Benzyl Bromide → 2-Benzyl-3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline

Temperature

70 °C

To a solution of 3-methylisoquinoline (1.0 g, 6.98 mmol) in THF (6 mL) was added benzyl bromide (0.78 mL, 6.63 mmol). After the addition was completed, the mixture was heated at 70° C. under N2 for 16 h. The mixture was cooled down to RT and THF (10 mL). Then, the mixture was cooled to 0° C. and (4-(trifluoromethyl)phenyl)magnesium bromide was added, and then stirred at RT for 16 h. After quenching with saturated ammonium chloride solution, the mixture was extracted several times with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated. The residue was mixed with silica gel and the solid mixture was purified by silica gel flash column chromatography (30%-100% EtOAc/hexane, then 20% MeOH in DCM) to give a mixture of 2-benzyl-3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline & 2-benzyl-3-methyl-1-(4-(trifluoromethyl)phenyl)-isoquinolinium, which was used without further purification. This mixture was dissolved in THF (45 mL) and sodium borohydride (2.6 g, 68.9 mmol) was added. The resulting mixture was stirred at RT 15 min, and then glacial acetic acid (1 mL) was added. The mixture was stirred at RT for 2 h, and then at 55° C. for an additional 2 h. After cooling down to RT, it was basified with NaOH (10 N) (to pH>12). The organic layer was collected and the aqueous layer was extracted several times with EtOAc. The combined organic extracts were then dried over MgSO4 and concentrated. The residue was dissolved MeOH (5 mL) and the solution mixture was purified by preparative HPLC (0% MeCN 0.1% TFA/H2O 0.1% TFA). All fractions of the product were combined and MeCN was removed in vacuo. The aqueous phase was basified with NaHCO3 and extracted with EtOAc. The combined organic extracts were dried over MgSO4, concentrated, and dried to give the title compound as a yellow oil.

1. additionAfter the addition
2. temperatureThe mixture was cooled down to RT
3. temperatureThen, the mixture was cooled to 0° C.
4. customAfter quenching with saturated ammonium chloride solution
5. extractionthe mixture was extracted several times with EtOAc
6. dry with materialThe combined organic extracts were dried over MgSO4
7. concentrationconcentrated
8. additionThe residue was mixed with silica gel
9. customthe solid mixture was purified by silica gel flash column chromatography (30%-100% EtOAc/hexane
10. custom20% MeOH in DCM) to give
11. customwas used without further purification
12. dissolutionThis mixture was dissolved in THF (45 mL)
13. stirringThe resulting mixture was stirred at RT 15 min
14. stirringThe mixture was stirred at RT for 2 h
15. waitat 55° C. for an additional 2 h
16. temperatureAfter cooling down to RT
17. customThe organic layer was collected
18. extractionthe aqueous layer was extracted several times with EtOAc
19. dry with materialThe combined organic extracts were then dried over MgSO4
20. concentrationconcentrated
21. dissolutionThe residue was dissolved MeOH (5 mL)
22. customthe solution mixture was purified by preparative HPLC (0% MeCN 0.1% TFA/H2O 0.1% TFA)
23. customMeCN was removed in vacuo
24. extractionextracted with EtOAc
25. dry with materialThe combined organic extracts were dried over MgSO4
26. concentrationconcentrated
27. customdried

ORD record

ord-43b56b047cb44bce9f8baf188d489f70

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08476297B2