Preparation method of tetra-substituted olefin and its pyrazole derivatives

A tetra-substituted, alkene technology, used in the preparation of organic compounds, the preparation of aminohydroxy compounds, chemical instruments and methods, etc., can solve the problems of poor stereoselectivity, harsh reaction conditions, and complicated preparation routes, and achieve simple steps and reaction conditions. Mild, inexpensive and easily available effects

Inactive Publication Date: 2014-03-05
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 by the corresponding alkane (Hungarian Patant178253,1979) or the corresponding alcohol dehydration (Nemeth, G.; Kapiller-Dezsofi, R.; Lax, G.; Simig, G.Tetrahedron1996,52, 12821), but the stereoselectivity of the product is poor, and the product is a mixture of (Z) and (E) configurations, which requires multiple recrystallizations to obtain (Z)-Tamoxifen
Miller and Itami prepared (Z)-Tamoxifen and its derivatives stereospecifically by using the carbometalation reaction of alkynyl silane, but the preparation route was cumbersome (up to nine steps), the reaction conditions were harsh, and the raw materials were 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 derivatives
  • Preparation method of tetra-substituted olefin and its pyrazole derivatives
  • Preparation method of tetra-substituted olefin and its pyrazole derivatives

Examples

Experimental program
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Effect test

Embodiment 1

[0030]

[0031] 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, 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 was obtained (100 mg, yield 97%). Intermediate products were confirmed by NMR and high-resolution mass spectrometry.

[0032] Under a nitrogen atmosphere, add 3a (103mg, 0.50mmol), phenylhydrazine 4a (65mg, 0.60mmol), potassium tert-butoxide (112mg, 1.0mmol) and 5mL solvent tert-butanol to a 25mL reaction flask in sequ...

Embodiment 2

[0034] 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

[0036] 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 pyrazole derivatives and a clinic breast cancer treatment drug tetra-substituted olefin (Z)-Tamoxifen from sulfopolysubstituted olefin. The method comprises the following steps: carrying out a condensation cyclization reaction of a raw material alpha-carbonyloxo ketene monothioacetal and a nucleophilic reagent hydrazine to prepare the pyrazole derivatives; and carrying out a coupling reaction of the alpha-carbonyloxo ketene monothioacetal raw material and arylboric acid to prepare the tetra-substituted olefin Tamoxifen. Compared with pyrazole derivatives and (Z)-Tamoxifen prepared through reported preparation methods, the above products in the invention have the advantages of good regioselectivity and stereoselectivity, easily available raw materials, 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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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/12C07D405/04C07D409/04C07D401/04C07C217/18C07C213/08C07D307/46
CPCC07C213/08C07C217/18
Inventor 余正坤金伟伟
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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