New fulvestrant synthesis method

A technology of fulvestrant and a synthesis method, applied in the field of pharmaceutical organic chemistry synthesis, can solve problems such as increasing difficulty, increasing project cost, and long route

Active Publication Date: 2014-08-13
天津孚音生物科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the prior art has provided a synthetic method for preparing fulvestrant from intermediate X or Y, the route is still relatively long and requires column chromatography purification, which not only increases the difficulty of industrial production, but also virtually increases the project cost

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Preparation of Intermediate X:

[0046](1) Heat and melt 1 kg of industrial-grade 1,9-nonanediol, wash it with water three times, and obtain 673 g of 1,9-nonanediol containing 0.057% of 1,8-octanediol;

[0047] (2) Add 1,9-nonanediol (1 kg) to toluene (20 L), add hydrobromic acid (40%, 2.5 L) under stirring, and heat to reflux (internal temperature 90-100°C) for 24 hrs. Stop heating, cool to 40°C, add ethyl acetate (4L) and cold water (4L), stir and separate layers, the organic phase is washed with saturated sodium bicarbonate aqueous solution and aqueous solution successively, dried with anhydrous sodium sulfate, and spin-dried to obtain 1.6 kg Add 4.8 L of n-hexane to the crude product, stir and heat to dissolve, cool and crystallize to obtain 1.1 kg 9-bromo-1-nonanol.

[0048] (3) Add 9-bromo-1-nonanol (1.1 kg), N,N-dimethylformamide (2.86 L), imidazole (363 g) into a 10 L reaction flask, add di Methyl tert-butylchlorosilane (772 g), the temperature is lower than 2...

Embodiment 2

[0055] (1) Add 4,4,5,5,5-pentafluoropentanol (10 g) and dichloromethane (100 mL) into the reaction flask, add triethylamine (11.3 g), dropwise under ice-cooling Methanesulfonyl chloride (6.72 g) was added dropwise, and returned to room temperature to react for 2 hours. Excess triethylamine and methanesulfonyl chloride were washed with water, dried over anhydrous sodium sulfate, and spin-dried to obtain 14.14 g of compound II.

[0056] (2) Add 4,4,5,5,5-pentafluoropentanol (10 g), toluene (80 mL), and hydrobromic acid (40%, 26 mL) into the reaction flask in sequence, heat to reflux, and react After 24 hours, it was cooled to room temperature, washed successively with aqueous sodium bicarbonate solution and water, dried over sodium sulfate, and used directly in the next reaction.

[0057] (3) Add 4,4,5,5,5-pentafluoropentanol (10 g) and 1,2-dichloromethane (80 mL) into the reaction flask in turn, add thionyl chloride ( 6.7 g), the dropwise addition was completed, heated to 30°...

Embodiment 3

[0059] (1) Dissolve compound II (20g) in N,N-dimethylformamide (200 mL), add thiourea (6.6g), heat to reflux overnight, cool to room temperature, and put it directly into the next reaction.

[0060] (2) Add the toluene solution of compound II to the reaction flask, add methanol (20 mL) and thiourea (3.84 g) in sequence, heat to reflux overnight, cool to room temperature, extract with water (100 mL), and use the aqueous phase directly for Next reaction.

[0061] (3) Add the 1,2-dichloromethane solution of compound II into the reaction flask, add methanol (20 mL) and thiourea (3.84 g) in sequence, heat to reflux overnight, cool to room temperature, and extract with water (100 mL) , and the aqueous phase was directly used for the next reaction.

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Abstract

The invention discloses a new fulvestrant synthesis method, which comprises the following steps: by taking an intermediate X and pentafluoropentanol as starting materials, carrying out four-step reaction to obtain fulvestrant; the column chromatography purification is not required in the route, the fulvestrant meeting the pharmacopoeia criterion can be obtained only by recrystallizing the crude final product, the total yield achieves 50-60%, raw materials are all industrial products and easily available, and the quality is easily controlled.

Description

technical field [0001] The invention belongs to the technical field of organic chemical synthesis of medicines, and relates to a new synthesis method of fulvestrant, a drug for treating postmenopausal advanced breast cancer. Background technique [0002] Fulvestrant, molecular formula C 32 h 47 f 5 o 3 S, the chemical name is 7-α-[9-(4,4,5,5,5-pentafluoropentasulfinyl)nonyl]estra-1,3,5-(10)-triene- 3,17-beta-diol. [0003] [0004] [0005] Fulvestrant is a new type of anti-breast cancer drug developed by Astrazeneca. It is mainly used for the treatment of postmenopausal advanced breast cancer who are ineffective in the treatment of anti-estrogen therapy and estrogen receptor positive. Since it was launched in the United States in 2002 and approved in Europe in 2004, its good curative effect and relatively small side effects have enabled postmenopausal women with breast cancer to see the gospel. In view of the large demand and high price of fulvestrant, a large num...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J31/00
Inventor 刘文娟莫岚
Owner 天津孚音生物科技发展有限公司
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