diethyl (2S,3S)-2,3-dihydroxybutanedioate

反応条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.6 kg (5.0 mol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole was dissolved in 5.01 of ethyl acetate. To the solution was added 31 ml (1.7 mol) of water. To the mixture was added 856 ml (5.0 mol) of (-)-diethyl D-tartrate, 744 ml (2.5 mol) of titanium(IV) isopropoxide and 435 ml (2.5 mol) of diisopropylethylamine at room temperature. The addition of 830 ml (4.5 mol) cumene hydroperoxide was then performed at 30° C. After stirring for one hour at 30° C. the reaction was complete. Chiral and achiral chromatographic analyses showed that the mixture consisted of 71.4% sulphoxide with an enantiomeric excess (e.e.) of 72.9%. The mixture was cooled to 10° C. and after addition of 1.7 l of isooctane, the product was extracted three times with an aqueous ammonia (12%) solution with a total volume of 10 l. The combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (3 l). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 l). The solvent of the combined organic solutions was removed and at the end of the evaporation acetonitrile (1.5 l) was added to facilitate the removal of solvent. Acetone (2.5 l ) was added to precipitate the racemate of omeprazole which was filtered off (254 g). HPLC-analyses (achiral and chiral columns) of the filtrate showed that this solution consited of 88% sulphoxide with an optical purity of 96.3% e.e. and thus the optical purity has been improved from 72.9% e.e. to 96.3% e.e. simply by one precipitation of racemic omeprazole. Further, a content analysis (HPLC) of the filtrate showed that the yield was 0.8 kg (46%). The (-)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole was not isolated in its neutral form but further processed to corresponding sodium salt. was then performed at 30° C The mixture was cooled to 10° C. the product was extracted three times with an aqueous ammonia (12%) solution with a total volume of 10 l The combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (3 l) The phases were separated the aqueous phase was extracted with ethyl acetate (3 l) The solvent of the combined organic solutions was removed and at the end of the evaporation acetonitrile (1.5 l) was added the removal of solvent Acetone (2.5 l ) was added to precipitate the racemate of omeprazole which was filtered off (254 g) thus the optical purity has been improved from 72.9% e.e. to 96.3% e.e. simply by one precipitation of racemic omeprazole

反応条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.6 kg (5.0 mol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole was dissolved in 5.01 of ethyl acetate. To the solution was added 31 ml (1.7 mol) of water. To the mixture was added 856 ml (5.0 mol) of (-)-diethyl D-tartrate, 744 ml (2.5 mol) of titanium(IV) isopropoxide and 435 ml (2.5 mol) of diisopropylethylamine at room temperature. The addition of 830 ml (4.5 mol) cumene hydroperoxide was then performed at 30° C. After stirring for one hour at 30° C. the reaction was complete. Chiral and achiral chromatographic analyses showed that the mixture consisted of 71.4% sulphoxide with an enantiomeric excess (e.e.) of 72.9%. The mixture was cooled to 10° C. and after addition of 1.7 l of isooctane, the product was extracted three times with an aqueous ammonia (12%) solution with a total volume of 10 l. The combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (3 l). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 l). The solvent of the combined organic solutions was removed and at the end of the evaporation acetonitrile (1.5 l) was added to facilitate the removal of solvent. Acetone (2.5 l ) was added to precipitate the racemate of omeprazole which was filtered off (254 g). HPLC-analyses (achiral and chiral columns) of the filtrate showed that this solution consited of 88% sulphoxide with an optical purity of 96.3% e.e. and thus the optical purity has been improved from 72.9% e.e. to 96.3% e.e. simply by one precipitation of racemic omeprazole. Further, a content analysis (HPLC) of the filtrate showed that the yield was 0.8 kg (46%). The (-)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole was not isolated in its neutral form but further processed to corresponding sodium salt. was then performed at 30° C The mixture was cooled to 10° C. the product was extracted three times with an aqueous ammonia (12%) solution with a total volume of 10 l The combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (3 l) The phases were separated the aqueous phase was extracted with ethyl acetate (3 l) The solvent of the combined organic solutions was removed and at the end of the evaporation acetonitrile (1.5 l) was added the removal of solvent Acetone (2.5 l ) was added to precipitate the racemate of omeprazole which was filtered off (254 g) thus the optical purity has been improved from 72.9% e.e. to 96.3% e.e. simply by one precipitation of racemic omeprazole

