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Preparation method of chiral 2-fluoromethyl phenyl ethylamine

A technology of fluoromethylphenylethylamine and fluoromethyl, which is applied in the field of preparation of chiral 2-fluoromethylphenylethylamine, can solve the problems of high cost, complex synthesis method, long synthesis route and the like, and achieves simple and convenient EFFECT OF EFFECTIVE SYNTHETIC ROUTES

Active Publication Date: 2013-03-20
SHANGHAI STA PHARMA R&D CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the problems that the current synthesis method of chiral 2-fluoromethylphenylethylamine compound is complicated, the cost is high, the synthesis route is relatively long, and it cannot be produced industrially

Method used

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  • Preparation method of chiral 2-fluoromethyl phenyl ethylamine
  • Preparation method of chiral 2-fluoromethyl phenyl ethylamine
  • Preparation method of chiral 2-fluoromethyl phenyl ethylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Embodiment 1: Preparation of (R)-2-fluoromethylphenylethylamine

[0016] 1: Preparation of (2-fluoromethyl-1-phenyl-ethyl)-(R)-tert-butylsulfinimide

[0017] Reaction formula:

[0018]

[0019] Steps:

[0020] Get a 1000ml round-bottomed flask and put it into a magnetic stirrer and install a reflux condenser, add 2-fluoro-1-phenylethanone (80 g, 579 mmol), (R)-tert-butylsulfinamide ( 80 g, 600 mmol ), tetraethyl titanate (160 g, 700 mmol) and 200 ml tetrahydrofuran. The reaction mixture was stirred at room temperature under nitrogen protection for 15 hours, the reaction solution was poured into 1L of water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain (2-fluoromethyl-1-phenyl-ethyl)-( R)-tert-butylsulfinimide crude product (98 g), this crude product was directly used in the next reaction.

[0021] 2: Preparation of (R)-(2-fluoromethyl-1-phenyl-ethyl)-(R)-tert-butylsulfinamide

[0022] Reaction formula: ...

Embodiment 2

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

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

[0035] Reaction formula:

[0036]

[0037] Steps:

[0038] Get a 1000ml round-bottomed flask and put it into a magnetic stirrer and install a reflux condenser, add 2-fluoro-1-phenylethanone (50 g, 362 mmol), (S)-tert-butylsulfinamide ( 50 g, 376 mmol ), tetraethyl titanate (100 g, 438 mmol) and 200 ml tetrahydrofuran. The reaction mixture was stirred at room temperature under nitrogen protection for 15 hours, the reaction solution was poured into 1L of water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain (2-fluoromethyl-1-phenyl-ethyl)-( S)-tert-butylsulfinimide (65 g, 75%), this crude product was directly used in the next reaction.

[0039] 2: Preparation of (S)-(2-fluoromethyl-1-phenyl-ethyl)-(S)-tert-butylsulfinamide

[0040] Reaction formula:

[0041] ...

Embodiment 3

[0051] Embodiment 3: Preparation of (R)-2-fluoromethylphenylethylamine

[0052] 1: Preparation of (2-fluoromethyl-1-phenyl-ethyl)-(R)-tert-butylsulfinimide

[0053] Reaction formula:

[0054]

[0055] Steps:

[0056] Get a 100ml round-bottomed flask and put it into a magnetic stirrer and install a reflux condenser, add 2-fluoro-1-phenylethanone (5 g, 36 mmol), (R)-tert-butylsulfinamide ( 5 g, 41 mmol ), tetraisopropyl titanate (14.2 g, 50 mmol) and 50 ml tetrahydrofuran. This reaction mixture was stirred at room temperature under nitrogen protection for 15 hours, this reaction solution was poured into 100mL water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain (2-fluoromethyl-1-phenyl-ethyl)-( R)-tert-butylsulfinimide crude product (10 g), this crude product was directly used in the next reaction.

[0057] 2: Preparation of (R)-(2-fluoromethyl-1-phenyl-ethyl)-(R)-tert-butylsulfinamide

[0058] Reaction formula: ...

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Abstract

The invention relates to a preparation method of chiral 2-fluoromethyl phenyl ethylamine, and mainly solves the technical problems of complex and high cost in a conventional synthesis method of the chiral 2-fluoromethyl phenyl ethylamine compound. The preparation method of the chiral 2-fluoromethyl phenyl ethylamine comprises the steps of a first step reaction for obtaining chiral (2-fluoromethyl-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-fluoro-1-acetophenone (1) as a raw material; a second step reaction for obtaining chiral (2-fluoromethyl-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 2-fluoromethyl phenyl ethylamine by hydrolyzing the compound (3) in a mixed condition of the solvent and hydrochloric acid.

Description

technical field [0001] The invention relates to a preparation method of chiral 2-fluoromethylphenylethylamine. Background technique [0002] 1-Arylethylamines are important intermediates in the preparation of biologically active compounds. It has been confirmed that the introduction of fluorine atoms into the α-position of the amine group can effectively reduce the electron cloud density of the nitrogen atom, thereby changing the basicity of the compound. [0003] This property can be applied to change the characteristics of the building blocks of screening drugs, increase bioavailability, reduce toxicity, and increase the metabolic stability of drugs. 1-Arylethylamine is a classic drug synthesis building block, and the modification of such building blocks with fluorine is attracting extensive attention. Although people have done a lot of research on optically active fluorinated arylethylamines, there are still few reports on the synthesis routes of monofluorinated aryleth...

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 SHANGHAI STA PHARMA R&D CO LTD
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