2-(fluoromethyl)morpholine;hydrochloride

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

Procedure: To a solution of N-benzyl-2-fluoromethylmorpholine hydrochloride (1.46 g) in ethanol (85 ml) is added 10% palladium-carbon (0.2 g), and the mixture is stirred under hydrogen atmosphere (maximum hydrogen pressure: 6 kg/cm2) at room temperature. After completion of absorption of hydrogen gas, palladium-carbon is filtered off, and the filtrate is concentrated under reduced pressure. To the residue are added ether (2 ml) and ethanol (0.5 ml), and the precipitated crystals are separated by filtration and dried under reduced pressure to give the title compound (0.6 g). After completion of absorption of hydrogen gas, palladium-carbon is filtered off the filtrate is concentrated under reduced pressure To the residue are added ether (2 ml) and ethanol (0.5 ml) the precipitated crystals are separated by filtration dried under reduced pressure

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

Procedure: To a solution of N-benzyl-2-fluoromethylmorpholine hydrochloride (1.46 g) in ethanol (85 ml) is added 10% palladium-carbon (0.2 g), and the mixture is stirred under hydrogen atmosphere (maximum hydrogen pressure: 6 kg/cm2) at room temperature. After completion of absorption of hydrogen gas, palladium-carbon is filtered off, and the filtrate is concentrated under reduced pressure. To the residue are added ether (2 ml) and ethanol (0.5 ml), and the precipitated crystals are separated by filtration and dried under reduced pressure to give the title compound (0.6 g). After completion of absorption of hydrogen gas, palladium-carbon is filtered off the filtrate is concentrated under reduced pressure To the residue are added ether (2 ml) and ethanol (0.5 ml) the precipitated crystals are separated by filtration dried under reduced pressure

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl 4-cyano-3-iodo-5-(methylsulfonyl)thiophene-2-carboxylate (718 mg, 0.00186 mol), 2-(fluoromethyl)morpholine hydrochloride (348 mg, 0.00224 mol) and TEA (1.0 mL, 0.0072 mol) in THF (7.1 mL, 0.088 mol) was flushed with argon and then heated at 90° C. overnight. The reaction mixture was concentrated and purified by column chromatography to give ethyl 4-cyano-5-(2-(fluoromethyl)morpholino)-3-iodothiophene-2-carboxylate (288 mg, 36.4%). LCMS: (FA) ES+ 425, 1H NMR (400 MHz, d1-chloroform) δ: 4.57 (d, 1H), 4.46 (d, 1H), 4.34 (q, 2H), 4.12-4.05 (m, 1H), 4.02-3.77 (m, 4H), 3.34-3.25 (m, 1H), 3.22-3.14 (m, 1H), 1.37 (t, 3H). was flushed with argon The reaction mixture was concentrated purified by column chromatography

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl 4-cyano-3-iodo-5-(methylsulfonyl)thiophene-2-carboxylate (718 mg, 0.00186 mol), 2-(fluoromethyl)morpholine hydrochloride (348 mg, 0.00224 mol) and TEA (1.0 mL, 0.0072 mol) in THF (7.1 mL, 0.088 mol) was flushed with argon and then heated at 90° C. overnight. The reaction mixture was concentrated and purified by column chromatography to give ethyl 4-cyano-5-(2-(fluoromethyl)morpholino)-3-iodothiophene-2-carboxylate (288 mg, 36.4%). LCMS: (FA) ES+ 425, 1H NMR (400 MHz, d1-chloroform) δ: 4.57 (d, 1H), 4.46 (d, 1H), 4.34 (q, 2H), 4.12-4.05 (m, 1H), 4.02-3.77 (m, 4H), 3.34-3.25 (m, 1H), 3.22-3.14 (m, 1H), 1.37 (t, 3H). was flushed with argon The reaction mixture was concentrated purified by column chromatography

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

Procedure: To a solution of N-benzyl-2-fluoromethylmorpholine hydrochloride (1.46 g) in ethanol (85 ml) is added 10% palladium-carbon (0.2 g), and the mixture is stirred under hydrogen atmosphere (maximum hydrogen pressure: 6 kg/cm2) at room temperature. After completion of absorption of hydrogen gas, palladium-carbon is filtered off, and the filtrate is concentrated under reduced pressure. To the residue are added ether (2 ml) and ethanol (0.5 ml), and the precipitated crystals are separated by filtration and dried under reduced pressure to give the title compound (0.6 g). After completion of absorption of hydrogen gas, palladium-carbon is filtered off the filtrate is concentrated under reduced pressure To the residue are added ether (2 ml) and ethanol (0.5 ml) the precipitated crystals are separated by filtration dried under reduced pressure