ethyl 4-amino-3-bromobenzoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 4-amino-3-bromobenzoate (23.5 g, 96.3 mmol) in methylene chloride at −10° C. is treated dropwise with tert-butyl nitrite (14.0 mL, 118.4 mmol), followed by boron trifluoride diethyl etherate (18.4 mL, 146.5 mmol). The reaction mixture is allowed to come to room temperature, stirred for 4 h, diluted with ethyl ether and filtered. The filtercake is dried, dispersed in toluene, cooled to 0° C., treated with a solution of copper (I) cyanide (11.5 g, 129.2 mmol) and sodium cyanide (15.8 g, 323.1 mmol) in water, stirred at 0° C. for 30 min., warmed to 60° C., stirred for 1 h, cooled to room temperature and diluted with EtOAc and water. The organic phase is separated, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether/hexanes to give the ethyl ester of the title compound as an off-white solid, 18.6 g (76% yield). A solution of this ester (8.5 g, 33.6 mmol) in THF is treated with a solution of NaOH (30 mL, 2.5 N) and ethanol, stirred for 20 h, acidified with 2N HCl and extracted with ethyl ether. The ether extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether/hexanes to afford the title compound as a beige solid, 6.81 g (90% yield), identified by HNMR and mass spectral analyses. MS m/e 223 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J=9.76, 1.37 Hz 1 H), 8.09 (d, J=8.08 Hz, 1H), 8.29 (d, J=1.37 Hz, 1H). to come to room temperature filtered The filtercake is dried dispersed in toluene stirred at 0° C. for 30 min. warmed to 60° C. stirred for 1 h cooled to room temperature The organic phase is separated dried over MgSO4 concentrated in vacuo The resultant residue is crystallized from ethyl ether/hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of bromine (7.0 mL, 137.3 mmol) in dichloromethane is added dropwise to a cold (−10° C.) solution of ethyl 4-aminobenzoate (22.0 g, 133.3 mmol) in dichloromethane. The reaction mixture is allowed to come to room temperature, stirred for 18 h and diluted with water. The organic phase is separated, washed twice with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (SiO2, 8/1 hexanes/EtOAc as eluent) to afford the title compound as a white solid, 28.6 g (88% yield), identified by HNMR and mass spectral analyses. MS m/e 242 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.01 Hz, 3 H), 4.22 (q, J=7.16 Hz, 2 H), 6.18 (brs, 2 H), 6.81 (d, J=7.91 Hz, 1H), 7.65 (dd, J=8.54, 1.98 Hz 1 H), 7.89 (d, J=1.83 Hz, 1H). to come to room temperature The organic phase is separated washed twice with brine dried over MgSO4 concentrated in vacuo The resultant residue is purified by flash chromatography (SiO2, 8/1 hexanes/EtOAc as eluent)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of bromine (7.0 mL, 137.3 mmol) in dichloromethane is added dropwise to a cold (−10° C.) solution of ethyl 4-aminobenzoate (22.0 g, 133.3 mmol) in dichloromethane. The reaction mixture is allowed to come to room temperature, stirred for 18 h and diluted with water. The organic phase is separated, washed twice with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (SiO2, 8/1 hexanes/EtOAc as eluent) to afford the title compound as a white solid, 28.6 g (88% yield), identified by HNMR and mass spectral analyses. MS m/e 242 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.01 Hz, 3 H), 4.22 (q, J=7.16 Hz, 2 H), 6.18 (brs, 2 H), 6.81 (d, J=7.91 Hz, 1H), 7.65 (dd, J=8.54, 1.98 Hz 1 H), 7.89 (d, J=1.83 Hz, 1H). to come to room temperature The organic phase is separated washed twice with brine dried over MgSO4 concentrated in vacuo The resultant residue is purified by flash chromatography (SiO2, 8/1 hexanes/EtOAc as eluent)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 4-aminobenzoate (10.0 g, 59.3 mmol) and triethylamine (18.4 mL, 130 mmol) in acetic acid (30 mL) was slowly added dropwise bromine (3.04 mL, 59.3 mmol) under stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hr and cold water (400 mL) was added. The precipitated solid was collected by filtration, washed with cold water and vacuum dried to give crude ethyl 4-amino-3-bromobenzoate (15.0 g) as red-pink crystals. The obtained crystals were dissolved in ethyl acetate (60 mL), and 4 M hydrogen chloride/ethyl acetate solution was added. The precipitated solid was collected by filtration, washed with a mixed solvent (1:1) of ethyl acetate-diethyl ether, and vacuum dried to give a mixture (8.99 g) of ethyl 4-aminobenzoate hydrochloride and ethyl 4-amino-3-bromobenzoate hydrochloride as colorless crystals. Successively, to a solution of the obtained mixture (1.00 g) in pyridine (12 mL) were added acetic anhydride (0.69 mL, 7.13 mmol) and 4-dimethylaminopyridine (catalytic amount) with stirring at room temperature, and the mixture was stirred overnight at the same temperature. The reaction solution was concentrated under reduced pressure, brine was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=1/1) to give the title compound (758 mg, yield 40%, 3 steps) as colorless crystals. The reaction mixture was stirred at room temperature for 2 hr The precipitated solid was collected by filtration washed with cold water and vacuum dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 4-aminobenzoate (10.0 g, 59.3 mmol) and triethylamine (18.4 mL, 130 mmol) in acetic acid (30 mL) was slowly added dropwise bromine (3.04 mL, 59.3 mmol) under stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hr and cold water (400 mL) was added. The precipitated solid was collected by filtration, washed with cold water and vacuum dried to give crude ethyl 4-amino-3-bromobenzoate (15.0 g) as red-pink crystals. The obtained crystals were dissolved in ethyl acetate (60 mL), and 4 M hydrogen chloride/ethyl acetate solution was added. The precipitated solid was collected by filtration, washed with a mixed solvent (1:1) of ethyl acetate-diethyl ether, and vacuum dried to give a mixture (8.99 g) of ethyl 4-aminobenzoate hydrochloride and ethyl 4-amino-3-bromobenzoate hydrochloride as colorless crystals. Successively, to a solution of the obtained mixture (1.00 g) in pyridine (12 mL) were added acetic anhydride (0.69 mL, 7.13 mmol) and 4-dimethylaminopyridine (catalytic amount) with stirring at room temperature, and the mixture was stirred overnight at the same temperature. The reaction solution was concentrated under reduced pressure, brine was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=1/1) to give the title compound (758 mg, yield 40%, 3 steps) as colorless crystals. The reaction mixture was stirred at room temperature for 2 hr The precipitated solid was collected by filtration washed with cold water and vacuum dried

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 4-amino-3-bromobenzoate (23.5 g, 96.3 mmol) in methylene chloride at −10° C. is treated dropwise with tert-butyl nitrite (14.0 mL, 118.4 mmol), followed by boron trifluoride diethyl etherate (18.4 mL, 146.5 mmol). The reaction mixture is allowed to come to room temperature, stirred for 4 h, diluted with ethyl ether and filtered. The filtercake is dried, dispersed in toluene, cooled to 0° C., treated with a solution of copper (I) cyanide (11.5 g, 129.2 mmol) and sodium cyanide (15.8 g, 323.1 mmol) in water, stirred at 0° C. for 30 min., warmed to 60° C., stirred for 1 h, cooled to room temperature and diluted with EtOAc and water. The organic phase is separated, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether/hexanes to give the ethyl ester of the title compound as an off-white solid, 18.6 g (76% yield). A solution of this ester (8.5 g, 33.6 mmol) in THF is treated with a solution of NaOH (30 mL, 2.5 N) and ethanol, stirred for 20 h, acidified with 2N HCl and extracted with ethyl ether. The ether extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether/hexanes to afford the title compound as a beige solid, 6.81 g (90% yield), identified by HNMR and mass spectral analyses. MS m/e 223 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J=9.76, 1.37 Hz 1H), 8.09 (d, J=8.08 Hz, 1H), 8.29 (d, J=1.37 Hz, 1H). to come to room temperature filtered The filtercake is dried dispersed in toluene stirred at 0° C. for 30 min. warmed to 60° C. stirred for 1 h cooled to room temperature The organic phase is separated dried over MgSO4 concentrated in vacuo The resultant residue is crystallized from ethyl ether/hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of bromine (7.0 mL, 137.3 mmol) in dichloromethane is added dropwise to a cold (−10° C.) solution of ethyl 4-aminobenzoate (22.0 g, 133.3 mmol) in dichloromethane. The reaction mixture is allowed to come to room temperature, stirred for 18 h and diluted with water. The organic phase is separated, washed twice with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (SiO2, 8/1 hexanes/EtOAc as eluent) to afford the title compound as a white solid, 28.6 g (88% yield), identified by HNMR and mass spectral analyses. MS m/e 242 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.01 Hz, 3H), 4.22 (q, J=7.16 Hz, 2H), 6.18 (brs, 2H), 6.81 (d, J=7.91 Hz, 1H), 7.65 (dd, J=8.54, 1.98 Hz 1H), 7.89 (d, J=1.83 Hz, 1H). to come to room temperature The organic phase is separated washed twice with brine dried over MgSO4 concentrated in vacuo The resultant residue is purified by flash chromatography (SiO2, 8/1 hexanes/EtOAc as eluent)

