Benzoic acid, 4-amino-3-(trifluoromethyl)-, methyl ester

b) 4-Amino-3-trifluoromethyl-benzoic acid methyl ester; To a solution of 4.0 g (16.1 mmol) 4-nitro-3-trifluoromethyl-benzoic acid methyl ester in 50 mL methanol 0.4 g 10percent palladium on charcoal was added and the suspension stirred for 2 h at room temperature under an atmosphere of hydrogen (1.7 bar). After the addition of 100 mL ethyl acetate the catalyst was filtered off, the filtrate evaporated and dried under high vacuum to give the title compound as a white solid (98percent) which was used in the next step without further purification.The title compound was prepared following the procedure described in step-2 of Intermediate6 by using methyl 4-nitro-3-(trifluoromethyl)benzoate (4.0 g, 0.016 mmol) 10percent Pd/C in MeOH (50 mL) to afford 3.5 g of title product. ‘H NMR (300 MHz, DMSO-d6): 7.89 (s, 1H), 7.82-7.79 (d, J = 8.7 Hz, 1H), 6.87-6.84 (d, J = 8.7 Hz, 1H), 6.49 (s, 2H); MS [M+Hj:220.Thionyl chloride (1.43g, 0.012 mol) was added dropwise to methanol (8 mL) chilled to -0.6 °C at a rate that did not allow the temperature to exceed 0, 7 °C. The resulting mixture was stirred at 0 °C for 45 min., then 4- amino-3-(trifluoromethyl) benzoic acid (0.5g, 0.0024 mol) [Matrix Scientific] was added in one portion. The reaction mixture was stirred at 0 °C for one hr., allowed to come to ambient temperature and was stirred for ~3 days. The mixture was concentrated in vacuo. Water (10 mL) was added to the residue and sodium bicarbonate (0.3 g, 3.6 mmol) was added in one portion and the mixture was stirred at ambient temperature for 45 min. The mixture was extracted several times with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give 0.49g (93percent) of methyl 4-amino-3- (trifiuoromethyl)benzoate as a pinkish-tan colored solid. MS: m/z 220.1 (MHTo a 250 mL round bottom flask was added 4-amino-3-(trifluoromethyl)benzoic acidA-.Sa (8 g, 39.0 mmol, 1.0 equiv.), tetrahydrofuran (40 mL), methanol (40 mL), andTMSCI·IN2 (40 mL, 2.0 equiv.). The resulting mixture wa.s stirred at room temperatureovemight and then concentrated in vacuo. The resulting residue vvas purified via silica gelcolumn eluting with ethyl acetate/petroleum ether (1:5) to give ofmethyl4-amino-3-10 (trifluoromethyl)benzoate A-5b (7 g, 82percent;) as a colorless solid.Under nitrogen or argon, 0.4 mmol, 0.2mmol, Ir (ppy) 3 (2mg) and DMF1 ml was added to the reaction flask, followed by blue LEDlights (7W) at room temperature irradiation straight trivalent iodine reagent completeconversion of the reaction. Add 10 ml of saturated Na 2CO 3Aqueous solution, andextracted three times with ethyl acetate, washed with a saturated brine, dried overanhydrous Na 2SO 4The organic layer was dried. Column chromatography (eluent: petroleum ether 60-90: ethyl acetate = 15: 1-8: 1) to give the product in 67 percent.81.70 g (439 mmol) 4-amino-3-trifluoromethyl-benzonitrile are dissolved in 1000 ml of methanol, cooled to 0° C. Within 1.2 hours hydrochloric acid is added in gaseous form. Then the reaction mixture is refluxed for 5 hours with stirring, then diluted with water, cooled to 3° C. and suction filtered. The precipitate is washed with water and dried. Yield: 73.10 g (76percent of theoretical)To a 250 mL round bottom flask was added 4-amino-3-(trifluoromethyl)benzoic acid A- 5a (8 g, 39.0 mmol, 1.0 equiv.), THF (40 mL), MeOH (40 mL), and TMSCHN2 (40 mL, 2.0 equiv.). