(S)-(+)-2-氯-1-苯乙醇

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

实验步骤: Sixteen grammes of enzyme (produced by Amano pharmaceutical Co. Ltd., Lipase "Amano CES"), 7.9g (0.05mol) of (R,S)-2-chloro-1-phenylethanol and 17.8g (0.059mol) of tributyrin were charged into three-necked flask and reacted with stirring for 16days at 35° C. After the reaction was stopped, the enzyme was removed by filtration, the filtrate was concentrated by distillation under reduced pressure, and the desired compounds were isolated by column chromatography. As the result, 4.0g of (R)-2-chloro-1-phenylethanol (yield: 50%, 58% ee) and (S)-2-chloro-1-phenylethyl butyrate were obtained. The obtained (S)-2-chloro-1-phenylethyl butyrate was hydrolyzed in an acidic solution of hydro chloric acid, and (S)-2-chloro-1-phenylethanol (yield: 23%, >99% ee) was obtained. Optical purity of the obtained compounds was determined by HPLC of optical resolution.

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

实验步骤: Sixteen grammes of enzyme (produced by Amano pharmaceutical Co. Ltd., Lipase "Amano CES"), 7.9g (0.05mol) of (R,S)-2-chloro-1-phenylethanol and 17.8g (0.059mol) of tributyrin were charged into three-necked flask and reacted with stirring for 16days at 35° C. After the reaction was stopped, the enzyme was removed by filtration, the filtrate was concentrated by distillation under reduced pressure, and the desired compounds were isolated by column chromatography. As the result, 4.0g of (R)-2-chloro-1-phenylethanol (yield: 50%, 58% ee) and (S)-2-chloro-1-phenylethyl butyrate were obtained. The obtained (S)-2-chloro-1-phenylethyl butyrate was hydrolyzed in an acidic solution of hydro chloric acid, and (S)-2-chloro-1-phenylethanol (yield: 23%, >99% ee) was obtained. Optical purity of the obtained compounds was determined by HPLC of optical resolution.

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

实验步骤: 4-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-1-(4-hydroxy-3-methoxy-phenyl)-ethylamino]-benzonitrile (1 g, 2.43 mmoles) was dissolved in tetrahydrofuran (30 ml) and triphenylphosphine (1.27 g, 4.84 mmoles), (S)-2-chloro-1-phenyl-ethanol (1.13 g, 7.26 mmoles) added. The reaction was cooled to 0° C. and diethylazodicarboxylate (0.842 g, 4.8 mmoles) added. The reaction temperature was allowed to come to room temperature and the reaction stirred for 2.5 hours. The solvent was removed in vacuo and the residue taken up in ethyl acetate, washed with 0.5 N sodium hydroxide several times, washed once with brine and dried over anhydrous sodium sulfate. The crude product was purified by flash chromatography on silica gel (30% ethyl acetate in hexanes) to yield 1.1 g of 4-[1-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile, (82%). to come to room temperature The solvent was removed in vacuo washed with 0.5 N sodium hydroxide several times washed once with brine dried over anhydrous sodium sulfate The crude product was purified by flash chromatography on silica gel (30% ethyl acetate in hexanes)

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

实验步骤: 4-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-1-(4-hydroxy-3-methoxy-phenyl)-ethylamino]-benzonitrile (1 g, 2.43 mmoles) was dissolved in tetrahydrofuran (30 ml) and triphenylphosphine (1.27 g, 4.84 mmoles), (S)-2-chloro-1-phenyl-ethanol (1.13 g, 7.26 mmoles) added. The reaction was cooled to 0° C. and diethylazodicarboxylate (0.842 g, 4.8 mmoles) added. The reaction temperature was allowed to come to room temperature and the reaction stirred for 2.5 hours. The solvent was removed in vacuo and the residue taken up in ethyl acetate, washed with 0.5 N sodium hydroxide several times, washed once with brine and dried over anhydrous sodium sulfate. The crude product was purified by flash chromatography on silica gel (30% ethyl acetate in hexanes) to yield 1.1 g of 4-[1-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile, (82%). to come to room temperature The solvent was removed in vacuo washed with 0.5 N sodium hydroxide several times washed once with brine dried over anhydrous sodium sulfate The crude product was purified by flash chromatography on silica gel (30% ethyl acetate in hexanes)

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a slurry solution of 143 mg (0.5 mmol) of (R)-1,1′-bi-2-naphthol in 10 ml of toluene was added 102 mg (0.5 mmol) of aluminum triisopropoxide at room temperature, and the mixture was stirred at room temperature for 20 minutes and further at 50° C. for 1 hour. Thereto 1.52 ml (20 mmol) of 2-propanol was added and the mixture was stirred further at room temperature for 30 minutes. Thereto 1.55 g (10 mmol) of phenacyl chloride was added and the mixture was further stirred at 50° C. for 4 hours. To the mixture were added 2 ml of 1N hydrochloric acid and 20 ml of water to conduct hydrolysis. The mixture was extracted with ethyl acetate and concentrated to obtain an oily product. The after-treatment and the analysis of the product were then carried out in the same manner as described in Example 2. the mixture was stirred further at room temperature for 30 minutes the mixture was further stirred at 50° C. for 4 hours hydrolysis The mixture was extracted with ethyl acetate concentrated to obtain an oily product

