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Method for asymmetrically synthesizing chiral quaternary carbon compound containing trifluoromethyl

A technology of trifluoromethyl and carbon compounds, applied in organic chemistry and other directions, can solve the problems of low yield, non-reaction, poor reaction activity, etc., and achieve the effect of high reaction yield and high optical purity

Inactive Publication Date: 2015-07-01
CHINA AGRI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] Compounds containing trifluoromethyl groups have extensive and important applications in medicine, pesticides and materials (Nature, 2011, 473, 470-477; Chem.Rev.2008, 108, 1–43; J.Med.Chem.2014, 57,2989-3004; J.Med.Chem.2014,57,9522-9538) Due to the large steric hindrance of the quaternary carbon center, the reaction activity is usually poor, the yield is low or even no reaction, so the preparation of quaternary carbon compounds containing trifluoromethyl is a major challenge in fluorine chemistry

Method used

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  • Method for asymmetrically synthesizing chiral quaternary carbon compound containing trifluoromethyl
  • Method for asymmetrically synthesizing chiral quaternary carbon compound containing trifluoromethyl
  • Method for asymmetrically synthesizing chiral quaternary carbon compound containing trifluoromethyl

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Experimental program
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Effect test

Embodiment 1

[0031] Synthesis of 2-trifluoromethyl-2-phenyl-1-nitroethene:

[0032] Add lithium trifluoroacetate (3g, 25mmol) and magnesium chips (0.6g, 25mmol) to a dry 100mL single-necked bottle, replace the N 2 Three times, add THF (tetrahydrofuran 20mL) under ice bath, stir for 5min and then add bromobenzene (4.71g, 30mmol) dropwise. After the reaction is complete, add 10 mL of aqueous HCl solution with a concentration of 1 mol / L to the reaction flask, stir for 5 minutes and then filter with suction. After adding water, extract the obtained filtrate with 3×50 mL of ethyl acetate, combine the organic phases and wash with concentrated brine, anhydrous sodium sulfate After drying and desolvation, the crude product was obtained, which was separated by silica gel column (volume ratio ethyl acetate:petroleum ether=1:50) to obtain yellow liquid trifluoromethyl phenyl ketone (0.87g, 20% yield).

[0033] Add trifluoromethyl phenyl ketone (1.25g, 7.18mmol) to a 100mL single-necked bottle, then ...

Embodiment 2

[0036] Synthesis of (R)-3-trifluoromethyl-4-nitro-3-phenyl-1-(2-thiazole)-1-butanone:

[0037]

[0038] Add bisoxazoline ligand 9.2mg (0.0275mmol) to a dry 10mL round bottom flask, Ni(AcAc) 2 (6.5mg, 0.0254mmol), add 1mL of isopropanol under nitrogen protection, stir at room temperature for 30min, then add 2-acetylthiazole (32.4mg, 0.25mmol) dissolved in 0.2mL of isopropanol, and stir at 0°C for 30min , add 0.3 mL of 2-trifluoromethyl-2-phenyl-1-nitroethylene dissolved in isopropanol. After adding the sample, react at 0°C for 24h. After the reaction was completed, the reaction mixture was directly separated and purified by silica gel chromatography (ethyl acetate:petroleum ether=1:10, volume ratio) after desolvation under reduced pressure to obtain a white solid 3-trifluoromethyl-4-nitro- 3-Phenyl-1-(2-thiazole)-1-butanone 81.8 mg (99% yield).

Embodiment 3

[0040] (R)-3-trifluoromethyl-3-phenyl-4-nitro-1-(2-pyridine)-1-butanone:

[0041]

[0042] Add bisoxazoline ligand 9.2 mg (0.0275 mmol), Ni(AcAc) to a dry 10 mL round bottom flask 2 (6.5 mg, 0.0254 mmol), add 1 mL of isopropanol, stir at room temperature for 30 minutes under nitrogen protection, then add 2-acetylpyridine (30.25 mg, 0.25 mmol) dissolved in 0.2 mL of isopropanol, and stir at 0 ° C for 30 minutes , 2-trifluoromethyl-2-phenyl-1-nitroethylene (81.4 mg, 0.375 mmol) dissolved in 0.3 mL of isopropanol was added. After adding the sample, react at 0°C for 24h. After the reaction was completed, the reaction mixture was directly separated and purified by silica gel chromatography (ethyl acetate:petroleum ether=1:4, volume ratio) after desolvation under reduced pressure to obtain a white solid 3-trifluoromethyl-4-nitro- 3-Phenyl-1-(2-pyridine)-1-butanone 80.3 mg (95% yield).

[0043] m.p.: 148-149°C; [α]=–16.24 (c=0.46, CH 2 Cl 2 ); 92%ee, determined by HPLC analys...

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Abstract

The invention belongs to the technical field of an organic synthesis method, and particularly relates to a method for asymmetrically synthesizing a chiral quaternary carbon compound containing trifluoromethyl. The method comprises the following step: reacting trifluoromethyl nitroolefin with a 2-acetylaza aromatic compound to asymmetrically synthesize (R)-3- trifluoromethyl-3-nitryl methyl-1-(aza aromatic ring-2-yl)-butyl-1-acetone under the catalysis of bisoxazoline chiral ligand and a nickel catalyst in an organic solvent by adopting asymmetrically catalytic Michael addition reaction. The method is high in reaction yield and high in optical purity. The method disclosed by the invention can be used for a preparation tool for providing a trifluoromethyl quaternary carbon chiral compound.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis methods, in particular to a method for asymmetrically synthesizing trifluoromethyl-containing chiral quaternary carbon compounds. Background technique [0002] Compounds containing trifluoromethyl groups have extensive and important applications in medicine, pesticides and materials (Nature, 2011, 473, 470-477; Chem.Rev.2008, 108, 1–43; J.Med.Chem.2014, 57,2989-3004; J.Med.Chem.2014,57,9522-9538) Due to the large steric hindrance of the quaternary carbon center, the reaction activity is usually poor, the yield is low or even no reaction, so the preparation of quaternary carbon compounds containing trifluoromethyl It is a great challenge of fluorine chemistry. At present, the method for synthesizing the quaternary carbon chiral center compound containing trifluoromethyl mainly contains: one, nitromethane is to the β containing trifluoromethyl, and the Michael addition reaction of β-disub...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/24C07D213/50C07D263/32C07D277/64C07D233/64C07D241/12C07D241/42C07D215/14C07D239/74
CPCC07D213/50C07D215/14C07D233/64C07D239/74C07D241/12C07D241/42C07D263/32C07D277/24C07D277/64
Inventor 傅滨侯绪和麻红利张振华覃兆海
Owner CHINA AGRI UNIV
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