Iodine → HCID 90389278, compound

Temperature

0 °C

A solution of n-Butyllithium (2.5M in hexanes, 42.9 mL, 107 mmol) was added drop wise to a solution of freshly distilled 2,2,6,6-tetramethylpiperidine (18.11 mL, 107 mmol) in THF (220 mL) at −78° C. The solution was warmed to 0° C. for 30 minutes and then cooled again to −78° C. In a separate flask, a solution of 2-bromo-5-fluorobenzyl alcohol (10 g, 48.8 mmol) in THF (60 mL) was cooled to −78° C. and was transferred via cannula to the LiTMP solution. The resulting reaction mixture was stirred for 2 h at −78° C. Subsequently, a solution of iodine (14.86 g, 58.5 mmol) in THF (60 mL) was added dropwise and the reaction mixture was stirred 40 minutes before the reaction was quenched with saturated aqueous ammonium chloride at −78° C. After diluting with aqueous sodium thiosulfate and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous ammonium chloride, water, brine, and dried over sodium sulfate. The filtrate was concentrated in vacuo and the resulting crude product was taken up in THF (48 ml) and DMF (8 ml) and cooled to 0° C. Sodium hydride (60% in mineral oil, 0.341 g, 8.52 mmol) was added in one portion and after 15 minutes, 4-methoxybenzyl chloride (1.253 ml, 9.23 mmol) was added and the solution was stirred overnight at room temperature. The reaction mixture was cooled to 0° C. and quenched with 1N HCl. After dilution with water and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with aqueous lithium bromide solution, brine, and dried over sodium sulfate. The filtrate was concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography, eluting with 1:30 Et2O in heptane, to afford 1-bromo-4-fluoro-5-iodo-2-(((4-methoxybenzyl)oxy)methyl)benzene as a ˜2:1 mixture with 1-bromo-4-fluoro-2-(((4-methoxybenzyl)oxy)methyl)benzene. LC/MS (ESI+) m/z=472.9/474.8 (M+Na).

1. temperaturecooled again to −78° C
2. customThe resulting reaction mixture
3. stirringthe reaction mixture was stirred 40 minutes before the reaction
4. customwas quenched with saturated aqueous ammonium chloride at −78° C
5. additionAfter diluting with aqueous sodium thiosulfate and EtOAc
6. customthe layers were separated
7. extractionthe aqueous layer was extracted with EtOAc
8. washThe combined organic extracts were washed with saturated aqueous ammonium chloride, water, brine
9. dry with materialdried over sodium sulfate
10. concentrationThe filtrate was concentrated in vacuo
11. temperatureDMF (8 ml) and cooled to 0° C
12. stirringthe solution was stirred overnight at room temperature
13. temperatureThe reaction mixture was cooled to 0° C.
14. customquenched with 1N HCl
15. customAfter dilution with water and EtOAc, the layers were separated
16. extractionthe aqueous layer was extracted with EtOAc
17. washThe combined organic extracts were washed with aqueous lithium bromide solution, brine
18. dry with materialdried over sodium sulfate
19. concentrationThe filtrate was concentrated in vacuo
20. customto give the crude material
21. customThe crude material was purified by silica gel chromatography
22. washeluting with 1:30 Et2O in heptane

ORD record

ord-cdefdeb6ed9b4f29a05d8fea87f0bfa4

Source dataset

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09085576B2