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

HRID 386585Notes

Reaction equation

HRID 386585 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.[F:37][CH:38]([F:50])[O:39][C:40]1[CH:41]=[N:42][C:43](S(C)(=O)=O)=[N:44][CH:45]=1.CCOC(C)=O>CN1C(=O)CCC1>[F:37][CH:38]([F:50])[O:39][C:40]1[CH:41]=[N:42][C:43]([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:44][CH:45]=1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 81531DiisopropylethylamineHCID 670726245-(Difluoromethoxy)-2-(methylsulfonyl)pyrimidineHCID 674455661-(4-(methylsulfonyl)phenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl

Product 1

HCID 446212264-(1-(5-(Difluoromethoxy)pyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrileYield 15.4%

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 (example 47 step A) (41 mg, 0.10 mmol) in NMP (3 mL) at room temperature under argon was added DIPEA (38.8 mg, 0.30 mmol) and 5-(difluoromethoxy)-2-(methylsulfonyl)pyrimidine (22.4 mg, 0.1.0 mmol). The resulting reaction mixture was heated at 100° C. under argon overnight. After cooling to room temperature, 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 24 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 8 mg (15% for two steps) of 4-(1-(5-(difluoromethoxy)pyrimidin-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) 519 (M+H).

Workup

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

Sources & evidence

ORD record
ord-71d3d892421d4dfda8f0b0f427335d39
Source dataset
uspto-grants-2013_02
Patent number
US08372837B2

Reaction notes

Loading…