(S)-(-)-阿替洛尔

反应条件: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: P-Hydroxyphenylacetamide (1 g) and (S)-glycidyl p-toluenesulfonate (1.51 g, 99.3% e.e.) were dissolved in acetone (30 ml). Potassium carbonate (1.19 g) was added to the solution and stirred for 30 hours under refluxing. After the reaction, inorganic materials were filtered off and acetone was removed to give 1.43 g of crude (S)-1-[p-(carbamoylmethyl)phenoxy-2,3-epoxypropane. Then, crude (S)-1-[p-(carbamoylmethyl)phenoxy-2,3-epoxypropane (1.43 g) was dissolved in methanol (8 ml). The solution was dropped in isopropylamine (6.8 g) under cooling to 10° C. over a period of 1 hour and the reaction temperature was raised to room temperature and stirred for 7 hours. After the reaction, the mixture was condensed in vacuo until crystals beginning to separate, cooled, filtrated by suction and dried in vacuo to give crude (S)-atenolol (1.29 g). The optical purity of it was 62.8% e.e. by measurement of Chiral column OD (Daisel Chemical industries Ltd.). the reaction temperature was raised to room temperature After the reaction condensed in vacuo until crystals to separate cooled filtrated by suction dried in vacuo

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: p-Hydroxyphenylacetamide (30.02 g) was dissolved in 106.5 g of water containing sodium hydroxide (9.6 g) and the solution was cooled to 5° C. Epichlorohydrin (18.5 g, 98.9% e.e.) was dropped in the solution over a period of 10 minutes and the mixture was stirred for 24 hours at the same temperature. After confirmation of the progress of the reaction being 98% by HPLC, the reaction mixture was neutralized with 0.1 N hydrochloric acid at the same temperature and then dropped in isopropylamine (240 g) under cooling to 10° C. over a period of 1 hour and the reaction temperature was raised to room temperature and stirred for 3.5 hours. After the reaction, the reaction mixture was condensed in vacuo until crystals beginning to separate, cooled and filtrated by suction and dried in vacuo to give crude (S)-atenolol (51.26 g). The optical purity of it was 91.2% e.e. by measurement of Chiral column OD (Daisel Chemical Industries Ltd.). under cooling to 10° C. over a period of 1 hour the reaction temperature was raised to room temperature stirred for 3.5 hours After the reaction condensed in vacuo until crystals to separate cooled filtrated by suction dried in vacuo

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: p-Hydroxyphenylacetamide (1 g) was dissolved in DMF (5 ml) under nitrogen atmosphere and the solution was cooled to 0° C. Cesium fluoride (3.02 g) and sodium iodide (0.1 g) were added thereto and the mixture was stirred for 1 hour. Then (R)-epichlorohydrin (0.62 g, 98.4% e.e.) was added thereto and the mixture was stirred for 30 hours at the same temperature. After the reaction, the reaction mixture was dropped over a period of one hour in isopropylamine (9 g) previously cooled to 10° C. The temperature of the solution was raised to room temperature and stirred for 12 hours. Then the product was treated in the same manner as Example 1 to give 1.53 g of (S)-atenolol (yield 87%, optical purity 98.3% e.e.) as colorless crystals. the mixture was stirred for 30 hours at the same temperature After the reaction previously cooled to 10° C The temperature of the solution was raised to room temperature stirred for 12 hours Then the product was treated in the same manner as Example 1

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The S-atenolol having an optical purity of 96.5% ee (10.77 g) thus obtained and p-toluic acid (5.54 g) are dissolved in acetone (1 liter) by heating with stirring and the mixture is sitrred at room temperature for 10 hours. The precipitated crystals are separated by filtration and the filtrate is concentrated under reduced pressure to give S-atenolol p-toluate having an optical purity of 98.5% ee (14.47 g). by heating The precipitated crystals are separated by filtration the filtrate is concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The S-atenolol having an optical purity of 96.5% ee (10.77 g) thus obtained and p-toluic acid (5.54 g) are dissolved in acetone (1 liter) by heating with stirring and the mixture is sitrred at room temperature for 10 hours. The precipitated crystals are separated by filtration and the filtrate is concentrated under reduced pressure to give S-atenolol p-toluate having an optical purity of 98.5% ee (14.47 g). by heating The precipitated crystals are separated by filtration the filtrate is concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: S-atenolol (optical purity, 91 % ee, 4.43 g) and p-toluic acid (2.28 g) are dissolved in acetone (300 ml) by heating, and the mixture is allowed to stand overnight at room temperature. The precipitated crystals are separated by filtration, and the filtrate is concentrated under reduced pressure to give S-atenolol toluate having an optical purity of 98.8% ee (5.01 g). by heating The precipitated crystals are separated by filtration the filtrate is concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 20 μg (R,S)-atenolol is injected in 20 μl of the eluant acetonitrile/acetic acid (v/v, 93/7). k'R =1.18 k'S =2.34 α=2.0 RS =0.5

