ethyl 4-benzylmorpholine-2-carboxylate

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

Procedure: Add a solution of 4-benzyl-morpholine-2-carboxylic acid ethyl ester (1.12 g, 4.49 mmol) in tetrahydrofuran (5 mL) to a stirred solution of 2-methoxybenzylmagnesium chloride (54 mL, 0.25M solution in tetrahydrofuran, commercially available from Rieke Metals) at −10° C. under nitrogen atmosphere. After 1 hour, add a saturated aqueous solution of sodium bicarbonate and extract with diethyl ether. Combine the organic layers and extract with brine, dry over magnesium sulfate, filter, and concentrate under reduced pressure to give a residue to be taken forward without further purification. MW 447.58; C28H33NO4; LCMS (12 minute method):m/z)=448.2 [M+H]+) RT 4.8 min. at −10° C. extract with diethyl ether extract with brine dry over magnesium sulfate filter concentrate under reduced pressure to give a residue to be taken forward without further purification LCMS (12 minute method) RT 4.8 min.

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

Procedure: To a stirred suspension of N,N-dimethylhydroxylamine (6.6 g, 67.6 mmol) in anhydrous DCM (200 mL) under nitrogen at 0° C. is added dropwise a solution of trimethylaluminium (2M solution in hexane, 34 mL, 67.6 mmol) over 30 minutes. The reaction mixture is allowed to warm up to room temperature and left stirring for 1 hour. A solution of the ester 1 (6.74 g, 27 mmol) in anhydrous DCM (100 mL) is then added dropwise over 30 minutes and the reaction mixture is left stirring overnight before quenching by cautious addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution. The precipitate is removed by filtration through a celite pad and the residue washed with chloroform. The organic phase is then concentrated in vacuo and washed with water. The aqueous layer is re-extracted with chloroform and the organic phases are combined, washed with brine, dried over magnesium sulphate and the solvent evaporated in vacuo to give 2 as a yellow oil. Alternatively, the reaction could be worked up as follows: upon addition of a solution of the ester 1 (1 eq) the reaction mixture is left stirring for 1 hour before quenching by addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution, followed by addition of water. The aqueous layer is re-extracted with DCM and the organic phases are combined, dried over magnesium sulphate and the DCM evaporated in vacuo to give 2 as a yellow oil (3.36 g, 47%). MW 264.33; C14H20N2O3; 1H NMR (CDCl3): 7.47-7.22 (5H, m), 4.55 (1H, d, 1.5 Hz), 4.00 (1H, dd, 11.5 Hz, 1.7 Hz), 3.75 (1H, dt, 11.5 Hz, 2.2 Hz), 3.65 (3H, s), 3.56 (2H, m), 3.17 (3H, s), 2.93 (1H, d, 11.3 Hz), 2.68 (1H, d, 11.3 Hz), 2.30 (2H, 11.3 Hz); LCMS: (6 min method) m/z 265 [M+H]+, RT 0.65 min. left the reaction mixture is left stirring overnight before quenching by cautious addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution The precipitate is removed by filtration through a celite pad the residue washed with chloroform The organic phase is then concentrated in vacuo washed with water The aqueous layer is re-extracted with chloroform washed with brine dried over magnesium sulphate the solvent evaporated in vacuo

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

Procedure: A stirred solution of 4-benzyl-morpholine-2-carbonitrile (113.0 g, 0.56 mol) in ethanol (1030 mL) is treated with concentrated sulphuric acid (165 mL) added in portions. (exothermic, internal temperature rises from ambient to 65° C.). The mixture is then warmed under reflux for 66 hrs. The solution is cooled and then concentrated in vacuo to half volume, basified with aqueous potassium carbonate (beware frothing) and the product extracted into diethyl ether. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness in vacuo to yield an oil. This material is evacuated further under high vacuum. Yield=121.3 g (87%). added in portions (exothermic, internal temperature rises from ambient to 65° C.) The mixture is then warmed under reflux for 66 hrs The solution is cooled concentrated in vacuo to half volume the product extracted into diethyl ether The organic phase is dried over magnesium sulphate filtered evaporated to dryness in vacuo to yield an oil This material is evacuated further under high vacuum

