반응 #468895

반응 방정식

methyl iodide

lovastatin phenylboronate

pyrrolidine

n-Butyllithium

→

simvastatin phenylboronate

수율 98.4%

용매

THF

THF

반응 조건

후처리

1. 1
   온도The solution was maintained at this temperature for 30 minutes
2. 2
   workup.ADDITIONwas between −50 and −55° C. during the addition
3. 3
   기타quenched with 500 mL of 2M HCl at a temperature below 0° C
4. 4
   온도After warming to 20° C.
5. 5
   기타the layers were separated
6. 6
   추출the aqueuous layer was extracted with ethyl acetate
7. 7
   세척The combined organic layers were washed with 5% NaHSO3 solution
8. 8
   여과The solution was filtered through a Celite pad
9. 9
   농축concentrated

실험 절차

A 2L 3-necked flask was charged with pyrrolidine (56 mL, 0.67 mol) and dry THF (453 g) under a nitrogen atmosphere. n-Butyllithium (419 mL, 1.6 M hexane solution, 0.67 mol) was added dropwise at a temperature between −20 and −25° C. over a period of 1 hour. The solution was maintained at this temperature for 30 minutes and then cooled to −55 to −60° C. A solution of lovastatin phenylboronate (101.7 g, 0.20 mol) in 274.7 g of THF was cooled to a temperature of −50° C. and then added to the cold lithium pyrrolidide solution at a rate such that the internal temperature was between −50 and −55° C. during the addition. The reaction was held at this temperature for 4 hours and then methyl iodide (116.4 g, 0.82 mol) was added at a temperature below −55°C. The reaction was stirred for 13 hours at −15 to −20° C. and then quenched with 500 mL of 2M HCl at a temperature below 0° C. After warming to 20° C., the layers were separated and the aqueuous layer was extracted with ethyl acetate. The combined organic layers were washed with 5% NaHSO3 solution and deionized water. The solution was filtered through a Celite pad and concentrated to yield 102.8 g (98.4%) of crude simvastatin phenylboronate at >95% purity by HPLC. A portion of the above material (50.0 g) was charged into a nitrogen purged flask with acetonitrile (100 mL). The suspension was heated at 110° C. for 3 hours and then cooled to −5 to −10° C. for 1 hour. The product was filtered and washed with 25 mL of −5° C. acetonitrile and dried under vacuum to provide 43.7 g of simvastatin phenylboronate at >99% purity by HPLC.

출처