2-Bromopyridine → HCID 131734186, compound

Temperature

-78 °C

A solution of 2-bromopyridine (506 mg, 3.20 mmol) in THF (6 mL) was cooled to about −78° C. under nitrogen. A solution of BuLi (2.5M solution in hexanes, 1.26 mL, 3.14 mmol) was added dropwise while maintaining reaction temperature below −75° C. The reaction was stirred for about 15 min at about −78° C. then a solution of (3R,4aR,12bS)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile; compound with (3R,4aR,12bS)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-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, Rg=TES) (350 mg, 0.628 mmol) in THF (2.5 mL) was added dropwise maintaining reaction temperature below −74° C. The reaction was stirred for about 30 min and then quenched by addition of 2 N aq. HCl (5 mL). The mixture was stirred about 6 h at rt and then cooled to rt. The reaction was neutralized by addition of sat. aq. NaHCO3 (20 mL) and the products extracted with EtOAc (2×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified on silica gel (25 g) using a gradient of 25-50% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL), water (5 mL) was added and the mixture was concentrated to about 5 mL volume. The product was filtered off and dried under reduced pressure at about 50° C. to yield ((3R,4aR,12bS)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)(pyridin-2-yl)methanone compound with ((3R,4aR,12bS)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)(pyridin-2-yl)methanone (11, R1=4-Fluorophenyl, R2=2-Pyridylcarbonyl, R3=Trifluoromethyl) (49 mg, 15%) as a yellow solid; Major isomer: LC/MS, method 2, Rt=2.80 min, MS m/z 524 (M+H)+, 1H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 8.63 (d, J=4.0 Hz, 1H), 8.09-8.02 (m, 1H), 7.94-7.88 (m, 2H), 7.66-7.60 (m, 1H), 7.35-7.29 (m, 2H), 7.25-7.18 (m, 2H), 6.98 (s, 1H), 6.19 (s, 1H), 3.16-3.05 (m, 1H), 2.77-2.65 (m, 1H), 2.19-1.86 (m, 6H), 1.77-1.58 (m, 3H), 1.53-1.39 (m, 1H), 1.37-1.23 (m, 1H). Evidence of two hemi-ketal forms is observed in both the NMR and the LC/MS.

1. temperaturewhile maintaining
2. customreaction temperature below −75° C
3. temperaturemaintaining
4. customreaction temperature below −74° C
5. stirringThe reaction was stirred for about 30 min
6. customquenched by addition of 2 N aq. HCl (5 mL)
7. stirringThe mixture was stirred about 6 h at rt
8. temperaturecooled to rt
9. additionThe reaction was neutralized by addition of sat. aq. NaHCO3 (20 mL)
10. extractionthe products extracted with EtOAc (2×20 mL)
11. dry with materialdried over Na2SO4
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. customThe product was purified on silica gel (25 g)
15. concentrationconcentrated under reduced pressure
16. dissolutionThe residue was dissolved in MeOH (10 mL)
17. additionwater (5 mL) was added
18. concentrationthe mixture was concentrated to about 5 mL volume
19. filtrationThe product was filtered off
20. customdried under reduced pressure at about 50° C.

ORD record

ord-9ca5b71b99c0456faefc149790f05a7a

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193744B2