2-Amino-5-chloro-3-methylbenzoic acid

Light yellow crystalline powder

In 100ml of round flask , add 20ml of 3-methyl-2-amino-benzoic acid, 50ml of DMF, 30ml mmol of N- chlorosuccinimide(or N- bromosuccinimide ) and after stirred atreflux for 3h, the reaction solution was poured into ice water and dilutehydrochloric acid acidifying to pH = 6. Filtered andthe resulting solid was washed small amount of ethanol to give a gray solidchlorinated or brominated anthranilate III.yield 83percent. Y selected from :cholrine and bromine.To a 100 ml round bottom flask was added 3.0 g of 20 mmol 3-methyl-2-aminobenzoic acid X, 30 ml of DMF, 6.7 grams of 30 millimoles of NCS (or 30 millimoles of NBS), After stirring for 3 hours, The reaction solution was poured into ice water, Dilute hydrochloric acid to pH = 6, filter, The resulting solid was washed with a small amount of ethanol to give 2-amino-3-methyl-5-halo-benzoic acid III, Gray solid, 4.6 grams or more, Yield is greater than 83percent.Y selected from:chlorine, bromine, The 2-amino-3-methyl-5-halo-benzoic acid III is selected from the group consisting of -2-amino-3-methyl-5-chlorobenzoic acid, 2-amino-3-methyl-5-bromo-benzoic acidPreparation of methyl 2-amino-5-chloro-3-methylbenzoateStep A: Preparation of 2-amino-5-chloro-3-methylbenzoic acidTo a solution of 2-amino-3-methylbenzoic acid (Aldrich, 15.0 g, 99.2 mmol) in Ny/V-dimethylformamide (5O mL) was added TV-chlorosuccinimide (13.3 g, 99.2 mmol) and the reaction mixture was heated to 100 °C for 30 minutes. The heat was removed and the reaction mixture was cooled to room temperature and allowed to stand overnight. The reaction mixture was then slowly poured into ice water (250 mL) to precipitate a white solid.The solid was filtered and washed four times with water and then taken up in ethyl acetate (900 mL). The ethyl acetate solution was dried (MgSOStep A: Preparation of 2-Amino-3-methyl-5-chlorobenzoic acidStep A: Preparation of2-Amino-3-methyl-5-chlorobenzoic acid To a solution of 2-amino-3-methylbenzoic acid (Aldrich, 15.0 g, 99.2 mmol) in N, N-dimethylformamide (50 mE) wasadded N-chlorosuccimide (13.3 g, 99.2 mmol) and the reac35 tion mixture was heated to 100° C. for 30 minutes. The heatwas removed, the reaction was cooled to room temperatureand let stand overnight. The reaction mixture was then slowlypoured into ice-water (250 mE) to precipitate a white solid.The solid was filtered and washed four times with water andthen taken up in ethyl acetate (900 mE). The ethyl acetatesolution was dried over magnesium sulfate, evaporated underreduced pressure and the residual solid was washed with etherto afford the desired intermediate as a white solid (13.9 g).‘H NMR (DMSO-d5) ö 2.1 (s, 3H), 7.22 (s, 1H), 7.55 (s, 1H).[0521] The 5-CHLORO-7-METHYL-LH-INDOLE-2, 3-dione (25.0 g, 0.13 mol), potassium hydroxide (8.4 g, 0.15 mmol) and 30percent hydrogen peroxide (21.6 g, 0.18 mol) were mixed together in methanol (300 mL) at 0°C for 2 h followed by 16 h at room temperature. The solution was poured into ethyl acetate (500 mL) and extracted with 1 N hydrochloric acid (3 x 200 mL) followed by brine (1 x 50 mL). The solution was dried over sodium sulfate and solvent removed at reduced pressure. The 2-amino-5-chloro-3-methylbenzoic acid (18.0 g, 0.10 mmol) was isolated as a yellow solid (75percent yield). HRMS 7NEZ 185.0238 ; calcd 185.0244.The procedure of Example 3 was modified by using aqueous methylamine (40percent solution, 10.75 g, 0.138 mol) instead of anhydrous methylamine. Obtained after collection of solid and drying was 18.57 g of crude product, which ηPLC showed containing the title compound in only 92.4 wt. percent purity, thus corresponding to 87.3percent yield. ηPLC showed the crude product also containing about 3.4 wt. percent of 6-chJoro-3, 8-dimethyl-2, 4(lH, 3H)- quinazolinedione derived from cyclization of the 5-chloro-3-methyl-2-[[(methylamino)- carbonyl]amino]benzoic acid by-product, and about 1.7percent of the hydrolysis product 2-amino- 5-chloro-3-methylbenzoic acid. This Example demonstrates that water has a detrimental effect on the yield and purity of the product.

Molecular Weight:185.61
XLogP3:2.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:185.0243562
Monoisotopic Mass:185.0243562
Topological Polar Surface Area:63.3
Heavy Atom Count:12
Complexity:186
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes