Ethyl Acetate → 4-(1-(5-Chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile

HRID 386576Notes

Reaction equation

HRID 386576 reaction equation
Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:14]([C:26]#[N:27])=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[Cl:37][C:38]1[CH:39]=[N:40][C:41](I)=[N:42][CH:43]=1.CCOC(C)=O>CN1C(=O)CCC1>[Cl:37][C:38]1[CH:39]=[N:40][C:41]([N:23]2[CH2:24][CH2:25][CH:20]([O:19][C:15]3[C:14]([C:26]#[N:27])=[N:13][N:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:11][CH:10]=4)[C:17](=[O:18])[CH:16]=3)[CH2:21][CH2:22]2)=[N:42][CH:43]=1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 81531DiisopropylethylamineHCID 299380055-Chloro-2-iodopyrimidineHCID 674455661-(4-(methylsulfonyl)phenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl

Product 1

HCID 446211434-(1-(5-Chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrileYield 75.3%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
100 °C

Procedure

To a stirring solution of 1-(4-(methylsulfonyl)phenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl (124 mg, 0.33 mmol) in NMP (3 mL) at room temperature under argon was added DIPEA (128 mg, 0.99 mmol) and 5-chloro-2-iodopyrimidine (159 mg, 0.66 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 (˜3 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. 121 mg (75%) of 4-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile was obtained as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.75-2.27 (m, 4H) 3.08 (s, 3H) 3.66-3.97 (m, 2H) 3.97-4.24 (m, 2H) 4.54-4.95 (m, 1H) 6.34 (s, 1H) 7.84 (d, J=8.79 Hz, 2H) 8.07 (d, J=8.79 Hz, 2H) 8.24 (s, 2H). MS (ESI) 487 (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 (˜3 ml)
  7. washwas eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes

Sources & evidence

ORD record
ord-ffb0d5d3dcb245dc9d3ea2289bc37e1b
Source dataset
uspto-grants-2013_02
Patent number
US08372837B2

Reaction notes

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