Trifluoroacetic acid → (4aS,5R,7aS)-7a-(2-fluoro-5-(1H-imidazol-2-yl)phenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

温度

100 °C

di-tert-Butyl{(4aS,5R,7aS)-7a-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl}imidodicarbonate (0.1 g, 0.17 mmol) was dissolved in 1,2-dimethoxyethane (1.5 mL), water (0.7 mL) and ethanol (0.5 mL). The resulting solution was heated to 100° C. and to it was added 2-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (0.1 g, 0.31 mmol), cesium carbonate (0.33 g, 1.0 mmol) and dichloropalladium-triphenylphosphane (0.02 g, 0.03 mmol) and the reaction was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with saturated aqueous NaHCO3 and extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified using column chromatography (gradient 0-100% EtOAc in hexane) to give a mixture of mono and bis BOC products. 1H NMRs consistent with desired structures. The residues were combined and dissolved in DCM (2 mL). Trifluoroacetic acid (1 mL) was added and the solution stirred at room temperature for 1 hour. The solvents were removed in vacuo and saturated aqueous NaHCO3 added. The solution was extracted with DCM (×3). The combined organics were dried (MgSO4), filtered and concentrated to give the title compound (48 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 7.76-7.89 (m, 2 H), 7.06-7.13 (m, 3 H), 4.57 (d, J=9.1 Hz, 1 H), 4.32-4.40 (m, 1 H), 3.81 (dd, J=8.8, 1.8 Hz, 1 H), 3.07 (dd, J=13.4, 3.5 Hz, 1 H), 2.71 (dd, J=13.3, 3.9 Hz, 1 H), 2.57-2.64 (m, 1 H), 1.37 (d. J=6.1 Hz, 3 H)

1. temperatureThe reaction mixture was cooled to room temperature
2. extractionextracted with EtOAc (×3)
3. dry with materialThe combined organic layers were dried (MgSO4)
4. filtrationfiltered
5. concentrationconcentrated in vacuo
6. customThe residue was purified
7. customto give
8. stirringthe solution stirred at room temperature for 1 hour
9. customThe solvents were removed in vacuo and saturated aqueous NaHCO3
10. additionadded
11. extractionThe solution was extracted with DCM (×3)
12. dry with materialThe combined organics were dried (MgSO4)
13. filtrationfiltered
14. concentrationconcentrated

ORDレコード

ord-6482be790bac44298a4f2ee490d04bfe

出典データセット

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08822455B2