2-Chloro-5-(trifluoromethyl)benzoic acid

Off-white powder

Preparation of 2-chloro-5-trifluoromethylbenzoic acid [Show Image]n-BuLi (2.5M in hexanes, 22 mL, 55 mmol) was added over 8 minutes to a stirred solution of 4-chlorobenzotrifluoride (9.177 g, 50.8 mmol) and TMEDA (6.3030 g, 54.2 mmol) in THF (89 mL) at -78°C under nitrogen. After 52 min the solution was transferred via cannula into dry ice (.similar.200g) over 20 min. Care was required to sufficiently lag the cannula as the anion solution was found to darken rapidly on slight warming. The mixture was allowed to warm to ambient temperature with stirring and was evaporated (<30°C) to give and orange/yellow solid. The solid was dissolved in water (70 mL) and washed with diethyl ether (3x30 mL). The aqueous layer was acidified to pH 1 and extracted with DCM (3x30 mL). The organic layer was evaporated to dryness (< 30°C) and the residue was dissolved in refluxing hexanes, hot filtered and crystallised by cooling to 4°C overnight. The sandy coloured solid was isolated by vacuum filtration (4.5243 g). The mother liquors were concentrated by half and a second crop of lemon yellow crystals was obtained (2.2998 g). The products were dried under vacuum to give 4.5030 g and 2.2093 g respectively, giving a combined yield of 6.712 g (59 percent). LCMS: Rn-BuLi (2.5M in hexanes, 22 mL, 55 mmol) was added over 8 minutes to a stirred solution of 4-chlorobenzotrifluoride (9.177 g, 50.8 mmol) and TMEDA (6.3030 g, 54.2 mmol) in THF (89 mL) at -78°C under nitrogen. After 52 min the solution was transferred via cannula into dry ice (~200g) over 20 min. Care was required to sufficiently lag the cannula as the anion solution was found to darken rapidly on slight warming. The mixture was allowed to warm to ambient temperature with stirring and was evaporated (<30°C) to give and orange/yellow solid. The solid was dissolved in water (70 mL) and washed with diethyl ether (3x30 mL). The aqueous layer was acidified to pH 1 and extracted with DCM (3x30 mL). The organic layer was evaporated to dryness (< 30°C) and the residue was dissolved in refluxing hexanes, hot filtered and crystallised by cooling to 4°C overnight. The sandy coloured solid was isolated by vacuum filtration (4.5243 g). The mother liquors were concentrated by half and a second crop of lemon yellow crystals was obtained (2.2998 g). The products were dried under vacuum to give 4.5030 g and 2.2093 g respectively, giving a combined yield of 6.712 g (59 percent). LCMS: Rn-BuLi (2.5M in hexanes, 22 mL, 55 mmol) was added over 8 minutes to a stirred solution of 4-chlorobenzotrifluoride (9.177 g, 50.8 mmol) and TMEDA (6.3030 g, 54.2 mmol) in THF (89 mL) at -78 °C under nitrogen. After 52 min the solution was transferred via cannula into dry ice (~200g) over 20 min. Care was required to sufficiently lag the cannula as the anion solution was found to darken rapidly on slight warming. The mixture was allowed to warm to ambient temperature with stirring and was evaporated ((3x30 mL) . The organic layer was evaporated to dryness (< 30°C) and the residue was dissolved in refluxing hexanes, hot filtered and crystallized by cooling to 4°C overnight. The sandy coloured solid was isolated by vacuum filtration (4.5243 g) . The mother liquors were concentrated by half and a second crop of lemon yellow crystals was obtained (2.2998 g) . The products were dried under vacuum to give 4.5030 g and 2.2093 g respectively, giving a combined yield of 6.712 g (59 percent) . LCMS : RGeneral procedure: For a typical reaction, a Vapourtec 2R+ Series was used as the platform with a Vapourtec Gas/Liquid Membrane Reactor to load the carbon monoxide. The HPLC pump were both set at 0.125 mL/min, temperature of the reactor at 110 °C, pressure of CO at 15 bar with a back pressure regulator of 250 psi (17.24 bar). The system was left running for 2 h to reach steady state after which time the flow streams were switched to pass from the loops where the substrates and catalysts were loaded. The first loop (5 mL) was filled with a solution