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Preparation method of chiral alpha-difluoromethyl phenyl ethylamine

A technology of difluoromethylphenylethylamine and difluoromethyl is applied in the field of chiral α-difluoromethylphenylethylamine compound and preparation, and can solve the problem of high cost, unobtainable raw materials, incapable of industrialized production, etc. question

Inactive Publication Date: 2013-03-20
上海药明康德新药开发有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It mainly solves the problems that the synthesis method of chiral α-difluoromethylphenylethylamine compound is complicated, the cost is high, the raw materials are not easy to obtain, and it cannot be produced industrially

Method used

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  • Preparation method of chiral alpha-difluoromethyl phenyl ethylamine
  • Preparation method of chiral alpha-difluoromethyl phenyl ethylamine
  • Preparation method of chiral alpha-difluoromethyl phenyl ethylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Embodiment 1: Preparation of (R)-α-difluoromethylphenylethylamine

[0015] 1: Preparation of (2,2-difluoromethyl-1-phenyl-ethyl)-(R)-tert-butylsulfinimide

[0016] Reaction formula:

[0017]

[0018] Steps:

[0019] Take a 1000ml round bottom flask and put it into a magnetic stirrer and a reflux condenser, add 2,2-difluoro-1-phenylethanone (74 g, 470 mmol), (R)-tert-butylene Sulfonamide (68.9 g, 570 mmol), tetraethyl titanate (159 g, 700 mmol) and 400 ml tetrahydrofuran. The reaction mixture was refluxed for 3 hours under nitrogen protection. After cooling to room temperature, the reaction solution was poured into 1L of water, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and purified by silica gel chromatography to obtain (2,2-difluoromethyl-1-phenyl-ethyl)- (R)-tert-Butylsulfinimide (89 g, 73%).

[0020] 1 : (CDCl 3 , 400 MHz) δ: 8.09 (br, 2H, Ar-H); 7.55 (m, 3H, Ar-H); 1.34 (s, 9H, t-Bu).

[0021] 2: Preparatio...

Embodiment 2

[0033] Embodiment 2: Preparation of (S)-α-difluoromethylphenylethylamine

[0034] 1: Preparation of (2,2-difluoromethyl-1-phenyl-ethyl)-(S)-tert-butylsulfinimide

[0035] Reaction formula:

[0036]

[0037] Steps:

[0038] Take a 1000ml round bottom flask and put it into a magnetic stirring bar and install a reflux condenser, add 2,2-difluoro-1-phenylethanone (66g, 420 mmol) to it, (S)-tert-butylene Sulfonamide (60 g, 500 mmol), tetraethyl titanate (134 g, 625 mmol) and 400 ml tetrahydrofuran. The reaction mixture was refluxed for 3 hours under nitrogen protection. After cooling to room temperature, the reaction solution was poured into 1L of water, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and purified by silica gel chromatography to obtain (2,2-difluoromethyl-1-phenyl-ethyl)- (R)-tert-Butylsulfinimide (80 g, 74%).

[0039] 1 : (CDCl 3 , 400 MHz) δ: 8.09 (br, 2H, Ar-H); 7.55 (m, 3H, Ar-H); 1.34 (s, 9H, t-Bu) 。

[0...

Embodiment 3

[0052] Embodiment 3: Preparation of (R)-α-difluoromethylphenylethylamine

[0053] 1: Preparation of (2,2-difluoromethyl-1-phenyl-ethyl)-(R)-tert-butylsulfinimide

[0054] Reaction formula:

[0055]

[0056] Steps:

[0057] Take a 100ml round-bottomed flask and put it into a magnetic stirrer and a reflux condenser, add 2,2-difluoro-1-phenylethanone (5 g, 32 mmol), (R)-tert-butylene Sulfonamide (5 g, 41 mmol ), tetraisopropyl titanate (14.2 g, 50 mmol) and 50 ml tetrahydrofuran. The reaction mixture was refluxed for 3 hours under nitrogen protection. After cooling to room temperature, the reaction solution was poured into 200ml of water, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and purified by silica gel chromatography to obtain (2,2-difluoromethyl-1-phenyl-ethyl)- (R)-tert-Butylsulfinimide (5.3 g, 64%).

[0058] 1 : (CDCl 3 , 400 MHz) δ: 8.09 (br, 2H, Ar-H); 7.55 (m, 3H, Ar-H); 1.34 (s, 9H, t-Bu).

[0059] 2: Prepara...

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Abstract

The invention relates to a preparation method of chiral alpha-difluoromethyl phenyl ethylamine, and mainly solves the technical problems of complex and high cost in a conventional synthesis method of the chiral alpha-difluoromethyl phenyl ethylamine compound. The preparation method of the chiral alpha-difluoromethyl phenyl ethylamine comprises the steps of a first step reaction for obtaining chiral (2,2-difluoromethyl-1-phenyl-ethyl)-tert-butyl sulfoximine (2) in a solvent via lewis acid catalytic condensation reaction and the effect with chiral tert-butanesulfinyl amide by using 2,2-difluoro-1-acetophenone (1) as a raw material; a second step reaction for obtaining chiral (2,2-difluoromethyl-1-phenyl-ethyl)-tert-butyl sulfinamide (3) by reacting the compound (2) with a reducing agent; and a third step reaction for obtaining a target product of chiral alpha-difluoromethyl phenyl ethylamine (A) by hydrolyzing the compound (3) in a mixed condition of the solvent and hydrochloric acid.

Description

technical field [0001] The invention relates to a chiral α-difluoromethylphenylethylamine compound and a preparation method. Background technique [0002] α-Fluoroamine compounds are very important synthetic intermediates in drug synthesis. α-Trifluoromethyl amino compounds have been widely used in the pharmaceutical industry, and the corresponding difluoromethyl compounds have always received less attention because they are more difficult to synthesize than trifluoromethyl compounds. (-CF2H) is the electron isostere of methylene hydroxyl (-CH2OH), and it is also a good hydrogen bond donor and a good lipophilic group, so α-difluoromethylamine is becoming more and more It has received extensive attention, and the chiral α-difluoromethylphenylethylamine compound involved in the present invention is an important member of this class of compounds. [0003] [0004] The efficient synthesis method of the chiral α-difluoromethylphenylethylamine compound that the present invent...

Claims

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Application Information

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IPC IPC(8): C07C211/29C07C209/62
Inventor 张歆宁柏祝陈先印石卫华肖贻崧贺海鹰陈曙辉
Owner 上海药明康德新药开发有限公司
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