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In order to prevent the reaction of produced atenolol with the optically active glycidyl ether (4) it is preferable to add the optically active glycidyl ether (4) to isopropyl amine in a solvent. The removal of excess isopropyl amine by distillation gave desired (S)-atenolol (1). Preferably, the distillation is carried out at atmospheric pressure at the initial stages and under reduced pressure at later stages, keeping the reaction mass temperature below 60° to 70° C., through out the distillation process. The crude residue may be purified, if required, by dissolving it in 1N HCl, treating this solution with activated charcoal, filtering the charcoal followed by treatment of alkali to precipitate the product. Thus, the solid product was isolated by conventional method such as filtration to get (S)-atenolol (1) of optical purity of 98% ee and above. If, necessary, the optically active (S)-atenolol (1) may be crystallized from an appropriate solvent such as water, alcohols, such as methanol, ethanol, isopropyl alcohol, butanol etc., ethers, such as diethyl ether, methyl tbutyl ether, diisopropyl ether or ketones, such as acetone, ethyl methyl ketone, methyl isobutyl ketone etc. The removal of excess isopropyl amine by distillation

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The S-atenolol having an optical purity of 96.5% ee (10.77 g) thus obtained and p-toluic acid (5.54 g) are dissolved in acetone (1 liter) by heating with stirring and the mixture is stirred at room temperature for 10 hours. The precipitated crystals are separated by filtration and the filtrate is concentrated under reduced pressure to give S-atenolol p-toluate having an optical purity of 98.5% ee (14.47 g). by heating the mixture is stirred at room temperature for 10 hours The precipitated crystals are separated by filtration the filtrate is concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: S-atenolol (optical purity, 91% ee, 4.43 g) and p-toluic acid (2.28 g) are dissolved in acetone (300 ml) by heating, and the mixture is allowed to stand overnight at room temperature. The precipitated crystals are separated by filtration, and the filtrate is concentrated under reduced pressure to give S-atenolol toluate having an optical purity of 98.8% ee (5.01 g). by heating The precipitated crystals are separated by filtration the filtrate is concentrated under reduced pressure

反应条件: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: P-Hydroxyphenylacetamide (1 g) and (S)-glycidyl p-toluenesulfonate (1.51 g, 99.3% e.e.) were dissolved in acetone (30 ml). Potassium carbonate (1.19 g) was added to the solution and stirred for 30 hours under refluxing. After the reaction, inorganic materials were filtered off and acetone was removed to give 1.43 g of crude (S)-1-[p-(carbamoylmethyl)phenoxy-2,3-epoxypropane. Then, crude (S)-1-[p-(carbamoylmethyl)phenoxy-2,3-epoxypropane (1.43 g) was dissolved in methanol (8 ml). The solution was dropped in isopropylamine (6.8 g) under cooling to 10° C. over a period of 1 hour and the reaction temperature was raised to room temperature and stirred for 7 hours. After the reaction, the mixture was condensed in vacuo until crystals beginning to separate, cooled, filtrated by suction and dried in vacuo to give crude (S)-atenolol (1.29 g). The optical purity of it was 62.8% e.e. by measurement of Chiral column OD (Daisel Chemical industries Ltd.). the reaction temperature was raised to room temperature After the reaction condensed in vacuo until crystals to separate cooled filtrated by suction dried in vacuo

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: p-Hydroxyphenylacetamide (30.02 g) was dissolved in 106.5 g of water containing sodium hydroxide (9.6 g) and the solution was cooled to 5° C. Epichlorohydrin (18.5 g, 98.9% e.e.) was dropped in the solution over a period of 10 minutes and the mixture was stirred for 24 hours at the same temperature. After confirmation of the progress of the reaction being 98% by HPLC, the reaction mixture was neutralized with 0.1 N hydrochloric acid at the same temperature and then dropped in isopropylamine (240 g) under cooling to 10° C. over a period of 1 hour and the reaction temperature was raised to room temperature and stirred for 3.5 hours. After the reaction, the reaction mixture was condensed in vacuo until crystals beginning to separate, cooled and filtrated by suction and dried in vacuo to give crude (S)-atenolol (51.26 g). The optical purity of it was 91.2% e.e. by measurement of Chiral column OD (Daisel Chemical Industries Ltd.). under cooling to 10° C. over a period of 1 hour the reaction temperature was raised to room temperature stirred for 3.5 hours After the reaction condensed in vacuo until crystals to separate cooled filtrated by suction dried in vacuo