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

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

Procedure: Add a solution of 4-benzyl-morpholine-2-carboxylic acid ethyl ester (1.12 g, 4.49 mmol) in tetrahydrofuran (5 mL) to a stirred solution of 2-methoxybenzylmagnesium chloride (54 mL, 0.25M solution in tetrahydrofuran, commercially available from Rieke Metals) at −10° C. under nitrogen atmosphere. After 1 hour, add a saturated aqueous solution of sodium bicarbonate and extract with diethyl ether. Combine the organic layers and extract with brine, dry over magnesium sulfate, filter, and concentrate under reduced pressure to give a residue to be taken forward without further purification. MW 447.58; C28H33NO4; LCMS (12 minute method):m/z)=448.2 [M+H]+) RT 4.8 min. at −10° C. extract with diethyl ether extract with brine dry over magnesium sulfate filter concentrate under reduced pressure to give a residue to be taken forward without further purification LCMS (12 minute method) RT 4.8 min.

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

Procedure: To a stirred suspension of N,N-dimethylhydroxylamine (6.6 g, 67.6 mmol) in anhydrous DCM (200 mL) under nitrogen at 0° C. is added dropwise a solution of trimethylaluminium (2M solution in hexane, 34 mL, 67.6 mmol) over 30 minutes. The reaction mixture is allowed to warm up to room temperature and left stirring for 1 hour. A solution of the ester 1 (6.74 g, 27 mmol) in anhydrous DCM (100 mL) is then added dropwise over 30 minutes and the reaction mixture is left stirring overnight before quenching by cautious addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution. The precipitate is removed by filtration through a celite pad and the residue washed with chloroform. The organic phase is then concentrated in vacuo and washed with water. The aqueous layer is re-extracted with chloroform and the organic phases are combined, washed with brine, dried over magnesium sulphate and the solvent evaporated in vacuo to give 2 as a yellow oil. Alternatively, the reaction could be worked up as follows: upon addition of a solution of the ester 1 (1 eq) the reaction mixture is left stirring for 1 hour before quenching by addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution, followed by addition of water. The aqueous layer is re-extracted with DCM and the organic phases are combined, dried over magnesium sulphate and the DCM evaporated in vacuo to give 2 as a yellow oil (3.36 g, 47%). MW 264.33; C14H20N2O3; 1H NMR (CDCl3): 7.47-7.22 (5H, m), 4.55 (1H, d, 1.5 Hz), 4.00 (1H, dd, 11.5 Hz, 1.7 Hz), 3.75 (1H, dt, 11.5 Hz, 2.2 Hz), 3.65 (3H, s), 3.56 (2H, m), 3.17 (3H, s), 2.93 (1H, d, 11.3 Hz), 2.68 (1H, d, 11.3 Hz), 2.30 (2H, 11.3 Hz); LCMS: (6 min method) m/z 265 [M+H]+, RT 0.65 min. left the reaction mixture is left stirring overnight before quenching by cautious addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution The precipitate is removed by filtration through a celite pad the residue washed with chloroform The organic phase is then concentrated in vacuo washed with water The aqueous layer is re-extracted with chloroform washed with brine dried over magnesium sulphate the solvent evaporated in vacuo

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

Procedure: A stirred solution of 4-benzyl-morpholine-2-carbonitrile (113.0 g, 0.56 mol) in ethanol (1030 mL) is treated with concentrated sulphuric acid (165 mL) added in portions. (exothermic, internal temperature rises from ambient to 65° C.). The mixture is then warmed under reflux for 66 hrs. The solution is cooled and then concentrated in vacuo to half volume, basified with aqueous potassium carbonate (beware frothing) and the product extracted into diethyl ether. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness in vacuo to yield an oil. This material is evacuated further under high vacuum. Yield=121.3 g (87%). added in portions (exothermic, internal temperature rises from ambient to 65° C.) The mixture is then warmed under reflux for 66 hrs The solution is cooled concentrated in vacuo to half volume the product extracted into diethyl ether The organic phase is dried over magnesium sulphate filtered evaporated to dryness in vacuo to yield an oil This material is evacuated further under high vacuum

