methyl 3-amino-4-bromobenzoate

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

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

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add zinc cyanide (1.5 g, 12.77 mmol), palladium tetrakis (675 mg, 0.584 mmol), to 3-amino-4-bromo-benzoic acid methyl ester (1.328 g, 5.77 mmol) in anhydrous DMF (3 ml). Purge with nitrogen for few minutes and keep under nitrogen atmosphere while heating to 120° C. overnight. Cool the mixture to room temperature and add water. Extract the product with EtOAc (×2). Wash the combined organic layers with 2N ammonium hydroxide solution (×2), water (×2), saturated aq. sodium chloride and dry over anhydrous sodium sulfate, filter and concentrate to yield the crude product. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields 3-amino-4-cyano-benzoic acid methyl ester (94%). Purge with nitrogen for few minutes Cool the mixture to room temperature add water Extract the product with EtOAc (×2) Wash the combined organic layers with 2N ammonium hydroxide solution (×2), water (×2), saturated aq. sodium chloride dry over anhydrous sodium sulfate filter concentrate to yield the crude product Purification by flash chromatography (Silica gel-hexane/EtOAc)

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

Procedure: Dissolve 4-bromo-3-nitro-benzoic acid methyl ester (4.25 g, 16.3 mmol) in ethanol (100 ml) and water (30 ml). Add sodium dithionite (15 g, 75 mmol) in a single portion and heat the mixture under reflux for 4 h. Evaporate ethanol and add water. Basify the aqueous layer with 10% sodium carbonate solution. Extract the product with EtOAc (×2). Dry the combined organic layers over anhydrous sodium sulfate, filter and concentrate to yield 3-amino-4-bromo-benzoic acid methyl ester (51%). under reflux for 4 h Extract the product with EtOAc (×2) Dry the combined organic layers over anhydrous sodium sulfate filter concentrate

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

Procedure: Add Na2SO4 (0.12 mmol) to a suspension of 4-Bromo-3-amino-benzoic acid methyl ester (0.1 mmol) and Et3N (0.1 mmol) in dichloromethane at 0° C. Stir 4 h at RT. Add a saturated solution of NaCl (15 mL), and extract with dichloromethane (2×50 mL). Dry over NaSO4, filter and evaporate to dryness. Purify the residue utilizing flash chromatography (Silica gel-hexane/EtOAc) to provide the title compound. extract with dichloromethane (2×50 mL) Dry over NaSO4 filter evaporate to dryness Purify the residue utilizing flash chromatography (Silica gel-hexane/EtOAc)

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

Procedure: Add Na2SO4 (0.12 mmol) to a suspension of 4-Bromo-3-amino-benzoic acid methyl ester (0.1 mmol) and Et3N (0.1 mmol) in dichloromethane at 0° C. Stir 4 h at RT. Add a saturated solution of NaCl (15 mL), and extract with dichloromethane (2×50 mL). Dry over NaSO4, filter and evaporate to dryness. Purify the residue utilizing flash chromatography (Silica gel-hexane/EtOAc) to provide the title compound. extract with dichloromethane (2×50 mL) Dry over NaSO4 filter evaporate to dryness Purify the residue utilizing flash chromatography (Silica gel-hexane/EtOAc)

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

Procedure: Add Na2SO4(8.5 mmol) to a solution of 4-Bromo-3-nitro-benzoic acid methyl ester (1.2 mmol) in EtOH (40 mL). Heat the reaction at 70° C. for 30 min and then at room temperature overnight. Add a saturated solution of NaHCO3(pH=11-12) and extract with EtOAc (2×50 mL). Dry over NaSO4, filter and evaporate to dryness to provide 4-Bromo-3-amino-benzoic acid methyl ester. Heat the reaction at 70° C. for 30 min at room temperature overnight Add a saturated solution of NaHCO3(pH=11-12) extract with EtOAc (2×50 mL) Dry over NaSO4 filter evaporate to dryness

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (16.1 g, 70 mmol), methyl 3-amino-4-bromobenzoate (21.9 g, 84 mmol), polyphosphoric acid (120 g) and dioxane (120 mL) was heated at 110° C. for 4 hours. After cooling to room temperature, the mixture was poured into ice water, filtered and the filtrate was extracted with EtOAc (500 mL×3). The combined organic layers were dried, and concentrated to give crude residue, which was chromatographed on silica gel using gradient eluant of 20% to 50% ethyl acetate in petroleum ether to give the crude product. Then the crude product was dissolved in MeOH (1 L), TMSCl (150 mL) was added, and the mixture was stirred at reflux for 12 h. After cooling to room temperature, the solvent was evaporated and the residue was recrystallized from MeOH to afford methyl 2-benzyl-9-bromo-5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate (7.6 g). 1H NMR (CDC3-d1) δ 10.9 (s, 1H), 8.06 (d, 1H, J=7.8 Hz), 7.51-7.74 (m, 5H), 7.20 (d, 1H, J=7.8 Hz), 4.36-4.62 (m, 4H), 3.82 (s, 3H), 3.67-3.72 (m, 2H), and 2.82-2.83 (m, 2H). MS (ESI) m/e [M+1]+427.0. After cooling to room temperature filtered the filtrate was extracted with EtOAc (500 mL×3) The combined organic layers were dried concentrated to give crude residue, which was chromatographed on silica gel using gradient eluant of 20% to 50% ethyl acetate in petroleum ether to give the crude product at reflux for 12 h After cooling to room temperature the solvent was evaporated the residue was recrystallized from MeOH

