Triethylamine → (R)-5-Methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one

Participants

Reaction Conditions

Reaction Steps

Combine (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (53.55 g, 270.96 mmol), triethylamine (37.77 mL, 1.1 eq), 4-(1-(2-pyrrolidin-1-yl-ethyl)-4-(tetrahydro-pyran-4-yl)-1H-imidazol-2-yl)-piperidine (81.9 g, 1.0 eq) and N-methylpyrrolidinone (246 mL). Stir at 110° C. overnight. Cool the reaction mixture to room temperature and dilute with ethyl acetate (400 mL) and water (1200 mL). Adjust the pH to 10 with 2 M aqueous sodium hydroxide and separate layers. Wash the aqueous phase with ethyl acetate (2×200 mL). Wash the organics with aqueous saturated sodium chloride. Add water (1 L) to the organics and adjust the pH to 3 with aqueous 85% phosphoric acid. Separate the layers and wash the resulting acidic aqueous phase with ethyl acetate (2×200 mL). Adjust the pH of the aqueous phase to 10 with 2 M aqueous sodium hydroxide. Extract with ethyl acetate (3×200 mL). Wash the organics with saturated aqueous sodium chloride (250 mL), dry over anhydrous magnesium sulfate, and concentrate in vacuo. Purify the residue by HPLC (Chiralpak AD, 70/30 hexanes/isopropyl alcohol w/0.2% dimethylethylamine) to give the final compound (51.0 g, 42%). MS (ES) m/z=494 [M]+.

Provenance & Evidence