(4-benzylmorpholin-2-yl)methanol

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

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

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

Procedure: 4-Benzyl-2-hydroxymethylmorpholine (prepared by the method disclosed in Synthetic Communication, Vol. 10, pages 59-73, 1980) (200 g) and triethylamine (122 g) are dissolved in chloroform (1.5 liter), and thereto is added dropwise benzoyl chloride (135 g) with stirring under ice cooling. The mixture is stirred at room temperature for 16 hours and thereafter to the mixture is added water. The chloroform layer is separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous saline solution in this order, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue is dissolved in ethyl acetate (150 ml) and thereto is added 4N hydrogen chloride/ethyl acetate (250 ml) with stirring under ice cooling, and the precipitated crystals are separated by filtration, washed with ethyl acetate and acetone in this order to give the title compound (240 g) as colorless crystals. The mixture is stirred at room temperature for 16 hours The chloroform layer is separated washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous saline solution in this order dried over anhydrous magnesium sulfate distilled under reduced pressure to remove the solvent The residue is dissolved in ethyl acetate (150 ml) is added 4N hydrogen chloride/ethyl acetate (250 ml) with stirring under ice cooling the precipitated crystals are separated by filtration washed with ethyl acetate and acetone in this order

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

Procedure: N-Benzyl-2-hydroxymethylmorpholine prepared in the same manner as described in Synthetic Communication, Vol. 10 (1), pages 59-73, 1980 (1.3 g) is subjected to hydrogenolysis in hydrogen chloride-containing ethanol in the same manner as described in Reference Example 15 to give 2-hydroxymethylmorpholine hydrochloride (1.3 g).

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.30 g of 4-benzyl-2-hydroxymethylmorpholine, 930 mg of potassium tert-butoxide and 4 ml of dimethyl sulfoxide was heated to 80° C. Thereto was dropwise added 2.50 g of styrene oxide over 20 minutes. The resulting mixture was stirred for 2 hours at the same temperature. The reaction mixture was added to a mixture of 30 ml of diethyl ether and 30 ml of ice water. The organic layer was separated and mixed with 10 ml of water. The mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The aqueous layer was separated and mixed with 30 ml of diethyl ether. The mixture was adjusted to pH 11 with a 2N aqueous sodium hydroxide solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=1/1) to obtain 2.00 g of oily 1-phenyl-2-[(4-benzylmorpholin-2-yl)methoxy]ethanol (compound No. 144). over 20 minutes The organic layer was separated mixed with 10 ml of water The aqueous layer was separated mixed with 30 ml of diethyl ether The organic layer was separated washed with a saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure The residue was purified by column chromatography (eluant: toluene/ethyl acetate=1/1)

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

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-benzylethanolamine (302.4 g, 2.0 mol), 2-propanol (185 ml) and water (185 ml) was added dropwise at 15 to 25° C. (S)-epichlorohydrin (185.0 g, 2.0 mol, 99% ee). After reaction at 15 to 25° C. for 7 hr, aqueous 24% NaOH solution (NET 104 g, 2.6 mol) was added at 5 to 10° C. After reaction at 25° C. for 20 hr, the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol. To the residue was added toluene (555 ml) and, after partitioning, the organic layer was concentrated under reduced pressure to give a mixture of N-benzyl-2-hydroxymethylmorpholine, N-benzyl-1,4-oxazepane and other byproducts (410.4 g, N-benzyl-2-hydroxymethylmorpholine:N-benzyl-1,4-oxazepane compound=75.2:24.8). To this mixture were added methanol (830 ml) and palladium carbon (40.0 g when dry), and the mixture was reacted under a hydrogen stream at 25° C. for 15 hr. Palladium carbon was filtered off, methanol was evaporated under reduced pressure to give a mixture of 2-hydroxymethylmorpholine and a 1,4-oxazepane compound (265.7 g, 2-hydroxymethylmorpholine:1,4-oxazepane compound=75.8:24.2). To the mixture (20.0 g) were added methanol (100 ml) and p-nitrobenzoic acid (25.2 g, 0.151 mol) and the mixture was stirred for 30 min. Then, methanol was evaporated under reduced pressure. To the residue was added 2-propanol (50 ml) and the mixture was subjected twice to azeotropic distillation with dehydrating. To the residue after azeotropic distillation with dehydrating was added ethyl acetate (100 ml) at 40° C., and the mixture was cooled to 10° C. After crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (25 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine p-nitrobenzoate (17.7 g) (yield from (S)-epichlorohydrin 41.3%). The obtained (R)-2-hydroxymethylmorpholine p-nitrobenzoate was analyzed by HPLC to find an optical purity of 99% ee. After reaction at 15 to 25° C. for 7 hr After reaction at 25° C. for 20 hr the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol To the residue was added toluene (555 ml) after partitioning the organic layer was concentrated under reduced pressure to give the mixture was reacted under a hydrogen stream at 25° C. for 15 hr Palladium carbon was filtered off methanol was evaporated under reduced pressure to give Then, methanol was evaporated under reduced pressure To the residue was added 2-propanol (50 ml) the mixture was subjected twice to azeotropic distillation with dehydrating To the residue after azeotropic distillation with dehydrating was added ethyl acetate (100 ml) at 40° C. After crystallization the mixture was cooled to 0° C. stirred for 1 hr The crystals were collected by filtration washed dried (1 mmHg, 40° C.)

