Thiourea → (4aS,8aS)-8a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-4,4a,5,6,7,8a-hexahydropyrano[2,3-d][1,3]thiazin-2-amine

Participants

Reaction Steps

To a solution of 5-((tert-butyldimethylsilyl)oxy)-1-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-2-methylenepentan-1-one (Preparation 16, 606 mg, 1.448 mmol) in HOAc (7239 μL) was added thiourea (441 mg, 5.79 mmol), and a suspension was formed. The reaction mixture was stirred at rt for 12 h, and a clear yellowish solution was formed. TBAF (2172 μL, 2.172 mmol) in THF was added, and the reaction mixture was stirred at rt for 5 h, followed by heating at 60° C. for 12 h. This crude reaction mixture was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 10% MeOH/90% water/0.1% TFA; B: 90% MeOH/10% water/0.1% TFA) over 12 min to give a mixture of two isomers. This mixture was purified by preparative TLC on silica gel (0.50 mm thickness) eluting with 90% DCM/9% MeOH/1% ammonium hydroxide to give (4aS,8aS)-8a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-4,4a,5,6,7,8a-hexahydropyrano[2,3-d][1,3]thiazin-2-amine (13 mg, 0.034 mmol, 2.354% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.22 (s, 1H), 8.91 (d, J=1.4 Hz, 2H), 7.43 (t, J=8.5 Hz, 1H), 7.02 (dd, J=10.8, 10.2 Hz, 1H), 5.0-4.5 (broad s, 2H), 4.00-3.92 (m, 1H), 3.88-3.80 (m, 1H), 2.95 (dd, J=12.6, 4.0 Hz, 1H), 2.81-2.71 (m, 1H), 2.67 (dd, J=12.6, 2.8 Hz, 1H), 2.01-1.83 (m, 2H), 1.75-1.57 (m, 2H). MS (M+H)+: 363.03.

Provenance & Evidence