Reaction Steps
In a round bottom flask under argon was placed tetrahydrofuran (15 mL) and 1,1,1,3,3,3-hexamethyldisilazane (0.57 mL, 2.72 mmol) and it was cooled to −78° C. in a dry ice/acetone bath. To this cooled solution was then added n-butyl lithium (2.5 M solution in hexanes, 1.0 mL, 2.55 mmol) and it was stirred for 15 min at −78° C. To this was then dropwise added a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in PCT WO 2003/095438 A1, Example 4, 0.56 g, 2.44 mmol) in tetrahydrofuran (5 mL). The reaction was then stirred for 15 min at −78° C. then at 0° C. for 1 h. After such time, it was cooled back to −78° C. and a solution of 3-iodomethyl-oxetane (0.58 g, 2.93 mmol) in tetrahydrofuran (5 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.44 mL, 3.64 mmol) was added dropwise at −78° C. The reaction was stirred at 0° C. for 3 h and then it was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium chloride solution. The organics were dried over sodium sulfate, filtered and then concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 30% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-oxetan-3-yl-propionic acid methyl ester (0.51 g, 70%) as a clear oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.97-2.13 (m, 1H, CH of CH2), 2.22-2.34 (m, 1H, CH of CH2), 2.46 (s, 3H, SCH3), 2.71-2.87 (m, 1H, CH), 3.54-3.66 (m, 1H, ArCHCO), 3.57 (s, 3H, OCH3), 4.09 (t, J=6.2 Hz, 1H, OCH of OCH2), 4.23 (t, J=6.2 Hz, 1H, OCH of OCH2), 4.40 (dd, J=7.8, 5.9 Hz, 1H, OCH of OCH2), 4.53 (dd, J=7.8, 5.9 Hz, 1H, OCH of OCH2), 7.23-7.26 (m, 2H, Ar), 7.36 (brs, 1H, Ar).
