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The synthetic method of toremifene

A synthesis method and toremifene technology are applied in chemical instruments and methods, preparation of organic compounds, preparation of aminohydroxy compounds, etc., and can solve the problems of low product synthesis rate and poor stereoselectivity, and achieve high stereoselectivity, The effect of easy separation and increased reaction yield

Active Publication Date: 2016-08-24
ASYMCHEM LAB TIANJIN +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The present invention aims to provide a synthetic method of toremifene to solve the problem that the poor stereoselectivity of the Z-type triaryl butenol intermediate in the prior art leads to a low synthesis rate of the product

Method used

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  • The synthetic method of toremifene
  • The synthetic method of toremifene
  • The synthetic method of toremifene

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preparation example Construction

[0033]In a typical embodiment of the present invention, a synthetic method of toremifene is provided, the synthetic method comprises: Step S1, making the compound B having the structural formula II react with the compound C having the structural formula III in a McMurray reaction , to obtain a compound D having the structural formula IV; Step S2, making the compound D and the compound E having the structural formula V or the hydrochloride of the compound E undergo a selective alkylation reaction on the phenolic hydroxyl group to obtain a compound F having the structural formula VI; Step S3, reacting compound F with thionyl chloride to obtain toremifene, wherein the structural formula II is: Structural formula III is: Structural formula IV is Structural formula Ⅴ is ClCH 2 CH 2 N(CH 3 ) 2 ; Structural formula Ⅵ is

[0034] The synthetic route of above-mentioned synthetic method is as follows:

[0035]

[0036] The above-mentioned synthetic route that the present ...

Embodiment 1

[0050] Synthesis of Z configuration compound D:

[0051] Add 130.8g (2mol) zinc powder and 1.5L THF to the 5L reaction flask, stir evenly to form the first mixed system, control the temperature of the first mixed system to be lower than -15°C, and slowly add 189.7g ( 1mol) of titanium tetrachloride, the dropwise addition is completed, and the second mixed system is formed after continuing to stir for 2 hours; the temperature of the second mixed system is controlled at 20-25°C, and 156.2g (0.8mol) Compound B and 1.5L tetrahydrofuran solution of 150g (1mol) compound C form a third mixed system. After the dropwise addition, the temperature of the third mixed system is raised to 60-65°C. After stirring for 5 hours, the temperature is lowered to 25°C to obtain the first Product system; slowly pour the first product system into 2L of water, add sodium carbonate to neutralize until the pH value of the first product system is between 9 and 10 to obtain the first neutralization system,...

Embodiment 2

[0057] Synthesis of Z configuration compound D:

[0058] Add 294.2g (4.5mol) of zinc powder and 2.25L of ethylene glycol dimethyl ether into a 5L reaction bottle, stir evenly to form the first mixed system, control the temperature of the first mixed system to be lower than -15°C, and slowly transfer to the first mixed system Add 462.6g (3mol) titanium trichloride dropwise to the mixture, after the dropwise addition is complete, continue to stir for 2 hours to form the second mixed system; control the temperature of the second mixed system to be 20-25°C, and slowly add dropwise the second mixed system containing 237.8g (1.2mol) of compound B and 150g (1mol) of compound C in 2.25L ethylene glycol dimethyl ether solution form a third mixed system, after the dropwise addition is completed, the temperature of the third mixed system is raised to 60-65°C, kept stirring for 5 Hours later, cool down to 25°C to obtain the first product system; slowly pour the first product system into 2L ...

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Abstract

The invention provides a synthetic method of toremifene. The synthesis method comprises: step S1, making a MacMurray reaction between compound B having structural formula II and compound C having structural formula III to obtain compound D having structural formula IV; step S2, making compound D react with compound E having structural formula V or The hydrochloride of compound E undergoes a selective alkylation reaction on the phenolic hydroxyl group to obtain compound F with structural formula VI; step S3, reacting compound F with thionyl chloride to obtain toremifene, wherein structural formula II is : Structural formula III is: Structural formula IV is Structural formula Ⅴ is ClCH 2 CH 2 N(CH 3 ) 2 ; Structural formula Ⅵ is The stereoselectivity of the obtained compound D is higher, so when using it as an intermediate to synthesize toremifene, the reaction yield of the toremifene of the Z configuration can be increased, and the toremifene of the Z configuration can be improved. purity; and the process is stable, the reaction conditions are mild, the intermediates are easy to separate, and can be used for large-scale production.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a synthesis method of toremifene. Background technique [0002] Toremifene, the chemical name is (Z)-4-chloro-1,2-diphenyl-1-[4-(2-(N,N-dimethylamino)ethoxy)benzene Base]-1-butene, having structure I. Toremifene is an analogue of Tamoxifen (Tamoxifen), which has anti-estrogen activity and can be used to treat hormone-dependent breast cancer, while its E-type isomer has estrogen activity, and the existence of E-type isomer May counteract the antiestrogenic activity of toremifene, so the isomeric purity of toremifene is critical. Toremifene was developed by Finnish company Famos in 1983. It was launched in the European Union by Orion in 1996 under the trade name of Fareston. It entered my country in 2002 under the trade name of Fareston. [0003] [0004] R.J.Toivola etc. disclose the synthetic route of toremifene in European patent EP95875, U.S. Patent US469...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C213/08C07C217/18
Inventor 洪浩詹姆斯·盖吉李九远张恩选
Owner ASYMCHEM LAB TIANJIN
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