Novel method for preparing chromanol derivative

A compound and mixture technology, applied in the field of preparation of chiral active chromanol derivatives, can solve the problems of high production cost, inapplicability to large-scale production, low yield, etc., achieve excellent yield, and benefit large-scale The effect of large-scale production and high optical purity

Pending Publication Date: 2018-03-27
HK INNO N CORP
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the method disclosed in the above publication states a low chiral stereoselectivity of 86% ee during the first crystallization process, and a purification process is necessary to increase the chiral stereoselectivity
For these reasons, despite the high production cost and the additional purification process of the method disclosed in the above publication, the yield was very low at 58%
Moreover, since it uses silica gel column chromatography in the first solid purification, this method is not suitable for large-scale production

Method used

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  • Novel method for preparing chromanol derivative
  • Novel method for preparing chromanol derivative
  • Novel method for preparing chromanol derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: Preparation of (R)-5,7-difluorochroman-4-ol

[0063] Put 30g of triethylamine into the reactor and cool to -10°C. 27 g of formic acid were added slowly at a temperature below 10°C. 56 mg of ruthenium catalyst RuCl(p-cymene)[(R,R)-Ts-DPEN] was added to the reactor. 33 g of 5,7-difluorochroman-4-one dissolved in 87 g of tetrahydrofuran was added to the reactor at a temperature below 10°C. The reaction temperature was raised to 40°C. After the reaction was completed, it was cooled to room temperature, 293 g of ethyl acetate and 163 g of pure water were added with stirring, and the organic layer was separated. Concentrate under reduced pressure at a temperature lower than 40°C, add 222 g of heptane, stir at 25°C, and filter the resulting solid. It was then dried under vacuum at 40°C to afford (R)-5,7-difluorochroman-4-ol (30 g, 91% and 100% ee).

[0064] 1 H-NMR (270MHz, CDCl 3 )δ:6.47-6.36(m,2H),5.05-4.97(m,1H),4.36-4.20(m,2H),2.16-1.92(m,3H)ppm

[0065]...

Embodiment 2

[0066] Example 2: Preparation of (S)-5,7-difluorochroman-4-ol

[0067] Put 30g of triethylamine into the reactor and cool to -10°C. 27 g of formic acid were added slowly at a temperature below 10°C. 56 mg of ruthenium catalyst RuCl(p-cymene)[(S,S)-Ts-DPEN] was added to the reactor. 33 g of 5,7-difluorochroman-4-one dissolved in 87 g of tetrahydrofuran was added to the reactor at a temperature below 10°C. The reaction temperature was raised to 40°C. After the reaction was completed, it was cooled to room temperature, 293 g of ethyl acetate and 163 g of pure water were added with stirring, and the organic layer was separated. Concentrate under reduced pressure at a temperature lower than 40°C, add 222 g of heptane, stir at 25°C, and filter the resulting solid. It was then dried under vacuum at 40°C to give (S)-5,7-difluorochroman-4-ol (28 g, 85% and 100% ee).

[0068] 1 H-NMR: Spectrum data are the same as those of (R)-5,7-difluorochroman-4-ol (ie Example 1).

[0069] Chi...

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Abstract

The present invention relates to a novel method for preparing a chromanol derivative. According to the present invention, unlike a conventionally known optically active reduction technique, a method for preparing a chromanol derivative having optical activity has advantages of: not needing an additional purification process since chromanol, to be prepared, exhibits a high optical purity; being favorable for mass production since no severe reaction conditions are contained and no dangerous reagents are used; and having an excellent preparation yield.

Description

[0001] This application claims priority from Korean Patent Application No. 10-2015-0110248 filed in the Korean Intellectual Property Office on Aug. 4, 2015, the entire disclosure of which is incorporated herein by reference. technical field [0002] The present invention relates to a new method for preparing chromanol derivatives with chiral activity. Background technique [0003] In the fields of pharmacy and chemistry, chiral chromanol derivatives compound (chiral chromanol derivatives compound) is a substance with various activities, and there are a large number of chiral chromanol derivatives in the pharmaceuticals currently under development compound of. However, even with the same chromanol derivative compound having the same molecular formula, its medicinal effect varies depending on the three-dimensional structure. Therefore, the stereoselective synthesis of chiral chromanol derivatives is very important in medicine and organic synthesis. However, simple methods fo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/22C07F15/00B01J23/46
CPCB01J23/46C07D311/22C07F15/00
Inventor 金银仙高东贤权在洪金泳周李圣雅崔光道许承平李枝润
Owner HK INNO N CORP
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