Potassium Carbonate → 1-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-3-carboxamide

HRID 626564Notes

Reaction equation

HRID 626564 reaction equation
[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3]1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[O:30])=[N:26][CH:27]=2)[CH:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]([NH:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[N:26][C:25]([NH:28][C:29]([NH:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:34])[CH3:36])=[O:30])=[CH:24][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[O:9])[CH2:3]1

Participants

8

Reactant 5

HCID 11430Potassium CarbonateHCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 3225981-Methylpyrrolidine-3-carboxylic acidHCID 90409811N-((5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide

Product 1

HCID 862741881-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-3-carboxamideYield 56.4%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 1-methyl-pyrrolidine-3-carboxylic acid (0.082 g, 0.638 mmol) in thionyl chloride (3 mL, 41.1 mmol) and DCM (3 mL) was stirred at RT for 3 h, concentrated to dryness, suspended in THF (5 mL), added to a 0° C. solution of Example C1 (0.15 g, 0.455 mmol) and DIEA (0.239 mL, 1.366 mmol) in THF (5 mL), allowed to warm to RT and stirred overnight. The mixture was treated with 10% K2CO3, extracted with DCM (4×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via preparative TLC (MeOH/DCM/TEA) to afford 1-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-3-carboxamide (113 mg, 56%). 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 10.54 (s, 1H), 10.44 (s, 1H), 8.25 (d, J=2.9 Hz, 1H), 8.19 (d, J=5.7 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.74 (dd, J=9.0, 2.9 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 6.72 (dd, J=5.7, 2.4 Hz, 1H), 3.11 (m, 1H), 2.71 (t, J=8.5 Hz, 1H), 2.45-2.32 (m, 3H), 2.21 (s, 3H), 1.96-1.84 (m, 2H), 1.21 (s, 9H); MS (ESI) m/z: 441.2 (M+H+).

Workup

  1. concentrationconcentrated to dryness
  2. extractionextracted with DCM (4×)
  3. washthe combined organics were washed with brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated to dryness
  6. custompurified via preparative TLC (MeOH/DCM/TEA)

Sources & evidence

ORD record
ord-2371295a417f4b74a436f0e01939acf9
Source dataset
uspto-grants-2016_04
Patent number
US09309224B2

Reaction notes

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