2,6-Lutidine → (S)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

Participants

Reaction Steps

A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.29 mmol, prepared as in Example 1) in methylene chloride (5 mL) and N,N-dimethylformamide (5 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 200 μL, 0.40 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (5 mL) and then added dropwise to a separate reaction flask containing a mixture of (R)-3-(3-amino-pyrazol-1-yl)-propane-1,2-diol (prepared as in US 20080021032, Example 35, 70 mg, 0.45 mmol) and 2,6-lutidine (250 μL) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was then stirred room temperature for 2 h. The reaction mixture was quenched by the addition of methanol and then diluted with methylene chloride. The organic layer was then washed with a 1 N aqueous hydrochloric acid solution. The organic layer was then concentrated in vacuo with silica gel (2.0 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 100% ethyl acetate to 10% methanol/ethyl acetate) to afford (S)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (98 mg, 69%) as a white foam: [α]29D=+12.0°, (c=0.15, methanol); HR-ES(+) m/e calcd for C23H27N4O4F3 [M+H]+ 481.2057, observed 481.2055; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (s, 1H), 7.94-8.05 (m, 2H), 7.71-7.79 (m, 1H), 7.53 (d, J=2.34 Hz, 1H), 6.40 (d, J=2.13 Hz, 1H), 4.99-5.11 (m, 2H), 4.93 (d, J=5.33 Hz, 1H), 4.67-4.76 (m, 2H), 4.09 (dd, J=3.84, 13.85 Hz, 1H), 3.81-3.91 (m, 1H), 3.76 (br. s., 1H), 3.23-3.31 (m, 2H), 1.05-2.13 (m, 11H).

Provenance & Evidence