4-(Methylamino)-3-nitrobenzoic acid

Yellow Solid

Methyl 4-(methylamino)-3-nitrobenzoate (1.82 g, 8.66 mmol) was dissolved in a 1:1 ratio of tetrahydrofuran (THF) (41 .4 mL) and water (41.4 mL). To this was added lithium hydroxide (1.817 g, 43.3 mmol) and the reaction stirred at r.t. for 16 h. The reaction mixture wascooled to 0C and acidified by the addition of 5M HCI (—20 mL, until the pH reached —5) - a bright yellow precipitate formed, the slurry was filtered and the residue washed with distilled H20 (2 x 30 mL). The residue was collected and dried in vacuo at 50 00 to afford the product as a yellow solid (1.43 g, 7.29 mmol, 84 percent yield). This was used without further purification in the subsequent reactions.LCMS (Method B): Rt = 0.92 mi MHIntermediate 19: 4-(Methylamino)-3-nitrobenzoic acid Methyl 4-(methylamino)-3-nitrobenzoate (1.82 g, 8.66 mmol) was dissolved in a 1 : 1 ratio of tetrahydrofuran (THF) (41.4 mL) and water (41.4 mL). To this was added lithium hydroxide (1.817 g, 43.3 mmol) and the reaction stirred at rt for 16 h. The reaction mixture was cooled to 0 °C and acidified by the addition of 5M HC1 (-20 mL, until the pH reached -5) - a bright yellow precipitate formed, the slurry was filtered and the residue washed with distilled HTo a solution of 4-fluoro-3-nitrobenzoic acid (4.9 g, 27 mmol) in MeOH was added MeNHStep 1.Step 1: 4- (METHYLAMINO)-3-NITROBENZOIC acid (279) [0435] A 40percent solution of methylamine in water (11 mL; 128MMOL) (or any other primary amine) was slowly added to a stirring suspension of 4-fluoro-3-nitrobenzoic acid (278, 6. 1G ; 32. 9mmol) in DMF (20mL) at room temperature. After the addition was completed the mixture was stirred at the same temperature for 60min ; concentrated in vacuo, and suspended in 5percent KHSO4 (final pH=2). The suspension was stirred overnight; the precipitate was collected by filtration, washed with water, then with ether and dried to afford the title compound 279 (6.5g ; 100percent YIELD). 1H NMR: (400.2 MHz, DMSO) 8 (ppm): 12.8 (bs; 1H). 8.59 (d, J= 2.0 Hz; 1H); 8.55 (q, J= 5.0 Hz; 1H); 7.96 (dd, J= 2.0, 9.1 Hz; 1H); 7.04 (d, J= 9.1 Hz; 1H); 3.00 (d, J= 5. 0 Hz; 3H). MS: CALC : 196.2 ; found: 197.1 (M+H)(a) 4-Methylamino-3-nitrobenzoic acidTEA (13 ml.) and methylamine (2 M in MeOH, 35 ml_, 70 mmol) was added to 3, 4- dinitrobenzoic acid (10 g, 47.2 mmol) in EtOH (50 ml.) at rt. After 24 h at rt the mixture was concentrated and HA solution of 4-chloro-3-nitrobenzoic acid (30 g, 1.0 eq) in 200 mL CHA 250-mL round-bottom flask was charged with4-chloro-3-nitrobenzoic acid (20 g, 0.1 mol) and a solutionof ethylamine in water (60 percent, 86 mL, 0.8 mol).The mixturewas refluxed at 80 °C for 5 h. The solution was adjusted topH 4–5 with acetic acid. The precipitations of yellow solidswere filtered to get products 5 (19.6 g, 100 percent).a)400 g (1.98 mol) of 4-chloro-3-nitrobenzoic acid were suspended in 1025 g of a 25-30percent aqueous solution of methylamine. After heating to reflux temperature, an orange solution was obtained. The solution was kept at reflux temperature for 4 hours. The solution was cooled to room temperature, and pH was adjusted to about 2 by addition of 2M aqueous sulphuric acid. Precipitation of an orange solid was observed, which was isolated by filtration. The filtered cake was washed with 500 mL of water. The wet solid was mixed with 1.5 L of ethanol and heated to reflux temperature for 1 hour. After cooling to room temperature, the resulting suspension was filtered and the cake was dried at 60°C under vacuum to obtain 371 g of 4-(methylamino)-3-nitrobenzoic acid as