反应详情

温度

50 °C

3-Hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid (5.00 g, 22.10 mmol) and tetra n-butyl phosphonium chloride (6.53 g, 22.1 mmol) were suspended in 2-methyltetrahydrofuran (25 ml, 5 vol rel. to the benzoic acid) and 22 mL water at ambient temperature under nitrogen. Solid potassium carbonate (27.98 g, 202.4 mmol) was charged portionwise with vigorous mechanical stirring. At the end of addition KOH liquor (2.46 g 50% wt/wt in water, 22.1 mmol) was added before the biphasic slurry was heated to 50° C. Once the temperature had stabilised, 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (4.586 g, 23.21 mmol) was charged portionwise over 40 minutes and the mixtures was stirred over night under nitrogen at 50° C. The phases were split and the lower aqueous phase was run off 25 ml of toluene and 50 mL water were added to the remaining dark red organic phase. The pH of the aqueous phase was then adjusted to 7.0 using conc. hydrochloric acid. The jacket temperature was adjusted to 20° C. and the phases were separated again (the lower aqueous phase was run off and retained; the upper organic phase was discarded). The aqueous phase was washed with more toluene (25 mL). After phase separation the toluene phase was removed again. The pH of the retained aqueous phase was adjusted to 2.1 using 5M hydrochloric acid solution (7.1 mL). Isopropyl acetate (34.9 g) was charged and the jacket temperature was raised to 80° C. Equilibration was performed with the jacket temperature set to 80° C. After phase split the lower aqueous phase was run off again and back-extracted with more isopropyl acetate (17.4 g). The organic phases were combined and homogenised at 80° C. before being washed with water (10 mL). The organic phase was dried by azeotropic distillation under slight vacuum at constant batch volume (batch partially crystallised). The suspension was cooled to 0° C. over 13.5 h and the batch was isolated by filtration followed by a cake-wash with isopropyl acetate (17.4 g). After drying at 40° C. in a vacuum oven overnight 5.25 g at 96% strength (59% corrected yield) of the desired product was obtained as white solid.

1. customat ambient temperature
2. additionwas added before the biphasic slurry
3. customThe phases were split
4. additionwere added to the remaining dark red organic phase
5. customwas adjusted to 20° C.
6. customthe phases were separated again (the lower aqueous phase
7. washThe aqueous phase was washed with more toluene (25 mL)
8. customAfter phase separation the toluene phase
9. customwas removed again
10. additionIsopropyl acetate (34.9 g) was charged
11. temperaturethe jacket temperature was raised to 80° C
12. customset to 80° C
13. customAfter phase split the lower aqueous phase
14. extractionback-extracted with more isopropyl acetate (17.4 g)
15. stirringhomogenised at 80° C.
16. washbefore being washed with water (10 mL)
17. customThe organic phase was dried by azeotropic distillation under slight vacuum at constant batch volume (batch
18. custompartially crystallised)
19. temperatureThe suspension was cooled to 0° C. over 13.5 h
20. customthe batch was isolated by filtration
21. washa cake-wash with isopropyl acetate (17.4 g)
22. dry with materialAfter drying at 40° C. in a vacuum oven overnight 5.25 g at 96% strength (59% corrected yield) of the desired product
23. customwas obtained as white solid