Trifluoroacetic acid → HCID 10545451, compound

Temperature

50 °C

A toluene solution S)-2-{4-methoxy-2-[(2,2,2-trifluoro-ethylamino)-methyl]-benzyl}-succinic acid dimethyl ester (950 mL, 212 mmol) was placed in a 2 L round bottom flask and concentrated under rotary evaporation to a volume of 460 mL (to remove residual water). Toluene (450 mL) was added and the mixture was transferred to a 3 neck 2 L flask. The flask was fitted with reflux condenser, thermometer, nitrogen inlet/outlet, and stir bar. The mixture was de-gassed under a flow of nitrogen gas. The mixture was heated to 50° C. and trifluoroacetic acid (200 mmol, 22.8 g) was added over a 5 min period. The mixture was heated to reflux. After 2.5 h, HPLC analysis (Waters Cosmosil 4.6×150 mm, 60% CH3CN/40% 0.1% TFA, 220 nm, 0.5 mL/min) showed less than 0.2% (area %) of (S)-2-{4-methoxy-2-[(2,2,2-trifluoro-ethylamino)-methyl]-benzyl}-succinic acid dimethyl ester remaining. The mixture was cooled to 25° C. and was washed with 1×400 ml NaHCO3 solution (satd.), and 1×400 mL water. The solvent was removed by vacuum distillation. The residue was treated with hexane (800 ml) and was heated to reflux with rapid stirring. This resulted in a solution with some oily residue. Toluene (20 mL) was added and a clear solution was obtained. The mixture was allowed to cool to 25° C. with rapid stirring over a 1 hour period. The mixture was then cooled to 0-5° C. for 1 hour. The resulting solid was isolated by filtration, washed with hexane (70 mL) and air dried to provide the product as an off-white solid (64.4 g, 88%).

1. concentrationconcentrated under rotary evaporation to a volume of 460 mL (to remove residual water)
2. additionToluene (450 mL) was added
3. customThe flask was fitted
4. temperaturewith reflux condenser
5. customThe mixture was de-gassed under a flow of nitrogen gas
6. temperatureThe mixture was heated to reflux
7. temperatureThe mixture was cooled to 25° C.
8. washwas washed with 1×400 ml NaHCO3 solution (satd.), and 1×400 mL water
9. customThe solvent was removed by vacuum distillation
10. additionThe residue was treated with hexane (800 ml)
11. temperaturewas heated
12. temperatureto reflux with rapid stirring
13. customThis resulted in a solution with some oily residue
14. customa clear solution was obtained
15. temperatureto cool to 25° C.
16. stirringwith rapid stirring over a 1 hour period
17. temperatureThe mixture was then cooled to 0-5° C. for 1 hour
18. customThe resulting solid was isolated by filtration
19. washwashed with hexane (70 mL) and air
20. customdried

ORD record

ord-c4388361286c417ba61cddf394eea177

Source dataset

uspto-grants-2008_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07368566B2