Triphenylphosphine → HCID 178420716, compound

A mixture of 3-(3-hydroxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (400 mg, 1.25 mmol), triphenylphosphine (Ph3P, 1.31 g, 5.00 mmol, 4.00 equiv.), 4.00 mL THF, 4-(2-hydroxyethyl)morpholine (656 mg, 5.00 mmol, 4.00 equiv.), and diethyl azodicarboxylate (DEAD, 871 mg, 5.00 mmol, 4.00 equiv.) were stirred at room temperature for 3 days. The reaction was diluted with EtOAc and washed with 2×6.0 N aq. HCl. The combined aqueous layers were extracted with 2×EtOAc The acidic aqueous layer was allowed to stand at room temperature for 5 h, and then added to enough 6.0 N aq. NaOH such that the final pH>12.0. The aqueous layer was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated. Purification by silica gel chromatography using 0–5% MeOH in EtOAc as eluent afforded an oil. A mixture of the oil (1.25 mmol), azidotributyltin (Bu3SnN3, 2.35 g, 7.08 mmol, 5.66 equiv.), and 13.5 mL toluene was refluxed for 17.5 h and concentrated to an oil. To the oil was added 6.5 mL of dioxane and 6.5 mL of 6.0 N aq. HCl. The mixture was stirred at room temperature for 4 h and then added to 25 mL of 6.0 N aq. NaOH. The mixture was extracted with 3×hexanes, and 3×Et2O. The aqueous layer was filtered to remove particulates. The pH was adjusted with 6.0 N aq. HCl to give maximum visual turbidity (approximately pH 5.0–5.5) and the mixture was extracted with 2×EtOAc. The combined organics were dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography using 0–20% MeOH in EtOAc as eluents afforded the title compound (43.1 mg, 8.82% yield): 1H NMR (DMSO-d6) δ13.54 (s, 1H), 8.72 (s, 1H), 8.10 (d, 1H), 7.77 (d, 1H), 7.61 (d, 1H), 7.52–7.45 (m, 2H), 7.06 (d, 1H), 4.23 (t, 2H), 3.65–3.56 (m, 4H), 2.82 (t, 2H), 2.52–2.45 (m, 4H); ES-MS (m/z) 392 [M+1]+.

1. washwashed with 2×6.0 N aq. HCl
2. extractionThe combined aqueous layers were extracted with 2×EtOAc The acidic aqueous layer
3. waitto stand at room temperature for 5 h
4. additionadded to enough 6.0 N aq. NaOH such that the final pH>12.0
5. extractionThe aqueous layer was extracted with EtOAc
6. dry with materialThe organic layer was dried (Na2SO4)
7. filtrationfiltered
8. concentrationconcentrated
9. customPurification by silica gel chromatography
10. customafforded an oil
11. temperaturewas refluxed for 17.5 h
12. concentrationconcentrated to an oil
13. additionTo the oil was added 6.5 mL of dioxane and 6.5 mL of 6.0 N aq. HCl
14. stirringThe mixture was stirred at room temperature for 4 h
15. additionadded to 25 mL of 6.0 N aq. NaOH
16. extractionThe mixture was extracted with 3×hexanes, and 3×Et2O
17. filtrationThe aqueous layer was filtered
18. customto remove particulates
19. customto give maximum visual turbidity (approximately pH 5.0–5.5) and the mixture
20. extractionwas extracted with 2×EtOAc
21. dry with materialThe combined organics were dried (Na2SO4)
22. filtrationfiltered
23. concentrationconcentrated
24. customPurification by silica gel chromatography

ORD record

ord-2e91bfd97dc143229607576ce067e10f

Source dataset

uspto-grants-2007_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07220771B2