methyl 2-bromo-5-hydroxybenzoate

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

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

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

Procedure: A mixture of methyl-2-bromo-5-hydroxybenzoate (1.0 g, 4.33 mmol), benzyl bromide (0.62 mL, 5.19 mmol), and K2CO3 (780 mg, 5.63 mmol) in anhydrous DMF (8 mL) was stirred at room temperature for 21 h under nitrogen atmosphere. The mixture was poured into equal volumes of water and EtOAc (1:1, 20 mL), then the layers were separated. The aqueous layer was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give methyl 5-(benzyloxy)-2-bromobenzoate (1.39 g, 100%). the layers were separated The aqueous layer was further extracted with equal volume of EtOAc before the organic layers dried over anhydrous Na2SO4 filtered The solvent was removed under reduced pressure The residue was purified by silica gel column

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

Procedure: A mixture of methyl-2-bromo-5-hydroxybenzoate (1.0 g, 4.33 mmol), benzyl bromide (0.62 mL, 5.19 mmol), and K2CO3 (780 mg, 5.63 mmol) in anhydrous DMF (8 mL) was stirred at room temperature for 21 h under nitrogen atmosphere. The mixture was poured into equal volumes of water and EtOAc (1:1, 20 mL), then the layers were separated. The aqueous layer was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give methyl 5-(benzyloxy)-2-bromobenzoate (1.39 g, 100%). the layers were separated The aqueous layer was further extracted with equal volume of EtOAc before the organic layers dried over anhydrous Na2SO4 filtered The solvent was removed under reduced pressure The residue was purified by silica gel column

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 2-bromo-5-hydroxybenzoate (5.63 mmol, 1.30 g) in DMF (8 mL) was added cesium carbonate (11.3 mmol, 3.67 g) and methyl chlorodifluoroacetate (6.75 mmol, 0.71 mL), and the reaction mixture stirred at 90° C. for 16 h. After cooling to rt and dilution with ethyl acetate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using hexane/EtOAc (9:1, v/v) as the eluent. The product was obtained as a light yellow oil (560 mg, 35%). GC-MS m/z: 280 (MH+). After cooling to rt dilution with ethyl acetate, the mixture was filtered concentrated under reduced pressure The residue was purified by silica gel chromatography

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

Procedure: To a cold solution (ice water bath) of the methyl-2-bromo-5-methoxybenzoate (2.00 g, 8.16 mmol) in dichloromethane (15 mL) was added AlCl3(5.44 g, 40.8 mmol) under argon, and the reaction temperature was maintained below 10° C. using an ice-water bath. The light brown suspension was stirred for 10 min, then EtSH (3.02 mL, 40.8 mmol) was added dropwise at such a rate that the reaction temperature was maintained below 5° C. After 2.5 h of stirring below 10° C., the reaction mixture was slowly poured into ice water with agitation. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to afford a light yellow oil which was used in the next step without further purification. the reaction temperature was maintained below 10° C. was maintained below 5° C After 2.5 h of stirring below 10° C. The organic layer was separated the aqueous layer was extracted with DCM The combined organic layers were washed with water dried over MgSO4 filtered concentrated under reduced pressure to afford a light yellow oil which was used in the next step without further purification

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

Procedure: To a cold solution (ice water bath) of the methyl-2-bromo-5-methoxybenzoate (2.00 g, 8.16 mmol) in dichloromethane (15 mL) was added AlCl3(5.44 g, 40.8 mmol) under argon, and the reaction temperature was maintained below 10° C. using an ice-water bath. The light brown suspension was stirred for 10 min, then EtSH (3.02 mL, 40.8 mmol) was added dropwise at such a rate that the reaction temperature was maintained below 5° C. After 2.5 h of stirring below 10° C., the reaction mixture was slowly poured into ice water with agitation. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to afford a light yellow oil which was used in the next step without further purification. the reaction temperature was maintained below 10° C. was maintained below 5° C After 2.5 h of stirring below 10° C. The organic layer was separated the aqueous layer was extracted with DCM The combined organic layers were washed with water dried over MgSO4 filtered concentrated under reduced pressure to afford a light yellow oil which was used in the next step without further purification

