2,6-Lutidine → 2,6-Difluorobenzenesulfonic acid 1-phenethyl-3-(1-methylpiperidin-4-yl)-1H-indol-5-yl ester hydrochloride

HRID 1766265Notes

Reaction equation

HRID 1766265 reaction equation
[CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[S:34]([Cl:37])(=[O:36])=[O:35].N1C(C)=CC=CC=1C>O1CCCC1.CO>[ClH:37].[CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][S:34]([C:28]3[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])(=[O:36])=[O:35])=[CH:15][CH:16]=2)[C:11]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1

Participants

6

Reactant 3

HCID 79372,6-LutidineHCID 27342712,6-Difluorobenzenesulfonyl chlorideHCID 179801211-phenethyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole

Product 1

HCID 878265972,6-Difluorobenzenesulfonic acid 1-phenethyl-3-(1-methylpiperidin-4-yl)-1H-indol-5-yl ester hydrochlorideYield 67.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 1-phenethyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (175 mg, 0.52 mmol) and 2,6-difluorobenzenesulfonyl chloride (133 mg, 0.58 mmol) in tetrahydrofuran (20 mL), stirring at room temperature, was added 2,6-lutidine dropwise (134 mL, 1.16 mmol). The reaction mixture was stirred for 72 hours at room temperature, before diluting it with methanol (15 mL) and applying it directly to a 5 g SCX column. After thoroughly washing with methanol, the column was eluted with a 9:1 mixture of dichloromethane and 2 N ammonia in methanol. The eluent was concentrated in vacuo to a residue, which was purified on silica gel. Elution with a 9:1 mixture of dichloromethane and methanol provided 191 mg (64%) of the free base of the desired compound as a tan gum. The gum was further purified by preparative reverse-phase HPLC, which provided 156 mg (44%) of the title hydrochloride as an off-white solid: mp=209-212° C.; 1H NMR (400 MHz, dmso-d6): 10.55 (br s, 1H), 7.95-7.82 (m, 1H), 7.48-7.34 (m, 3H), 7.30 (s, 1H), 7.25-7.08 (m, 6H), 6.76 (br d, 1H, J=8.4 Hz), 4.29 (t, 2H, J=7.4 Hz), 3.41 (br d, 2H, J=12.4 Hz), 3.10-2.97 (m, 2H), 2.96 (t, 2H, J=7.0 Hz), 2.94-2.82 (m, 2H), 2.72 (s, 3H), 1.96-1.75 (m, 4H); MS (APCI): m/e 511.2 (M+1); Calculated (for C28H28F2N2O3S.HCl.0.6H2O): C 60.39, H 5.28, N 5.03; found: C 60.43, H 5.41, N 5.14.

Workup

  1. washAfter thoroughly washing with methanol
  2. washthe column was eluted with a 9:1 mixture of dichloromethane and 2 N ammonia in methanol
  3. concentrationThe eluent was concentrated in vacuo to a residue, which
  4. customwas purified on silica gel
  5. washElution
  6. additionwith a 9:1 mixture of dichloromethane and methanol

Sources & evidence

ORD record
ord-0ed025d7ed324b9d86053be654687b02
Source dataset
uspto-grants-2007_06
Patent number
US07230011B2

Reaction notes

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