5-AMINO-2-METHYL-BENZOIC ACID METHYL ESTER

Methyl 2-methyl-5-nitrobenzoate (5.0 g, 25.6 mmol) was dissolved in [ETOH] with Raney nickel under a 35 psi atmosphere of H2. The reaction was stirred for 20 h, then filtered through Celite washed with [MEOH] and concentrated in vacuo to afford 4.2 g (100percent) of methyl [5-AMINO-2-METHYLBENZOATE.]5-Amino-2-methylbenzoic Acid Methyl Ester (41). To a solution of nitro 35 (635 mg, 3.3 mmol) in EtOAc (10 mL) was added 10percent Pd-C (30 mg) and it was allowed to stir for 16 h at 23° C. under H6.3 g (32 mmol) of methyl 2-methyl-5-nitrobenzoate are dissolved in 80 ml of anhydrous methanol and then transferred into a steel reactor. The mixture is degassed with nitrogen and then 630 mg of Pd/C (5percent) are added. The reaction medium is then subjected to a hydrogen pressure of 4 bar and to a temperature of 80° C. for 14 hours and then brought to ambient pressure and temperature and filtered. The residue, after evaporation, is purified by chromatography on a silica column. A brown oil is obtained (m=4.6 g, Y=86percent).153.1 Methyl 5-amino-2-methylbenzoate (1.0 eq, 3.75 g) was dissolved in acetic acid (70 ml). N-Iodosuccinimide (1.0 eq, 5.27 g) was added portionwise over 60 minutes. The mixture was stirred at room temperature for 30 minutes. Acetic acid was evaporated. The residue was diluted with ethyl acetate (80 ml) and neutralized with saturated sodium carbonate (80 ml). The organic layer was washed with 1M sodium thiosulfate (2×40 ml), then water (2×40 ml) and brine (2×40 ml). The material was purified by flash chromatography on silica gel (gradient 10% to 30% ethyl acetate in hexanes) to provide methyl 5-amino-4-iodo-2-methylbenzoate as a yellow-orange solid (3.19 g, 49% yield). GCMS>95% pure, m/z 291. 1H NMR (400 MHz, DMSO, d6) delta 2.30 (s, 3H), 3.78 (s, 3H), 5.27 (br s, 2H), 7.24 (s, 1H), 7.54 (s, 1H).Iodine monochloride dichloromethane solution (1 M, 13.1 mL) was added to a mixture of 16 (1.58 g), methanol (16 mL), water (1.6 mL), and calcium carbonate (2.45 g) at 0 C. and stirred at room temperature for overnight. The reaction mixture was quenched with a solution of sodium sulfite (1 g) in water (4 mL) at room temperature for 1 hour, filtered and concentrated under reduced pressure. The concentrated solution was diluted with ethyl acetate (700 mL) and washed with water twice (50 mL each) followed by brine (30 mL), dried (Na2SO4), and evaporated. The residue was purified with flash chromatography (silica gel, 20:1 to 9:1 n-hexane/ethyl acetate) to give 17 (0.81 g, 34%). 17: pale-brown solid. Mp 77 C., 1H NMR (CDCl3, 400 MHz) delta 7.53 (s, 1H), 7.29 (s, 1H), 4.04 (s, 2H), 3.86 (s, 3H), 2.42 (s, 3H): 13C NMR (CDCl3, 100 MHz).General procedure: Pd/C (0.1 eq.) was added to a solution of the nitrobenzene (1.0 eq.) in EtOH (0.2 m). The suspension was degassed with H2and the reaction was stirred at room temperature upon complete consumption of the starting material. Then, the mixture was passed through a Celite pad and the filtrate was concentrated in vacuum. The product was used without any further purification.General procedure: To a solution of 6-bromopicolinic acid (50.0 g, 248 mmol) in methanol (350 mL) was added concentrated sulfuric acid (5 mL) dropwise at it After the addition, the mixture was heated to reflux until the reaction was completed, the solvent was distilled off in vacuo and the residue was diluted with water (300 mL). The system was adjusted with saturated sodium bicarbonate aqueous solution to weakly alkaline. The resulting mixture was extracted with EtOAc (200 mL x 2), and the combined organic layers were dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to give the title compound as a white solid (51.5 g, 96%).General procedure: 10.3 2-Chloro-5-(2-chloro-pyrimidin-4-ylamino)-N-(1-hydroxy-cyclohexylmethyl)-benzamide To a solution of intermediate 10.2 (179 mg) and DIPEA (0.431 mL) in DCM (3.2 mL) was added PyCloP (345 mg) and 1-aminomethyl-cyclohexanol hydrochloride (125 mg) at 0 C. The reaction mixture was stirred for 18 h at RT and diluted with DCM. The organic phase was washed with H2O, sat.-NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by CC (EtOAc) to give 122 mg of the titled compound as a white foam.3-(4-(2, 4, 4-trimethylpentan-2-yl)phenoxy)propanoic acid (1.0 equiv) and (E)-3-(4-(2, 4, 4-trimethylpentan-2-yl)phenoxy)acrylic acid (1.0 equiv) and

Molecular Weight:165.19
XLogP3:2.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:165.078978594
Monoisotopic Mass:165.078978594
Topological Polar Surface Area:52.3
Heavy Atom Count:12
Complexity:170
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes