Water → Tert-butyl 4-(1-(4-cyano-3-fluorophenyl)-3-(hydroxymethyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate

HRID 386582

Reaction equation

HRID 386582 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:31](OC)=[O:32])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CCOC(C)=O.O>C1COCC1.CO>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([N:18]2[C:19](=[O:21])[CH:20]=[C:15]([O:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[C:16]([CH2:31][OH:32])=[N:17]2)=[CH:23][C:24]=1[F:30])#[N:29]

Participants

6

Reactant 4

HCID 962WaterHCID 8857Ethyl AcetateHCID 4311764Sodium borohydrideHCID 44620996Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate

Product 1

HCID 44621180Tert-butyl 4-(1-(4-cyano-3-fluorophenyl)-3-(hydroxymethyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylateYield 83.2%

Reagents, catalysts & solvents 1

HCID 21899815MeOH tetrahydrofuranSolvent

Procedure

To a stirring solution of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (27.2 mg, 0.1 mmol) in THF/MeOH (1:1) (3 mL) at room temperature under argon was added NaBH4 (18.9 mg, 0.5 mmol) at 0° C. in an ice bath under argon carefully. The reaction mixture was allowed to warm to room temperature gradually and stirred 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. 37 mg (82%) of tert-butyl 4-(1-(4-cyano-3-fluorophenyl)-3-(hydroxymethyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.39-1.53 (m, 9H) 1.68-1.88 (m, 2H) 1.88-2.09 (m, 2H) 2.51 (t, J=5.93 Hz, 1H) 3.20-3.49 (m, 2H) 3.54-3.76 (m, 2H) 4.43-4.63 (m, 1H) 4.69 (d, J=5.71 Hz, 2H) 6.23 (s, 1H) 7.53-7.85 (m, 3H). MS (ESI) 389 (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-70b72e3bf25048bc951e13769396ed39
Source dataset
uspto-grants-2013_02
Patent number
US08372837B2

Linked notes

Loading…