反应详情

温度

-20 °C

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).

1. temperaturebefore cooling back to −78° C.
2. temperatureWarmed
3. customthe reaction slowly to room temperature over 2 hours
4. customquenched with 1N HCl (50 mL)
5. extractionExtracted into ethyl acetate
6. washwashed with saturated aqueous sodium hydrogencarbonate
7. dry with materialdried over magnesium sulfate
8. customFlash column chromatography gave a 1:1 mixture
9. concentrationAfter 2 hours the reaction mixture was concentrated to dryness, and flash column
10. customchromatographed on silica gel with ammonium hydroxide/methylene chloride/methanol