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-benzylethanolamine (302.4 g, 2.0 mol), 2-propanol (185 ml) and water (185 ml) was added dropwise at 15 to 25° C. (S)-epichlorohydrin (185.0 g, 2.0 mol, 99% ee). After reaction at 15 to 25° C. for 7 hr, aqueous 24% NaOH solution (NET 104 g, 2.6 mol) was added at 5 to 10° C. After reaction at 25° C. for 20 hr, the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol. To the residue was added toluene (555 ml) and, after partitioning, the organic layer was concentrated under reduced pressure to give a mixture of N-benzyl-2-hydroxymethylmorpholine, N-benzyl-1,4-oxazepane and other byproducts (410.4 g, N-benzyl-2-hydroxymethylmorpholine:N-benzyl-1,4-oxazepane compound=75.2:24.8). To this mixture were added methanol (830 ml) and palladium carbon (40.0 g when dry), and the mixture was reacted under a hydrogen stream at 25° C. for 15 hr. Palladium carbon was filtered off, methanol was evaporated under reduced pressure to give a mixture of 2-hydroxymethylmorpholine and a 1,4-oxazepane compound (265.7 g, 2-hydroxymethylmorpholine:1,4-oxazepane compound=75.8:24.2). To the mixture (20.0 g) were added methanol (100 ml) and p-nitrobenzoic acid (25.2 g, 0.151 mol) and the mixture was stirred for 30 min. Then, methanol was evaporated under reduced pressure. To the residue was added 2-propanol (50 ml) and the mixture was subjected twice to azeotropic distillation with dehydrating. To the residue after azeotropic distillation with dehydrating was added ethyl acetate (100 ml) at 40° C., and the mixture was cooled to 10° C. After crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (25 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine p-nitrobenzoate (17.7 g) (yield from (S)-epichlorohydrin 41.3%). The obtained (R)-2-hydroxymethylmorpholine p-nitrobenzoate was analyzed by HPLC to find an optical purity of 99% ee. After reaction at 15 to 25° C. for 7 hr After reaction at 25° C. for 20 hr the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol To the residue was added toluene (555 ml) after partitioning the organic layer was concentrated under reduced pressure to give the mixture was reacted under a hydrogen stream at 25° C. for 15 hr Palladium carbon was filtered off methanol was evaporated under reduced pressure to give Then, methanol was evaporated under reduced pressure To the residue was added 2-propanol (50 ml) the mixture was subjected twice to azeotropic distillation with dehydrating To the residue after azeotropic distillation with dehydrating was added ethyl acetate (100 ml) at 40° C. After crystallization the mixture was cooled to 0° C. stirred for 1 hr The crystals were collected by filtration washed dried (1 mmHg, 40° C.)