an orange powder. Yield: 95.5 percent. Purity (HPLC, method 2): 99.4 percent.300 g (1 .49mo1) of 4-chloro-3-nitrobenzoic acid was suspended in 769 g of a 25-30percent aqueous solution of methylamine. After heating to reflux temperature, a clear solution was obtained. The solution was kept at reflux temperature for 2 hours and the completion of reaction was checked by TLC. The solution was cooled to room temperature, and pH of reaction mixture was adjusted to about 1 by addition of 2M aqueous sulphuric acid. Precipitation of a yellow solid was observed, which was isolated by filtration. The filtered cake was washed with water and subsequently with methanol to obtain 338 g of wet 4-(methylamino)-3-nitrobenzoic acid as a yellow powder.Yield: 280g (95.90percent); Purity by HPLC: 99.10 percent.In 3-nitro-4-chlorobenzoic acid (258, 0.124 1101) added 25percent -30percent methylamine aqueous solution 1501 ^, the system at higher than 100 ° C for 5-6h. After concentration under reduced pressure, glacial acetic acid was added to adjust the pH to 4-5. After standing overnight, a large amount of yellow solid precipitated and the solution was filtered off. The precipitate was recrystallized at least twice with 95percent ethanol to give 4-aminomethyl-3-nitro-benzoic acid as a yellow solid (18.5 g, yield 76percent ). Mass spectrum (ESI-MS): 197.2 (M + H) +, 219.4 (M + Na) +; C8H8N2O4 (196)A mixture of 4-chloro-3-nitrobenzoic acid compound of formula-8 (200 g) and 40percent solution of methyl amine (660 ml) was taken into autoclave and heated to 85-90° C. and stirred for 5 hours. (a) A solution of 4-chloro-3-nitrobenzoic acid (30 g, 1.0 eq) in 200 mL CH3NH2 (aq) was stirred at 100 C for 14 h, cooled, and concentrated in vacuo. The residue was poured into 200 mL 2N HC1 (aq) at C. The suspension was filtered and washed with water to give the product as yellow solid (quant). 'H NMR (400 MHz, DMSO-cf) delta 8.58 (d, J= 2.0 Hz, 1H), 8.51 (d, J= 5.2 Hz, 1H), 7.95 (dd, J= 9.2 Hz, 2.0 Hz, 1H), 7.02 (d, J= 9.2 Hz, 1H), 2.98 (s, 3H).A 250-mL round-bottom flask was charged with4-chloro-3-nitrobenzoic acid (20 g, 0.1 mol) and a solutionof ethylamine in water (60 %, 86 mL, 0.8 mol).The mixturewas refluxed at 80 C for 5 h. The solution was adjusted topH 4-5 with acetic acid. The precipitations of yellow solidswere filtered to get products 5 (19.6 g, 100 %).a) 4-(Methylamino)-3-nitrobenzoic acid 400 g (1.98 mol) of 4-chloro-3-nitrobenzoic acid were suspended in 1025 g of a 25-30% aqueous solution of methylamine. After heating to reflux temperature, an orange solution was obtained. The solution was kept at reflux temperature for 4 hours. The solution was cooled to room temperature, and pH was adjusted to about 2 by addition of 2M aqueous sulphuric acid. Precipitation of an orange solid was observed, which was isolated by filtration. The filtered cake was washed with 500 mL of water. The wet solid was mixed with 1.5 L of ethanol and heated to reflux temperature for 1 hour. After cooling to room temperature, the resulting suspension was filtered and the cake was dried at 60C under vacuum to obtain 371 g of 4-(methylamino)-3-nitrobenzoic acid as an orange powder. Yield: 95.5 %. Purity (HPLC, method 2): 99.4 %.400 g (1.98 mol) of 4-chloro-3-nitrobenzoic acid were suspended in 1025 g of a 25-30% aqueous solution of methylamine. After heating to reflux temperature, an orange solution was obtained. The solution was kept at reflux temperature for 4 hours. The solution was cooled to room temperature, and pH was adjusted to about 2 by addition of 2M aqueous sulphuric acid. Precipitation of an orange