Asymmetric oxidation synthesis method of zirconium-catalyzed dexlansoprazole

Abstract

The invention discloses an asymmetric oxidation synthesis method of zirconium-catalyzed dexlansoprazole. In an organic solvent, a zirconium catalyst and a ligand of the zirconium catalyst have a complex reaction in the presence of a 4A molecular sieve, then a product is mixed with cumyl hydroperoxide in a certain proportion, and 2-[[[3-methyl-4-(2,2,2 trifluoroethoxy)-2-pyridyl]methyl]thio]-1H-benzimidazole is oxidized at the low temperature for synthesis of the dexlansoprazole. The enantiomer excess value of the dexlansoprazole synthesized with the method is higher than 99.3%, the yield is higher than 82%, and the method is good in process stability and high in enantioselectivity and has the bright industrial production prospect.

Description

technical field [0001] The invention belongs to the application field of chemical synthesis, and in particular relates to a zirconium-catalyzed asymmetric oxidation synthesis method of D-lansoprazole. Background technique [0002] Dexlansoprazole (dexlansoprazole) is a new generation of proton pump inhibitors developed by Takeda Corporation of Japan. The chemical name is 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1Hbenzimidazole, which can efficiently rapid inhibition of H + / K + -ATPase, so as to achieve the effect of inhibiting gastric acid secretion, it is mainly used clinically to treat heartburn and different degrees of erosive esophagitis associated with non-erosive gastroesophageal reflux disease. Its biphasic controlled-release capsules were approved by the US FDA in 2009, under the trade name: Dexliant TM . [0003] The synthetic method of existing dexlansoprazole mainly is divided into two kinds: (1). Chiral resolution: chiral reagent i...

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Problems solved by technology

[0003] The synthetic method of existing dexlansoprazole mainly is divided into two kinds: (1). Chiral resolution: chiral reagent is relatively expensive in the traditional chiral resolution method, and the dexlansoprazole obtained after the resolution Larazole cannot be reused, resulting in waste of raw materials. Patent DE403545 describes a method for selective nitrogen derivatization of lansoprazole, by introducing a new chiral center in the molecule, so that the original racemate is separated , and then the newly introduced chiral group is dissociated to obtain dexlansoprazole. This method needs to use two-step reactions, the process is more complicated and the yield is not high, and it is not suitable for industrial production; (2). Asymmetric oxidation Patent CN102558151 discloses a kind of application of trivalent iodine ligand in the synthetic chiral sulfoxide compound, it comprises the method for synthesizing dexlansoprazole with trivalent iodine ligand, trivalent iodine ligand is synthetic loaded down with trivial details in the method , and the more toxic chloroform is used as the reaction solvent; patent WO9208716 uses a chiral titanium complex and an organic base to obtain a chiral sulfoxide structure through hydrogen peroxide derivatives, but the post-treatment is cumbersome and requires A large amount of irritating ammonia extraction is used; other patents such as CN103113351, CN102558150, CN102977076, CN103694225, etc. report that the various chiral alcohols or chiral amine ligands of titanium salts used are relatively expensive, some of which The dosage is more than 1.5 times that of sulfide, which is not suitable for industrial production

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