4-piperidin-4-ylmorpholin-3-one

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

Procedure: 4-(Piperidin-4-yl)morpholin-3-one (0.18 g) obtained in Example 7c), (2S)-3[(6-chloronaphthalen-2-yl)sulfony]-2-hydroxypropionic acid (0.31 g) and HOBt (0.23 g) were dissolved in DMF (10 mL), WSC (0.29 g) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The extract was washed successively with water, an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (from ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound (0.20 g, 42%) as a colorless powder. The reaction mixture was concentrated under reduced pressure the residue was diluted with an aqueous sodium bicarbonate solution extracted with ethyl acetate The extract was washed successively with water an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate the solvent was distilled off under reduced pressure The residue was purified by silica gel column chromatography (from ethyl acetate to ethyl acetate/methanol=5/1)

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

Procedure: Benzyl 4-(3-oxo-4-morpholinyl)piperidin-1-carboxylate (3.8 g) obtained in Example 7b) was dissolved in ethanol (50 mL), 10% palladium on carbon (containing 50% water; 0.38 g) was added thereto, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction mixture was filtered and the solvent was distilled off under reduced pressure to obtain the title compound (2.2 g, quantitative) as a light yellow oil. The reaction mixture was filtered the solvent was distilled off under reduced pressure

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

Procedure: 4-(Piperidin-4-yl)morpholin-3-one (0.18 g) obtained in Example 7c), (2S)-3[(6-chloronaphthalen-2-yl)sulfony]-2-hydroxypropionic acid (0.31 g) and HOBt (0.23 g) were dissolved in DMF (10 mL), WSC (0.29 g) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The extract was washed successively with water, an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (from ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound (0.20 g, 42%) as a colorless powder. The reaction mixture was concentrated under reduced pressure the residue was diluted with an aqueous sodium bicarbonate solution extracted with ethyl acetate The extract was washed successively with water an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate the solvent was distilled off under reduced pressure The residue was purified by silica gel column chromatography (from ethyl acetate to ethyl acetate/methanol=5/1)

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

Procedure: Benzyl 4-(3-oxo-4-morpholinyl)piperidin-1-carboxylate (3.8 g) obtained in Example 7b) was dissolved in ethanol (50 mL), 10% palladium on carbon (containing 50% water; 0.38 g) was added thereto, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction mixture was filtered and the solvent was distilled off under reduced pressure to obtain the title compound (2.2 g, quantitative) as a light yellow oil. The reaction mixture was filtered the solvent was distilled off under reduced pressure

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

Procedure: 4-(Piperidin-4-yl)morpholin-3-one (0.18 g) obtained in Example 7c), (2S)-3[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropionic acid (0.31 g) and HOBt (0.23 g) were dissolved in DMF (10 mL), WSC (0.29 g) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The extract was washed successively with water, an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (form ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound (0.20 g, 42%) as a colorless powder. The reaction mixture was concentrated under reduced pressure the residue was diluted with an aqueous sodium bicarbonate solution extracted with ethyl acetate The extract was washed successively with water an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate the solvent was distilled off under reduced pressure The residue was purified by silica gel column chromatography (form ethyl acetate to ethyl acetate/methanol=5/1)

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

Procedure: 4-(Piperidin-4-yl)morpholin-3-one (0.18 g) obtained in Example 7c), (2S)-3[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropionic acid (0.31 g) and HOBt (0.23 g) were dissolved in DMF (10 mL), WSC (0.29 g) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The extract was washed successively with water, an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (form ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound (0.20 g, 42%) as a colorless powder. The reaction mixture was concentrated under reduced pressure the residue was diluted with an aqueous sodium bicarbonate solution extracted with ethyl acetate The extract was washed successively with water an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate the solvent was distilled off under reduced pressure The residue was purified by silica gel column chromatography (form ethyl acetate to ethyl acetate/methanol=5/1)

