Water → 1-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide

HRID 626555Notes

Reaction equation

HRID 626555 reaction equation
[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[NH2:14][C:15]1[N:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[O:30])[CH:23]=2)=[CH:17][CH:16]=1.O>ClCCCl.C1COCC1>[CH3:37][N:34]1[CH2:35][CH2:36][CH:31]([C:29]([NH:28][C:24]2[CH:23]=[C:22]([O:21][C:18]3[CH:19]=[N:20][C:15]([NH:14][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[CH:16][CH:17]=3)[CH:27]=[CH:26][N:25]=2)=[O:30])[CH2:32][CH2:33]1

Participants

7

Reactant 4

HCID 962WaterHCID 12957TrimethylacetamideHCID 65578Oxalyl chlorideHCID 90409884N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-1-methylpiperidine-4-carboxamide

Product 1

HCID 862729771-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-4-carboxamideYield 28%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 2,2,2-trimethylacetamide (0.042 g, 0.412 mmol) in DCE (2 mL) was treated with oxalyl chloride (0.036 mL, 0.412 mmol), stirred at RT for 0.5 h, then heated at 75° C. for 1 h. The mixture was cooled to RT, added to a mixture of Example A8 (0.09 g, 0.275 mmol) and TEA (0.1 mL) in THF (2 mL) and stirred at RT for 1.5 h. The mixture was treated with water, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was layered with EtOAc, allowed to stand overnight and the resulting solid collected via filtration to afford 1-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide (35 mg, 27%) as a peach-colored solid. 1H NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H), 10.52 (s, 1H), 10.50 (s, 1H), 8.25 (d, J=2.9 Hz, 1H), 8.20 (d, J=5.7 Hz, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.74 (dd, J=9.0, 2.9 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 6.73 (dd, J=5.7, 2.4 Hz, 1H), 2.77 (m, 2H), 2.38 (m, 1H), 2.13 (s, 3H), 1.82 (m, 2H), 1.66 (m, 2H), 1.55 (m, 2H), 1.22 (s, 9H); MS (ESI) m/z: 455.3 (M+H+).

Workup

  1. temperatureheated at 75° C. for 1 h
  2. temperatureThe mixture was cooled to RT
  3. stirringstirred at RT for 1.5 h
  4. extractionextracted with EtOAc (3×)
  5. dry with materialthe combined organics were dried over Na2SO4
  6. concentrationconcentrated to dryness
  7. waitto stand overnight
  8. filtrationthe resulting solid collected via filtration

Sources & evidence

ORD record
ord-1b34db19087d44f9bbe173a039dd802c
Source dataset
uspto-grants-2016_04
Patent number
US09309224B2

Reaction notes

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