Ethyl Acetate → 4-(1-(5-Cyclopropylpyrimidin-2-yl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile

HRID 386556Notes

Reaction equation

HRID 386556 reaction equation
Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]([C:24]#[N:25])=[N:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].CCN(C(C)C)C(C)C.Cl[C:36]1[N:41]=[CH:40][C:39]([CH:42]2[CH2:44][CH2:43]2)=[CH:38][N:37]=1.CCOC(C)=O>CN1C(=O)CCC1>[CH:42]1([C:39]2[CH:38]=[N:37][C:36]([N:21]3[CH2:20][CH2:19][CH:18]([O:17][C:13]4[C:12]([C:24]#[N:25])=[N:11][N:10]([C:5]5[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=5)[C:15](=[O:16])[CH:14]=4)[CH2:23][CH2:22]3)=[N:41][CH:40]=2)[CH2:44][CH2:43]1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 81531DiisopropylethylamineHCID 468640872-Chloro-5-cyclopropylpyrimidineHCID 674465361-(3,4-dichlorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl

Product 1

HCID 446216584-(1-(5-Cyclopropylpyrimidin-2-yl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrileYield 40.8%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
100 °C

Procedure

To a stirring solution of 1-(3,4-dichlorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl (50 mg, 0.137 mmol) in NMP (2 mL) at room temperature under argon was added DIPEA (53.1 mg, 0.411 mmol) and 2-chloro-5-cyclopropylpyrimidine (31.7 mg, 0.205 mmol). The resulting reaction mixture was heated at 100° C. under argon overnight. 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 27 mg (38.8%) of 4-(1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.50-0.66 (m, 2H) 0.82-0.98 (m, 2H) 1.64-1.79 (m, 1H) 1.83-1.99 (m, 2H) 1.99-2.16 (m, 2H) 3.60-3.90 (m, 2H) 3.96-4.25 (m, 2H) 4.56-4.87 (m, 1H) 6.31 (s, 1H) 7.41-7.50 (m, 1H) 7.50-7.60 (m, 1H) 7.73 (d, J=2.20 Hz, 1H) 8.05-8.18 (m, 2H). MS (ESI) 483 (M+H).

Workup

  1. customThe resulting reaction mixture
  2. washThe reaction mixture was washed with water (15 mL), and brine (15 mL)
  3. dry with materialOrganic phase was dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. dissolutionThe crude product was dissolved in a small amount of DCM (˜2 ml)
  7. washwas eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes

Sources & evidence

ORD record
ord-c2592222cad144cf9a1b7e0b46052c98
Source dataset
uspto-grants-2013_02
Patent number
US08372837B2

Reaction notes

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