Hydrochloric Acid → 6-bromo-3,4-dihydro-1H-2-benzopyran-1-one

Temperature

-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 minutes maintaining the internal temp <−55° C. Upon completion the reaction mixture was warmed up to −40° C. where it was stirred for 30 minutes. To the resulting solution of LDA was added 4-bromo-2-methylbenzoic acid (90 g, 419 mmol) slowly (over 15 minutes) 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 minutes 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 color. 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 were 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 ion exchange 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 and dried to afford the title compound.

1. temperaturemaintaining the internal temp <−55° C
2. stirringThe reaction mixture was stirred for 30 minutes 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 were 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 ion exchange 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

ORD record

ord-ee8c4db7ed4c41a2b68f6051615ba4f9

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09139585B2