反应详情

温度

20 °C

To a suspension of LiOH monohydrate (1.06 g, 25.2 mmol) in THF (20 mL) at 0° C. to 5° C. was added 3.78 g (22.2 mmol) of N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine, followed by a 5 mL THF rinse. To this solution was added a solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) in 20 mL of THF. Following a 5 mL THF rinse, 0.5 mL of water was added, and the reaction mixture was allowed to warm to 20° C. with stirring. After 6 hours, the reaction was cooled to 10° C. and quenched with water (55 mL). The THF was removed under reduced pressure, MTBE (50 mL) was added, and the biphasic solution was adjusted to pH 9.0 with 4 N HCl. The layers were separated and the aqueous layer was washed with an additional 50 mL of MTBE. The aqueous layer was sitrred with 130 mL of toluene and adjusted to pH 3 with 4 N HCl, and the phases were separated. The aqueous, product-containing layer was stirred with 50 mL of toluene and adjusted to pH=3.0 with 4N HCl. The aqueous layer was separated and extracted once more with 50 mL of toluene. The combined organic extracts were concentrated in vacuo. The residue obtained was redissolved in toluene, filtered and rinsed with toluene (approx. 50 mL total). The combined filtrates were concentrated in vacuo to an oil. Toluene (25 mL) and heptane (25 mL) were added and warmed to 50° C. The clear solution was allowed to cool until cloudy and then was seeded with N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-Valine. The resulting slurry was stirred for at least 12 hours and the product was collected by filtration and washed with heptane (5 mL). The resulting solid was dried in a vacuum oven at 50° C. to yield the desired product as a white powder.

1. washrinse
2. washrinse
3. addition0.5 mL of water was added
4. temperaturethe reaction was cooled to 10° C.
5. customquenched with water (55 mL)
6. customThe THF was removed under reduced pressure, MTBE (50 mL)
7. additionwas added
8. customThe layers were separated
9. washthe aqueous layer was washed with an additional 50 mL of MTBE
10. customthe phases were separated
11. additionThe aqueous, product-containing layer
12. stirringwas stirred with 50 mL of toluene
13. customThe aqueous layer was separated
14. extractionextracted once more with 50 mL of toluene
15. concentrationThe combined organic extracts were concentrated in vacuo
16. customThe residue obtained
17. filtrationfiltered
18. washrinsed with toluene (approx. 50 mL total)
19. concentrationThe combined filtrates were concentrated in vacuo to an oil
20. additionToluene (25 mL) and heptane (25 mL) were added
21. temperaturewarmed to 50° C
22. temperatureto cool until cloudy
23. stirringThe resulting slurry was stirred for at least 12 hours
24. filtrationthe product was collected by filtration
25. washwashed with heptane (5 mL)
26. customThe resulting solid was dried in a vacuum oven at 50° C.