Stereoselective synthesis of chiral β-amino trifluoromethyl alcohol: development of a manufacturing process for a key intermediate in the production of a novel elastase inhibitor, AE-3763

We have successfully synthesized chiral β-amino trifluoromethyl alcohol (2S,3S)-7a, which is a key intermediate in the production of AE-3763, by stereoselective reduction of N-Cbz-protected 5-hydroxy-5-(trifluoromethyl)-1,3-oxazolidine 4 prepared from L-valine in 3 steps followed by alkaline hydrolysis. This new method can be applied to the industrial-scale synthesis of AE-3763.

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Benzyl (S)-5-oxo-4-(propan-2-yl)-1,3-oxazolidine-3-carboxylateC14H17NO4[α]D24=+98.2 (c 1.0, CHCl3)Source of chirality: l-valine as starting materialAbsolute configuration: (4S)

Benzyl (4S,5R)-5-hydroxy-4-(propan-2-yl)-5-(trifluoromethyl)-1,3-oxazolidine-3-carboxylateC15H18F3NO4[α]D24=+48.2 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5R)

Benzyl [(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl]carbamateC14H18F3NO3[α]D24=-20.3 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S)

(4S,5S)-3-Benzyl-4-(propan-2-yl)-5-(trifluoromethyl)-1,3-oxazolidin-2-oneC14H16F3NO2[α]D24=-48.1 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5S)

(4S,5R)-3-benzyl-4-(propan-2-yl)-5-(trifluoromethyl)-1,3-oxazolidin-2-oneC14H16F3NO2[α]D24=-15.0 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5R)

(4S,5R)-3-Hydroxymethyl-4-(propan-2-yl)-5-(trifluoromethyl)-1,3-oxazolidin-2-oneC14H16F3NO2[α]D24=+9.5 (c 0.2, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5R)