(3R)-3-amino-3,5-dihydro-2H-1,5-benzothiazepin-4-one

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

Procedure: A mixture of 3(R)-amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.7 g) and ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (5.4 g) is heated at 100°-130° C. for 3 hours. After cooling, the mixture is dissolved in ethylacetate (200 ml) and the solution is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.9 g) as a colorless oil. is heated at 100°-130° C. for 3 hours After cooling the solution is washed with water dried over anhydrous magnesium sulfate concentrated in vacuo The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1)

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

Procedure: A mixture of 3(R)-phthalimido-2,3-dihydro-1,5-(5H)-benzothiazepin-4-one (10 g), ethanol (500 ml) and hydrazine hydrate (6.2 g) is refluxed for 1 hour. After ethanol is removed by evaporation under reduced pressure, water (300 ml) is added, and the mixture is extracted with ethyl acetate (400 ml). The extract is washed with 0.1 N sodium hydroxide solution (100 ml×2) and water (100 ml) successively, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3(R)-amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (3.75 g) as colorless leaflets. is refluxed for 1 hour After ethanol is removed by evaporation under reduced pressure, water (300 ml) is added the mixture is extracted with ethyl acetate (400 ml) The extract is washed with 0.1 N sodium hydroxide solution (100 ml×2) and water (100 ml) successively dried over anhydrous magnesium sulfate concentrated in vacuo

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

Procedure: A mixture of 3(R)-amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.7 g) and ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (5.4 g) is heated at 100°-130° C. for 3 hours. After cooling, the mixture is dissolved in ethylacetate (200 ml) and the solution is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.9 g) as a colorless oil. is heated at 100°-130° C. for 3 hours After cooling the solution is washed with water dried over anhydrous magnesium sulfate concentrated in vacuo The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1)

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

Procedure: A mixture of 3(R)-amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.7 g) and ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (5.4 g) is heated at 100°-130° C. for 3 hours. After cooling, the mixture is dissolved in ethylacetate (200 ml) and the solution is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.9 g) as a colorless oil. is heated at 100°-130° C. for 3 hours After cooling the solution is washed with water dried over anhydrous magnesium sulfate concentrated in vacuo The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1)

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

Procedure: A mixture of 3(R)-amino-2,3-dihydro-1,5-(5H)-benzothiazepin-4-one (1.0 g), ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate (6.0 g), acetic acid (0.37 g), molecular sieves 3A (3.0 g) and ethanol (25 ml) is stirred at room temperature for 20 minutes. To the stirred mixture is added dropwise a solution of sodium cyanoborohydride (0.66 g) in ethanol (20 ml) over a period of 5 hours. After the reaction mixture is concentrated under reduced pressure, the residue is diluted with a mixture of ethyl acetate (80 ml) and water (100 ml). After the insoluble substance is removed by filtration, the ethyl acetate layer is washed with diluted hydrochloric acid, water and sodium bicarbonate solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (1.1 g) as a colorless oil. After the reaction mixture is concentrated under reduced pressure the residue is diluted with a mixture of ethyl acetate (80 ml) and water (100 ml) After the insoluble substance is removed by filtration the ethyl acetate layer is washed with diluted hydrochloric acid, water and sodium bicarbonate solution successively dried over anhydrous sodium sulfate concentrated in vacuo The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1)

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

Procedure: A mixture of 3(R)-amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.7 g) and ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (5.4 g) is heated at 100°-130° C. for 3 hours. After cooling, the mixture is dissolved in ethylacetate (200 ml) and the solution is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.9 g) as a colorless oil. is heated at 100°-130° C. for 3 hours After cooling the solution is washed with water dried over anhydrous magnesium sulfate concentrated in vacuo The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1)

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

Procedure: A mixture of 3(R)-phthalimido-2,3-dihydro-1,5-(5H)-benzothiazepin-4-one (10 g), ethanol (500 ml) and hydrazine hydrate (6.2 g) is refluxed for 1 hour. After ethanol is removed by evaporation under reduced pressure, water (300 ml) is added, and the mixture is extracted with ethyl acetate (400 ml). The extract is washed with 0.1 N sodium hydroxide solution (100 ml×2) and water (100 ml) successively, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3(R)-amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (3.75 g) as colorless leaflets. is refluxed for 1 hour After ethanol is removed by evaporation under reduced pressure, water (300 ml) is added the mixture is extracted with ethyl acetate (400 ml) The extract is washed with 0.1 N sodium hydroxide solution (100 ml×2) and water (100 ml) successively dried over anhydrous magnesium sulfate concentrated in vacuo

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

Procedure: A mixture of 3(R)-amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.7 g) and ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (5.4 g) is heated at 100°-130° C. for 3 hours. After cooling, the mixture is dissolved in ethylacetate (200 ml) and the solution is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.9 g) as a colorless oil. is heated at 100°-130° C. for 3 hours After cooling the solution is washed with water dried over anhydrous magnesium sulfate concentrated in vacuo The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1)

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

Procedure: A mixture of 3(R)-amino-2,3-dihydro-1,5-(5H)-benzothiazepin-4-one (1.0 g), ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate (6.0 g), acetic acid (0.37 g), molecular sieves 3A (3.0 g) and ethanol (25 ml) is stirred at room temperature for 20 minutes. To the stirred mixture is added dropwise a solution of sodium cyanoborohydride (0.66 g) in ethanol (20 ml) over a period of 5 hours. After the reaction mixture is concentrated under reduced pressure, the residue is diluted with a mixture of ethyl acetate (80 ml) and water (100 ml). After the insoluble substance is removed by filtration, the ethyl acetate layer is washed with diluted hydrochloric acid, water and sodium bicarbonate solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (1.1 g) as a colorless oil. After the reaction mixture is concentrated under reduced pressure the residue is diluted with a mixture of ethyl acetate (80 ml) and water (100 ml) After the insoluble substance is removed by filtration the ethyl acetate layer is washed with diluted hydrochloric acid, water and sodium bicarbonate solution successively dried over anhydrous sodium sulfate concentrated in vacuo The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1)