Synthesis
Example 14. Synthesis of 5-chloro-2-phenoxyphenylacetic acid (Compound XIVa)
200 g (0.81 mol) of 5-chloro-2-phenoxyacetophenone (Compound XV) obtained in Example 13, 112.3 g (1.29 mol) of morpholine, and 40 g (1.25 mol) of sulfur were mixed and the reaction was stirred at 110°C for 12 hours. Upon completion of the reaction, the mixture was cooled to room temperature and 1 L of glacial acetic acid and 1 L of concentrated aqueous hydrochloric acid were added sequentially, followed by continued stirring at reflux temperature for 8 hours. The reaction mixture was concentrated to about 1/3 of the original volume and then extracted by adding 800 mL of water and 800 mL of methyl tert-butyl ether. The aqueous layer was separated, washed with 400 mL of methyl tert-butyl ether and discarded. The organic phases were combined and washed sequentially with 500mL, 250mL, and 250mL of 8% aqueous sodium carbonate. All aqueous phases were combined and washed with 2 x 200 mL of methyl tert-butyl ether before adjusting the pH with concentrated hydrochloric acid to 1. 400 mL of petroleum ether was added and the mixture was stirred at room temperature for 30 min. The resulting suspension was filtered and the solid was dried to constant weight to give 143 g of 5-chloro-2-phenoxyphenylacetic acid (Compound XIVa) in 67.1% yield.
References
[1] Patent: EP2468751, 2012, A2. Location in patent: Page/Page column 21
[2] Journal of Medicinal Chemistry, 1982, vol. 25, # 7, p. 855 - 858
[3] Journal of Medicinal Chemistry, 1983, vol. 26, # 10, p. 1353 - 1360
