Hydrochloric Acid → (+)-(trans)-2-(4-{[(3-{[3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]amino}phenyl)cyclopropanecarboxy lic Acid

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To a mixture of (+)-(trans)-ethyl-2-(4-aminophenyl)cyclopropanecarboxylate (III-1b) (0.093 g, 0.453 mmol) in dichloroethane (3.5 mL) was added 3-{[3-(trifluoromethyl)phenyl]oxy}benzaldehyde (70 uL, 0.404 mmol). The mixture was stirred for 18 h followed by addition of sodium triacetoxyborohydride (0.135 g, 0.637 mmol). The mixture was stirred for 12 h at RT. Water was added (10 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give ethyl 2-(4-{[(3-{[3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]amino}phenyl)cyclopropanecarboxylate as a colorless oil (0.159 g, mixture of ethyl and methyl ester). The material was dissolved in THF/EtOH (1 mL each) and a 1M sodium hydroxide solution was added (1 mL). The mixture was heated at 85 C for 3.5 h. Upon cooling, the mixture was acidified (pH=2-3) with a 5M hydrochloric acid solution. Water was added (5 mL), and the mixture was extracted with CH2Cl2 (3×10 mL). The organics were washed with water and brine (1×10 mL each) and dried with MgSO4 to give the title compound as an orange oil (0.153 g, >100%, residual THF present). 1H NMR (400 MHz, DMSO-d6): δ 7.41 (t, J=8.1 Hz, 1H), 7.30-7.35 (m, 2H), 7.20 (m, 1H), 7.10-7.17 (m, 2H), 7.02 (m, 1H), 6.92 (d, J=8.4 Hz, 2H), 6.90 (m, 1H), 6.56 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 2.50 (m, 1H), 1.77 (m, 1H), 1.57 (m, 1H), 1.32 (m, 1H). ES-MS m/z 428.16 (MH+).

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