Methylamine → tert-Butyl 4-(5-((4-((6-(2-ethoxyethoxy)-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridin-2-yl)carbamoyl)pyridin-2-yl)piperidine-1-carboxylate

HRID 1427049Notes

Reaction equation

HRID 1427049 reaction equation
C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[NH2:36][C:37]1[CH:42]=[C:41]([O:43][C:44]2[CH:45]=[C:46]3[C:50](=[CH:51][C:52]=2[O:53][CH2:54][CH2:55][O:56][CH2:57][CH3:58])[N:49]([C:59]([NH:61][CH3:62])=[O:60])[CH:48]=[CH:47]3)[CH:40]=[CH:39][N:38]=1.CN>CN(C)C=O.ClCCl.O.C(OCC)(=O)C>[CH2:57]([O:56][CH2:55][CH2:54][O:53][C:52]1[CH:51]=[C:50]2[C:46]([CH:47]=[CH:48][N:49]2[C:59](=[O:60])[NH:61][CH3:62])=[CH:45][C:44]=1[O:43][C:41]1[CH:40]=[CH:39][N:38]=[C:37]([NH:36][C:24]([C:23]2[CH:27]=[CH:28][C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:13])[CH2:15][CH2:16]3)=[N:21][CH:22]=2)=[O:25])[CH:42]=1)[CH3:58]

Participants

10

Reactant 5

HCID 6329MethylamineHCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 867303445-((2-Aminopyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl-1H-indole-1-carboxamideHCID 867303496-(1-((Tert-butoxy)carbonyl)piperidin-4-yl)pyridine-3-carboxylic acid

Product 1

HCID 86730351tert-Butyl 4-(5-((4-((6-(2-ethoxyethoxy)-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridin-2-yl)carbamoyl)pyridin-2-yl)piperidine-1-carboxylateYield 56%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

Oxalyl chloride (74 μL, 0.864 mmol) and one drop of N,N-dimethylformamide were added to a solution of 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)nicotinic acid described in Production Example 28-3 (80 mg, 0.216 mmol) in dichloromethane (2 mL) at 0° C., and the mixture was stirred for 30 minutes. The reaction liquid was concentrated under vacuum. The residue was dissolved in tetrahydrofuran (2 mL), then triethylamine (301 μL, 2.16 mmol) and 5-((2-aminopyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl-1H-indole-1-carboxamide described in Production Example 24-8 (80 mg, 0.216 mmol) were added, and the mixture was stiffed for 5 hours. An excessive quantity of methylamine was added to the reaction liquid, and then the mixture was diluted with water and ethyl acetate for partition. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=1:1) to obtain the title compound (80 mg, 56%).

Workup

  1. customThe reaction liquid
  2. concentrationwas concentrated under vacuum
  3. dissolutionThe residue was dissolved in tetrahydrofuran (2 mL)
  4. additionwere added
  5. waitthe mixture was stiffed for 5 hours
  6. customfor partition
  7. washThe organic layer was washed with a saturated saline solution
  8. dry with materialdried over anhydrous sodium sulfate
  9. customThe drying agent was separated by filtration
  10. concentrationthe filtrate was concentrated under vacuum
  11. customThe residue was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=1:1)

Sources & evidence

ORD record
ord-f297cf237bfe456e84b430f0c25c0e93
Source dataset
uspto-grants-2015_01
Patent number
US08933099B2

Reaction notes

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