2-Chloroaniline → 2-[4-(2-chloro-phenylamino)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide

HRID 2381545Notes

Reaction equation

HRID 2381545 reaction equation
[CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23](I)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:82][C:83]1[CH:89]=[CH:88][CH:87]=[CH:86][C:84]=1[NH2:85]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([NH:85][C:84]4[CH:86]=[CH:87][CH:88]=[CH:89][C:83]=4[Cl:82])[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1

Participants

7

Reactant 4

HCID 72402-ChloroanilineHCID 11430Potassium CarbonateHCID 634876Binap, (A+-)-HCID 579192872-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide2×

Product 1

HCID 668931232-[4-(2-chloro-phenylamino)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amideYield 80%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

A vial containing 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Intermediate 94, 51.5 mg, 0.10 mmol), potassium carbonate (23.5 mg, 0.170 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (6.9 mg, 0.01 mmol), and palladium (II) acetate (2.7 mg, 0.0120 mmol) was evacuated, charged with a nitrogen atmosphere, and treated with toluene (1 mL) and 2-chloroaniline (12.6 μL, 0.12 mmol). The vial was sealed, and the reaction was warmed to 120° C., where it stirred for 3.5 h, followed by stirring at 25° C. overnight. At this point, the reaction was partitioned between ethyl acetate (5 mL) and water (5 mL). The organic layer was washed with a 10% aqueous ammonium chloride solution (5 mL) and a saturated aqueous sodium chloride solution (5 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo onto silica gel. Chromatography (20-90% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenylamino)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white/yellow solid (41.2 mg, 80%).

Workup

  1. customwas evacuated
  2. additioncharged with a nitrogen atmosphere
  3. customThe vial was sealed
  4. stirringby stirring at 25° C. overnight
  5. customAt this point, the reaction was partitioned between ethyl acetate (5 mL) and water (5 mL)
  6. washThe organic layer was washed with a 10% aqueous ammonium chloride solution (5 mL)
  7. dry with materialThe organics were dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo onto silica gel

Sources & evidence

ORD record
ord-d82bad281ec540ad818bb325e45fe193
Source dataset
uspto-grants-2012_09
Patent number
US08258134B2

Reaction notes

Loading…