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

Procedure: In the same manner as in Example 3, a mixture containing N-benzyl-2-hydroxymethylmorpholine, N-benzyl-1,4-oxazepane and other byproducts (121.1 g, N-benzyl-2-hydroxymethylmorpholine:N-benzyl-1,4-oxazepane compound=75.1:24.9). To this mixture were added methanol (200 ml), trifluoroacetic acid (61.8 g, 0.540 mol), and palladium carbon (11.0 g when dry), and the mixture was reacted under a hydrogen stream at 25° C. for 15 hr. Palladium carbon was filtered off, and methanol was evaporated under reduced pressure. The residue was subjected twice to azeotropic distillation with dehydrating with 2-propanol (100 ml). To the residue after azeotropic distillation with dehydrating was added ethyl acetate (450 ml) at 40° C., and the mixture was cooled to 20° C. Seed crystal was added and, after crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (100 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine trifluoroacetate (53.7 g) (yield from (S)-epichlorohydrin: 43.0%). The obtained (R)-2-hydroxymethylmorpholine trifluoroacetate was analyzed by HPLC to find an optical purity of 99% ee. the mixture was reacted under a hydrogen stream at 25° C. for 15 hr Palladium carbon was filtered off methanol was evaporated under reduced pressure The residue was subjected twice to azeotropic distillation To the residue after azeotropic distillation with dehydrating was added ethyl acetate (450 ml) at 40° C. Seed crystal was added after crystallization the mixture was cooled to 0° C. The crystals were collected by filtration washed dried (1 mmHg, 40° C.)

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

Procedure: To a mixture of N-benzylethanolamine (81.7 g, 0.540 mol), 2-propanol (50 ml) and water (50 ml) was added dropwise at 15 to 25° C. (S)-epichlorohydrin (50.0 g, 0.540 mol, 99% ee). After reaction at 10 to 25° C. for 7 hr, aqueous 24% NaOH solution (NET 28.1 g, 0.703 mol) was added at 5 to 10° C. After reaction at 25° C. for 20 hr, the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol. To the residue was added toluene (150 ml) and, after partitioning, the organic layer was concentrated under reduced pressure to give a mixture of N-benzyl-2-hydroxymethylmorpholine and N-benzyl-1,4-oxazepane (125.3 g, N-benzyl-2-hydroxymethylmorpholine:N-benzyl-1,4-oxazepane compound=74.4:25.6). To this mixture were added methanol (200 ml) and palladium carbon (11.0 g when dry), and the mixture was reacted under a hydrogen stream at 25° C. for 15 hr. Palladium carbon was filtered off, trifluoroacetic acid (61.8 g, 0.540 mol) was added to the filtrate at 5 to 10° C., and methanol was evaporated under reduced pressure. The residue was subjected twice to azeotropic distillation with dehydrating with 2-propanol (100 ml). To the residue after azeotropic distillation with dehydrating was added ethyl acetate (450 ml) at 40° C., and the mixture was cooled to 20° C. Seed crystal was added and, after crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (100 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine trifluoroacetate (51.3 g) (yield from (S)-epichlorohydrin 41.1%). The obtained (R)-2-hydroxymethylmorpholine trifluoroacetate was analyzed by HPLC to find an optical purity of 99% ee. After reaction at 10 to 25° C. for 7 hr After reaction at 25° C. for 20 hr the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol To the residue was added toluene (150 ml) after partitioning the organic layer was concentrated under reduced pressure to give the mixture was reacted under a hydrogen stream at 25° C. for 15 hr Palladium carbon was filtered off methanol was evaporated under reduced pressure The residue was subjected twice to azeotropic distillation To the residue after azeotropic distillation with dehydrating was added ethyl acetate (450 ml) at 40° C. Seed crystal was added after crystallization the mixture was cooled to 0° C. The crystals were collected by filtration washed dried (1 mmHg, 40° C.)