of palladium acetate (20 mg, 0.08 mmol), triphenylphosphine (48 mg, 0.168 mmol) in 6 mL of 1, 4-dioxane while the second loop (5 mL) was filled with a solution made from the ortho-substituted iodoarene substrate (1.68 mmol), triethylamine (0.272 g, 0.374 mL, 2.69 mmol) and water (0.505 g, 28 mmol) in 5.8 mL of 1, 4-dioxane. An OmnifitReference Example 2-9 Production Example 3 Step A: Preparation of 2-Chloro-5-trifluoromethylbenzoic acid A solution of 570 g (2.77 moles) of 2-chloro-5-trifluoromethylbenzonitrile (1) and 1140 g (28.5 moles) NaOH in 2.3 L water was heated at reflux in a 12 L flask overnight. TLC (silica gel, 20% ethyl acetate-hexane with 1 drop acetic acid/10 ml solution) showed reaction was complete. The solution was cooled, diluted with 3.5 L ice water and extracted with 1 liter ether. The aqueous extract was cooled in an ice bath, acidified to pH 2 with cold 50% H2 SO4 and extracted with four 1.3 liter portions of ether. The ether extracts were dried over Na2 SO4 and evaporated and the residue was triturated with 1.2 liters hot hexane, cooled, and filtered to afford 615 g (9%) of 2-chloro-5-trifluoromethylbenzoic acid as white needles, m.p. 93-94 C. Anal. Calcd. for C8 H4 O2 F3 Cl: C, 42.79; H, 1.79; Cl, 15.79; F, 25.38. Found: C, 42.73; H, 1.74; Cl, 15.43; F, 25.01.Step A: Preparation of 2-Chloro-5-trifluoromethylbenzoic acid A solution of 570 g (2.77 moles) of 2-chloro-5-trifluoromethylbenzonitrile (1) and 1140 g (28.5 moles) NaOH in 2.3 L water was heated at reflux in a 12 L flask overnight. TLC (silica gel, 20% ethyl acetate-hexane with 1 drop acetic acid/10 ml solution) showed reaction was complete. The solution was cooled, diluted with 3.5 L ice water and extracted with 1 liter ether. The aqueous extract was cooled in an ice bath, acidified to pH 2 with cold 50% H2 SO4 and extracted with four 1.3 liter portions of ether. The ether extracts were dried over Na2 SO4 and evaporated and the residue was triturated with 1.2 liters hot hexane, cooled, and filtered to afford 615 g (9%) of 2-chloro-5-trifluoromethylbenzoic acid as white needles, m.p. 93-94 C. Anal. Calcd. for C8 H4 O2 F3 Cl: C, 42.79; H, 1.79; Cl, 15.79; F, 25.38. Found: C, 42.73; H, 1.74; Cl, 15.43; F, 25.01.Reference Example 2-9 2-Chloro-5-(trifluoromethyl)benzoic acid The title compound was prepared according to the method described in Tetrahedron Lett., vol.37, p.2767 (1996). To a solution of 1-chloro-4-(trifluoromethyl)benzene (25.8 g, 143 mmol) and tetramethylethylene diamine (16.6 g, 143 mmol) in tetrahydrofuran (250 mL) cooled to -78 C., was added a solution of 1.6M butyllithium in hexane (89.4 mL, 143 mmol) was added dropwise under an argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. The solution was carefully poured onto crushed dry ice, and the resulting mixture was allowed to warm to room temperature. The solution was concentrated under reduced pressure, and the residue was poured into water. The solution was washed with diethylether, and subsequently made acidic by the addition of conc. hydrochloric acid, and organic matter was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was crystallized from hexane to give the title compound (20.6 g, 64% yield). NMR (CDCl3) delta: 7.65. (1H, d, J=8.4 Hz), 7.75 (1H, dd, J=2.2 Hz. 8.4 Hz), 8.31 (1H, d, J=2.2 Hz), hidden (1H)5.48 g of anthranilic acid, 8.98 g of 2-chloro-5-bromobenzoic acid, 5.52 g of K2CO3, 0.378 g of copper powder, and 1.14 g of CuI were added to a round-bottomed flask, and then DMF was added to the reaction at reflux 3 hours. After cooling, it was filtered, and dilute hydrochloric acid was added to the filtrate until the solution became weakly acidic, and the solid product 2-((2-carboxyphenyl) amino) -5-trifluoromethylbenzoic acid was obtained by stirring and suction filtration.

Molecular Weight:224.56
XLogP3:3.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:223.9851915
Monoisotopic Mass:223.9851915
Topological Polar Surface Area:37.3
Heavy Atom Count:14
Complexity:229
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes