ethyl 4-fluoro-1H-pyrrole-2-carboxylate

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

Procedure: To a solution of 4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.57 g, 10.0 mmol) in 20 ml DMF is added potassium tert-butylate (2.24 g, 20.0 mmol) under nitrogen. After stirring at room temperature for 90 minutes, the chloroamine solution from above (110 ml, ca. 25 mmol) is added slowly, after which the mixture is stirred for 5 minutes at room temperature. The reaction mixture is partitioned between saturated sodium bisulfite solution and tert-butyl methyl ether. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/dichloromethane as eluent to afford 1-amino-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester as white solid; HPLC/MS 2.21 min (B), [M+H] 173; after which the mixture is stirred for 5 minutes at room temperature The reaction mixture is partitioned between saturated sodium bisulfite solution and tert-butyl methyl ether The organic phase is dried over sodium sulfate evaporated The residue is chromatographed on a silica gel column with cyclohexane/dichloromethane as eluent

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

Procedure: 4-Fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.57 g, 10.0 mmol) is dissolved in acetonitrile (10 ml), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™, 3.54 g, 10.0 mmol) is added and the mixture is irradiated in a Biotage Initiator microwave synthesizer for 5 minutes at 70° C. The reaction mixture is allowed to cool to room temperature and partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 4,5-difluoro-1H-pyrrole-2-carboxylic acid ethyl ester as white solid; HPLC/MS 1.78 (C), [M+H] 176; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 12.93 (s, 1H), 6.67 (d, J=4.5 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H). the mixture is irradiated in a Biotage Initiator microwave synthesizer for 5 minutes at 70° C partitioned between water and dichloromethane The organic phase is dried over sodium sulfate evaporated The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent

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

Procedure: 4-Fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.57 g, 10.0 mmol) is dissolved in acetonitrile (10 ml), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™, 3.54 g, 10.0 mmol) is added and the mixture is irradiated in a Biotage Initiator microwave synthesizer for 5 minutes at 70° C. The reaction mixture is allowed to cool to room temperature and partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 4,5-difluoro-1H-pyrrole-2-carboxylic acid ethyl ester as white solid; HPLC/MS 1.78 (C), [M+H] 176; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 12.93 (s, 1H), 6.67 (d, J=4.5 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H). the mixture is irradiated in a Biotage Initiator microwave synthesizer for 5 minutes at 70° C partitioned between water and dichloromethane The organic phase is dried over sodium sulfate evaporated The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent

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

Procedure: 4-Fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.57 g, 10.0 mmol) is dissolved in acetonitrile (10 ml), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™, 3.54 g, 10.0 mmol) is added and the mixture is irradiated in a Biotage Initiator microwave synthesizer for 5 minutes at 70° C. The reaction mixture is allowed to cool to room temperature and partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 4,5-difluoro-1H-pyrrole-2-carboxylic acid ethyl ester as white solid; HPLC/MS 1.78 (C), [M+H] 176; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 12.93 (s, 1H), 6.67 (d, J=4.5 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H). the mixture is irradiated in a Biotage Initiator microwave synthesizer for 5 minutes at 70° C partitioned between water and dichloromethane The organic phase is dried over sodium sulfate evaporated The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent

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

Procedure: 4-Fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.07 g; 6.83 mmol) and 1-{4-[4-(2-bromo-acetyl)-phenyl]-piperidin-1-yl}-2,2,2-trifluoro-ethanone (2.00 g; 5.26 mmol) are dissolved in acetone (20 ml). To this clear brown solution potassium carbonate (1.45 g; 10.51 mmol) is added and the reaction mixture is stirred at ambient temperature over night. The reaction mixture is diluted with acetone, filtered off by suction and washed with acetone. The filtrate is evaporated to dryness. The crude product is purified by flashchromatography to afford 4-fluoro-1-(2-oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-phenyl}-ethyl)-1H-pyrrole-2-carboxylic acid ethyl ester as off-white solid; HPLC/MS 2.67 min (A), [M+H] 455. filtered off by suction washed with acetone The filtrate is evaporated to dryness The crude product is purified by flashchromatography

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

Procedure: 4-Fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.07 g; 6.83 mmol) and 1-{4-[4-(2-bromo-acetyl)-phenyl]-piperidin-1-yl}-2,2,2-trifluoro-ethanone (2.00 g; 5.26 mmol) are dissolved in acetone (20 ml). To this clear brown solution potassium carbonate (1.45 g; 10.51 mmol) is added and the reaction mixture is stirred at ambient temperature over night. The reaction mixture is diluted with acetone, filtered off by suction and washed with acetone. The filtrate is evaporated to dryness. The crude product is purified by flashchromatography to afford 4-fluoro-1-(2-oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-phenyl}-ethyl)-1H-pyrrole-2-carboxylic acid ethyl ester as off-white solid; HPLC/MS 2.67 min (A), [M+H] 455. filtered off by suction washed with acetone The filtrate is evaporated to dryness The crude product is purified by flashchromatography

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

Procedure: 4-Fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.07 g; 6.83 mmol) and 1-{4-[4-(2-bromo-acetyl)-phenyl]-piperidin-1-yl}-2,2,2-trifluoro-ethanone (2.00 g; 5.26 mmol) are dissolved in acetone (20 ml). To this clear brown solution potassium carbonate (1.45 g; 10.51 mmol) is added and the reaction mixture is stirred at ambient temperature over night. The reaction mixture is diluted with acetone, filtered off by suction and washed with acetone. The filtrate is evaporated to dryness. The crude product is purified by flashchromatography to afford 4-fluoro-1-(2-oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-phenyl}-ethyl)-1H-pyrrole-2-carboxylic acid ethyl ester as off-white solid; HPLC/MS 2.67 min (A), [M+H] 455. filtered off by suction washed with acetone The filtrate is evaporated to dryness The crude product is purified by flashchromatography

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 15.7 g (100 mmol) 4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester and 27.8 g (100 mmol) 2,4′-dibromoacetophenone in 150 ml acetone is added 16.6 g (120 mmol) cesium carbonate. The resulting suspension is stirred at 35° C. for 3 days. The reaction mixture is added to 600 ml water under stirring. The resulting precipitate is filtered off, washed with water and dried under vacuum to afford 1-[2-(4-bromo-phenyl)-2-oxo-ethyl]-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester as light yellow solid; HPLC/MS 3.14 (B), [M+H] 354/356; under stirring The resulting precipitate is filtered off washed with water dried under vacuum

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 15.7 g (100 mmol) 4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester and 27.8 g (100 mmol) 2,4′-dibromoacetophenone in 150 ml acetone is added 16.6 g (120 mmol) cesium carbonate. The resulting suspension is stirred at 35° C. for 3 days. The reaction mixture is added to 600 ml water under stirring. The resulting precipitate is filtered off, washed with water and dried under vacuum to afford 1-[2-(4-bromo-phenyl)-2-oxo-ethyl]-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester as light yellow solid; HPLC/MS 3.14 (B), [M+H] 354/356; under stirring The resulting precipitate is filtered off washed with water dried under vacuum

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

Procedure: To a solution of 4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.57 g, 10.0 mmol) in 20 ml DMF is added potassium tert-butylate (2.24 g, 20.0 mmol) under nitrogen. After stirring at room temperature for 90 minutes, the chloroamine solution from above (110 ml, ca. 25 mmol) is added slowly, after which the mixture is stirred for 5 minutes at room temperature. The reaction mixture is partitioned between saturated sodium bisulfite solution and tert-butyl methyl ether. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/dichloromethane as eluent to afford 1-amino-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester as white solid; HPLC/MS 2.21 min (B), [M+H] 173; after which the mixture is stirred for 5 minutes at room temperature The reaction mixture is partitioned between saturated sodium bisulfite solution and tert-butyl methyl ether The organic phase is dried over sodium sulfate evaporated The residue is chromatographed on a silica gel column with cyclohexane/dichloromethane as eluent