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Method for realizing high-stereoselectivity synthesis of Toremifene by configuration conversion method

A technology of stereoselectivity and toremifene, applied in the field of medicine and chemical industry, achieves the effects of high stereoselectivity, high reaction yield and easy operation

Inactive Publication Date: 2011-07-20
NINGBO TEAM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The main problem that this method exists is that when triaryl butanediol (III) is eliminated in hydrochloric acid ethanol, the generated triaryl butenol (IV) has Z / E configuration, and the ratio of the two is about 2: 1, And there are 5% cyclization by-products (VII)
Unfortunately, when we repeated the reaction conditions, in most cases, we did not obtain the results reported by the patent, and the results showed that, contrary to the conclusion of the patent, the E-type isomer was the main form in the reaction solution, which indicated that Explain that the patent is basically an invalid patent

Method used

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  • Method for realizing high-stereoselectivity synthesis of Toremifene by configuration conversion method
  • Method for realizing high-stereoselectivity synthesis of Toremifene by configuration conversion method
  • Method for realizing high-stereoselectivity synthesis of Toremifene by configuration conversion method

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Effect test

example 1

[0034] 8.10 g (20 mmol) of triarylbutanediol was suspended in 80 ml of concentrated hydrochloric acid, heated to 65° C., and the solid was completely dissolved, and stirring was continued for 2 hours. TLC (silica gel plate, CH 2 Cl 2 : CH 3 OH=9:1 development, UV detection) showed that the triarylbutanediol had disappeared and three spots mainly appeared. Rf0.75, accounting for about 5%, is the cyclization product (VII), Rf0.60, accounting for about 10%, is Z-type triarylbutenol; Rf0.50, accounting for about 85%, is E-type triaryl butenol.

[0035] The above mixture was gradually cooled to 40°C, and under vigorous stirring and induced by seed crystals, the reaction mixture began to become mixed and a solid precipitated. After 10 hours a large amount of solid precipitated out. TLC detection of the precipitated solid showed only the point of Rf 0.60, indicating that it was Z-type triarylbutenol hydrochloride. The TLC in the solution shows that there are almost no cyclizati...

example 2

[0038] Suspend 8.10 g (20 mmol) of triaryl butanediol in 80 ml of concentrated hydrochloric acid, stir at room temperature for 1 hour, then stir at 35°C for 15 hours, then cool to 10°C and stir for more than 2 hours, collect the resulting solid by filtration, and Suspend it in 150ml toluene, alkalinize carefully with 100ml 10% aqueous sodium hydroxide solution, separate the water layer and wash with 2×25ml water, dry over anhydrous sodium sulfate, filter and concentrate to a total volume of about 30ml, 0~5℃ After standing overnight, the precipitated white solid was collected and air-dried to obtain 6.8 g of white solid, m.p.119°C, yield 89%. The purity was 99% by HPLC.

example 3

[0040] Suspend 8.10g (20mmol) of triarylbutanediol in 40ml of concentrated hydrochloric acid, stir at room temperature for 1 hour, then stir at 35°C for 3 hours, then stir at 45°C for 7 hours, add 40ml of water to dilute for filtration, and then cool to 10°C Stir for 2 hours. By the same operation as above, 6.5 g of Z-type triaryl butenol was obtained, with a yield of 84%.

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Abstract

The invention discloses a method for realizing high-stereoselectivity synthesis of Toremifene (Z-type). In the method, configuration conversion is performed on an intermediate triaryl butenol under acid catalysis; and the required Z-type triaryl butenol is separated out continuously according to the difference of solubility, so that balance is damaged and E-type triaryl butenol is converted into the Z-type triaryl butenol continuously. The obtained Z-type triaryl butenol is chloridized by thionyl chloride to obtain an antitumor medicament, namely the Toremifene.

Description

technical field [0001] The invention relates to a stereoselective synthesis method of an antitumor drug toremifene, and belongs to the field of medicine and chemical industry. Background technique [0002] Toremifene is an estrogen receptor antagonist anti-tumor drug developed by the Finnish company Famos in 1983. It was marketed in the European Union by Orion in 1996 under the trade name Fareston. It entered my country in 2002 under the trade name Fare Pass. Our company was approved by my country's SFDA in 2002 and listed in China under the trade name of Shurui. [0003] Toremifene is an analog of tamoxifen (Tamoxifen), which is a triarylbutene structure, and its mechanism of action is similar to that of tamoxifen. It is an anti-estrogen drug. Toremifene is administered orally in the form of citrate, but the dose is calculated as toremifene, 60 mg orally per day. [0004] The chemical name of toremifene is: (Z)-4-chloro-1,2-diphenyl-1-[4-(2-(N,N-dimethylamino)ethoxy)pheny...

Claims

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Application Information

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IPC IPC(8): C07C217/18C07C213/08C07C213/00
Inventor 吕刚黄道飞
Owner NINGBO TEAM PHARMA
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