Tetrahydrofuran → HCID 90234048, compound

HRID 1748837Notes

Reaction equation

HRID 1748837 reaction equation
[F-].[Cs+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH:14]1[C:23]2[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:21][N:20]([CH3:30])[C:19]=2[CH2:18][C:17](=[O:31])[CH2:16][CH2:15]1)[C:7]([O:9][CH3:10])=[O:8].[F:32][C:33]([Si](C)(C)C)([F:35])[F:34].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>COCCOC>[OH:31][C@:17]1([C:33]([F:35])([F:34])[F:32])[CH2:18][C:19]2[N:20]([CH3:30])[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:23]=2[C@@H:14]([C:13]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[CH3:3])[CH2:15][CH2:16]1

Participants

7

Reactant 5

HCID 8028TetrahydrofuranHCID 25953Cesium fluorideHCID 552549(Trifluoromethyl)trimethylsilane2×HCID 2724141Tetrabutylammonium FluorideHCID 86724157HCID 86724157, compound

Product 1

HCID 90234048HCID 90234048, compoundYield 8%

Reagents, catalysts & solvents 1

HCID 80711,2-DimethoxyethaneSolvent

Procedure

Cesium fluoride (0.037 g, 0.244 mmol) was added to a solution of rac-methyl 3-methyl-4-(1-methyl-7-oxo-3-(pyridin-2-yl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)benzoate (0.190 g, 0.488 mmol) in DME (50 mL). The mixture was stirred at rt for about 20 min then it was cooled in an ice bath and (trifluoromethyl)trimethylsilane (1.44 mL, 9.76 mmol) was added in a dropwise manner. After about 30 min, (trifluoromethyl)trimethylsilane (1.44 mL, 9.76 mmol) was added. After about 45 min, the mixture was partitioned between EtOAc (100 mL) and saturated aqueous NH4Cl solution (100 mL). The organic layer was washed with brine (100 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and 1 M tetrabutylammonium fluoride in THF (0.54 mL, 0.54 mmol) was added. The mixture was stirred at rt for about 1 h then it was washed with saturated NH4Cl (2×50 mL) and brine (50 mL). The organic layer was dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 25-50% EtOAc/heptane) to give rac-methyl 4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.018 g, 8%): LC-MS (Table 1, Method g) Rt=2.28 min, m/z 460 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.31-8.27 (m, 1H), 7.75-7.72 (m, 1H), 7.69-7.67 (m, 1H), 7.65-7.60 (m, 1H), 7.53-7.49 (m, 1H), 7.10-7.05 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.30 (s, 1H), 5.22-5.14 (m, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.34-3.32 (m, 2H), 2.62 (s, 3H), 2.20-2.08 (m, 1H), 1.98-1.90 (m, 1H), 1.86-1.74 (m, 2H). and rac-methyl 4-((4R,7R)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.034 g, 15%): LC-MS (Table 1, Method g) Rt=2.28 min, m/z 460 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.35-8.38 (m, 1H), 7.77-7.74 (m, 1H), 7.71-7.69 (m, 1H), 7.68-7.63 (m, 1H), 7.57-7.52 (m, 1H), 7.14-7.10 (m, 1H), 6.96-6.93 (m, 1H), 6.18 (s, 1H), 5.51-5.45 (m, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 3.36-3.17 (m, 2H), 2.56 (s, 3H), 2.29-2.20 (m, 1H), 1.90-1.79 (m, 1H), 1.76-1.65 (m, 2H).

Workup

  1. temperatureit was cooled in an ice bath
  2. waitAfter about 30 min
  3. waitAfter about 45 min
  4. customthe mixture was partitioned between EtOAc (100 mL) and saturated aqueous NH4Cl solution (100 mL)
  5. washThe organic layer was washed with brine (100 mL)
  6. dry with materialdried with Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. dissolutionThe residue was dissolved in EtOAc (20 mL)
  10. stirringThe mixture was stirred at rt for about 1 h
  11. washit was washed with saturated NH4Cl (2×50 mL) and brine (50 mL)
  12. dry with materialThe organic layer was dried with Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. customThe residue was purified by column chromatography (SiO2, 25-50% EtOAc/heptane)

Sources & evidence

ORD record
ord-67a8f4566cf7442ca83214fa70722d95
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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