[(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add tert-butyldimethylchlorosilane (193.7 g, 1.29 mol) to a mixture of [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol (148.9 g, 0.58 mol), 1H-imidazole (202.9 g, 2.92 mol), 4-dimethylaminopyridine (0.72 g, 5.84 mmol) and N,N-dimethylformamide (1.04 L) in dichlormethane (2.61 L) at 20° C. and stir in an appropriate vessel. After 3 hours, cool the mixture to 10° C. and add saturated aqueous ammonium chloride solution (1.3 L). Extract the aqueous with dichloromethane and wash the combined organic extracts with brine (2×2 L), dry over anhydrous sodium sulfate and concentrate under reduced pressure to give a residue. Dissolve the residue in methyl tert-butyl ether (1.5 L) and wash with brine (2×1 L). Dilute the organic phase with toluene (5 L) and concentrate under reduced pressure to give a residue. Add toluene (2.6 L) to the residue and concentrate under reduced pressure to give the title compound (210 g, 0.53 mol). MS (m/z). 356(M+1 (79Br)), 358(M+1 (81Br)). Extract the aqueous with dichloromethane wash the combined organic extracts with brine (2×2 L) dry over anhydrous sodium sulfate concentrate under reduced pressure to give a residue wash with brine (2×1 L) Dilute the organic phase with toluene (5 L) concentrate under reduced pressure to give a residue Add toluene (2.6 L) to the residue and concentrate under reduced pressure

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

Procedure: Add trifluoroacetic acid (75.5 mL, 998.3 mmol) to solution of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (15.5 g, 45.3 mmol) in dichloromethane (226 mL) at room temperature. Stir 30 min and concentrate under reduced pressure. Dry under vacuum to give [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid as a wet solid. Dissolve [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid in dichloromethane (753 mL). Add 1H-imidazole (51.3 g, 753 mmol), N,N-Dimethyl-4-pyridinamine (460 mg, 3.77 mmol), and t-butyldimethylchlorosilane (13.6 g, 90.4 mmol). Stir at room temperature overnight. Add saturated ammonium chloride solution and extract with dichloromethane. Dry the dichloromethane extracts over sodium sulfate, filter, and concentrate under reduced pressure. Combine with the crude product from a substantially same reaction run with 19.4 mmol of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate. Purify the residue by silica gel chromatography eluting with ethyl acetate: hexanes (5-40% gradient) to give the title compound (14.3 g, 40.1 mmol). MS (m/z): 356 (M+1). Add saturated ammonium chloride solution and extract with dichloromethane Dry the dichloromethane filter concentrate under reduced pressure Combine with the crude product from a substantially same reaction Purify the residue by silica gel chromatography eluting with ethyl acetate

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

Procedure: Add trifluoroacetic acid (75.5 mL, 998.3 mmol) to solution of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (15.5 g, 45.3 mmol) in dichloromethane (226 mL) at room temperature. Stir 30 min and concentrate under reduced pressure. Dry under vacuum to give [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid as a wet solid. Dissolve [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid in dichloromethane (753 mL). Add 1H-imidazole (51.3 g, 753 mmol), N,N-Dimethyl-4-pyridinamine (460 mg, 3.77 mmol), and t-butyldimethylchlorosilane (13.6 g, 90.4 mmol). Stir at room temperature overnight. Add saturated ammonium chloride solution and extract with dichloromethane. Dry the dichloromethane extracts over sodium sulfate, filter, and concentrate under reduced pressure. Combine with the crude product from a substantially same reaction run with 19.4 mmol of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate. Purify the residue by silica gel chromatography eluting with ethyl acetate: hexanes (5-40% gradient) to give the title compound (14.3 g, 40.1 mmol). MS (m/z): 356 (M+1). concentrate under reduced pressure Dry under vacuum

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add lithium aluminum hydride (2 L, 2.00 mol, 1M in THF) to (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (325.4 g, 1.11 mol) in tetrahydrofuran (4.88 L) at −35° C. in an appropriate vessel, then warm to 25° C. over 60 minutes and stir. After 3 hours, cool the mixture to −5° C. then add water (76 mL), 15% w/w aqueous sodium hydroxide (76 mL) and water (228 mL). Heat the mixture to 25° C., add anhydrous magnesium sulfate (750 g) and stir. Filter the mixture and concentrate under reduced pressure to give a solid. Add dichloromethane (690 mL) to the solid and slurry for 30 minutes before filtration to give a solid. Dry the solid under vacuum at 35° C. to give the title compound (148.9 g, 0.55 mol). MS (m/z): 242(M+1 (79Br)), 244(M+1 (81Br)). cool the mixture to −5° C. Heat the mixture to 25° C. stir Filter the mixture concentrate under reduced pressure to give a solid Add dichloromethane (690 mL) to the solid and slurry for 30 minutes before filtration to give a solid Dry the solid under vacuum at 35° C.