Tetrahydrofuran → HCID 89994499, compound

Temperature

0 °C

A solution of (3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (33, R1=4-Fluorophenyl, R3=Trifluoromethyl) (79 mg, 0.158 mmol) was dissolved in THF (2 mL) and cooled to about 0° C. under nitrogen. The mixture was treated dropwise with DIBAL-H (1M in cyclohexane, 0.90 mL, 0.90 mmol). The reaction was stirred at about 0° C. for about 2 h, then quenched by addition of 6% acetic acid in sat. aq. sodium acetate solution (3 mL). The reaction was concentrated to about 3 mL volume and extracted with DCM (2×20 mL). The organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Intermediate LC/MS, method 3, Rt=3.14 min, MS m/z 537 (M+H)+. The residue was dissolved in EtOH (3 mL) and treated with NaBH4 (18 mg, 0.47 mmol) at rt for about 1 h. The reaction was quenched with aq. NH4Cl solution (2 mL) and stirred about 15 min at rt. The mixture was further diluted with water (2 mL) and extracted with DCM (2×5 mL). The combined DCM layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to yield (3R,4aR,12bS)-9-(4-fluorophenyl)-12b-(hydroxymethyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol), (37, R1=4-Fluorophenyl, R3=Trifluoromethyl) (85 mg, 100%) as a glass: LC/MS, method 3, Rt=3.02 min, MS m/z 539 (M+H)+. The residue was used in step #2 without further purification.

1. customquenched by addition of 6% acetic acid in sat. aq. sodium acetate solution (3 mL)
2. concentrationThe reaction was concentrated to about 3 mL volume
3. extractionextracted with DCM (2×20 mL)
4. dry with materialThe organic extracts were dried over Na2SO4
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure
7. dissolutionThe residue was dissolved in EtOH (3 mL)
8. customThe reaction was quenched with aq. NH4Cl solution (2 mL)
9. stirringstirred about 15 min at rt
10. additionThe mixture was further diluted with water (2 mL)
11. extractionextracted with DCM (2×5 mL)
12. washThe combined DCM layers were washed with water
13. dry with materialdried over Na2SO4
14. filtrationfiltered
15. concentrationconcentrated under reduced pressure

ORD record

ord-95fd60fe7f4246d09fe681aa8cf0354e

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193744B2