Water → N-(4-(2-(6-oxo-3-phenylpyridazin-1(6H)-yl)ethoxy)pyridin-2-yl)pyrrolidine-1-carboxamide

HRID 1878756Notes

Reaction equation

HRID 1878756 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12]2)[CH:5]=[CH:4][N:3]=1.[N:24]1([C:29]([NH2:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.O.CC(C)([O-])C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[O:17]=[C:16]1[N:11]([CH2:10][CH2:9][O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:31][C:29]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:30])[CH:7]=2)[N:12]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15]1

Participants

8

Reactant 5

HCID 962WaterHCID 1383351-PyrrolidinecarboxamideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 23676156Sodium t-butoxideHCID 25016596HCID 25016596, compound

Product 1

HCID 25016598N-(4-(2-(6-oxo-3-phenylpyridazin-1(6H)-yl)ethoxy)pyridin-2-yl)pyrrolidine-1-carboxamideYield 12%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

This procedure was based on the method described in Antonio Abad, Consuelo Agulló, Ana Carmen Cuñat, Cristina Vilanova Synthesis, 2005, 915. To a 10 mL round-bottomed flask was added 2-(2-(2-chloropyridin-4-yloxy)ethyl)-6-phenylpyridazin-3(2H)-one (0.10 g, 0.31 mmol), pyrrolidine-1-carboxamide (0.038 g, 0.34 mmol) (see John E. Barry, Manuel Finkelstein, Gudrun A. Hutchins and Sidney D. Ross Tetrahedron 1983, 39, 2151-2156 and Charles A. Weisel, Harry S. Mosher, and F. C. Whitmore J. Am. Chem. Soc. 1945, 67, 1055), p-dioxane (2.5 mL), H2O (0.0082 mL, 0.46 mmol) and sodium tert-butoxide (0.044 g, 0.46 mmol). The mixture was carefully evacuated and backfilled with N2. This was repeated 3 times. To the mixture was added 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.018 g, 0.031 mmol) and palladium(II) acetate (0.0034 g, 0.015 mmol). Once again the mixture was carefully evacuated and backfilled with N2. This was repeated 3 times. The mixture was then stirred at 90° C. After 17 h, the mixture was poured into aq. NaHCO3 (100 mL) and extracted with EtOAc(3×75 mL). The combined extracts were washed with water (100 mL) and brine (100 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (1.0 to 5.0% MeOH (2M in NH3)/CH2Cl2) afforded N-(4-(2-(6-oxo-3-phenylpyridazin-1(6H)-yl)ethoxy)pyridin-2-yl)pyrrolidine-1-carboxamide (0.015 g, 12% yield) as a yellow solid. MS (ESI, pos. ion.) m/z: 406 (MH+). Calc'd exact mass for C22H23N5O3: 405. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77-1.86 (m, 4 H), 3.33-3.40 (m, 4 H), 4.46-4.55 (m, 4 H), 6.58 (dd, J=5.8, 2.4 Hz, 1 H), 7.07 (d, J=9.8 Hz, 1 H), 7.43-7.50 (m, 3H), 7.52 (d, J=2.3 Hz, 1 H), 7.84-7.89 (m, 2 H), 8.00 (d, J=5.7 Hz, 1 H), 8.05 (d, J=9.8 Hz, 1 H), 8.51 (s, 1 H).

Workup

  1. customdescribed in Antonio Abad, Consuelo Agulló, Ana Carmen Cuñat, Cristina Vilanova Synthesis, 2005, 915
  2. customThe mixture was carefully evacuated
  3. customOnce again the mixture was carefully evacuated
  4. additionthe mixture was poured into aq. NaHCO3 (100 mL)
  5. extractionextracted with EtOAc(3×75 mL)
  6. washThe combined extracts were washed with water (100 mL) and brine (100 mL)
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated onto silica
  9. customPurification by silica gel chromatography (1.0 to 5.0% MeOH (2M in NH3)/CH2Cl2)

Sources & evidence

ORD record
ord-732991fc6a6c4d82a41ba77cbabf58ef
Source dataset
uspto-grants-2012_11
Patent number
US08314087B2

Reaction notes

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