Methanol → HCID 86662636, compound

Temperature

0 °C

2-Chloro-8-methylquinoline-3-carboxaldehyde (5 g, 24.6 mmol) in dry THF (75 mL) was treated with titanium(IV) isopropoxide (14.5 mL, 48 mmol). After 5 minutes, (R)-(−)-2-methyl-2-propanesulfinamide (2.95 g, 24 mmol) was added in one portion and the mixture was stirred for 60 h. The mixture was cooled to 0° C. in a water/ice bath and NaBH4 (1.9 g, 48 mmol) was added. The mixture was stirred for 3 h and cooled to 10° C. MeOH (20 mL) was added dropwise, followed by water (5 mL). The resulting slurry was filtered through Celite and washed thoroughly with EtOAc. The organic layer was washed with water and brine, dried (MgSO4) and the solvent removed in vacuo. The residue was dissolved in MeOH (20 mL) and HCl (4M in 1,4-dioxane; 30 mL). The mixture was stirred for 2 h and, after removing the solvent in vacuo, the residue was dissolved in DCM. The organic layer was washed with sat. NaHCO3 solution, water and brine, then dried (MgSO4), filtered and the solvent removed in vacuo. The residue was redissolved in MeOH and passed through an SCX cartridge, eluting with 0-0.1M MeOH/NH3 in MeOH. The solvent was removed in vacuo and the residue purified by column chromatography on silica, eluting with 0-5% MeOH in EtOAc, to afford the title compound (3 g, 60%). δH (DMSO-d6) 8.50 (1H, s), 7.89 (1H, d, J=8.1 Hz), 7.67 (1H, d, J=7.0 Hz), 7.57 (1H, t, J=7.6 Hz), 4.00 (2H, s), 2.70 (3H, s).

1. stirringThe mixture was stirred for 3 h
2. temperaturecooled to 10° C
3. filtrationThe resulting slurry was filtered through Celite
4. washwashed thoroughly with EtOAc
5. washThe organic layer was washed with water and brine
6. dry with materialdried (MgSO4)
7. customthe solvent removed in vacuo
8. dissolutionThe residue was dissolved in MeOH (20 mL)
9. stirringThe mixture was stirred for 2 h
10. customafter removing the solvent in vacuo
11. dissolutionthe residue was dissolved in DCM
12. washThe organic layer was washed with sat. NaHCO3 solution, water and brine
13. dry with materialdried (MgSO4)
14. filtrationfiltered
15. customthe solvent removed in vacuo
16. dissolutionThe residue was redissolved in MeOH
17. washeluting with 0-0.1M MeOH/NH3 in MeOH
18. customThe solvent was removed in vacuo
19. customthe residue purified by column chromatography on silica
20. washeluting with 0-5% MeOH in EtOAc

ORD record

ord-220368bce79c49249efed03b09590958

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08785628B2