ethyl 2-fluorobenzoate

Conditions: temp:80.01; pressure:0.00; stir:

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

Procedure: 2.15 g (12.8 mmol) of ethyl 2-fluorobenzoate and 1.9 g (14 mmol) of potassium carbonate are successively added to a solution of 4 g (12.8 mmol) of tert-butyl (4′-hydroxybiphenyl-3-ylmethyl)methylcarbamate in 45 ml of dimethylacetamide. The reaction medium is refluxed for 48 hours, cooled, diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 3.1 g of ethyl 2-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yloxy}benzoate are obtained in the form of a colorless oil, in a yield of 53%. The reaction medium is refluxed for 48 hours cooled extracted with ethyl acetate The organic phase is dried over sodium sulfate filtered concentrated under vacuum The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture

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

Procedure: 2.15 g (12.8 mmol) of ethyl 2-fluorobenzoate and 1.9 g (14 mmol) of potassium carbonate are successively added to a solution of 4 g (12.8 mmol) of tert-butyl (4′-hydroxybiphenyl-3-ylmethyl)methylcarbamate in 45 ml of dimethylacetamide. The reaction medium is refluxed for 48 hours, cooled, diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 3.1 g of ethyl 2-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yloxy}benzoate are obtained in the form of a colorless oil, in a yield of 53%. The reaction medium is refluxed for 48 hours cooled extracted with ethyl acetate The organic phase is dried over sodium sulfate filtered concentrated under vacuum The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture

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

Procedure: A mixture of 35 g of 2-fluoro-benzoyl chloride and 400 ml of ethanol was stirred for three hours and was allowed to stand overnight. The mixture was distilled to dryness at 50° C. and 30-40 mm Hg and the residue was taken up in methylene chloride The solution was washed with 5% aqueous sodium bicarbonate and then with water, dried and evaporated to dryness under reduced pressure. The product was rectified at 14 mm Hg to obtain 34 g of ethyl 2-fluoro-benzoate with a boiling point of 90°-91° C. at 14 mm Hg. to stand overnight The mixture was distilled to dryness at 50° C. was washed with 5% aqueous sodium bicarbonate with water, dried evaporated to dryness under reduced pressure

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

Procedure: A mixture of 35 g of 2-fluoro-benzoyl chloride and 400 ml of ethanol was stirred for three hours and was allowed to stand overnight. The mixture was distilled to dryness at 50° C. and 30-40 mm Hg and the residue was taken up in methylene chloride The solution was washed with 5% aqueous sodium bicarbonate and then with water, dried and evaporated to dryness under reduced pressure. The product was rectified at 14 mm Hg to obtain 34 g of ethyl 2-fluoro-benzoate with a boiling point of 90°-91° C. at 14 mm Hg. to stand overnight The mixture was distilled to dryness at 50° C. was washed with 5% aqueous sodium bicarbonate with water, dried evaporated to dryness under reduced pressure

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

Procedure: To a stirred solution of commercially available 2-Fluoro-benzoic acid ethyl ester (1 g, 6.01 mmol) and 2-Ethoxy-ethylamine (0.500 g, 2.97 mmole) in dry N,N′dimethylformamide (10 mL) in a screw cap vial was added diisopropylethylamine (1.1 eq, 0.223 g, 3.27 mmole, 1.1 mL). The resulting solution was heated to 120° C. for 4 hours. Reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 2-(2-Ethoxy-ethylamino)-benzoic acid ethyl ester as a clear liquid (0.493 g, 70%, LCMS calc M+H 238, obs M+H 238). Reaction mixture was cooled to room temperature extracted with ethyl acetate (25 mL×3) Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate Organic phase was evaporated the residue was purified by flash chromatography

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

Procedure: To a stirred solution of commercially available 2-Fluoro-benzoic acid ethyl ester (1 g, 6.01 mmol) and 2-Ethoxy-ethylamine (0.500 g, 2.97 mmole) in dry N,N′dimethylformamide (10 mL) in a screw cap vial was added diisopropylethylamine (1.1 eq, 0.223 g, 3.27 mmole, 1.1 mL). The resulting solution was heated to 120° C. for 4 hours. Reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 2-(2-Ethoxy-ethylamino)-benzoic acid ethyl ester as a clear liquid (0.493 g, 70%, LCMS calc M+H 238, obs M+H 238). Reaction mixture was cooled to room temperature extracted with ethyl acetate (25 mL×3) Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate Organic phase was evaporated the residue was purified by flash chromatography

