Tetrahydro-4H-pyran-4-one → 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(1-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-3-yl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

HRID 1530617Notes

Reaction equation

HRID 1530617 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.[O:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.[BH3-]C#N.[Na+]>C(O)C>[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]([CH:39]6[CH2:40][CH2:41][O:36][CH2:37][CH2:38]6)[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 3

HCID 121599Tetrahydro-4H-pyran-4-oneHCID 5003444Sodium cyanoborohydrideHCID 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]oxazepine

Product 1

HCID 665585112-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(1-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-3-yl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineYield 50%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
20 °C

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 (60 mg, 0.13 mmol) and tetrahydropyran-4-one (26 mg, 0.26 mmol) in ethanol (10 mL) was added Ti(Oi-Pr)4 (74 mg, 0.26 mmol). After being stirred at 20° C. for 20 min, NaBH3CN (16 mg, 0.26 mmol) was added and stirred at 20° C. for 16 h. The solvent was removed and several drops of water were added. 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 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 226 (35 mg, 50% yield). LCMS (ESI): RT=4.97 min, m/z: 557.4 [M+H+]. 1H NMR (500 MHz, MeOH-d4) δ 8.48 (d, J=8 Hz, 1H), 7.25 (s, 1H), 7.41 (s, 1H), 7.09 (d, J=8 Hz, 1H), 7.00 (s, 1H), 5.94 (t, J=13 Hz, 1H), 4.54 (d, J=5 Hz, 4H), 3.95 (d, J=6.5 Hz, 5H), 3.35 (t, J=25 Hz, 3H), 3.25 (s, 1H), 3.00 (d, J=6.5 Hz, 2H), 2.51-2.54 (m, 2H), 2.38 (s, 3H), 2.12 (d, J=11 Hz, 1H), 1.86-1.62 (m, 6H), 1.56-1.49 (m, 6H)

Workup

  1. stirringstirred at 20° C. for 16 h
  2. customThe solvent was removed
  3. additionseveral drops of water were added
  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 0-50% gradient of CH3CN in 0.3% NH4HCO3

Sources & evidence

ORD record
ord-e6cdb1fd04d042ff81de56763ce83a47
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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