Practical and efficient synthesis of the (R)-atropisomer of a 4-phenyl 1,2,4-triazole derivative as a selective GlyT1 inhibitor

Herein we describe a novel and efficient method for synthesizing the (R)-atropisomer of 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile 1, a novel GlyT1 inhibitor. The diastereomeric salt formation of 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzoic acid 7 with (1R,2S)-(−)-2-amino-1,2-diphenylethanol afforded the desired (R)-atropisomer. We also report the determination of the absolute configuration of (R)-7 by powder X-ray diffraction.

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(1R,2S)-2-Amino-1,2-diphenylethanol(−)-(R)-3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzoateC23H20N4O2·C14H15NO[α]D25=-163 (c 1.0, MeOH)Source of chirality: resolutionAbsolute configuration: (R)

(−)-(R)-3-[3-Ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzoic acidC23H20N4O2[α]D25=-200 (c 1.0, CHCl3)Source of chirality: resolutionAbsolute configuration: (R)

(−)-(R)-3-[3-Ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzamideC23H21N5O[α]D25=-170 (c 1.0, CHCl3)Source of chirality: resolutionAbsolute configuration: (R)

(−)-(R)-3-[3-Ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrileC23H19N5ee = 99.8%[α]D25=-211 (c 1.0, CHCl3)Source of chirality: resolutionAbsolute configuration: (R)