5-Bromo-2-chloroanisole → Tert-butyl 4-(4-chloro-3-methoxyphenyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate

Temperature

-78 °C

To a solution of 5-bromo-2-chloro-anisole (1.613 g, 7.3 mmol) in THF (15 mL) at −78° C. was added n-butyl lithium (4.75 mL, 7.6 mmol, 1.6 M) dropwise over 15 min and the resulting solution was allowed to stir at −78° C. for 1 h. A solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (prepared in the manner described in International Patent Application WO 04/043965, 754 mg, 3.32 mmol) in THF (5 mL) was added dropwise via canula. The reaction was stirred for 2 h at −78° C. then allowed to warm to rt slowly over 30 min at which time the mixture was heated at 50° C. for 30 min. The reaction was cooled to rt, quenched by the addition of aq NH4Cl, diluted with water and extracted into EtOAc. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified via column chromatography (15% to 33% to 50% EtOAc/heptane to afford tert-butyl 4-(4-chloro-3-methoxyphenyl)-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (728 mg, 60% yield).

1. additionwas added dropwise via canula
2. stirringThe reaction was stirred for 2 h at −78° C.
3. temperatureto warm to rt slowly over 30 min at which time the mixture
4. temperaturewas heated at 50° C. for 30 min
5. temperatureThe reaction was cooled to rt
6. customquenched by the addition of aq NH4Cl
7. additiondiluted with water
8. extractionextracted into EtOAc
9. dry with materialThe combined organic extracts were dried over magnesium sulfate
10. filtrationfiltered
11. concentrationconcentrated
12. customThe residue was purified via column chromatography (15% to 33% to 50% EtOAc/heptane

ORD record

ord-5754e42a781244f2871f3c7d057395ed

Source dataset

uspto-grants-2011_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07985861B2