Potassium Carbonate → 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(6-hydroxy-2-naphthalenyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.256 mmol) in dioxane (1.5 mL) was treated with (6-hydroxy-2-naphthalenyl)boronic acid (0.281 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg), and 2M aq potassium carbonate (0.767 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave (Biotage Initiator) at 150° C. for 15 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The aqueous phase was then diluted with brine (50 mL) and extracted with tetrahydrofuran, which was subsequently combined with the dichloromethane organic phase. The resulting organic phase was treated with Si-Thiol (Silicycle, 20 mg), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (20-50% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions from the HPLC were combined, adjusted to pH˜5 with the addition of saturated aq sodium bicarbonate, further diluted with brine, and extracted with tetrahydrofuran. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting product was purified by reverse phase HPLC (10-40% acetonitrile/water+0.1% NH4OH) to afford the title compound as an amorphous white solid (23%). MS(ES)+ m/e 455.0 [M+H]+.

1. customThe reaction mixture was purged with nitrogen
2. customsealed
3. customirradiated in a microwave (Biotage Initiator) at 150° C. for 15 min
4. additionwas diluted with water (50 mL)
5. extractionwas extracted with dichloromethane
6. additionThe aqueous phase was then diluted with brine (50 mL)
7. extractionextracted with tetrahydrofuran, which
8. additionThe resulting organic phase was treated with Si-Thiol (Silicycle, 20 mg)
9. dry with materialdried over magnesium sulfate
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. customThe crude residue was purified by reverse phase HPLC (20-50% acetonitrile w/0.1% TFA/water w/0.1% TFA)
13. additionadjusted to pH˜5 with the addition of saturated aq sodium bicarbonate
14. additionfurther diluted with brine
15. extractionextracted with tetrahydrofuran
16. dry with materialThe organic layer was dried over magnesium sulfate
17. filtrationfiltered
18. concentrationconcentrated in vacuo
19. customThe resulting product was purified by reverse phase HPLC (10-40% acetonitrile/water+0.1% NH4OH)

ORDレコード

ord-4a640c9edeef4708b0a1fbde57fd8cc5

出典データセット

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08802864B2