Phosphorus oxychloride → 5-chloro-7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine

To a solution of 7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5(6H)-one (Step B, 772 mg, 2.33 mmol) in dry DCM (15 mL) was added DIEA (1.22 mL, 6.99 mmol) and the mixture was stirred at ambient temperature for 5 minutes. The mixture was cooled to 0° C. and POCl3 (855 μL, 9.32 mmol) was added. The mixture was stirred for 1 hour at 0° C. then at ambient temperature for 18 hours. The reaction mixture was concentrated and the residual syrup was dissolved in EtOAc (15 mL). The solution was added dropwise to stirred 1M K2CO3 (20 mL) cooled to 0° C. and stirred for 30 minutes. The mixture was allowed to reach ambient temperature and the EtOAc layer was removed. The remaining aqueous layer was extracted with EtOAc (2×) and the combined EtOAc fractions were washed with saturated NaCl. The EtOAc solution was dried over MgSO4/activated carbon, filtered through a packed Celite plug (EtOAc elution) and concentrated. The residual dark syrup was dissolved in Et2O, treated with activated carbon and filtered through a packed Celite pug (Et2O elution). The Et2O solution was concentrated to give a brittle tan foam that was pulverized to a flowing solid and dried in vacuum. This afforded the title compound (416 mg, 51.0% yield) as a light tan solid. MS (apci) m/z=350.1 (M+H).

1. temperatureThe mixture was cooled to 0° C.
2. stirringThe mixture was stirred for 1 hour at 0° C.
3. waitat ambient temperature for 18 hours
4. concentrationThe reaction mixture was concentrated
5. dissolutionthe residual syrup was dissolved in EtOAc (15 mL)
6. additionThe solution was added dropwise
7. stirringto stirred 1M K2CO3 (20 mL)
8. temperaturecooled to 0° C.
9. stirringstirred for 30 minutes
10. customto reach ambient temperature
11. customthe EtOAc layer was removed
12. extractionThe remaining aqueous layer was extracted with EtOAc (2×)
13. washthe combined EtOAc fractions were washed with saturated NaCl
14. dry with materialThe EtOAc solution was dried over MgSO4/activated carbon
15. filtrationfiltered through a packed Celite plug (EtOAc elution)
16. concentrationconcentrated
17. dissolutionThe residual dark syrup was dissolved in Et2O
18. additiontreated with activated carbon
19. filtrationfiltered through a packed Celite pug (Et2O elution)
20. concentrationThe Et2O solution was concentrated
21. customto give a brittle tan foam that
22. customdried in vacuum

ORD record

ord-52373ab28583499f948cd57fb9a9d71e

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08962596B2