1,2-Dichloroethane → Tert-butyl 4-(1-(3,4-dichlorophenyl)-3-(methylcarbamoyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate

HRID 386549Notes

Reaction equation

HRID 386549 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:30](O)=[O:31])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:39][C:37]=2C=1.C(Cl)CCl.CN.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Cl:29][C:24]1[CH:23]=[C:22]([N:18]2[C:19](=[O:21])[CH:20]=[C:15]([O:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]3)[C:16]([C:30](=[O:31])[NH:39][CH3:37])=[N:17]2)[CH:27]=[CH:26][C:25]=1[Cl:28]

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 6329MethylamineHCID 14798Sodium HydroxideHCID 757711-HydroxybenzotriazoleHCID 670726944-(1-(Tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid

Product 1

HCID 44621628Tert-butyl 4-(1-(3,4-dichlorophenyl)-3-(methylcarbamoyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylateYield 42.8%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a mixture of 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (23 mg, 0.047 mmol) in THF (1 ml) at room temperature under argon was added HOBt (8.0 mg, 0.052 mmol), EDC (10.01 mg, 0.052 mmol), and was followed by 1 M methylamine in THF (0.237 mL, 0.237 mmol). The reaction mixture was stirred at room temperature overnight. EtOAc (10 mL) and 1 N NaOH (10 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (10 mL), and brine (10 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give tert-butyl 4-(1-(3,4-dichlorophenyl)-3-(methylcarbamoyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (10 mg, white solid, 40.9%). 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (s, 9H) 1.78-2.05 (m, 4H) 2.96 (d, J=5.27 Hz, 3H) 3.43-3.57 (m, 2H) 3.57-3.72 (m, 2H) 4.49-4.71 (m, 1H) 6.28 (s, 1H) 6.58-6.69 (m, J=3.95 Hz, 1H) 7.46 (dd, 1H) 7.54 (d, 1H) 7.70 (d, J=2.20 Hz, 1H). MS (ESI) 441 (M+H-tBu).

Workup

  1. customLayers were separated
  2. washOrganic layer were washed with water (10 mL), and brine (10 mL)
  3. dry with materialOrganic phase was dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude product was purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA)

Sources & evidence

ORD record
ord-08d2c732ee8a4c908910863ad1f153a2
Source dataset
uspto-grants-2013_02
Patent number
US08372837B2

Reaction notes

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