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

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

Procedure: Add a solution of 4-benzyl-morpholine-2-carboxylic acid ethyl ester (1.12 g, 4.49 mmol) in tetrahydrofuran (5 mL) to a stirred solution of 2-methoxybenzylmagnesium chloride (54 mL, 0.25M solution in tetrahydrofuran, commercially available from Rieke Metals) at −10° C. under nitrogen atmosphere. After 1 hour, add a saturated aqueous solution of sodium bicarbonate and extract with diethyl ether. Combine the organic layers and extract with brine, dry over magnesium sulfate, filter, and concentrate under reduced pressure to give a residue to be taken forward without further purification. MW 447.58; C28H33NO4; LCMS (12 minute method):m/z)=448.2 [M+H]+) RT 4.8 min. at −10° C. extract with diethyl ether extract with brine dry over magnesium sulfate filter concentrate under reduced pressure to give a residue to be taken forward without further purification LCMS (12 minute method) RT 4.8 min.

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

Procedure: To a stirred suspension of N,N-dimethylhydroxylamine (6.6 g, 67.6 mmol) in anhydrous DCM (200 mL) under nitrogen at 0° C. is added dropwise a solution of trimethylaluminium (2M solution in hexane, 34 mL, 67.6 mmol) over 30 minutes. The reaction mixture is allowed to warm up to room temperature and left stirring for 1 hour. A solution of the ester 1 (6.74 g, 27 mmol) in anhydrous DCM (100 mL) is then added dropwise over 30 minutes and the reaction mixture is left stirring overnight before quenching by cautious addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution. The precipitate is removed by filtration through a celite pad and the residue washed with chloroform. The organic phase is then concentrated in vacuo and washed with water. The aqueous layer is re-extracted with chloroform and the organic phases are combined, washed with brine, dried over magnesium sulphate and the solvent evaporated in vacuo to give 2 as a yellow oil. Alternatively, the reaction could be worked up as follows: upon addition of a solution of the ester 1 (1 eq) the reaction mixture is left stirring for 1 hour before quenching by addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution, followed by addition of water. The aqueous layer is re-extracted with DCM and the organic phases are combined, dried over magnesium sulphate and the DCM evaporated in vacuo to give 2 as a yellow oil (3.36 g, 47%). MW 264.33; C14H20N2O3; 1H NMR (CDCl3): 7.47-7.22 (5H, m), 4.55 (1H, d, 1.5 Hz), 4.00 (1H, dd, 11.5 Hz, 1.7 Hz), 3.75 (1H, dt, 11.5 Hz, 2.2 Hz), 3.65 (3H, s), 3.56 (2H, m), 3.17 (3H, s), 2.93 (1H, d, 11.3 Hz), 2.68 (1H, d, 11.3 Hz), 2.30 (2H, 11.3 Hz); LCMS: (6 min method) m/z 265 [M+H]+, RT 0.65 min. left the reaction mixture is left stirring overnight before quenching by cautious addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution The precipitate is removed by filtration through a celite pad the residue washed with chloroform The organic phase is then concentrated in vacuo washed with water The aqueous layer is re-extracted with chloroform washed with brine dried over magnesium sulphate the solvent evaporated in vacuo

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

Procedure: A stirred solution of 4-benzyl-morpholine-2-carbonitrile (113.0 g, 0.56 mol) in ethanol (1030 mL) is treated with concentrated sulphuric acid (165 mL) added in portions. (exothermic, internal temperature rises from ambient to 65° C.). The mixture is then warmed under reflux for 66 hrs. The solution is cooled and then concentrated in vacuo to half volume, basified with aqueous potassium carbonate (beware frothing) and the product extracted into diethyl ether. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness in vacuo to yield an oil. This material is evacuated further under high vacuum. Yield=121.3 g (87%). added in portions (exothermic, internal temperature rises from ambient to 65° C.) The mixture is then warmed under reflux for 66 hrs The solution is cooled concentrated in vacuo to half volume the product extracted into diethyl ether The organic phase is dried over magnesium sulphate filtered evaporated to dryness in vacuo to yield an oil This material is evacuated further under high vacuum