solid was observed, which was isolated by filtration. The filtered cake was washed with 500 mL of water. The wet solid was mixed with 1.5 L of ethanol and heated to reflux temperature for 1 hour. After cooling to room temperature, the resulting suspension was filtered and the cake was dried at 60C under vacuum to obtain 371 g of 4-(methylamino)-3-nitrobenzoic acid as an orange powder. Yield: 95.5 %. Purity (HPLC, method 2): 99.4 %.300 g (1 .49mo1) of 4-chloro-3-nitrobenzoic acid was suspended in 769 g of a 25-30% aqueous solution of methylamine. After heating to reflux temperature, a clear solution was obtained. The solution was kept at reflux temperature for 2 hours and the completion of reaction was checked by TLC. The solution was cooled to room temperature, and pH of reaction mixture was adjusted to about 1 by addition of 2M aqueous sulphuric acid. Precipitation of a yellow solid was observed, which was isolated by filtration. The filtered cake was washed with water and subsequently with methanol to obtain 338 g of wet 4-(methylamino)-3-nitrobenzoic acid as a yellow powder.Yield: 280g (95.90%); Purity by HPLC: 99.10 %.In 3-nitro-4-chlorobenzoic acid (258, 0.124 1101) added 25% -30% methylamine aqueous solution 1501 ^, the system at higher than 100 C for 5-6h. After concentration under reduced pressure, glacial acetic acid was added to adjust the pH to 4-5. After standing overnight, a large amount of yellow solid precipitated and the solution was filtered off. The precipitate was recrystallized at least twice with 95% ethanol to give 4-aminomethyl-3-nitro-benzoic acid as a yellow solid (18.5 g, yield 76% ). Mass spectrum (ESI-MS): 197.2 (M + H) +, 219.4 (M + Na) +; C8H8N2O4 (196)Example-1: 500 g of 4-chloro-3-nitrobenzoic acid and 2 L of mono methyl amine were added stirred for 10-15 minutes at 25C to 35C. The reaction mixture was heated to 55C and maintained for 12 hours. The reaction mixture was dumped in ice-water and stirred for 15 minutes and pH was adjusted to 2 by cone. HC1. The reaction mixture was stirred for 15 minutes and filtered. The wet-cake was washed with water and dried to obtain 4- (methylamino)-3-nitrobenzoic acid of Formula (A).500 g of 4-chloro-3-nitrobenzoic acid and 2 L of mono methyl amine were added stirred for 10-15 minutes at 25 C. to 35 C. The reaction mixture was heated to 55 C. and maintained for 12 hours. The reaction mixture was dumped in ice-water and stirred for 15 minutes and pH was adjusted to 2 by conc. HCl. The reaction mixture was stirred for 15 minutes and filtered. The wet-cake was washed with water and dried to obtain 4-(methylamino)-3-nitrobenzoic acid of Formula (A).A mixture of 4-chloro-3-nitrobenzoic acid compound of formula-8 (200 g) and 40% solution of methyl amine (660 ml) was taken into autoclave and heated to 85-90 C. and stirred for 5 hours. After completion of the reaction, the reaction mixture was cooled to 25-35 C. Water was added to the reaction mixture and acidified with hydrochloric acid. Filtered the precipitated solid, washed with water and then dried to get title compound. Yield: 195 g.General procedure: A mixture of 4-chloro-3-nitrobenzoic acid 3 (50 mmol) and the corresponding amine solution (865 mmol) was stirred at 75 C for 5 h. After cooling, the resulting solution was poured into water, acidified to pH 4-5 with concentrated HCl, and the solid formed was isolated by filtration and dried to obtain 4-substituted-3-nitrobenzoic acid (4a-4g).A 250-mL round-bottom flask was chargedwith 4-(ethylamino)-3-nitrobenzoic acid (9.0 g, 0.046 mol).30 mL of dichloromethane and 5 drops of N, N-dimethylformamidewere