Tetrabutylammonium Fluoride → (5S,6S,9R)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl acetate

HRID 1879364Notes

Reaction equation

HRID 1879364 reaction equation
[C:1]([O:4][C@@H:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([O:16][Si](C(C)C)(C(C)C)C(C)C)[CH2:8][CH2:7][C@H:6]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[F:34])(=[O:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[C:1]([O:4][C@@H:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7][C@H:6]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[F:34])(=[O:3])[CH3:2]

Participants

4

Reactant 2

HCID 2724141Tetrabutylammonium FluorideHCID 67116262(5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl acetate

Product 1

HCID 67115825(5S,6S,9R)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl acetateYield 87%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

In a 100 mL round-bottom flask was dissolved (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl acetate (1098 mg, 2.243 mmol) (azeotroped with dry benzene) in tetrahydrofuran (20 mL) to give a colorless solution. TBAF (2.69 mL, 2.69 mmol) was added, and the resulting light yellow solution was stirred at room temperature for 2 h (8:30 am). LCMS indicated complete conversion. Tetrahydrofuran was removed in vacuo and the residue was diluted with water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried, and concentrated to give a colorless oil. Purification by FCC up to 70% ethyl acetate/hexane afforded the desired product (648 mg, 87% for 2 steps) as a colorless oil. MS(ESI)[M+H+]=334.21; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.47 (dd, J=4.78, 1.51 Hz, 1H) 7.69 (d, J=7.30 Hz, 1H) 7.28 (dd, J=7.81, 5.04 Hz, 1H) 6.94-7.10 (m, 3H) 6.20 (d, J=10.32 Hz, 1H) 5.95 (br. s., 1H) 4.95 (dd, J=11.21, 1.64 Hz, 1H) 3.16-3.31 (m, 1H) 2.27-2.41 (m, 2H) 2.06-2.19 (m, 1H) 1.80 (s, 3H) 1.48-1.63 (m, 1H); 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 168.96 (s, 1C) 157.96 (s, 1C) 149.66-151.75 (d, J=12.6 and 199 Hz, 1C) 147.21-149.29 (d, J=13 and 198 Hz, 1C) 146.00 (s, 2C) 133.43 (s, 1C) 132.23 (d, J=11.56 Hz, 1C) 131.99 (s, 2C) 123.90-124.24 (m, 2C) 122.89 (br. s., 1C) 122.66 (s, 2C) 115.36 (d, J=16.95 Hz, 2C) 72.77 (s, 2C) 71.14 (s, 3C) 42.12 (br. s., 1C) 35.66 (s, 2C) 32.68 (s, 2C) 20.28 (s, 2C); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −138.20-−137.93 (m, 1F) −143.38-−143.16 (m, 1F).

Workup

  1. customto give a colorless solution
  2. customTetrahydrofuran was removed in vacuo
  3. additionthe residue was diluted with water and ethyl acetate
  4. customThe layers were separated
  5. washThe organic layer was washed with brine
  6. customdried
  7. concentrationconcentrated
  8. customto give a colorless oil
  9. customPurification by FCC up to 70% ethyl acetate/hexane

Sources & evidence

ORD record
ord-476947106fcf4567992252bcefeb52bd
Source dataset
uspto-grants-2012_11
Patent number
US08314117B2

Reaction notes

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