反应详情

Optically-enriched tert-butyl (1R,2R)-1-(2-bromopyridin-4-yl)-2-hydroxy-2-phenylethylcarbamate (1.85 g, 2.35 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 40 mL) and stirred at room temperature for 1 h. LC/MS shows clean conversion to product. The reaction was concentrated, dissolved in methanol, and loaded onto a strong cation exchange cartridge. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated. The resulting residue was suspended in tetrahydrofuran (50 mL), cooled to 0° C., and treated with carbonyldiimidazole (0.763 g, 4.70 mmol) in a single portion. The resulting suspension was stirred at 0° C. for 5 min. The ice bath was removed and stirring continued for 1 h. The reaction was re-cooled to 0° C., and treated with an additional portion of carbonyldiimidazole (160 mg) and stirred at room temperature for 2 h. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The resulting residue was purified by column chromatography (25%-->50% EtOAc/Hex) to give the optically-enriched product. The minor enantiomer was removed by SFC Prep HPLC (Chiralpak AS-H, 25% MeOH in CO2) to give 452 mg (30%). 1H-NMR (CDCl3, 500 MHz) δ 8.42 (d, J=5.2, 1H), 7.40-7.56 (m, 4H), 7.33 (m, 2H), 7.19 (dd, J=5.2, 1.2, 1H), 6.95 (bs, 1H), 5.21 (d, J=7.3, 1H), 4.81 (d, J=7.3, 1H). 13C-NMR (CDCl3, 126 MHz) δ 158.9, 151.1, 150.6, 143.3, 136.4, 129.9, 129.4, 126.2, 125.6, 120.3, 85.3, 63.4. Mass spec.: 319.04 (MH)+.

1. concentrationThe reaction was concentrated
2. dissolutiondissolved in methanol
3. customThe cartridge was flushed with several volumes of methanol which
4. washThe product was eluted with 2M ammonia in methanol
5. concentrationconcentrated
6. temperaturecooled to 0° C.
7. stirringThe resulting suspension was stirred at 0° C. for 5 min
8. customThe ice bath was removed
9. stirringstirring
10. waitcontinued for 1 h
11. temperatureThe reaction was re-cooled to 0° C.
12. additiontreated with an additional portion of carbonyldiimidazole (160 mg)
13. stirringstirred at room temperature for 2 h
14. customThe reaction was quenched by addition of 2M ammonia in methanol
15. concentrationconcentrated
16. customThe resulting residue was purified by column chromatography (25%-->50% EtOAc/Hex)
17. customto give the optically-enriched product
18. customThe minor enantiomer was removed by SFC Prep HPLC (Chiralpak AS-H, 25% MeOH in CO2)
19. customto give 452 mg (30%)