Methyl 3-amino-2-methylbenzoate

off-white powder

10percent Palladium on carbon (500 mg) was added to a nitrogen flushed solution of methyl 2-methyl-3-nitrobenzoate (11.75 g, 60.2 mmol) in methanol (150 ml) and the resulting mixture hydrogenated at 50 psi until H2 uptake ceased. The catalyst was removed by filtration and the filtrate evaporated to dryness to give the title compound as a clear oil (9.9 g, 100 percent). H NMR (400 MHz, CDCL3) 8 2.34 (3H, s), 3.72 (2H, br s), 3.87 (3H, s), 6.80 (LH, dd, J 7.9 and 1.0), 7.04 (1H, t, J 7. 8), 7.20 (LH, dd, J 7. 8 and 1.0).A. A. A. -amino-2-methylbenzoate[01 1 62] To stirred solution of methyl 3-amino-2-methylbenzoic acid (5 g, 33.1 mmol) in methanol (50 mL), was added cone. H3-amino-4-methylbenzoic acid (15.00 g, 0.099 mol) was suspended in MEOH (150 mL) and thionyl chloride (25. 33 mL, 0.347 mol, 3.5 equiv. ) was added dropwise. The mixture was heated overnight at 70 C. After cooling to RT, volatiles were removed under reduced pressure and the residue triturated with ether (150 mL). The solid was filtered off and dried (18.36 g). The solid was suspended in DCM (600 mL) and saturated aqueous NAHC03 (250 mL) was added. After stirring for 15 minutes, the organic layer was separated and washed successively with NAHC03 solution (2 x 250 mL), water (250 mL) and brine (250 ML). The solution was dried (NA2SO4), filtered and evaporated to dryness to give the desired aniline (14. 8 G, 90percent yield).STEP 1 : To 3-amino-2-methylbenzoic acid (500 mg, 3.3 mmol) in methanol (20 ml) was added sulfuric acid (500 μl) and heated to 7OMethyl-3-amino-2-methyl benzoate (0.3 g, 1.96 mmol) was stirred in aqueous NaNO2 (0.62 g, 2 mmol) followed by addition of 7 mL dilute glacial acetic acid in water (7 mL, 3 mmol) (0.2:10). The reaction mixture was allowed to stir for 4-6 hrs. The mixture was then extracted with EtOAc and washed with water (2.x.10 mL). The organic layer was dried over Na2SO4, concentrated and subjected to column chromatography to obtain yellow powder. The yield was 0.22 g, 69percent; m.p. 153-155° C. 1H NMR (400 MHz CDCl3, TMS, ppm) delta 2.55 (s, 3H), 7.37 (t, 1H, J=14.32 Hz), 7.53 (s, 1H), 7.67 (d, 1H, J=8.12 Hz), 7.82 (d, 1H, J=8.16 Hz), 9.79 (s, 1H).Reference methyl 1H-indazole-4-carboxylate A mixture of methyl 3-amino-o-toluate (100 g, 605 mmol), a solution of ammonium tetrafluoroborate (83.0 g, 787 mmol) in water (600 mL) and concentrated hydrochloric acid (121 mL, 3.93 mmol) was cooled to 0°C, and a solution of sodium nitrite (41.8 g, 605 mmol) in water (88 mL) was added dropwise to the mixture over 25 min. This mixture was stirred for 35 min, and the resulting solid was collected by filtration. This solid was washed with water, methanol and diethyl ether, dried under nitrogen atmosphere, and added to a solution of potassium acetate (65.4 g, 666 mmol) and 18-crown-6 (4.50 g, 17.0 mmol) in chloroform (1.37 L). The resulting mixture was stirred at room temperature for 2 hr, and water (700 mL) was added. The partitioned organic layer was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with hexane, and collected by filtration to give the title compound (63.0 g, yield 59percent). 1H-NMR (CDCl3) delta: 4.03 (3H, s), 7.47 (1H, dd, 8.4, 7.2 Hz), 7.73 (1H, d, J = 8.4 Hz), 7.96 (1H, d, J = 7.2 Hz), 8.61 (1H, s), MS (ESI+): 177 (M+H).Step 3: methyl 1 H-indazole-4-carboxylate; To a cold (0°-5° C) solution of methyl-3-amino-2-methyl benzoate (16.6 mL, 19.0 g, 0.12 mol) in chloroform (200 mL) was added dropwise acetic anhydride (24.8 mL, 0.26 mol) followed by stirring for 5 minutes. The resulting mixture was allowed to warm to room temperature and stirred for 1 hour and then was added potassium acetate (3.35g, 0.034 mol) and isoamyl nitrite (33.0 mL, 0.25 mol) and heated under reflux for 20 hours. The mixture was cooled to room temperature and solvent was evaporated to yield a brown solid. Water was added to the solid, followed by evaporation to yield a solid residue. The residue was treated with concentrated hydrochloric acid and the resulting mixture was heated at 500C for 2 hours. After cooling with an ice bath, the solution was basified to pH 14 with a 50percent potassium hydroxide solution. The resulting solid was collected by filtration, washed with water and dried to yield 17.8 g of methyl 1 H-indazole-4-carboxylate as a beige solid. MS: 177.0 [M+H].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.Step 1: Methyl 3-(chlorosulfonyl)-2-methylbenzoateInto a 100-mL round-bottom flask, was placed methyl

Molecular Weight:165.19
XLogP3:1.5
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