2,6-Lutidine → 3-((R)-1-(1H-indol-3-yl)propan-2-ylamino)-2-fluoro-2-methylpropan-1-ol

Trifluoromethanesulfonic anhydride (1.151 ml, 6.80 mmol) was added to a solution of 2-fluoro-2-methylpropane-1,3-diol (0.70 g, 6.47 mmol) in DCM (17.85 ml) at 0° C., followed by 2,6-lutidine (0.908 ml, 7.77 mmol). The reaction was allowed to warm to room temperature over 30 min, then was washed with 2M HCl. The organic phase was passed through a phase separator cartridge and concentrated in vacuo. The residue was dissolved in dioxane (12 mL), then (R)-1-(1H-indol-3-yl)propan-2-amine (1.128 g, 6.47 mmol) and DIPEA (1.678 ml, 9.71 mmol) were added and the reaction was heated to 90° C. for 2 h. After cooling, the reaction was diluted with DCM and washed with water. The aqueous was extracted with DCM, then the organics were concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-fluoro-2-methylpropan-1-ol (0.815 g, 47.6%) as a brown gum. m/z (ES+), [M+H]+=265.

1. washwas washed with 2M HCl
2. concentrationconcentrated in vacuo
3. dissolutionThe residue was dissolved in dioxane (12 mL)
4. temperaturethe reaction was heated to 90° C. for 2 h
5. temperatureAfter cooling
6. washwashed with water
7. extractionThe aqueous was extracted with DCM
8. concentrationthe organics were concentrated in vacuo
9. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM
10. customPure fractions were evaporated to dryness

ORD record

ord-7354c235205243079f0f0b4c2a3f2c1f

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09155727B2