Binap, (A+-)- → 4-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methylamino)-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one

HRID 530826Notes

Reaction equation

HRID 530826 reaction equation
Br[C:2]1[C:3](=[O:22])[N:4]([CH3:21])[N:5]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:12][C@@H:11]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=2)[CH:7]=1.[CH2:23]([C:25]1[CH:29]=[C:28]([CH2:30][NH2:31])[N:27]([CH3:32])[N:26]=1)[CH3:24].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:23]([C:25]1[CH:29]=[C:28]([CH2:30][NH:31][C:2]2[C:3](=[O:22])[N:4]([CH3:21])[N:5]=[C:6]([O:8][CH2:9][C@H:10]3[CH2:12][C@@H:11]3[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=3)[CH:7]=2)[N:27]([CH3:32])[N:26]=1)[CH3:24]

Participants

8

Reactant 4

HCID 634876Binap, (A+-)-HCID 23006075(3-Ethyl-1-methyl-1H-pyrazol-5-yl)methanamineHCID 23676156Sodium t-butoxideHCID 904192134-bromo-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl) methoxy)-2-methylpyridazin-3(2H)-one

Product 1

HCID 904544054-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methylamino)-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 4-bromo-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one (70 mg, 0.19 mmol) in toluene (5 mL) under N2, ((3-ethyl-1-methyl-1H-pyrazol-5-yl)methanamine (32.2 mg, 0.23 mmol), Pd2(dba)3 (18 mg, 0.019 mmol), BINAP (35 mg, 0.06 mmol) and NaOtBu (27 mg, 0.285 mmol) were added. After the reaction mixture was stirred at 100° C. overnight, 15 mL water was added. The mixture was extracted with EtOAc (2×10 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC to give the title compound as oil. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.73 (d, 1H), 7.21 (d, 1H), 6.14 (s, 1H), 5.75 (s, 1H), 4.45-4.28 (m, 3H), 4.00 (d, 4H), 3.89 (s, 3H), 3.67 (s, 3H), 2.66 (d, 2H), 2.53 (s, 1H), 1.88 (s, 1H), 1.41 (s, 2H), 1.22 (t, 3H).

Workup

  1. extractionThe mixture was extracted with EtOAc (2×10 mL)
  2. dry with materialThe combined organics were dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by Prep-HPLC

Sources & evidence

ORD record
ord-cc22ce6dda9f43ebbf0b3ece51937e9d
Source dataset
uspto-grants-2016_05
Patent number
US09353104B2

Reaction notes

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