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

HRID 1050076Notes

Reaction equation

HRID 1050076 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[N:6][CH:7]=1.[CH2:17]([O:19][C:20]1[C:25](=[O:26])[NH:24][CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[C:29]([F:37])[CH:28]=2)[CH:21]=1)[CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)C[Cl:50].CCN(CC)CC>CN(C=O)C>[ClH:50].[C:9]([C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:34](=[O:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[CH:21]=[C:20]([O:19][CH2:17][CH3:18])[C:25](=[O:26])[NH:24][CH:23]=3)=[CH:28][C:29]=2[F:37])=[CH:3][C:4]=1[C:13]([F:16])([F:14])[F:15])([CH3:12])[CH3:11])#[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 904159142-(5-Amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropanenitrile

Product 1

HCID 90423327N-(6-(2-cyanopropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide, hydrochlorideYield 26.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

A suspension of 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropanenitrile (13.91 mg, 0.061 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 (52 mg, 0.061 mmol) in DMF (5 mL). HOBt (13.94 mg, 0.091 mmol), EDC (17.45 mg, 0.091 mmol) and Et3N (0.025 mL, 0.182 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 an off white solid of N-(6-(2-cyanopropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride (8.62 mg, 0.016 mmol, 26.4% yield). TLC (DCM/MeOH=10:1, Rf=0.3): 1H NMR (400 MHz, CD3OD) δ: 8.95 (d, J=2.2 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H), 7.26-7.47 (m, 5H), 4.14 (q, J=7.0 Hz, 2H), 3.81-3.90 (m, 2H), 1.77-1.91 (m, 6H), 1.47 (t, J=6.9 Hz, 3H); ES-LCMS m/z 503.1 (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-cdd5eb82059e4fb79243d5ffedcd8fc4
Source dataset
uspto-grants-2016_07
Patent number
US09382238B2

Reaction notes

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