反应详情

温度

-40 °C

A solution of DIPA (4 M, 270 mL, 1080 mmol) in THF (900 mL) was cooled to −65° C. and HexLi (2.1 M, 505 mL, 1061 mmol) was added dropwise over 15 min maintaining the internal temp <−55° C. Upon completion the reaction mixture was warmed up to −40° C. where it was stirred 30 min. To the resulting solution of LDA was added 4-bromo-2-methylbenzoic acid (90 g, 419 mmol) slowly (over 15 min) as a solution in THF (400 mL) during which time the reaction mixture turned into a bright red suspension. The reaction mixture was stirred for 30 min at −40° C. and then warmed to 15° C. at which point paraformaldehyde (50.3 g, 1674 mmol) was added in 3 portions as a solid keeping the internal temperature (ice water bath) below <18° C. Stirring was then continued at room temperature for 1 hour during which time the mixture turned an orange-yellow colour. After a second hour of stirring, the vessel was immersed in an ice water bath and 3N HCl (650 mL) was added at such a rate to keep the internal temperature less than 30° C. The contents of the reaction vessel was subsequently transferred to a separatory funnel where it was extracted 3× 400 mL EtOAc and the combined organic phases were then concentrated to ˜800 mL total volume. To this was added Amberlyst 15 resin (12 g) and the resulting mixture stirred at 48° C. overnight (˜14 h). HPLC analysis the following morning indicated that cyclization to the desired halolactone was nearly complete. The resin was removed by filtration and the yellow solution concentrated to ˜200 mL total volume at which point the desired product began to crystallize as a yellow solid which was then collected by filtration. The cake was subsequently washed with MTBE (2× 80 mL) to give the first crop of product. Additional material was salvaged by washing the collected supernatant 2× with 200 mL 10% K2CO3,aq followed by 200 mL 1M H3PO4. After concentration to ˜100 mL the crystallized material was collected by filtration, washed with MTBE and then combined with the first crop of and dried to afford the title compound. LCMS: m/z 227, 229 (M+1)+;

1. temperaturemaintaining the internal temp <−55° C
2. stirringThe reaction mixture was stirred for 30 min at −40° C.
3. additionwas added in 3 portions as a solid
4. custombelow <18° C
5. stirringStirring
6. waitwas then continued at room temperature for 1 hour during which time
7. stirringAfter a second hour of stirring
8. customthe vessel was immersed in an ice water bath
9. customthe internal temperature less than 30° C
10. customThe contents of the reaction vessel was subsequently transferred to a separatory funnel
11. extractionwhere it was extracted 3× 400 mL EtOAc
12. concentrationthe combined organic phases were then concentrated to ˜800 mL total volume
13. additionTo this was added Amberlyst 15 resin (12 g)
14. stirringthe resulting mixture stirred at 48° C. overnight (˜14 h)
15. customThe resin was removed by filtration
16. concentrationthe yellow solution concentrated to ˜200 mL total volume at which point the desired product
17. customto crystallize as a yellow solid which
18. filtrationwas then collected by filtration
19. washThe cake was subsequently washed with MTBE (2× 80 mL)
20. customto give the first crop of product
21. washby washing the collected supernatant 2× with 200 mL 10% K2CO3,aq
22. concentrationAfter concentration to ˜100 mL the crystallized material
23. filtrationwas collected by filtration
24. washwashed with MTBE
25. customdried