Hydroxylamine HCl → 6-ethyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

Temperature

40 °C

4′-{[6-Ethyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.70 g) was dissolved in dimethyl sulfoxide (5 mL), and the mixture was added to a mixture of hydroxylammonium chloride (0.93 g), sodium hydrogencarbonate (1.30 g) and dimethyl sulfoxide (10 mL), which had been stirred at 40° C. for 30 min in advance. The reaction mixture was stirred at 90° C. for 16 hr, diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.39 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methylene chloride (10 mL), HIO3 (0.44 g) was added and the mixture was stirred at room temperature overnight. Activated carbon was added to the reaction mixture and the mixture was heated to 45° C. and filtered. The filtrate was concentrated, and purified by preparative HPLC to give the title compound as colorless crystals (0.078 g, 16%).

1. stirringThe reaction mixture was stirred at 90° C. for 16 hr
2. washwashed successively with water and saturated brine
3. dry with materialdried over anhydrous magnesium sulfate
4. customThe solvent was evaporated under reduced pressure
5. customThe residue was purified by silica gel column chromatography
6. dissolutiondissolved in tetrahydrofuran (10 mL)
7. additionN,N′-carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.39 mL) were added
8. stirringthe mixture was stirred at room temperature for 2 hr
9. additionThe reaction mixture was diluted with chloroform
10. washwashed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine
11. dry with materialdried over anhydrous magnesium sulfate
12. customThe solvent was evaporated under reduced pressure
13. dissolutionThe obtained residue was dissolved in methylene chloride (10 mL)
14. additionHIO3 (0.44 g) was added
15. stirringthe mixture was stirred at room temperature overnight
16. additionActivated carbon was added to the reaction mixture
17. temperaturethe mixture was heated to 45° C.
18. filtrationfiltered
19. concentrationThe filtrate was concentrated
20. custompurified by preparative HPLC

ORD record

ord-91fab048e7094fc1a2bf224484a30690

Source dataset

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08501750B2