18-Crown-6 → N-(4-{4-amino-7-[(diphenylmethylene)amino]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide

HRID 1270961Notes

Reaction equation

HRID 1270961 reaction equation
[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].C1OCCOCCOCCOCCOCCOC1.[C:57](=[NH:70])([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([N:70]=[C:57]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=[CH:4][N:3]=1

Participants

7

Reactant 4

HCID 2855718-Crown-6HCID 136809Benzophenone imineHCID 18451298N-[4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamideHCID 23676156Sodium t-butoxide

Product 1

HCID 18451290N-(4-{4-amino-7-[(diphenylmethylene)amino]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamideYield 64.8%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of N-[4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (4.03 g, 7.72 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.283 g, 0.31 mmol, 9,9-dimethyl-4–5-bis(diphenylphosphino)xanthene (0.536 g, 0.93 mmol), sodium tert-butoxide (1.00 g, 10.42 mmol), 18-crown-6 (2.75 g, 10.42 mmol), and benzophenone imine (1.16 mL, 6.9 mmol) were combined in N,N-dimethylformamide (100 mL), and the solution was heated at 95° C. for 12 h. The reaction mixture was cooled to ambient temperature and concentrated. The residue was diluted with brine (100 mL) and extracted with methanol/dichloromethane (1:33, 3×150 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by flash column chromatography on silica gel which had been deactivated with triethylamine (10% by volume of silica gel used), using a gradient of ethyl acetate/heptane (1:3 to 4:1) as the mobile phase afforded the title compound (2.71 g, 4.47 mmol) as a yellow foam: MS: (MH)+ 608; LCMS (Conditions a), Rt 2.27 min.

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. concentrationconcentrated
  3. additionThe residue was diluted with brine (100 mL)
  4. extractionextracted with methanol/dichloromethane (1:33, 3×150 mL)
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customPurification of the residue by flash column chromatography on silica gel which

Sources & evidence

ORD record
ord-c25ebb9ff0cc4302aa82ccab7aeac994
Source dataset
uspto-grants-2007_04
Patent number
US07202363B2

Reaction notes

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