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a three necked 3 L round bottomed flask with a mechanical stirrer was added 3 M aqueous HCl (790 mL), followed by ethyl 4-amino-3-brombenzoate (195 g, 0.8 mol) and the mixture was stirred for 15 min. After cooling to 5° C., a solution of 4M aqueous NaNO2 (240 mL, 0.96 mol) was added over a period of 30–45 min. The resulting mixture was further stirred for 30 min. and an almost homogenous solution was obtained. The mixture was filtered through glass wool to remove the insoluble residue. The solution was then added to a vigorously stirred solution of CuCN (111 g, 1.24 mol) and NaCN (162 g, 3.3 mol) in H2O (1 L) and EtOAc (500 mL) at room temperature in a 6 L Erlenmeyer flask over ˜45 min. The resulting mixture was further stirred at r.t. for 30 min., filtered through celite and extracted with EtOAc. The EtOAc extract was washed with brine, 0.5 M aqueous NaOH, dried (MgSO4) and concentrated. Chromatography over silica gel and elution with hexanes:EtOAc (6:1), then (3:1), swished with hexanes and small amount of Et2O to give a light brown powder. The mother liquor was concentrated and swished again. Combined yield of the title compound was 119 g (58%). The resulting mixture was further stirred for 30 min. an almost homogenous solution was obtained The mixture was filtered through glass wool to remove the insoluble residue The resulting mixture was further stirred at r.t. for 30 min. filtered through celite extracted with EtOAc The EtOAc extract was washed with brine, 0.5 M aqueous NaOH dried (MgSO4) concentrated Chromatography over silica gel and elution with hexanes:EtOAc (6:1) to give a light brown powder The mother liquor was concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mechanically stirred solution of ethyl 4-aminobenzoate (165 g, 1 mol) in THF (1.2 L) and pyridine (200 mL) at ˜10° C. was added portionwise (˜10–20 g each time) of pyridine hydrobromide perbromide (tech. 90%, 365 g, 1.02 mol) over a period of 1 h. Internal temperature was kept at 10–15° C. After completion of addition, the mixture was stirred for 30 min, then filtered through celite and the filter cake was washed with THF (1 L). The filtrate was diluted with Et2O, washed with 0.5 M of aqueous NaHSO3 (2×, 400 mL), brine, dried (MgSO4) and concentrated. The residue contained too much H2O and therefore was dissolved in EtOAc (1 L), washed with brine, dried (MgSO4) and concentrated to give a semi-solid residue. The residue was swished with hexanes-Et2O (2:1) to yield 187 g (77%) of the title compound as a white powder. The mother liquor was evaporated and swished again to give 19 g (8%) of additional title compound as a light brown powder. was kept at 10–15° C After completion of addition filtered through celite the filter cake was washed with THF (1 L) The filtrate was diluted with Et2O washed with 0.5 M of aqueous NaHSO3 (2×, 400 mL), brine dried (MgSO4) concentrated was dissolved in EtOAc (1 L) washed with brine dried (MgSO4) concentrated to give a semi-solid residue

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 4-amino-3-bromobenzoate (23.5 g, 96.3 mmol) in methylene chloride at −10° C. is treated dropwise with tert-butyl nitrite (14.0 mL, 118.4 mmol), followed by boron trifluoride diethyl etherate (18.4 mL, 146.5 mmol). The reaction mixture is allowed to come to room temperature, stirred for 4 h, diluted with ethyl ether and filtered. The filtercake is dried, dispersed in toluene, cooled to 0° C., treated with a solution of copper (I) cyanide (11.5 g, 129.2 mmol) and sodium cyanide (15.8 g, 323.1 mmol) in water, stirred at 0° C. for 30 min., warmed to 60° C., stirred for 1 h, cooled to room temperature and diluted with EtOAc and water. The organic phase is separated, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether/hexanes to give the ethyl ester of the title compound as an off-white solid, 18.6 g (76% yield). A solution of this ester (8.5 g, 33.6 mmol) in THF is treated with a solution of NaOH (30 mL, 2.5 N) and ethanol, stirred for 20 h, acidified with 2N HCl and extracted with ethyl ether. The ether extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether/hexanes to afford the title compound as a beige solid, 6.81 g (90% yield), identified by HNMR and mass spectral analyses. MS m/e 223 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J=9.76, 1.37 Hz 1 H), 8.09 (d, J=8.08 Hz, 1H), 8.29 (d, J=1.37 Hz, 1H). to come to room temperature filtered The filtercake is dried dispersed in toluene stirred at 0° C. for 30 min. warmed to 60° C. stirred for 1 h cooled to room temperature The organic phase is separated dried over MgSO4 concentrated in vacuo The resultant residue is crystallized from ethyl ether/hexanes