2-Bromopyridine → (RS)-N-((S)-Cyclopentyl(pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide

A solution of 2-bromopyridine (11.8 mL, 19.5 g, 123.5 mmolin dry THF (50 mL) was added carefully to i-PrMgCl.LiCl (1.3 M in THF, 95.0 mL, 123.5 mmol). The resulting solution was stirred at rt for 3 h after which it was added dropwise, over 45 min, to a −48° C. solution of (R,E)-N-(cyclopentylmethylene)-2-methylpropane-2-sulfinamide (19.1 g, 95.0 mmol) in dry CH2Cl2 (250 mL). The resulting mixture was stirred at −48° C. for 1 h before being allowed to slowly warm up to rt over 16 h. The reaction was quenched by addition of saturated aq NH4Cl (200 mL). H2O (200 mL) was added and the mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine (150 mL). The organic layer was dried (Na2SO4) and was concentrated under reduced pressure yielding the crude product (28.6 g, 5:1 d.r. (RS,S)—(RS,R)) as a clear red oil. The crude product was purified by repeated flash chromatography on silica gel using 1:19 MeOH-EtOAc as eluent in combination with trituration of the obtained solids with cyclohexane which eventually gave the pure product (8.80 g, 33%) as a white solid; 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (d, J=4.5 Hz, 1H), 7.63 (dt, J=1.0, 7.5 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 7.16 (dd, J=4.5, 7.5 Hz, 1H), 4.26 (dd, J=5.0, 8.5 Hz, 1H), 3.95 (d, J=5.0 Hz, 1H), 2.44-2.31 (m, 1H), 1.94-1.83 (m, 1H), 1.68-1.44 (m, 5H), 1.44-1.32 (m, 1H), 1.30-1.17 (m, 1H), 1.13 (s, 9H).

1. stirringThe resulting mixture was stirred at −48° C. for 1 h
2. temperatureto slowly warm up to rt over 16 h
3. customThe reaction was quenched by addition of saturated aq NH4Cl (200 mL)
4. additionH2O (200 mL) was added
5. extractionthe mixture was extracted with CH2Cl2 (3×100 mL)
6. washThe combined organic extracts were washed with brine (150 mL)
7. dry with materialThe organic layer was dried (Na2SO4)
8. concentrationwas concentrated under reduced pressure
9. customyielding the crude product (28.6 g, 5:1 d.r. (RS,S)—(RS,R)) as a clear red oil
10. customThe crude product was purified by repeated flash chromatography on silica gel using 1:19 MeOH-EtOAc as eluent in combination with trituration of the obtained solids with cyclohexane which

ORD record

ord-2a91fc619fa4433a9e247c5190eadca0

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08980934B2