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a slurry solution of 143 mg (0.5 mmol) of (R)-1,1′-bi-2-naphthol in 10 ml of toluene was added 102 mg (0.5 mmol) of aluminum triisopropoxide at room temperature, and the mixture was stirred at room temperature for 20 minutes and further at 50° C. for 1 hour. Thereto 1.52 ml (20 mmol) of 2-propanol was added and the mixture was stirred further at room temperature for 30 minutes. Thereto 1.55 g (10 mmol) of phenacyl chloride was added and the mixture was further stirred at 50° C. for 4 hours. To the mixture were added 2 ml of 1N hydrochloric acid and 20 ml of water to conduct hydrolysis. The mixture was extracted with ethyl acetate and concentrated to obtain an oily product. The after-treatment and the analysis of the product were then carried out in the same manner as described in Example 2. the mixture was stirred further at room temperature for 30 minutes the mixture was further stirred at 50° C. for 4 hours hydrolysis The mixture was extracted with ethyl acetate concentrated to obtain an oily product

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

实验步骤: To a slurry solution of 143 mg (0.5 mmol) of (R)-1,1′-bi-2-naphthol in 10 ml of toluene was added 0.5 ml (0.5 mmol) of toluene solution of diisobutylaluminum hydride (1.0 M) at room temperature, and the mixture was stirred at room temperature for 1 hour. Thereto 1.52 ml (20 mmol) of 2-propanol was added and the mixture was stirred further at room temperature for 30 minutes. Thereto 1.55 g (10 mmol) of phenacyl chloride was added and the mixture was stirred at 50° C. for 4 hours. To the mixture were added 6 ml of 1N hydrochloric acid and 20 ml of water to conduct hydrolysis. The mixture was extracted with ethyl acetate and concentrated to obtain an oily product. The after-treatment and the analysis of the product were then carried out in the same manner as described in Example 2. the mixture was stirred further at room temperature for 30 minutes the mixture was stirred at 50° C. for 4 hours hydrolysis The mixture was extracted with ethyl acetate concentrated to obtain an oily product

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

实验步骤: To 0.5 ml (0.5 mmol) of hexane solution of triisobutylaluminum (1.0 M) was added a slurry solution of 143 mg (0.5 mmol) of (R)-1,1′-bi-2-naphthol in 10 ml of toluene at room temperature, and the mixture was stirred at room temperature for 30 minutes. Thereto 1.84 g (20 mmol) of benzhydrol was added and the mixture was stirred further at room temperature for 30 minutes. Thereto 1.55 g (10 mmol) of phenacyl chloride was added and the mixture was stirred further at room temperature for 2 hours. The after-treatment and the analysis of the product were then carried out in the same manner as described in Example 2. the mixture was stirred further at room temperature for 30 minutes the mixture was stirred further at room temperature for 2 hours

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

实验步骤: To 0.5 ml (0.5 mmol) of hexane solution of triisobutylaluminum (1.0 M) was added a slurry solution of 143 mg (0.5 mmol) of (R)-1,1′-bi-2-naphthol in 10 ml of toluene at room temperature, and the mixture was stirred at room temperature for 30 minutes. Thereto 1.84 g (20 mmol) of benzhydrol was added and the mixture was stirred further at room temperature for 30 minutes. Thereto 1.55 g (10 mmol) of phenacyl chloride was added and the mixture was stirred further at room temperature for 2 hours. The after-treatment and the analysis of the product were then carried out in the same manner as described in Example 2. the mixture was stirred further at room temperature for 30 minutes the mixture was stirred further at room temperature for 2 hours

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: After preparing the reducing agent by the same method as described in Example 1. 1.55 g (10 mmol) of phenacyl chloride was added to the reducing agent and the mixture was stirred at 50° C. for 2 hours. To the mixture were added 2 ml of 1N hydrochloric acid and 20 ml of water to conduct hydrolysis. The mixture was extracted with ethyl acetate and concentrated to obtain an oily product. The obtained oil was analyzed by HPLC. After preparing the reducing agent by the same method hydrolysis The mixture was extracted with ethyl acetate concentrated to obtain an oily product

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 5 mL of DMF are added to a suspension of 60 mg (1.51 mmol) of sodium hydride in 5 mL of DMF. The reaction mixture is heated at 50° C. for 10 minutes. After addition of 142 mg (0.91 mmol) of (S)-2-chloro-1-phenylethanol, the reaction is continued at 90° C. overnight. The reaction medium is evaporated to dryness. The residue is purified by chromatography on a column of silica (eluent: 90/10 DCM/MeOH). The isolated fraction is recrystallized from acetonitrile to give 33 mg of (8S)-9-((S)-2-hydroxy-2-phenylethyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows: The reaction medium is evaporated to dryness The residue is purified by chromatography on a column of silica (eluent: 90/10 DCM/MeOH) The isolated fraction is recrystallized from acetonitrile

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 5 mL of DMF are added to a suspension of 60 mg (1.51 mmol) of sodium hydride in 5 mL of DMF. The reaction mixture is heated at 50° C. for 10 minutes. After addition of 142 mg (0.91 mmol) of (S)-2-chloro-1-phenylethanol, the reaction is continued at 90° C. overnight. The reaction medium is evaporated to dryness. The residue is purified by chromatography on a column of silica (eluent: 90/10 DCM/MeOH). The isolated fraction is recrystallized from acetonitrile to give 33 mg of (8S)-9-((S)-2-hydroxy-2-phenylethyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows: The reaction medium is evaporated to dryness The residue is purified by chromatography on a column of silica (eluent: 90/10 DCM/MeOH) The isolated fraction is recrystallized from acetonitrile