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-oxocyclooctanecarboxylate (32.0 g, 174 mmol), methyl 3-amino-4-bromobenzoate (20.0 g, 87 mmol) and ethanol (120 mL) was heated to reflux, at an oil bath of 130° C., acetic acid (1.5 mL) was added and the mixture was reflux for 1.5 hours. Hot PPA (200 g, 120° C.) was added to the reaction mixture carefully. The reaction mixture was heated at an oil bath of 130° C. for 3 hours. After cooling for a while, ice (200 g), ethyl acetate (60 mL) and petroleum ether (60 mL) were added to the reaction mixture, the mixture was concentrated until 200 mL solvent was removed. Then water (600 mL) and ethyl acetate (60 mL) were added, the resulting mixture was stayed at room temperature overnight. A light brown solid was slowly formed. The mixture was filtered and the filtered cake was dried to give a light brown solid, which was placed into methanol (90 mL). SOCl2 (30 mL) was added dropwise with cooling with an ice-bath. The resulting mixture was heated to reflux for 4 hours, concentrated and treated with saturated NaHCO3 solution (60 mL) and ethyl acetate (30 mL), filtered and the filtered cake was dried to give desired product (6.6 g) as a pale white solid (21%). 1H NMR (DMSO-d6) δ10.25 (s, 1H), 7.96-7.98 (d, 1H, J=7.6 Hz), 7.09-7.11 (d, 1H, J=7.6 Hz), 3.02-3.06 (m, 2H), 2.63-2.66 (m, 2H), 1.75-1.77 (m, 2H), 1.53-1.55 (m, 2H), and 1.36-1.39 (m, 4H). MS (ESI) m/e [M+1]+ 364/366. was heated the mixture was reflux for 1.5 hours Hot PPA (200 g, 120° C.) was added to the reaction mixture carefully The reaction mixture was heated at an oil bath of 130° C. for 3 hours were added to the reaction mixture the mixture was concentrated until 200 mL solvent was removed Then water (600 mL) and ethyl acetate (60 mL) were added A light brown solid was slowly formed The mixture was filtered the filtered cake was dried to give a light brown solid, which with cooling with an ice-bath The resulting mixture was heated to reflux for 4 hours concentrated treated with saturated NaHCO3 solution (60 mL) and ethyl acetate (30 mL) filtered the filtered cake was dried

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-hydroxy-5,5-dimethylcyclohex-1-enecarboxylate (26 g, 0.141 mol), methyl 3-amino-4-bromobenzoate (25 g, 0.109 mol), polyphosphoric acid (220 g) and dioxane (220 mL) was heated at 130° C. for 5 hours. After cooling, the mixture was diluted with water. The resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (400 mL), and TMSCl (90 mL) was added. The mixture was stirred at reflux for 5 hours, concentrated and treated with water (80 mL), extracted with ethyl acetate (250 mL). The organic layer was separated, concentrated and recrystallized with methanol to afford desired compound (10.6 g, 27%). 1H NMR (DMSO-d6) δ 10.32 (s, 1H), 7.98 (d, 1H, J=7.2 Hz), 7.10 (d, 1H, J=7.2 Hz), 3.80 (s, 3H), 2.90 (t, 2H, J=6.6 Hz), 2.22 (s, 2H), 1.56 (t, 2H, J=6.6 Hz), and 0.97 (s, 6H). MS (ESI) m/e [M+1]+364. After cooling The resulting precipitate was collected by filtration dried TMSCl (90 mL) was added at reflux for 5 hours concentrated treated with water (80 mL) extracted with ethyl acetate (250 mL) The organic layer was separated concentrated recrystallized with methanol

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-hydroxy-5,5-dimethylcyclohex-1-enecarboxylate (26 g, 0.141 mol), methyl 3-amino-4-bromobenzoate (25 g, 0.109 mol), polyphosphoric acid (220 g) and dioxane (220 mL) was heated at 130° C. for 5 hours. After cooling, the mixture was diluted with water. The resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (400 mL), and TMSCl (90 mL) was added. The mixture was stirred at reflux for 5 hours, concentrated and treated with water (80 mL), extracted with ethyl acetate (250 mL). The organic layer was separated, concentrated and recrystallized with methanol to afford desired compound (10.6 g, 27%). 1H NMR (DMSO-d6) δ 10.32 (s, 1H), 7.98 (d, 1H, J=7.2 Hz), 7.10 (d, 1H, J=7.2 Hz), 3.80 (s, 3H), 2.90 (t, 2H, J=6.6 Hz), 2.22 (s, 2H), 1.56 (t, 2H, J=6.6 Hz), and 0.97 (s, 6H). MS (ESI) m/e [M+1]+364. After cooling The resulting precipitate was collected by filtration dried TMSCl (90 mL) was added at reflux for 5 hours concentrated treated with water (80 mL) extracted with ethyl acetate (250 mL) The organic layer was separated concentrated recrystallized with methanol