Triethylamine → HCID 68503961, compound

To 65C (10 mmol) in CH2Cl2 (100 mL) at −15° C. was added Et3N (1.4 mL, 10 mmol) followed by TiCl4 (1.0 M in CH2Cl2, 20 mL, 20 mmol). The mixture was stirred from −15° C. to rt over 3.0 h before it was quenched with sat. K2CO3 (100 mL) at 0° C. and stirred at rt for 1.0 h. Methylene chloride was removed under vacuum and the crude was diluted with EtOAc. The mixture was filtered through a pad of wet Celite®, extracted with EtOAc (3×40 mL). The organic layer was washed with water, dried over Na2SO4. A small portion of the dried organic layer was concentrated to give crude ethyl 2-(3-(isopropylthio)pyridin-2-yl)pyrrolidine-3-carboxylate: 1H NMR indicated a mixture of cis and trans isomer in ca. 1:3 ratio. LC-MS 295 (M+H). To the above ethyl 2-(3-(isopropylthio)pyridin-2-yl)pyrrolidine-3-carboxylate in THF (10 mL) was added Et3N (1.4 mL) and di-tert-butyl dicarbonate (1.0 M in THF, 10 mL, 10 mmol). The mixture was stirred at rt over night before it was quenched with 0.5 N HCl (50 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (gradient ethyl acetate in hexanes) to provide a major product trans 65D (1.8 g, 45% yield) and a minor product cis 65E (900 mg still contaminated with 65D, 20% yield). 65D: 1H NMR (400 MHz, CDCl3) δ ppm two rotomers: 1.07-1.16 (m, 6H) 1.25 (t, J=6.81 Hz, 3H) 1.30 and 1.39 (s, 9 H) 2.12-2.20 (m, 1H) 2.22-2.32 (m, 1H) 2.93-3.04 (m, 1H) 3.32-3.44 (m, 1H) 3.60-3.70 (m, 1H) 3.73-3.83 (m, 1H) 4.17 (q, J=7.18 Hz, 2H) 5.61 and 5.75 (d, J=3.95 Hz, 1H) 7.11 (dd, J=7.47, 4.83 Hz, 1H) 7.62 (d, J=7.91 Hz, 1H) 8.38 (d, J=3.52 Hz, 1H); LC-MS 395 (M+H). 65E: 1H NMR (400 MHz, CDCl3) δ ppm two rotomers: 0.93 (t, J=6.81 Hz, 3H) 1.12-1.33 (m, 15H) 2.48-2.58 (m, 1H) 3.35-4.12 (m, 6H) 5.67 and 5.88 (d, J=7.91 Hz, 1H) 7.08 (dd, J=7.47, 4.39 Hz, 1H) 7.53-7.65 (m, 1H) 8.36 (d, J=3.08 Hz, 1H). LC-MS 395 (M+H).

1. customwas quenched with sat. K2CO3 (100 mL) at 0° C.
2. stirringstirred at rt for 1.0 h
3. customMethylene chloride was removed under vacuum
4. additionthe crude was diluted with EtOAc
5. filtrationThe mixture was filtered through a pad of wet Celite®
6. extractionextracted with EtOAc (3×40 mL)
7. washThe organic layer was washed with water
8. dry with materialdried over Na2SO4
9. concentrationA small portion of the dried organic layer was concentrated

ORD record

ord-9714247a59054c8780af83907d3890f5

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08222453B2