Citric Acid → (2R,4S)-(2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinolin-4-yl)-carbamic acid benzyl ester

Temperature

-12 °C

A clean, dry and nitrogen gas purged flask was charged with (3R)-[3-(4-trifluoromethyl-phenylamino)-pentanoyl]-carbamic acid benzyl ester (11.51 g, 29.18 mmol) and 95% ethanol (80 mL) and the solution was cooled in an ice/acetone bath (˜−12° C.). Sodium borohydride (0.773 g, 20.4 mmol) was then added to the solution. The internal temperature of the reaction was −11.5° C. To the reaction flask was slowly added a solution of MgCl2.6H2O (6.23 g, 30.6 mmol, in 13 mL H2O). The internal temperature was maintained below −5° C. by adjusting the addition rate. Once all of the magnesium solution was added, the solution temperature was raised to 0° C. and stirred for 30 minutes. The reaction was then quenched by the addition of methylene chloride (115 mL), 1N hydrochloric acid (115 mL) and citric acid (14.02 g, 72.97 mmol). This bilayer was stirred at room temperature. After 3.75 hours, the cyclization reaction was found to be complete by HPLC analysis and the phases were separated. Water (58 mL) and citric acid (8.41 g, 43.77 mmol) were added to the organic layer and the mixture was stirred at room temperature for 45 minutes. The phases were separated and g-60 Darco® activated charcoal (1.52 g) (Atlas Powder Co., Wilmington, Del.) was added to the organic layer. After stirring for 45 minutes, the solution was filtered through Celite® and washed with methylene chloride (2×15 mL). The filtrate was then displaced with hexanes (approximately 350 mL) by distillation under atmospheric pressure and concentration of the mixture to a total volume of 230 mL. The mixture was stirred at room temperature for 14 h, filtered, and dried to afford 9.0872 g (82%) of the title compound.

1. customA clean, dry
2. customnitrogen gas purged flask
3. customwas −11.5° C
4. temperatureThe internal temperature was maintained below −5° C.
5. temperaturethe solution temperature was raised to 0° C.
6. stirringThis bilayer was stirred at room temperature
7. waitAfter 3.75 hours
8. customthe cyclization reaction
9. customthe phases were separated
10. stirringthe mixture was stirred at room temperature for 45 minutes
11. customThe phases were separated
12. additiong-60 Darco® activated charcoal (1.52 g) (Atlas Powder Co., Wilmington, Del.) was added to the organic layer
13. stirringAfter stirring for 45 minutes
14. filtrationthe solution was filtered through Celite®
15. washwashed with methylene chloride (2×15 mL)
16. distillationThe filtrate was then displaced with hexanes (approximately 350 mL) by distillation under atmospheric pressure and concentration of the mixture to a total volume of 230 mL
17. stirringThe mixture was stirred at room temperature for 14 h
18. filtrationfiltered
19. customdried

ORD record

ord-373f05465ba3423b9168395f4ab3f0fe

Source dataset

uspto-grants-2004_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06706881B2