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

Procedure: To a mixture of N-benzylethanolamine (81.7 g, 0.540 mol), 2-propanol (50 ml) and water (50 ml) was added dropwise at 15 to 25° C. (S)-epichlorohydrin (50.0 g, 0.540 mol, 99% ee). After reaction at 10 to 25° C. for 7 hr, aqueous 24% NaOH solution (NET 28.1 g, 0.703 mol) was added at 5 to 10° C. After reaction at 25° C. for 20 hr, the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol. To the residue was added toluene (150 ml) and, after partitioning, the organic layer was concentrated under reduced pressure to give a mixture of N-benzyl-2-hydroxymethylmorpholine and N-benzyl-1,4-oxazepane (125.3 g, N-benzyl-2-hydroxymethylmorpholine:N-benzyl-1,4-oxazepane compound=74.4:25.6). To this mixture were added methanol (200 ml) and palladium carbon (11.0 g when dry), and the mixture was reacted under a hydrogen stream at 25° C. for 15 hr. Palladium carbon was filtered off, trifluoroacetic acid (61.8 g, 0.540 mol) was added to the filtrate at 5 to 10° C., and methanol was evaporated under reduced pressure. The residue was subjected twice to azeotropic distillation with dehydrating with 2-propanol (100 ml). To the residue after azeotropic distillation with dehydrating was added ethyl acetate (450 ml) at 40° C., and the mixture was cooled to 20° C. Seed crystal was added and, after crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (100 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine trifluoroacetate (51.3 g) (yield from (S)-epichlorohydrin 41.1%). The obtained (R)-2-hydroxymethylmorpholine trifluoroacetate was analyzed by HPLC to find an optical purity of 99% ee. After reaction at 10 to 25° C. for 7 hr After reaction at 25° C. for 20 hr the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol To the residue was added toluene (150 ml) after partitioning the organic layer was concentrated under reduced pressure to give the mixture was reacted under a hydrogen stream at 25° C. for 15 hr Palladium carbon was filtered off methanol was evaporated under reduced pressure The residue was subjected twice to azeotropic distillation To the residue after azeotropic distillation with dehydrating was added ethyl acetate (450 ml) at 40° C. Seed crystal was added after crystallization the mixture was cooled to 0° C. The crystals were collected by filtration washed dried (1 mmHg, 40° C.)

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

Procedure: To a mixture of N-benzylethanolamine (81.7 g, 0.540 mol), 2-propanol (50 ml) and water (50 ml) was added dropwise at 15 to 25° C. (S)-epichlorohydrin (50.0 g, 0.540 mol, 99% ee). After reaction at 10 to 25° C. for 7 hr, aqueous 24% NaOH solution (NET 28.1 g, 0.703 mol) was added at 5 to 10° C. After reaction at 25° C. for 20 hr, the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol. To the residue was added toluene (150 ml) and, after partitioning, the organic layer was concentrated under reduced pressure. The residue was distilled (0.5 mmHg, 150 to 180° C.) to give a mixture of N-benzyl-2-hydroxymethylmorpholine and N-benzyl-1,4-oxazepane compound (76.3 g, N-benzyl-2-hydroxymethylmorpholine:N-benzyl-1,4-oxazepane compound=76.5:23.5). To this mixture were added methanol (153 ml), trifluoroacetic acid (44.1 g, 0.387 mol) and palladium carbon (15.3 g when dry), and the mixture was reacted under a hydrogen stream at 25° C. for 15 hr. Palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected twice to azeotropic distillation with dehydrating with 2-propanol (76 ml). To the residue after azeotropic distillation with dehydrating was added ethyl acetate (382 ml) at 40° C., and the mixture was cooled to 20° C. Seed crystal was added and, after crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (76 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine trifluoroacetate (50.22 g) (yield from (S)-epichlorohydrin: 40.2%). The obtained (R)-2-hydroxymethylmorpholine trifluoroacetate was analyzed by HPLC to find an optical purity of 99% ee. After reaction at 10 to 25° C. for 7 hr After reaction at 25° C. for 20 hr the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol To the residue was added toluene (150 ml) after partitioning the organic layer was concentrated under reduced pressure The residue was distilled (0.5 mmHg, 150 to 180° C.) to give the mixture was reacted under a hydrogen stream at 25° C. for 15 hr Palladium carbon was filtered off the filtrate was concentrated under reduced pressure The residue was subjected twice to azeotropic distillation To the residue after azeotropic distillation with dehydrating was added ethyl acetate (382 ml) at 40° C. Seed crystal was added after crystallization the mixture was cooled to 0° C. The crystals were collected by filtration washed dried (1 mmHg, 40° C.)