反应详情

To the crude solution of (3S,4S)-3,4-difluoro-3,4-dihydro-2H-pyrrole (0.52 mmol) in MeOH under argon were successively added (3-acetyl-indol-1-yl)-acetic acid (57 mg, 0.26 mmol) and 1-chloro-2-fluoro-3-(isocyanomethyl)benzene (44 mg, 0.26 mmol) in MeOH (0.2 mL). The reaction mixture was stirred at RT for 60 h and poured into a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (Gold RediSep column, 24 g, CH2Cl2 to CH2Cl2/MeOH 95-5), the fractions containing the desired material as a mixture of 2 diastereosiomers were concentrated and the residue was purified again by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, eluent: 5% to 100% CH3CN in H2O in 25 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) to give (2S,3S,4S)-1-[2-(3-acetyl-indol-1-yl)-acetyl]-3,4-difluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide: Rf (EtOAc): 0.60; MS (UPLC): 492.2/494.2 [M+H]+, 536.2/538.2 [M+HCOO]− and (2R,3S,4S)-1-[2-(3-acetyl-indol-1-yl)-acetyl]-3,4-difluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide; Rf (EtOAc): 0.50; MS (UPLC): 492.2/494.2 [M+H]+, 536.2/538.2 [M+HCOO]−; tR (HPLC conditions a): 3.37 min. The absolute stereochemistry has been assigned tentatively based on comparison of 1H-NMR spectra and test results in the biological assay measured for both diastereosiomers.

1. extractionextracted with CH2Cl2 (×2)
2. dry with materialThe combined organic extracts were dried (Na2SO4)
3. filtrationfiltered
4. concentrationconcentrated
5. customThe crude residue was purified by flash column chromatography on silica gel (Gold RediSep column, 24 g, CH2Cl2 to CH2Cl2/MeOH 95-5)
6. additionthe fractions containing the desired material
7. additionas a mixture of 2 diastereosiomers
8. concentrationwere concentrated
9. customthe residue was purified again by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, eluent: 5% to 100% CH3CN in H2O in 25 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min)