Diisopropylethylamine → Lemborexant

Participants

Reaction Conditions

Reaction Steps

(1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-cyclopropanecarboxylic acid (13, 12.80 g, 0.040 mol, 1.0 equiv.), and 2-amino-5-fluoropyridine (4.76 g, 0.0425 mol, 1.05 equiv.) were dissolved in ethyl acetate (102.4 mL), under nitrogen. The solution was cooled to 0-5° C., and N,N-diisopropylethylamine (14.10 mL, 0.081 mol, 2.0 equiv.) was added to the reaction mixture while maintaining the internal temperature at 0-15° C. The reaction mixture was stirred at 0-10° C. for 20-30 minutes. n-Propylphosphonic anhydride (T3P; 50% w/w solution in ethyl acetate, 36.1 g, 1.4 equiv.) was added to the reaction mixture while maintaining the internal temperature at 0-15° C., The reaction was stirred at 20-25° C. for at least 20-24 hour and monitored by HPLC and TLC (EtOAc/Heptane=1/1), Upon completion of the reaction, the reaction mixture was cooled to 0-5° C. and then was quenched with water (64.0 mL) while maintaining the internal temperature below 10-15° C. The aqueous layer was back extracted once with MTBE (76.8 mL). The organic layers were combined and washed once with saturated aqueous NaHCO3 solution (38.4 mL) and once with water (38.4 mL). The organic layer was polish filtered and the filter rinsed with MTBE (12.8 mL). The organic layer was then concentrated under reduced pressure to a minimum stirrable volume. Ethyl acetate (60.8 mL) was added to the reaction mixture and the mixture was heated to no more than 50° C. to achieve a clear solution. n-Heptane (86.3 mL) was added slowly with agitation. The reaction mixture was cooled to 20-25° C., and the suspension was stirred for at least 1 h at 20-25° C. and then stirred at least for 1 h at 0-5° C. The suspension was filtered and the cake was washed two times with 5:1 heptane/ethyl acetate (2× 12.8 mL). The cake was dried under nitrogen and/or vacuum to provide the title compound, (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide, (14, 12.54 g, >99% ee) as a white to off white solid.

Provenance & Evidence