4-ISOPROPYLPHENOXYACETIC ACID

14062-21-6

1643-16-9

1. 4-Isopropylphenol (1.007 g, 7.39 mmol) was dissolved in 15 mL of dimethylformamide as starting material, potassium carbonate (2.04 g, 14.79 mmol) and ethyl bromoacetate (1.23 mL, 11.09 mmol) were added. The reaction mixture was stirred at room temperature for 48 hours. After completion of the reaction, the mixture was diluted with 500 mL of water and extracted with ether (2 x 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by fast column chromatography (eluent: 10% ethyl acetate/hexane) to give 1.61 g (98%) of ethyl 4-isopropylphenoxyacetate as a colorless oil.MS (APCI) m/z: 223.3 [M + H]+. 1H NMR (400 MHz, CDCl3) δ: 7.14 (d, 2H), 6.84 (d, 2H) , 4.59 (s, 2H), 4.27 (q, 2H), 2.86 (m, 1H), 1.30 (t, 3H), 1.21 (d, 6H). 2. A mixture of ethyl 4-isopropylphenoxyacetate (1.61 g, 7.24 mmol) and 2 N NaOH aqueous solution (10.9 mL) in 20 mL of methanol was stirred at room temperature for 3 hr and then concentrated under reduced pressure. The residue was dissolved in 100 mL of water, acidified with 1 N aqueous hydrochloric acid to pH < 7, and then extracted with ethyl acetate (2 x 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.32 g (94%) of 4-isopropylphenoxyacetic acid as a white solid.MS (APCI) m/z: 195.3 [M + H]+.1H NMR (400 MHz, CDCl3) δ: 7.17 (d, 2H), 6.86 (d, 2H), 4.66 (s, 2H) , 2.87 (m, 1H), 1.22 (d, 6H). 3. Benzyl 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionate (30 mg, 0.085 mmol) was dissolved in 1 mL of dichloromethane, 4-isopropylphenoxyacetic acid (33 mg, 0.17 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol) were added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by fast column chromatography (eluent: 30% ethyl acetate/hexane) to afford 35 mg (78%) of benzyl 2-(3-{1-{(4-isopropylphenoxy)acetyl]piperidin-3-yl}-phenoxy)-2-methyl-propanoate as a colorless oil.LC-MS m/z: 530.6 [M + H]+. 1H NMR (400 MHz, CDCl3) δ: 7.24 (m, 5H), 7.14 (m, 3H), 6.89 (m, 2H), 6.83 (m, 1H), 6.71 (s, 1H), 6.61 (d, 1H), 5.19 (s, 2H), 4.64 (m, 3H), 4.07 (d, 1H), 3.04 (t, 1H), 2.97 (m, 1H), 2.89 (m, 1H), 2.47 (m, 2H), 1.95 (m, 1H), 1.82 (m, 1H), 1.61 (s, 6H), 1.21 (d, 6H). 4. Benzyl 2-(3-{1-[(4-isopropylphenoxy)acetyl]piperidin-3-yl}-phenoxy)-2-methyl-propanoate (35 mg, 0.066 mmol) was dissolved in 2 mL of methanol, 10% palladium-carbon (4 mg, 10 wt%) was added, and hydrogenated at atmospheric pressure for 3 hours. The reaction mixture was filtered through diatomaceous earth and washed well with ethyl acetate. The filtrates were combined and concentrated under reduced pressure to give 29 mg (99%) of 2-(3-{1-[(4-isopropylphenoxy)acetyl]piperidin-3-yl}-phenoxy)-2-methyl-propanoic acid as a colorless oil.LC-MS m/z: 440.5 [M + H]+. 1H NMR (400 MHz, CDCl3) δ: 7.19 (t, 1H), 7.14 (t, 2H), 6.87 (m, 3H), 6.81 (m, 2H), 4.66 (m, 3H), 4.04 (dd, 1H), 3.05 (m, 1H), 2.85 (m, 1H), 2.65 (m, 2H), 2.02 (t, 1H), 1.82 (t, 1H), 1.65 (m, 1H), 1.59 (s, 6H), 1.21 (d, 6H). 1.21 (d, 6H).