Sodium Carbonate → (R)-tert-Butyl 2-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate

Temperatur

80 °C

NaH (0.024 g, 0.569 mmol) was added to a solution of 2-chloro-5-iodopyridin-4-amine (0.121 g, 0.474 mmol) in DMF (2.8 mL) at room temperature and stirred for 10 min. The temperature was raised to 80° C. and (R)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate (0.264 g, 0.711 mmol) in DMF (0.6 mL) was added. The reaction mixture was stirred for 2 h before further NaH (0.024 g, 0.569 mmol) was added at room temperature. The reaction mixture was heated at 80° C. for a further 1 h then cooled. Water was added and the mixture was partitioned between ethyl acetate (20 mL) and aq. NaHCO3 (20 mL). The organic phase was washed with brine, dried (MgSO4) and concentrated. The mixture was purified by flash column chromatography on silica gel, eluting with ethyl acetate and hexane (2/4), to give an inseparable mixture of starting material and product. LC-MS (4) Rt=2.66 min; m/z (ESI+) 397 [MH+]. A solution of the crude (R)-tert-butyl 2-((2-chloro-5-iodopyridin-4-ylamino)methyl)morpholine-4-carboxylate (0.040 g, 0.088 mmol), sodium carbonate (0.5 M, 0.26 mL), 4-methoxyphenyl boronic acid (0.013 g, 0.088 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.011 g, 0.01 mmol) in acetonitrile (2 mL) was heated under microwave irradiation at 100° C. for 20 min. The reaction mixture was concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1/1), to give the title compound as colorless oil (0.036 g, 94%).

1. additionwas added at room temperature
2. temperatureThe reaction mixture was heated at 80° C. for a further 1 h
3. temperaturethen cooled
4. customthe mixture was partitioned between ethyl acetate (20 mL) and aq. NaHCO3 (20 mL)
5. washThe organic phase was washed with brine
6. dry with materialdried (MgSO4)
7. concentrationconcentrated
8. customThe mixture was purified by flash column chromatography on silica gel
9. washeluting with ethyl acetate and hexane (2/4)
10. customto give
11. additionan inseparable mixture of starting material and product
12. concentrationThe reaction mixture was concentrated in vacuo
13. customThe mixture was purified by flash column chromatography on silica gel
14. washeluting with ethyl acetate/hexane (1/1)

ORD-Eintrag

ord-397f8314b3d740f7845ca002148fdbf5

Quelldatensatz

uspto-grants-2013_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08367658B2