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0 °C

A stirred solution of 6.87 mL 2-bromomesitylene (44.78 mmol, 2.0 eq) in 44 mL THF was cooled to −45° C. 35.8 mL n-butyllithium in hexane (2.5 M, 89.56 mmol, 4.0 eq) were added within 20 min. The resulting white suspension was then allowed to warm to 0° C. within 2.5 h. At −10° C. the reaction mixture became a clear solution. Stirring was continued for an additional hour at 0° C. The solution was cooled to −10° C. and a solution of 5.00 g 4-(2-ethyl-[1,3]dioxan-2-yl)-2-methoxy-pyridine (22.39 mmol), as obtainable from Example 3, in 15 mL THF was added over 15 min under vigorous stirring. The resulting brown suspension was allowed to warm to 10° C. within 2.5 h. The cooling bath was then removed and stirring was continued at room temperature for an additional hour. The clear brown solution was then cooled to −23° C. and 5.19 mL DMF (67.17 mmol, 3.0 eq) were added. The mixture was allowed to slowly warm up to room temperature overnight. The reaction was quenched by addition of 100 mL saturated aqueous NH4Cl. After 15 min, 50 mL water were added. The mixture was extracted three times with 150 mL, in total with 450 mL TBME. The combined organic phases were washed two times with 300 mL, in total 600 mL brine, dried over 20 g Na2SO4 (30 min) and filtered. The filter cake was washed with 40 mL TBME. After evaporation of solvent in a rotary evaporator (40° C./10 mbar), the crude product (12.048 g, 214% by weight) was obtained as a brown oil which was then purified by silica gel filtration (97 g silica gel) using a gradient elution with 2.0 L heptane/ethyl acetate (30:1) and 1.4 L heptane/ethyl acetate (5:1). Evaporation to dryness of the second fraction in a rotary evaporator (40° C./10 mbar) yielded the title compound (3.832 g, 15.2 mmol, 68% by weight).

1. customAt −10° C.
2. waitwas continued for an additional hour at 0° C
3. temperatureThe solution was cooled to −10° C.
4. temperatureto warm to 10° C. within 2.5 h
5. customThe cooling bath was then removed
6. stirringstirring
7. waitwas continued at room temperature for an additional hour
8. temperatureThe clear brown solution was then cooled to −23° C.
9. temperatureto slowly warm up to room temperature overnight
10. customThe reaction was quenched by addition of 100 mL saturated aqueous NH4Cl
11. addition50 mL water were added
12. extractionThe mixture was extracted three times with 150 mL
13. washThe combined organic phases were washed two times with 300 mL
14. dry with materialin total 600 mL brine, dried over 20 g Na2SO4 (30 min)
15. filtrationfiltered
16. washThe filter cake was washed with 40 mL TBME
17. customAfter evaporation of solvent
18. customin a rotary evaporator (40° C./10 mbar)
19. customthe crude product (12.048 g, 214% by weight) was obtained as a brown oil which
20. filtrationwas then purified by silica gel filtration (97 g silica gel)
21. washa gradient elution with 2.0 L heptane/ethyl acetate (30:1) and 1.4 L heptane/ethyl acetate (5:1)
22. customEvaporation to dryness of the second fraction
23. customin a rotary evaporator (40° C./10 mbar)