Benzoic acid, 4-(acetylamino)-2-hydroxy-, methyl ester

Light Brown Solid

A solution of Methyl 4-amino-2-hydroxy benzoate (50.7 grams, 303.6 mmol, obtained in above step) in ethyl acetate (750 mL) was added to a stirred solution of water (250 mL) and sodium bicarbonate (34.9 grams, 415.5 mmol) cooled at 0 °C followed by acetyl chloride (29.7 mL, 415.5 mmol) over a period of 15 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. The two layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to obtain methyl 4-acetylamino-2-hydroxy benzoate (63.5 grams).Yield: 99 percent.Ή - NMR (CDC1A solution of Methyl 4-amino-2-hydroxy benzoate (50.7 grams, 303.6 mmol, obtained in above step) in ethyl acetate (750 mL) was added to a stirred solution of water (250 mL) and sodium bicarbonate (34.9 grams, 415.5 mmol) cooled at 0° C. followed by acetyl chloride (29.7 mL, 415.5 mmol) over a period of 15 minutes. Compound 77.1 (2.0 g, 12.0 mmol, 1.0 eq) in EtOAc (30 mL) was added to a cooled solution of NaHCOTo a 2 L three-necked flask, 2 (108 g, 0.65 mol) and glacial acetic acid (540 mL) were added, the temperature was raised to 40 ° C after stirring, Acetic anhydride (79.2 g, 0.78 mol) was added dropwise and the reaction mixture was gradually clarified. Bi completed, TLC monitoring, the reaction was added water (1000mL) about 1h, Precipitation of a large amount of solid. After cooling to room temperature, suction filtration, Filter cake was washed with water and dried to give a white solid 125g, yield 92.4percent, purity 99.9percentTo a solution of compound 1b (2.46 g, 15.3 mmol) in anhydrous acetone (25 ml) was added acetic anhydride (3 ml, 31.7 mmol) in an ice bath with magnetic stirring. After being stirred for 19 h, the solvent was evaporated in vacuo, and the solid residue was washed with water and filtered to provide compound 2b (2.74 g, 86percent) as white powders.Compound 2b: Mwt: 209.20; RStage 2; Methyl 4-(acetylamino)-2-hydroxybenzoate; Methyl 4-aminosalicylate (1.0 eq.) was dissolved in 9 vol dichloromethane atTAcetic anhydride (Ac20) (66.50 mL, 0.704 mole) was added drop wise to a stirred solution of methyl 4-amino-2-hydroxy benzoate (98 grams, 0.586 mole, obtained in the above step) in DCM (980 mL) at 0 °C. Then reaction mass was slowly brought to 10 °Cand stirred for 4 hours at the same temperature, while monitoring the progress of the reaction by TLC. Reaction mass was poured into chilled water (1000 mL) and stirred for 30 minutes. The solid obtained was filtered and dissolved in ethyl acetate (EtOAc) (1000 mL). The organic phase was washed with brine solution (500 mL), dried over Na2SO4 and concentrated under vacuum to obtain the title compound.Weight: 88.8 grams (Yield: 72.4 percent).1H - NMR (δ ppm): 2.03 (3H, s), 3.82 (3H, s), 7.00 - 7.03 (1H, dd, 3 8.68, 1.60 Hz), 7.33- 7.34 (1H, d, J = 1.72 Hz), 7.66 - 7.68 (1H, d, J = 8.72 Hz), 10.18 (1H, bs), 10.57 (1H, s); Mass (m/z): 210.2 (M+H).(136.8 g, 1.0 mol) sodium acetate trihydrate was added to the reaction solution of methyl p-amino salicylate, the pH of the reaction solution was controlled at 6.5-7.5 with 10percent sodium carbonate or 10percent acetic acid, and the temperature was controlled at 35-40°C. Then, 40.0g of acetylase was added, the temperature and pH were strictly controlled, the reaction was carried out for 2 hours and the reaction was completed. The methanol was recovered under reduced pressure, and 500 g of ethyl acetate was added to the mother liquor for extraction, then carried out liquid separation, drying and concentration, followed by crystallization under reduced pressure, suction filtration, and drying at 50° C to obtain 199.2 g of Methyl p-acetaminosalicylate. The yield was 95.2percent and the purity was 99.1percent(3) Methyl 4-acetamido-2-hydroxybenzoate NMR (CDCl3, delta): 2.33 (3H, s), 4.97 (3H, s), 6.90 (1H, t, J=8 Hz), 7.56 (1H, d, J=8 Hz), 7.81 (1H, br s), 