Citric Acid → 2-(3-Amino azetidin-1-yl)-5'-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3'-bipyridine]-5-carboxamide

Temperature

110 °C

2-Chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Stage 236.1, 70 mg, 0.160 mmol) and DIPEA (0.070 mL, 0.4 mmol) were added to a vial with iPrOH (1 mL). tert-Butyl azetidin-3-ylcarbamate (70.2 mg, 0.4 mmol) was added. The mixture was stirred at 110° C. for 5 h. tert-Butyl azetidin-3-ylcarbamate (35 mg) was added and the RM was stirred for further 5 h at 110° C. The RM was treated with citric acid 10% (10 mL) and extracted with EtOAc. The combined extracts were washed with an aq. sat. solution of NaHCO3 (10 mL) and with brine (2×10 mL), dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to afford the crude product that was purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 99:1 to 9:1). The resulting intermediate (33 mg, 0.054 mmol) was dissolved in DCM (1 mL). TFA (0.167 mL, 2.170 mmol) was added and the RM was stirred for 2 h at RT. The RM was treated sat. aq. Na2CO3 (20 mL) and extracted with DCM. The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a crude product that was purified by preparative HPLC. Fractions containing product were combined and treated with 100 mg Na2CO3 and the MeCN was removed. The aq. residue was extracted with DCM (3×10 mL) and the combined extracts were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to afford the title product as a white foam. HPLC (Condition 10) tR=5.77 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=448.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.36 (dd, J=8.60, 5.47 Hz, 2H) 3.56-3.68 (m, 1H) 3.84 (t, J=7.82 Hz, 2H) 7.35 (d, J=8.99 Hz, 2H) 7.85 (m, J=9.40 Hz, 3H) 8.06 (d, J=2.35 Hz, 1H) 8.53 (s, 1H) 8.62 (d, J=2.74 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 10.20 (s, 1H).

1. additionwas added
2. extractionextracted with EtOAc
3. washThe combined extracts were washed with an aq. sat. solution of NaHCO3 (10 mL) and with brine (2×10 mL)
4. dry with materialdried over Na2SO4
5. filtrationfiltered
6. customthe filtrate was evaporated off under reduced pressure
7. customto afford the crude product that
8. customwas purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 99:1 to 9:1)
9. stirringthe RM was stirred for 2 h at RT
10. extractionextracted with DCM
11. washThe combined extracts were washed with brine (20 mL)
12. dry with materialdried over Na2SO4
13. filtrationfiltered
14. customthe filtrate was evaporated off under reduced pressure
15. customto give a crude product that
16. customwas purified by preparative HPLC
17. additionFractions containing product
18. additiontreated with 100 mg Na2CO3
19. customthe MeCN was removed
20. extractionThe aq. residue was extracted with DCM (3×10 mL)
21. dry with materialthe combined extracts were dried over Na2SO4
22. filtrationfiltered
23. customthe filtrate was evaporated off under reduced pressure

ORD record

ord-36b50289ff434472ac9c429d63ad3f57

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09278981B2