1,2-Dimethoxyethane → HCID 67543715, compound

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Reaction Steps

A stirred mixture of (3R*,4R*)-4-(3-bromo-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester (173.8 mg, 0.35 mmol), 4-ethoxycarbonylphenyl boronic acid (135.8 mg, 0.70 mmol), dimethoxyethane (4.5 mL), H2O (1.5 mL), tetrakis-(triphenylphosphin)-palladium (46.2 mg, 0.04 mmol) and Na2CO3 (111.3 mg, 1.05 mmol) is heated at reflux under argon for 14 h. The mixture is cooled to RT, dimethoxyethane is removed in vacuo and the residue is diluted with aqueous 2N Na2CO3 solution containing a few mL of concentrated NH4OH. The aqueous layer is extracted three times with CH2Cl2. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography of the dark residue (SiO2, hexane/ethyl acetate) affords (3R*,4R*)-4-(4′-ethoxycarbonyl-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester as a yellowish resin. A stirred mixture of this ester and CH3NH2 (8M in EtOH, 5 mL, 40 mmol) is heated at 80° C. for 24 h in a pressure bottle. The reaction mixture is evaporated in vacuo to afford (3R*,4R*)-4-(4′-methylcarbamoyl-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester as a viscous yellowish oil. A mixture of this compound (62.4 mg, 0.11 mmol) and HCl (5M in 2-propanol, 3 mL, 15 mmol) is stirred for 1 h at RT. The reaction mixture is evaporated in vacuo to afford 3′-[(3R*,4R*)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-biphenyl-4-carboxylic acid methylamide hydrochloride as a white solid. MS 451.7 [M+H]+; Rf 0.13 (DCM/MeOH 9:1).

Provenance & Evidence