Lithium hexamethyldisilazane → (R)-4-benzyl-3-[2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one

온도

-75 °C

Stir a mixture of (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (345 g, 1.33 mol) and THF (1.8 L) in a 12 L 3-neck round bottom flask, with internal temperature probe/nitrogen inlet and addition funnel, under a nitrogen atmosphere and cool to −75° C. Transfer 1 M LiHMDS (1.6 L) to the addition funnel and add at a rate such that the internal temperature does not reach above −60° C. After the addition is complete, allow the reaction to stir at −25° C. for 30 min then cool to about −60° C. At this point add solid 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzene portionwise over 5 min. After the addition is complete, transfer the reaction vessel to a −10° C. acetone bath and maintain the internal reaction temperature below 10° C. for 1 hr. Cool the mixture to 0° C. then quench with 2 L aqueous 1N hydrochloric acid. Transfer the mixture to a 22 L separatory funnel and dilute with 2.5 L water and 2 L ether. Separate the layers and extract the aqueous layer with ether. Dry the combined organic phase over anhydrous magnesium sulfate, filter and concentrate to 800 g of a thick oil. Purify by silica gel chromatography using hexanes:ethyl acetate to obtain 597 g, (86%) of a colorless oil.

1. additionwith internal temperature probe/nitrogen inlet and addition funnel
2. additionadd at a rate such that the internal temperature
3. customdoes not reach above −60° C
4. additionAfter the addition
5. customthe reaction
6. stirringto stir at −25° C. for 30 min
7. temperaturethen cool to about −60° C
8. additionAfter the addition
9. customto a −10° C.
10. temperaturemaintain the internal reaction temperature below 10° C. for 1 hr
11. temperatureCool the mixture to 0° C.
12. customthen quench with 2 L aqueous 1N hydrochloric acid
13. additionTransfer the mixture to a 22 L separatory funnel and dilute with 2.5 L water and 2 L ether
14. customSeparate the layers
15. extractionextract the aqueous layer with ether
16. dry with materialDry the combined organic phase over anhydrous magnesium sulfate
17. filtrationfilter
18. concentrationconcentrate to 800 g of a thick oil
19. customPurify by silica gel chromatography

ORD 기록

ord-4af5c767445b423ea0b3c873eb20bfd4

출처 데이터셋

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08088776B2