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With potassium carbonate In acetone at 20℃; for 24 h;
To a mixture of 4-methyl-3-(trifluoromethyl) benzoic acid (1 equiv), K2C03 (1.5 equiv) in acetone (15 times) was added Mel (1.5 equiv) at room temperature. Stirring was continued for 24h. Reaction was monitored by thin layer chromatography. The salts were filtered and resulting filtrate was concentrated, diluted with water, extracted with ethyl acetate. Concentration of organic layer afforded the pale yellow oil (95percent yield). ESI MS m/z -219 (M+H l)+.
20 mmol of 3-trifluoromethyl-4-methyl-benzoic acid was dissolved in a round-bottomed flask containing 60 mL of methanol.A catalytic amount (3percent mmol) of concentrated sulfuric acid was added and the reaction was stirred at reflux overnight.The solvent was removed on a rotary evaporator, and 30 ml of a saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate (2×50 ml) and drying over anhydrous sodium sulfate.The solvent was removed on a rotary evaporator to give 3-trifluoromethyl-4-methyl-benzoic acid methyl ester compound a (yield: 96percent).
95%
for 6 h; Reflux
Example 88: preparation of methyl 5-(5-(4~((3-(dimethylamino)pyrrolidin~1-yl)methyl)-3- (trifluoro-methyl)benzamido)-2-methylbenzamido)-1H~pyrrolof2,3-b]pyridine-2- carboxylate (ND0119); Step 1: preparation of methyl 3-(trifluoromethyl)-4-methylbenzoate; A reactor is charged with 1q (4.9mmol) of 3-(trifluoromethylH-methylbenzoic acid in 10ml methanol in the presence of a catalytic amount of sulphuric acid. The mixture is heated for 6 hours at reflux. The solvent is then evaporated under reduced pressure and 100ml of a saturated sodium bicarbonate solution is added to the mixture. The solution is extracted by 3*30ml ethyl acetate. The organic phases are combined, dried on sodium sulphate and evaporated under reduced pressure to give the expected product (1α. 95percent).
95%
Reflux
General procedure: General procedure for esterification: 4-methyl-3 -substituted benzoic acid (24 mmol) in methanol (50 mL) with H2SO4 (0.260 mL, 4.8 mmol) are stirred and heated to reflux for one night. Methanol is evaporated and product is extracted at pH = 7 with EtOAc.
88.4%
Stage #1: at 0 - 20℃; for 1 h; Stage #2: at 80℃; for 5 h;
To a stirred methanol (300 mL) was added dropwisely sulfurous dichloride (30 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. To this stirred solution was added 4-methyl-3-(trifluoromethyl)benzoic acid (30 g, 0.15 mol) in one portion at room temperature. The mixture was stirred at 80 °C for 5 hrs. The solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate and brine. The organic phase was dried over sodium sulfate anhydrous and concentrated. The residue (28.3 g, yield: 88.4percent) was used into next step directly. 1H NMR (400 MHz, CDC13) δ 8.24 (s, 1H), 8.03 (d, J= 8.0 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 3.90 (s, 3H), 2.50 (s, 3H)ppm.
84.8%
for 24 h; Reflux
4-methyl-3-(trifluoromethyl) benzoic acid (2.04 g, 10 mmol, 1.0 eq) in 25 mL of MeOH was added 2 mL of concentrated sulfuric acid. And the reaction monitored by TLC was completed after 24 hours under reflux with stirring. MeOH was distilled off and DCM was added to dissolved the residue. The solution was washed successively with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution and water. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give the product (1.85 g, 84.8percent yield) for the next step.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 1.5h;Heating / reflux; irradiated with a 125 W lamp;
Step 11.4: 4-Bromomethyl-3-trifluoromethyl-benzoic acid A suspension containing 16.33 g (0.08 mol) <strong>[261952-01-6]4-methyl-3-(trifluoromethyl)-benzoic acid</strong>, 17.08 g (0.096 mol) N-bromosuccinimide and 0.96 g (0.003 mol) dibenzoyl-peroxide in 500 mL tetrachloromethane is heated under reflux and irradiated with a 125 W lamp for 1.5 h. The mixture is cooled to 10° C. filtered and the filtrate concentrated to about 50 mL. The solid is filtered off, washed with a small amount of cold tetrachloromethane and dried. The title compound was used without further purification: mp. 136-140° C.; HPLC tR=3.40 min.
With sodium bromate; sodium hydrogensulfite; In Isopropyl acetate; water; at 30 - 60℃;Heating / reflux;
Step 1 4-(bromomethyl)-3-trifluoromethylbenzoic acid To 60.0 g of <strong>[261952-01-6]4-methyl-3-trifluoromethylbenzoic acid</strong> was added 600 ml of isopropyl acetate. Under stirring at room temperature, a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water were added in turn. The mixture was gradually heated from 30°C up to 50°C at intervals of 10°C and stirred until the color of the reaction solution disappeared. The aqueous layer was separated to remove, and to the organic layer were added a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water, and then the mixture was gradually heated up to 60°C as above. After separation, to the organic layer were further added a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water, and the mixture was gradually heated as above and heated to the temperature the mixture was finally refluxed. After the completion of the reaction, the reaction solution was separated, the organic layer was washed twice with a 5percent aqueous sodium thiosulfate solution and twice with 15percent saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the residue was added 120 ml of n-heptane, the mixture was stirred, and then the crystals were collected by filtration to obtain 50.0 g of the objective compound as colorless crystals. Melting point: 140-143°C
With sodium bromate; sodium hydrogensulfite; In water; ethyl acetate; at 20 - 50℃;
Step 1: synthesis of 4-(bromomethyl)-3-(trifluoromethyl)benzoic acid (35) To a solution of sodium bromate (1109 mg, 7.35 mmol) in H20 (3.3 mL) was added 4- methyl-3-trifluoromethyl-benzoic acid (500 mg, 2.449 mmol) in ethyl acetate (5 mL), followed by a solution of sodium bisulfite (765 mg, 7.35 mmol) in H20 (9 mL) over a period of about 15 min. The mixture was stirred overnight at room temperature and overnight at 50 °C. The mixture was poured in ether (50 mL). The aqueous layer was extracted twice with ether and the combined organic layer was washed with anhydrous Na2S203 solution, dried, filtered and concentrated in vacuo to give the crude 4- (bromomethyl)-3-(trifluoromethyl)benzoic acid 35 (563 mg, 81percent) which was used without further purification, (m/z) = 282 and 284 (M+H)+.
