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Preparation method of tetra-substituted olefin and its pyrazole derivative

A technology for pyrazole derivatives and substituents, which is applied in the field of preparation of tetrasubstituted olefins and pyrazole derivatives, can solve the problems of harsh reaction conditions, poor stereoselectivity, and cumbersome preparation routes, and achieve simple steps, easy operation, The effect of cheap and easy-to-obtain raw materials

Inactive Publication Date: 2012-08-01
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(Z)-Tamoxifen is generally dehydrogenated from the corresponding alkanes (Hungarian Patant 178253, 1979) or dehydrated from the corresponding alcohols (Nemeth, G.; Kapiller-Dezsofi, R.; Lax, G.; Simig, G. Tetrahedron 1996, 52, 12821), but the stereoselectivity of the product is poor, and the product obtained is a mixture of (Z) and (E) configurations, and multiple recrystallizations are required to obtain (Z)-Tamoxifen
Miller and Itami have prepared (Z)-Tamoxifen and its derivatives stereospecifically by using the carbometalation reaction of alkynyl silane, but the preparation route is cumbersome (up to nine steps), the reaction conditions are harsh, and the raw materials are rare (Miller, R.B.; Al-Hassan, M.I.J.Org.Chem.1985, 50, 2121; Kamei, T.; Itami, K.; Yoshda, J.Adv.Synth.Catal.2004, 346, 1824)

Method used

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  • Preparation method of tetra-substituted olefin and its pyrazole derivative
  • Preparation method of tetra-substituted olefin and its pyrazole derivative
  • Preparation method of tetra-substituted olefin and its pyrazole derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]

[0030] Under nitrogen atmosphere, α-carbonyl dithioketene 5b (95mg, 0.50mmol), arylboronic acid 6b (91mg, 0.75mmol), Pd(PPh 3 ) 4 (43mg, 0.0375mmol), CuTC (191mg, 1.0mmol), Cs 2 CO 3 (326mg, 1.0mmol) and 5mL solvent THF were stirred at 50°C for 2h. After the reaction was finished, the mixture was cooled to room temperature, the reaction solution was filtered with diatomaceous earth, the filter cake was washed with 10 mL of dichloromethane, the filtrate was decompressed to remove volatile components, and then separated by silica gel column chromatography (eluent was petroleum ether ( 60-90° C.) / ethyl acetate, v / v=30:1), the yellow liquid intermediate 3a (100 mg, yield 97%) was obtained. Intermediate products were confirmed by NMR and high-resolution mass spectrometry.

[0031] Under nitrogen atmosphere, 3a (103mg, 0.50mmol), phenylhydrazine 4a (65mg, 0.60mmol), potassium tert-butoxide (112mg, 1.0mmol) and 5mL solvent tert-butanol were added successively to a 25m...

Embodiment 2

[0033] The reaction steps and operations are the same as those in Example 1, except that the reaction temperature in the second step is room temperature 25° C., and the reaction time is 24 hours. The reaction was stopped, and the target product 1a (10 mg, yield 9%) was obtained through the same post-treatment as above. It shows that the reaction temperature decreases and the reaction becomes slower.

Embodiment 3

[0035] The reaction steps and operations are the same as in Example 1, except that the second step reaction solvent is toluene. The reaction was stopped, and the target product 1a (30 mg, yield 26%) was obtained after post-processing. It shows that the use of aprotic solvent is not conducive to the condensation and cyclization reaction of 3 and hydrazine 4.

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Abstract

The invention discloses a method for preparing a pyrazole derivative and a tetra-substituted olefin (Z)-Tamoxifen which is a clinical drug for treating the breast cancer from a polysubstituted sulfo-olefin. The pyrazole derivative is prepared by carrying out a condensation cyclization reaction on a raw material alpha-oxoketone monothioacetal which is easy to prepare and has a structure diversity and various reaction centers and a nucleophilic reagent hydrazine at a reflux temperature; and the tetra-substituted olefin (Z)-Tamoxifen is prepared by carrying out a coupling reaction on the raw material alpha-oxoketone monothioacetal and arylboric acid at 50DEG under the catalysis of Pd. Compared with reported preparation methods of the pyrazole derivative and (Z)-Tamoxifen, the preparation method makes products have the advantages of good regioselectivity and stereoselectivity, easily available raw material, simple operation, mild preparation reaction conditions, and high efficiency.

Description

technical field [0001] The invention relates to a method for preparing pyrazole derivatives and a tetrasubstituted alkene (Z)-Tamoxifen clinical drug for treating breast cancer. At reflux temperature, pyrazole derivatives are prepared by condensation and cyclization reaction of α-carbonyl monothioketene, which is easy to prepare, has structural diversity and multiple reaction centers, and nucleophile hydrazine; Under certain conditions, a tetrasubstituted olefin (Z)-Tamoxifen was prepared by stepwise coupling reaction of α-carbonyl dithioketene with aryl boronic acid. Compared with the reported preparation methods of pyrazole derivatives and (Z)-Tamoxifen, the present invention has good product regioselectivity and stereoselectivity, readily available raw materials, simple operation, mild preparation reaction conditions and high efficiency. Background technique [0002] Pyrazoles are an important class of five-membered N-heterocyclic compounds with potential biological and ...

Claims

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Application Information

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IPC IPC(8): C07D231/12C07D405/04C07D409/04C07D401/04C07C217/18C07C213/08
CPCC07C213/08C07C217/18
Inventor 余正坤金伟伟
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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