反应详情

A 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 1390 mL of dry THF and 389.3 g of potassium ethyl malonate. MgCl2 (217.8 g) was added in three equal portions so that the internal temperature was less than 50° C. The resulting grey slurry was heated to 55° C. to 60° C. using a temperature controlled heating mantle. The mixture was stirred at 55° C. to 60° C. for 5 hours. A 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 680 mL of dry THF and 286.8 g of 1,1′-carbonyldiimidazole (CDI). The addition funnel was charged portion-wise with a solution of 219.9 g of (2R,3R)-2,3-dimethyl-hexanoic acid in 350 mL of dry THF. The entire dimethyl-hexanoic acid acid/THF solution was added dropwise to the stirred CDI/THF suspension at such a rate so as to control the evolution of CO2 and to maintain the reaction at a temperature of 20° C. to 25° C. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry became a pale yellow solution. After the 5-hour reaction time, the malonate/MgCl2 reaction mixture was cooled to 20° C. to 25° C. and the condenser was replaced with a 1 L addition funnel. The addition funnel was charged portion-wise with the dimethylhexanoic acid/CDI/THF reaction mixture. This entire reaction mixture was added dropwise to the stirred malonate/MgCl2/THF reaction mixture over about 10 minutes. After the addition was completed, the reaction mixture was heated to 35° C. to 40° C. Some effervescence was noted. The reaction mixture was stirred at 35° C. to 40° C. for 16 hour. The reaction mixture was cooled to 20° C. to 25° C. A 12 L 3-neck round bottom flask, equipped with a mechanical stirrer and thermometer, was charged with 3060 mL of 2N aq. HCl. The reaction mixture (a grey suspension) was added portion-wise to the aq. HCl solution while maintaining an internal temperature of 20° C.–25° C. The reaction temperature was moderated with an ice/water bath; the reaction mixture pH was about 1. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 2 hours. The reaction mixture was subsequently charged with 4000 mL of EtOAc and was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with 2000 mL of EtOAc. The combined organic extract was washed sequentially with: 1N aq. HCl (2×1 500 mL); 1000 mL of water (incomplete phase separation); half saturated aq. Na2CO3 (2×1500 mL); 1000 mL water; and brine (2×1000 mL). (The aqueous base wash removed unreacted malonate ester-acid.) The straw colored organic solution was concentrated under vacuum (35° C.–40° C.) to give a cloudy, pale yellow oil with some white solid present. The oil was redissolved in 1500 mL of n-heptane and was filtered. The filtrate was concentrated under vacuum (40° C.–45° C.) to give 327 g of the titled compound as a pale yellow oil: 1H NMR (400 MHz, CHLOROFORM-D) d ppm 0.82 (t, J=7.1 Hz, 3 H), 0.85 (d, J=6.8 Hz, 3 H), 0.99 (d, J=7.1 Hz, 3 H), 1.20 (t, J=7.3 Hz, 3 H), 2.42–2.49 (m, 1 H), 3.39 (s, 2 H) 4.12 (q, J=7.16 Hz, 3 H). GC Chemical purity: 96.24%.

1. customA 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet
2. customwas less than 50° C
3. temperatureThe resulting grey slurry was heated to 55° C. to 60° C.
4. temperaturecontrolled heating mantle
5. customA 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet
6. temperatureto maintain
7. customthe reaction at a temperature of 20° C. to 25° C
8. additionthe addition
9. stirringthe reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry
10. customAfter the 5-hour reaction time
11. temperaturewas cooled to 20° C. to 25° C.
12. additionthe condenser was replaced with a 1 L addition funnel
13. additionThe addition funnel was charged portion-wise
14. customThis entire reaction mixture
15. additionAfter the addition
16. temperaturethe reaction mixture was heated to 35° C. to 40° C
17. stirringThe reaction mixture was stirred at 35° C. to 40° C. for 16 hour
18. temperatureThe reaction mixture was cooled to 20° C. to 25° C
19. customA 12 L 3-neck round bottom flask, equipped with a mechanical stirrer
20. temperaturewhile maintaining an internal temperature of 20° C.–25° C
21. customThe reaction temperature was moderated with an ice/water bath
22. additionthe addition
23. stirringthe reaction mixture was stirred at 20° C. to 25° C. for 2 hours
24. stirringwas stirred for 5 minutes
25. customThe phases were separated
26. extractionthe aqueous phase was extracted with 2000 mL of EtOAc
27. extractionThe combined organic extract
28. washwas washed sequentially with: 1N aq. HCl (2×1 500 mL)
29. wash(The aqueous base wash
30. customremoved unreacted malonate ester-acid
31. concentration) The straw colored organic solution was concentrated under vacuum (35° C.–40° C.)
32. customto give a cloudy, pale yellow oil with some white solid present
33. filtrationwas filtered
34. concentrationThe filtrate was concentrated under vacuum (40° C.–45° C.)