tert-butyl N-[[(2R)-morpholin-2-yl]methyl]carbamate

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

Procedure: To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.500 g, 2.29 mmol) in 1:1 (MeOH/CHCl3) (25 mL) were added 1,1-dimethylethyl [(2R)-2-morpholinyl-methyl]carbamate (0.500 g, 2.29 mmol) and Na2SO4 (0.100 g) and the resulting solution stirred at ambient temperature for 18 h. Na(OAc)3BH (1.46 g, 6.87 mmol) was added and the solution stirred an additional 2 g. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column) [0-100% Hexanes/EtOAc] to yield a yellowish oil. (0.460 g, 48%) the solution stirred an additional 2 g The reaction mixture was concentrated onto silica gel chromatographed on a silica gel column) [0-100% Hexanes/EtOAc] to yield a yellowish oil

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

Procedure: To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.500 g, 2.29 mmol) in 1:1 (MeOH/CHCl3) (25 mL) were added 1,1-dimethylethyl [(2R)-2-morpholinyl-methyl]carbamate (0.500 g, 2.29 mmol) and Na2SO4 (0.100 g) and the resulting solution stirred at ambient temperature for 18 h. Na(OAc)3BH (1.46 g, 6.87 mmol) was added and the solution stirred an additional 2 g. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column) [0-100% Hexanes/EtOAc] to yield a yellowish oil. (0.460 g, 48%) the solution stirred an additional 2 g The reaction mixture was concentrated onto silica gel chromatographed on a silica gel column) [0-100% Hexanes/EtOAc] to yield a yellowish oil

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

Procedure: To a solution of 1,1-dimethylethyl {[(2S)-4-(phenylmethyl)-2-morpholinyl]methyl}carbamate (4.9 g, 16 mmol) in ethanol (160 mL) was added 10% Pd/C (1.5 g). The suspension was hydrogenated at 50 psi using a Parr Shaker apparatus for 8 h. The reaction was filtered through a pad of Celite® and the pad was washed several times with methanol. The filtrate was concentrated to afford the title compound (3.35 g, 97%) as a colorless solid which was not purified further: LC/MS (ES) m/e 217 (M+H)+. The absolute stereochemistry of the title compound was determined by vibrational circular dichroism (VCD). for 8 h The reaction was filtered through a pad of Celite® the pad was washed several times with methanol The filtrate was concentrated

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,4-dichlorobenzoic acid (0.5 g), 1-hydroxybenzotriazole (0.376 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.432 g), and N,N-diisopropylethylamine (0.485 ml) in N,N-dimethylformamide (10 ml) was stirred at 20° C. for 10 min. The mixture was treated with tert-butyl(2R)-morpholin-2-ylmethylcarbamate (0.500 g, known compound WO 9639407A1) and stirred at 20° C. for 24 h. The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueous hydrochloric acid (50 ml). The phases were separated and the organic extract washed with 2N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (2×50 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo to give the title compound as a yellow oil, (0.774 g). stirred at 20° C. for 24 h The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueous hydrochloric acid (50 ml) The phases were separated the organic extract washed with 2N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (2×50 ml) dried (MgSO4) filtered The solvent was removed in vacuo

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

Procedure: To a solution of 1,1-dimethylethyl {[(2S)-4-(phenylmethyl)-2-morpholinyl]methyl}carbamate (4.9 g, 16 mmol) in ethanol (160 mL) was added 10% Pd/C (1.5 μg). The suspension was hydrogenated at 50 psi for 8 h. The reaction was filtered through a pad of Celite® and the pad was washed several times with methanol. The filtrate was concentrated to afford the title compound (3.35 g, 97%) as a colorless solid which was not purified further: LC/MS (ES) m/e 217 (M+H)+. The absolute stereochemistry of the title compound was determined by vibrational circular dichroism (VCD). The reaction was filtered through a pad of Celite® the pad was washed several times with methanol The filtrate was concentrated

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,4-dichlorobenzoic acid (0.5 g), 1-hydroxybenzotriazole (0.376 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.432 g), and N,N-diisopropylethylamine (0.485 ml) in N,N-dimethylformamide (10 ml) was stirred at 20° C. for 10 min. The mixture was treated with tert-butyl(2R)-morpholin-2-ylmethylcarbamate (0.500 g, known compound WO 9639407A1) and stirred at 20° C. for 24 h. The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueous hydrochloric acid (50 ml). The phases were separated and the organic extract washed with 2N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (2×50 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo to give the title compound as a yellow oil, (0.774 g). stirred at 20° C. for 24 h The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueous hydrochloric acid (50 ml) The phases were separated the organic extract washed with 2N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (2×50 ml) dried (MgSO4) filtered The solvent was removed in vacuo

