Water → Omeprazole

HRID 583546Notes

Reaction equation

HRID 583546 reaction equation
[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.O.C([C@@H]([C@H](C(OCC)=O)O)O)(OCC)=[O:26].C(N(C(C)C)CC)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1>C(OCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(CC(C)(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[O:26])=[N:9][C:5]=2[CH:4]=1

Participants

9

Reactant 5

HCID 962WaterHCID 81531DiisopropylethylamineHCID 6993580Diethyl tartrateHCID 53627471Cumen hydroperoxideHCID 178488125HCID 178488125, compound

Product 1

HCID 4594Omeprazole

Reagents, catalysts & solvents 3

HCID 11026Titanium isopropoxideCatalystHCID 8857Ethyl AcetateSolvent2×HCID 109072,2,4-TrimethylpentaneSolvent

Conditions

Temperature
30 °C

Procedure

1.6 kg (5.0 mol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole was dissolved in 7.51 of ethyl acetate. To the solution was added 31 ml (1.7 mol) water. To the mixture was added 856 ml (5.0 mol) of (+)-diethyl L-tartrate, 744 ml (2.5 mol) of titanium(IV) isopropoxide and 436 ml (2.5 mol) 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 consited of 75% sulphoxide with an enantiomeric excess (e.e.) of 80%. The mixture was cooled to 10° C. and after addition of 1.5 l of isooctane and ethyl acetate (0.5 l), the product was extracted three times with an aqueous ammonia (12%) solution with a total volume of 14 l. The combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (4 l). The phases were separated and the aqueous phase was extracted with ethyl acetate (4 l). The solvent of the combined organic solutions was removed. Acetone (3.0 l) was added to precipitate the racemate of omeprazole which was filtered off. HPLC--analyses (achiral and chiral columns) of the filtrate showed that this solution consisted of 90% sulphoxide with an optical purity of 95% e.e. and thus the optical purity has been improved from 80% e.e. to 95% e.e. simply by one precipitation of racemic omeprazole. Further, a content analysis (HPLC) of the filtrate showed that the yield was 1.0 kg (58%). 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.

Workup

  1. customwas then performed at 30° C
  2. temperatureThe mixture was cooled to 10° C.
  3. extractionthe product was extracted three times with an aqueous ammonia (12%) solution with a total volume of 14 l
  4. additionThe combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (4 l)
  5. customThe phases were separated
  6. extractionthe aqueous phase was extracted with ethyl acetate (4 l)
  7. customThe solvent of the combined organic solutions was removed
  8. additionAcetone (3.0 l) was added
  9. customto precipitate the racemate of omeprazole which
  10. filtrationwas filtered off
  11. customthus the optical purity has been improved from 80% e.e. to 95% e.e. simply by one precipitation of racemic omeprazole

Sources & evidence

ORD record
ord-628bb4d767b548779a96f80c9d6393ad
Source dataset
uspto-grants-1999_07
Patent number
US05929244

Reaction notes

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