Dichloromethane → 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol

To a solution of 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (3.0 g, 8.79 mmol) in chloroform (60 mL) at rt was added m-chloroperbenzoic acid (m-CPBA, 3.2 g, 10.5 mmol). After 2 h, the solution was transferred to a separatory funnel and washed with 10% Na2CO3 (100 mL). The aqueous layer was back-extracted with chloroform. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to yield a light orange solid. To the solid was added dichloromethane (30 mL). Trichloroacetyl isocyanate (1.05 mL, 8.79 mL) was added dropwise. After 1 h, additional trichloroacetyl isocyanate (0.3 equivalent) was added. After 1 h, the volatiles were removed under reduced pressure and the residue was dissolved in methanol (30 mL). A solution of sodium methoxide in methanol (25%, 5.0 mL) was added and the solution stirred overnight at rt and concentrated under reduced pressure. The residue was partitioned between dichloromethane (100 mL) and water (100 mL). The aqueous layer was extracted with dichlormethane (2×100 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 10% methanol/dichloromethane) to afford a clear oil that was triturated with isopropanol (50 mL) to afford white crystals. The crystals were dissolved in methanol, concentrated under reduced pressure, and dried in a vacuum oven at 80° C. to provide 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (1.27 g, 41%) as a white frothy solid, mp 212-214° C. 1H NMR (300 MHz, DMSO-d6) δ 8.33 (dd, J=8.3, 1.1 Hz, 1H), 7.60 (dd, J=8.3, 1.2 Hz, 1H), 7.40 (ddd, J=8.3, 7.0, 1.4 Hz, 1H), 7.22 (ddd, J=8.3, 7.0, 1.4 Hz, 1H), 6.37 (br s, 2H), 4.90 (br s, 2H), 4.88 (s, 1H), 4.70 (br s, 2H), 3.62-3.47 (m, 6H), 1.87-1.74 (m, 2H), 1.28 (m, 2H), 1.14 (t, J=7.0 Hz, 3H); MS (APCI) m/z 357 (M+H)+; Anal. Calcd for C19H24N4O3: C, 64.03; H, 6.79; N, 15.72.

1. customthe solution was transferred to a separatory funnel
2. washwashed with 10% Na2CO3 (100 mL)
3. extractionThe aqueous layer was back-extracted with chloroform
4. dry with materialdried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure
7. customto yield a light orange solid
8. waitAfter 1 h
9. waitAfter 1 h
10. customthe volatiles were removed under reduced pressure
11. dissolutionthe residue was dissolved in methanol (30 mL)
12. additionA solution of sodium methoxide in methanol (25%, 5.0 mL) was added
13. concentrationconcentrated under reduced pressure
14. customThe residue was partitioned between dichloromethane (100 mL) and water (100 mL)
15. extractionThe aqueous layer was extracted with dichlormethane (2×100 mL)
16. dry with materialdried over MgSO4
17. filtrationfiltered
18. concentrationconcentrated under reduced pressure
19. customThe crude product was purified by flash chromatography (silica gel, eluted with 10% methanol/dichloromethane)
20. customto afford a clear oil that
21. customwas triturated with isopropanol (50 mL)
22. customto afford white crystals
23. concentrationconcentrated under reduced pressure
24. customdried in a vacuum oven at 80° C.

ORD 기록

ord-482403473c4d4ed79eb24ae6b1638b40

출처 데이터셋

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08541438B2