Acetic Acid → [1-(3,5-Diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-(5-methanesulfonyl-pyridin-2-yl)-amine

HRID 2355630Notes

Reaction equation

HRID 2355630 reaction equation
[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:30][CH2:31][CH3:32])[C:28]=1[F:29])[CH:24]=O)[CH3:19].C(N(C(C)C)C(C)C)C.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:30][CH2:31][CH3:32])[C:28]=1[F:29])[CH2:24][N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][N:9]=2)[CH2:13][CH2:14]1)[CH3:19]

Participants

9

Reactant 6

HCID 176Acetic AcidHCID 10340Sodium CarbonateHCID 81531DiisopropylethylamineHCID 5003444Sodium cyanoborohydrideHCID 591282733,5-Diethoxy-4-fluoro-benzaldehyde2×HCID 59383087(5-Methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine

Product 1

HCID 67400612[1-(3,5-Diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-(5-methanesulfonyl-pyridin-2-yl)-amineYield 71%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of (5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (0.12 g, 0.5 mmol, 1.0 equiv; intermediate B16) and 3,5-diethoxy-4-fluoro-benzaldehyde (0.11 g, 0.5 mmol, 1.0 equiv; intermediate E5) in ethanol (5 mL) under an atmosphere of Ar was added N-ethyl diisopropylamine (0.19 mL, 0.15 g, 1.2 mmol, 2.3 equiv) and glacial acetic acid (0.05 mL, 0.06 g, 1.0 mmol, 2.0 equiv) and the mixture heated to 50° C. for 2 h. After cooling down to 35° C., sodium cyanoborohydride (0.16 g, 2.5 mmol, 5.1 equiv) was added and the reaction mixture heated again to 50° C. for 1.5 h. It was then poured into crashed ice, the pH of the water phase adjusted to ˜10 by addition of a sat. solution of sodium carbonate and the mixture extracted twice with dichloromethane. The combined organic phases were washed with water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.16 g (71%) of the title compound as colorless foam. MS (ISP): 452.1 [M+H]+.

Workup

  1. temperatureAfter cooling down to 35° C.
  2. temperaturethe reaction mixture heated again to 50° C. for 1.5 h
  3. additionIt was then poured
  4. extractionthe mixture extracted twice with dichloromethane
  5. washThe combined organic phases were washed with water
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated by evaporation under reduced pressure
  9. customThe crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol

Sources & evidence

ORD record
ord-1305341e87004d59bddc3044224887cb
Source dataset
uspto-grants-2010_07
Patent number
US07754744B2

Reaction notes

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