Water → (r)-2-(4-Fluoro-1h-indol-1-yl)propanoic acid

온도

2.5 °C

To a cooled (0-5° C.) solution of 4-fluoro-indole (44.2 g, 327 mmol) in dry DMF (400 mL) was added sodium hydride (55-65% dispersion in mineral oil, 36 g, 817 mmol) in portions. The resulting suspension was stirred at 0-5° C. for 20 minutes. (2S)-(−)-2-Bromopropionic acid (31.8 mL, 343 mmol) was added dropwise. During the addition, the temperature was kept below 10° C. by cooling in an ice-bath. Upon completion of addition, the mixture was stirred at RT for 2 hours. The mixture was poured into water (1300 mL), and the aqueous solution was washed with heptanes (400 mL) and EtOAc (2×400 mL). The aqueous layer was acidified with concentrated aqueous HCl solution (85 mL, pH<1), and extracted with EtOAc (2×400 mL). The combined organic layers were washed with 1 N aq. HCl solution (2×300 mL) and with a saturated aqueous NaCl solution (300 mL). The solution was dried over sodium sulfate, filtered, and evaporated to dryness to afford a yellow oil (67.6 g, 99%, 82% ee). This oil (67.6 g, 323 mmol) was dissolved in 200 mL n-butyl acetate and (S)-L-(−)-α-methylbenzylamine (41.1 mL, 323 mmol) was added to the warm (50° C.) solution. The mixture was left crystallizing over the weekend. The formed solid was collected by filtration and washed with butyl acetate and heptanes (2×) (68.7 g, 91% ee). This material was recrystallized twice from 500 mL water/15% ethanol (1st recr.: 95% ee, 2nd recr.: 97.5% ee). This material was dissolved in EtOAc (300 mL) and washed with 1 N aqueous HCl (2×200 mL) and saturated aqueous NaCl solution (200 mL), dried over sodium sulfate, filtered, and evaporated to dryness giving (2R)-2-(4-fluoro-indol-1-yl)-propionic acid (18.7 g, 28%) as a greenish oil (purity: 97.5%).

1. additionDuring the addition
2. customwas kept below 10° C.
3. temperatureby cooling in an ice-bath
4. additionUpon completion of addition
5. stirringthe mixture was stirred at RT for 2 hours
6. washthe aqueous solution was washed with heptanes (400 mL) and EtOAc (2×400 mL)
7. extractionextracted with EtOAc (2×400 mL)
8. washThe combined organic layers were washed with 1 N aq. HCl solution (2×300 mL) and with a saturated aqueous NaCl solution (300 mL)
9. dry with materialThe solution was dried over sodium sulfate
10. filtrationfiltered
11. customevaporated to dryness
12. customto afford a yellow oil (67.6 g, 99%, 82% ee)
13. temperaturewarm (50° C.) solution
14. waitThe mixture was left
15. customcrystallizing over the weekend
16. filtrationThe formed solid was collected by filtration
17. washwashed with butyl acetate and heptanes (2×) (68.7 g, 91% ee)
18. customThis material was recrystallized twice from 500 mL water/15% ethanol (1st recr.: 95% ee, 2nd recr.: 97.5% ee)
19. dissolutionThis material was dissolved in EtOAc (300 mL)
20. washwashed with 1 N aqueous HCl (2×200 mL) and saturated aqueous NaCl solution (200 mL)
21. dry with materialdried over sodium sulfate
22. filtrationfiltered
23. customevaporated to dryness

ORD 기록

ord-7bcebbbff55b4685b1eaa33b79d8878a

출처 데이터셋

uspto-grants-2010_09

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US07799822B2