Diisopropylethylamine → N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-5-trifluoromethoxy-1H-indazole-3-carboxamide

HRID 1864617Notes

Reaction equation

HRID 1864617 reaction equation
[F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=O.Cl.Cl.[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[CH:22]([CH2:28][NH2:29])[CH2:21]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1.CN(C)C=O>[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[CH:22]([CH2:28][NH:29][C:13]([C:7]1[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:17])[F:16])[CH:5]=3)[NH:9][N:8]=1)=[O:15])[CH2:21]2

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 299215515-(trifluoromethoxy)-1H-indazole-3-carboxylic acidHCID 67230636{1-Azabicyclo[2.2.2]octan-3-yl}methanamine dihydrochloride

Product 1

HCID 11668790N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-5-trifluoromethoxy-1H-indazole-3-carboxamideYield 20%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 5-(trifluoromethoxy)-1H-indazole-3-carboxylic acid (0.40 mmol) in tetrahydrofuran (5.0 mL) and N,N-dimethylformamide (5.0 mL) was added 1-(1-azabicyclo[2.2.2]oct-3-yl)methanamine dihydrochloride (0.40 mmol) and HATU (0.40 mmol). N,N-Diisopropylethylamine (10.0 mmol) was added and the reaction mixture was maintained for 16 h. The reaction mixture was heated at 60° C. for 1 h, and was filtered and concentrated. The residue was redissolved in methanol and loaded on a 5 g SCX column. The column was washed with methanol and the product was eluted with methanoudimethylethylamine (9/1) and concentrated. The residue was purified by preparative HPLC to produce the desired product in 20% yield. 1H NMR (CDCl3) δ 8.47 (s, 1 H), 8.10 (s, 1 H), 7.67 (d, J=9.1, 1H), 7.36 (d, J=9.1, 1H), 3.63-3.52 (m, 3 H), 3.48-3.23 (m, 4 H), 3.08-3.01 (m, 1 H), 2.66-2.44 (m, 1 H), 2.32-2.22 (m, 1 H), 2.14-2.08 (m, 1 H), 2.06-1.85 (m, 3 H); LC/MS (EI) tR 4.8 min, m/z 369 (M++1).

Workup

  1. temperaturethe reaction mixture was maintained for 16 h
  2. filtrationwas filtered
  3. concentrationconcentrated
  4. dissolutionThe residue was redissolved in methanol
  5. washThe column was washed with methanol
  6. washthe product was eluted with methanoudimethylethylamine (9/1)
  7. concentrationconcentrated
  8. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-00e01259b8a747a48649d131ca370d60
Source dataset
uspto-grants-2009_12
Patent number
US07625924B2

Reaction notes

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