Water → 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(1-methyl-5-(1-methylpiperidin-3-yl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

HRID 1530635Notes

Reaction equation

HRID 1530635 reaction equation
[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]3[CH:22]=[N:23][N:24]([CH3:32])[C:25]=3[CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[CH:14]=2)[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[CH2:43]1COCC1>>[CH:33]([N:4]1[C:5]([C:7]2[N:8]=[C:9]3[C:10]4[CH:11]=[CH:12][C:13]([C:21]5[CH:22]=[N:23][N:24]([CH3:32])[C:25]=5[CH:26]5[CH2:31][CH2:30][CH2:29][N:28]([CH3:43])[CH2:27]5)=[CH:14][C:15]=4[O:16][CH2:17][CH2:18][N:19]3[CH:20]=2)=[N:6][C:2]([CH3:1])=[N:3]1)([CH3:35])[CH3:34]

Participants

5

Reactant 4

HCID 962WaterHCID 8028TetrahydrofuranHCID 21226445Aluminium lithium hydrideHCID 683127572-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine2×

Product 1

HCID 665588452-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(1-methyl-5-(1-methylpiperidin-3-yl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineYield 79%

Procedure

To a solution of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-[1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1 (14),2,4,10,12-pentaene, also named as 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (220 mg, 0.39 mmol) in dry THF (5.0 mL), was added LiAlH4 (59.3 mg, 1.56 mmol) in small portions at room temperature. The resultant mixture was heated to reflux for 1 h. Water (2.0 mL) was added to quench the reaction. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give racemic 246 (150 mg, 79% yield), which was separated by chiral SFC (Cellulose-2 column, 0.1% DEA in MeOH isocratic) to give: 5.5 mg of one enantiomer and 70 mg of the other (39% total yield). LCMS (ESI): RT=4.96 min, m/z: 487.4 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.42 (d, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 7.09-7.06 (m, 1H), 6.93 (d, J=1.5 Hz, 1H), 5.87-5.84 (m, 1H), 4.54 (d, J=6.0 Hz, 4H), 3.90 (s, 3H), 3.17 (s, 1H), 2.78-2.74 (m, 2H), 2.26 (s, 3H), 2.18-2.13 (m, 3H), 1.64-1.48 (m, 5H), 1.45 (d, J=7.0 Hz, 6H)

Workup

  1. temperatureto reflux for 1 h
  2. customto quench
  3. customthe reaction
  4. dry with materialThe organic layer was dried over Na2SO4
  5. concentrationconcentrated
  6. customThe residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min)

Sources & evidence

ORD record
ord-83771add89c2457fb3d1a21d1db32fb5
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

Loading…