Mevidalen

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add tetra-n-butylammonium fluoride (651.71 mL, 651.71 mmol, 1M in THF) to a solution of 1-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone (400 g, 566.71 mmol) in tetrahydrofuran (4 L) at 5° C. in an appropriate vessel. Heat the mixture to 20° C. and stir. After 3 hours, remove 3 L of tetrahydrofuran by concentrating under reduced pressure and dilute the residues with ethyl acetate (2.5 L). Wash the organics with saturated aqueous ammonium chloride (2 L), water (2 L) and brine (2×2 L). Dry the ethyl acetate solution over anhydrous sodium sulfate and concentrate under reduced pressure to give an oil. Dissolve this oil in 2-propanol (2.5 L) and concentrate under reduced pressure to give an oil. Purify by chiral SFC using AS-H column (50×250 mm, 5 micron particle size) eluting with 80% supercritical carbon dioxide and 20% of a 0.2% solution of diethylmethylamine in isopropyl alcohol at 280 g/min to give the title compound (182.8 g, 389.62 mmol). MS (m/z): 450.2 (M+1 (35C1)), 452.2 (M+1 (37Cl)). Optical rotation: [α]20D −39.4° (c=0.95, MeOH). remove 3 L of tetrahydrofuran by concentrating under reduced pressure dilute the residues with ethyl acetate (2.5 L) Wash the organics with saturated aqueous ammonium chloride (2 L), water (2 L) and brine (2×2 L) Dry the ethyl acetate solution over anhydrous sodium sulfate concentrate under reduced pressure to give an oil concentrate under reduced pressure to give an oil Purify by chiral SFC eluting with 80% supercritical carbon dioxide and 20% of a 0.2% solution of diethylmethylamine in isopropyl alcohol at 280 g/min

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve 1-[(1S,3R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone (0.16 g, 0.28 mmol) in THF (2.8 mL). Add tetrabutylammonium fluoride (0.30 mL, 0.30 mmol, 1M in THF). Stir 40 min. Add saturated ammonium chloride solution and extract with ethyl acetate. Combine the ethyl acetate extracts; wash with water and brine, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 0-60%) to give the title compound as a white foam (0.12 g, 0.26 mmol). MS (m/z): 450 (M+1). Add saturated ammonium chloride solution and extract with ethyl acetate wash with water and brine dry over sodium sulfate filter concentrate under reduced pressure to give a residue Purify the residue by silica gel chromatography eluting with ethyl acetate