Ammonia → 5-(4-(1-Cyclopentylpiperidin-4-yl)phenylamino)-3-(methylthio)-1,2,4-triazine-6-carboxamide

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Reaction Steps

To ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (1) (120 mg, 0.50 mmol) in acetonitrile (10 mL) was added 4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (140 mg, 0.50 mmol) and then DIEA (180 μL, 1.0 mmol). The mixture was stirred at RT for 30 min. To the mixture was then added ammonia (7.0 N solution in methanol, 15 mL). The mixture turned cloudy in 10 min and then into a suspension. The mixture was stirred for 2 hours, concentrated in vacuo to ½ of the volume, and the solid was isolated by filtration. It was washed with cold acetonitrile (10 mL×2) and then washed with hexane (10 mL×3). The solid was dried in a vacuum oven to afford 5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-3-(methylthio)-1,2,4-triazine-6-carboxamide (480) (170 mg, 0.41 mmol, 82% yield) in high purity. It was dissolved in 10 mL NMP. To it was added dry mCPBA (77% strength, 320 mg, 1.44 mmol). The mixture was stirred at RT for 2 hours. To the mixture was added DIEA (720 μL, 4.10 mmol) and (R)-(3-BOC-amino)piperidine (3) (170 mg, 0.82 mmol). The mixture was stirred at 80° C. for 2 hours. The mixture was cooled to RT, diluted with water 30 mL, extracted with EtOAc 25 mL×5. The combined organic extract phase was washed with brine, dried, concentrated and subjected to silica flash column using 0 to 40% MeOH in DCM to isolate (R)-4-(4-(3-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-6-carbamoyl-1,2,4-triazin-5-ylamino)phenyl)-1-cyclopentylpiperidine 1-oxide (481). It was dissolved in 10 mL dry MeCN and 3 mL NMP. To the stirred solution was added bis(pinacolato)diborane (100 mg, 0.39 mmol). The mixture was stirred at RT for 10 min, quenched with 5 mL MeOH, stirred for 30 min, concentrated and subjected to silica flash column using 0 to 15% MeOH in DCM to isolate (R)-tert-butyl 1-(6-carbamoyl-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (482) (160 mg, 69% yield for 2 steps). It was treated with 20 mL commercial 4N HCl in dioxane at RT for 1.5 hour to give (R)-3-(3-aminopiperidin-1-yl)-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide hydrochloride (483) in quantitative yield. Compound 483 (88 mg, 0.19 mmol) was dissolved in 5 mL NMP. To it were added DIEA (330 μL, 1.9 mmol) and then dimethylcarbamoyl chloride (70 μL, 0.76 mmol). The mixture was stirred at RT for 1.5 hour, quenched with 0.5 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate the title compound, (R)-5-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-3-(3-(3,3-dimethylureido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (484), as HCl salt (49 mg). LC-MS (ESI): m/z (M+1) 536.3. UV: λ=260 nm.

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