1-Methyl-4-(pyrrolidin-2-yl)piperidine → 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-(1-methylpiperidin-4-yl)pyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

HRID 1530525Notes

Reaction equation

HRID 1530525 reaction equation
Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=1)[N:7]=3.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([CH:31]2[CH2:35][CH2:34][CH2:33][NH:32]2)[CH2:27][CH2:26]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:19]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([N:32]5[CH2:33][CH2:34][CH2:35][CH:31]5[CH:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]

Participants

6

Reactant 3

HCID 45663131-Methyl-4-(pyrrolidin-2-yl)piperidineHCID 23676156Sodium t-butoxideHCID 582043138-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene2×

Product 1

HCID 665585932-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-(1-methylpiperidin-4-yl)pyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineYield 16%

Reagents, catalysts & solvents 2

HCID 178418851HCID 178418851, compoundCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene, also named as 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 95 (300 mg, 0.80 mmol), 1-methyl-4-pyrrolidin-2-ylpiperidine (338 mg, 2.00 mmol), NaOtBu (232 mg, 2.40 mmol) and Pd(PtBu3)2 (20 mg, 0.04 mmol) in toluene (6 mL) was heated at 110° C. for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (C18, gradient 10-65% MeOH in H2O) then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was freeze-dried from MeCN/H2O to afford 141 (20 mg, 16%) as a white solid. LCMS: RT 2.91 min [M+H]+ 462.4. 1H NMR (DMSO, 400 MHz): δ 8.18 (1H, d, J=8.95 Hz), 7.87 (1H, s), 7.77 (1H, s), 6.49 (1H, dd, J=9.03, 2.41 Hz), 6.13 (1H, d, J=2.36 Hz), 5.94-5.93 (1H, m), 4.45-4.40 (4H, m), 3.74 (1H, s), 3.45-3.43 (1H, m), 3.14-3.11 (1H, m), 2.78 (2H, s), 2.12 (3H, s), 1.99-1.72 (5H, m), 1.71-1.51 (3H, m), 1.47 (6H, dd, J=6.60, 1.90 Hz), 1.33-1.31 (3H, m)

Workup

  1. washwas washed with MeOH
  2. washthe product eluted with 2M NH3/MeOH
  3. customThe resulting residue was purified by column chromatography (C18, gradient 10-65% MeOH in H2O)
  4. washwas washed with MeOH
  5. washthe product eluted with 2M NH3/MeOH
  6. dry with materialThe resulting residue was freeze-dried from MeCN/H2O

Sources & evidence

ORD record
ord-e3924cb6d6d54106900a9c1c5f2e4079
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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