1,2-Dichloroethane → 2-(4-pyrazolo[1,5-b]pyridazin-3-ylphenyl)-N-[(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl]acetamide

HRID 474150

Reaction equation

HRID 474150 reaction equation
[N:1]1[N:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[Cl-].[Cl-].[NH3+:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][NH+:26]=1)[CH3:24].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]1[N:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:22][C@@H:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:34])[F:35])=[CH:27][N:26]=3)[CH3:24])=[O:19])=[CH:14][CH:15]=2)[CH:2]=1

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 59535942(4-Pyrazolo[1,5-b]pyridazin-3-ylphenyl)acetic acidHCID 178462209HCID 178462209, compound

Product 1

HCID 252425402-(4-pyrazolo[1,5-b]pyridazin-3-ylphenyl)-N-[(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl]acetamideYield 68.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 0.69 g (2.74 mmol) (4-pyrazolo[1,5-b]pyridazin-3-ylphenyl)acetic acid in 10.0 ml CH2Cl2 was added 0.96 g (3.28 mmol) of 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.48 g (3.56 mmol) of HOAt, 0.68 g (3.56 mmol) of EDC, and 1.43 mL (8.21 mmol) of DIEA. After 1 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed three times with water, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, gradient 0-100% EtOAc in hexanes) afforded 0.85 g (68%) of 2-(4-pyrazolo[1,5-b]pyridazin-3-ylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CD3OD, 400 MHz) 8.40 (m, 2-H); 8.28 (s, 1H); 8.27 (d, J=2.93 Hz, 1H); 7.61 (dd, J=1.83, 6.41 Hz, 2H); 7.43 (m, 3H); 7.31 (d, J=8.61 Hz, 1H); 7.22 (dd, J=4.58, 9.07 Hz, 1H); 5.04 (quintet, J=6.86 Hz, 1H); 4.62 (q, J=8.43 Hz, 2H); 3.61 (s, 2H); 1.46 (d, J=7.05 Hz, 31-1). HRMS (ES) [M+1]+calcd for C23H21F3N5O2: 456.1647, Found: 456.1652. FLEPR alpha1I IP=5.0 nM.

Workup

  1. washwashed three times with water
  2. washwashed with brine
  3. dry with materialThe organic layer was dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customPurification by flash chromatography (silica gel, gradient 0-100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-be2d7a5a747b42c0b911d1049f79c717
Source dataset
uspto-grants-2014_01
Patent number
US08637513B2

Linked notes

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