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

Procedure: To methyl 2-bromo-5-hydroxybenzoate (20 g, 87 mmol) in pyridine (100 mL) was added acetic anhydride (10.2 g, 100 mmol) at 0° C. The mixture was stirred at ambient temperature for 16 hours, concentrated, and ethyl acetate was added. The mixture was washed with saturated NH4Cl(aq) to afford the crude title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.79 (d, J=8.7 Hz, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.30 (dd, J=8.7, 2.8 Hz, 1H), 3.86 (s, 3H), and 2.28 (s, 3H). concentrated ethyl acetate was added The mixture was washed with saturated NH4Cl(aq)

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

Procedure: To methyl 2-bromo-5-hydroxybenzoate (20 g, 87 mmol) in pyridine (100 mL) was added acetic anhydride (10.2 g, 100 mmol) at 0° C. The mixture was stirred at ambient temperature for 16 hours, concentrated, and ethyl acetate was added. The mixture was washed with saturated NH4Cl(aq) to afford the crude title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.79 (d, J=8.7 Hz, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.30 (dd, J=8.7, 2.8 Hz, 1H), 3.86 (s, 3H), and 2.28 (s, 3H). concentrated ethyl acetate was added The mixture was washed with saturated NH4Cl(aq)

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

Procedure: To a solution of 2-Bromo-5-hydroxy-benzoic acid methyl ester (80 g, 347 mmol) and K2CO3 (71.9 g, 520 mmol) in DMF (800 mL) was added BnBr (500 g, 416.2 mmol) at RT. The mixture was stirred at RT under N2 for 5 hr. The reaction mixture was diluted with H2O (500 mL) and extracted with ethyl acetate (100 mL*3). The organic phase was washed with saturated sodium bicarbonate solution 500 mL, dried over Na2SO4. After concentration, the crude product was purified by silica gel chromatography eluted with PE:EA=4:1 to give title product (100 g, 90% yield) as an off-white solid. extracted with ethyl acetate (100 mL*3) The organic phase was washed with saturated sodium bicarbonate solution 500 mL dried over Na2SO4 After concentration the crude product was purified by silica gel chromatography eluted with PE

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

Procedure: To a solution of 2-Bromo-5-hydroxy-benzoic acid methyl ester (80 g, 347 mmol) and K2CO3 (71.9 g, 520 mmol) in DMF (800 mL) was added BnBr (500 g, 416.2 mmol) at RT. The mixture was stirred at RT under N2 for 5 hr. The reaction mixture was diluted with H2O (500 mL) and extracted with ethyl acetate (100 mL*3). The organic phase was washed with saturated sodium bicarbonate solution 500 mL, dried over Na2SO4. After concentration, the crude product was purified by silica gel chromatography eluted with PE:EA=4:1 to give title product (100 g, 90% yield) as an off-white solid. extracted with ethyl acetate (100 mL*3) The organic phase was washed with saturated sodium bicarbonate solution 500 mL dried over Na2SO4 After concentration the crude product was purified by silica gel chromatography eluted with PE

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

Procedure: To a solution of compound methyl 2-bromo-5-methoxybenzoate (100 g, 410 mmol) in DCM (2000 mL) was added and BBr3 (1N, 150 mL) at −78° C. under N2 The mixture was stirred at 0° C. under N2 for 24 hr. The reaction was quenched with MeOH (500 mL), concentrated to dryness, diluted with H2O (50 mL), and extracted with ethyl acetate (800 mL*3), The organic phase was washed with saturated sodium bicarbonate solution 50 mL, dried over Na2SO4. After concentration, the crude product was purified by silica gel chromatography eluted with PE:EA=1:1 to give title product (80 g, 85% yield) as yellow oil. LCMS (10-80 AB—2MIN.M): Rt=0.820, purity=85%, M+1=231. The reaction was quenched with MeOH (500 mL) concentrated to dryness diluted with H2O (50 mL) extracted with ethyl acetate (800 mL*3) The organic phase was washed with saturated sodium bicarbonate solution 50 mL dried over Na2SO4 After concentration the crude product was purified by silica gel chromatography eluted with PE