Methyl 3-amino-4-hydroxybenzoate

Beige Solid

Orthoform is a benzoate ester.

4-Hydroxy-3-nitro-benzoic acid methyl ester (500 mg, 2.54 mmol) is dissolved in MEOH (10 mL), then 10percent palladium on carbon (50 mg of 50percent wet) is added, and the reaction is placed under 1 atm of H2 overnight. The mixture is filtered through CELITE# TO remove the catalyst and the filtrate is concentrated under reduced pressure to afford the sub-title compound (435 mg, >100percent) which is used without further purification. H NMR (300 MHz, DMSO-d6) 8 3.74 (s, 3H), 4.78 (br s, 2H), 6.70 (d, J= 8.2 Hz, 1H), 7.09 (DD, J = 2.1, 8.2 Hz, 1H), 7. 24 (d, J= 2.1 Hz, 1H), -10 (br s, 1H). APCI MS MLZ 168 [C8H9NO3 + H] +.Step 1. A solution of 4-hydroxy-3-nitro-benzoic acid methyl ester (5.0 g, 25.4 mmol) in ethanol (120 mL) was treated with 5percent palladium on active carbon (0.24 g, 2.3 mmol, 0.1 equiv.) and the flask was evacuated and placed under an hydrogen atmosphere. The mixture was stirred vigorously for 2 h and 45, the palladium was filtered off, washing extensively with ethanol. The solvent was removed in vacuo to yield 3-amino-4-hydroxy-benzoic acid methyl ester as a white solid, 4.2 g (100percent), MS (ISP): m/e=168.3 (M+HTo a [2000ML] three-necked flask containing [3-NITRO-4-HYDROXY-BENZOIC] acid methyl ester [(43G, ] 218mmol) in [MEOH] [(860ML] ; 20vols) was added palladium on carbon in water (2g in [10ML] of water). Ammonium formiate (68.76g, 5eq.) was added in a single portion under stirring. After 2 to 3 minutes a suspension was observed, and temperature rised from [20°C] to [30°C.] Ice bath was used to cool reaction mixture to [20°C] and the reaction was stirred at [20°C] for 40minutes until completion (no more yellow color). Reaction mixture was filtered on silica plug, rinsed with [MEOH, ] and the filtrate was concentrated under vacuum to give a green oil which was taken up in ethyl acetate (400ml). The organic phase was washed twice with water, dried over [MGS04, ] filtered and concentrated to give a cream solid m=31. 35g (86percent). LC-MS: M/Z ESI: 0.81 min, 168.37 [(M+1)]A heterogeneous methanol solution (150 mL) of 10 (9.40 g, 48 mmol) and 10percent Pd/C (3.42 g) was stirred overnight under hydrogen atmosphere and the palladium catalysts were removed by Celite pad filtration. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography with hexane/ethyl acetate (2:1) to give 11 (6.31 g, 38 mmol, 74percent) as a white solid. A solution (0.2 M) of acetyl chloride (3.0 eq. ) in MeOH was prepared at 0 °C then allowed to warm to 20 °C. 3-amino-4-hydroxybenzoic acid (1.0 eq. ) was added and the mixture was heated under reflux for 12 h then cooled and concentrated in VACUO. The residue was triturated with H20 and dried to afford the title compound (99percent) as a solid. H NMR (300 MHz, DMSO-D6, 300 K) 8 3.83 (s, 3H), 7.15 (d, J 8.5 Hz, 1H), 7.79 (dd, J2. 1, 8. 5 Hz, 1H), 7.93 (d, J 2. 1 Hz, 1H), 11.65 (br s, 1H).Hydrogen chloride (1.25M in Methanol, lOOmL) was placed in a reactor at 0°C. Then 3- amino-4-hydroxybenzoic acid (5g, 0.032mo1) was added in portions. The reaction mixture was stirred 5 minutes at 0°C and 24 hours at room temperature. The solvent was removed under reduced pressure and the crude was partitioned between ethyl acetate and satu-rated bicarbonate. The organics layer were combined, dried, filtered and the solvent was removed under reduced pressure to obtain the title compound as a solid (5.38g, 98percent), which was used in the next step without further purification.LRMS (m/z): 168 (M+1)+3-Amino-4-hydroxybenzoic acid (0.40 g, 2.61 mmol) was dissolved in anhydrous methanol (10 ml) and treated with TMSCl (0.75 ml, 5.94 mmol). The mixture was stirred at 55 °C for 2 days. After evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel eluting with ethyl acetate (yield: 0.25 g, 1.50 mmol, 57percent, white solid). 