Methanol → 3-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-1-ol

HRID 132910Notes

Reaction equation

HRID 132910 reaction equation
C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][S:8]([N:11]1[CH2:16][CH2:15][C:14]2[NH:17][N:18]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[C:13]=2[CH2:12]1)(=[O:10])=[O:9].Br[CH2:31][CH2:32][CH2:33][OH:34].CO>CN(C=O)C.O>[CH3:7][S:8]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]([CH2:31][CH2:32][CH2:33][OH:34])[N:18]=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)[C:13]=2[CH2:12]1)(=[O:9])=[O:10]

Participants

7

Reactant 4

HCID 887MethanolHCID 10796Cesium carbonate2×HCID 123083-Bromo-1-propanol2×HCID 120720305-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

Product 1

HCID 222936223-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propan-1-olYield 54.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent

Procedure

Cs2CO3 (33.74 g, 103.5 mmol) was added to a solution of 5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (29.8 g, 86.3 mmol) in anhydrous DMF (70 mL) and stirred for 25 min. 3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol) was added and stirred under N2 at room temperature for 18 h. Water (500 mL) was added to the reaction and stirred for 5 min. The precipitated material was filtered out and washed with water (4×100 mL) and dried in a Freeze Drying System. The crude material (31.0 g) was taken up in anhydrous DMF (65 mL) and Cs2CO3 (33.74 g, 103.5 mmol) was added, and stirred for 10 min. 3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol) and MeOH (6.0 mL, 4.75 g, 148 mmol) were added and stirring continued under N2 at room temperature for 15 h. Water (500 mL) was added to the reaction and stirred for 10 min. The precipitated material was filtered and washed with water (3×100 mL). The filter cake was dissolved in CH2Cl2 (200 mL) and washed with brine (50 mL), dried (Na2SO4), and concentrated. The solid was triturated with Et2O (200 mL), filtered, washed with Et2O, and dried to furnish 16.0 g of the desired compound. The mother liquor was chromatographed (silica, 0-10% acetone/EtOAc) to obtain an additional 3.0 g of the title compound. The combined yield was 54.6%. MS (electrospray): calculated for C17H20F3N3O3S, 403.12; m/z found, 404.0 [M+H]+, 426.0 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.71 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 4.55 (s, 2H), 4.23 (t, J=6.5 Hz, 2H), 3.70-3.63 (m, 4H), 2.90 (s, 3H), 2.90 (t, J=5.1 Hz, 2H), 2.62 (t, J=5.9 Hz, 1H), 2.06 (q, J=6.1 Hz, 2H).

Workup

  1. stirringstirred under N2 at room temperature for 18 h
  2. stirringstirred for 5 min
  3. filtrationThe precipitated material was filtered out
  4. washwashed with water (4×100 mL)
  5. customdried in a Freeze
  6. customDrying System
  7. stirringstirred for 10 min
  8. stirringstirring
  9. waitcontinued under N2 at room temperature for 15 h
  10. stirringstirred for 10 min
  11. filtrationThe precipitated material was filtered
  12. washwashed with water (3×100 mL)
  13. dissolutionThe filter cake was dissolved in CH2Cl2 (200 mL)
  14. washwashed with brine (50 mL)
  15. dry with materialdried (Na2SO4)
  16. concentrationconcentrated
  17. customThe solid was triturated with Et2O (200 mL)
  18. filtrationfiltered
  19. washwashed with Et2O
  20. customdried

Sources & evidence

ORD record
ord-5b76cbea07ef4f3fb4e168067384375b
Source dataset
uspto-grants-2008_06
Patent number
US07388011B2

Reaction notes

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