1-Methylpyrrolidine → N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide

HRID 626560Notes

Reaction equation

HRID 626560 reaction equation
[C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=O)[O:25]C(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[NH:32]1[CH2:35][CH2:34][CH2:33]1.CN1CCCC1>O1CCOCC1>[C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([N:32]3[CH2:35][CH2:34][CH2:33]3)=[O:25])[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]

Participants

5

Reactant 3

HCID 84541-MethylpyrrolidineHCID 12308726Azetidine hydrochlorideHCID 90445670Prop-1-en-2-yl (4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate

Product 1

HCID 86273946N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)azetidine-1-carboxamideYield 26.5%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A mixture of Example C2 (0.265 g, 0.641 mmol), azetidine hydrochloride (0.120 g, 1.282 mmol) and N-methylpyrrolidine (0.065 g, 0.769 mmol) in dioxane (6 mL) was heated at 80° C. overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was further purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA); the organics were removed under reduced pressure and the aqueous residue was treated with satd. NaHCO3, extracted with EtOAc (4×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide (70 mg, 25%). 1H NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H), 10.43 (s, 1H), 9.09 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.11-8.06 (m, 2H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7, 2.4 Hz, 1H), 3.92 (t, J=7.5 Hz, 4H), 2.12-2.10 (m, 2H), 1.21 (s, 9H); MS (ESI) m/z: 413.2 (M+H+).

Workup

  1. concentrationconcentrated to dryness
  2. custompurified via silica gel chromatography (MeOH/DCM)
  3. customThe material was further purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA)
  4. customthe organics were removed under reduced pressure
  5. additionthe aqueous residue was treated with satd
  6. extractionNaHCO3, extracted with EtOAc (4×)
  7. dry with materialthe combined organics were dried over Na2SO4
  8. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-ef3dde09e187483b93e42364f9a783c2
Source dataset
uspto-grants-2016_04
Patent number
US09309224B2

Reaction notes

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