Esomeprazole magnesium preparation method

Abstract

The invention discloses an esomeprazole preparation method and an esomeprazole magnesium preparation method. The esomeprazole preparation method is characterized in that a catalytic oxidation of omeprazole sulfide is carried out under the action of an added oxidant in the presence of bidentate chiral aminoalcohol and titanium alkoxide at room temperature to obtain a chiral proton pump inhibitor esomeprazole in a single enantiomer or enriched enantiomer form. The above preparation methods have the advantages of no need of the addition of an alkaline reagent, easy obtaining and reuse of the bidentate chiral aminoalcohol participating in the above reaction, increase of the utilization rate of the chiral aminoalcohol, substitution of expensive D-(-)-diethyl tartrate, and production cost reduction; and the chemical purity and the reaction overall yield of the prepared esomeprazole magnesium reach 99.7% and 66% respectively.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a new preparation method of esomeprazole magnesium. Background technique [0002] Esomeprazole magnesium, chemical name bis-S-5-methoxy-2{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl] Sulfinamido}-1H-benzimidazole magnesium hydrate, which is a dihydrate in the present invention, molecular formula: (C 17 h 18 N 3 o 3 S) 2 Mg 2H 2 O, molecular weight: 749.12, its structural formula is shown in the following general formula 1, which is obtained from omeprazole sulfide (shown in the following general formula 2) through asymmetric oxidation and then salified. [0003] The S-enantiomer of omeprazole, commonly known as esomeprazole, has improved pharmacokinetic properties and improved therapeutic effects such as a lower degree of inter-individual variability (WO94 / 27988). Esomeprazole magnesium is a well-known gastric proton pump inhibitor and has been commercially available from Astra...

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Problems solved by technology

[0006] CN102702172A discloses a kind of taking pyridinemethanol as starting raw material, adopts ultrasonic microwave to coordinate chemical reaction, depressurization reaction, jet drying and other techniques to synthesize nano esomeprazole sodium. A series of reactions of this invention require strict experimental conditions. The requirements for instruments and equipment are also high, and it is not suitable for large-scale industrial production

[0008] CN102603261A invented a kind of raw material (((4-methoxy-3,5-dimethylpyridin-2-yl) methyl) sulfinyl) ethyl thioformate obtained by self-provided oxidant (S) -(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)ethyl thioformate and 4-methoxy o-diphenylamine reflux reaction target product , the raw materials selected by this method are not easy to obtain, and there are many steps, so it is not suitable for industrial production

Among them, (S)-binaphthol is expensive

[0013] In CN102408412A, a kind of (1R,2S)-1-amino-2-indanol was invented to replace traditional D-(-)-diethyl tartrate, acetonitrile was used as solvent, and 4-methyl-2-indanol was used for product post-treatment. Pentanone, the yield is low, acetonitrile is more toxic, and 4-methyl-2-pentanone increases the production cost, so it is not suitable for industrial production

[0014] CN1810803A invented a (R,R) or (S,S)-1,2-diaryl-1,2-diol compound (especially (R,R) or (S,S)-1, 2-bis(2-bromo-phenyl)-1,2-diol) and metal titanium reagent in the presence of oxidant tert-butyl hydroperoxide, selective catalytic oxidation of omeprazole sulfide, but the chemical purity is not reached Pharmacopoeia requirements, and the cost of the chiral bidentate ligand is high, and the toxic solvent toluene is used in the reaction

[0015] WO9427988, WO04/002982 mentioned the method of adopting chiral resolution reagent to resolve racemic omeprazole, but traditional resolution methods are difficult to effectively resolve

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