tert-butyl N-(2-fluoro-6-formylphenyl)carbamate

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

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

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 2-fluoro-6-formylphenylcarbamate (48.0 g, 201 mmol) in ethanol (100 mL) was added 4-amino-1-benzylpiperidine (41.0 mL, 201 mmol). The solution was concentrated in vacuo, and then water was removed by twice dissolving the residue in toluene and concentrating the solution in vacuo. The resulting oil was dissolved in tetrahydrofuran (250 mL), cooled to 0° C., and treated with sodium borohydride (3.80 g, 100 mmol). The ice bath was removed and stirring continued overnight. The reaction was treated with ethanol (250 mL), an additional portion of sodium borohydride (2.00 g, 53 mmol), and an additional portion of 4-amino-1-benzylpiperidine (2.0 mL, 9.8 mmol). The resulting solution was stirred for 4 h at room temperature. The reaction was cooled to 0° C., quenched by addition of saturated ammonium chloride, filtered to remove solids, and concentrated to remove most (but not all) of the tetrahydrofuran. The reaction was extracted with diethyl ether (2×). The ethereal layer was washed with water (3×), then brine, dried over magnesium sulfate, and concentrated to give 83 g (100%) as a viscous yellow oil which was pure enough to use in the following step. Mass spec.: 414.51 (MH)+. The solution was concentrated in vacuo water was removed by twice dissolving the residue in toluene concentrating the solution in vacuo The resulting oil was dissolved in tetrahydrofuran (250 mL) The ice bath was removed The reaction was treated with ethanol (250 mL) The resulting solution was stirred for 4 h at room temperature The reaction was cooled to 0° C. quenched by addition of saturated ammonium chloride filtered to remove solids concentrated to remove most (but not all) of the tetrahydrofuran The reaction was extracted with diethyl ether (2×) The ethereal layer was washed with water (3×) brine, dried over magnesium sulfate concentrated to give 83 g (100%) as a viscous yellow oil which

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 2-fluorophenylcarbamate (42.7 g, 202 mmol) was concentrated from toluene in vacuo (3×) to remove any traces of water. The resulting residue was dissolved in tetrahydrofuran (600 mL), and cooled to −78° C. To this was added tert-butyllithium (1.7 M in pentane, 285 mL, 485 mmol) in dropwise fashion. After addition was complete, the reaction was stirred at −78° C. for 30 minutes. The solution was allowed to gradually warm to −20° C. before re-cooling to −78° C. To this was added dimethylformamide (46.9 mL, 606 mmol). The reaction was allowed to gradually warm to room temperature overnight. The reaction was poured into a separatory funnel containing diethyl ether and water. The organics were washed with water (3×) and concentrated. The combined aqueous washes were neutralized with 1 M potassium bisulfate and extracted with diethyl ether. The ethereal layers were combined with the other organics, washed with water, then brine, dried over magnesium sulfate, and concentrated to give 48.1 g (100%) as a yellow oil which was used without further purification. 1H-NMR (CDCl3, 500 MHz) δ 1.50 (s, 9H), 7.27 (m, 1H), 7.35 (m, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.85 (bs, 1H), 9.99 (d, J=1.2 Hz, 1H). Mass spec.: 262.16 (MNa)+. to remove any traces of water The resulting residue was dissolved in tetrahydrofuran (600 mL) After addition to gradually warm to −20° C. before re-cooling to −78° C to gradually warm to room temperature overnight The reaction was poured into a separatory funnel The organics were washed with water (3×) concentrated extracted with diethyl ether washed with water brine, dried over magnesium sulfate concentrated to give 48.1 g (100%) as a yellow oil which was used without further purification

