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...

AI Technical Summary

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 omeprazole free base, and This method wastes too much raw material

[0016] In WO9617076 and WO9617077, it is mentioned that omeprazole sulfide is oxidized or omeprazole sulfone is reduced by biological enzymes to obtain a single enantiomer of omeprazole, but the initial investment in industrial production of this method is relatively large

[0017] CN101012141A discloses a method for obtaining esomeprazole by catalytic oxidation of omeprazole sulfide in the presence of chiral amino alcohol and alkoxy zirconium or alkoxy titanium compound, wherein the chiral amino alcohol is S-2- Aminopropanol, S-2-Amino-1-butanol, S-3-Amino-1-butanol, S-Phenylglycine, S-Phenylalaninol, S-Leucinol, S-Glycine Alcohol, S-Methioninol, S-Tryptophanol, S-Aspartanol, S-Arginine, S-Prolinol, S-Valinol, S-Isoleucinol, S-Serine Alcohol, S-hydroxyprolinol, S-threoninol, S-arginine alcohol, the method yield is low

[0018] In CN101070315A, a kind of omeprazole racemate was synthesized by using 1-hydroxyl-1,2-phenyliodyl-3(1hydrogen)-ketone-1-oxide as oxidant and quaternary ammonium compound as catalyst. Unsolved problem of obtaining single enantiomer esomeprazole

But still not solve the problem of toxic solvent toluene

[0021] In WO2010043601, in the presence of complex metal complexes and hydrogen peroxide, esomeprazole salt is obtained in the solvent acetonitrile, but the chemical purity is not high

[0022] In WO2011120475, derivatives of S-mandelic acid were used and in WO2007074099, 1,1,2-triphenyl-1,2-diol was used instead of D-(-)-diethyl tartrate. The products had high chemical purity, but the yield It is very low, and the post-treatment also requires column chromatography to purify the crude product, which is complicated to operate and increases the production cost

[0023] The synthesis method mentioned in WO2011012957 is also a traditional esomeprazole, but the experimental conditions are harsh and nitrogen protection reaction is required

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