Dimethyl Disulfide → tert-butyl 4-[(1R,2R)-2-({[5-(methylthio)pyridin-2-yl]methoxy}methyl)cyclopropyl]piperidine-1-carboxylate

Temperature

-78 °C

To a solution of the aryl bromide from step B (680 mg, 1.60 mmol) dissolved in THF (10.7 mL) cooled at −78° C. was added N-butyllithium in hexanes (1.5 M, 1.12 mL, 1.68 mmol). After 10 min, dimethyldisulfide (0.16 mL, 1.76 mmol) was added. At 45 min, the reaction was quenched at −78° C. with saturated aqueous NH4Cl (2 mL). The mixture was warmed to room temperature, diluted with EtOAc and washed with H2O (1×) and saturated aqueous NaCl (1×). The aqueous was back-extracted with EtOAc (3×), and the combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to yield a crude oil that was purified by silica gel column chromatography (10-70%, EtOAc-hexanes) to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J 2.0 Hz, 1H), 7.62 (dd, J 8.0 & 2.0 Hz, 1H), 7.39 (d, J 8.0 Hz, 1H), 4.68 (d, J 13.5 Hz, 1H), 4.59 (d, J 13.5 Hz, 1H), 4.18-3.98 (br m, 2H), 3.66-3.60 (m, 1H), 3.57-3.51 (m, 1H), 2.75-2.58 (m, 2H), 2.53 (s, 3H), 1.88-1.82 (m, 1H), 1.77-1.69 (m, 1H), 1.47 (s, 9H), 1.37-1.21 (m, 3H), 0.98-0.90 (m, 1H), 0.79-0.68 (m, 2H), 0.07-0.03 (m, 1H).

1. waitAt 45 min
2. customthe reaction was quenched at −78° C. with saturated aqueous NH4Cl (2 mL)
3. temperatureThe mixture was warmed to room temperature
4. additiondiluted with EtOAc
5. washwashed with H2O (1×) and saturated aqueous NaCl (1×)
6. extractionThe aqueous was back-extracted with EtOAc (3×)
7. dry with materialthe combined organic layer was dried over Na2SO4
8. filtrationfiltered
9. customevaporated in vacuo
10. customto yield a crude oil that
11. customwas purified by silica gel column chromatography (10-70%, EtOAc-hexanes)

ORD record

ord-7f69be2bf6574d30a6c4d4aa3f37c360

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09006228B2