(2R)-2-(chloromethyl)oxirane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This reaction is very exothermic so care must be taken if the reaction is scaled up. Acetonitrile (100 mL) and (R)-(−)-epichlorohydrin (47 mL, 55.6 g, 0.60 mol) were added to benzenesulfonamide (20.0 g, 0.127 mol), followed by cesium carbonate (83 g, 0.255 mol). The mixture was heated at reflux for 6 hours with mechanical stirring and then was stirred overnight at room temperature. Water was added (100 mL), the organic phase separated and then concentrated under reduced pressure. The residual oil was chromatographed over silica, eluting with dichloromethane then dichloromethane:ethyl acetate (19:1), to give the sub-title compound as an oil (14.8 g, 43%). The mixture was heated at reflux for 6 hours was stirred overnight at room temperature the organic phase separated concentrated under reduced pressure The residual oil was chromatographed over silica eluting with dichloromethane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Potassium carbonate (414 g) and (R)-(−)-epichlorohydrin (800 mL) were added to a stirred solution of p-cyanophenol (238 g) in 2.0 L MeCN and the reaction mixture was refluxed under an inert atmosphere for 2 h. The hot solution was filtered and the filtrate concentrated, giving a clear oil which was crystallised from di-iso-propyl ether giving the product in 90% yield. the reaction mixture was refluxed under an inert atmosphere for 2 h The hot solution was filtered the filtrate concentrated giving a clear oil which was crystallised from di-iso-propyl ether giving the product in 90% yield

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Alternatively, a mixture of 0.42 g (3.7 mmole) of 2-nitroimidazole, 85 mg (0.62 mole) of anhydrous potassium carbonate, and 5 mL of (R)-(-)-epichlorohydrin is refluxed for 10 minutes then filtered while hot. The filtrate is concentrated and cooled to give a solid. Crystallization from ethanol and further processing as above gives 0.56 g of the product. is refluxed for 10 minutes then filtered while hot The filtrate is concentrated cooled to give a solid Crystallization from ethanol and further processing as

反応条件: temp:250.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 1 L 3-neck round bottom flask, fitted with mechanical stirring, thermocouple and addition funnel, was charged morpholine (91.5 g, 91.5 ml, 1.05 mole, 1.0 eq.) and 200 ml of methanol. The solution was stirred rapidly while adding R-epichlorohydrin (100 g, 84.5 ml, 1.08 mole, 1.03 eq.) from the addition funnel over about 30 minutes. The temperature was monitored and when the pot temperature reached 27° C., the reaction was cooled with an ice water bath. The clear solution was stirred for 18 hours. The reaction was assayed by GC (dilute 5 drops of reaction mixture into 1 ml of ethanol and inject onto a 15 m DB-5 capillary GC column with the following run parameters, Injector 250° C., detector 250° C., initial oven temperature 28° C. warming to 250° C. at 10° C. per minute.) The reaction was complete with less than 3% morpholine remaining. The solution was cooled to 10° C. and a 25 wt. % solution of sodium methoxide in methanol (233 g, 1.08 mole, 247 ml) was added dropwise keeping the temperature less than 15° C. The resulting white slurry was stirred at 10–15° C. for 2 hours and checked by GC using the above conditions. None of the chlorohydrin could be observed. The mixture was concentrated on the rotoevaporator using 50° C. bath and full house vacuum. The resulting mixture was diluted with water (500 ml) and methylene chloride. The phases were separated and the aqueous phase washed with methylene chloride (500 ml). The combined organic layers were dried over sodium sulfate and concentrated to a clear, colorless oil. This provided 145 g, 97% yield of 1,2-epoxy-3-morpholin-4-ylpropane. 1H NMR (400 MHz, DMSO-d6) δ 3.3 (dd, 4H), 3.1 (m, 1H), 2.6 (dd, 1H), 2.5 (dd, 1H), 2.4 (m, 4H), 2.2 (dd, 2H); 13C NMR (100 MHz, DMSO-d6) δ 65.4, 60.1, 53.1, 48.9, 43.4. To 1 L 3-neck round bottom flask, fitted with mechanical stirring thermocouple and addition funnel reached 27° C. the reaction was cooled with an ice water bath The clear solution was stirred for 18 hours dilute with the following run parameters, Injector 250° C. detector 250° C. The solution was cooled to 10° C. the temperature less than 15° C The resulting white slurry was stirred at 10–15° C. for 2 hours The mixture was concentrated on the rotoevaporator using 50° C. The resulting mixture was diluted with water (500 ml) and methylene chloride The phases were separated the aqueous phase washed with methylene chloride (500 ml) The combined organic layers were dried over sodium sulfate concentrated to a clear, colorless oil

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Triethylamine (0.28 ml) was added to a solution of N-hydroxyphthalimide (5.00 g, 30 mmol) and (R)-(−)-epichlorohydrin (2.40 ml, 30.6 mmol) in anhydrous dioxane (10 ml) under nitrogen. The mixture was stirred at 50° C. for 48 h, further (2R)-2-(chloromethyl)oxirane (0.24 ml) and triethylamine (0.28 ml) were added and stirring continued at 50° C. for 24 h. Methanol (10 ml) and further triethylamine (4.27 ml) were added and stirring continued at 50° C. for 2 h. The mixture was evaporated under reduced pressure, the residue dissolved in saturated aqueous sodium bicarbonate solution (100 ml) and extracted with ethyl acetate (6×100 ml). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallised from ethyl acetate to give the sub-title compound (3.4 g). stirring continued at 50° C. for 24 h stirring continued at 50° C. for 2 h The mixture was evaporated under reduced pressure the residue dissolved in saturated aqueous sodium bicarbonate solution (100 ml) extracted with ethyl acetate (6×100 ml) Combined organic extracts were dried over anhydrous magnesium sulfate filtered evaporated under reduced pressure The residue was recrystallised from ethyl acetate

