4-Methylmorpholine → Asciminib

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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.

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