ethyl 6-amino-5-bromo-1-benzofuran-3-carboxylate

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

Procedure: To a solution of ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58 g, 204 mmol) in 1,4-dioxane and H2O (850 mL and 150 mL) was add LiOH.H2O (42.8 g, 1.02 mol). The reaction mixture was refluxed for 2 hours, and then 400 mL H2O was added to the reaction mixture. After acidifying to pH 4˜5 with HCl, the resulting solid was filtered to give the product of 6-amino-5-bromobenzofuran-3-carboxylic acid (51 g, yield: 97%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.36 (s, 1H), 7.87 (s, 1H), 7.02 (s, 1H), 5.51 (br s, 2H). MS (M+H)+: 256/258. The reaction mixture was refluxed for 2 hours the resulting solid was filtered

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

Procedure: A mixture of crude ethyl 5-bromo-6-nitrobenzofuran-3-carboxylate (95 g, 302 mmol), iron filings (50.67 g, 907 mmol) and NH4Cl (97 g, 1.82 mol) in MeOH-THF—H2O (2:2:1, 1000 mL) were stirred at refluxing for 3 hours. After filtered and concentrated in vacuum, the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1) to furnish the pure product of ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58.0 g, yield: 68%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.46 (s, 1H), 7.85 (s, 1H), 7.03 (s, 1H), 5.55 (br s, 2H), 4.31 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H). MS (M+H)+: 284/286. at refluxing for 3 hours After filtered concentrated in vacuum the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1)

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

Procedure: A mixture of crude ethyl 5-bromo-6-nitrobenzofuran-3-carboxylate (95 g, 302 mmol), iron filings (50.67 g, 907 mmol) and NH4Cl (97 g, 1.82 mol) in MeOH-THF—H2O (2:2:1, 1000 mL) were stirred at refluxing for 3 hours. After filtered and concentrated in vacuum, the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1) to furnish the pure product of ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58.0 g, yield: 68%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.46 (s, 1H), 7.85 (s, 1H), 7.03 (s, 1H), 5.55 (br s, 2H), 4.31 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H). MS (M+H)+: 284/286. at refluxing for 3 hours After filtered concentrated in vacuum the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1)

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

Procedure: To a solution of LDA (6.32 g, 59.0 mmol) in THF (60 mL) was added dropwise ethyl 6-amino-5-bromobenzofuran-3-carboxylate (5 g, 17.6 mmol) at −78° C. under N2. After the mixture was stirred for 1 hour, cyclopentanone (4.44 g, 52.8 mmol) in THF (40 mL) was added dropwise at −78° C. After the mixture was stirred for 1 h, NH4Cl (a.q.) was added, then the mixture was extracted with EtOAc (100 mL*3) and dried over Na2SO4 After concentration, the residue was purified by column chromatography (PE:EtOAc=10:1) to give the product of ethyl 6-amino-5-bromo-2-(1-hydroxycyclopentyl)benzofuran-3-carboxylate (2.9 g, yield: 44%). 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 6.86 (s, 1H), 6.07 (s, 1H), 4.46 (q, J=7.2 Hz, 2H), 4.20 (s, 1H), 2.12˜2.17 (m, 4H), 1.99 (t, J=5.6 Hz, 2H), 1.79 (t, J=3.2 Hz, 2H), 1.50 (t, J=7.2 Hz, 3H). MS (M+H)+: 368/370. After the mixture was stirred for 1 h the mixture was extracted with EtOAc (100 mL*3) dried over Na2SO4 After concentration the residue was purified by column chromatography (PE:EtOAc=10:1)

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

Procedure: To a solution of LDA (6.32 g, 59.0 mmol) in THF (60 mL) was added dropwise ethyl 6-amino-5-bromobenzofuran-3-carboxylate (5 g, 17.6 mmol) at −78° C. under N2. After the mixture was stirred for 1 hour, cyclopentanone (4.44 g, 52.8 mmol) in THF (40 mL) was added dropwise at −78° C. After the mixture was stirred for 1 h, NH4Cl (a.q.) was added, then the mixture was extracted with EtOAc (100 mL*3) and dried over Na2SO4 After concentration, the residue was purified by column chromatography (PE:EtOAc=10:1) to give the product of ethyl 6-amino-5-bromo-2-(1-hydroxycyclopentyl)benzofuran-3-carboxylate (2.9 g, yield: 44%). 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 6.86 (s, 1H), 6.07 (s, 1H), 4.46 (q, J=7.2 Hz, 2H), 4.20 (s, 1H), 2.12˜2.17 (m, 4H), 1.99 (t, J=5.6 Hz, 2H), 1.79 (t, J=3.2 Hz, 2H), 1.50 (t, J=7.2 Hz, 3H). MS (M+H)+: 368/370. After the mixture was stirred for 1 h the mixture was extracted with EtOAc (100 mL*3) dried over Na2SO4 After concentration the residue was purified by column chromatography (PE:EtOAc=10:1)

