Trifluoroacetic acid → HCID 6102824, compound

A solution of tert-butyl(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5, 1.00 g, 2.80 mmol, 1 equiv) in a 4:1 mixture of dichloromethane and trifluoroacetic acid (20 mL) was stirred for 30 minutes, then concentrated. The residue was dried via benzene azeotrope (1×50 mL), then dissolved in DMP (30 mL). (2S)-[(tert-butoxycarbonyl)amino](cyclopropyl)ethanoic acid (0.903 g, 4.20 mmol, 1.50 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.805 g, 4.20 mmol, 1.50 equiv), 1-hydroxy-7-azabenzotriazole (0.571, 4.20 mmol, 1.50 equiv) and triethylamine (1.95 mL, 14.0 mmol, 5.00 equiv) were added, and the resulting mixture was stirred at 23° C. for 5 days. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was dissolved in a 4:1 mixture of dichloromethane and trifluoroacetic acid. The resulting solution was allowed to stand for 25 minutes, then concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present). The desired fractions were partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL), and the combined organic layers were washed with aqueous sodium bicarbonate solution (2×100 mL), then brine (100 mL), and dried over sodium sulfate and concentrated to provide (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanamine (16-7) as a white solid. 1H NMR (500 MHz, CD3OD) major rotamer: δ 7.41 (t, 2H, J=7.6 Hz), 7.33 (m, 3H), 7.26 (m, 1H), 7.18 (m, 1H), 7.09 (m, 1H), 6.46 (s, 1H), 5.91 (m, 1H), 5.02 (d, 2H, J=13.9 Hz), 4.96 (ddd, 1H, J=13.9, 4.4, 1.7 Hz), 3.08 (d, 1H, J=7.6 Hz), 1.04 (m, 1H), 0.52 (m, 3H), 0.37 (m, 1H). LRMS m/z (M+H) 355.0 found, 355.2 required.

1. concentrationconcentrated
2. dry with materialThe residue was dried via benzene
3. dissolutiondissolved in DMP (30 mL)
4. stirringthe resulting mixture was stirred at 23° C. for 5 days
5. customThe reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×100 mL)
6. dry with materialThe combined organic layers were dried over sodium sulfate
7. concentrationconcentrated
8. dissolutionThe residue was dissolved in a 4:1 mixture of dichloromethane and trifluoroacetic acid
9. waitto stand for 25 minutes
10. concentrationconcentrated
11. customThe residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present)
12. customThe desired fractions were partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL)
13. washthe combined organic layers were washed with aqueous sodium bicarbonate solution (2×100 mL)
14. dry with materialbrine (100 mL), and dried over sodium sulfate
15. concentrationconcentrated

ORD record

ord-0882890b105743618c7bc6df303314ee

Source dataset

uspto-grants-2008_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07348440B2