Methyl 4-amino-2-hydroxybenzoate

P-Aminosalicylic acid methyl ester is an aromatic amine.

Step 2: 2-Methoxy-4-nitrobenzoic acid (1) in CH2Cl2 (97percent) is reacted with BBr3 to provide the intermediate 2-hydroxy-4-nitro-benzoic acid, which upon treatment with SOCl2 in solvent such as MeOH (95percent), followed by hydrogenation and treatment with 10percent Pd/C in EtOAc (98percent) yields 4-amino-2-hydroxy-benzoic acid methyl ester (2).To a stirred solution of 4-aminosalicylic acid (50 grams, 326.7 mmol) in methanol (375 mL) at 0 °C was added concentrated sulfuric acid (99.7 mL, 1.87 mmol) maintaining temperature of the reaction below 20 °C. The reaction mixture was gradually heated to reflux and upon completion of the reaction after 6 hours it was cooled to ice bath temperature and basified with aqueous sodium hydroxide solution (10.0 N, 214.5 mL). The white precipitate that formed was filtered, washed with water, ether and dried under vacuum to obtain Methyl 4-amino-2-hydroxy benzoate (50.70 grams). Yield: 93percent.Ή - NMR (DMSO-dTo a stirred solution of 4-aminosalicylic acid (50 grams, 326.7 mmol) in methanol (375 mL) at 0° C. was added concentrated sulfuric acid (99.7 mL, 1.87 mmol) maintaining temperature of the reaction below 20° C. In an oven-dried 500 mL roundbottom flask, 4-aminosalicylic acid (16) (5.00 g, 32.6 mmol) was dissolved in methanol (100 mL) under nitrogen atmosphere. c-H2SO4 (7mL) was added dropwise and the reaction mixture was stirred at 80 oC. After 22 h, it was cooled to room temperature and neutralized with NaHCO3 until no further gas evolution was observed. Then, the solid was filtered and washed with MeOH (100 mL). The filtrate was evaporated under reduced pressure. The crude residue was diluted with ethyl acetate (200 mL) and H2O (200 mL), and aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, and filtered. Evaporation under reduced pressure afforded methyl ester 17 (4.99 g, 92percent) as a grey solid.TLC: RPara-aminosalicylic acid (50 g, 0.327 mol) and methanol (300 mL) were added to a 1 L three-necked flask, and the mixture was stirred well and concentrated sulfuric acid (100 mL)To ensure that the temperature control between 0 ~ 5 ° C , after the addition is complete, Transferred to an oil bath and heated to 80 ° C reflux 6h.The reaction was monitored by TLC, cooled to room temperature, Add 10mol / L sodium hydroxide solution (about 200mL) adjusted to pH 4 ~ 5, precipitated a large amount of solid, filtration, washing, drying, Obtained product 50.3g, yield 92.1percent, purity of 99.6percentTo a stirred solution of 4-amino-2-hydroxybenzoic acid (2.0g, 13.1mmol, 1.0 eq.) in MeOH (40mL) was added dropwise concentrated aqueous solution of HSulfuric acid (HExample 4a; 4-Amino-5-chloro-λ/-{[1-(tetrahydro-2H-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1 -benzofuran-7-carboxamide hydrochloride (E4a); The compound of the invention was also prepared according to Scheme 3 as follows: To a solution of p-aminosalicyclic acid (15.3 g, 100.1 mmol) in anhydrous methanol (230 ml) was added concentrated HConcentrated sulfuric acid (10 mL) was added to a solution of 4-aminosalicylic acid (30.6 g, 0.2 mol) in methanol (500ml). The reaction mixture was then heated to reflux for 24 h, after which the solvent was removed. The residue was partitioned between EtOAc (1 L) and water (1 L). The organic phase was dried over NaConcentrated sulfuric acid (1.25 ml) was added dropwise tomethanol (6 ml) with cooling on a cryostatic bath. The mixture wasstirred for 1 h at room temperature, and 4-ASA (1.53 g, 10 mmol)was added to it. After refluxing at 60e70 C for 6 h, the mixture wasadjusted to pH 7e8 with 10percent Na2CO3 solution in ice-bath. Themixture was filtered to afford crude solid product. The crudeproduct was recrystallized from hot methanol, followed by coolingto 0 C. White crystals were collected and dried under high vacuumto give compound 2 (1.29 g, yield: 77percent). mp: 119e121 C; Rf 0.73in petroleum ether/diethyl ether/ethyl acetate/acetic acid (4/3/3/0.02); IR (KBr): 3260 cm1 phenolic OeH stretching vibration, 3474 cm1 and 3380 cm1 NeH stretching bimodal vibration, 1638 cm1 NeH bending vibration; 1662 cm1 C]O stretchingvibration, 1284 cm1 CeOeC stretching vibration; 1H NMR (DMSOd6, d ppm): 3.79 (s, 3H, -COOCH3), 6.00 (d, 1H, J 2.1 Hz, HeC3), 6.13(dd, 1H, J 8.7 Hz, 2.2 Hz, HeC5), 6.14 (s, 2H, Ph-NH2), 7.46 (d, 1H, J 8.7 Hz, HeC6), 10.77 (s, 1H, Ph-OH); HRMS (ESI): Calcd forC8H9NO3, [M H], 168.0655; Found, 168.0655.4-Aminosalicylic acid (10.0 g, 65 mmol) was dissolved in MeOH (200 mL) and was refluxed in the presence of 10 mL concentrated sulfuric acid for 4 h. After the reaction, the solution was concentrated to approximately 20 mL and was neutralized by adding a 10percent NaHCO

Molecular Weight:167.16
XLogP3:1.6
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:167.058243149
Monoisotopic Mass:167.058243149
Topological Polar Surface Area:72.6
Heavy Atom Count:12
Complexity:172
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes