4-Methylbenzaldehyde → 6-Methylisoquinoline

Temperature

90 °C

Para-tolualdehyde (53 mL, 0.486 mol) was stirred in a solvent of chloroform (900 mL). Aminoacetaldehyde dimethyl acetal (59.3 mL, 0.486 mol) was slowly added thereto, followed by stirring at 90° C. until about one-half of the reaction solution was evaporated. The reaction solution was cooled to room temperature, and the resulting yellow reaction solution was dissolved in chloroform (400 mL), followed by cooling the solution to 0° C. or below. Ethyl chloroformate (48 mL, 0.486 mol) and triethylphosphite (104 mL, 0.583 mol) were slowly added to the reaction solution. The reaction solution was stirred for 24 hours at room temperature. The reaction solution was cooled to 0° C. or below, slowly added with titanium tetrachloride (213.6 mL, 1.94 mol), and refluxed for 12 hours or more. The reaction solution was cooled to room temperature, and stirred for 12 hours or more. The reaction mixture was poured to an ice water to separate the organic layer and the aqueous layer, and the aqueous layer was washed with dichloromethane. A saturated sodium tartrate solution was added to the aqueous layer, adjusted to pH 9 by adding ammonia water, and subjected to extraction with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (46.3 g, 66%).

1. customwas evaporated
2. temperatureThe reaction solution was cooled to room temperature
3. dissolutionthe resulting yellow reaction solution was dissolved in chloroform (400 mL)
4. temperatureby cooling the solution to 0° C. or below
5. stirringThe reaction solution was stirred for 24 hours at room temperature
6. temperatureThe reaction solution was cooled to 0° C. or below
7. temperaturerefluxed for 12 hours or more
8. temperatureThe reaction solution was cooled to room temperature
9. stirringstirred for 12 hours or more
10. customto separate the organic layer
11. washthe aqueous layer, and the aqueous layer was washed with dichloromethane
12. additionA saturated sodium tartrate solution was added to the aqueous layer
13. additionby adding ammonia water
14. extractionsubjected to extraction with dichloromethane
15. dry with materialThe obtained organic layer was dried over anhydrous sodium sulfate
16. concentrationconcentrated under reduced pressure

ORD record

ord-a587ded8c4e244a19f990846c470ec47

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09156852B2