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With hydrogenchloride; In water; for 2.5h;Heating / reflux;
Example 12 Synthesis of Ester Precursors to Compounds of Formula II Methyl 3-fluoro-5-trifluorophenylacetate A mixture of <strong>[195447-79-1]3-Fluoro-5-trifluoromethyl-phenylacetic acid</strong> (4.72 g, 21.2 mmol) and concentrated HCl (1.2 mL) in MeOH (50 mL) was refluxed for 2.5 h, then concentrated in vacuo. The residue was partitioned between 100 mL of EtOAc and washed sequentially with 0.5N aqueous NaOH (30 mL), 2% NaHCO3 solution (30 mL), and brine (30 mL). The EtOAc layer was dried (Na2SO4), filtered, and concentrated to provide 5.01 g (quantitative) of methyl 3-fluoro-5-trifluoromethyl-phenylaceiate as a colorless oil: 1H NMR (CDCl3, 300 MHz) delta 3.69 (s, 2H), 3.73 (s, 3H), 7.21-7.73 (m, 3H).
Example 13 Synthesis of Aldehyde Precursors to Compounds of Formula II 3-Fluoro-5-trifluoromethyl-phenylacetaldehyde To a solution of 5.0 g (21.2 mmol) of methyl-3-fluoro-5-trifluorophenylacetate in 21.2 mL of CH2Cl2 and 10.6 mL of hexane, cooled to -70 C. in an argon atmosphere, was added 17.0 mL (25.4 mmol) of a 1.5M solution of DIBAL-H in toluene over approximately two minutes. The mixture was allowed to warm to -50 C. over 1 h, and 21.2 mL of MeOH was added, followed by 14 mL of 6 N HCl and 21.2 mL of H2O. The mixture was extracted with EtOAc, and the EtOAc layer was washed sequentially with H2O and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (¼ EtOAc/hexane) to provide 4.10 g (94%) of product as a colorless oil: 1H NMR (CDCl3) delta 3.82 (s, 2H), 7.11-7.31 (m, 3H), 9.80 (s, 1H).
Example 25; Synthesis of {3-[4-(2,2-Dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid (Compound 32)To benzyl alcohol (1.1 g, 10 mmol) in NMP (20 mL) was added sodium hydride (60% in mineral oil; 0.44 g, 11 mmol), and the mixture was stirred for 30 minutes at room temperature. The mixture was then added to a vial containing <strong>[195447-79-1]3-fluoro-5-(trifluoromethyl)phenylacetic acid</strong> (1 g, 4.5 mmol), and the reaction was stirred at 120 C. for 3 hours. Acidic work-up gave (3-benzyloxy-5-trifluoromethyl-phenyl)-acetic acid the title compound.
methyl 4-(3-fluoro-5-(trifluoromethyl)phenyl)-3-oxobutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
To a solution of 2-(3-fluoro-5-(trifluoromethyl)phenyl)aceticacid (9.96 g, 44.8 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione(8.40 g, 58.3 mmol) and EDCI (11.2 g, 58.3 mmol) in anhydrous DMF (30 mL) was added N,N-dimethylaminopyridine (8.76 g,71.7 mmol) at room temperature. The mixture was stirred for 4 h. The mixture was poured into 1 N aqueous HCl solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in MeOH (50 mL). The mixture was refluxed overnight. After cooling, the mixture was concentrated in vacuo.The residue was purified by column chromatography (silica gel,eluted with 0-10% EtOAc in hexane) to give 7.7 g (48%) of 36 as a yellow oil. 1H NMR (300 MHz, CDCl3) d 3.53 (2H, s), 3.76 (3H, s),3.93 (2H, s), 7.08-7.38 (3H, m).
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