Triethylamine → HCID 67441180, compound

To 35B (23.4 mmol) in CH2Cl2 (200 mL) at −15° C. was added Et3N (5.7 mL, 41 mmol) followed by TiCl4 (1.0 M in CH2Cl2, 41 mL, 41 mmol). The mixture was stirred from −15° C. to rt over 3.0 h before it was quenched with sat. K2CO3 (200 mL) at 0° C. and stirred at rt for 1.0 h. The mixture was filtered through a pad of wet Celite®, extracted with CH2Cl2 (3×60 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-(2-(ethylthio)-5-nitrophenyl)pyrrolidine-3-carboxylate: 1H NMR indicated a mixture of cis and trans isomer in ca. 1:1 ratio, LC-MS 325 (M+H). To the above ethyl 2-(2-(ethylthio)-5-nitrophenyl)pyrrolidine-3-carboxylate in THF (100 mL) was added Et3N (3.3 mL) and di-tert-butyl dicarbonate (1.0 M in THF, 24 mL, 24 mmol). The mixture was stirred at rt for 3.0 h before it was quenched with 0.5 N HCl (50 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was first triturated with EtOAc, the precipitate was collected by filtration and washed with EtOAc to give the trans 35C (1.7 g). The filtrate was concentrated and further purified by flash silica gel column chromatography using gradient EtOAc in hexane to give predominantly cis isomer 35D (1H NMR indicated presence of 30% trans isomer). To this cis isomer was added mixture of EtOAc/hexane (1:3), the precipitate was collected and washed with the same mixture of EtOAc/hexanes (1:3) to give a second crop of the trans 35C (0.8 g, total 2.5 g, 25% yield). The filtrate was concentrated to give enriched cis isomer 35D (3.0 g, >92% purity, 30% yield). 35C: 1H NMR (500 MHz, DMSO-d6, 90° C.) δ ppm 1.20 and 1.23 (m, 12H) 1.33 (t, J=7.42 Hz, 3H) 2.08-2.19 (m, 2H) 2.90 (br s, 1H) 3.15 (q, J=7.15 Hz, 2H) 3.48-3.58 (m, 1H) 3.70 (m, 1H) 4.10-4.19 (m, 2H) 5.31 (br s, 1H) 7.58 (d, J=8.79 Hz, 1H) 7.84 (s, 1H) 8.02-8.09 (m, 1H). LC-MS 425 (M+H). 35D: 1H NMR (500 MHz, DMSO-d6, 90° C.) δ ppm 0.86 (t, J=6.87 Hz, 3H) 1.18 (s, 9H) 1.34 (t, J=7.15 Hz, 3H) 2.12-2.22 (m, 2H) 3.09-3.17 (m, 2H) 3.56-3.67 (m, 3H) 3.69-3.83 (m, 2H) 5.43 (d, J=8.79 Hz, 1H) 7.50-7.58 (m, 1H) 7.81 (s, 1H) 8.03 (d, J=8.79 Hz, 1H); LC-MS 425 (M+H).

1. customwas quenched with sat. K2CO3 (200 mL) at 0° C.
2. stirringstirred at rt for 1.0 h
3. filtrationThe mixture was filtered through a pad of wet Celite®
4. extractionextracted with CH2Cl2 (3×60 mL)
5. washThe organic layer was washed with water
6. dry with materialdried over Na2SO4
7. concentrationA small portion of the dried organic layer was concentrated

ORD record

ord-8e89fe5a79094bd39b06138669a89567

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08222453B2