Dimethylformamide → N-((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-1,3-dihydroxycyclopentanecarboxamide

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Reaction Steps

The above acid (300 mg, 1.15 mmol) and the compound of Reference Example 4 (491 mg, 1.27 mmol) were dissolved in 2 mL of DMF. HOBT (31 mg, 0.23 mmol) and EDCI (254 mg, 1.33 mmol) were added, and the mixture was made basic with triethylamine (117 mg, 1.15 mmol). After 1.5 hours at ambient temperature, 5 mL of water and 5 mL of 10% sodium bicarbonate were added, and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in 10 mL of THF and 10 mL of 1 N HCl was added. The reaction mixture was stirred at ambient temperature for 1 hour, and then the pH of the reaction was adjusted to 8.5 by addition of saturated aqueous sodium bicarbonate solution. Extraction with EtOAc followed by washing of the combined extracts with brine and drying over sodium sulfate afforded crude product. Chromatography on silica gel eluting with 1 to 2% methanol in chloroform afforded the title compound as a racemic mixture of cis and trans isomers, which gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 479.2 for M+H+: 1H NMR (500 MHz, CDCl3) δ 8.21 (s, 1H), 7.35 (d, J=9 Hz, 1H), 7.26 (m, 2H), 5.44 (m, 1H), 4.35 (s, 3H), 2.43-1.82 (m, 6H), 1.46 (d, J=7 Hz, 3H).

Provenance & Evidence