1,2-Dichloroethane → 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide, hydrochloride

HRID 1050074Notes

Reaction equation

HRID 1050074 reaction equation
[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[NH2:10])[CH:6]=1.[CH2:18]([O:20][C:21]1[C:26](=[O:27])[NH:25][CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[C:30]([F:38])[CH:29]=2)[CH:22]=1)[CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)C[Cl:51].CCN(CC)CC>CN(C=O)C>[ClH:51].[CH2:18]([O:20][C:21]1[C:26](=[O:27])[NH:25][CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:10][C:9]3[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=[C:7]([N:5]4[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]4)[CH:8]=3)=[O:36])=[C:30]([F:38])[CH:29]=2)[CH:22]=1)[CH3:19]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 120028253-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)anilineHCID 904154342-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid

Product 1

HCID 904230892-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide, hydrochlorideYield 10.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
50 °C

Procedure

A suspension of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (6.63 mg, 0.027 mmol) in DMF (5 mL) was added to a solution of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (8 mg, 0.027 mmol) in DMF (5 mL). HOBt (6.31 mg, 0.041 mmol), EDC (7.90 mg, 0.041 mmol) and Et3N (0.011 mL, 0.082 mmol) were added and the mixture was stirred at 50° C. for 12 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield an off white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide hydrochloride (1.60 mg, 2.90 μmol, 10.6% yield). TLC (DCM/MeOH=10:1, Rf=0.3): 1H NMR (400 MHz, CD3OD) δ: 9.41 (d, J=1.54 Hz, 1H), 8.37-8.45 (m, 1H), 7.96 (s, 1H), 7.73-7.88 (m, 2H), 7.18-7.52 (m, 5H), 4.14 (q, J=7.06 Hz, 2H), 3.87 (s, 2H), 2.43 (s, 3H), 1.46 (t, J=6.95 Hz, 3H); ES-LCMS m/z 515.1 (M+H).

Workup

  1. concentrationThen the solution was concentrated
  2. extractionThe combined organic extract
  3. washwas washed with brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition)

Sources & evidence

ORD record
ord-96ef228154cd4265afc64a44254e3bab
Source dataset
uspto-grants-2016_07
Patent number
US09382238B2

Reaction notes

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