Hydrochloric Acid → Hydrochloric Acid

The mixture of (R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87, 240 mg, 0.71 mmol), 4-(1-methylpiperidin-4-yl)aniline (280 mg, 1.42 mmol), fine-powder cesium carbonate (930 mg, 2.84 mmol), Pd(OAc)2 (32 mg, 0.14 mmol), BINAP (88 mg, 0.14 mmol) in 20 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2 hours. 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 15% MeOH in chloroform to isolate (R)-tert-butyl 1-(5-cyano-6-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (204) in >90% yield. It was dissolved in 30 mL MeOH and 3 mL DMSO. To it were added two NaOH solid bead (about 200 mg) and then 1 mL 30% H2O2. The mixture was stirred at RT for 2 hours, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 120 mL EtOAc, washed with water, concentrated in vacuo to dryness to give crude (R)-tert-butyl 1-(5-carbamoyl-6-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (205). It was treated with 40 mL commercial 4N HCl in dioxane for 40 min, and concentrated in vacuo to afford crude (R)-5-(3-aminopiperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (206) hydrochloride. Crude 206 hydrochloride (60 mg, 0.12 mmol) was dissolved in 3 mL DMF. To it were added DIEA (210 μL, 1.2 mmol) and dimethylcarbamoyl chloride (34 μL, 0.36 mmol). The mixture was stirred at RT for 1.5 hour, acidified with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-O-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (207) as HCl salt (36 mg). MS found for C25H36N8O2 as (M+H)+ 481.2, (M−H)− 479.3. UV: λ=268, 277, 306, 336, 372 nm.

ORD record

ord-407eefc4e7304a6c99ce5334c68dd478

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09382246B2