ethyl 4-amino-3-fluorobenzoate

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:0.00; pressure:0.00; stir:

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

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

Procedure: 4-amino-3-fluoro-benzoic acid ethyl ester (490 mg, 2.7 mmol) was dissolved in acetonitrile (20 mL, 400 mmol) at ambient temperature. The solution was cooled to −5° C. in an acetone bath. 37% HCl (37:63, HCl:water, 2 mL) was added slowly. A solution of sodium nitrite (203 mg, 2.94 mmol) in water (1 mL, 60 mmol) was added slowly. The reaction mixture turned orange over the course of the addition. After addition was complete, the reaction mixture was stirred at ˜0° C. for 35 min. A 0° C. solution of sulfur dioxide in AcOH (8:25, sulfur dioxide:AcOH, 20 mL) was added followed by copper(II)chloride dihydrate (460 mg, 2.7 mmol). No gas evolution was evident. The mixture warmed to ambient temperature and stirred for 1.5 hours. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The concentrate contained a large excess of AcOH. The residue was diluted with acetonitrile and water, frozen, and lyophilized to afford a mauve powder (559 mg, 74%). The reaction mixture turned orange over the course of the addition After addition The mixture warmed to ambient temperature stirred for 1.5 hours extracted with ethyl acetate (3×) The combined organic layers were washed with brine dried over sodium sulfate filtered concentrated in vacuo The residue was diluted with acetonitrile and water frozen

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

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

Procedure: A solution of 4-benzylbenzoic acid (1.06 g, 5 mmole) in dichloromethane (10 mL) was added oxalyl dichloride (1 mL) followed by a few drops of DMF at 0° C. The resulting mixture was stirred room temperature for 3 hours. Removal of the solvents gave the residue which was dissolved in dichloromethane (2 mL) and added to the solution of triethylamine (1.4 mL, 10 mmol) and ethyl 4-amino-3-fluorobenzoate (916 mg, 5 mmole) in dichloromethane (50 mL) at 0° C. After stirring at room temperature for 48 hours, the mixture was washed with saturated sodium bicarbonate and 1 N HCl. The combined organic extracts were washed with brine, dried and concentrated under reduced pressure to give the residue which was purification by silica gel chromatography on ISCO system. The desired product was obtained as an off white solid: 1H NMR (400 MHz, CDCl3) δ 8.63 (t, J=8.8 Hz, 1H), 8.20 (s, 1H), 7.83 (m, 4H), 7.18-7.35 (m, 6H), 4.39 (q, J=7.2 Hz, 1H), 4.07 (s, 2H), 1.40 (t, J=7.2 Hz, 3H). Removal of the solvents gave the residue which After stirring at room temperature for 48 hours the mixture was washed with saturated sodium bicarbonate and 1 N HCl The combined organic extracts were washed with brine dried concentrated under reduced pressure to give the residue which purification by silica gel chromatography on ISCO system

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

Procedure: A solution of 4-benzylbenzoic acid (1.06 g, 5 mmole) in dichloromethane (10 mL) was added oxalyl dichloride (1 mL) followed by a few drops of DMF at 0° C. The resulting mixture was stirred room temperature for 3 hours. Removal of the solvents gave the residue which was dissolved in dichloromethane (2 mL) and added to the solution of triethylamine (1.4 mL, 10 mmol) and ethyl 4-amino-3-fluorobenzoate (916 mg, 5 mmole) in dichloromethane (50 mL) at 0° C. After stirring at room temperature for 48 hours, the mixture was washed with saturated sodium bicarbonate and 1 N HCl. The combined organic extracts were washed with brine, dried and concentrated under reduced pressure to give the residue which was purification by silica gel chromatography on ISCO system. The desired product was obtained as an off white solid: 1H NMR (400 MHz, CDCl3) δ 8.63 (t, J=8.8 Hz, 1H), 8.20 (s, 1H), 7.83 (m, 4H), 7.18-7.35 (m, 6H), 4.39 (q, J=7.2 Hz, 1H), 4.07 (s, 2H), 1.40 (t, J=7.2 Hz, 3H). Removal of the solvents gave the residue which After stirring at room temperature for 48 hours the mixture was washed with saturated sodium bicarbonate and 1 N HCl The combined organic extracts were washed with brine dried concentrated under reduced pressure to give the residue which purification by silica gel chromatography on ISCO system

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

Procedure: Prepared analogously to Example 46a from (2-chloro-ethoxy)-acetylchloride and ethyl 4-amino-3-fluoro-benzoate with TEA in THF.

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

Procedure: Prepared analogously to Example 46a from (2-chloro-ethoxy)-acetylchloride and ethyl 4-amino-3-fluoro-benzoate with TEA in THF.

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

Procedure: 4-amino-3-fluoro-benzoic acid ethyl ester (490 mg, 2.7 mmol) was dissolved in acetonitrile (20 mL, 400 mmol) at ambient temperature. The solution was cooled to −5° C. in an acetone bath. 37% HCl (37:63, HCl:water, 2 mL) was added slowly. A solution of sodium nitrite (203 mg, 2.94 mmol) in water (1 mL, 60 mmol) was added slowly. The reaction mixture turned orange over the course of the addition. After addition was complete, the reaction mixture was stirred at ˜0° C. for 35 min. A 0° C. solution of sulfur dioxide in AcOH (8:25, sulfur dioxide:AcOH, 20 mL) was added followed by copper(II)chloride dihydrate (460 mg, 2.7 mmol). No gas evolution was evident. The mixture warmed to ambient temperature and stirred for 1.5 hours. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The concentrate contained a large excess of AcOH. The residue was diluted with acetonitrile and water, frozen, and lyophilized to afford a mauve powder (559 mg, 74%). The reaction mixture turned orange over the course of the addition After addition The mixture warmed to ambient temperature stirred for 1.5 hours extracted with ethyl acetate (3×) The combined organic layers were washed with brine dried over sodium sulfate filtered concentrated in vacuo The residue was diluted with acetonitrile and water frozen