Water → 1-Amino-6-methoxy-3-methylisoquinoline

HRID 478701Notes

Reaction equation

HRID 478701 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](=O)[CH3:11])[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)(Cl)=O.[N:18]#[C:19][NH2:20].O>C1(C)C=CC=CC=1.CCOCC.[Ti](Cl)(Cl)(Cl)Cl>[NH2:20][C:19]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:9]=[C:10]([CH3:11])[N:18]=1

Participants

8

Reactant 4

HCID 962WaterHCID 9864CyanamideHCID 24813Phosphorus oxychlorideHCID 764101-(3-Methoxyphenyl)acetone

Product 1

HCID 180026781-Amino-6-methoxy-3-methylisoquinolineYield 17.3%

Reagents, catalysts & solvents 3

HCID 24193Titanium TetrachlorideCatalystHCID 1140TolueneSolventHCID 3283Diethyl EtherSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 2.12 g of 3-methoxyphenylacetone and 1.26 mL of phosphoryl chloride in 45 mL of anhydrous toluene was heated under reflux. After 30 minutes the mixture was cooled to 0° C. and a solution of 0.57 g of cyanamide in 23 mL of anhydrous ether was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for one hour. Then the stirred mixture was cooled to 0° C. and 1.5 mL of titanium tetrachloride was added dropwise. The reaction mixture was heated under reflux for 2.5 hours, cooled, 34 mL of water added, the mixture filtered and the sediment was washed with ethyl acetate. The filtrate was made basic using 2N aqueous sodium hydroxide and acted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by silica chromatography (dichloromethane/methanol=95/5) yielding 0.42 g of the title compound. 1H-NMR 400 MHz (CDCl3) δ: 2.45 (3H, s), 3.91 (3H, s), 5.0 (2H, br. s), 6.81 (1H, s), 6.90 (1H, d, J=3 Hz), 7.02 (1H, dd, J=3 Hz and J=9 Hz), 7.65 (1H, d, J=9 Hz).

Workup

  1. temperatureunder reflux
  2. temperatureto warm to room temperature
  3. temperatureThen the stirred mixture was cooled to 0° C.
  4. temperatureThe reaction mixture was heated
  5. temperatureunder reflux for 2.5 hours
  6. temperaturecooled
  7. filtrationthe mixture filtered
  8. washthe sediment was washed with ethyl acetate
  9. washThe organic extracts were washed with brine
  10. dry with materialdried over magnesium sulfate
  11. concentrationconcentrated
  12. customThe residue was purified by silica chromatography (dichloromethane/methanol=95/5)

Sources & evidence

ORD record
ord-812ba15855fb414ea1ba770d17afe3a1
Source dataset
uspto-grants-2003_11
Patent number
US06642253B2

Reaction notes

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