反应详情

A solution of 2-isopropylthiazole-4-carboxylic acid (12 g) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride [WuXi PharmaTech] (20 g) in 2-methyltetrahydrofuran (140 mL) was cooled in ice-water and treated with triethylamine (47 mL), followed by T3P (1.6M in THF, 54 mL). The mixture was allowed to warm to RT and was stirred for 1 h. Water (140 mL) was added with stirring, then the phases were separated. The organic phase was washed with water (80 mL), and then concentrated to a volume of (˜100 mL) under reduced pressure using a temperature of <30° C. IPA (75 mL) was added, and the mixture was concentrated to a volume of (˜100 mL). More IPA (75 mL) was added, and the mixture was again concentrated to a volume of (˜100 mL). A solution of hydrogen chloride in IPA (˜6M, 81 mL) was added with cooling in ice-water, then the mixture was warmed to 40° C. and stirred for 3.5 h. The mixture was cooled to RT, diluted with MTBE (34 mL) and stirred for 30 min. The resulting precipitated solid was removed by filtration and dried in a vacuum oven at 55° C. overnight. Yield 20.5 g.

1. stirringwith stirring
2. customthe phases were separated
3. washThe organic phase was washed with water (80 mL)
4. concentrationconcentrated to a volume of (˜100 mL) under reduced pressure
5. customa temperature of <30° C
6. additionIPA (75 mL) was added
7. concentrationthe mixture was concentrated to a volume of (˜100 mL)
8. additionMore IPA (75 mL) was added
9. concentrationthe mixture was again concentrated to a volume of (˜100 mL)
10. additionA solution of hydrogen chloride in IPA (˜6M, 81 mL) was added
11. temperaturewith cooling in ice-water
12. temperaturethe mixture was warmed to 40° C.
13. stirringstirred for 3.5 h
14. temperatureThe mixture was cooled to RT
15. additiondiluted with MTBE (34 mL)
16. stirringstirred for 30 min
17. customThe resulting precipitated solid
18. customwas removed by filtration
19. customdried in a vacuum oven at 55° C. overnight