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

実験手順: 1.2 g (3.6 mmol) of 2-{[(4-chloro-3,5-dimethyl-2-pyridinyl)methyl]thio}-5-methoxy-1H-benzimidazole was mixed with toluene (40 mL). The mixture was concentrated until half the volume was left. Water (38 mg, 2.1 mmol), (S,S)-diethyl tartrate (1.85 g, 9.0 mmol) and titanium tetraisopropoxide (1.0 g, 3.6 mmol) were added in the given order while stirring. The mixture was then stirred at 50° C. for an hour and then N,N-diisopropylethylamine (0.46 g, 3.6 mmol) was added at room temperature. After 15 minutes cumene hydroperoxide (80% in cumene, 0.69 g, 3.6 mmol) was added dropwise and stirring was then continued for 2 h at room temperature. The optical purity of crude sulfoxide turned out to be 75% ee as determined by chiral HPLC analysis of the solution. The mixture was washed with water and then evaporated. The product was purified by chromatography on silica gel using methanol/dichloromethane as eluent (gradient, 1-7% MeOH) and this afforded 1.0 g of a crude product as a solid. Recrystallisation from hot acetonitrile gave 0.35 g of a white solid with an enantiomeric excess of 51%. Next, the mother liqueur from the filtration was concentrated and this material was then also recrystallised from acetonitrile to give 0.35 g of the title compound as a crystalline product with an enantiomeric excess of 92.5%. The mixture was concentrated until half the volume was left The mixture was then stirred at 50° C. for an hour stirring The mixture was washed with water evaporated The product was purified by chromatography on silica gel Recrystallisation from hot acetonitrile

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

実験手順: A 250-mL oven dried three necked round bottomed flask was equipped with a magnetic stir bar, argon inlet, and temperature probe charged with oven dried powdered molecular sieves 4A° (9.0 g). DCM (30 mL) was added to the flask and the resulting suspension was stirred room temperature for 5 minutes. Diethyl D-tartrate (2.13 g, 10.32 mmol) in DCM (18 mL) was added at room temperature and the mixture was cooled to −30° C. Keeping the temperature at −30° C., titanium (IV) isopropoxide (2.665 mL, 9.03 mmol) was added. The reaction mixture was stirred at −30° C. for 30 minutes followed by 15 minutes at −15° C. The mixture was cooled to −30° C. To this mixture, a solution of compound 16 (4.5 g, 12.9 mmol) in DCM (18 mL) was added. The mixture was stirred for 30 minutes at −30° C. followed by addition of a solution of tert-butyl hydroperoxide (5.0–6.0 M; 9.40 mL, 5.176 mmol). The reaction mixture was stirred between −30° C. to −20° C. for 3 hours to complete the reaction. The reaction was quenched by addition of water (45 mL). The reaction mixture was stirred with vigorous mixing and allowed to warm up to room temperature (15 to 20° C). When the temperature reached ˜15° C., 30% sodium hydroxide solution (10 mL) was added slowly to give a milky white slurry. This slurry was added into a 3.0-L Erlenmeyer flask containing tert-butyl methyl ether (1100 mL). The mixture was stirred for 30 minutes and then filtered on a bed of diatomaceous earth (Celite®). The aqueous layer was separated from the filtrate and discarded. The organic layer was washed with 10% aqueous sodium thiosulfate (100 mL) and water (2×160 mL). The combined organic layer was washed with water (100 mL), brine (50 mL), and dried over magnesium sulfate. The organic layer was concentrated in vacuo to give the title compound in quantitative yield (5.47 g) as an oil. A 250-mL oven dried three necked round bottomed flask was equipped with a magnetic stir bar, argon inlet temperature probe charged with oven dried DCM (30 mL) was added to the flask the mixture was cooled to −30° C at −30° C. The reaction mixture was stirred at −30° C. for 30 minutes followed by 15 minutes at −15° C The mixture was cooled to −30° C The mixture was stirred for 30 minutes at −30° C. The reaction mixture was stirred between −30° C. to −20° C. for 3 hours the reaction The reaction was quenched by addition of water (45 mL) The reaction mixture was stirred with vigorous mixing to warm up to room temperature (15 to 20° C) reached ˜15° C. 30% sodium hydroxide solution (10 mL) was added slowly to give a milky white slurry This slurry was added into a 3.0-L Erlenmeyer flask The mixture was stirred for 30 minutes filtered on a bed of diatomaceous earth (Celite®) The aqueous layer was separated from the filtrate The organic layer was washed with 10% aqueous sodium thiosulfate (100 mL) and water (2×160 mL) The combined organic layer was washed with water (100 mL), brine (50 mL) dried over magnesium sulfate The organic layer was concentrated in vacuo