With sodium bromate; sodium hydrogensulfite; In Isopropyl acetate; water;Reflux;
Step 1.Synthesis of 4-(bromomethyl)-3-(trifluoromethyl)benzoic acid1.0 g of <strong>[261952-01-6]4-methyl-3-(trifluoromethyl)benzoic acid</strong> was dissolved in isopropyl acetate (q.s.).To the mixture, sodium bromate aqueous solution (10 ml, containing 2.2 g of sodium bromate) and sodium bisulfite aqueous solution (10 ml, containing 1.52 g of sodium bisulfite) were added alternatively with stirring.After addition, the solution became brownish red.The mixture was heated to reflux until the solution became colorless.Then the organic layer was separated.Again, to the mixture, sodium bromate aqueous solution (10 ml, containing 2.2 g sodium bromate) and sodium bisulfite aqueous solution (10 ml, containing 1.52 g sodium bisulfite) were added alternatively and the mixture was heated to reflux until the solution became colorless.Then the organic layer was separated.Continually, to the mixture, a sodium bromate aqueous solution (10 ml, containing 2.2 g sodium bromate) and a sodium bisulfite aqueous solution (10 ml, containing 1.52 g sodium bisulfite) were added alternatively, and the mixture was heated to reflux until the solution became colorless.Then the organic layer was separated.The organic layer was washed with 5percent sodium sulfate solution twice and 15percent sodium chloride solution twice, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to dry.The is residue was stirred in petroleum ether, and filtered to give a white solid. m.p. 140-145° C.
With sodium bromate; sodium hydrogensulfite; In water; ethyl acetate; at 20 - 50℃;
Step 1: synthesis of 4-(bromomethyl)-3-(trifluoromethyl)benzoic acid (35) To a solution of sodium bromate (1109 mg, 7.35 mmol) in H2O (3.3 mL) was added <strong>[261952-01-6]4-methyl-3-trifluoromethyl-benzoic acid</strong> (500 mg, 2.449 mmol) in ethyl acetate (5 mL), followed by a solution of sodium bisulfite (765 mg, 7.35 mmol) in H2O (9 mL) over a period of about 15 min. The mixture was stirred overnight at room temperature and overnight at 50° C. The mixture was poured in ether (50 mL). The aqueous layer was extracted twice with ether and the combined organic layer was washed with anhydrous Na2S2O3 solution, dried, filtered and concentrated in vacuo to give the crude 4-(bromomethyl)-3-(trifluoromethyl)benzoic acid 35 (563 mg, 81percent) which was used without further purification. (m/z)=282 and 284 (M+H)+.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 100℃; for 19h;
A mixture of <strong>[261952-01-6]4-methyl-3-(trifluoromethyl)benzoic acid</strong> (3.95 g, 19.4 mmol), N-bromosuccinimide (3.84 g, 21.6 mmol) and 2,2?-azobisisobutyronitrile (300 mg, 1.82 mmol) in 200 mL carbontetrachloride was heated at 100 oC. After 18 h, additional portions of N-bromosuccinimide (800 mg, 4.49 mmol) and 2,2?-azobisisobutyronitrile (100 mg, 0.61 mmol) were added, and the mixture was heated at 100 oC for 1 h. The reaction mixture was cooled to room temperature, and filtered. The filtrate was concentrated to yield 4-(bromomethyl)-3-(trifluoromethyl)benzoic acid (4.6 g, 84 percent) which was taken onto the next step without purification.
A solution of commercially available <strong>[261952-01-6]4-methyl-3-trifluoromethylbenzoic acid</strong> (24.5 g, 120mmol) and cone, sulfuric acid (6.5 ml) in dry ethanol (245 ml) is refluxed for 23h. Afterreaching room temperature the solvent is evaporated and the residue is neutralized by addition of saturated aqueous NaHCO3 solution. The mixture is extracted with ethyl acetate (3x 40 ml). The organic extracts are combined, dried over Na2SO4 and evaporated to dryness to afford a pale yellow oil: HPLC: tR = 7.15 min (purity: > 96percent, gradient A), ESI-MS: 233.3 [MH]+.
With sulfuric acid;Reflux; Inert atmosphere;
Intermediate 19: Ethyl 4-methyl-3-(trifluoromethyl)benzoate; To a slight suspension of <strong>[261952-01-6]4-methyl-3-(trifluoromethyl)benzoic acid</strong> (2.18 g, 10.7 mmol, ABCR) in ethanol (30 ml) was added concentrated sulphuric acid specific gravity 1.84 (0.5 ml, 9.38 mmol). The resulting solution was heated to reflux overnight under nitrogen. The solution was diluted with DCM (100 ml) and then water (100 ml). The phases were separated and the organic extract washed with saturated aqueous sodium hydrogen carbonate (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a mobile pale yellow oil(2.27 g).; LCMS: (System 4) MH+= 233, tRET = 3.29 min.
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