Ammonium Chloride → ((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)(pyrimidin-2-yl)methanol

Temperature

-78 °C

To a stirred solution of 2-(tributylstannyl)pyrimidine (185 mg, 0.5 mmol) in anhydrous THF (1 mL) was added butyllithium solution (1.6 M in hexanes, 0.31 mL, 0.5 mmol) dropwise at −78° C. under nitrogen. The mixture was stirred at −78° C. for 2 hr before magnesium bromide (90 mg, 0.5 mmol) was added. After the reaction mixture was stirred at −78° C. for additional 30 min, (5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinoline-6-carbaldehyde (Example 1g, 20 mg, 0.065 mmol) was added. The mixture was stirred at −78° C. for 45 min and at RT for 5 min. Saturated aqueous ammonium chloride solution (2 mL) was added. The reaction mixture was extracted with ethyl acetate (3×1 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (50-100% ethyl acetate in heptanes and then 0-20% methanol in ethyl acetate) gave ((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)(pyrimidin-2-yl)methanol which was used as such for the subsequent step without further purification.

1. additionwas added
2. stirringThe mixture was stirred at −78° C. for 45 min and at RT for 5 min
3. extractionThe reaction mixture was extracted with ethyl acetate (3×1 mL)
4. dry with materialThe combined organic solutions were dried (Na2SO4)
5. concentrationconcentrated

ORD record

ord-b471998a285c4e16aba9a205a1a76797

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08309730B2