1,2-Dimethoxyethane → HCID 67542666, 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 (300 mg, 0.6 mmol), 3-ethoxycarbonylphenyl boronic acid (136.8 mg, 0.71 mmol), dimethoxyethane (3 mL), H2O (1 mL), tetrakis-(triphenylphosphin)-palladium (46.5 mg, 0.04 mmol) and Na2CO3 (96 mg, 0.91 mmol) is heated at reflux under argon for 16 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-(3′-ethoxycarbonyl-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester as a yellowish resin. The ester (138.7 mg, 0.245 mmol) is dissolved in MeOH (1 mL) and THF (1 mL), treated with aqueous NaOH (2 M, 0.5 mL, 1 mmol) and the mixture is stirred for 14 h at RT. The solvents are removed in vacuo, the residue is diluted with H2O and the pH adjusted to 5 by the addition of 1N HCl. The aqueous phase is extracted twice with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo to afford (3R*,4R*)-4-(3′-carboxy-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester as a white amorphous solid. A mixture of this acid (110.1 mg, 0.20 mmol) and HCl (5M in 2-propanol, 2 mL, 10 mmol) is stirred for 1 h at RT. The reaction mixture is evaporated in vacuo and the residue purified using preparative HPLC (H2O/CH3CN). The combined pure fractions are treated with solid K2CO3 and CH3CN is removed in vacuo. The aqueous layer is extracted twice with CH2Cl2. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. The residue is stirred with HCl (5M in 2-propanol, 1 mL, 5 mmol) for 2 h at RT. Evaporation of the solvent affords 3′-[(3R*,4R*)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-biphenyl-3-carboxylic acid hydrochloride as a white solid: MS 438.6 [M+H]+; retention time 5.23 min (HPLC, Nucleosil C18; 5→100% CH3CN in H2O within 8 min).

Provenance & Evidence