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Method for preparing chiral beta-trifluoromethyl-beta-hydroxy-alpha-amino acid and derivatives thereof

A technology of trifluoromethyl and trifluoromethyl ketone, applied in the field of compound preparation, can solve the problems of few methods, many reaction steps, harsh conditions and the like

Active Publication Date: 2020-06-12
SHANGHAI NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Known methods for synthesizing chiral β-trifluoromethyl β-hydroxy-α-amino acid esters are less or require more reaction steps and harsh conditions

Method used

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  • Method for preparing chiral beta-trifluoromethyl-beta-hydroxy-alpha-amino acid and derivatives thereof
  • Method for preparing chiral beta-trifluoromethyl-beta-hydroxy-alpha-amino acid and derivatives thereof
  • Method for preparing chiral beta-trifluoromethyl-beta-hydroxy-alpha-amino acid and derivatives thereof

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Experimental program
Comparison scheme
Effect test

preparation example Construction

[0062] In the preparation process of the above-mentioned chiral pyridoxal catalyst, according to the needs of the obtained object product, R 1 , R 2 , R 3 Can be adjusted arbitrarily within the following ranges:

[0063] R 1 Can be hydrogen or C 1 -C 24 Hydrocarbyl, R 2 and R 3 independently hydrogen or C 1 -C 24 Hydrocarbyl; R 1 The chosen C 1 -C 24 Hydrocarbyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, (1-phenyl) ethyl, 1-naphthyl, 2-naphthyl or halogen, etc.; R 2 or R 3 The chosen C 1 -C 24 Hydrocarbyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, 2-biphenyl, 3-biphenyl , 4-biphenyl, 2,6-biphenyl, 3,5-biphenyl, 1-naphthyl or 2-naphthyl, etc.

[0064] In addition, the types and dosages of the corresponding reagents can also be adjusted as needed within the following ranges (i.e. choose any midpoint or end value):

[0065...

Embodiment 1

[0070] Synthesis of chiral β-trifluoromethyl-β-hydroxy-α-amino acid ester 4a catalyzed by chiral pyridoxal catalyst (S)-1

[0071]

[0072] Trifluoromethyl ketone 3a (0.252g, 1.0mmol), glycine tert-butyl ester 2 (0.195g, 1.50mmol), CH 3 COOH (0.030g, 0.50mmol) and chiral pyridoxal catalyst (S)-1 (0.0005g, 0.001mmol) were added to a 5mL reaction flask, a stirring bar was added, a rubber stopper was covered, and the N 2 Three times, inject CH 2 Cl 2 (4.0 mL), reacted at -10°C for 48 hours, added hydroxylamine hydrochloride (HONH 2 HCl, 0.070g, 1.0mmol) and sodium bicarbonate (NaHCO 3 , 0.084g, 1.0mmol), stirring at room temperature for 1 hour, spin off the organic solvent, column chromatography to obtain compound anti-4a (light yellow solid) and syn-4a (light yellow solid), (the total product weight 0.324g, total Yield 85%).

[0073] The dr value of 4a is obtained by 1 H NMR analysis of the reaction crude product, its dr value is 1:5; the ee value of anti-4a is obtained...

Embodiment 2

[0077] Synthesis of chiral β-trifluoromethyl-β-hydroxy-α-amino acid ester 4b catalyzed by chiral pyridoxal catalyst (S)-1

[0078]

[0079] Trifluoromethyl ketone 3b (0.278g, 1.0mmol), glycine tert-butyl ester 2 (0.195g, 1.50mmol), CH 3 COOH (0.030g, 0.50mmol) and chiral pyridoxal catalyst (S)-1 (0.0005g, 0.001mmol) were added to a 5mL reaction flask, a stirring bar was added, a rubber stopper was covered, and the N 2 Three times, inject CH 2 Cl 2 (4.0mL), reacted at -10°C for 48 hours, added hydroxylamine hydrochloride (HONH 2 HCl, 0.070g, 1.0mmol) and sodium bicarbonate (NaHCO 3 , 0.084g, 1.0mmol), stirring at room temperature for 1 hour, spin off the organic solvent, column chromatography to obtain compound anti-4b (light yellow solid) and syn-4b (light yellow solid), (the total product weight 0.372g, total Yield 91%).

[0080] The dr value of 4b is obtained by 1 H NMR analysis of the reaction crude product, its dr value is 1:6; the ee value of anti-4b is obtained ...

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Abstract

The invention relates to a method for preparing chiral beta-trifluoromethyl-beta-hydroxy-alpha-amino acid and derivatives thereof, which specifically comprises the following steps: weighing tert-butylglycinate and derivatives thereof, trifluoromethyl ketone, acid and chiral N-methyl pyridoxal catalyst, adding a solvent, and carrying out a reaction to generate the target product chiral beta-trifluoromethyl-beta-hydroxy-alpha-amino acid and derivatives thereof. Compared with the prior art, the pyridoxal catalyst does not need to protect and deprotect amino, and simple, so that convenient and efficient synthesis of the chiral beta-trifluoromethyl-beta-hydroxyl-alpha-amino acid derivative is achieved.

Description

technical field [0001] The invention belongs to the technical field of compound preparation, and relates to a method for preparing chiral β-trifluoromethyl-β-hydroxy-α-amino acid and derivatives thereof. Background technique [0002] In organisms, compounds containing free amino groups can directly participate in the reaction. For example, under the catalysis of enzymes, glycine can undergo aldol reaction with electrophile aldehyde to generate β-hydroxyl α-amino acid. The reaction conditions are mild, and glycine does not require any Protection is directly involved in the response. In this reaction, the active center of the enzyme is vitamin B 6 , which exists mainly in the form of phosphate derivatives (PMP and PLP) in the body, is a water-soluble vitamin, and its main function is to participate in reactions catalyzed by various enzymes as a coenzyme factor. The chemists discovered that pyridoxal can also induce the addition of glycine to aldehydes in the absence of enzym...

Claims

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Application Information

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IPC IPC(8): C07C227/16C07C229/36C07C229/28C07C229/30C07F7/18B01J31/02C07B41/02
CPCC07C227/16C07F7/1892C07D213/65B01J31/0271B01J31/0247C07B41/02C07B2200/07C07C2601/14B01J2231/341C07C229/36C07C229/28C07C229/30
Inventor 赵宝国章亮亮赵国庆程奥林
Owner SHANGHAI NORMAL UNIVERSITY
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