added in one portion. The mixture was stirredat room temperature (30 C). Thionyl chloride (20 mL, 0.23 mol) was added dropwise via addition funnel. Thereaction solution was stirred at room temperature for 5-6 h.The progress of the reaction was monitored by thin layerchromatography using ethyl acetate: petroleum ether (1:1)as solvent system. The reaction solvent was evaporated invacuo to dryness to give the product 6 without further operation. (20.0 g, 102 mmol) was suspended in SOCI2 (156 mL, 2.14 mol), anhydrous DMF (0.80 mL) was added and refluxed for 45 minutes. After leaving the solution to cool down, the SOCI2 was distilled at low pressure. Next, the yellow solid residue obtained was suspended in toluene (60 mL) and the solvent was distilled at low pressure. This operation was performed three times.The solid obtained was suspended under Ar in anhydrous tetrahydrofuran (THF) (1 18 mL) and Et3N (30 mL, 215 mmol) was slowly added. Next, it was chilled down to 0 C, an ethyl N-(2-pyridyl)-3-aminopropionate (VIII) solution (16.7 g, 86.0 mmol) in anhydrous THF (62 mL) was slowly added, and stirred at r.t. for 1 h and 30 minutes. The solvent was distilled at low pressure, the residue was redissolved in CH2CI2 (207 mL) and washed with H2O (46 mL) and NaOH 1 N (36 mL) and dried over anhydrous MgSO4, and the solvent was distilled at low pressure.The brown oil obtained (36.8 g) was dissolved in THF (167 mL). The precipitated triethylammonium chloride residues were filtered out, washed with THF (10 mL), and onto the mixed filtrates 48% HBr (1 1 .2 mL, 98.9 mmol) was added dropwise for 5 minutes. Next it was seeded with VII-HBr (form I) and after a few moments the solid crystallized. The suspension was stirred at room temperature (r.t.) for 30 minutes and next in a water/ice bath for 1 h. The solid was filtered out, washed with THF (16 mL) and dried under vacuum at r.t., obtaining form I of VII-HBr (34.3 g, 88% yield from VIII, 93% a/a purity according to HPLC/MS).100 g (0.SOmol) of General procedure: A mixture of 4-chloro-3-nitrobenzoic acid 3 (50 mmol) and the corresponding amine solution (865 mmol) was stirred at 75 C for 5 h. After cooling, the resulting solution was poured into water, acidified to pH 4-5 with concentrated HCl, and the solid formed was isolated by filtration and dried to obtain 4-substituted-3-nitrobenzoic acid (4a-4g). To a solution of 4-substituted-3-nitrobenzoic acid (4a-4g) (16 mmol) in DCM (100 mL) containing N, N-dimethylformamide (DMF, 0.5 mL), thionyl chloride (18.5 mmol) was slowly added at room temperature and then the mixture was stirred at reflux temperature for 2 h. After cooling to room temperature, the reaction mixture was concentrated to near dryness in vacuo to obtain an oily residue (5a-5g).4-Methylamino-3-nitro-benzoic acid (11.6 g, 0.059 mol) was dissolved in 150 mol of thionyl chloride and refluxed for 1.5 h. After concentration under reduced pressure, 50-60 ml of CH2C12 was added to completely dissolve it, Methylamino-3-nitro-benzoyl chloride in CH2CI2. Mass spectrum (ESI-MS): 215.3 (M + H) +; C8H7ClN2O3 (214)Step 1): At room temperature, add DMF (0.6 mL) to a mixed solution of compound 4 (5.8 g, 30 mmol) and dichlorosulfoxide (30 mL), heat to 70 C, and stir for 12 hours.Compound 5 was concentrated under reduced pressure and used directly in the next synthesis.

Molecular Weight:196.16
XLogP3:1.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:196.04840674
Monoisotopic Mass:196.04840674
Topological Polar Surface Area:95.2
Heavy Atom Count:14
Complexity:238
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes