2,6-dimethyl-4-(pyrrolidin-1-ylmethyl)phenol

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

Procedure: A solution of intermediate 54, 2,6-Dimethyl-4-(pyrrolidin-1-ylmethyl)phenol (1.31 g, 3.2 mmol) and potassium tert-butoxide (0.36 g, 3.2 mmol) in DMSO (15 mL) was heated to 90° C. under vigorous stirring in a flow of argon. The mixture was stirred at this temperature for 15 min. A solution of intermediate 41, cis-3-(Morpholin-4-ylmethyl)cyclobutyl methanesulfonate (0.4 g, 1.6 mmol) in DMSO (10 mL) and tetrabutylammonium bromide (1 g, 0.1 mmol) were added. The mixture was stirred at 90-100° C. for 2 h, cooled, and diluted with CHCl3 (100 mL). The solution was washed with water (100 mL), 1N NaOH (3×25 mL), brine, dried with Na2SO4, and evaporated. The residue was purified by chromatography (silica gel 63-100μ, 8 mL, CHCl3/MeOH 100:0→70:30). The obtained product was dissolved in ether, and 4M HCl/dioxane (0.75 mL) was added. The precipitate was separated by filtration, washed with ether, and dried in vacuo to give the title compound (75 mg, 23%) as white crystals. LCMS-data: 359.2 and 360.2 (M+H)+, 474.2 and 473.2 (M+H+FTA)+, (calculated for C22H34N2O2 358.3). 1H NMR data (DMSO-d6): 10.70-11.21 (m, 2H, N+H2); 7.28 (s, 2H, Ar—H); 4.36-4.51 (m, 1H); 4.09-4.29 (m, 2H); 3.76-4.02 (m, 4H); 3.14-3.46 (m, masked); 2.92-3.10 (m, 4H); 2.68-2.84 (m, 1H); 2.31-2.45 (m, masked); 1.76-2.08 (m, 4H). The mixture was stirred at this temperature for 15 min The mixture was stirred at 90-100° C. for 2 h cooled The solution was washed with water (100 mL), 1N NaOH (3×25 mL), brine dried with Na2SO4 evaporated The residue was purified by chromatography (silica gel 63-100μ, 8 mL, CHCl3/MeOH 100:0→70:30) The obtained product was dissolved in ether 4M HCl/dioxane (0.75 mL) was added The precipitate was separated by filtration washed with ether dried in vacuo

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

Procedure: NaB(OAc)3H (22.1 g, 0.104 mol) was added in portions for 15 min to a mixture of pyrrolidine (8.1 mL, 0.098 mol) and 3,5-dimethyl-4-hydroxybenzaldehyde (12.5 g, 0.083 mol) in CH2Cl2 (100 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 20 h and cooled with an ice bath. Concentrated HCl (19 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 9 (30 mL) and extracted with chloroform (2×100 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (14 g, 82%) was obtained as white crystals. LCMS-data: 206.1 and 207.1 (M+H)+ (calculated for C13H19NO 205.1). 1H NMR (400 MHz)-data (DMSO-d6, J, Hz): 7.99 (br s, 1H, OH); 6.80 (s, 2H, ArH); 3.36 (s, 2H, CH2); 2.32-2.41 (m, 4H, CH2CH2CH2CH2); 2.13 (s, 6H, (CH3)2); 1.61-1.70 (m, 4H, CH2CH2CH2CH2). cooling with an ice bath in an atmosphere of argon Ar The mixture was stirred for 20 h cooled with an ice bath The organic layer was separated extracted with chloroform (2×100 mL) The combined extracts were dried with Na2SO4 evaporated