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Application of chiral aminophenol ligand to asymmetric synthesis of efavirenz

A technology of efavirenz and aminophenol, applied in the field of asymmetric synthesis of chiral aminophenol ligands in efavirenz, can solve the problems of chiral resolution and application lag

Active Publication Date: 2014-09-03
SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Aminophenol compounds have been synthesized as early as the beginning of the last century, but their chiral resolution and application are lagging behind

Method used

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  • Application of chiral aminophenol ligand to asymmetric synthesis of efavirenz
  • Application of chiral aminophenol ligand to asymmetric synthesis of efavirenz
  • Application of chiral aminophenol ligand to asymmetric synthesis of efavirenz

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] (S)-6-Chloro-4-cyclopropynyl-4-trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazin-2-one (Efavirenz) asymmetric synthesis

[0054]Add (R)-1-(phenyl(pyrrolidin-1-yl)methyl)naphthalene-2-alcohol (23mg, 0.75mmol) and zinc p-toluenesulfonate (20mg, 0.5mmol) to the sealed tube, and extract Ventilate, add cyclopropylacetylene (0.4mL), triethylamine (0.14mL, 10mmol), stir for 3h, add (4-chloro-2-trifluoroacetylphenyl) ethyl carbamate (30mg, 0.1 mmol), the reaction was stirred at room temperature for 24h. Organic solvent such as ethyl acetate (EA) was transferred, washed with 6M hydrochloric acid, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Column chromatography, (S)-(4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)carbamic acid Ethyl ester 35.5mg, yield 96%, ee value 81%. (The separation here is only for data analysis, and this step of separation may not be performed during actual synthesis)

[0055] 1 H NMR (300MHz, ...

Embodiment 2

[0065] (S)-6-Chloro-4-cyclopropynyl-4-trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazin-2-one (Efavirenz) asymmetric synthesis

[0066] Add (R)-1-(phenyl(pyrrolidin-1-yl)methyl)naphthalene-2-alcohol (68mg, 2.25mmol) and zinc p-toluenesulfonate (61mg, 1.5mmol) to the sealed tube, and extract Ventilate, add cyclopropylacetylene (0.4mL), triethylamine (0.14mL, 10mmol), stir for 8h, add (4-chloro-2-trifluoroacetylphenyl) ethyl carbamate (30mg, 0.1 mmol), the reaction was stirred at room temperature for 24h. Add water to quench, extract with EA, wash with 6M hydrochloric acid, wash with saturated sodium chloride, and dry over anhydrous sodium sulfate. After concentration, add toluene to reflux reaction for 4 hours to obtain 31.1 mg of efavirenz with a yield of 98% and an ee value of 91%.

Embodiment 3

[0068] (S)-6-Chloro-4-cyclopropynyl-4-trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazin-2-one (Efavirenz) asymmetric synthesis

[0069] Add (R)-2-(phenyl(pyrrolidin-1-yl)methyl)naphthalene-1-ol (68mg, 2.25mmol) and zinc p-toluenesulfonate (61mg, 1.5mmol) to the sealed tube, and extract Ventilate, add cyclopropylacetylene (0.4mL), triethylamine (0.14mL, 10mmol), transfer to 40°C oil bath, stir for 3h, add (4-chloro-2-trifluoroacetylphenyl) carbamic acid Ethyl ester (30mg, 0.1mmol), stirred at room temperature for 24h. Add water to quench, extract with EA, wash with 6M hydrochloric acid, wash with saturated sodium chloride, and dry over anhydrous sodium sulfate. After concentration, add toluene to reflux reaction for 4 hours to obtain 31.5 mg of efavirenz with a yield of 94% and an ee value of 95%.

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Abstract

The invention relates to an application of a chiral aminophenol ligand to asymmetric synthesis of efavirenz. A chiral aminophenol ligand compound is used for inducing asymmetric synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazine-2-ketone (Efavirenz). The ligand is cheap, easily available, safe and recoverable, is used in asymmetric synthesis of efavirenz, and has the advantages of high yield, good enantioselectivity, simplicity and convenience in operation, capability of realizing industrialized production and good product quality.

Description

technical field [0001] The invention relates to the application of a chiral aminophenol ligand in the asymmetric synthesis of efavirenz. The chiral aminophenol ligand compound is used to induce (S)-6-chloro-4-cyclopropynyl-4- Asymmetric synthesis of trifluoromethyl-1,4-dihydro-2H-1,3-benzoxazin-2-one (Efavirenz). The ligand is cheap, easy to obtain, safe and recyclable; used in the asymmetric synthesis of efavirenz, and has the advantages of high yield, good enantioselectivity, simple operation, industrial production and good product quality. Background technique [0002] Aminophenol compounds have been synthesized as early as the beginning of last century, but their chiral resolution and application are lagging behind. In 1998, Naso et al. reported that chiral aminophenol was used in the asymmetric addition of diethylzinc to aromatic aldehydes, and an enantioselectivity of 99% could be obtained. In the ensuing years, chiral aminophenols have been increasingly used in asym...

Claims

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Application Information

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IPC IPC(8): C07D265/18B01J31/22
CPCC07C215/50C07D265/18B01J31/1805B01J31/182B01J31/2217B01J31/2252B01J2231/341B01J2531/26
Inventor 姜标李晓贤李金华邢萍
Owner SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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