methyl 4-amino-3-bromobenzoate

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl-4-amino-3-bromobenzoate (32 g, 139 mmol) is combined with 250 mL conc. hydrochloric acid and cooled to −10° C. A solution of sodium nitrite (10.2 g, 146 mmol) in 120 mL water is added dropwise such that the temperature does not exceed −5° C. After 40 min stirring at −10° C. a solution of tin(II)chloride dihydrate (128 g, 556 mmol) in 130 mL conc. hydrochloric acid is added dropwise to the suspension, while the reaction temperature does not exceed −5° C. The thick liquid suspension is stirred for 1.5 h at RT, before being adjusted to pH 10 with NaOH (12 N). The reaction mixture is combined with 500 mL dichloromethane and water and after 30 min stirring it is filtered. The filter cake is combined with 300 mL dichloromethane and 100 mL water and refluxed for 30 min. After filtration the filtrate is extracted with chloroform. The combined organic phases are dried on magnesium sulphate, filtered and evaporated to dryness. Yield: 34 g. does not exceed −5° C is added dropwise to the suspension, while the reaction temperature does not exceed −5° C stirring it is filtered refluxed for 30 min After filtration the filtrate is extracted with chloroform The combined organic phases are dried on magnesium sulphate filtered evaporated to dryness

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl-4-amino-3-bromobenzoate (32 g, 139 mmol) is combined with 250 mL conc. hydrochloric acid and cooled to −10° C. A solution of sodium nitrite (10.2 g, 146 mmol) in 120 mL water is added dropwise such that the temperature does not exceed −5° C. After 40 min stirring at −10° C. a solution of tin(II)chloride dihydrate (128 g, 556 mmol) in 130 mL conc. hydrochloric acid is added dropwise to the suspension, while the reaction temperature does not exceed −5° C. The thick liquid suspension is stirred for 1.5 h at RT, before being adjusted to pH 10 with NaOH (12 N). The reaction mixture is combined with 500 mL dichloromethane and water and after 30 min stirring it is filtered. The filter cake is combined with 300 mL dichloromethane and 100 mL water and refluxed for 30 min. After filtration the filtrate is extracted with chloroform. The combined organic phases are dried on magnesium sulphate, filtered and evaporated to dryness. Yield: 34 g. does not exceed −5° C is added dropwise to the suspension, while the reaction temperature does not exceed −5° C stirring it is filtered refluxed for 30 min After filtration the filtrate is extracted with chloroform The combined organic phases are dried on magnesium sulphate filtered evaporated to dryness

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

Procedure: A solution of 4-amino-3-bromo-benzoic acid methyl ester (5.0 g, 22.0 mmol from Aldrich) in acetone (35 mL) was treated with 6M HCl (35 mL). The solution was cooled to 0° C. and treated dropwise with NaNO2 (1.84 g, 26.1 mmol) dissolved in 10 mL water. After stirring for 2 hours at 0° C., the reaction was slowly treated with potassium iodide (5.47 g, 32.6 mmol) dissolved in 20 mL water. The reaction mixture was allowed to warm to room temperature and stir for 1 hour. Reaction mixture was diluted with water and extracted with EtOAc (2×150 mL). The combined organic phase was dried (Na2SO4) and concentrated under vacuum The residue was chromatographed (80 g Redi-Sep column) eluting from 100% heptane to 20:80 EtOAc:heptane to afford the intermediate (4.1 g, 55%) as a solid. 1HNMR (CDCl3): 8.27 (1H), 7.98 (1H), 7.64 (1H), 3.94 (3H). to warm to room temperature stir for 1 hour Reaction mixture extracted with EtOAc (2×150 mL) The combined organic phase was dried (Na2SO4) concentrated under vacuum The residue was chromatographed (80 g Redi-Sep column) eluting from 100% heptane to 20:80 EtOAc

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of methyl 4-amino-3-bromobenzoate (2 g, 8.69 mmol) in isopropanol (10 mL) was added Meldrum's acid (1.63 g, 11 mmol) and triethyl orthoformate (5.26 mL, 31.6 mmol). The resulting mixture was heated at 100° C. for 4 hr and cooled to room temperature. The resulting precipitates were filtered off and washed with 10% Et2O/hexanes to yield methyl 3-bromo-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate. (M+Na)+: 408. cooled to room temperature The resulting precipitates were filtered off washed with 10% Et2O/hexanes

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

Procedure: A solution of 4-amino-3-bromo-benzoic acid methyl ester (5.0 g, 22.0 mmol from Aldrich) in acetone (35 mL) was treated with 6M HCl (35 mL). The solution was cooled to 0° C. and treated dropwise with NaNO2 (1.84 g, 26.1 mmol) dissolved in 10 mL water. After stirring for 2 hours at 0° C., the reaction was slowly treated with potassium iodide (5.47 g, 32.6 mmol) dissolved in 20 mL water. The reaction mixture was allowed to warm to room temperature and stir for 1 hour. Reaction mixture was diluted with water and extracted with EtOAc (2×150 mL). The combined organic phase was dried (Na2SO4) and concentrated under vacuum. The residue was chromatographed (80 g Redi-Sep column) eluting from 100% heptane to 20:80 EtOAc:heptane to afford the intermediate (4.1 g, 55%) as a solid. 1HNMR (CDCl3) δ ppm: 8.27 (1H), 7.98 (1H), 7.64 (1H), 3.94 (3H). to warm to room temperature stir for 1 hour Reaction mixture extracted with EtOAc (2×150 mL) The combined organic phase was dried (Na2SO4) concentrated under vacuum The residue was chromatographed (80 g Redi-Sep column) eluting from 100% heptane to 20:80 EtOAc

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl-4-amino-3-bromobenzoate (32 g, 139 mmol) is combined with 250 mL conc. hydrochloric acid and cooled to −10° C. A solution of sodium nitrite (10.2 g, 146 mmol) in 120 mL water is added dropwise such that the temperature does not exceed −5° C. After 40 min stirring at −10° C. a solution of tin(II)chloride dihydrate (128 g, 556 mmol) in 130 mL conc. hydrochloric acid is added dropwise to the suspension, while the reaction temperature does not exceed −5° C. The thick liquid suspension is stirred for 1.5 h at RT, before being adjusted to pH 10 with NaOH (12 N). The reaction mixture is combined with 500 mL dichloromethane and water and after 30 min stirring it is filtered. The filter cake is combined with 300 mL dichloromethane and 100 mL water and refluxed for 30 min. After filtration the filtrate is extracted with chloroform. The combined organic phases are dried on magnesium sulphate, filtered and evaporated to dryness. Yield: 34 g. does not exceed −5° C is added dropwise to the suspension, while the reaction temperature does not exceed −5° C stirring it is filtered refluxed for 30 min After filtration the filtrate is extracted with chloroform The combined organic phases are dried on magnesium sulphate filtered evaporated to dryness