3-(4-piperidyl)-1H-indole → N-(4-Fluoro-3-methoxy-benzyl)-4-(3-piperidin-1-yl-indole-1-sulfonyl)-benzamide Hydrochloride

HRID 737055Notes

Reaction equation

HRID 737055 reaction equation
[N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([Cl:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:19][C:18]=1[O:37][CH3:38]>O1CCOCC1.CCOC(C)=O>[ClH:34].[F:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][C:23](=[O:24])[C:25]2[CH:26]=[CH:27][C:28]([S:31]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8]3)(=[O:33])=[O:32])=[CH:29][CH:30]=2)=[CH:19][C:18]=1[O:37][CH3:38]

Participants

5

Reactant 2

HCID 870923-(4-piperidyl)-1H-indoleHCID 589751944-(4-Fluoro-3-methoxy-benzylcarbamoyl)-benzenesulfonyl chloride

Product 1

HCID 67023396N-(4-Fluoro-3-methoxy-benzyl)-4-(3-piperidin-1-yl-indole-1-sulfonyl)-benzamide HydrochlorideYield 50.1%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

Add KotBu (211 mg, 1.88 mmol) to a solution of 3-piperidin-1-yl-1H-indole (299 mg, 1.49 mmol) in dioxane (15 mL). Stir the yellow solution at RT for 30 min then treat with 4-(4-fluoro-3-methoxy-benzylcarbamoyl)-benzenesulfonyl chloride (560 mg, 1.56 mmol). Stir the solution at RT for an additional 2 h, then dilute with EtOAc (50 mL) and wash with satd NaHCO3 (25 mL). Remove the organic phase and extract the aqueous layer with additional EtOAc (50 mL). Combine the organic solutions, dry over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography (3×) using an oversized silica column and a gradient of 100% hexanes to 40% EtOAc/hexanes. Concentrate fractions containing pure material then redissolve in CH2Cl2 (10 mL) and treat with 4M HCl/dioxane (0.5 mL). Filter the off-white precipitate and dry under vacuum to give the title compound as a white powder (417 mg). MS (ES+) 522.1 (M+1)+, (ES−) 520.2 (M−1)−. 1H NMR (400 MHz, DMSO-d6): δ 9.19 (m, 1H), 8.03 (d, 2H, J=8.4), 7.97 (m, 1H), 7.95 (d, 2H, J=8.4), 7.61 (d, 1H, J=7.5), 7.37 (t, 1H, J=7.6), 7.26 (t, 2H, J=7.5), 7.06-7.13 (m, 2H), 6.81 (m, 1H), 6.12 (br s, 1H), 4.39 (d, 2H, J=5.7), 3.78 (s, 3H), 3.06 (s, 4H), 1.72 (s, 4H), 1.56 (s, 2H).

Workup

  1. stirringStir the solution at RT for an additional 2 h
  2. washwash with satd NaHCO3 (25 mL)
  3. customRemove the organic phase
  4. extractionextract the aqueous layer with additional EtOAc (50 mL)
  5. dry with materialCombine the organic solutions, dry over Na2SO4
  6. filtrationfilter
  7. concentrationconcentrate
  8. customPurify the crude material by flash chromatography (3×)
  9. additionConcentrate fractions containing pure material
  10. dissolutionthen redissolve in CH2Cl2 (10 mL)
  11. additiontreat with 4M HCl/dioxane (0.5 mL)
  12. filtrationFilter the off-white precipitate
  13. customdry under vacuum

Sources & evidence

ORD record
ord-657371b0357b41ac885280eb1e192d23
Source dataset
uspto-grants-2009_09
Patent number
US07595339B2

Reaction notes

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