1,2-Dichloroethane → N-(6-(cyanomethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide, hydrochloride

HRID 1050081Notes

Reaction equation

HRID 1050081 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]1[C:23](=[O:24])[NH:22][CH:21]=[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[C:27]([F:35])[CH:26]=2)[CH:19]=1)[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)C[Cl:48].CCN(CC)CC>CN(C=O)C>[ClH:48].[C:9]([CH2:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:20]3[CH:19]=[C:18]([O:17][CH2:15][CH3:16])[C:23](=[O:24])[NH:22][CH:21]=3)=[CH:26][C:27]=2[F:35])=[CH:3][C:4]=1[C:11]([F:14])([F:12])[F:13])#[N:10]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 904154342-(4-(5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acidHCID 904165325-Amino-3-(trifluoromethyl)pyridine-2-acetonitrile

Product 1

HCID 90422662N-(6-(cyanomethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide, hydrochlorideYield 2.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

A suspension of 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (16.00 mg, 0.080 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 (46.33 mg, 0.080 mmol) in DMF (5 mL). HOBt (18.27 mg, 0.119 mmol), EDC (22.87 mg, 0.119 mmol) and Et3N (0.033 mL, 0.239 mmol) and the mixture was 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 a yellow solid of N-(6-(cyanomethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride (0.96 mg, 1.879 μmol, 2.4% yield). TLC (DCM/MeOH=10:1, Rf=0.3): 1H NMR (400 MHz, CD3OD) δ: 8.87-8.96 (m, 1H), 8.56 (d, J=2.21 Hz, 1H), 7.19-7.50 (m, 5H), 4.08-4.18 (m, 2H), 3.85 (s, 3H), 3.58 (s, 2H), 1.29-1.35 (m, 3H); ES-LCMS m/z 475.0 (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-205d0844a8a54de593ef0d8d4718e647
Source dataset
uspto-grants-2016_07
Patent number
US09382238B2

Reaction notes

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