Preparation method for high-enantioselectivity synthesized (S)-omeprazole and salt thereof

Abstract

The invention relates to a preparation method for high-enantioselectivity synthesized (S)-omeprazole. The method comprises under catalysis of a complex formed by chiral alcohol ligand (R)-(+)-1, 1, 2-triphenyl-1, 2, glycol and alkoxy titanium, utilizing an oxidant to a prochiral compound omeprazole thioether to perform selective catalytic oxidation to obtain optically pure enantiomer (S)-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridyl)-methyl] sulfinyl]-1H-benzimidazole ((S)-omeprazole). (S)-omeprazole further reacts with alkali to form salt, and (S)-omeprazole metal salt with medical values is obtained. The preparation method is economical and simple and convenient to operate, optical purity and chemical purity of a product are high, and the preparation method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis medicine preparation, and relates to a method for preparing (S)-omeprazole and its salt with anti-peptic ulcer activity through enantioselective catalytic oxidation. Background technique [0002] The chemical structure of Omeprazole is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfoxide]-1H-benzene Bimidazole is a new class of anti-peptic ulcer drugs and proton pump inhibitors, developed by the Swedish company Astra, listed in Sweden in 1988, is the world's first clinical proton pump inhibitor (proton pump inhibitor, PPI). Because omeprazole has strong acid-suppressing effect, high cure rate, short cure time, can eliminate refractory ulcer crisis, and is safe and reliable, it has become an important drug for gastric and duodenal ulcer and flow esophagitis. It not only became one of the best-selling drugs in the world at that time, but also greatly promoted the development...

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Problems solved by technology

[0015] As can be seen from the above, the method for preparing optically active chiral omeprazole mainly contains: the one is to adopt the method for chiral resolution reagent to resolve racemate omeprazole, but traditional resolution method is very It is difficult to effectively split omeprazole, and this method will waste half of the omeprazole raw material; the second is to use biochemical methods, using biological enzymes to oxidize omeprazole sulfide or to omeprazole Meprazole sulfone is reduced to obtain (S)-omeprazole, but this method requires special experimental equipment and experimental methods, which can only be limited to the laboratory and is difficult to carry out industrialized production; the third is the use of asymmetric oxidation method, this method is convenient and easy to implement compared with the former two, and has obvious advantages

[0016] However, the existing asymmetric oxidation method also has some deficiencies, such as excessive use of chiral ligands (such as WO 9602535, WO 03 / 089408), the reaction requires low temperature (such as CN1810803), reflecting that the enantioselectivity is not high (such as 201010255206.0)

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