New chemo-enzymatic synthesis of (R)-1-chloro-3-(piperidin-1-yl) propan-2-ol

The present study deals with the efficient chemo-enzymatic synthesis of enantiopure (R)-1-chloro-3-(piperidin-1-yl) propan-2-ol 3, as an intermediate for (R)-arimoclomol. This intermediate was synthesized from racemic alcohol (RS)-3 using lipases with vinylacetate as the acyl donor in three different ionic liquids (1-butyl-3-methyl imidazolium tetrafluoroborate [BMIM][BF4], 1-butyl-3-methyl imidazolium hexafluorophosphate [BMIM][PF6] ,and 1-ethyl-3-methyl imidazolium tetrafluoroborate [EMIM][BF4]) in combination with an organic solvent (toluene). Various reaction parameters, such as temperature, time, substrate and enzyme concentration, and reaction medium (organic solvent and ionic liquid) were optimized using Pseudomonas aeruginosa MTCC 5113 lipases (PAL). It was observed that 30 mM of (RS)-3 and 30 mg/mL of PAL in 4 mL of solvent (toluene:[BMIM][BF4]::70:30) using vinyl acetate as the acyl donor at 30 °C gave good conversion (C = 50.02%) and enantiomeric excess (eeP = 98.91% and eeS = 99%) in 18 h. The (S)-1-chloro-3-(piperidin-1-yl) propan-2-yl acetate 4 and (R)-3 were separated by flash chromatography. Compound (R)-3 is a key intermediate for the synthesis of enantiopure arimoclomol and bimoclomol.

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(R)-1-Chloro-3-(piperidin-1-yl)propan-2-olC8H16ClNO[α]D20=-37.6 (c 1.0, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (S)

(S)-1-Chloro-3-(piperidin-1-yl)propan-2-yl acetateC10H18ClNO2[α]D20=+43.5 (c 1.0, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (R)