反应详情

A slurry of carbidopa monohydrate (20.0 g, 82 mmol), sodium bicarbonate (7.57 g, 90 mmol), water (200 mL), and THF (100 mL) was cooled to 5° C. to 10° C. and N-(benzyloxycarbonyloxy)succinimide (20.4 g, 82 mmol) was added. The mixture was warmed to ambient temperature and became a nearly homogeneous solution over 5 hours, when LC-MS showed nearly complete reaction. The solution was diluted with MTBE (100 mL), the layers separated, and organic layer extracted with saturated aqueous NaHCO3 (100 mL). The aqueous layers were acidified with 2 N HCl (160 mL) and the acidic aqueous layer was extracted with MTBE (2×100 mL). During the second back-extraction, a small amount of product began to precipitate. The combined organic layers were washed with brine (20 mL) and residual solid rinsed out of the separatory funnel with MTBE (20 mL). The resulting mixture was concentrated to 43 g total mass and 10% THF/MTBE (60 mL) was added. The mixture was too thick to stir, so additional MTBE (60 mL to 6 vol 5% THF/MTBE) was added. The resulting white slurry was then heated to 50° C. The slurry was cooled to ambient temperature over one hour and then stirred for 14 hours. The white solid was filtered, washed with 5% THF/MTBE (20 mL), and dried in a vacuum oven (50° C.), giving (S)-2-(2-((benzyloxy)carbonyl)-hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid compound with THF (4:3) (31.1 g, 71.9 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J=9.0 Hz, 2H), 8.18 (br s, 1H), 7.49-7.17 (m, 5H), 6.59 (dd, J=5.0, 3.0 Hz, 2H), 6.44 (dd, J=8.0, 2.0 Hz, 1H), 5.04 (s, 2H), 2.73 (d, J=13.4 Hz, 1H), 2.59 (d, J=13.3 Hz, 1H), 1.07 (s, 3H); MS (ESI) m/z 361 [M+H]+.

1. customover 5 hours
2. customreaction
3. customthe layers separated
4. extractionorganic layer extracted with saturated aqueous NaHCO3 (100 mL)
5. extractionthe acidic aqueous layer was extracted with MTBE (2×100 mL)
6. extractionDuring the second back-extraction
7. customto precipitate
8. washThe combined organic layers were washed with brine (20 mL) and residual solid
9. washrinsed out of the separatory funnel with MTBE (20 mL)
10. concentrationThe resulting mixture was concentrated to 43 g total mass and 10% THF/MTBE (60 mL)
11. additionwas added
12. additionso additional MTBE (60 mL to 6 vol 5% THF/MTBE) was added
13. temperatureThe resulting white slurry was then heated to 50° C
14. temperatureThe slurry was cooled to ambient temperature over one hour
15. stirringstirred for 14 hours
16. filtrationThe white solid was filtered
17. washwashed with 5% THF/MTBE (20 mL)
18. customdried in a vacuum oven (50° C.)