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 2-fluorophenylcarbamate (42.7 g, 202 mmol) was concentrated from toluene in vacuo (3×) to remove any traces of water. The resulting residue was dissolved in tetrahydrofuran (600 mL), and cooled to −78° C. To this was added tert-butyllithium (1.7 M in pentane, 285 mL, 485 mmol) in dropwise fashion. After addition was complete, the reaction was stirred at −78° C. for 30 minutes. The solution was allowed to gradually warm to −20° C. before re-cooling to −78° C. To this was added dimethylformamide (46.9 mL, 606 mmol). The reaction was allowed to gradually warm to room temperature overnight. The reaction was poured into a separatory funnel containing diethyl ether and water. The organics were washed with water (3×) and concentrated. The combined aqueous washes were neutralized with 1 M potassium bisulfate and extracted with diethyl ether. The ethereal layers were combined with the other organics, washed with water, then brine, dried over magnesium sulfate, and concentrated to give 48.1 g (100%) as a yellow oil which was used without further purification. 1H-NMR (CDCl3, 500 MHz) δ 1.50 (s, 9H), 7.27 (m, 1H), 7.35 (m, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.85 (bs, 1H), 9.99 (d, J=1.2 Hz, 1H). Mass spec.: 262.16 (MNa)+. to remove any traces of water The resulting residue was dissolved in tetrahydrofuran (600 mL) After addition to gradually warm to −20° C. before re-cooling to −78° C to gradually warm to room temperature overnight The reaction was poured into a separatory funnel The organics were washed with water (3×) concentrated extracted with diethyl ether washed with water brine, dried over magnesium sulfate concentrated to give 48.1 g (100%) as a yellow oil which was used without further purification

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 2-fluoro-6-formylphenylcarbamate (48.0 g, 201 mmol) in ethanol (100 mL) was added 4-amino-1-benzylpiperidine (41.0 mL, 201 mmol). The solution was concentrated in vacuo, and then water was removed by twice dissolving the residue in toluene and concentrating the solution in vacuo. The resulting oil was dissolved in tetrahydrofuran (250 mL), cooled to 0° C., and treated with sodium borohydride (3.80 g, 100 mmol). The ice bath was removed and stirring continued overnight. The reaction was treated with ethanol (250 mL), an additional portion of sodium borohydride (2.00 g, 53 mmol), and an additional portion of 4-amino-1-benzylpiperidine (2.0 mL, 9.8 mmol). The resulting solution was stirred for 4 h at room temperature. The reaction was cooled to 0° C., quenched by addition of saturated ammonium chloride, filtered to remove solids, and concentrated to remove most (but not all) of the tetrahydrofuran. The reaction was extracted with diethyl ether (2×). The ethereal layer was washed with water (3×), then brine, dried over magnesium sulfate, and concentrated to give 83 g (100%) as a viscous yellow oil which was pure enough to use in the following step. Mass spec.: 414.51 (MH)+. The solution was concentrated in vacuo water was removed by twice dissolving the residue in toluene concentrating the solution in vacuo The resulting oil was dissolved in tetrahydrofuran (250 mL) The ice bath was removed The reaction was treated with ethanol (250 mL) The resulting solution was stirred for 4 h at room temperature The reaction was cooled to 0° C. quenched by addition of saturated ammonium chloride filtered to remove solids concentrated to remove most (but not all) of the tetrahydrofuran The reaction was extracted with diethyl ether (2×) The ethereal layer was washed with water (3×) brine, dried over magnesium sulfate concentrated to give 83 g (100%) as a viscous yellow oil which

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 2-fluorophenylcarbamate (42.7 g, 202 mmol) was concentrated from toluene in vacuo (3×) to remove any traces of water. The resulting residue was dissolved in tetrahydrofuran (600 mL), and cooled to −78° C. To this was added tert-butyllithium (1.7 M in pentane, 285 mL, 485 mmol) in dropwise fashion. After addition was complete, the reaction was stirred at −78° C. for 30 minutes. The solution was allowed to gradually warm to −20° C. before re-cooling to −78° C. To this was added dimethylformamide (46.9 mL, 606 mmol). The reaction was allowed to gradually warm to room temperature overnight. The reaction was poured into a separatory funnel containing diethyl ether and water. The organics were washed with water (3×) and concentrated. The combined aqueous washes were neutralized with 1 M potassium bisulfate and extracted with diethyl ether. The ethereal layers were combined with the other organics, washed with water, then brine, dried over magnesium sulfate, and concentrated to give 48.1 g (100%) as a yellow oil which was used without further purification. 1H-NMR (CDCl3, 500 MHz) δ 1.50 (s, 9H), 7.27 (m, 1H), 7.35 (m, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.85 (bs, 1H), 9.99 (d, J=1.2 Hz, 1H). Mass spec.: 262.16 (MNa)+. to remove any traces of water The resulting residue was dissolved in tetrahydrofuran (600 mL) After addition to gradually warm to −20° C. before re-cooling to −78° C to gradually warm to room temperature overnight The reaction was poured into a separatory funnel The organics were washed with water (3×) concentrated extracted with diethyl ether washed with water brine, dried over magnesium sulfate concentrated to give 48.1 g (100%) as a yellow oil which was used without further purification

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