Binap, (A+-)- → 4-((2,6-dimethylpyridin-3-yl)methylamino)-2-methyl-6-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyridazin-3(2H)-one

HRID 530799Notes

Reaction equation

HRID 530799 reaction equation
[CH3:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.Br[C:12]1[C:13](=[O:30])[N:14]([CH3:29])[N:15]=[C:16]([O:18][CH2:19][C@H:20]2[CH2:22][C@@H:21]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:17]=1.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.C(O[Na])(C)(C)C>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]>[CH3:1][C:2]1[C:7]([CH2:8][NH:9][C:12]2[C:13](=[O:30])[N:14]([CH3:29])[N:15]=[C:16]([O:18][CH2:19][C@H:20]3[CH2:22][C@@H:21]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:17]=2)=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1

Participants

7

Reactant 4

HCID 634876Binap, (A+-)-HCID 21065647(2,6-Dimethylpyridin-3-yl)methanamineHCID 904191564-bromo-2-methyl-6-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyridazin-3(2H)-oneHCID 178418730sodium 2-methylpropan-2-olate

Product 1

HCID 862716134-((2,6-dimethylpyridin-3-yl)methylamino)-2-methyl-6-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyridazin-3(2H)-one

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of (2,6-dimethylpyridin-3-yl)methanamine (30 mg, 0.2 mmol), 4-bromo-2-methyl-6-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyridazin-3(2H)-one (68 mg, 0.2 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), BINAP (18 mg, 0.03 mmol) and t-BuONa (38 mg, 0.4 mmol) in toluene (4 mL) under N2 was heated at 80° C. for 4 h. The mixture was filtered and concentrated to give crude product which was purified by Prep-HPLC to give the title compound as oil. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, 1H), 7.67-7.62 (m, 1H), 7.47 (d, 1H), 7.21 (d, 1H), 7.16-7.13 (m, 1H), 7.05 (d, 1H), 5.67 (s, 1H), 4.35 (s, 2H), 4.20-4.16 (m, 1H), 4.03-3.98 (m, 1H), 3.63 (s, 3H), 2.50 (s, 3H), 2.46 (s, 3H), 2.11-2.07 (m, 1H), 1.84-1.79 (m, 1H), 1.26-1.21 (m, 1H), 1.09-1.04 (m, 1H), LCMS m/z (M+H) 392.2 found, 392.2 required.

Workup

  1. filtrationThe mixture was filtered
  2. concentrationconcentrated
  3. customto give crude product which
  4. customwas purified by Prep-HPLC

Sources & evidence

ORD record
ord-dc006279657f474889cfbc73192a5f34
Source dataset
uspto-grants-2016_05
Patent number
US09353104B2

Reaction notes

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