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

HRID 1427042Notes

Reaction equation

HRID 1427042 reaction equation
S(Cl)(Cl)=O.N1C2C=CC=CC=2N=N1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.[NH2:43][C:44]1[CH:49]=[C:48]([O:50][C:51]2[CH:52]=[C:53]3[C:57](=[CH:58][C:59]=2[O:60][CH2:61][CH2:62][O:63][CH2:64][CH3:65])[N:56]([C:66]([NH:68][CH3:69])=[O:67])[CH:55]=[CH:54]3)[CH:47]=[CH:46][N:45]=1.CN>ClCCl.CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C.O>[CH2:64]([O:63][CH2:62][CH2:61][O:60][C:59]1[CH:58]=[C:57]2[C:53]([CH:54]=[CH:55][N:56]2[C:66](=[O:67])[NH:68][CH3:69])=[CH:52][C:51]=1[O:50][C:48]1[CH:47]=[CH:46][N:45]=[C:44]([NH:43][C:31]([C:30]2[CH:34]=[CH:35][C:27]([CH:24]3[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:20])[CH2:22][CH2:23]3)=[CH:28][CH:29]=2)=[O:32])[CH:49]=1)[CH3:65]

Participants

12

Reactant 6

HCID 6329MethylamineHCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 224928594-(4-Carboxy-phenyl)-piperidine-1-carboxylic acid tert-butyl esterHCID 867303445-((2-Aminopyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl-1H-indole-1-carboxamideHCID 178418385HCID 178418385, compound

Product 1

HCID 86730345tert-Butyl 4-(4-((4-((6-(2-ethoxyethoxy)-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridin-2-yl)carbamoyl)phenyl)piperidine-1-carboxylateYield 43%

Reagents, catalysts & solvents 5

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

Thionyl chloride (370 μL, 5.06 mmol) was added to a solution of benzotriazole (603 mg, 5.06 mmol) in dichloromethane (20 mL) under nitrogen atmosphere at room temperature. The mixture was stirred at room temperature for 5 minutes, then 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid described in Production Example 1-12 (1.03 g, 3.38 mmol) was added, and the mixture was stirred for 1 hour. The reaction liquid was filtered through anhydrous sodium sulfate on the glass filter, and the resultant was washed with dichloromethane. Triethylamine (1.87 mL, 13.5 mmol), 4-dimethylaminopyridine (16.5 mg, 0.135 mmol), and a solution of 5-((2-aminopyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl-1H-indole-1-carboxamide described in Production Example 24-8 (500 mg, 1.35 mmol) in tetrahydrofuran (5 mL) were serially added to the resultant filtrate under nitrogen atmosphere at 0° C., and the mixture was stirred at room temperature for 4 hours. An excessive quantity of methylamine was added to the reaction liquid and then the resultant was diluted with ethyl acetate and water for partition. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate, and the drying agent was separated by filtration. The filtrate was concentrated under vacuum. The resultant residue was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=2:3-0:1) to obtain the title compound (383 mg, 43%).

Workup

  1. additionwas added
  2. stirringthe mixture was stirred for 1 hour
  3. customThe reaction liquid
  4. filtrationwas filtered through anhydrous sodium sulfate on the glass
  5. filtrationfilter
  6. washthe resultant was washed with dichloromethane
  7. stirringthe mixture was stirred at room temperature for 4 hours
  8. customfor partition
  9. washThe organic layer was washed with a saturated saline solution
  10. dry with materialdried over anhydrous sodium sulfate
  11. customthe drying agent was separated by filtration
  12. concentrationThe filtrate was concentrated under vacuum
  13. customThe resultant residue was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=2:3-0:1)

Sources & evidence

ORD record
ord-1976c34a23c845e89c5195d1f0444ffd
Source dataset
uspto-grants-2015_01
Patent number
US08933099B2

Reaction notes

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