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

HRID 386582

반응식

HRID 386582 반응식
[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]

참가 물질

6

반응물 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

생성물 1

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

시약·촉매·용매 1

HCID 21899815MeOH tetrahydrofuran용매

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-70b72e3bf25048bc951e13769396ed39
출처 데이터셋
uspto-grants-2013_02
특허 번호
US08372837B2

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