0.20 g of the obtained methyl 3-amino-4-hydroxybenzoate, dissolved in anhydrous THF (10 ml), was mixed with TCDI (0.26 g, 1.46 mmol) under an inert atmosphere. The solution was stirred overnight at room temperature. After evaporation of the solvent the residue was treated with water (15 ml) and extracted with ethyl acetate (3 .x. 15 ml). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The remaining crude product was recrystallized from ethanol yielding 0.22 g (1.05 mmol, 88percent) of methyl 2-sulfanylbenzo[d]oxazole-5-carboxylate (21) as a brown solid. Mp: 203-205 °C.To a solution [OF 3-AMINO-4-HYDROXYBENZOIC] acid [(100G, ] 0. [65MOL)] in methanol (1. [5L)] was added [THIONYLCHLORIDE] (233g, 1. [96MOL)] drop-wise at [5-10°C] with stirring and allowed to reflux at [65°C] for 16h. Excess methanol and thionylchloride was distilled off and crude dissolved in ethylacetate [(500ML).] The organic layer was washed with 5percent aqueous [NAHC03] solution, water, brine and dried. The solvent was removed under vacuum to give methyl-3-amino-4-hydroxybenzoate [(105G, ] 95percent).A solution (0.2 M) of acetyl chloride (3.0 eq) in MeOH was prepared at 0 °C then allowed to warm to 20 °C. 3-amino-4-hydroxybenzoic acid (1.0 eq) was added and the mixture was heated under reflux for 12 h then cooled and concentrated in vacuo. The residue was triturated with H20 and dried to afford the title compound (99 percent) as a solid. H NMR (300 MHz, DMSO-d6) S 3.83 (s, 3H), 7.15 (d, J 8. 5 Hz, 1H), 7.79 (dd, J 2. 1, J 8.5 Hz, 1H), 7.93 (d, J 2.1 Hz, 1H), 11.65 (br s, 1H)3-(dimethylamino)-4-hvdroxybenzoic acid: 3-Amino-4-hydroxybenzoic acid (459mg, 3 mmol) was dissolved in methanol (12ml) and toluene (36ml) was added. A 2.0M solution of (trimethylsilyl)diazomethane in hexanes (1.5ml, 3.0 mmol) was added dropwise and the mixture stirred for 0.5h. The reaction mixture was concentrated under vacuum and the residue purified by flash column chromatography on silica to afford methyl 3-amino-4-hydroxybenzoate as a pink solid (254mg, 51percent).A buffer solution at pH 5.5 was prepared by the addition of acetic acid to a 1M aqueous sodium acetate solution. Methyl 3-amino-4-hydroxybenzoate (254mg, 1.5 mmol) was dissolved in a mixture of buffer (1ml) and methanol (2ml). Formaldehyde solution (37percent by weight in water; 0.75ml, lOmmol) was added, the mixture stirred for 15 minutes, and then sodium cyanoborohydride (283mg, 4.5mmol) was added portionwise. The reaction mixture was stirred for an additional 0.5h and then concentrated. The residual oil was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with water, brine and dried over sodium sulfate. The solvent was removed and the crude product was purified by flash column chromatography on silica to give methyl 3-dimethylamino-4-hydroxybenzoate as a yellow gum (213mg, 73percent).To a solution of methyl 3-dimethylamino-4-hydroxybenzoate (210mg, 1.1 mmol) in 1, 4-dioxane (2ml) was added 1 M LiOH (aq) (4mmol). After stirring for 4Oh, the mixture was acidified to pH 2 by addition of 1 M HCI (aq). The mixture was partitioned between water and ethyl acetate, and the aqueous layer was lyophilized to give a mixture of sodium chloride and 3-dimethylamino-4- hydroxybenzoic acid as a brown semi-solid (378mg). The crude material was used in the subsequent reaction.4.14 3-(dimethylamino)-4-hvdroxybenzoic acid; 3-Amino-4-hydroxybenzoic acid (459 mg, 3 mmol) was dissolved in methanol (12 ml) and toluene (36 ml) was added. A 2.0 M solution of (trimethylsilyl)diazomethane in hexanes (1.5 ml, 3.0 mmol) was added dropwise and the mixture stirred for 0.5h. The reaction mixture was concentrated under vacuum and the residue purified by flash column chromatography on silica to afford methyl 3-amino-4-hydroxybenzoate as a pink solid (254 mg, 51 percent).

Anesthetic (topical).

Molecular Weight:167.16
XLogP3:1
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