Water → Omeprazole

Beteiligte Stoffe

Reaktionsbedingungen

Reaktionsschritte

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.

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