1,2-Dichloroethane → HCID 68776336, compound

To a solution of Example 254 (300 mg, 0.44 mmol) in DCM (20 mL) was added triethylamine (0.6 mL, 4.35 mmol), EDC (334 mg, 1.74 mmol) and 1-hydroxybenzo-triazole (10 mg, 0.09 mmol) and the reaction mixture was stirred at room temperature for 2 h. (3R)-(+)-3-(tert-Butoxycarbonylamino)pyrrolidine (323 mg, 1.74 mmol) was then added and stirring was continued at room temperature for 18 h. Water (30 mL) was added and the mixture was extracted into DCM (100 mL). The organic phase was washed with saturated aqueous sodium hydrogencarbonate solution (30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 75-100% EtOAc/heptane). The obtained solid was taken up in DMF (5.0 mL) and sodium hydride (60% dispersion in oil, 14 mg, 0.36 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, then iodomethane (20 μL, 0.36 mmol) was added and stirring was continued for 1 h. Water (20 mL) was added and the reaction mixture was extracted with EtOAc (80 mL). The organic phase was washed with water (6×20 mL) and brine (20 mL), then dried (magnesium sulfate). The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 75-100% EtOAc/heptane). The obtained solid was taken up in DCM (5.0 mL) and trifluoroacetic acid (1.0 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes and the solvent was removed in vacuo. The residue was purified by preparative HPLC (pH 5.8) and the obtained product was partitioned between sodium hydrogencarbonate solution (20 mL) and DCM (2×75 mL). The combined organic phases were dried (magnesium sulfate) and the solvent was removed in vacuo to give the title compound (25 mg, 8%) as an off-white solid. δH (CD3OD) 8.75 (1H, d, J 5.1 Hz), 8.28-8.13 (2H, m), 8.01 (1H, s), 7.69-7.60 (2H, m), 7.51-7.45 (1H, m), 3.88-3.50 (7H, m), 3.41-3.22 (2H, m), 3.14-3.02 (4H, m), 2.64 (2H, s), 2.46 (3H, 2×s), 2.33 (2H, s), 2.30-2.06 (1H, m), 1.98-1.80 (1H, m), 1.05 (6H, s). LCMS (ES+) 545.3 (M+H)+.

1. additionwas then added
2. extractionthe mixture was extracted into DCM (100 mL)
3. washThe organic phase was washed with saturated aqueous sodium hydrogencarbonate solution (30 mL)
4. dry with materialdried (magnesium sulfate)
5. customThe solvent was removed in vacuo
6. customthe residue was purified by column chromatography (SiO2, 75-100% EtOAc/heptane)
7. stirringThe reaction mixture was stirred at room temperature for 30 minutes
8. stirringstirring
9. waitwas continued for 1 h
10. extractionthe reaction mixture was extracted with EtOAc (80 mL)
11. washThe organic phase was washed with water (6×20 mL) and brine (20 mL)
12. dry with materialdried (magnesium sulfate)
13. customThe solvent was removed in vacuo
14. customthe residue was purified by column chromatography (SiO2, 75-100% EtOAc/heptane)
15. additiontrifluoroacetic acid (1.0 mL) was added
16. stirringThe reaction mixture was stirred at room temperature for 30 minutes
17. customthe solvent was removed in vacuo
18. customThe residue was purified by preparative HPLC (pH 5.8)
19. customthe obtained product was partitioned between sodium hydrogencarbonate solution (20 mL) and DCM (2×75 mL)
20. dry with materialThe combined organic phases were dried (magnesium sulfate)
21. customthe solvent was removed in vacuo

ORD record

ord-0b4969e16908421f89c0309e021bebd2

Source dataset

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08324204B2