Sodium hydride → 4-(2-Chloro-3-methyl-pyridin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester

Temperature

23 °C

4-Hydroxy-piperidine-1-carboxylic acid isopropyl ester (0.496 mL, 2.90 mmol) was dissolved in anhydrous dimethylacetamide (DMA, 5 mL), NaH (60% oil dispersion, 116 mg, 2.90 mmol) was added and this mixture was stirred at 23° C. for 45 min, then this mixture was added dropwise to 2,4-dichloro-3-methyl-pyridine, which was dissolved in anhydrous DMA (4 mL). This mixture was stirred at 23° C. for 2 h then heated at 50° C. for 15 h, after which time the mixture was diluted with Et2O (140 mL), washed with water (14 mL), then brine twice (2×14 mL). The organic layer was separated, dried with MgSO4, and the solvent was evaporated in vacuo to give an oil which was purified by flash chromatography using hexanes-EtOAc, 75:25, v/v, then hexanes-EtOAc, 50:50, v/v, to give 4-(2-chloro-3-methyl-pyridin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as a solid (223 mg, 27%). 1H NMR (CDCl3, 400 MHz) δ 8.09 (d, 1H), 6.69 (d, 1H), 4.91 (m, 1H), 4.60 (m, 1H), 3.61 (m, 2H), 3.52 (m, 2H), 2.24 (s, 3H), 1.91 (m, 2H), 1.80 (m, 2H), 1.24 d, 6H). LRMS calculated for C15H21ClN2O3: 312.12, Found: (MH)+ 313.4.

1. stirringThis mixture was stirred at 23° C. for 2 h
2. temperaturethen heated at 50° C. for 15 h
3. washwashed with water (14 mL)
4. customThe organic layer was separated
5. dry with materialdried with MgSO4
6. customthe solvent was evaporated in vacuo
7. customto give an oil which
8. customwas purified by flash chromatography

ORD record

ord-915fb548e3d541ffaaaed90e3aa01bc6

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08546429B2