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

HRID 1530631Notes

Reaction equation

HRID 1530631 reaction equation
C(O1[CH2:11][CH:10]([C:12]2[N:16]([CH3:17])[N:15]=[CH:14][C:13]=2[C:18]2[CH:19]=[C:20]3[C:29](=[CH:30][CH:31]=2)[C:28]2[N:24]([CH:25]=[C:26]([C:32]4[N:36]([CH:37]([CH3:39])[CH3:38])[N:35]=[C:34]([CH3:40])[N:33]=4)[N:27]=2)[CH2:23][CH2:22][O:21]3)[CH2:9][CH2:8][NH:7][C:6]1=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO>C1COCC1>[CH:37]([N:36]1[C:32]([C:26]2[N:27]=[C:28]3[C:29]4[CH:30]=[CH:31][C:18]([C:13]5[CH:14]=[N:15][N:16]([CH3:17])[C:12]=5[CH:10]5[CH2:9][CH2:8][N:7]([CH3:6])[CH2:11]5)=[CH:19][C:20]=4[O:21][CH2:22][CH2:23][N:24]3[CH:25]=2)=[N:33][C:34]([CH3:40])=[N:35]1)([CH3:39])[CH3:38]

Participants

5

Reactant 3

HCID 887MethanolHCID 21226445Aluminium lithium hydrideHCID 178432609HCID 178432609, compound

Product 1

HCID 665588462-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(1-methyl-5-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineYield 51.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 1-tert-butyl-6-(1-methyl-4-{4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}-1H-pyrazol-5-yl)-λ3,3-oxazepan-2-one (150 mg, 0.269 mmol) and LiAlH4 (51 mg, 1.3 mmol) in THF (5 mL) was refluxed for 1 hr. MeOH was added to quench reaction, The solid was filtered off and the filtrate was evaporated to afford the crude product, which was purified by reverse phase Combiflash eluting with a 0-70% gradient of CH3CN in 0.3% NH4HCO3 to give racemic 240 (65 mg, 51% yield), which was separated by chiral SFC (Cellulose-2 column, 10% MeOH (0.1% DEA) isocratic) to give: 22.5 mg of one enantiomer and 35.5 mg of the other (46% total yield). LCMS (ESI): RT=4.79 min, m/z: 473.4 [M+H+]. 1H-NMR (500 MHz, DMSO-d6) δ 8.41 (d, J=8.5 Hz, 1H), 7.90 (s, 1H), 7.52 (s, 1H), 7.12 (dd, J=1.5 Hz, J=8.5 Hz, 1H), 6.99 (s, 1H), 5.77 (t, J=7.0 Hz, J=13.5 Hz, 1H), 4.53 (s, 4H), 3.97 (s, 3H), 3.74 (s, 1H), 2.80-2.74 (m, 2H), 2.65 (t, J=9.5 Hz, J=18.5 Hz, 1H), 2.49-2.46 (m, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 2.19-2.17 (m, 1H), 1.96-1.93 (m, 1H), 1.46 (s, 6H)

Workup

  1. temperaturewas refluxed for 1 hr
  2. customto quench
  3. customreaction
  4. filtrationThe solid was filtered off
  5. customthe filtrate was evaporated
  6. customto afford the crude product, which
  7. customwas purified by reverse phase Combiflash
  8. washeluting with a 0-70% gradient of CH3CN in 0.3% NH4HCO3

Sources & evidence

ORD record
ord-eb2fb0ba10e94aebb0b3acea21c04ff3
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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