Acetic Acid → 6-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylamino)pyridin-2(1H)-one

HRID 468729Notes

Reaction equation

HRID 468729 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[N:20]=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.C(O)(=O)C.Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]4[NH:20][C:21](=[O:25])[CH:22]=[CH:23][CH:24]=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1

Participants

4

Reactant 3

HCID 176Acetic AcidHCID 260Hydrogen BromideHCID 679767437-(5-fluoro-2-methylphenyl)-N-(6-methoxypyridin-2-yl)isoquinolin-3-amine

Product 1

HCID 679763986-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylamino)pyridin-2(1H)-oneYield 3.2%

Conditions

Temperature
100 °C

Procedure

To a solution of 7-(5-fluoro-2-methylphenyl)-N-(6-methoxypyridin-2-yl)isoquinolin-3-amine (80% pure, 175 mg, 0.390 mmol) in acetic acid (3 mL, 50 mmol) was added hydrogen bromide (2 mL, 20 mmol) (48% in acetic acid). The reaction mixture was stirred at 100° C. under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and then evaporated in vacuo. The resulting residue was dissolved in dichloromethane, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-5% methanol in dichloromethane) followed by reverse phase HPLC purification and lyophilization to yield 4.3 mg (3.2%) of 6-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylamino)pyridin-2(1H)-one. LCMS (ESI): RT (min)=5.219, M+H=346.0, method=E; 1H NMR (400 MHz, DMSO-d6) δ 9.85 (broad s, 1H), 9.15 (s, 1H), 8.00 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.54-7.29 (m, 2H), 7.16 (t, J=9.6 Hz, 2H), 5.93 (m, 2H), 2.27 (s, 3H).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. customevaporated in vacuo
  3. dissolutionThe resulting residue was dissolved in dichloromethane
  4. washwashed with saturated aqueous NaHCO3
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. customevaporated in vacuo
  8. customThe crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-5% methanol in dichloromethane)
  9. customfollowed by reverse phase HPLC purification and lyophilization

Sources & evidence

ORD record
ord-88ebc91ac6744125afa2bb5322f0c50a
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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