Triethylamine → Cyclopropyl-(1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidin-4-ylmethyl)-carbamic Acid Tert-butyl Ester

HRID 220936Notes

Reaction equation

HRID 220936 reaction equation
[C:1]([O:5][C:6]([N:8]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=2[CH3:31])[CH2:15][CH2:14]1)[CH:9]1[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][N:41]1[C:50]2[NH:49][C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[NH:46][CH2:45][C:44]=2[CH:43]=[N:42]1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH:9]1[CH2:11][CH2:10]1)[CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19](=[O:32])[CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:46]3[CH2:45][C:44]4[CH:43]=[N:42][N:41]([CH3:40])[C:50]=4[NH:49][C:48]4[CH:51]=[CH:52][CH:53]=[CH:54][C:47]3=4)=[O:27])=[CH:24][C:23]=2[CH3:31])[CH2:17][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 575553264-(3-{4-[(tert-Butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic AcidHCID 1357419771-Methyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-e][1,4]diazepine

Product 1

HCID 136128441Cyclopropyl-(1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidin-4-ylmethyl)-carbamic Acid Tert-butyl EsterYield 62%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

WSCD (1.08 g, 5.6 mmol) and DMAP (343 mg, 2.8 mmol) were added to a solution of 4-(3-{4-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic acid from Example E86.2 (1.25 g, 2.8 mmol) in dichloromethane (100 ml) and triethylamine (0.783 ml, 5.6 mmol). The mixture was stirred for 1 h at room temperature then 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (676 mg, 3.4 mmol) was added. The mixture was heated at reflux for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% methanol:98% EtOAc to 5% methanol:95% EtOAc) to yield the title compound (1.1 g, 62%).

Workup

  1. temperatureThe mixture was heated
  2. temperatureat reflux for 2 days
  3. washwashed with saturated NaHCO3
  4. dry with materialbrine, dried
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by flash chromatography on silica gel (eluant; 2% methanol:98% EtOAc to 5% methanol:95% EtOAc)

Sources & evidence

ORD record
ord-7cd0e9d317a14011b000fb7e68cf319e
Source dataset
uspto-grants-2012_06
Patent number
US08202858B2

Reaction notes

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