Diisopropylethylamine → [4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-carbamic Acid Tert-butyl Ester

HRID 220788Notes

Reaction equation

HRID 220788 reaction equation
[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[F:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:29][N:30]1[C:39]2[NH:38][C:37]3[CH:40]=[C:41]([CH3:44])[CH:42]=[CH:43][C:36]=3[NH:35][CH2:34][C:33]=2[CH:32]=[N:31]1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:35]2[CH2:34][C:33]3[CH:32]=[N:31][N:30]([CH3:29])[C:39]=3[NH:38][C:37]3[CH:40]=[C:41]([CH3:44])[CH:42]=[CH:43][C:36]2=3)=[O:16])=[CH:12][C:11]=1[F:19])([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 230231654-((((Tert-butoxy)carbonyl)amino)methyl)-3-fluorobenzoic acidHCID 1357360353,6-Dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene

Product 1

HCID 136128399[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-carbamic Acid Tert-butyl EsterYield 32%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

A solution of 4-(tert-butoxycarbonylamino-methyl)-3-fluorobenzoic acid from Example E3.1 (538 mg, 2.0 mmol) and DMAP (220 mg, 1.8 mmol) in dichloromethane (20 ml) at room temperature was treated with DIEA (0.93 ml, 5.4 mmol) and WSCD (460 mg, 2.4 mmol), and the resulting solution was stirred at room temperature for 1 h. 3,6-Dimethyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E2 (385 mg, 1.8 mmol) was added and the resulting solution was heated at reflux for 20 h and allowed to cool to room temperature. The solution was diluted with dichloromethane, washed with saturated NaHCO3 and brine and concentrated in vacuo. The residue was purified by preparative HPLC (eluant 10% methanol:90% dichloromethane) to yield the title compound (265 mg, 32%).

Workup

  1. customat room temperature
  2. temperaturethe resulting solution was heated
  3. temperatureat reflux for 20 h
  4. temperatureto cool to room temperature
  5. washwashed with saturated NaHCO3 and brine
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by preparative HPLC (eluant 10% methanol:90% dichloromethane)

Sources & evidence

ORD record
ord-0ee1672c8ea043fd9d2e8f09f60e17e5
Source dataset
uspto-grants-2012_06
Patent number
US08202858B2

Reaction notes

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