Dichloromethane → Tert-butyl({5-[5-chloro-3-fluoro-2-(2-methyl-2h-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}methyl)carbamate

Temperature

90 °C

A mixture of potassium acetate (3.10 g, 31.6 mmol), tert-butyl[(5-bromo-3-fluoropyridin-2-yl)methyl]carbamate (3.21 g, 10.5 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.94 g, 11.6 mmol) in a sealed tube reaction vessel capped with a rubber septum was dissolved in 10 mL of DMSO. This heterogeneous mixture was then evacuated and purged with nitrogen three times prior to introduction of [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), complex with DCM (1:1) (0.385 g, 0.530 mmol). The heterogeneous mixture was then evacuated and purged with nitrogen twice before the septum was replaced with a teflon screw-top cap. This sealed vessel was then heated to 90° C. for 2 hours. After cooling to ambient temperature, potassium carbonate (2.91 g, 21.1 mmol), water (10.5 mL), 5-(2-bromo-4-chloro-6-fluorophenyl)-2-methyl-2H-tetrazole (3.38 g, 11.6 mmol) and additional palladium catalyst (0.385 g, 0.530 mmol) were added and the reaction was sealed again. After heating to 80° C. for 1 hour, the reaction was cooled, quenched with water, and partitioned between EtOAc and water. The mixture was filtered through a plug of celite with EtOAc. The aqueous layer was extracted once with EtOAc. The combined organic layers were washed with additional water and then brine prior to drying over sodium sulfate. Filtration and solvent removal provided material which was subjected to chromatography on silica gel eluting with 0-15% EtOAc in hexanes to yield tert-butyl({5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}methyl)carbamate.

1. customcapped with a rubber septum
2. customThis heterogeneous mixture was then evacuated
3. custompurged with nitrogen three times
4. customThe heterogeneous mixture was then evacuated
5. custompurged with nitrogen twice before the septum
6. temperatureAfter cooling to ambient temperature
7. customthe reaction was sealed again
8. temperatureAfter heating to 80° C. for 1 hour
9. temperaturethe reaction was cooled
10. customquenched with water
11. custompartitioned between EtOAc and water
12. filtrationThe mixture was filtered through a plug of celite with EtOAc
13. extractionThe aqueous layer was extracted once with EtOAc
14. washThe combined organic layers were washed with additional water
15. dry with materialbrine prior to drying over sodium sulfate
16. filtrationFiltration and solvent removal
17. customprovided material which

ORD record

ord-02e498d686ee46afafcb6b4c10abf340

Source dataset

uspto-grants-2010_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07816380B2