Potassium Iodide → HCID 67097267, compound

HRID 2078723Notes

Reaction equation

HRID 2078723 reaction equation
[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Br)[CH:15]=2)[CH:10]=[C:9]1[C:22]1[C:23]2[S:36][C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:34][C:24]=2[N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:15]=2)[CH:10]=[C:9]1[C:22]1[C:23]2[S:36][C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:34][C:24]=2[N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 4875Potassium IodideHCID 8082PiperidineHCID 11430Potassium CarbonateHCID 57637347HCID 57637347, compound2×

Product 1

HCID 67097267HCID 67097267, compound

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [300 mg, 0.460 mmol, Intermediate 50)], piperidine (60.2 mg, 0.707 mmol), potassium carbonate (191 mg, 1.38 mmol), potassium iodide (40.0 mg, 0.241 mmol), and anhydrous acetonitrile (5.0 mL) was heated at 70° C. with shaking at 200 rpm. After 20 hours, the reaction was cooled to ambient temperature, filtered, the insolubles washed three times with dichloromethane (5 mL), and the filtrate concentrated under reduced pressure to give a dark residue. The residue was chromatographed on silica, eluting with 10%-1 M ammonia in methanol/90% dichloromethane, to give 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-[3-(piperidin-1-yl)-propoxy]-indole-1-carboxylic acid tert-butyl ester (310 mg) as a brittle green foam: LC/MS: 657.3, (M+H), RT=3.92 minutes, 50% UV purity). A mixture of this material (300 mg), 4 M aqueous potassium carbonate (5.0 mL), tetrahydrofuran (5.0 mL) and methanol (5.0 mL) was heated at 60° C. for 2 hours. After cooling to room temperature, the solvent was removed in vacuo to give a solid. The crude solid was suspended in water (25 ml) and the mixture stirred at room temperature for 0.5 hours. The solid was collected by filtration and dried to give a grey solid. Trituration of the solid with 20% methanol/ether provided 2-(5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-piperidin-1-yl-propoxy)-1H-indole [90.0 mg, 43%, Example 58] as a grey solid. TLC Rf 0.37 (silica, 14% 1 M ammonia in methanol/86% dichloromethane); LC/MS: 457.3 (M+H), RT=2.93 minutes; 1H NMR [300 Mhz, (CD3)2SO]: δ 13.30 (br s 1H), 11.39 (br s, 1H), 7.78 (d, J=7 Hz, 2H), 7.64 (s, 1H), 7.49-7.35 (m, 4H), 6.92 (s, 1H), 6.65 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 3.98 (t, J=6 Hz, 2H), 2.43-2.33 (m, 6H), 1.88 (m, 2H), 1.50-1.39 (m, 6H).

Workup

  1. temperaturethe reaction was cooled to ambient temperature
  2. filtrationfiltered
  3. washthe insolubles washed three times with dichloromethane (5 mL)
  4. concentrationthe filtrate concentrated under reduced pressure
  5. customto give a dark residue
  6. customThe residue was chromatographed on silica
  7. washeluting with 10%-1 M ammonia in methanol/90% dichloromethane

Sources & evidence

ORD record
ord-358b89848ef64b72b2eb9210827d6dca
Source dataset
uspto-grants-2011_04
Patent number
US07928231B2

Reaction notes

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