Cesium carbonate → 2-(5-Bromo-2-chloropyridin-3-yloxy)propanenitrile

A dry 5 mL, one neck round bottom flask was charged with a 95-5 mixture of 5-bromo-2-chloropyridin-3-ol and 3-bromo-2-chloropyridin-5-ol (0.2031 g, 0.9744 mmol), a stirbar, 2 mL dry DMF and 2-chloropropanenitrile (0.4310 ml, 4.872 mmol). To the mixture was added cesium carbonate (CS2CO3) (0.3492 g, 1.072 mmol), and the flask was sealed with a septa. The reaction was heated using a 100° C. oil bath for 4 h, and cooled. The DMF was diluted with 4 mL THF, and the slurry was loaded onto 5 g of SiO2 wet-packed with THF. The silica was eluted with 50 mL THF, and the eluted volume was concentrated in vacuo. A sample was scouted for prep purification using a 2.1×50 mm Xterra MS C18 column with a 3.5 μm particle size (PN 186000400); A=10 mM NH4 HCO3 in water, pH adjusted with concentrated NH4OH to 9.6; B=ACN; gradient: initial@1 mL/min, 10% B; 0→5 min@1 mL/min, linear gradient to 100% B; 5→6.9 min@1 mL/min, isocratic at 100% B; 6.9→6.95 min@1 mL/min, linear gradient to 10% B, 8 min end. A major peak was observed at 2.87 minutes. The sample was purified using a 30×100 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186001942); Gradient: 0→5 min@35 mL/min, 10% B; 5→20 min@35 mL/min, linear gradient to 40% B; 20→24.9 min@35 mL/min, isocratic at 40% B; 25.0 min→29.9 min@35 mL/min, step to 100% B; 30→40 min@35 mL/min, step to 10% B; 40 min end. A=10 mM NH4 HCO3 in water, pH adjusted with concentrated NOH to 9.6; B=ACN. A band that eluted from 23.6 to 25.4 minutes was isolated. The solvent was removed in vacuo to afford 2-(5-bromo-2-chloropyridin-3-yloxy)propanenitrile and 2-(5-bromo-2-chloropyridin-3-yloxy)propanenitrile (0.1316 g).

1. customthe flask was sealed with a septa
2. temperatureThe reaction was heated
3. customusing a 100° C.
4. customfor 4 h
5. temperaturecooled
6. washThe silica was eluted with 50 mL THF
7. concentrationthe eluted volume was concentrated in vacuo
8. customA sample was scouted for prep purification
9. custom0→5 min@1 mL/min, linear gradient
10. custom5→6.9 min@1 mL/min
11. custom6.9→6.95 min@1 mL/min, linear gradient
12. customto 10% B, 8 min end
13. customThe sample was purified
14. custom0→5 min@35 mL/min, 10% B
15. custom5→20 min@35 mL/min, linear gradient
16. custom20→24.9 min@35 mL/min
17. custom25.0 min→29.9 min@35 mL/min, step
18. custom30→40 min@35 mL/min, step
19. custom40 min end
20. washA band that eluted from 23.6 to 25.4 minutes
21. customwas isolated
22. customThe solvent was removed in vacuo

ORD record

ord-4032c4450a094e499f6f8fa3c551c477

Source dataset

uspto-grants-2011_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07928140B2