Triethylamine → HCID 89648980, compound

Temperature

130 °C

A solution of 5-bromo-8-methoxy-3,4-dihydro-isoquinoline (312 mg, 1.3 mmol, 1.0 eq.) in chlorobenzene (18.4 mL) was treated with aluminium chloride (520 mg, 3.9 mmol, 3.0 eq.) and stirred at 130° C. for 1 hour. After cooling to r.t., sat. aq. NaHCO3 soln. was added and the mixture was extracted with AcOEt (2×). The combined org. layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was partially purified by flashmaster (column: 25 g, flow: 30 mL/min, 25 fractions of 30 mL, AcOEt+10% MeOH) to yield a yellow oil. To an ice-cooled solution of the residue in MeOH (13.1 mL), NaBH4 (98 mg, 2.6 mmol, 2.0 eq.) was added. The mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and AcOEt. The layers were separated and the aq. phase was extracted with AcOEt (2×). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo. To an ice-cooled solution of the residue and triethylamine (0.54 mL, 3.9 mmol, 3.0 eq.) in DCM (36 mL), benzyl chloroformate (0.21 mL, 1.43 mmol, 1.1 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (36 mL). The layers were separated. The aq. phase was extracted with DCM (3×). The comb. org. phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 27 fractions of 30 mL, Heptane 100% to Heptane+20% AcOEt). The residue was dissolved in THF (5 mL) and 1M aq. NaOH soln. (5 mL) was added. The mixture was stirred at r.t. for 18 hours. The org. solvent was removed in vacuo. The resulting aq. layer was acidified with 2N aq. HCl soln. and extracted with DCM (3×10 ml). The comb. org. phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a beige solid.

1. temperatureAfter cooling to r.t.
2. additionwas added
3. extractionthe mixture was extracted with AcOEt (2×)
4. dry with materiallayers were dried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customThe residue was partially purified by flashmaster (column: 25 g, flow: 30 mL/min, 25 fractions of 30 mL, AcOEt+10% MeOH)
8. customto yield a yellow oil
9. stirringThe mixture was stirred at 0° C. for 30 min
10. concentrationThe reaction mixture was concentrated in vacuo
11. customThe residue was partitioned between water and AcOEt
12. customThe layers were separated
13. extractionthe aq. phase was extracted with AcOEt (2×)
14. dry with materialphases were dried over MgSO4
15. filtrationfiltered
16. concentrationconcentrated in vacuo
17. additionwas added dropwise
18. additionUpon completion of the addition
19. customthe cooling bath was removed
20. stirringthe suspension was stirred at r.t. for 4 hours
21. customThe reaction was quenched with 1M aq. citric acid soln
22. customThe layers were separated
23. extractionThe aq. phase was extracted with DCM (3×)
24. dry with materialphases were dried over MgSO4
25. filtrationfiltered
26. concentrationconcentrated in vacuo
27. customThe residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 27 fractions of 30 mL, Heptane 100% to Heptane+20% AcOEt)
28. dissolutionThe residue was dissolved in THF (5 mL)
29. addition(5 mL) was added
30. stirringThe mixture was stirred at r.t. for 18 hours
31. customsolvent was removed in vacuo
32. extractionand extracted with DCM (3×10 ml)
33. dry with materialphases were dried over MgSO4
34. concentrationconcentrated in vacuo

ORD record

ord-68f6c1c9d8cb42af859c1bdb6f498ec7

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09255090B2