Acetic Acid → 3-{4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-furan-3-yl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester

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Reaction Steps

To a stirred solution of trimethylsilyldiazomethane (2M in diethyl ether, 18.64 mL, 37.289 mmol) in 1,2-dimethoxyethane (DME, 100 mL) was added methyl lithium (1.6M in diethyl ether, 23.32 mL, 37.289 mmol) at −78° C. over period of 10 minutes and stirred reaction mixture for 30 minutes at −78° C. Pre-dissolved 3-{4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-butyryl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (Example 1, Intermediate 1) (5 g, 9.322 mmol, 1eq.) in DME (50 mL) was added at −78° C. in drop wise manner over period of 10 minutes. Resulting reaction mixture was stirred for 1 hour at same temperature and then at room temperature for 2 hours. Acetic acid (1.60 mL, 27.967 mmol, 3 eq.) was added at room temperature over period of 5 minutes followed by addition of TBAF (27.92 mL, 27.967 mmol, 3 eq.) at room temperature over period of 10 minutes. After consumption of starting material, reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (5×150 mL). Combined organic layer was dried over sodium sulphate and concentrated in vacuo to get orange semisolid (6.1 g, crude). Crude was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 10% ethyl acetate in hexane to afford off white semisolid (1.6 g, Impure). The product was again purified by trituration using DCM: pentane (1:5, 2×20 mL) to afford product as off white solid (0.45 g, 9.18%). Yield: −0.45 g (9.18%). 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 9H), 3.20 (d, J=17.24 Hz, 1H), 3.30 (d, J=17.24 Hz, 1H), 4.14-4.21 (m, 2H), 4.33-4.41 (m, 2H), 7.32-7.38 (m, 4H), 7.40 (t, J=1.78 Hz, 1H), 7.52 (d, J=1.36 Hz, 2H). LC-MS (m/z): =529.9 (M−H).

Provenance & Evidence