Methyl iodide → 1-tert-Butyl 4-ethyl 4-methylpiperidine-1,4-dicarboxylate

Temperature

-20 °C

A 250-mL round bottom flask equipped with an overhead mechanical stirrer, addition funnel, N2-inlet and temperature probe was charged with diisopropylamine (7.31 g, 71.5 mmol) and tetrahydrofuran (22 g) then chilled to less than −15° C. (internal temperature). Hexyllithium (2.25 M in hexane: 21.8 g, 68.5 mmol) was carefully charged to the addition funnel. The hexyllithium solution was added through the addition funnel over 45 minutes with a maximum internal temperature of −17° C. The reaction was mixed for 1 hour at an internal temperature of approximately −15° C. to 0° C. The flask was equipped with another addition funnel and the toluene solution obtained from Example 7 (15.01 g, 58.33 mmol) was added through the addition funnel, followed by 4 g of tetrahydrofuran. The total addition time was 1 hour 45 minutes with a maximum internal temperature of −15° C. The solution was stirred at about −20° C. for 30 minutes. The flask was equipped with an addition funnel, which was charged with methyl iodide (9.3 g, 64-64 mmol) and tetrahydrofuran (3 g); this solution was added to the reaction mixture over 30 minutes, maintaining the internal temperature at no more than −15° C. After 30 minutes, the reaction was quenched into a chilled (˜5° C.) 2M HCl solution (prepared from 31 mL, water and 8 g of concentrated HCl) while maintaining the temperature below 10° C. The reaction flask was rinsed with toluene (10 mL), which was added to the quench flask. The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was rinsed with 17% NaCl solution (prepared by dissolving 2.5 g of NaCl in 15 g water). The tetrahydrofuran/toluene solution was used directly in the next step.

1. customA 250-mL round bottom flask equipped with an overhead mechanical stirrer, addition funnel, N2-inlet
2. temperaturethen chilled to less than −15° C. (internal temperature)
3. additionThe reaction was mixed for 1 hour at an internal temperature of approximately −15° C. to 0° C
4. customThe flask was equipped with another addition funnel
5. additionThe total addition time
6. customThe flask was equipped with an addition funnel
7. additionthis solution was added to the reaction mixture over 30 minutes
8. temperaturemaintaining the internal temperature at no more than −15° C
9. waitAfter 30 minutes
10. customthe reaction was quenched into
11. temperaturea chilled (˜5° C.) 2M HCl solution (prepared from 31 mL, water and 8 g of concentrated HCl)
12. temperaturewhile maintaining the temperature below 10° C
13. washThe reaction flask was rinsed with toluene (10 mL), which
14. additionwas added to the quench flask
15. customThe mixture was transferred to a separatory funnel
16. customthe layers were separated
17. washThe organic layer was rinsed with 17% NaCl solution (prepared by dissolving 2.5 g of NaCl in 15 g water)

ORD record

ord-209e5daeb74640d99949533234adbd36

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09260411B2