1,2-Dichloroethane → 2-(4-pyrazin-2-ylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide

HRID 474151Notes

Reaction equation

HRID 474151 reaction equation
[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.[Cl-].[Cl-].[NH3+:19][C@@H:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][NH+:23]=1)[CH3:21].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([NH:19][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])=[CH:24][N:23]=2)[CH3:21])=[O:16])=[CH:11][CH:12]=1

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 595359382-(4-(Pyrazin-2-yl)phenyl)acetic acidHCID 178462209HCID 178462209, compound

Product 1

HCID 426100142-(4-pyrazin-2-ylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamideYield 70%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 0.10 g (0.48 mmol) (4-pyrazin-2-ylphenyl)acetic acid in 2.00 ml of CH2Cl2 was added 0.17 g (0.58 mmol) of 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.085 g (0.63 mmol) of HOAt, 0.12 g (0.63 mmol) of EDC, and 0.25 mL (1.44 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, linear gradient 50-100% EtOAc in hexanes) afforded 0.14 g (70%) of 2-(4-pyrazin-2-ylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CD3OD, 400 MHz) 9.09 (d, J=1.46 Hz, 1H); 8.65 (t, J=1.74 Hz, 1H); 8.51 (d, J=2.57 Hz, 1H); 8.26 (d, J=3.02 Hz, 1H); 8.03 (d, J=8.15 Hz, 2H); 7.46 (d, J=8.15 Hz, 2H); 7.43 (dd, J=3.02, 8.70 Hz, 1H); 7.30 (d, J=8.70 Hz, 1H); 5.03 (quintet, J=6.96 Hz, 1H); 4.62 (q, J=8.34 Hz, 2H); 3.64 (s, 2H); 1.46 (d, 3H, J=6.96 Hz). HRMS (ES) [M+1]+calcd for C21H20F3N4O2: 417.1538, Found: 417.1523. FLIPR alpha1I IP=30 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, linear gradient 50-100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-73b54622e3234f7abc35736c24bc9d69
Source dataset
uspto-grants-2014_01
Patent number
US08637513B2

Reaction notes

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