Dimethylcarbamoyl Chloride → HCID 118115004, compound

Participants

Reaction Steps

Commercial (4aR,8aR)-decahydro-1,5-naphthyridine (423, 120 mg, 0.86 mmol) was dissolved in 2 mL NMP. To it were added DIEA (150 μL, 0.86 mmol) and then 3,5-dichloropyrazine-2-carbonitrile (150 mg, 0.86 mmol). The mixture was stirred at RT for 1.5 hour, and to it were added DIEA (450 μL, 2.58 mmol) and dimethylcarbamoyl chloride (240 μL, 2.58 mmol). The mixture was stirred at RT for overnight. It was diluted with 100 mL EtOAc, washed with water ×2, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 3% MeOH in DCM to isolate (4aR,8aR)-5-(6-chloro-5-cyanopyrazin-2-yl)-N,N-dimethyloctahydro-1,5-naphthyridine-1(2H)-carboxamide (424, 56 mg, 19%). It was mixed with 4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (90 mg, 0.32 mmol), fine-powder cesium carbonate (210 mg, 0.64 mmol), Pd(OAc)2(11 mg, 0.05 mmol), BINAP (31 mg, 0.05 mmol) in 15 mL dioxane. The mixture was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 1.5 hour. The mixture was cooled to RT, diluted with 100 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 11% MeOH in DCM to isolate (4aR,8aR)-5-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-1,5-naphthyridine-1(2H)-carboxamide (425). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added one NaOH solid bead (about 100 mg), Et3N (60 μL) and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 30 min, diluted with 10 mL MeCN, stirred for 5 min, and concentrated, acidified with 0.3 mL TFA, and subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (4aR,8aR)-5-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-1,5-naphthyridine-1(2H)-carboxamide (426) as HCl salt (23 mg). LC-MS (ESI): m/z (M+1) 575.8. UV: λ=269, 276, 305, 335, 372 nm.

Provenance & Evidence