2-(4-Chloro-phenoxy)-2-methyl-N-thiazol-2-yl-propionamide

Example Al : 2-(4-Chloro-phenoxy)-2-methyl-N-thiazol-2-yl-propionamide:

To a solution of 2-(4-Chloro-phenoxy)-2-methyl-propionic acid (0.3g, 1.4 mmol) in DCM (10 ml) was added triethylamine (0.23 ml, 1.68 mmol) and HOBt (0.23 g, 1.68 mmol) at 0 ⁰C. After stirring at this temperature for 5 min. added 2-aminothiazole (0.168 g, 1.68 mmol) and followed by EDCI (0.332 g, 1.68 mmol). The resulting solution was stirred for 12 h. then quenched with saturated aqueous NH₄Cl solution (15 mL). The aqueous phase was extracted with CH₂Cl₂ (3 x 50 mL). The organic phase was successively washed with 2% HCl (50 mL), brine (50 mL) and dried over Na₂SO₄. After evaporation, the residue was purified by flash chromatography (1 :10 ethyl acetate: hexanes) to give 2-(4-Chloro-phenoxy)-2-methyl- N-thiazol-2-yl-propionamide (0.325 g, 78 %). ¹H NMR (400 MHz, CDCl₃): δ 1.58 (s, 6H), 6.76 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 3.6 Hz, IH), 7.18 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 3.6 Hz, IH), MS (EI) m/z 296.9 (M+l).





Preparation of 2-(4-Chloro-phenoxy)-2-methyl-propionic acid used in Typical Example Al is described below:

2-(4-Chloro-phenoxy)-2-methyl-propionic acid ethyl ester (Al-I):

To a solution of 4-cholo-phenol (4 g, 31.11 mmol) in DMF (10 ml) anhydrous potassium carbonate (10.73 g, 77.77 mmol) and ethyl-2-bromo-isobutyrate (12.13 g, 62.22 mmol) were added. The resulting mixture was heated at 70 ° C for 12 hours. Upon completion (-25 h), the solution was diluted with EtOAc (100 ml) and washed with brine (2X20 ml). The aqueous layer was then extracted for two additional times with EtOAc (20 ml) and the combined organic fractions were washed with brine (20 ml). The solution was then dried over
Na₂SO₄ and concentrated to give brown oil. Purification on silica gel (hexanes/acetone) yielded 6.O g (79%) of ester as pale yellow oil which was used as such for the next step without further purification.





2-(4-Chloro-phenoxy)-2-methyl-propionic acid (Al-II):

To a solution of 2-(4-Chloro-phenoxy)-2-methyl-propionic acid ethyl ester ( 6 g, 24.79 mmol) in THF (20 ml) was added a solution of LiOH ( 3 g, 74.38 mmol) in H₂O ( 4 mil). The resulting solution was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was diluted with ethyl acetate (100 ml); cool to OoC, acidified with IN HCl (PH- 3-4). The organic phase were washed with, brine (20 ml) and dried over Na₂SO₄. After evaporation, the residue was purified by flash chromatography (1:1 hexanes/ EtOAc) to give 2-(4-Chloro-phenoxy)-2-methyl-propionic acid (1.1 g, 20 %). ¹H NMR (400 MHz, CDCl₃): δ 1.60 (s, 6H), 6.85 (d, J=8.7 Hz, 2H), 7.22 (d, J=8.7 Hz, 2H). MS (EI) mlz: 215.5 (M + 1).

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