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

Procedure: To a solution of the compound ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58 g, 204 mmol) in 1,4-dioxane and H2O (850 mL and 150 mL) was added LiOH.H2O (42.8 g, 1.02 mol). The reaction mixture was refluxed for 2 hours, and then 400 mL H2O was added to the reaction mixture. After acidifying to pH 4˜5 with HCl, the resulting solid was filtered to give 6-amino-5-bromobenzofuran-3-carboxylic acid (51 g, yield: 97%). 1H-NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.87 (s, 1H), 7.02 (s, 1H), 5.51 (br s, 2H). The reaction mixture was refluxed for 2 hours the resulting solid was filtered

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

Procedure: A mixture of crude compound ethyl 5-bromo-6-nitrobenzofuran-3-carboxylate (95 g, 302 mmol), iron filings (50.67 g, 907 mmol) and NH4Cl (97 g, 1.82 mol) in MeOH-THF—H2O (2:2:1, 1000 mL) were stirred at reflux for 3 hours. After being filtered and concentrated in vacuum, the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1) to furnish ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58.00 g, yield: 68%). 1H-NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.85 (s, 1H), 7.03 (s, 1H), 5.55 (br s, 2H), 4.31 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H). at reflux for 3 hours After being filtered concentrated in vacuum the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1)

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

Procedure: A mixture of crude compound ethyl 5-bromo-6-nitrobenzofuran-3-carboxylate (95 g, 302 mmol), iron filings (50.67 g, 907 mmol) and NH4Cl (97 g, 1.82 mol) in MeOH-THF—H2O (2:2:1, 1000 mL) were stirred at reflux for 3 hours. After being filtered and concentrated in vacuum, the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1) to furnish ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58.00 g, yield: 68%). 1H-NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.85 (s, 1H), 7.03 (s, 1H), 5.55 (br s, 2H), 4.31 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H). at reflux for 3 hours After being filtered concentrated in vacuum the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1)

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

Procedure: To a solution of ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58 g, 204 mmol) in 1,4-dioxane and H2O (850 mL and 150 mL) was add LiOH.H2O (42.8 g, 1.02 mol). The reaction mixture was refluxed for 2 hours, and then 400 mL H2O was added to the reaction mixture. After acidifying to pH 4˜5 with HCl, the resulting solid was filtered to give the product of 6-amino-5-bromobenzofuran-3-carboxylic acid (51 g, yield: 97%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.36 (s, 1H), 7.87 (s, 1H), 7.02 (s, 1H), 5.51 (br s, 2H). MS (M+H)+: 256/258. The reaction mixture was refluxed for 2 hours the resulting solid was filtered

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

Procedure: A mixture of crude ethyl 5-bromo-6-nitrobenzofuran-3-carboxylate (95 g, 302 mmol), iron filings (50.67 g, 907 mmol) and NH4Cl (97 g, 1.82 mol) in MeOH-THF—H2O (2:2:1, 1000 mL) were stirred at refluxing for 3 hours. After filtered and concentrated in vacuum, the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1) to furnish the pure product of ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58.0 g, yield: 68%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.46 (s, 1H), 7.85 (s, 1H), 7.03 (s, 1H), 5.55 (br s, 2H), 4.31 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H). MS (M+H)+: 284/286. at refluxing for 3 hours After filtered concentrated in vacuum the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1)

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

Procedure: To a solution of LDA (6.32 g, 59.0 mmol) in THF (60 mL) was added dropwise ethyl 6-amino-5-bromobenzofuran-3-carboxylate (5 g, 17.6 mmol) at −78° C. under N2. After the mixture was stirred for 1 hour, cyclopentanone (4.44 g, 52.8 mmol) in THF (40 mL) was added dropwise at −78° C. After the mixture was stirred for 1 h, NH4Cl (a.q.) was added, then the mixture was extracted with EtOAc (100 mL*3) and dried over Na2SO4 After concentration, the residue was purified by column chromatography (PE:EtOAc=10:1) to give the product of ethyl 6-amino-5-bromo-2-(1-hydroxycyclopentyl)benzofuran-3-carboxylate (2.9 g, yield: 44%). 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 6.86 (s, 1H), 6.07 (s, 1H), 4.46 (q, J=7.2 Hz, 2H), 4.20 (s, 1H), 2.12˜2.17 (m, 4H), 1.99 (t, J=5.6 Hz, 2H), 1.79 (t, J=3.2 Hz, 2H), 1.50 (t, J=7.2 Hz, 3H). MS (M+H)+: 368/370. After the mixture was stirred for 1 h the mixture was extracted with EtOAc (100 mL*3) dried over Na2SO4 After concentration the residue was purified by column chromatography (PE:EtOAc=10:1)

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

Procedure: To a solution of the compound ethyl 6-amino-5-bromobenzofuran-3-carboxylate (58 g, 204 mmol) in 1,4-dioxane and H2O (850 mL and 150 mL) was added LiOH.H2O (42.8 g, 1.02 mol). The reaction mixture was refluxed for 2 hours, and then 400 mL H2O was added to the reaction mixture. After acidifying to pH 4˜5 with HCl, the resulting solid was filtered to give 6-amino-5-bromobenzofuran-3-carboxylic acid (51 g, yield: 97%). 1H-NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.87 (s, 1H), 7.02 (s, 1H), 5.51 (br s, 2H). The reaction mixture was refluxed for 2 hours the resulting solid was filtered