ethyl 2-chloroethanimidate

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

Procedure: The HCl salt of ethyl 2-chloro-acetimidate (3.90 g, 24.58 mmol) is added to a solution of N4-ethyl-6-trifluoromethyl-pyridine-3,4-diamine (1.44 g, 7.02 mmol) in EtOH (20 mL) and refluxed for 3 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is diluted with CH2Cl2, washed with NaHCO3 solution, dried over Na2SO4, and concentrated to obtain 2-chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine. 1H NMR (300 MHz, CDCl3): δ 9.14(s, 1H), 7.66 (s,1H), 7.26 (s, 1H), 4.87 (s, 2H), 4.40 (t, J=7.5 Hz, 2H), 1.58 (t, J=7.5 Hz, 3H). refluxed for 3 h concentrated under reduced pressure The residue is diluted with CH2Cl2 washed with NaHCO3 solution dried over Na2SO4 concentrated

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

Procedure: The HCl salt of ethyl 2-chloro-acetimidate (3.90 g, 24.58 mmol) is added to a solution of N4-ethyl-6-trifluoromethyl-pyridine-3,4-diamine (1.44 g, 7.02 mmol) in EtOH (20 mL) and refluxed for 3 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is diluted with CH2Cl2, washed with NaHCO3 solution, dried over Na2SO4, and concentrated to obtain 2-chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine. 1H NMR (300 MHz, CDCl3): δ 9.14(s, 1H), 7.66 (s,1H), 7.26 (s, 1H), 4.87 (s, 2H), 4.40 (t, J=7.5 Hz, 2H), 1.58 (t, J=7.5 Hz, 3H). refluxed for 3 h concentrated under reduced pressure The residue is diluted with CH2Cl2 washed with NaHCO3 solution dried over Na2SO4 concentrated

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

Procedure: The HCl salt of ethyl 2-chloro-acetimidate (3.90 g, 24.58 mmol) is added to a solution of N-ethyl-6-trifluoromethyl-pyridine-3,4-diamine (1.44 g, 7.02 mmol) in EtOH (20 mL) and refluxed for 3 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is diluted with CH2Cl2, washed with NaHCO3 solution, dried over Na2SO4, and concentrated to obtain 2-chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine. 1H NMR (300 MHz, CDCl3): δ 9.14 (s, 1H), 7.66 (s, 1H), 7.26 (s, 1H), 4.87 (s, 2H), 4.40 (t, J=7.5 Hz, 2H), 1.58 (t, J=7.5 Hz, 3H). refluxed for 3 h concentrated under reduced pressure The residue is diluted with CH2Cl2 washed with NaHCO3 solution dried over Na2SO4 concentrated

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

Procedure: The HCl salt of ethyl 2-chloro-acetimidate (3.90 g, 24.58 mmol) is added to a solution of N4-ethyl-6-trifluoromethyl-pyridine-3,4-diamine (1.44 g, 7.02 mmol) in EtOH (20 mL) and refluxed for 3 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is diluted with CH2Cl2, washed with NaHCO3 solution, dried over Na2SO4, and concentrated to obtain 2-chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine. 1H NMR (300 MHz, CDCl3): δ 9.14 (s, 1H), 7.66 (s, 1H), 7.26 (s, 1H), 4.87 (s, 2H) 4.40 (t, J=7.5 Hz, 2H), 1.58 (t, J=7.5 Hz, 3H). refluxed for 3 h concentrated under reduced pressure The residue is diluted with CH2Cl2 washed with NaHCO3 solution dried over Na2SO4 concentrated

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

Procedure: Alternatively, chloroacetylchloride rather than ethyl chloroacetimidate can by used: To a solution of 3-amino-4-n-propylaminobenzonitrile (5.15 g, 29.4 mmol) and triethylamine (4.51 mL) in ethyl acetate (52 mL) at room temperature, chloroacetyl chloride (2.57 mL) is added slowly. After stirring the reaction mixture for 30 minutes at room temperature, acetic acid (5 mL) is added and the reaction mixture heated to reflux. After heating for 20 h, the reaction mixture is cooled to room temperature and diluted with water (50 mL). The organic solution is washed twice with 1.0 M sodium hydroxide (2×50 mL), then washed with an aqueous solution of 0.25 M KH2PO4 (50 mL), followed by brine (50 mL). The organic layer is dried (sodium sulfate), concentrated in vacuo, and the solid recrystallized by heating in ethyl acetate (20 mL), adding hexane (40 mL) and cooling to room temperature with stirring to afford 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole as brown crystals. 1H NMR (CDCl3): δ 8.08 (d, J=0.8 Hz, 1H), 7.57 (dd, J=1.65, 8.52 Hz, 1H), 7.45 (d, J=8.24 Hz, 1H), 7.26 (s, 1H), 4.84 (s, 2H) 4.24 (t, J=7.6 Hz, 2H), 1.94 (pentet, J=7.4. 7.6 Hz, 2H) 1.03 (t, J=7.4 Hz, 3H). the reaction mixture heated to reflux After heating for 20 h the reaction mixture is cooled to room temperature The organic solution is washed twice with 1.0 M sodium hydroxide (2×50 mL) washed with an aqueous solution of 0.25 M KH2PO4 (50 mL) The organic layer is dried (sodium sulfate) concentrated in vacuo the solid recrystallized by heating in ethyl acetate (20 mL) adding hexane (40 mL) cooling to room temperature with stirring

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

Procedure: A solution of 5 g (17.64 mmol) of (S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid hydrazide and 3.06 g (19.41 mmol) of ethyl chloroacetimidate in 40 ml of dimethylformamide and 10 ml of ethanol was stirred at 90° for 12 hours. The solvent was evaporated and the residue was partitioned between methylene chloride and water. The aqueous phase was back-washed once with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. Chromatography of the residue (silica gel, methylene chloride/methanol 93:3) yielded 3.26 g (55%) of (S)-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as a colourless foam, RF=0.5 (methylene chloride/methanol 10:1). The solvent was evaporated the residue was partitioned between methylene chloride and water The aqueous phase was back-washed once with methylene chloride The organic phases were dried with magnesium sulfate filtered evaporated

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

Procedure: The HCl salt of ethyl 2-chloro-acetimidate (3.90 g, 24.58 mmol) is added to a solution of N4-ethyl-6-trifluoromethyl-pyridine-3,4-diamine (1.44 g, 7.02 mmol) in EtOH (20 mL) and refluxed for 3 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is diluted with CH2Cl2, washed with NaHCO3 solution, dried over Na2SO4, and concentrated to obtain 2-chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine. 1H NMR (300 MHz, CDCl3): δ 9.14(s, 1H), 7.66 (s,1H), 7.26 (s, 1H), 4.87 (s, 2H), 4.40 (t, J=7.5 Hz, 2H), 1.58 (t, J=7.5 Hz, 3H). refluxed for 3 h concentrated under reduced pressure The residue is diluted with CH2Cl2 washed with NaHCO3 solution dried over Na2SO4 concentrated