反应详情

4-Dimethylaminopyridine (0.19 g, 1.6 mmol) was added to a solution of 2-(4-(bis(benzyloxy)phosphoryloxy)phenyl)acetic acid (0.67 g, 1.6 mmol), 2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-1-(3,3′-difluoro-4′-(hydroxymethyl)-5′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)propan-2-ol (prepared in the manner described in PCT Publication No. WO 2010/138598, 0.4 g, 0.6 mmol), and N,N′-dicyclohexylcarbodiimide (0.37 g, 1.8 mmol) in CH2Cl2 (5 mL). The mixture was stirred at rt for 30 mins. After this time, the reaction mixture was filtered, and the organic solvents were removed under reduced pressure to yield the crude product. The crude product was purified by column chromatography using a mixture of CHCl3 and methanol (9:1) to afford (4′-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)-3,3′-difluoro-5-(methylsulfonyl)biphenyl-4-yl)methyl 2-(4-(bis(benzyloxy)phosphoryloxy)phenyl)acetate (0.4 g, 0.4 mmol, 60% yield). 1H NMR (400 MHz, CHCl3-d) δ 1.60 (s, 6H), 2.03 (s, 6H), 2.99 (s, 3H), 3.65 (s, 2H), 5.11 (d, J=8.4, 2H), 5.67 (s, 2H), 6.62 (s, 1H), 6.88 (t, J=7.6, 1H), 6.8-7.98 (m, 22H), 7.98 (s, 1H). LCMS: (Ascentis Express C18, 5×2.1 mm, 2.7 μm; Solvent A=2% MeCN: 98% H2O: 10 mM NH4COOH; Solvent B=98% MeCN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min) retention time: 2.38 min; LCMS (ES-API), m/z 1005.2 (M+H).

1. customprepared in the manner
2. filtrationAfter this time, the reaction mixture was filtered
3. customthe organic solvents were removed under reduced pressure
4. customto yield the crude product
5. customThe crude product was purified by column chromatography
6. additiona mixture of CHCl3 and methanol (9:1)