Tetrahydrofuran → HCID 10335345, compound

A clean, dry, 1 liter 4 neck round bottom flask equipped with mechanical stirring, nitrogen, temperature probe, and a dry ice/acetone bath, was charged with the product from step A (45.2 gr 0.198 moles) and N,N-dimethylformamide (271 ml). The pot was cooled below −60° C. and then lithium hexamethyldisilizane, 1 molar in tetrahydrofuran (198 ml 0.198 moles), was added while keeping the temperature below −60° C. After the addition was complete, the pot was further cooled to below −70° C. and stirred for 1 hour. While stirring, a solution of N-bromosuccinimide (35.24 g 0.198 moles) and N,N-dimethylformamide (105 ml), were stirred in a separate 500 ml round bottomed flask under nitrogen. After the one hour stir at −70° C., the solution of N-bromosuccinimide and N,N-dimethylformamide was slowly added to the anion keeping the temperature below −70° C. This temperature was critical to insure proper selectivity. After the addition was complete, the pot was stirred for one hour below −70° C. The batch was warmed to room temperature and quenched into methylene chloride (452 ml) and 1N sodium hydroxide (452 ml). The extraction was repeated with a second aliquot of methylene chloride (135 ml), and the combined organic layers washed with a second 1N sodium hydroxide (452 ml) wash. The organic layer was washed with saturated brine solution (452 ml), and dried over magnesium sulfate (50 gr). The magnesium sulfate was filtered off, washed with methylene chloride (135 ml) and the filtrate and wash combined for concentration. The methylene chloride was concentrated/displaced with isopropyl ether (226 ml) to a temperature of 42° C. A thick slurry formed upon cooling. The solids were granulated at 20 to 25° C. for two hours, filtered, washed with isopropyl ether (50 ml), and dried to afford 53.0 gr of light yellow solids, 96.4% purity (HPLC), 87% of theory.

1. customA clean, dry
2. custom1 liter 4 neck round bottom flask equipped with mechanical stirring, nitrogen, temperature probe, and a dry ice/acetone bath
3. temperatureThe pot was cooled below −60° C.
4. customthe temperature below −60° C
5. additionAfter the addition
6. temperaturethe pot was further cooled to below −70° C.
7. stirringWhile stirring
8. stirringAfter the one hour stir at −70° C.
9. customthe temperature below −70° C
10. additionAfter the addition
11. stirringthe pot was stirred for one hour below −70° C
12. customquenched into methylene chloride (452 ml) and 1N sodium hydroxide (452 ml)
13. extractionThe extraction
14. washthe combined organic layers washed with a second 1N sodium hydroxide (452 ml)
15. washwash
16. washThe organic layer was washed with saturated brine solution (452 ml)
17. dry with materialdried over magnesium sulfate (50 gr)
18. filtrationThe magnesium sulfate was filtered off
19. washwashed with methylene chloride (135 ml)
20. washthe filtrate and wash
21. concentrationcombined for concentration
22. customwas concentrated/displaced with isopropyl ether (226 ml) to a temperature of 42° C
23. customA thick slurry formed
24. temperatureupon cooling
25. waitThe solids were granulated at 20 to 25° C. for two hours
26. filtrationfiltered
27. washwashed with isopropyl ether (50 ml)
28. customdried

ORD record

ord-5dcc12e2bdf644b88797a08db42c4a8e

Source dataset

uspto-grants-2007_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07259171B2