Ammonia → 2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)-1-methoxyethanol

Temperature

0 °C

To a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (857 mg, 2.5 mmol) in anhydrous THF (10 mL) was added potassium bis((trimethylsilyl)amide (0.5 M in toluene, 4 mL, 2 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred at 0° C. for 10 min before a solution of (5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinoline-6-carbaldehyde (Example 1g, 155 mg in 5 mL of THF, 0.5 mmol) was added at the same temperature. The reaction mixture was stirred at 0° C. for 10 min and at RT for 2 hr. Next, hydrochloric acid solution (6 N, 2 mL) was then added at 0° C. The reaction mixture was stirred at RT for 1.5 hr before concentrated aqueous ammonia solution (1.5 mL) was added at 0° C. The reaction mixture was extracted with heptane (10 mL) and ethyl acetate (2×2 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (0-20% methanol in ethyl acetate) gave 2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)-1-methoxyethanol (170 mg, 0.48 mmol, 96% yield) as a solid. MS found: (M+H)+=357.3.

1. additionwas added at the same temperature
2. additionwas added at 0° C
3. extractionThe reaction mixture was extracted with heptane (10 mL) and ethyl acetate (2×2 mL)
4. dry with materialThe combined organic solutions were dried (Na2SO4)
5. concentrationconcentrated

ORD record

ord-d71ae4ffc3dc481c8d65096997a60963

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08309730B2