2-Nitro-4-trifluoromethylbenzoicacid

Off-White to Pale Yellow Solid

aa) 2-Nitro-4-trifluoromethylbenzoic Acid 11.97 g of 4 trifluoromethylbenzoic acid (63 mmol) were added slowly in portions at RT to 48 ml of HNOGeneral procedure: A solution of the carboxylic acid 8 (4.00 g, 1 equiv) in anhydrous THF (50 mL) at 0 C was treated dropwise with H3B·THF complex (1 M inTHF, 2 equiv). 18 The reaction was stirred for 1 h at 0 C, 1 h at 23 C and then at reflux until TLC indicated the reaction was complete. The mixture was cooled and 10 mL of sat. NaCl was cautiously added. The mixture was transferred to a separating funnel, sat. NaCl (50 mL) was added and the mixture was extracted with Et2O (3 × 50 mL). The combined extracts were washed with one additional portion of sat. NaCl (50 mL), dried (MgSO4), filtered, and concentrated under vacuum. The resulting solid was crystallized from 2 % Et2O in hexanes and used directly in the next step. Yields ranged from 85 - 90 %.a) 0.56 g (0.00238 mol) of 2-nitro-4-trifluoromethyl-benzoic acid was dissolved in 7 ml of thionyl chloride and boiled under reflux for 2 hrs. The reaction mixture was concentrated and the residue was taken up twice in toluene and evaporated to dryness each time. 0.53 g (94%) of 2-nitro-4-trifluoromethyl-benzoyl chloride was obtained as a yellow oil.To carboxylic acid (205) (500 mg, 2.13 mmol), were added toluene (10 ml) and oxalyl chloride (0.37 ml, 2 eq). The mixture was reacted at 110C for 0.5 hour. The residue (206) obtained by evaporating the solvent under reduced pressure was dissolved in tetrahydrofuran (10 ml). Aniline derivative (207) (274 mg, 0.8eq) and triethylamine (0.36 ml, 1.2eq) were added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was added to ice water (30 ml), extracted twice with acetic acid ethyl ester (30 ml), washed twice with water (30 ml) and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure (208) (560 mg) was used in the next step without purification.2-Nitro-4-(trifluoromethyl)benzoic acid (3.0 g) is suspended in chloroform (25 ml), and thereto are added oxalyl chloride (1.67 ml) and N, N-dimethylformamide (2 drops) followed by stirring at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure, and to the residue is poured chloroform (20 ml) to obtain a suspension. Chloroform (30 ml) is added to 5-chloro-2-aminopyridine (1.56 g) and pyridine (1.55 ml), and the solution is ice-cooled. To the solution is added dropwise the suspension prepared above. The reaction solution is stirred at room temperature for 8 hours and concentrated under reduced pressure. The residue is diluted with ethyl acetate, washed successively with 10% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended into n-hexane, filtered and dried to give N-(5-chloropyridin-2-yl)-2-nitro-9-(trifluoromethyl)-benzamide (4.73 g). APCI-MS M/Z: 346/348[M+H]+To a suspension of In the general procedure, 2-Nitro-4-(trifluoromethyl) benzoic acid was converted to the corresponding acid chloride via addition of 1.03 equivalents of oxalyl chloride in dichloromethane. 1 , 3-Cyclohexanedione was converted to the enol via addition of 3.0 equivalents of triethylamine followed by addition of the previously prepared acid chloride. Catalytic trimcthylsilyl cyanide, TMSCN, (0.05 equivalents) was added and the reaction stirred overnight. The reaction was washed with 2M hydrochloric acid, extracted into 1M sodium hydroxide at pi 1- 12, acidified to pH-2, extracted into isopropylacetate and crystallised to give Nitisinone.To a stirred solution of 4-(pentafluorosulfanyl) benzoic acid (100.0 mg, 0.40 mmol) in ethyl acetate (2 mL) was added oxalyl chloride (100 muL, 1.2 mmol) and DMF (1 drop). After 20 minutes, the mixture was concentrated under vacuum. Toluene (1 mL) was added and then removed under reduced pressure twice to remove excess oxalyl chloride. Methylene chloride (2 mL) was added and the resulting solution was treated with 4-(4-isopropylpiperazin-1-ylsulfonyl)aniline (96 mg, 0.34 mmol) and N, N-diisopropylethylamine (70 muL, 0.40 mmol). After stirring 3 hours at room temperature, the mixture was concentrated and the residue partitioned between ethyl acetate (75 mL) and saturated sodium carbonate (25 mL). The aqueous layer was extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with saturated sodium carbonate (2 x 25 mL), and then brine (2 x 25 mL), dried (Na2SO4), filtered and concentrated to give the desired product as a solid.(0084) Thionyl chloride (162 g, 1.36 mol) was added dropwise into a suspension of 2-Nitro-4- (trifluoromethyl) benzoic acid (42 g, 180 mmol) was dissolved in 180 ml of toluene, thionyl chloride (26 g, 216 mmol) and dimethylformamide (0.70 ml, 9.0 mmol) were sequentially added , And the mixture was heated and stirred at 100 C. for 1 hour.After distilling off the solvent under reduced pressure, 100 ml of toluene was added again and the solvent was evaporated under reduced pressure in the same manner, 2-nitro-4-trifluoromethylcarboxylic acid chloride was obtained.To this was added 2-bromo-4- (trifluoromethoxy) aniline (55 g, 216 mmol) and pyridine (2.9 g, 36.0 mmol) sequentially and heated and stirred at 100 C. for 1 hour.After completion of the reaction, 1M sodium hydroxide aqueous solution was slowly added under ice cooling, extracted with ethyl acetate, and washed with saturated brine.The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and 2'-bromo-2-nitro-4 '- (trifluoromethoxy) -4- (tri Fluoromethyl) benzanilide (yield: 86%).

Molecular Weight:235.12
XLogP3:1.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:1
Exact Mass:235.00924210
Monoisotopic Mass:235.00924210
Topological Polar Surface Area:83.1
Heavy Atom Count:16
Complexity:299
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes