To a solution of [5-fluoro-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(methyloxy)phenyl]acetaldehyde (D35) (80 mg) and ethyl 4-piperidinecarboxylate (138 mg) in dichloromethane (DCM) (15 mL) stirred at room temperature was added AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (74.6 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated. The residue was dissolved in isopropanol (10 mL) and water (10 mL), sodium hydroxide (50 mg) was added. Stirring continued for 2 h at room temperature. 1M HCl solution was added until PH=6˜7. Then iPrOH was removed by evaporation. The aqueous layer was extracted by EA/THF/MeCN for 3 times. The combined organic layers were concentrated, and purified by Mass Directed AutoPrep to give 1-{2-[5-fluoro-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(methyloxy)phenyl]ethyl}-4-piperidinecarboxylic acid (E13) (45 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.34 (6H, d), 1.57 (2H, m), 1.79 (2H, d), 2.06 (2H, t), 2.19 (1H, m), 2.58 (2H, t), 2.87 (4H, t), 3.80 (3H, s), 4.94 (1H, m), 7.45 (1H, dd), 7.51 (1H, d), 7.88 (1H, dd), 8.23 (1H, d), 8.29 (1H, dd). δF (DMSO-d6, 376 MHz): −117.4, −61.3. MS (ES): C27H29F4N3O4S requires 567. found 568.2 (M+H+).
