Hydrochloric Acid → (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile

Temperature

10 °C

2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (30 g, 145 mmol), (S)-tert-butyl-1-hydroxypropan-2-ylcarbamate (51.4 g, 291 mmol), triphenylphosphine (77 g, 291 mmol) and 210 ml of EtOAc were place in to the reaction vessel under nitrogen atmosphere and stirred for 15 min. DIAD (57.8 ml, 291 mmol) was added slowly in 1.5 h at RT keeping the temperature stable and the reaction was stirred overnight at RT. Concentrated HCl (134 ml, 1453 mmol) was added and the mixture was stirred at RT overnight. Water (165 ml) and DCM (240 ml) were added, the mixture was stirred for 30 min and layers were separated. Organic phase was washed with 2×270 ml of acidic water (pH˜1). Water phases were combined and washed with 2×120 ml of dichloromethane. Dichloromethane (150 ml) was added, pH set to 11.5 by 50% NaOH and the mixture was stirred for 75 min. The solution was filtered through the celite, layers were separated and organic phase was washed with 171 ml of water. DCM was distilled out at 33° C. under reduced pressure and 60 ml of heptanes was added. Precipitation was started, 60 ml of heptane added and the mixture was stirred overnight. Some DCM was evaporated, 60 ml heptanes was added and the mixture was cooled to 10° C. The precipitate was filtered, washed with 20 ml of IPA:heptane (10:90) and dried under vacuum to obtain 24.55 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 1.03 (d, 3H), 3.34-3.43 (d, 2H), 4.14 (d, 2H), 6.99 (d, 1H), 7.89 (d, 1H), 7.96 (dd, 1H), 7.99 (dd, 1H), 8.12-8.14 (m, 1H).

1. stirringthe reaction was stirred overnight at RT
2. stirringthe mixture was stirred at RT overnight
3. stirringthe mixture was stirred for 30 min
4. customlayers were separated
5. washOrganic phase was washed with 2×270 ml of acidic water (pH˜1)
6. washwashed with 2×120 ml of dichloromethane
7. additionDichloromethane (150 ml) was added
8. stirringthe mixture was stirred for 75 min
9. filtrationThe solution was filtered through the celite, layers
10. customwere separated
11. washorganic phase was washed with 171 ml of water
12. distillationDCM was distilled out at 33° C. under reduced pressure and 60 ml of heptanes
13. additionwas added
14. customPrecipitation
15. addition60 ml of heptane added
16. stirringthe mixture was stirred overnight
17. customSome DCM was evaporated
18. addition60 ml heptanes was added
19. filtrationThe precipitate was filtered
20. washwashed with 20 ml of IPA:heptane (10:90)
21. customdried under vacuum

ORD record

ord-8b5d68fbfa8148828f50a87a9f1d1ffc

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08921378B2