| 65.3% |
With potassium carbonate In dimethyl sulfoxide at 90 - 125℃; for 5 - 17h; |
14.A; 44.A; 65.A
Example 142-(4-(4-(3,4-Dichlorophenylcarbamoyl)phenoxy)-3-(methylsulfonamidomethyl)phenyl)-acetic acid[00178] Step A: tert-Butyl 2-(3-cyano-4-fluorophenyl)acetatc (2.6 g, 11.1 mmol) and methyl 4- hydroxybenzoate (3.36 g, 22.1 mmol) were diluted with DMSO (22 mL) followed by the addition of potassium carbonate (1.83 g, 13.3 mmol). The reaction mixture was heated to 125 0C and stirred for 5 hours. The reaction mixture was diluted with ethyl acetate and 10% aqueous sodium carbonate. The layers were separated and the organic layer was washed with 10% aqueous sodium carbonate two more times followed by water and brine. The organic material was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 4OM column eluting with hexanes:ethyl 29 acetate (9: 1) to yield methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoate (2.65 g, 65.3% yield) as a clear oil.; Example 44 2-(3-cyano-4-(4-(4-chlorophenethylcarbamoyl)phenoxy)phenyl)acetic acid[00230] Step A: A flask was charged with tert-bulyl 2-(3-cyano-4-fluorophenyl)acetate (9.410 g, 40.00 mmol), methyl 4-hydroxybenzoate (7.303 g, 48.00 mmol), K3CO3 (6.634 g, 48.00 mmol), and DMSO (160 mL). The mixture was heated to 90 0C under a nitrogen atmosphere for 17 hours. The mixture was cooled to ambient temperature and poured into a mixture of EtOAc (250 mL) and 10% K2CO3 solution (250 mL). The resulting insoluble residue was dissolved in water and added to the EtOAc-aqueous mixture. The mixture was stirred for 1 hour and layers were separated. The aqueous layer was extracted with EtOAc, and the combined extracts were washed with saturated KjCO3, water, and brine, dried over MgSO4, filtered through a Celite pad, and concentrated under reduced pressure to give 14.7 g of crude product as an oil. The crude material was purified by silica gel chromatography to provide methyl 4-(4-(2-tert-butoxy-2-oxocthyl)-2-cyanophcnoxy)benzoate (11.6 g, 79%) as a white solid.; Example 652-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-((N- methylmethylsulfonamido)methyl)phenyl)acetic acid 58(00271) Step A: To a stirred solution of tert-buty 2-(3-cyano-4-fluorophcnyl)acetatc (1.00 mg, 4.25 mmol) and methyl 4-hydroxybenzoate (776 mg, 5.10 mmol) in DMSO (20 ml) was added K2CO3 (704 mg, 5.10 mmol). The reaction was heated to 90 0C overnight via an oil bath. The reaction was diluted with ethyl acetate and 10% aqueous sodium carbonate. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with 10% aqueous sodium carbonate and brine, dried over MgSO4, concentrated and purified by silica gel chromatography to give methyl 4-(4-(2-ftτv-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoate (1.08 g). |
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