Hydrochloric Acid → 4-Fluoro-N-[(3R,4S)-3-hydroxy-6-piperazin-1-yl-chroman-4-yl]benzamide hydrochloride

참여 물질

반응 단계

Degas (bubble nitrogen through the mixture) a suspension of tri-t-butylphosphonium tetrafluoroborate (16.0 g, 54.6 mmol) and allylpalladium(II) chloride dimer (5.07 g, 27.3 mmol) in DMSO (1.40 L) with stirring at room temperature. Add N-tert-butoxycarbonylpiperazine (315 g, 1.64 mol, 97% pure) and N-[(3R,4S)-6-bromo-3-hydroxy-chroman-4-yl]-4-fluoro-benzamide (200.0 g, 546 mmol). Stir the mixture for 15 min under nitrogen and then heat at 80° C. Add sodium tert-butoxide (179 g, 1.80 mol) and heat at 93-98° C. for 45 min. Pour the mixture over a solution of 1 M phosphoric acid (2.73 L, 2.73 mol, adjusted to pH=2.3 with 50% sodium hydroxide) and ethyl acetate (800 mL) and stir for 10 min. Separate the layers and extract the aqueous layer with ethyl acetate (3×300 mL). Wash the combined organic layer with semi-saturated brine (2×500 mL). Treat the organic layer with activated carbon (20 g) and silica gel (200 g) and stir for 30 min. Filter through a pad of diatomaceous earth and concentrate under reduced pressure to obtain a dark oil. Dissolve the oil in methanol (800 mL), add 4 M hydrogen chloride in dioxane (410 mL), and stir the solution at 40° C. for 1 hr. Evaporate the solvent in vacuo, suspend the residue in acetonitrile (1.6 L) and stir at room temperature for 1 hr. Collect the solid by filtration under nitrogen to avoid hydration of the salt. Wash the filtrate with acetonitrile (500 mL) and methyl tert-butyl ether (1 L), and dry under vacuum to obtain the title compound (262 g, 73%). LC-ES/MS m/z 372 [M+H]+.

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