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

Procedure: Benzyl 4-(3-oxo-4-morpholinyl)piperidin-1-carboxylate (3.8 g) obtained in Example 7b) was dissolved in ethanol (50 mL), 10% palladium on carbon (containing 50% water; 0.38 g) was added thereto, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction mixture was filtered and the solvent was distilled off under reduced pressure to obtain the title compound (2.2 g, quantitative) as a light yellow oil. The reaction mixture was filtered the solvent was distilled off under reduced pressure

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

Procedure: 4-(Piperidin-4-yl)morpholin-3-one (0.18 g) obtained in Example 7c), (2S)-3[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropionic acid (0.31 g) and HOBt (0.23 g) were dissolved in DMF (10 mL), WSC (0.29 g) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The extract was washed successively with water, an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (form ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound (0.20 g, 42%) as a colorless powder. The reaction mixture was concentrated under reduced pressure the residue was diluted with an aqueous sodium bicarbonate solution extracted with ethyl acetate The extract was washed successively with water an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate the solvent was distilled off under reduced pressure The residue was purified by silica gel column chromatography (form ethyl acetate to ethyl acetate/methanol=5/1)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromopyridine hydrochloride (778 mg, 4.00 mmol), 3-morpholinone (404 mg, 4.00 mmol), K3PO4 (1.70 g, 8.00 mmol) and 1,2-trans-diaminocyclohexane (200 uL, 1.60 mmol) in dioxane (10 mL) was degassed with Ar before being charged with CuI (152 mg, 0.80 mmol). The mixture in a sealed tube was heated at 110° C. overnight. The mixture was applied to a silica gel column, which was then eluted with 2-5% MeOH in CH2Cl2 to give the desired product (85 mg). MS 179.5 (M+H). was degassed with Ar was then eluted with 2-5% MeOH in CH2Cl2

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromopyridine hydrochloride (778 mg, 4.00 mmol), 3-morpholinone (404 mg, 4.00 mmol), K3PO4 (1.70 g, 8.00 mmol) and 1,2-trans-diaminocyclohexane (200 uL, 1.60 mmol) in dioxane (10 mL) was degassed with Ar before being charged with CuI (152 mg, 0.80 mmol). The mixture in a sealed tube was heated at 110° C. overnight. The mixture was applied to a silica gel column, which was then eluted with 2-5% MeOH in CH2Cl2 to give the desired product (85 mg). MS 179.5 (M+H). was degassed with Ar was then eluted with 2-5% MeOH in CH2Cl2

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromopyridine hydrochloride (778 mg, 4.00 mmol), 3-morpholinone (404 mg, 4.00 mmol), K3PO4 (1.70 g, 8.00 mmol) and 1,2-trans-diaminocyclohexane (200 uL, 1.60 mmol) in dioxane (10 mL) was degassed with Ar before being charged with CuI (152 mg, 0.80 mmol). The mixture in a sealed tube was heated at 110° C. overnight. The mixture was applied to a silica gel column, which was then eluted with 2-5% MeOH in CH2Cl2 to give the desired product (85 mg). MS 179.5 (M+H) was degassed with Ar was then eluted with 2-5% MeOH in CH2Cl2

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

Procedure: 4-(Piperidin-4-yl)morpholin-3-one (0.18 g) obtained in Example 7c), (2S)-3[(6-chloronaphthalen-2-yl)sulfony]-2-hydroxypropionic acid (0.31 g) and HOBt (0.23 g) were dissolved in DMF (10 mL), WSC (0.29 g) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The extract was washed successively with water, an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (from ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound (0.20 g, 42%) as a colorless powder. The reaction mixture was concentrated under reduced pressure the residue was diluted with an aqueous sodium bicarbonate solution extracted with ethyl acetate The extract was washed successively with water an aqueous 5% citric acid solution, and saturated saline solution, and dried over sodium sulfate the solvent was distilled off under reduced pressure The residue was purified by silica gel column chromatography (from ethyl acetate to ethyl acetate/methanol=5/1)