Method for efficiently synthesizing chiral 1,2-amino alcohol by catalyzing alpha-aminoketone through Ir/f-amphox

An aminoketone and aminoalcohol technology, applied in the directions of organic chemistry methods, chemical instruments and methods, preparation of organic compounds, etc., can solve the problems of high cost, limited industrialization potential, difficulty in synthesizing chiral ligands, etc. High industrial value, good catalytic effect

Active Publication Date: 2017-08-08
WUHAN CATALYS TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis of spiro series chiral ligands is difficult and costly, which greatly limits the industrial potential of this system

Method used

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  • Method for efficiently synthesizing chiral 1,2-amino alcohol by catalyzing alpha-aminoketone through Ir/f-amphox
  • Method for efficiently synthesizing chiral 1,2-amino alcohol by catalyzing alpha-aminoketone through Ir/f-amphox
  • Method for efficiently synthesizing chiral 1,2-amino alcohol by catalyzing alpha-aminoketone through Ir/f-amphox

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Preparation of 2-(benzyl(methyl)amine)-1-phenylethanol from 2-(benzyl(methyl)amine)-1-acetophenone hydrochloride

[0029]

[0030] Under high-purity argon atmosphere, [Ir(COD)Cl] 2 (1.34mg, 2μmmol) and chiral ligand (2.32mg, R= t Bu, 4 μmmol) was dissolved in isopropanol (2 mL) and stirred at room temperature for 3 hours to obtain a clear orange solution. Take 100 μL of the orange clear solution, dilute it to 10 times the volume with isopropanol, take 20 μL (0.002 mol%) of the orange solution with a microsyringe, and add it to 2-(benzyl(methyl)amine)-1-acetophenone In a mixed system of hydrochloride (0.2mmol), isopropanol (2mL) and potassium tert-butoxide (1.3mol%). The reaction system was placed in an autoclave at room temperature and H 2 (40atm) and stirred for 12 hours. The solvent was removed under reduced pressure and separated by column chromatography (using a silica gel column, eluent: ethyl acetate) to obtain the pure product 2-(benzyl (methyl)...

Embodiment 2

[0031] Example 2: Preparation of 2-(benzyl(methyl)amine)-1-phenylethyl alcohol from 2-(benzyl(methyl)amine)-1-acetophenone hydrochloride (S / C=500 000)

[0032]

[0033] Under high-purity argon atmosphere, [Ir(COD)Cl] 2 (1.34mg, 2μmmol) and chiral ligand (2.32mg, R= t Bu, 4 μmmol) was dissolved in isopropanol (2 mL) and stirred at room temperature for 3 hours to obtain a clear orange solution. Take 100 μL of the orange clear solution, dilute it to 10 times the volume with isopropanol, take 40 μL (0.0002 mol%) of the orange solution with a microsyringe, and add it to 2-(benzyl(methyl)amine)-1-acetophenone In a mixed system of hydrochloride (4mmol), isopropanol (5mL) and potassium tert-butoxide (1.3mol%). The reaction system was placed in an autoclave at 30 °C and H 2 (40atm) and stirred for 48 hours. The solvent was removed under reduced pressure and separated by column chromatography (using a silica gel column, eluent: ethyl acetate) to obtain the pure product 2-(benzyl ...

Embodiment 3

[0034] Example 3: Preparation of 2-(benzyl (methyl)amine)-1-(4 '-methylphenyl)ethanol

[0035]

[0036] Under high-purity argon atmosphere, [Ir(COD)Cl] 2 (1.34mg, 2μmmol) and chiral ligand (2.32mg, R= t Bu, 4 μmmol) was dissolved in isopropanol (2 mL) and stirred at room temperature for 3 hours to obtain a clear orange solution. Take 100 μL of the orange clear solution, dilute it to 10 times the volume with isopropanol, take 20 μL (0.002 mol%) of the orange solution with a microsyringe, and add it to 2-(benzyl(methyl)amine)-1-(4' -in a mixed system of methylphenyl)ethanone hydrochloride (0.2mmol), isopropanol (2mL) and potassium tert-butoxide (1.3mol%). The reaction system was placed in an autoclave at room temperature and H 2 (40atm) and stirred for 12 hours. The solvent was removed under reduced pressure and separated by column chromatography (using silica gel column, eluent: ethyl acetate) to obtain pure product 2-(benzyl(methyl)amine)-1-(4'-methylphenyl)ethanol , ...

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Abstract

The invention discloses a method for efficiently synthesizing chiral 1,2-amino alcohol by catalyzing alpha-aminoketone through Ir / f-amphox. A ligand f-amphox used by the method can be more easily synthesized; the reaction has the characteristics of enantioselectivity, high yield and high TON (turn over number); most substrates achieve the conversion rate being 99 percent or higher and the ee value being 99 percent or higher under the condition of the catalyst dosage being 0.002 mol% (S / C=50000); the highest TON reaches 500000 and is the maximum value reported at the present. The chiral 1,2-amino alcohol can be successfully used for the synthesis of a series of important medicines; important significance is realized on medicine industrial production.

Description

technical field [0001] The invention relates to the field of organic and pharmaceutical synthetic chemistry, in particular to a method for efficiently synthesizing chiral 1,2-aminoalcohols by catalyzing α-aminoketones with Ir / f-amphox. Background technique [0002] Chiral 1,2-aminoalcohol is an important fragment that widely exists in a variety of drug molecules and natural products, such as (R)-phenylephrine, (R)-salbutamol, (R)-denopamine, (R)- Adrenaline, (R)-clorprenaline, (R)-arbutamine, (R)-mirabegron, (R)-Indacaterol, (R)-eluglustat, etc. At the same time, chiral 1,2-amino alcohols are widely used as chiral auxiliary agents and ligands in the field of asymmetric synthesis. [0003] [0004] Due to the great industrial value of chiral 1,2-amino alcohols in pharmaceutical and other fields, people have conducted in-depth research on the methodology of synthesizing chiral 1,2-amino alcohols, and developed a number of synthetic routes. Ultimately, asymmetric hydrogena...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C215/30C07C217/70C07D333/20C07D213/38C07C215/60
CPCC07B2200/07C07C213/00C07D213/38C07D333/20C07C215/30C07C217/70C07C215/60
Inventor 张绪穆胡杨武卫龙董秀琴
Owner WUHAN CATALYS TECH CO LTD
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