Ethyl Acetate → Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate

HRID 386547Notes

Reaction equation

HRID 386547 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[C:11]([C:17]([O:19][CH3:20])=[O:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].CS(O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)(=O)=O.CCOC(C)=O>CN(C=O)C.O>[C:41]([O:40][C:38]([N:35]1[CH2:36][CH2:37][CH:32]([O:16][C:12]2[C:11]([C:17]([O:19][CH3:20])=[O:18])=[N:10][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:14](=[O:15])[CH:13]=2)[CH2:33][CH2:34]1)=[O:39])([CH3:44])([CH3:42])[CH3:43]

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 41848691-(tert-Butoxycarbonyl)-4-(methanesulfonyloxy)piperidineHCID 54724062Methyl 1-(3,4-dichlorophenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxylate

Product 1

HCID 44621627Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylateYield 14.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
95 °C

Procedure

To a mixture of methyl 1-(3,4-dichlorophenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxylate (315 mg, 1.0 mmol) in DMF (3 mL) at room temperature under argon was added K2CO3 (415 mg, 3.0 mmol) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (419 mg, 1.5 mmol). The reaction mixture was heated at 95° C. overnight. EtOAc (20 mL) and water (20 mL) were added to the reaction mixture. Layers were separated. Organic layer were 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. 72 mg (14.2%) of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate was obtained as a gum. 1H NMR (400 MHz, CDCl3) δ ppm 1.40-1.50 (m, 9H) 1.68-1.82 (m, 1H) 1.92 (d, J=3.08 Hz, 3H) 3.23-3.45 (m, 2H) 3.49-3.59 (m, 1H) 3.59-3.73 (m, 1H) 3.82-4.03 (m, 3H) 4.48-5.43 (m, 1H) 6.12-6.38 (m, 1H) 7.38-7.64 (m, 2H) 7.75 (dd, J=7.91, 2.20 Hz, 1H). MS (ESI) 442 (M+H-tBu).

Workup

  1. customLayers were separated
  2. washOrganic layer were 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-d8fbc96eaf84416d9b0f2b092bc503dc
Source dataset
uspto-grants-2013_02
Patent number
US08372837B2

Reaction notes

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