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

Temperature

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 (S)-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, then further NaH (0.024 g, 0.569 mmol) was added at room temperature. The reaction mixture was further heated at 80° C. for 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/hexane (2/4), to give an inseparable mixture of starting material and product. LCMS (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. The crude product was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1/1), to give the title compound as a colorless oil (0.036 g, 94%).

1. stirringThe reaction mixture was stirred for 2 h
2. temperatureThe reaction mixture was further heated at 80° C. for 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/hexane (2/4)
10. customto give
11. additionan inseparable mixture of starting material and product
12. concentrationThe reaction mixture was concentrated
13. customThe crude product was purified by flash column chromatography on silica gel
14. washeluting with ethyl acetate/hexane (1/1)

ORD record

ord-2998c422ba974b37ba704f3c6e99b2af

Source dataset

uspto-grants-2013_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08367658B2