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The crude product was purified via silica gel column chromatography, eluting with EtOAc:PE (1 :5) to give methyl 4-amino-3-(trifluoromethyl)benzoate A~5b (7 g, 82%) as a colorless solid.To a 250 rnL rmmd-bottom Hask was added methyl4-amino-3-(trifluoromethyl)benzoate A-Sh (2.2 g, 10.04 mmol, 1.0 equiv), NaSCN (4 0 g, 49.34 mmoL 5.0 equiv), andAcOH (50 mL), followed by the dropwise addition of a solution of bromine (3.2 g, 20.0315 mrno1, 2.0 equiv) in AcOH (20 mL) at 0 C over l h. The reaction mixture vvas stirred f()r l hat 0 oe, and then at 40 C ovemight. After cooling to 0C, a second batch ofNaSCN (41 g, 50.57 mmol, 5.0 equiv) vvas added, follmved by the dropwise addition of a second batch ofbromine (3.2 g, 20.03 mmol, 2.0 equiv.) in AcOB (20 mL) over 1 h. The reaction mixturewas stirred at 0 C for 1 h and then at 40 C for 5 days. The reaction mixture was diluted20 with lOO mL ofvvater and the pH of the aqueous solution vvas adjusted to 9 with sodiumhydroxide pellets. The solids vvere collected by filtration, washed v.·ith water (20 mL x 2), and dried in an oven at 60 C for 6 h to provide 1.3 g (47%) ofmethyl2-arnino-4-(trifluoromethyl)-1, 3-benzothiazole-6-carboxylate A-.Sc (1.3 g, 47%) as a brov'll solid.To a 250 mL round-bottom flask was added methyl 4-amino~3- (trifluoromethyl)benzoate A-5b (2.2 g, 10.04 mmol, 1.0 equiv.), NaSCN (4.0 g, 49.34 mmol, 5.0 equiv.), and AcOH (50 mL), followed by the dropwise addition of bromine (3.2 g, 20.03 mmol, 2.0 equiv.) in AcOH (20 mL) at 0 C over 1 h. The reaction mixture was stirred for 1 h at 0 C, then overnight at 40 C. NaSCN (4.1 g, 50.57 mmol, 5, 0 equiv.) was added at 0 C, followed by the addition of bromine (3.2 g, 20.03 mmol, 2.0 equiv.) in AcOH (20 mL) over l h period. The reaction was stirred at 0 C for lh, then at 40 C for 5 days. The resulting mixture was diluted with of water (100 mL) and the pH of the resulting solution was adjusted to 9 using sodium hydroxide. The solids were collected by filtration, washed with water (20 ml x 2), and dried in an oven at 60 C for 6 h to provide 1.3 g (47%) of methyl 2-amino-4-(trifluoromethyl)-l, 3- benzothiazole-6-carboxylate A-5c (1.3 g, 47%) as a brown solid. The product was carried on to the next step without further purification.4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-(trifluoromethyl)benzoic acid (0821) (0822) To a solution of 300 mg (0.87 mmol) of the compound from in 3 ml of 49 DMF were added, at RT, 267 mg (0.96 mmol) of 407 4-(4, 6-dimethoxy-1, 3, 5-triazin-2-yl)-4-methylmorpholinium chloride and 211 mg (0.96 mmol) of 408 j00492] To a solution of methyl 4amino-3 -(trifluoromethyl)benzoate (220 mg, I mmoi) and DIPEA (390 mg, 3 inmol) in MeCN (5 mL) was added acryloyl chloride (108 mg, 1.2 mmol) dropwise at 0 C. The reaction was stirred at it for 1 h, then Na2CO3 aq.(sat.) was added, the resulting mixture was extracted with DCM (20 mL x 2). The combined organic layer was concentrated and purified with SGC (Hexane/EA=4/1) to give YLIUIiI400A (114mg, 35 %) as white solid. LCMS (ni/z): 328 [M + 1-11+.Sodium nitrite (1.21 g, 0.017 mmol) was added to tetrafluoro boric acid (20 mL) in lot wise manner at -10C. The solution was stirred for 1 h at same tempreture then added methyl 4- amino-3-(trifluoromethyl)benzoate (3.5 g, 0.0 15 mmol) and continued stirring for h at sametempreture followed by addition of solution of KI (3.18 g, 0.0 19 mmol) in acetone : water (40 mL:60 mL).The reaction mass was stirred at rt for 1 h. The reaction mass was diluted with water and filtered to afford 4.8 g of title compound. 'H NMR (300 MHz, CDC13): 8.28 (s, 1H), 8.15-8.12 (d, J= 8.1Hz, 1H), 7.84-7.81 (d, J= 8.1Hz, 1H), 3.95(s, 3H).

Molecular Weight:219.16
XLogP3:2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:2
Exact Mass:219.05071298
Monoisotopic Mass:219.05071298
Topological Polar Surface Area:52.3
Heavy Atom Count:15
Complexity:242
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes