2-AMINO-4'-FLUOROACETOPHENONE HYDROCHLORIDE

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

Procedure: A stirred solution of anhydrous sodium acetate (2.05 g, 25 mmol) in water (12.5 ml) was added with the solution of 5-tert-butoxycarbonylamino-3-oxo-pentanoic acid ethyl ester (3.23 g, 12.5 mmol) in anhydrous ethanol (2 ml), then the mixture was added with 2-amino-1-(4-fluoro-phenyl)-ethanone hydrochloride (2.37 g, 12.5 mmol), heated to reflux for 3 hours. The resulting mixture was extracted with ethyl acetate (50 ml×3) and the combined extracts were washed with brine (50 ml×3), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(2-tert-butoxycarbonylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (4.3 g, 91.7%) as a yellow solid. heated to reflux for 3 hours The resulting mixture was extracted with ethyl acetate (50 ml×3) the combined extracts were washed with brine (50 ml×3) dried with anhydrous sodium sulfate filtered concentrated under reduced pressure

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

Procedure: Triethyl amine (1.52 mL, 10.4 mmol) was added dropwise to a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (600 mg, 2.6 mmol) and 2-amino-1-(4-fluorophenyl)ethanone hydrochloride (500 mg, 2.6 mmol) in THF (12 mL), followed by T3P (propylphosphonic anhydride) (1.7 mL, 2.6 mmol, 50% in EtOAc) at 0° C. The reaction mixture was stirred 30 min, allowed to warm up to room temperature and stirred for an additional 8 h. The reaction mixture was then concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with aqueous 10% NaHCO3, water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether) to afford tert-butyl 3-((2-(4-fluorophenyl)-2-oxoethyl)carbamoyl)piperidine-1-carboxylate (500 mg, yield 52%). 1H NMR (400 MHz, DMSO-d6) δ 8.33-8.30 (t, J=5.6 Hz, 1H), 8.08-8.04 (dd, J=8.5 Hz, 5.8 Hz, 2H), 7.39-7.35 (t, J=8.7 Hz, 2H), 4.57-4.56 (m, 2H), 3.99-3.86 (m, 2H), 2.39-2.32 (m, 1H), 1.87-1.84 (m, 1H), 1.66-1.62 (m, 1H), 1.56-1.46 (m, 2H), 1.40 (s, 9H), 1.32-1.23 (m, 2H). stirred for an additional 8 h The reaction mixture was then concentrated under reduced pressure diluted with EtOAc The organic layer was washed with aqueous 10% NaHCO3, water and brine dried over anhydrous sodium sulfate concentrated under reduced pressure The crude product was purified by purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether)

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

Procedure: Hexamethylenetetramine (1.42 g, 10.1 mmol) was added dropwise over 30 min to a solution of 2-bromo-4-fluoroacetophenone (2.0 g, 9.2 mmol) in dry CHCl3 (40 mL) at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 16 h. After completion of the reaction the solid precipitate formed was collected by filtration and washed with CHCl3. The solid obtained was suspended in EtOH (40 mL) and conc. HCl (4 mL) was added. The mixture was heated to 80° C. for 3 h, cooled to room temperature, and the solid formed was filtered off. The clear filtrate was concentrated to afford 2-amino-1-(4-fluorophenyl)ethanone hydrochloride (1.5 g, crude) as yellow solid. MS (ESI) m/z: Calculated for C8H8FNO: 153.06. found: 153.9 (M+H)+ After completion of the reaction the solid precipitate formed was collected by filtration washed with CHCl3 The solid obtained The mixture was heated to 80° C. for 3 h cooled to room temperature the solid formed was filtered off The clear filtrate was concentrated

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

Procedure: Hexamethylenetetramine (1.42 g, 10.1 mmol) was added dropwise over 30 min to a solution of 2-bromo-4-fluoroacetophenone (2.0 g, 9.2 mmol) in dry CHCl3 (40 mL) at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 16 h. After completion of the reaction the solid precipitate formed was collected by filtration and washed with CHCl3. The solid obtained was suspended in EtOH (40 mL) and conc. HCl (4 mL) was added. The mixture was heated to 80° C. for 3 h, cooled to room temperature, and the solid formed was filtered off. The clear filtrate was concentrated to afford 2-amino-1-(4-fluorophenyl)ethanone hydrochloride (1.5 g, crude) as yellow solid. MS (ESI) m/z: Calculated for C8H8FNO: 153.06. found: 153.9 (M+H)+ After completion of the reaction the solid precipitate formed was collected by filtration washed with CHCl3 The solid obtained The mixture was heated to 80° C. for 3 h cooled to room temperature the solid formed was filtered off The clear filtrate was concentrated

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

Procedure: The compound was synthesized as hydrochloride salt starting from 5-aminobenzimidazole (0.665 g, 5 mmol), di(1H-imidazol-1-yl)methanone (0.891 g, 5.5 mmol), TEA (2.09 mL, 15 mmol), aminomethyl-(4-fluorophenyl)ketone hydrochloride (0.948 g, 5 mmol), TEA (1.39 mL, 10 mmol), PdC (10%, 0.02 g) as described in method 1.

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

Procedure: A mixture of 6.85 g (43.3 mmol) of ethyl isobutyrylacetate, 10.69 g (56.3 mmol) of 2-amino-4'-fluoracetophenone hydrochloride, 16.3 ml of acetic acid, 6.04 g of sodium acetate, and 10.8 ml of water is refluxed for 4 hours. After cooling, the reaction mixture is adjusted to pH 8 with saturated NaHCO3 and extracted with ether. The extract, 8.36 g, is subjected to column chromatography with silica gel, eluting with methylene chloride to give 6.12 g (Yield:51.3%) of the compound 1. is refluxed for 4 hours After cooling extracted with ether eluting with methylene chloride

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

Procedure: A mixture of 6.85 g (43.3 mmol) of ethyl isobutyrylacetate, 10.69 g (56.3 mmol) of 2-amino-4'-fluoracetophenone hydrochloride, 16.3 ml of acetic acid, 6.04 g of sodium acetate, and 10.8 ml of water is refluxed for 4 hours. After cooling, the reaction mixture is adjusted to pH 8 with saturated NaHCO3 and extracted with ether. The extract, 8.36 g, is subjected to column chromatography with silica gel, eluting with methylene chloride to give 6.12 g (Yield:51.3%) of the compound 1. is refluxed for 4 hours After cooling extracted with ether eluting with methylene chloride

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

Procedure: The compound was synthesized as hydrochloride salt starting from 5-aminobenzimidazole (0.665 g, 5 mmol), di(1H-imidazol-1-yl)methanone (0.891 g, 5.5 mmol), TEA (2.09 mL, 15 mmol), aminomethyl-(4-fluorophenyl)ketone hydrochloride (0.948 g, 5 mmol), TEA (1.39 mL, 10 mmol), PdC (10%, 0.02 g) as described in method 1.

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

Procedure: The compound was synthesized as hydrochloride salt starting from 5-aminobenzimidazole (0.665 g, 5 mmol), di(1H-imidazol-1-yl)methanone (0.891 g, 5.5 mmol), TEA (2.09 mL, 15 mmol), aminomethyl-(4-fluorophenyl)ketone hydrochloride (0.948 g, 5 mmol), TEA (1.39 mL, 10 mmol), PdC (10%, 0.02 g) as described in method 1.

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

Procedure: A stirred solution of anhydrous sodium acetate (2.05 g, 25 mmol) in water (12.5 ml) was added with the solution of 5-tert-butoxycarbonylamino-3-oxo-pentanoic acid ethyl ester (3.23 g, 12.5 mmol) in anhydrous ethanol (2 ml), then the mixture was added with 2-amino-1-(4-fluoro-phenyl)-ethanone hydrochloride (2.37 g, 12.5 mmol), heated to reflux for 3 hours. The resulting mixture was extracted with ethyl acetate (50 ml×3) and the combined extracts were washed with brine (50 ml×3), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(2-tert-butoxycarbonylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (4.3 g, 91.7%) as a yellow solid. heated to reflux for 3 hours The resulting mixture was extracted with ethyl acetate (50 ml×3) the combined extracts were washed with brine (50 ml×3) dried with anhydrous sodium sulfate filtered concentrated under reduced pressure

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

Procedure: The compound was synthesized as hydrochloride salt starting from 5-aminobenzimidazole (0.665 g, 5 mmol), di(1H-imidazol-1-yl)methanone (0.891 g, 5.5 mmol), TEA (2.09 mL, 15 mmol), aminomethyl-(4-fluorophenyl)ketone hydrochloride (0.948 g, 5 mmol), TEA (1.39 mL, 10 mmol), PdC (10%, 0.02 g) as described in method 1.

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

Procedure: A mixture of 6.85 g (43.3 mmol) of ethyl isobutyrylacetate, 10.69 g (56.3 mmol) of 2-amino-4'-fluoracetophenone hydrochloride, 16.3 ml of acetic acid, 6.04 g of sodium acetate, and 10.8 ml of water is refluxed for 4 hours. After cooling, the reaction mixture is adjusted to pH 8 with saturated NaHCO3 and extracted with ether. The extract, 8.36 g, is subjected to column chromatography with silica gel, eluting with methylene chloride to give 6.12 g (Yield:51.3%) of the compound 1. is refluxed for 4 hours After cooling extracted with ether eluting with methylene chloride