tert-butyl (3S)-3-(aminomethyl)morpholine-4-carboxylate

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

Procedure: To a solution of (S)-tert-butyl 3-(aminomethyl)morpholine-4-carboxylate (commercially available, 0.62 g, 2.87 mmol) in dichloromethane (28.0 ml) were added sequentially pyridine (0.5 ml, 5.73 mmol) and acetyl chloride (0.25 ml, 3.44 mmol). After 30 min the reaction was diluted with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The resulting mixture was extracted with ethyl acetate (×3), and the combined organic layers were then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting light yellow oil was purified by flash column chromatography (ISCO, SiO2, 0→10% methanol in ethyl acetate over 10 min) to afford (S)-tert-butyl 3-(acetamidomethyl)morpholine-4-carboxylate (0.741 g, yield: almost quantitative, INTERMEDIATE 86A STEP 1). The resulting mixture was extracted with ethyl acetate (×3) the combined organic layers were then dried over sodium sulfate filtered concentrated under reduced pressure The resulting light yellow oil was purified by flash column chromatography (ISCO, SiO2, 0→10% methanol in ethyl acetate over 10 min)

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

Procedure: A solution of (S)-tert-butyl 3-(aminomethyl)morpholine-4-carboxylate (1.0 g, 4.62 mmol) in MeOH (15 ml) was treated with acetaldehyde (0.204 g, 4.62 mmol). The reaction mixture was stirred at 0° C. for 15 minutes and sodium triacetoxyborohydride (2.450 g, 11.56 mmol) was added all at once. The resulting mixture was stirred for 24 h and the mixture was diluted with DCM (15 ml) and washed with saturated aq. sodium bicarbonate (15 ml). The organic phase dried over sodium sulfate, filtered, and concentrated under pressure to give a residue which was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→20% MeOH in DCM) to give (S)-tert-butyl 3-((diethylamino)methyl)morpholine-4-carboxylate (INTERMEDIATE 86, STEP 1). The resulting mixture was stirred for 24 h washed with saturated aq. sodium bicarbonate (15 ml) The organic phase dried over sodium sulfate filtered concentrated under pressure to give a residue which was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→20% MeOH in DCM)

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

Procedure: To a solution of (S)-tert-butyl 3-(aminomethyl)morpholine-4-carboxylate (commercially available, 0.62 g, 2.87 mmol) in dichloromethane (28.0 ml) were added sequentially pyridine (0.5 ml, 5.73 mmol) and acetyl chloride (0.25 ml, 3.44 mmol). After 30 min the reaction was diluted with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The resulting mixture was extracted with ethyl acetate (×3), and the combined organic layers were then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting light yellow oil was purified by flash column chromatography (ISCO, SiO2, 0-10% methanol in ethyl acetate over 10 min) to afford (S)-tert-butyl 3-(acetamidomethyl)morpholine-4-carboxylate (0.741 g, yield: almost quantitative, INTERMEDIATE 86A STEP 1). The resulting mixture was extracted with ethyl acetate (×3) the combined organic layers were then dried over sodium sulfate filtered concentrated under reduced pressure The resulting light yellow oil was purified by flash column chromatography (ISCO, SiO2, 0-10% methanol in ethyl acetate over 10 min)

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

Procedure: A solution of (S)-tert-butyl 3-(aminomethyl)morpholine-4-carboxylate (1.0 g, 4.62 mmol) in MeOH (15 ml) was treated with acetaldehyde (0.204 g, 4.62 mmol). The reaction mixture was stirred at 0° C. for 15 minutes and sodium triacetoxyborohydride (2.450 g, 11.56 mmol) was added all at once. The resulting mixture was stirred for 24 h and the mixture was diluted with DCM (15 ml) and washed with saturated aq. sodium bicarbonate (15 ml). The organic phase dried over sodium sulfate, filtered, and concentrated under pressure to give a residue which was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→20% MeOH in DCM) to give (S)-tert-butyl 3-((diethylamino)methyl)morpholine-4-carboxylate (INTERMEDIATE 86, STEP 1). The resulting mixture was stirred for 24 h washed with saturated aq. sodium bicarbonate (15 ml) The organic phase dried over sodium sulfate filtered concentrated under pressure to give a residue which was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→20% MeOH in DCM)