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

実験手順: To titanium tetraisopropoxide (1.49 ml) in dichloromethane (50 ml) were added diethyl (S,S)-tartrate (1.71 ml) and water (90 μl), and the mixture was stirred at room temperature for 20 minutes. After 1-methoxy-4-(methylthio)benzene (0.69 ml) was dropwise added, the reaction mixture was cooled to -20° C., dropwise added with 3.07M t-butylhydroperoxide-toluene solution (1.8 ml), and stirred at -20° C. for 15 hours. Water (0.9 ml) was added, and the mixture was stirred at -20° C. for 1 hour, and then at room temperature for 1 hour. A small amount of alumina was added, and the reaction mixture was suction-filtered with celite and washed well with dichloromethane. The filtrate and the washing were combined, added with 5% sodium hydroxide-saturated brine and stirred at room temperature for 1 hour. The organic layer was separated, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluate; ethyl acetate), and the residue (730 mg) was recrystallized from ether-pentane to give 586 mg of the title compound, [α]D -103° C. (c=1.98, acetone). the reaction mixture was cooled to -20° C. stirred at -20° C. for 15 hours the mixture was stirred at -20° C. for 1 hour at room temperature for 1 hour A small amount of alumina was added the reaction mixture was suction-filtered with celite washed well with dichloromethane added with 5% sodium hydroxide-saturated brine stirred at room temperature for 1 hour The organic layer was separated dried over magnesium sulfate concentrated The residue was purified by silica gel column chromatography (eluate; ethyl acetate) the residue (730 mg) was recrystallized from ether-pentane

反応条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.6 kg (5.0 mol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole was dissolved in 5.01 of ethyl acetate. To the solution was added 31 ml (1.7 mol) of water. To the mixture was added 856 ml (5.0 mol) of (-)-diethyl D-tartrate, 744 ml (2.5 mol) of titanium(IV) isopropoxide and 435 ml (2.5 mol) of diisopropylethylamine at room temperature. The addition of 830 ml (4.5 mol) cumene hydroperoxide was then performed at 30° C. After stirring for one hour at 30° C. the reaction was complete. Chiral and achiral chromatographic analyses showed that the mixture consisted of 71.4% sulphoxide with an enantiomeric excess (e.e.) of 72.9%. The mixture was cooled to 10° C. and after addition of 1.7 l of isooctane, the product was extracted three times with an aqueous ammonia (12%) solution with a total volume of 10 l. The combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (3 l). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 l). The solvent of the combined organic solutions was removed and at the end of the evaporation acetonitrile (1.5 l) was added to facilitate the removal of solvent. Acetone (2.5 l ) was added to precipitate the racemate of omeprazole which was filtered off (254 g). HPLC-analyses (achiral and chiral columns) of the filtrate showed that this solution consited of 88% sulphoxide with an optical purity of 96.3% e.e. and thus the optical purity has been improved from 72.9% e.e. to 96.3% e.e. simply by one precipitation of racemic omeprazole. Further, a content analysis (HPLC) of the filtrate showed that the yield was 0.8 kg (46%). The (-)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole was not isolated in its neutral form but further processed to corresponding sodium salt. was then performed at 30° C The mixture was cooled to 10° C. the product was extracted three times with an aqueous ammonia (12%) solution with a total volume of 10 l The combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (3 l) The phases were separated the aqueous phase was extracted with ethyl acetate (3 l) The solvent of the combined organic solutions was removed and at the end of the evaporation acetonitrile (1.5 l) was added the removal of solvent Acetone (2.5 l ) was added to precipitate the racemate of omeprazole which was filtered off (254 g) thus the optical purity has been improved from 72.9% e.e. to 96.3% e.e. simply by one precipitation of racemic omeprazole