Diisopropylethylamine → Lemborexant

Temperature

2.5 °C

(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.

1. temperaturewhile maintaining the internal temperature at 0-15° C
2. temperaturewhile maintaining the internal temperature at 0-15° C.
3. stirringThe reaction was stirred at 20-25° C. for at least 20-24 hour
4. temperaturethe reaction mixture was cooled to 0-5° C.
5. customwas quenched with water (64.0 mL)
6. temperaturewhile maintaining the internal temperature below 10-15° C
7. extractionThe aqueous layer was back extracted once with MTBE (76.8 mL)
8. washwashed once with saturated aqueous NaHCO3 solution (38.4 mL) and once with water (38.4 mL)
9. filtrationfiltered
10. washthe filter rinsed with MTBE (12.8 mL)
11. concentrationThe organic layer was then concentrated under reduced pressure to a minimum stirrable volume
12. additionEthyl acetate (60.8 mL) was added to the reaction mixture
13. temperaturethe mixture was heated to no more than 50° C.
14. additionn-Heptane (86.3 mL) was added slowly with agitation
15. temperatureThe reaction mixture was cooled to 20-25° C.
16. stirringthe suspension was stirred for at least 1 h at 20-25° C.
17. stirringstirred at least for 1 h at 0-5° C
18. filtrationThe suspension was filtered
19. washthe cake was washed two times with 5:1 heptane/ethyl acetate (2× 12.8 mL)
20. customThe cake was dried under nitrogen

ORD record

ord-0c6cb803cccc4afaa9c9cc4c36fb05eb

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09416109B2