiraterone acetate and a synthesis method, which is applied in chemical instruments and methods, steroids, androstane derivatives, etc., can solve the problems of difficult control of synthesis process, complicated reaction, low yield of key steps, etc. The effect of reducing the probability of side reactions, improving yield and purity, and high reactivity

Active Publication Date: 2020-12-25
HUNAN NORCHEM PHARMACEUTICAL CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Among them, the trifluoromethanesulfonate method is to use dehydroepiandrosterone acetate as a starting material, which is esterified by trifluoromethanesulfonic anhydride, and the final coupling reaction is to obtain abiraterone acetate; the preparation of the trifluoromethanesulfonate method The process is controllable and the product has high purity, but the raw material trifluoromethanesulfonic acid is expensive and not suitable for large-scale production
The iodo method is to use dehydroepiandrosterone as the starting material, and obtai...

Method used

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  • Synthetic method of abiraterone acetate and intermediate thereof
  • Synthetic method of abiraterone acetate and intermediate thereof
  • Synthetic method of abiraterone acetate and intermediate thereof

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preparation example Construction

[0035] One embodiment of the present invention provides a method for synthesizing an abiraterone acetate intermediate, comprising the following step S10.

[0036] Step S10, performing a chlorination reaction on the compound of formula (I), a chlorinating agent and a base to obtain an intermediate of abiraterone acetate; wherein, the mass ratio of the compound of formula (I) to the base is 1:(1.5~3); (I) The structures of the compound and the Abiraterone acetate intermediate are as follows:

[0037]

[0038] Formula (I) compound, chlorination reagent and alkali are carried out chlorination reaction, obtain the abiraterone acetate intermediate; Wherein the mass ratio of control formula (I) compound and alkali is 1:(1.5~3); The chlorination reagent The reaction activity is high. At the same time, by controlling the mass ratio of the compound of formula (I) and the base to 1: (1.5-3), the selectivity of the chlorination reaction is improved, so that the chlorination reaction ca...

Embodiment 1

[0094] 1) Put 400g of absolute ethanol, 72g of 80% hydrazine hydrate, and 100g of dehydroepiandrosterone into a three-necked flask in sequence, start stirring, then raise the temperature to 35°C, add 0.5g of hydrazine sulfate, and keep the reaction at 35°C for 20 hours. Then use TLC spot plate detection, the results show that the raw materials have reacted completely, then pump the reaction solution into ice water for water analysis, centrifuge after stirring for 40 minutes, rinse the filter cake with water, dry the wet material at 50°C for 30 hours, and obtain compound Ⅰ . The calculation results showed that the yield of compound Ⅰ was 98.5%.

[0095] Yield of compound I = molar amount of compound I / molar amount of dehydroepiandrosterone × 100%

[0096] 2) Take 100g of the intermediate I obtained in step 1), dissolve it with 800g of dichloromethane, and make a reserve solution for subsequent use. Put 1000g of dichloromethane into the three-necked bottle, cool down to -5°C, ...

Embodiment 2

[0103] Example 2 is substantially the same as Example 1, except that 300 g of tetramethylguanidine is added dropwise in step 2) of Example 2, and other steps and process parameters are the same as in Example 1.

[0104] After calculation, the yield of the abiraterone acetate intermediate is 83.6%, and the purity is 99.0%.

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Abstract

The invention relates to a synthetic method of abiraterone acetate and an abiraterone acetate intermediate. According to the synthetic method of the abiraterone acetate intermediate, chlorination reaction is carried out on a compound as shown in a formula (I), a chlorination reagent and alkali to obtain the abiraterone acetate intermediate as shown in a formula (II); the mass ratio of the compoundshown in the formula (I) to the alkali is controlled to be 1: (1.5-3); the structures of the compound shown as the formula (I) and the abiraterone acetate intermediate are described in the descriptions of the invention. The synthetic method can reduce the occurrence probability of side reaction in the chlorination process while maintaining high reaction activity, so that the yield and purity of the abiraterone acetate intermediate are improved, and the process is simple.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of abiraterone acetate and an intermediate thereof. Background technique [0002] Abiraterone acetate (ZYTIGA) is converted into abiraterone in the body. Abiraterone is an inhibitor of cytochrome oxidase P450 (CYP450)c17, which can inhibit androgen synthesis by inhibiting CYP450c17 enzyme, while CYP450c17 enzyme It is also the key to the synthesis of hormones in the testis and other parts of the human body. By inhibiting the synthesis of hormones, it can help patients with advanced prostate cancer prolong their lives, and has great application prospects and social significance. [0003] At present, there are three main synthetic routes of abiraterone acetate: triflate method, iodo method and Grignard method. Among them, the trifluoromethanesulfonate method is to use dehydroepiandrosterone acetate as a starting material, which is esterified by triflu...

Claims

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Application Information

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IPC IPC(8): C07J1/00C07J43/00
CPCC07J1/0003C07J43/003
Inventor 曾培玮曾春玲靳志忠刘喜荣黄成
Owner HUNAN NORCHEM PHARMACEUTICAL CO LTD
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