[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:3]1[CH3:18].[H-].[Na+].IC>C1COCC1.CCOC(C)=O.O>[CH3:18][C@@H:3]1[C@H:2]([N:1]2[CH2:7][CH2:2][CH2:3][N:4]([CH3:5])[C:8]2=[O:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9](2R,3R)-Benzyl 3-amino-2-methylpiperidine-1-carboxylate (323, 270 mg, 1.09 mmol) was dissolved in 10 mL dry THF. To it was added 3-chloropropyl isocyante (112 μL, 1.09 mmol), and the mixture was stirred at RT for 3 hours. To it was added NaH (60% in mineral oil, 87 mg, 2.18 mmol) and the mixture was stirred for overnight. Another batch of NaH (87 mg, 2.18 mmol) was then added to drive the cyclization to completion in 4 hours. To the mixture was added iodomethane (540 μL, 8.64 mmol), and it was stirred at RT for overnight. It was diluted with 120 mL EtOAc and 30 mL water. The organic phase was separated, washed with water, dried, concentrated and subjected to silica flash column with 0 to 4% MeOH in DCM to isolate (2R,3R)-benzyl 2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate (403) (350 mg, 93%) as a thick oil. It was dissolved in 100 mL MeOH, and with 10% Pd/C (0.5 g) it was hydrogenated at 40 psi on a Parr shaker for overnight. The mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford 1-methyl-3-((2R,3R)-2-methylpiperidin-3-yl)tetrahydropyrimidin-2(1H)-one (404).
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