Formic Acid → 2-Methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline

Temperatur

50 °C

Formic acid (9.4 mL, 250 mmol) was added dropwise to Ac2O (19 mL, 202 mmol) at 0° C. The solution was stirred at 50° C. for 45 min, then cooled to −18° C., diluted with THF (100 mL) and a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline [(a) Tercel, M.; et al., J. Med. Chem. 1996, 39, 1084-1094; (b) Zhu, Z., et al., J. Med. Chem. 2003, 46, 831-837] (251) (13.8 g, 5.0 mmol) in THF (100 mL) was added and stirred at −15 to −18° C. for 30 min. The solution was warmed to 20° C., the solvent evaporated and the residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL). The aqueous fraction was extracted with EtOAc (3×250 mL), dried and the solvent evaporated. The residue was dissolved in THF (200 mL), cooled to 10° C. and BH3-DMS solution (10 M, 19.4 mL, 194 mmol) was added. The solution was stirred at 20° C. for 1 h, diluted with MeOH (30 mL) and acidified with HCl solution (1 M, 45 mL). The solution was stirred at 40° C. for 15 min, the solvent evaporated and the residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL). The aqueous fraction was extracted with EtOAc (3×250 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give isoquinoline 252 (12.6 g, 85%) as an orange solid: 1H NMR δ 8.09 (dd, J=8.4, 2.3 Hz, 1H, H-6), 7.95 (d, J=2.3 Hz, 1H, H-8), 7.37 (d, J=8.4 Hz, 1H, H-5), 4.27 (d, J=16.1 Hz, 1H, H-1), 3.94 (d, J=16.1 Hz, 1H, H-1), 3.23-3.34 (m, 2H, CH2), 2.99-3.18 (m, 2H, CH2), 2.17 (s, 3H, NCH3); MS (APCI) m/z 193 (MH+, 100%).

1. temperaturecooled to −18° C.
2. stirringstirred at −15 to −18° C. for 30 min
3. temperatureThe solution was warmed to 20° C.
4. customthe solvent evaporated
5. customthe residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL)
6. extractionThe aqueous fraction was extracted with EtOAc (3×250 mL)
7. customdried
8. customthe solvent evaporated
9. dissolutionThe residue was dissolved in THF (200 mL)
10. temperaturecooled to 10° C.
11. stirringThe solution was stirred at 20° C. for 1 h
12. stirringThe solution was stirred at 40° C. for 15 min
13. customthe solvent evaporated
14. customthe residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL)
15. extractionThe aqueous fraction was extracted with EtOAc (3×250 mL)
16. customdried
17. customthe solvent evaporated
18. customThe residue was purified by chromatography
19. washeluting with a gradient (2-5%) of MeOH/DCM

ORD-Eintrag

ord-d4fb990755bf4ef8a420cb1d8e03749c

Quelldatensatz

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07989451B2