Potassium Carbonate → N-(4-(Chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-(4-methylpyrimidin-5-yl)benzamide

Temperature

130 °C

4-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (Stage 297.1, 94 mg, 0.429 mmol), K2CO3 (118 mg, 0.857 mmol) and Pd(PPh3)4 (33.0 mg, 0.029 mmol) were added to a solution of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide (Stage 244.1, 150 mg, 0.286 mmol) in DMF (2.5 mL). at RT in a vial. The vial was evacuated/purged with argon, sealed and stirred at 130° C. for 2 h. The RM was diluted in EtOAc (80 mL), washed with water (3×30 mL), dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure. The residue was dissolved in methanol (3 mL) and filtered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min) and by preparative HPLC. The obtained residue was treated with a aq. solution of Na2CO3 (3 mL) and extracted twice with EtOAc (2×30 mL). The combined organic phases were washed with water (2×15 mL), dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure to afford the title product as a beige solid. HPLC (Condition 10) tR=6.091 min, UPLC-MS (Condition 11) tR=0.93 min, m/z=491.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.19/2.40 (s, 3H) 2.65-2.78 (m, 2H) 3.06-3.22 (m, 2H) 3.80-3.90 (m, 2H) 5.01-5.12 (m, 2H) 6.93 (d, J=8.99 Hz, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.70-7.80 (m, 1H) 7.83-7.89 (d, J=8.60 Hz, 2H) 7.91-7.98 (m, 1H) 8.82 (s, 1H) 9.05 (s, 1H) 10.01-10.12 (m, 1H).

1. customat RT
2. customThe vial was evacuated/purged with argon
3. customsealed
4. additionThe RM was diluted in EtOAc (80 mL)
5. washwashed with water (3×30 mL)
6. dry with materialdried over Na2SO4
7. filtrationfiltered
8. customthe solvent was evaporated off under reduced pressure
9. dissolutionThe residue was dissolved in methanol (3 mL)
10. filtrationfiltered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol)
11. washthe cartridge was washed with MeOH
12. customthe solvent was evaporated off under reduced pressure
13. customto give a residue which
14. customwas purified by preparative SFC (Column 2-EP, from 20% to 25% in 6 min) and by preparative HPLC
15. additionThe obtained residue was treated with a aq. solution of Na2CO3 (3 mL)
16. extractionextracted twice with EtOAc (2×30 mL)
17. washThe combined organic phases were washed with water (2×15 mL)
18. dry with materialdried over Na2SO4
19. filtrationfiltered
20. customthe solvent was evaporated off under reduced pressure

ORD record

ord-c6dceb3a86b5437b8c5cce52c4bb972a

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09278981B2