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

Procedure: To a solution of 1,1-dimethylethyl {[(2S)-4-(phenylmethyl)-2-morpholinyl]methyl}carbamate (4.9 g, 16 mmol) in ethanol (160 mL) was added 10% Pd/C (1.5 μg). The suspension was hydrogenated at 50 psi for 8 h. The reaction was filtered through a pad of Celite® and the pad was washed several times with methanol. The filtrate was concentrated to afford the title compound (3.35 g, 97%) as a colorless solid which was not purified further: LC/MS (ES) m/e 217 (M+H)+. The absolute stereochemistry of the title compound was determined by vibrational circular dichroism (VCD). The reaction was filtered through a pad of Celite® the pad was washed several times with methanol The filtrate was concentrated

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,4-dichlorobenzoic acid (0.5 g), 1-hydroxybenzotriazole (0.376 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.4329), and N,N-diisopropylethylamine (0.485 ml) in N,N-dimethylformamide (10 ml) was stirred at 20° C. for 10 min. The mixture was treated with tert-butyl (2R)-morpholin-2-ylmethylcarbamate (0.500 g, known compound WO 9639407A1) and stirred at 20° C. for 24 h. The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueous hydrochloric acid (50 ml). The phases were separated and the organic extract washed with 2N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (2×50 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo to give the title compound as a yellow oil, (0.774 g). stirred at 20° C. for 24 h The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueous hydrochloric acid (50 ml) The phases were separated the organic extract washed with 2N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (2×50 ml) dried (MgSO4) filtered The solvent was removed in vacuo

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,4-dichlorobenzoic acid (0.5 g), 1-hydroxybenzotriazole (0.376 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.4329), and N,N-diisopropylethylamine (0.485 ml) in N,N-dimethylformamide (10 ml) was stirred at 20° C. for 10 min. The mixture was treated with tert-butyl (2R)-morpholin-2-ylmethylcarbamate (0.500 g, known compound WO 9639407A1) and stirred at 20° C. for 24 h. The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueous hydrochloric acid (50 ml). The phases were separated and the organic extract washed with 2N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (2×50 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo to give the title compound as a yellow oil, (0.774 g). stirred at 20° C. for 24 h The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueous hydrochloric acid (50 ml) The phases were separated the organic extract washed with 2N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (2×50 ml) dried (MgSO4) filtered The solvent was removed in vacuo

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,4-dichlorobenzoic acid (0.5 g), 1-hydroxybenzotriazole (0.376 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.4329), and N,N-diisopropylethylamine (0.485 ml) in N,N-dimethylformamide (10 ml) was stirred at 20° C. for 10 min. The mixture was treated with tert-butyl (2R)-morpholin-2-ylmethylcarbamate (0.500 g, known compound WO 9639407A1) and stirred at 20° C. for 24 h. The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueous hydrochloric acid (50 ml). The phases were separated and the organic extract washed with 2N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (2×50 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo to give the title compound as a yellow oil, (0.774 g). stirred at 20° C. for 24 h The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueous hydrochloric acid (50 ml) The phases were separated the organic extract washed with 2N aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (2×50 ml) dried (MgSO4) filtered The solvent was removed in vacuo

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

Procedure: tert-Butyl (2R)-morpholin-2-ylmethylcarbamate (2.00 g) in N,N-dimethylformamide (16 ml) was treated with N,N-diisopropylethylamine (1.6 ml) followed by 4-(1-bromoethyl)-1,2-dichlorobenzene (2.58 g). After stirring for five days at room temperature, further portions of 4-(1-bromoethyl)-1,2-dichlorobenzene (2.58 g) and N,N-diisopropylethylamine (1.6 ml) were added and stirring continued for 24 h at room temperature. The solution was treated with dichloromethane (70 ml) and saturated aqueous sodium hydrogen carbonate (30 ml) and the mixture shaken vigorously. The organic phase was separated and applied equally onto sulphonic acid ion exchange cartridges (5×10 g Isolute SCX, pre-treated with methanol). The cartridges were each eluted with methanol (one column volume) followed by 10% 0.880 ammonia in methanol (one column volume); evaporation in vacuo of the combined basic fractions gave the title compound as a clear colourless gum (3.22 g) stirring continued for 24 h at room temperature the mixture shaken vigorously The organic phase was separated applied equally onto sulphonic acid ion exchange cartridges (5×10 g Isolute SCX, pre-treated with methanol) each eluted with methanol (one column volume) evaporation in vacuo of the combined basic fractions

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

Procedure: To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.500 g, 2.29 mmol) in 1:1 (MeOH/CHCl3) (25 mL) were added 1,1-dimethylethyl [(2R)-2-morpholinyl-methyl]carbamate (0.500 g, 2.29 mmol) and Na2SO4 (0.100 g) and the resulting solution stirred at ambient temperature for 18 h. Na(OAc)3BH (1.46 g, 6.87 mmol) was added and the solution stirred an additional 2 g. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column) [0-100% Hexanes/EtOAc] to yield a yellowish oil. (0.460 g, 48%) the solution stirred an additional 2 g The reaction mixture was concentrated onto silica gel chromatographed on a silica gel column) [0-100% Hexanes/EtOAc] to yield a yellowish oil