Benzoic acid, 2-amino-3-methyl-, methyl ester

Pale brown liquid

Methyl 3-methyl-2-nitro benzoate (1g, 5.2mmol) was dissolved in ethanol (40mL) and then 10percent palladium on charcoal (0.1g) was added to the reaction mixture and stirred at rt for 10h. Then the mixture was filtrated, and evaporation of solvent under reduced pressure afforded the light yellow oil product. (0.85g, 99percent); δEXAMPLE 4Preparation of 2-amino-5-chloro-N, 3-dimethylbenzamideStep A: Preparation of methyl 2-amino-3-methylbenzoateMethyl 3-methyl-2-nitrobenzoate (98.5 g, 505 mmol), 5percent Pd/C (Degussa CE 105 XRCAV, 1.0 g), and acetonitrile (300 mL) were combined in a 600-mL pressure vessel. The mixture was heated to 70 °C and hydrogenated at 65 psi (450 kPa) for 8 h. More 5percent Pd/C (1.0 g) was added and hydrogenation was continued at 100 psi (690 kPa) for 8.5 h. Then the reaction mixture was cooled, purged with nitrogen, and filtered through Celite.(R). diatomaceous filter aid, rinsing with acetonitrile (3 x 25 mL). The combined filtrates were partly evaporated to a weight of ~ 160 g, and then diluted with acetonitrile to a total weight of 200 g. Quantitative HPLC of this solution showed 40.3 wtpercent of the title compound (80.6 g, 97.5percent yield).A mixture of 2-amino-3-methylbenzoic acid (15.2 g, 0.10 mol), dimethylformamide (333 mL) and CsCOTo a solution of 2-amino-3-methylbenzoic acid (66.9 mmol) in N, N-dimethylformamide (200 mL) was added cesium carbonate (102 mmol). The mixture was stirred for 30 min. A solution of methyl iodide (67.0 mmol) in NN-dimethylformamide (50 mL) was added dropwise and the reaction mixture was maintained for 18 h at rt. The reaction mixture was partitioned between water (1 L) and ether (200 mL) and the water layer was extracted with an additional volume of ether (100 mL). The combined extracts were washed with brine (500 mL), dried over anhydrous potassium carbonate, and concentrated, thus providing methyl 2-amino-3-methylbenzoate in 92percent yield.'H NMR (400 MHz, CDC13) 6 7.77 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 5.82 (bs, 2H), 3.86 (s, 3H), 2.17 (s, 3H). To a solution of the ester (106 mmol) in chloroform (300 mL) was added acetic anhydride (239 mmol) while maintaining the temperature below 40 °C. The reaction mixture was maintained at room temperature for 1 h when potassium acetate (30.6 mmol) and isoamyl nitrite (228 mmol) was added. The reaction mixture was heated at reflux for 24 h and was allowed to cool to room temperature. The reaction mixture was washed with a saturated, aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated. Methanol (100 mL) and 6 N hydrochloric acid (100 mL) were added to the residue and the mixture was maintained for 18 h at rt. The volatiles were removed under reduced pressure and the residue was triturated with ethyl acetate (100 mL). The product was isolated by filtration, washed with ethyl acetate (20 mL), and dried, thus providing methyl 1H-indazole-7-carboxylate hydrochloride in 68percent yield.'H NMR (500 MHz, Me2SO-d6) 8 13.3 (bs, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.25 (dd, 1H), 7.27 (t, 1H), 3.97 (s, 3H); MS (APCI) m/z 177 (M++1). A solution of the indazole (33.0 mmol) in methanol (100 mL) at 0 °C was treated with an 29percent aqueous solution of potassium hydroxide (20 mL). The reaction mixture was allowed to warm to rt and was maintained for 18 h. The pH of the solution was adjusted to 5.5 by the addition of concentrated hydrochloric acid and the volatiles were removed under reduced pressure. The residue was partitioned between brine (100 mL) and ethyl acetate (200 mL) and the aqueous layer was extracted with additional warm ethyl acetate (200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was triturated with ethyl acetate (30 mL) and the solids were isolated by filtration, thus providing the acid in 94percent yield.The synthesis was conducted in a round bottom flask where the 2-amino-3-methylbenzoic acid (0.3041 g; 2.0116 mmol) was suspended in 15 mL dry DMF and mixed with the catalyst CsTo a solution of 2-amino-3-methylbenzoic acid (10.1 g, 66.9 mmol) in N, N dimethylformamide (200 mL) was added cesium carbonate (33.2 g, 102 mmol, 1.5 eq). The mixture was stirred for 30 min. A solution of methyl iodide (4.17 mL, 67.0 mmol, 1.0 eq) in N, N-dimethylformamide (50 mL) was added dropwise and the reaction mixture was maintained for 18 h at rt. The reaction mixture was partitioned between water (1 L) and ether (200 mL) and the water layer was extracted with an additional volume of ether (100 mL). The combined extracts were washed with brine (500 mL), dried over anhydrous potassium carbonate, and concentrated to provide 10.2 g (92percent) of methyl 2-amino-3-methylbenzoate. 1H NMR (400 MHz, CDCl3) delta; 7.77 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 5.82 (bs, 2H), 3.86 (s, 3H), 2.17 (s, 3H)A solution of 2-amino-3-methylbenzoic acid (5.10 g) and concentrated sulfuric acid (5 mL) in methanol (200 mL) was heated under reflux for 24 hours. The reaction mixture was concentrated and was neutralized with a saturated sodium hydrogen carbonate aqueous solution. Insolubles were mixed with ethyl acetate and filtered. The filtrate was partitioned in a separatory funnel and the separated organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (dichloromethane/ethyl acetate 4:1) and 1.31 g (24percent) of the title compound was obtained as a light brown oil.To a solution of 2-amino-3-methylbenzoic acid (3.41 g, 27.1 mmol) in MeOH (70 mL) was added a 2.0M solution of TMSHCNA solution of To a solution of N-Bromosuccinimide (38.5 g, 216 mmol) was added to a mixture consisting of Step 1. To a solution of 17 (15.0 g, 90.8 mmol) in DMF (200 mL) was added NBS (16.2 g, 90.8 mmol) at 0C. After addition, the mixture was warmed to 15C and stirred for 14 hours. The reaction mixture was quenched by addition of water (200 mL) and then extracted with ethyl acetate (3 x 250 mL). The combined organic phase was washed with water (3 x 250 mL) and brine (2 x 200 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo to give 18 (21.0 g) as a gray solid which was used directly in the next transformation. 1H NMR (CDC13, 400MHz) delta 7.90-7.89 (d, 1H), 7.29-7.28 (d, 1H), 5.84 (s, 2H), 3.87 (s, 3H), 2.15 (s, 3H); LCMS (ESI): m/z 246.0 (M+H).

Molecular Weight:165.19
XLogP3:2
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