Methyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate → 2-(3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-phenyl)-2-methyl-propionic acid methyl ester

Alternatively, to 6-(4-bromo-furan-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (185 mg, 0.40 mmol) was added 2-methyl-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]propionic acid methyl ester (1.7 mL of a 0.47 M solution in 1,2-dimethoxyethane, 0.8 mmol). The mixture was diluted with 1,2-dimethoxyethane (2.3 mL) and nitrogen was bubbled through the solution as an aqueous solution of K2CO3 (0.4 mL of a 35% w/v solution in H2O, 1.0 mmol) was added. The addition of the K2CO3 solution caused the reaction mixture to turn dark. The mixture was then treated with dichloro[1,1′-bis(diphenylphosphino)ferrocene)palladium (II) dichloromethane adduct (33 mg, 40 μmol). After several minutes the nitrogen sparge was discontinued, and the vial was immersed in an oil bath held at 80° C. After stirring for 16 hours the dark reaction was allowed to cool to ambient temperature, and diluted with ether (30 mL), and H2O (10 mL). The aqueous layer was extracted with ether (1×10 ml), the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to afford a dark oil. The crude material was purified by flash chromatography eluting with a gradient from 0% to 20% ethyl acetate/hexane to afford bright yellow product containing fractions from the column. Some of these fractions deposited yellow crystals upon standing. The crystals were collected and found to be pure 2-(3-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-phenyl)-2-methyl-propionic acid methyl ester (74 mg, 33% yield). 1H-NMR (400 MHz, CDCl3): δ 7.89 (1H, br s), 7.41-7.28 (4H, m), 7.11-7.05 (2H, m), 6.91-6.82 (3H, m), 5.60 (2H, s), 3.67 (3H, s), 1.61 (6H, s).

1. customwas bubbled through the solution as an aqueous solution of K2CO3 (0.4 mL of a 35% w/v solution in H2O
2. addition1.0 mmol) was added
3. additionThe addition of the K2CO3 solution
4. customAfter several minutes the nitrogen sparge
5. customthe vial was immersed in an oil bath
6. customheld at 80° C
7. customthe dark reaction
8. extractionThe aqueous layer was extracted with ether (1×10 ml)
9. washthe combined organic layers were washed with brine (10 mL)
10. dry with materialdried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated
13. customto afford a dark oil
14. customThe crude material was purified by flash chromatography
15. washeluting with a gradient from 0% to 20% ethyl acetate/hexane
16. customto afford bright yellow product
17. additioncontaining fractions from the column
18. customThe crystals were collected

ORD record

ord-acd6e7f3a5614259a8817069babeb5cc

Source dataset

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08013001B2