4-Methylmorpholine → Asciminib

Temperature

25 °C

Alternatively, Stage 9.1 was prepared by adding 4-(chlorodifluoromethoxy)aniline (16.6 g, 84.9 mmol), NMM (21.7 g, 212.1 mmol), hydroxybenzotriazole hydrate (HOBt.H2O, 11.9 g, 77.77 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl, 20.9 g, 109.0 mmol) to a solution of 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acid (Stage 9.4, 29.83 g, 70.7 mmol) in THF (271 mL). The mixture was stirred for 1.5 h at 25° C. and then at 65° C. for 16 h. After cooling the RM to 35° C., further EDCI.HCl (13.3 g, 69.4 mmol) was added and the RM was stirred for 1.5 h at 35° C. then again at 65° C. for 16 h. After cooling the RM to 35° C., water (150 mL) was added, the THF was removed under reduced pressure, EtOAc (180 mL) was added and the mixture was stirred for at 35° C. for 1 h. The two layers were separated and the aq. phase was then extracted with EtOAc (60 mL). The combined organic layers were washed with water (90 mL), brine (90 mL). The solvent was evaporated off under reduced pressure to give a brown solid which was purified by column chromatography (Silica gel, DCM/MeOH 40:1 to 20:1) to afford the title compound as a yellow solid.

1. customAlternatively, Stage 9.1 was prepared
2. waitat 65° C. for 16 h
3. temperatureAfter cooling the RM to 35° C.
4. stirringthe RM was stirred for 1.5 h at 35° C.
5. waitagain at 65° C. for 16 h
6. temperatureAfter cooling the RM to 35° C.
7. customthe THF was removed under reduced pressure, EtOAc (180 mL)
8. additionwas added
9. stirringthe mixture was stirred for at 35° C. for 1 h
10. customThe two layers were separated
11. extractionthe aq. phase was then extracted with EtOAc (60 mL)
12. washThe combined organic layers were washed with water (90 mL), brine (90 mL)
13. customThe solvent was evaporated off under reduced pressure
14. customto give a brown solid which
15. customwas purified by column chromatography (Silica gel, DCM/MeOH 40:1 to 20:1)

ORD record

ord-7ddc1e2b8fbc4223b35ba5678f072ea8

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08829195B2