Water → HCID 178438852, compound

To a solution of 4′-{1-[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile (0.33 g) and rhodium acetate (dimer, 0.030 g) in toluene (4 mL) was added dropwise ethyldiazoacetate (0.36 mL) at 80° C., and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was crudely purified by silica gel column chromatography. This was dissolved in tetrahydrofuran (2 mL), methylmagnesium bromide (1.4 M tetrahydrofuran solution, 0.62 mL) was added dropwise at 0° C., and the mixture was stirred for 2 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. This was dissolved in dimethyl sulfoxide (1 mL), hydroxylammonium chloride (0.17 g) and sodium hydrogen carbonate (0.25 g) were added, and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.036 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.033 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.038 g, 34%).

1. extractionthe mixture was extracted with ethyl acetate
2. washThe organic layer was washed with water
3. dry with materialwith saturated brine, dried over anhydrous magnesium sulfate
4. concentrationconcentrated
5. customThe residue was crudely purified by silica gel column chromatography
6. dissolutionThis was dissolved in tetrahydrofuran (2 mL)
7. additionmethylmagnesium bromide (1.4 M tetrahydrofuran solution, 0.62 mL) was added dropwise at 0° C.
8. stirringthe mixture was stirred for 2 hr
9. additionTo the reaction mixture were added ethyl acetate
10. extractionsaturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate
11. washThe organic layer was washed with saturated brine
12. dry with materialdried over anhydrous magnesium sulfate
13. concentrationconcentrated
14. dissolutionThis was dissolved in dimethyl sulfoxide (1 mL)
15. additionhydroxylammonium chloride (0.17 g) and sodium hydrogen carbonate (0.25 g) were added
16. stirringthe mixture was stirred at 90° C. for 20 hr
17. additionThe reaction mixture was diluted with ethyl acetate
18. washwashed with water
19. dry with materialwith saturated brine, and dried over anhydrous magnesium sulfate
20. customThe solvent was evaporated under reduced pressure
21. dissolutionthe residue was dissolved in tetrahydrofuran (1 mL)
22. additionN,N′-Carbonyldiimidazole (0.036 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.033 mL) were added
23. stirringthe mixture was stirred at room temperature for 1 hr
24. additionThe reaction mixture was diluted with ethyl acetate
25. washwashed with 1 M hydrochloric acid
26. dry with materialwith saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate
27. customThe solvent was evaporated under reduced pressure
28. customthe residue was purified by silica gel column chromatography

ORD record

ord-4b09f97d9edf45e1bda54914b993c649

Source dataset

uspto-grants-2013_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08592431B2