Trifluoromethyl-containing bisoxazole compound, synthesis method thereof and application of trifluoromethyl-containing bisoxazole compound in anti-cancer drugs

A technology of trifluoromethylbisoxazole and anticancer drugs, which is applied in the field of asymmetric synthesis, and can solve the problems of limited and reduced carbanion nucleophilicity, etc.

Active Publication Date: 2021-06-04
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, α-CF 3 The types of compound-type nucleophiles and the asymmetric catalytic reactions directly involved as nucleophiles are still very limited. The main reasons are: α-CF 3 Carbanions and corresponding organometallic species generate difluoroalkene compounds via β-fluorine elimination; α-CF 3 The strong electron-withdrawing effect of the group reduces α-CF 3 Nucleophilicity of carbanions
Therefore, the development of α-CF 3 Compounds acting as nucleophiles to directly construct highly enantioselective and diastereoselective carbon-carbon (sulfur) bond formation reactions are challenging

Method used

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  • Trifluoromethyl-containing bisoxazole compound, synthesis method thereof and application of trifluoromethyl-containing bisoxazole compound in anti-cancer drugs
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  • Trifluoromethyl-containing bisoxazole compound, synthesis method thereof and application of trifluoromethyl-containing bisoxazole compound in anti-cancer drugs

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]

[0030] The synthetic steps of racemic compound 3 are as follows:

[0031] Add compound 1 (1.5eq, 0.15mmol), catalyst (0.1eq, 0.01mmol), 1mL solvent and compound 2 (1.0eq, 0.1mmol) into the reaction flask, react at 25°C for 72-96h, pass through the thin-layer plate (TLC) to monitor the reaction process, after the reaction is completed, spin the solvent to dry, and separate by column chromatography (the eluent is PE:EA=400:1-200:1, then mixed with DCM according to 4:1) to obtain Racemic compound 3. The catalyst is selected from organic or inorganic bases such as triethylamine, tetramethylguanidine, DBU, and sodium hydroxide. The solvent is selected from solvents such as halogenated alkanes, nitriles, ethers, benzenes, etc. The amount of the solvent only affects the reaction rate and has no other effects. In addition, this reaction can not only be carried out at normal temperature, but also can be carried out at low temperature and high temperature.

Embodiment 2

[0033]

[0034]

[0035]

[0036] a Unless otherwise stated, 1a (0.075mmol), Cat. (0.005mmol), 2a (0.05mmol), solvent (0.5mL). b separation yield. c The dr value was obtained by hydrogen spectrum analysis of the crude product. d The ee value was obtained by chiral column HPLC chiral analysis.

[0037]In the screening process of reaction conditions, the influence of different chiral catalysts on the reaction was first investigated (entries1-13), and it was found that C10 was the best chiral catalyst. In addition, in addition to the catalysts listed in the above table, there are many catalysts used Products with different ee values ​​can also be obtained, such as amino acid derivatives, quinines, quinidines and other alkaloid catalysts. Subsequently, the influence of different solvents on the reaction was investigated (entries 14-25), and pentafluorobenzene was finally determined to be the best solvent, and then the C10 enantiomer configuration C11 was used as the ...

Embodiment 3

[0041]

[0042] Compound 3b synthesis steps are as follows:

[0043] Add compound 1a (0.15mmol, 1.5eq), catalyst C10 (0.01mmol, 0.1eq), 1mL pentafluorobenzene and compound 2b (0.1mmol, 1.0eq) into the reaction flask, react at 25°C for 96h, and pass through a thin-layer plate (TLC) to monitor the reaction process, after the reaction is completed, spin the solvent to dry, and separate by column chromatography (the eluent is PE:EA=400:1-200:1, then mixed with DCM according to 4:1) to obtain White solid 3b, 89% yield, 94% ee. 1 H NMR (600MHz, CDCl 3 )δ7.53(d, J=8.0Hz, 2H), 7.32(d, J=8.0Hz, 2H), 4.50(dd, J=11.7, 4.8Hz, 1H), 4.03(dd, J=15.5, 11.7 Hz,1H),3.87(dd,J=15.5,4.8Hz,1H),2.44(s,3H),1.03(s,9H).

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Abstract

The invention discloses a trifluoromethyl-containing bisoxazole compound, a synthesis method thereof and application of the trifluoromethyl-containing bisoxazole compound in anti-cancer drugs, and belongs to the field of organic chemistry. 4-substituted-2-trifluoromethyl oxazolone (1) and aryl alkenyl oxazole (2) are subjected to a high-stereo and high-enantioselectivity reaction under the catalysis of a thiourea catalyst to obtain the trifluoromethyl-containing bisoxazole compound (3). The compound has certain inhibition effects on liver cancer, lung cancer, stomach cancer, esophageal cancer, breast cancer and ovarian cancer. According to the method, the raw materials are easy to obtain, the conditions are mild, the reaction efficiency is high, the reaction path is short, and the obtained trifluoromethyl-containing bisoxazole compound product has high stereoselectivity and high optical purity.

Description

technical field [0001] The invention belongs to the technical field of asymmetric synthesis in organic chemistry, and specifically relates to bisoxazole compounds containing trifluoromethyl, a synthesis method thereof and an application in anticancer drugs. Background technique [0002] Organofluorine compounds have become crucial in the development of new materials, diagnostic tools, biological research, pharmaceuticals, and agrochemicals. In these fields, F atoms or CF 3 The introduction of the group has an important impact on pKa, lipophilicity, molecular recognition, conformation and metabolic oxidation potential, and further improves the potency, selectivity, absorption and metabolism of the parent nucleus molecule. [0003] Candidates containing chiral trifluoromethyl groups have important medicinal value: Efavirenz is a non-nucleoside inhibitor of HIV type 1 reverse transcriptase (HIV-1); Befloxatone acts as a reversible Selective monoamine oxidase inhibitors are us...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/06C07D413/14A61P35/00
CPCC07D413/06C07D413/14A61P35/00C07B2200/07
Inventor 常俊标朱博李路瑶
Owner HENAN NORMAL UNIV
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