Dimethylformamide → N-(cyclopropylmethyl)-7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine

HRID 468746Notes

Reaction equation

HRID 468746 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.CN(C)C=O.[H-].[Na+].[CH:27]1([CH2:30]Br)[CH2:29][CH2:28]1>>[CH:27]1([CH2:30][NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:19])[CH:17]=3)[CH2:29][CH2:28]1

Participants

5

Reactant 4

HCID 6228DimethylformamideHCID 24758Sodium hydride2×HCID 81503Bromomethylcyclopropane2×HCID 574102447-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine

Product 1

HCID 67974709N-(cyclopropylmethyl)-7-(5-fluoro-2-methylphenyl)isoquinolin-3-amineYield 16%

Procedure

To a solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (61.7 mg, 0.244 mmol) in N,N-dimethylformamide (2.0 mL, 26 mmol) at room temperature was added sodium hydride (20.1 mg, 0.502 mmol, 60% dispersion in mineral oil). The reaction mixture was stirred at room temperature for 30 minutes, and then cyclopropylmethyl bromide (24.0 uL, 0.247 mmol) was added and the reaction mixture was heated at 50° C. for 3 hours. The reaction mixture was cooled to room temperature and sodium hydride (66 mg, 60% dispersion in mineral oil) was added, followed by cyclopropylmethyl bromide (30.0 uL). The reaction mixture was then stirred at room temperature overnight. The mixture was then partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-50% ethyl acetate in dichloromethane) to yield 11.8 mg (16%) of N-(cyclopropylmethyl)-7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine. LCMS (ESI): RT (min)=4.807, M+H=307.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.77 (s, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.40-7.30 (m, 1H), 7.17-7.06 (m, 2H), 6.64 (s, 1H), 6.54 (t, J=5.3 Hz, 1H), 3.16 (t, J=6.2 Hz, 2H), 2.25 (s, 3H), 1.12 (dd, J=12.4, 6.7 Hz, 1H), 0.46 (d, J=6.8 Hz, 2H), 0.26 (d, J=4.3 Hz, 2H).

Workup

  1. temperaturethe reaction mixture was heated at 50° C. for 3 hours
  2. temperatureThe reaction mixture was cooled to room temperature
  3. stirringThe reaction mixture was then stirred at room temperature overnight
  4. customThe mixture was then partitioned between ethyl acetate and water
  5. washthe organic layer was washed with water and brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customevaporated in vacuo
  9. customThe crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-50% ethyl acetate in dichloromethane)

Sources & evidence

ORD record
ord-17f371dc61dd42f9ae34fafad1a92bc4
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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