Triphenylphosphine → tert-Butyl 4-(5-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate

Temperature

120 °C

A suspension of tert-butyl 4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A44) (340 mg, 0.74 mmol), CuI (7 mg, 0.04 mmol), PPh3 (10 mg, 0.04 mmol) and Et3N (207 μL, 1.49 mmol) in DMF (2.5 mL) was sonicated for 5 minutes. PdCl2(PPh3)2 (26 mg, 0.04 mmol) and methyl 2-(2-ethynylphenyl)acetate (K1) (194 mg, 1.11 mmol) in DMF (1 mL) were added and the resulting mixture degassed with nitrogen for 5 minutes before heating under microwave irradiation at 120° C. for 20 minutes. The resulting mixture was adsorbed on silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in hexanes) to give a brown oil that was taken up in DMF (25 mL) and Et3N (2 mL) before 10% Pd/C (53% water; 75 mg) was added. The resulting mixture was stirred at room temperature for 44 hours under a hydrogen atmosphere then filtered through Celite, washing with EtOAc (200 mL). Activated charcoal (ca. 2.5 g) was added to the filtrate and the resulting suspension stirred at room temperature for 4 hours before filtration through Celite, washing with EtOAc (100 mL). The filtrate was washed with water (100 mL), brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure to give a brown oil. A suspension of 10% Pd/C (53% water; 200 mg) in DMF (100 mL) and Et3N (10 mL) was added and the resulting mixture stirred under a hydrogen atmosphere at room temperature for 4.5 days. The resulting mixture was filtered through Celite, washing with EtOAc (250 mL) then the combined filtrates were washed with water (3×100 mL) then brine (3×100 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A45 as a yellow oil (96 mg, 21%); 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=2.4 Hz, 1H), 8.55 (d, J=0.5 Hz, 1H), 8.14 (dd, J=8.5, 2.7 Hz, 1H), 7.55 (s, 1H), 7.25-7.18 (m, 4H), 7.16 (d, J=8.5 Hz, 1H), 4.26 (s, 2H), 3.74 (s, 2H), 3.68 (s, 3H), 3.11 (s, 4H), 2.88-2.79 (m, 3H), 1.92 (d, J=12.0 Hz, 2H), 1.77-1.64 (m, 2H), 1.47 (s, 9H). LCMS-A: rt 6.137 min; m/z 600 [M+H]+.

1. customwas sonicated for 5 minutes
2. customthe resulting mixture degassed with nitrogen for 5 minutes
3. custompurified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in hexanes)
4. customto give a brown oil that
5. filtrationthen filtered through Celite
6. washwashing with EtOAc (200 mL)
7. additionActivated charcoal (ca. 2.5 g) was added to the filtrate
8. stirringthe resulting suspension stirred at room temperature for 4 hours before filtration through Celite
9. washwashing with EtOAc (100 mL)
10. washThe filtrate was washed with water (100 mL), brine (100 mL)
11. dry with materialdried (Na2SO4)
12. concentrationconcentrated under reduced pressure
13. customto give a brown oil
14. additionwas added
15. stirringthe resulting mixture stirred under a hydrogen atmosphere at room temperature for 4.5 days
16. filtrationThe resulting mixture was filtered through Celite
17. washwashing with EtOAc (250 mL)
18. washthe combined filtrates were washed with water (3×100 mL)
19. dry with materialThe organic layer was dried (Na2SO4)
20. filtrationfiltered
21. concentrationconcentrated under reduced pressure
22. customThe residue was purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)

ORD record

ord-190232e1bcfe446bbdb718331a58f793

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09266864B2