1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (S)-4-Fluoro-N-(2-hydroxy-2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide

A solution of (S)-2-amino-1-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)ethanol (44 mg, 0.096 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (20 mg, 0.096 mmol), EDCI (28 mg, 0.14 mmol), HOBT (14 mg, 0.096 mmol) and a catalytic amount of DMAP in acetonitrile (3 mL) was stirred for 24 h at rt. The reaction mixture was diluted with EtOAc and washed successively with 1 N HCl, 1 N NaOH, sat. NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC Shimadzu-YMC Sunfire 5 μcolumn, 30×100 mm eluting with 50-100% MeOH (90% in H2O, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. (S)-4-Fluoro-N-(2-hydroxy-2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide (Example 311) was isolated as a colorless film (10 mg, 15% yield). HPLC: RT=4.143 minutes (Phenomenex Luna C18 5 u column eluting with 10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minute gradient monitoring at 220 nm). LCMS: [M+H] 648.0 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 8.23 (m, 1H), 7.37-6.9 (m, 15H), 5.41 (s, 1H).

1. washwashed successively with 1 N HCl, 1 N NaOH, sat. NaCl
2. dry with materialdried over MgSO4
3. filtrationfiltered
4. concentrationconcentrated
5. customThe residue was purified by preparative HPLC Shimadzu-YMC Sunfire 5 μcolumn, 30×100 mm
6. washeluting with 50-100% MeOH (90% in H2O, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm

ORD-Eintrag

ord-58284bd33424422790adc0c30f4e19a2

Quelldatensatz

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08642576B2