Trifluoroacetic acid → HCID 58092968, compound

Temperature

0 °C

To a solution of 2-chloropyridin-4-amine (1.286 g, 10.0 mmol) in dry THF (30 mL) cooled to 0° C. with an ice water bath under dry N2 was added a solution of NaHMDS in THF (1.0 M, 24 mL) via syringe. After the reaction mixture was stirred at 0° C. for 20 minutes, a solution of Boc2O (4.8 g, 22.0 mmol) in THF (30 mL) was added at 0° C. and then the ice-water bath was removed. After it was stirred at room temperature for 16 hours, 40 hours, and 64 hours, NaHMDS (1.0 M, 16 mL, 6 mL, and 6 mL) were added respectively and the reaction mixture was stirred continually. After 68 hours, the reaction mixture was poured into saturated NH4Cl solution (400 mL) and followed by addition of 100 mL of EtOAc. The organic phase was separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were washed with a 20% aqueous Na2CO3 solution (10 mL), brine (10 mL), dried over Na2SO4, and evaporated to result in crude tert-butyl 4-(tert-butoxycarbonylamino)-2-chloronicotinate which was then mixed with a mixture of DCM (80 mL) and TFA (20 mL). After it was stirred at 60° C. in a Teflon screwed pressure vessel for 4 hours, the reaction mixture was evaporated under reduced pressure and concentrated to result in a residue which was refluxed in thionyl chloride (40 mL) for 50 minutes. After it was evaporated under reduced pressure, the residue was diluted with ethyl ether (40 mL) resulting a solution which was added into ice cold 28% aqueous NH4OH (20 mL) solution. After it was stirred at 0° C. for 2 hours and at room temperature for another 2 hours, the reaction mixture was concentrated under reduced pressure, diluted with a mixed solvent of DCM/MeOH/28% aqueous NH4OH (190:10:1), loaded on silica gel (60 mL). Chromatography of the mixture with gradient mixed solvents from DCM/MeOH/28% aqueous NH4OH (190:10:1) to (73:10:1) afforded the title compound. 1H NMR (DMSO-d6) 6.23 (br s, 2H, NH), 6.57 (d, J=5.6 Hz, 1H), 7.64 (br s, 1H, NH), 7.76 (d, J=5.6 Hz, 1H), 7.92 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 109.3, 116.2, 146.8, 147.9, 153.5, 166.3; ESI-MS m/z 171.0 (MH+).

1. customthe ice-water bath was removed
2. stirringAfter it was stirred at room temperature for 16 hours, 40 hours
3. addition64 hours, NaHMDS (1.0 M, 16 mL, 6 mL, and 6 mL) were added respectively
4. stirringthe reaction mixture was stirred continually
5. waitAfter 68 hours
6. additionthe reaction mixture was poured into saturated NH4Cl solution (400 mL)
7. additionfollowed by addition of 100 mL of EtOAc
8. customThe organic phase was separated
9. extractionthe aqueous phase was extracted with EtOAc (3×50 mL)
10. washThe combined organic phases were washed with a 20% aqueous Na2CO3 solution (10 mL), brine (10 mL)
11. dry with materialdried over Na2SO4
12. customevaporated
13. customto result in crude tert-butyl 4-(tert-butoxycarbonylamino)-2-chloronicotinate which
14. customfor 4 hours
15. customthe reaction mixture was evaporated under reduced pressure
16. concentrationconcentrated
17. customto result in a residue which
18. customAfter it was evaporated under reduced pressure
19. additionthe residue was diluted with ethyl ether (40 mL)
20. customresulting a solution which
21. stirringAfter it was stirred at 0° C. for 2 hours and at room temperature for another 2 hours
22. concentrationthe reaction mixture was concentrated under reduced pressure
23. additiondiluted with a mixed solvent of DCM/MeOH/28% aqueous NH4OH (190:10:1)

ORD record

ord-fb15bda666a3452da8b6a2039de182d5

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08354526B2