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Triethylamine (0.28 ml) was added to a solution of N-hydroxyphthalimide (5.00 g, 30 mmol) and (R)-(−)-epichlorohydrin (2.40 ml, 30.6 mmol) in anhydrous dioxane (10 ml) under nitrogen. The mixture was stirred at 50° C. for 48 h, further (2R)-2-(chloromethyl)oxirane (0.24 ml) and triethylamine (0.28 ml) were added and stirring continued at 50° C. for 24 h. Methanol (10 ml) and further triethylamine (4.27 ml) were added and stirring continued at 50° C. for 2 h. The mixture was evaporated under reduced pressure, the residue dissolved in saturated aqueous sodium bicarbonate solution (100 ml) and extracted with ethyl acetate (6×100 ml). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallised from ethyl acetate to give the sub-title compound (3.4 g). stirring continued at 50° C. for 24 h stirring continued at 50° C. for 2 h The mixture was evaporated under reduced pressure the residue dissolved in saturated aqueous sodium bicarbonate solution (100 ml) extracted with ethyl acetate (6×100 ml) Combined organic extracts were dried over anhydrous magnesium sulfate filtered evaporated under reduced pressure The residue was recrystallised from ethyl acetate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenol (150 mg, 395 μmol) and (R)-epichlorohydrine (366 mg, 3.95 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at rt for 72 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using heptane:EA 1:1 to give 2-cyclopentyl-4-[5-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-6-methoxy-pyridine (96 mg) as a pale yellow oil; LC-MS**: tR=1.02 min, [M+H]+=436.18. washed with 1 M aq. NaOH solution (20 mL) dried over MgSO4 filtered concentrated The crude product is purified on prep

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenol (150 mg, 395 μmol) and (R)-epichlorohydrine (366 mg, 3.95 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at rt for 72 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using heptane:EA 1:1 to give 2-cyclopentyl-4-[5-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-6-methoxy-pyridine (96 mg) as a pale yellow oil; LC-MS**: tR=1.02 min, [M+H]+=436.18. washed with 1 M aq. NaOH solution (20 mL) dried over MgSO4 filtered concentrated The crude product is purified on prep

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-ethyl-4-{5-[2-(1-ethyl-propyl)-6-methoxy-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenol (355 mg, 931 μmol) and (R)-epichlorohydrine (861 mg, 9.31 mmol) in 3 M aq. NaOH (4 mL) and isopropanol (15 mL) is stirred at rt for 18 h before a second portion of (R)-epichlorohydrine (430 mg, 4.65 mmol) is added. Stirring is continued at rt for 8 h. The mixture is diluted with EA (100 mL) and washed twice with 1 N aq. NaOH solution (2×15 mL) followed by brine (25 mL). The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give 4-[(2S)-3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(1-ethyl-propyl)-6-methoxy-pyridine (272 mg) as a white powder; LC-MS: tR=1.25 min, [M+H]+=438.09. is added washed twice with 1 N aq. NaOH solution (2×15 mL) extract is dried over MgSO4 filtered concentrated The crude product is purified by prep

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-ethyl-4-{5-[2-(1-ethyl-propyl)-6-methoxy-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenol (355 mg, 931 μmol) and (R)-epichlorohydrine (861 mg, 9.31 mmol) in 3 M aq. NaOH (4 mL) and isopropanol (15 mL) is stirred at rt for 18 h before a second portion of (R)-epichlorohydrine (430 mg, 4.65 mmol) is added. Stirring is continued at rt for 8 h. The mixture is diluted with EA (100 mL) and washed twice with 1 N aq. NaOH solution (2×15 mL) followed by brine (25 mL). The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give 4-[(2S)-3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(1-ethyl-propyl)-6-methoxy-pyridine (272 mg) as a white powder; LC-MS: tR=1.25 min, [M+H]+=438.09. is added washed twice with 1 N aq. NaOH solution (2×15 mL) extract is dried over MgSO4 filtered concentrated The crude product is purified by prep

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of the starting phenol derivative (3.12 g) of the following formula: ##STR31## the same R-(-)-epichlorohydrin (4.627 g) as used in Preparation 2, 50 wt. % aqueous sodium hydroxide (0.88 g) and dimethylformamide (30 ml) is heated with stirring at 60° C. for 2.5 hours. The reaction mixture is cooled and distilled under reduced pressure to remove the solvent. The product is purified by silica gel chromatography to give S isomer of glycidyl ether (2.96 g) of the following formula: ##STR32## is heated The reaction mixture is cooled distilled under reduced pressure to remove the solvent The product is purified by silica gel chromatography

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The starting phenol derivative (1.01 g) of the following formula: ##STR29## the same R-(-)-epichlorohydrin (2.01 g) as used in Preparation 2 and benzyltriethylammonium chloride (16 mg) are mixed and heated at 70° C., and thereto is added dropwise 24 wt. % aqueous sodium hydroxide (650 mg). The mixture is stirred at 70° C. for 2 hours. The reaction mixture is cooled to room temperature and extracted three times with chloroform. The extract is dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue is recrystallized from hexane to give S isomer of glycidyl ether (380 mg) of the following formula: ##STR30## are mixed The reaction mixture is cooled to room temperature extracted three times with chloroform The extract is dried over anhydrous magnesium sulfate distilled under reduced pressure to remove the solvent The residue is recrystallized from hexane