Trifluoroacetic acid → 4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxamide

Temperature

25 °C

tert-Butyl 2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (3-2, 1.48 g, 3.82 mmol) was dissolved in anhydrous CH2Cl2 (25 mL) and treated with TFA (5 mL) for 1 hour. The reaction mixture was partitioned between sat. aq. NaHCO3 (100 mL) and ethyl acetate (3×20 mL). The combined organic layers were then washed with sat. aqueous NaCl, dried over sodium sulfate, filtered, and concentrated. The crude amine was then dissolved in CH2Cl2, and treated successively with Et3N (1.6 mL, 11.5 mmol) and dimethylcarbamoyl chloride (0.37 mL, 4.01 mmol), and the resulting solution was stirred 3.5 h at 25° C. Upon completion as judged by mass spectrometry, the reaction was concentrated, redissolved in CH2Cl2 (30 mL) and triethylamine trihydrofluroide complex (0.6 mL, 3.82 mmol) was added and the reaction stirred an additional 12 h at 25° C. Upon completion, the reaction was partitioned between NH4Cl (10 mL) and CH2Cl2 (3×10 mL), and the combined organic layers were concentrated. The desired compound crystallized from CH2Cl2 and as filtered to provide 4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxamide 4-1 as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.18 (t, J=7.8 Hz, 2H), 7.00 (m, 3H), 6.90 (s, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.74 (dd, J=7.9, 2.4 Hz, 1H), 4.90 (dd, J=13.4, 3.7 Hz, 1H), 4.50 (d, J=13.4 Hz, 1H), 2.91 (s, 6H). LRMS: m/z (M−CH3) 345.3 found, 345.4 required.

1. customThe reaction mixture was partitioned between sat. aq. NaHCO3 (100 mL) and ethyl acetate (3×20 mL)
2. washThe combined organic layers were then washed with sat. aqueous NaCl
3. dry with materialdried over sodium sulfate
4. filtrationfiltered
5. concentrationconcentrated
6. dissolutionThe crude amine was then dissolved in CH2Cl2
7. concentrationthe reaction was concentrated
8. dissolutionredissolved in CH2Cl2 (30 mL)
9. stirringthe reaction stirred an additional 12 h at 25° C
10. customUpon completion, the reaction was partitioned between NH4Cl (10 mL) and CH2Cl2 (3×10 mL)
11. concentrationthe combined organic layers were concentrated
12. customThe desired compound crystallized from CH2Cl2
13. filtrationas filtered

ORD record

ord-c76c25dbc8bc421d8512c563ea5310e3

Source dataset

uspto-grants-2008_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07329762B2