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

Procedure: To a stirred solution of commercially available 2-Fluoro-benzoic acid ethyl ester (1 g, 6.01 mmol) and 4-Fluoro-benzylamine (0.828 g, 6.62 mmol) in dry N,N′-dimethylformamide (10 mL) in a screw cap vial was added diisopropylethylamine (0.854 g, 6.62 mmole, 1.1 mL). The resulting solution was heated to 120° C. for 4 hours. Reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 2-(4-Fluoro-benzylamino)-benzoic acid ethyl ester as a clear liquid (1.23 g, 75%, LCMS calc M+H 274, obs M+H 274). Reaction mixture was cooled to room temperature extracted with ethyl acetate (25 mL×3) Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate Organic phase was evaporated the residue was purified by flash chromatography

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

Procedure: To a stirred solution of commercially available 2-Fluoro-benzoic acid ethyl ester (1 g, 6.01 mmol) and 4-Fluoro-benzylamine (0.828 g, 6.62 mmol) in dry N,N′-dimethylformamide (10 mL) in a screw cap vial was added diisopropylethylamine (0.854 g, 6.62 mmole, 1.1 mL). The resulting solution was heated to 120° C. for 4 hours. Reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 2-(4-Fluoro-benzylamino)-benzoic acid ethyl ester as a clear liquid (1.23 g, 75%, LCMS calc M+H 274, obs M+H 274). Reaction mixture was cooled to room temperature extracted with ethyl acetate (25 mL×3) Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate Organic phase was evaporated the residue was purified by flash chromatography

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

Procedure: To a stirred solution of commercially available 2-Fluoro-benzoic acid ethyl ester (1 g, 6.01 mmol) and 4-Fluoro-benzylamine (0.828 g, 6.62 mmol) in dry N,N′-dimethylformamide (10 mL) in a screw cap vial was added diisopropylethylamine (0.854 g, 6.62 mmole, 1.1 mL). The resulting solution was heated to 120° C. for 4 hours. Reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 2-(4-Fluoro-benzylamino)-benzoic acid ethyl ester as a clear liquid (1.23 g, 75%, LCMS calc M+H 274, obs M+H 274). Reaction mixture was cooled to room temperature extracted with ethyl acetate (25 mL×3) Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate Organic phase was evaporated the residue was purified by flash chromatography

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

Procedure: A mixture of 2-fluoro-benzoic acid ethyl ester (200 mg; 1.19 mmol; 10 eq.), (1H-imidazol-2-ylmethyl)-dimethyl-amine (149 mg; 1.19 mmol; 1 eq.) and cesium carbonate (775 mg; 2.38 mmol; 2 eq.) in DMSO (3 mL) was stirred at 120° C. for 16 hours. The mixture was diluted with EA, washed with water (3×), dried over magnesium sulfate and concentrated in vacuo to afford the title compound (58 mg, 18%) as a white solid. HPLC (max plot) 95.7%; Rt 1.80 min. washed with water (3×) dried over magnesium sulfate concentrated in vacuo

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

Procedure: As described for the general reaction of ethyl 2-fluorobenzoate with amines set forth in Tetrahedron, 53, 7557-7576 (1997), ethyl 2-fluorobenzoate was reacted with pyrazole by refluxing N, N-dimethylformamide to give ethyl 2-(1-pyrazolyl)benzoate, as a thick yellow oil. Anal. Calc'd: for C12H12N2O2 : C, 66.7; H, 5.6; N 13.0: Found: C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H). A sample (7.02 g) of this compound and 8.42 ml of 5N NaOH in 40 ml of ethanol-tetrahydrofuran (2:1) was refluxed for 2 hrs and the solvent removed. The residue was made acidic (pH6) with 2N citric acid and the precipated solid was filtered to obtain 3.7g of product. The pH of the filtrate was adjusted to 4:5 and extracted with ethyl acetate The extract was concentrated to dryness to give 1.5 g of product. The two crops were combined to give 5.2 g of 2-(1-pyrazolyl)benzoic acid, mp 140-142° C. To the preceding compound (2.07 g) in 5 ml CH2Cl2 (chilled in an ice bath )was added 11.1 ml of a 2 Molar solution of oxalyl chloride in CH2Cl2 and 0.085 ml of N,N-dimethylformamide. The mixture was allowed to warm to room temperature and stirred for 4 hours. The solvent was removed and 25 ml of toluene added (twice) and removed under vacuum to give 2-(1-pyrazolyl)benzoyl chloride as a yellow solid.