4-ISOPROPYLPHENOXYACETIC ACID synthesis

Yield: 94%

Reaction Conditions:

Stage #1:(4-isopropylphenyl)acetic acid ethyl ester with sodium hydroxide;water in methanol at 20; for 3 h;
Stage #2: with hydrogenchloride in methanol;water

Steps:

2 Example 2; 2-(3-{1-[(4-Isopropyl-phenoxy)-acetyl]-piperidin-3-yl}-phenoxy)-2-methyl-propionic acid
To a solution of 4-isopropylphenol (1. 007g, 7.39 mmol) in 15 mL DIMETHYLFORMAMIDE was added potassium carbonate (2.04g, 14.79 mmol) and ethyl bromoacetate (1.23 mL, 11.09 MMOL). The reaction was stirred for 48 h at ambient temperature. The mixture was diluted with 500 mL water and extracted with diethyl ether (2 x 200 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 10% ethyl acetate/hexanes to yield 1. 61G (98%) of ETHYL- (4-ISOPROPYLPHENOXY) acetate as a clear oil. MS (APCI) 223.3 (M + H) +. 'H NMR (400 MHz, CDCI3) 8 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). A mixture of ETHYL- (4-ISOPROPYLPHENOXY) acetate (1.61g, 7.24 mmol) and 2N NaOH (aq) (10.9 mL) in 20 mL of methanol was stirred at ambient temperature for 3 h and concentrated under reduced pressure. The resulting residue was taken up in water (100 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2 x 100 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 1. 32G (94%) of 4-isopropylphenoxyacetic acid as a white solid. MS (APCI) 195.3 (M + H) +. 'H NMR (400 MHz, CDCI3) 8 7.17 (d, 2H), 6.86 (d, 2H), 4.66 (s, 2H), 2.87 (m), 1 H), 1.22 (d, 6H). To a solution of 2-METHYL-2- (3-PIPERIDIN-3-YL-PHENOXY)-PROPIONIC acid benzyl ester (Preparation 2, Method C; 30 mg, 0.085 mmol) in 1 mL methylene chloride was added 4-isopropylphenoxyacetic acid (33mg, 0.17 mmol) and 1- (3- DIMETHYLAMINOPROPYL)-3-ETHYLCARBODIIMIDE HYDROCHLORIDE (33mg, 0.17 mmol) and allowed to stir 18 h at ambient temperature. The reaction was concentrated under reduced pressure and the resultant oil flash chromatographed with 30% ethyl acetate/hexanes to yield 35mg (78%) OF 2- (3- {1- [ (4-ISOPROPYL-PHENOXY)-ACETYL]- PIPERIDIN-3-YL}-PHENOXY)-2-METHYL-PROPIONIC acid benzyl ester as a clear oil. LC-MS 530.6 (M + H) +. 'H NMR (400 MHz, CDCI3) S 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, 1 H), 2.97 (m, 1 H), 2.89 (m, 1 H), 2.47 (m, 2H), 1.95 (m, 1 H), 1.82 (m, 1 H), 1.61, (s, 6H), 1.21 (d, 6H). 10% Palladium on carbon (4 mg, 10 wt%) was added to a solution of 2- (3- {1- [ (4-ISOPROPYL-PHENOXY)-ACETYL]-PIPERIDIN-3-YLL-PHENOXY)-2-METHYL-PROPIONIC ACID BENZYI ester (35 mg, 0.066 mmol) in methanol (2 mL) and the resulting mixture hydrogenated at atmospheric pressure for 3 h. The reaction mixture was filtered through a plug of celite and the celite plug washed thoroughly with ethyl acetate. The combined filtrates were concentrated under reduced pressure to provide 29 mg (99%) of 2-(3-{1-[(4-Isopropyl-phenoxy)-acetyl]-piperidin-3-yl]-phenoxy)-2-methyl- propionic acid as a clear oil. LC-MS 440.5 (M + H) +. 'H NMR (400 MHz, CDCI3) 8 7.19 (t, 1H), 7.14 (t, 2H), 6.87 (m, 3H), 6.81 (m, 2H), 4.66 (m, 3H), 4.04 (dd, 1 H), 3.05 (m, 1H), 2.85 (m, 1 H), 2.65 (m, 2H), 2.02 (t, 1H), 1.82 (t, 1H), 1.65 (m, 1H), 1.59, (s, 6H), 1.21 (d, 6H).

References:

PFIZER PRODUCTS INC. WO2004/48334, 2004, A1 Location in patent:Page 128-130