8.57 (1H, d, J=8 Hz).To a 2 L three-necked flask, 2 (108 g, 0.65 mol) and glacial acetic acid (540 mL) were added, the temperature was raised to 40 ° C after stirring, Acetic anhydride (79.2 g, 0.78 mol) was added dropwise and the reaction mixture was gradually clarified. Bi completed, TLC monitoring, the reaction was added water (1000mL) about 1h, Precipitation of a large amount of solid. After cooling to room temperature, suction filtration, Filter cake was washed with water and dried to give a white solid 125g, yield 92.4percent, purity 99.9percentTo a solution of compound 1b (2.46 g, 15.3 mmol) in anhydrous acetone (25 ml) was added acetic anhydride (3 ml, 31.7 mmol) in an ice bath with magnetic stirring. After being stirred for 19 h, the solvent was evaporated in vacuo, and the solid residue was washed with water and filtered to provide compound 2b (2.74 g, 86percent) as white powders.Compound 2b: Mwt: 209.20; Rf: 0.50 (ethyl acetate:hexane=1:1). 1H-NMR (DMSO-d6, 300 MHz) delta (ppm): 2.06 (3H, s, CH3), 3.85 (3H, s, OCH3), 7.04 (1H, dd, J=6.6, 2.1 Hz, Ar H-5), 7.37 (1H, d, J=1.8 Hz, Ar H-3), 7.70 (1H, d, J=8.7 Hz, Ar H-6), 10.22 (1H, s, ArNH), 10.6 (1H, s, OH).Stage 2; Methyl 4-(acetylamino)-2-hydroxybenzoate; Methyl 4-aminosalicylate (1.0 eq.) was dissolved in 9 vol dichloromethane atTOut=20°C to give a pale brown solution. The solution was cooled over 33 min. toTi=1°C. To the solution was added 1.2 eq. acetic acid anhydride in 2 vol Acetic anhydride (Ac20) (66.50 mL, 0.704 mole) was added drop wise to a stirred solution of methyl 4-amino-2-hydroxy benzoate (98 grams, 0.586 mole, obtained in the above step) in DCM (980 mL) at 0 °C. Then reaction mass was slowly brought to 10 °Cand stirred for 4 hours at the same temperature, while monitoring the progress of the reaction by TLC. Reaction mass was poured into chilled water (1000 mL) and stirred for 30 minutes. The solid obtained was filtered and dissolved in ethyl acetate (EtOAc) (1000 mL). The organic phase was washed with brine solution (500 mL), dried over Na2SO4 and concentrated under vacuum to obtain the title compound.Weight: 88.8 grams (Yield: 72.4 percent).1H - NMR (delta ppm): 2.03 (3H, s), 3.82 (3H, s), 7.00 - 7.03 (1H, dd, 3 8.68, 1.60 Hz), 7.33- 7.34 (1H, d, J = 1.72 Hz), 7.66 - 7.68 (1H, d, J = 8.72 Hz), 10.18 (1H, bs), 10.57 (1H, s); Mass (m/z): 210.2 (M+H).a) To a solution of 104.6 parts of General procedure: Methyl 4-acetamido-2-hydroxybenzoate (100 mmol) was dissolved in anhydrous DMF (100 mL), followed by the addition of anhydrous K2CO3 (150 mmol) or NaH (150 mmol) and alkyl bromides (150 mmol). The mixture was heated to 60 °C for 4'6 h, and the reaction mixture was cooled to room temperature and filtrated. The filtrate was concentrated in vacuo, and the resulting residue was recrystallized from ethyl acetate and petroleum ether to afford the target compounds.EXAMPLE 19 Methyl 2-allyloxy-4-acetylaminobenzoate To a solution of 10 g (47.8 mmol) of methyl 4-acetylaminosalicylate in 30 ml of DMF is added 19.8 g (143.4 mmol) of finely ground potassium carbonate in a single portion at room temperature, followed by 8.3 ml (95.6 mmol) of allyl bromide in a similar fashion. The reaction mixture is heated to 60° C. and stirred at that temperature for 4 hours. After cooling to room temperature the reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is dried over MgSO4, filtered and concentrated. Flash chromatography (10percent ethyl acetate/hexane) provides methyl 2-allyloxy-4-acetylaminobenzoate which can be used directly in the next step.

Methyl 4-Acetamido-2-hydroxybenzoate is a reagent used in the synthesis of Mosapride.

Molecular Weight:209.20
XLogP3:1.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:209.06880783
Monoisotopic Mass:209.06880783
Topological Polar Surface Area:75.6
Heavy Atom Count:15
Complexity:254
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes