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A method for the synthesis of chiral fluorine-containing propargylamine derivatives by biomimetic catalytic asymmetric hydrogenation

A biomimetic catalysis, asymmetric technology, applied in the preparation of organic compounds, organic chemical methods, preparation of amino compounds, etc., to achieve the effects of high chemical selectivity and enantioselectivity, specific products, and convenient separation

Active Publication Date: 2018-09-04
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

However, there is no report on the green, efficient, and atom-economical synthesis of chiral propargylamine compounds alkyne by selective asymmetric hydrogenation of C=N.

Method used

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  • A method for the synthesis of chiral fluorine-containing propargylamine derivatives by biomimetic catalytic asymmetric hydrogenation
  • A method for the synthesis of chiral fluorine-containing propargylamine derivatives by biomimetic catalytic asymmetric hydrogenation
  • A method for the synthesis of chiral fluorine-containing propargylamine derivatives by biomimetic catalytic asymmetric hydrogenation

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Embodiment 1: optimization of conditions

[0036] Add weighed (4-isopropyltoluene) ruthenium iodide dimer (0.001 mmol, 1.0 mg) and chiral phosphoric acid (0.0004 mmol), 8-methylphenanthridine (0.02 mg mol, 3.8 mg), fluoroalkynyl imine (0.2 mmol), 1,2-dichloroethane 2.0 ml, stirred for 2-5 minutes. Then put the ampule bottle into a stainless steel autoclave, feed hydrogen 1000psi, and react at room temperature for 20-48 hours. Slowly release hydrogen, remove the solvent with a rotary evaporator, and then directly column chromatography (the volume ratio of eluent petroleum ether and ethyl acetate is 30:1) to separate the pure product, the reaction formula and the ligand are as follows:

[0037]

[0038] The yield is the isolated yield, and the enantiomeric excess of the product is determined by chiral liquid chromatography, see Table 1.

[0039] Table 1. Screening of solvents and chiral phosphoric acids

[0040]

[0041] [a] Reaction conditions: 1a (0.1mmol), CPA...

Embodiment 2

[0042]Example 2: Synthesis of Chiral Fluorine-Containing Propargylamine Derivatives by Biomimetic Catalytic Asymmetric Selective Hydrogenation

[0043] Add weighed (4-isopropyltoluene) ruthenium iodide dimer (0.001 mmol, 1.0 mg) and chiral phosphoric acid ((R)-3f, 0.0004 mmol) to the ampoule, 8-methyl Kiphenanthridine (0.02 mmol, 3.8 mg), fluoroalkynyl imine (0.2 mmol), 1,2-dichloroethane 2.0 ml, stirred for 2-5 minutes. Then put the ampule bottle into a stainless steel autoclave, feed hydrogen 1000psi, and react at room temperature for 20-48 hours. Slowly release hydrogen, remove the solvent with a rotary evaporator and then directly column chromatography (the volume ratio of eluent sherwood oil and ethyl acetate is 30:1) to separate and obtain pure product, the reaction formula is as follows:

[0044]

[0045] (R)-4-Methoxy-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2-yl)aniline(2a): 95% yield, pale yellow oil, R f =0.60(petroleum ether / ethyl acetate=30 / 1), 95%ee, [α] 20 D =...

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Abstract

The method for synthesizing chiral fluorine-containing propargylamine derivatives by biomimetic catalysis asymmetric hydrogenation uses ruthenium and chiral phosphoric acid as the catalytic system. Reaction can be carried out in following conditions, temperature: 25-100 ℃; Solvent: 1,2-ethylene dichloride; Pressure: 13-80 atmospheric pressure; The ratio of substrate and catalyst is 100 / l; Catalyst is (4- cymene) ruthenium iodide dimer and chiral phosphoric acid. The selective hydrogenation of fluorine-containing alkynyl-substituted imines affords the corresponding chiral fluorine-containing propylamine derivatives with an enantiomeric excess of up to 98%. The invention has the advantages of simple and practical operation, readily available raw materials, high enantioselectivity, good yield, and the reaction has the advantages of green atom economy and environmental friendliness.

Description

technical field [0001] The invention relates to a method for synthesizing chiral fluorine-containing chiral propargylamine derivatives by hydrogenating fluorine-containing substituted alkynyl imines with high chemoselectivity and enantioselectivity using a biomimetic catalytic system. Background technique [0002] Chiral propargylamines are important synthons for the synthesis of many natural products, drugs, and complex chemical molecules, often possessing broad-spectrum physiological and pharmacological activities. These compounds have a variety of potential pharmaceutical activities, such as: anti-AIDS, sedative, hypnotic, anti-inflammatory and diuretic properties. A large number of studies have shown that the selective introduction of fluorine atoms or fluorine-containing groups into organic molecules can significantly change the physiological activity of the original molecules and increase their lipophilicity. Therefore, the research on the synthesis and biological act...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C213/02C07C217/84C07C209/52C07C211/52C07C211/47C07C211/46B01J31/22
CPCC07C209/52C07C213/02B01J31/2295C07B2200/07B01J31/0258B01J2531/0213B01J2231/643B01J2531/821B01J35/19C07C217/84C07C211/52C07C211/47C07C211/46
Inventor 周永贵陈木旺吴波陈章培孙蕾
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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