Ethyl 4-amino-3-methoxybenzoate

A 22-L 3-necked RBF equipped with an electrical heating mantle, a thermocouple probe, overhead mechanical stirrer, water-cooled condenser, nitrogen bubbler and addition funnel was charged with 4-amino-3-methoxybenzoic acid (1.0 kg, 5.98 mol, 1.0 equiv.) and ethanol (200 proof) (10.0 L, 10 vol.) to produce a stirrable slurry. Without external cooling, sulfuric acid (1.17 kg, 0.64 L, 12.0 mol, 2.0 equiv.) was then added slowly over 1 h, the slurry initially goes thick, but breaks up and eventually all solids dissolve to form a dark solution. The exothermic addition increased the temperature to -45 °C; additional heating was then applied to bring the solution to reflux and was held at reflux overnight. An HPLC sample was taken and showed -5percent starting benzoic acid remaining. The reflux head was switched to full takeoff and 2.5 L was distilled off. The reaction was cooled to 6 °C in an ice bath and the pH slowly adjusted to 12 by the addition of a solution of sodium hydroxide (50 wt percent, 1.03 kg, 681 ml, 12.9 mol, 2.15 equiv.) in water (3.5 L) keeping the temperature below 20 °C. Following a 30 min. post-stir, an additional quantity of water (4.0 L) was added and stirred at ca. 10 °C for 30 min. The solid were filtered, washed thoroughly with water (4.0 L), and then vacuum dried at 65 °C overnight. The yield of ethyl 4- amino-3-methoxybenzoate was 1.04 kg (89.1percent) as a light brown solid. m.p.= 83-87 °C (DSC); 1H NMR (300 MHz, CDC1[0553j To a solution of ethyl 3-methoxy-4-nitrobenzoate (5-B) (7.65 g, 34 mmol) in EtOH (20 mL) was added Pd/C (1.5 g), while stirring at rt under H2 for 12 h. The solid was removed by filtration and the mixture was extracted with EA. The solvent was removed to afford ethyl 4-amino-3-methoxybenzoate (5-C) (7.5 g).To a mixture of 2-(benzyloxycarbonylamino)acetic acid (5. 9 g, 28.17 mmol, 1.1 eq) and ethyl 4-amino-3-methoxy-benzoate (5 g, 25.61 mmol, 1 eq) in tetrahydrofuran (50 mL) was added 0-(7-azabenzotriazol-l-yl)-N, N, N, N-tetramethyluronium hexafluorophosphate (11.7 g, 30.74 mmol, 1.2 eq) and N, N-diisopropylethylamine (6.6 g, 51.23 mmol, 8.9 mL, 2 eq) at 0 C under nitrogen. The mixture was warmed to 20 C and stirred for 12 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (200 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1, 3/1 to 1/1) to give ethyl 4-[[2-(benzyloxycarbonylamino)acetyl]amino]-3-methoxy-benzoate (9 g, 23.29 mmol, 91% yield) as a yellow oil. 1H-NMR (400MHz, CDCb) d 8.41 (br d, J = 8.4 Hz, 2H), 7.68 (br d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.42 - 7.28 (m, 5H), 5.61 (br s, 1H), 5.18 (s, 2H), 4.42 - 4.32 (m, 2H), 4.11 - 4.01 (m, 2H), 3.88 (s, 3H), 1.40 (t, J = 1.2 Hz, 3H).

Molecular Weight:195.21
XLogP3:1.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:195.08954328
Monoisotopic Mass:195.08954328
Topological Polar Surface Area:61.6
Heavy Atom Count:14
Complexity:196
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes