反应详情

To 2-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-3H-imidazole-4-carboxylic acid ethyl ester (Ex. 8b, 230 mg, 0.44 mmol) in 3 mL of THF was added dropwise a 3.0 M THF solution of MeMgCl (0.85 mL, 2.55 mmol) at 0° C. The reaction was allowed to warm to room temperature, stirred for 5 h, and then quenched with saturated NaH2PO4 (20 mL). The mixture was extracted with Ethyl acetate (40+20 mL) and the combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography (3-30% Ethyl acetate/hexanes) to afford the title compound as a clear gum (202 mg, 90%). 1H NMR (400 MHz, CDCl3): δ 10.76 (bs, 0.4H), 10.72 (bs, 0.6H), 7.23 (s, 2H), 7.02 (s, 0.6H), 6.97 (s, 0.4H), 5.30 (s, 1H), 3.77-3.74 (m, 2H), 2.97-2.82 (m 3H), 1.98-1.95 (m, 2H), 1.69-1.57 (m, 8H), 1.41 (s, 18H). 13C NMR (100 MHz): δ 154.5, 152.1, 141.2, 140.9, 136.9, 132.9, 132.0, 125.8, 122.1, 113.2, 69.5, 68.4, 46.0, 44.6, 34.5, 31.7, 31.5, 30.6, 30.4, 30.2. ESI/CI-MS m/z 510 ([M+H]+), 508 ([M−H]−). Three HPLC (reverse-phase, C18) methods were used to determine the purity of the title compound. Method 1: gradient elution, 40% to 85% solvent B (A=aqueous 0.1% H3PO4, B=MeCN) in 15 min. Purity (UV-VIS): 98.6% (238 nm); Method 2: gradient elution, 40% to 95% solvent B (A=10 mM NH4OAc, B=MeCN) in 6 min. Purity (UV-VIS λ): 99.2% (238 nm), 99.4% (254 nm); Method 3: gradient elution, 50% to 99% solvent B (A=aqueous 0.1% H3PO4, B=MeCN) in 15 min. Purity (UV-VIS): 98.4% (215 nm), 98.9% (254 nm), 98.7 (238 nm).

1. customquenched with saturated NaH2PO4 (20 mL)
2. extractionThe mixture was extracted with Ethyl acetate (40+20 mL)
3. dry with materialthe combined organic phase was dried over Na2SO4
4. concentrationconcentrated under reduced pressure
5. customThe crude product was purified by chromatography (3-30% Ethyl acetate/hexanes)