Trifluoroacetic acid → 4-Chloro-2-piperidin-4-yl-1H-pyrrolo[3,2-c]pyridine

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Reaction Conditions

Reaction Steps

n-Butyllithium (3.36 mL of 2.5M in hexanes, 8.4 mmol) was added dropwise to a stirring solution of (2-chloro-3-methylpyridin-4-yl)carbamic acid tert-butyl ester (0.971 g, 4 mmol) in THF (50 mL) at −78° C., under nitrogen. Warmed the reaction mixture to −20° C. for 15 minutes, before cooling back to −78° C. and adding a solution of 4-(methoxymethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (1.089 g, 4 mmol) in THF (10 mL). Warmed the reaction slowly to room temperature over 2 hours, and quenched with 1N HCl (50 mL). Extracted into ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate, and dried over magnesium sulfate. Flash column chromatography gave a 1:1 mixture, by NMR, of the ring open and ring closed tautomers of the required intermediate {4-[(tert-butoxycarbonylamino-2-chloropyridin-3-yl)acetyl]piperidine-1-carboxylic acid tert-butyl ester and 2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-chloro-2-hydroxy-2,3-dihydropyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester}. This material (845 mg, 1.88 mmol) was dissolved in methylene chloride (40 mL) and stirred vigorously at room temperature during the dropwise addition of trifluoroacetic acid (4 mL). After 2 hours the reaction mixture was concentrated to dryness, and flash column chromatographed on silica gel with ammonium hydroxide/methylene chloride/methanol to give the pure free base product as a white powder (420 mg, 1.76 mmol). 1H NMR (d4-MeOH) δ 7.87 (d, 1H), 7.31 (d, 1H), 6.39 (s, 1H), 3.52-3.45 (m, 2H), 3.20-3.09 (m, 3H), 2.36-2.25 (m, 2H), 2.04-1.88 (m, 2H). ESI MS (M+1)+: 236, 238 (Cl).

Provenance & Evidence