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Method for antipodal selective synthesis of (R)-lansoprazole

A technology of dexlansoprazole and enantioselectivity, which is applied in the field of chemical synthesis drug preparation, can solve the problems of low optical purity of sulfoxide, difficult removal of sulfone, and increased post-processing difficulty, etc., to achieve optical purity and chemical purity of the product High, easy-to-operate effect

Inactive Publication Date: 2014-12-03
SHANGHAI HUILUN BIOLOGICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And use too much oxidizing agent can increase aftertreatment difficulty, more important is uneconomical environmental protection, because the oxidizing agent hydroperoxide of this disclosure has moderate toxicity
[0009] It can be seen from the above that the traditional asymmetric method has some shortcomings: for example, the optical purity of the sulfoxide produced by the reaction is not high, and more sulfones are generated that are difficult to remove; or too many toxic oxidants are required, which is not economical and environmentally friendly.

Method used

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  • Method for antipodal selective synthesis of (R)-lansoprazole
  • Method for antipodal selective synthesis of (R)-lansoprazole
  • Method for antipodal selective synthesis of (R)-lansoprazole

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Experimental program
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Embodiment 1

[0037] The preparation of embodiment 1 dexlansoprazole

[0038] In a 20L reactor, lansoprazole sulfide (1.77kg, 5.0mol) was suspended in toluene (8.8L), and L-(+)-diethyl tartrate (412g, 2.0mol) and water (9.0g, 0.5mol), heated at 50-60°C for 30 minutes. Tetraisopropyl titanate (284 g, 1.0 mol) was added dropwise, and the reaction was continued at 55-60°C for 50 minutes. Stop heating, cool to below 30°C, add diisopropylethylamine (194g, 1.5mol), continue cooling to below 10°C, then slowly add cumene hydroperoxide (78%, 1.37kg, 7.0mol ), react at 13-18°C for 3 hours. According to chromatographic analysis, sulfide is 1.6%, sulfone is 1.4%, sulfoxide is 96.8%, and ee value is 97.5%.

[0039] Na for system 2 S 2 o 3 Aqueous solution (30%, 3 L) was quenched and the layers were separated. Transfer the organic layer into a 50L reaction kettle, add water (1.7L), n-heptane (5.3L), tert-butyl methyl ether (7.0L), n-heptane (10.6L) dropwise at room temperature, and use Lower the ...

Embodiment 2

[0040] The preparation of embodiment 2 dexlansoprazole

[0041] In a 500mL three-necked flask, suspend lansoprazole sulfide (35.3g, 100mmol) in toluene (180mL), add L-(+)-diethyl tartrate (12.4g, 60mmol) and water (0.29g, 16mmol) , Heat the reaction at 50-60°C for 30 minutes. Tetraisopropyl titanate (5.7 g, 20 mmol) was added dropwise, and the reaction was continued under heating at 55-60°C for 1 hour. Stop heating, cool to below 30°C, add diisopropylethylamine (3.9g, 30mmol), continue cooling to below 10°C, then slowly add cumene hydroperoxide (78%, 25.4g, 130mmol) dropwise , 15-25°C for 3 hours. According to chromatographic analysis, sulfide is 1.9%, sulfone is 1.6%, sulfoxide is 96.2%, and ee value is 96.5%.

[0042] Refer to Example 1 for subsequent steps.

Embodiment 3

[0043] The preparation of embodiment 3 dexlansoprazole

[0044] In a 500mL three-necked flask, lansoprazole sulfide (35.3g, 100mmol) was suspended in toluene (180mL), added L-diisopropyl tartrate (10.3g, 50mmol) and water (0.15g, 8mmol), 50- The reaction was heated at 60°C for 30 minutes. Tetraisopropyl titanate (5.7 g, 20 mmol) was added dropwise, and the reaction was continued at 55-60° C. for 50 minutes. Stop heating, cool to below 30°C, add diisopropylethylamine (3.9g, 30mmol), continue cooling to 5°C, then slowly add cumene hydroperoxide (78%, 29.3g, 150mmol) dropwise, React at 10-15°C for 3 hours. According to chromatographic analysis, sulfide 1.5%, sulfone 1.5%, sulfoxide 96.5%, ee value 96.8%.

[0045] Refer to Example 1 for subsequent steps.

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Abstract

The invention relates to a preparation method for efficient synthesis of (R)-lansoprazole, and according to the method, in the presence of an asymmetric induction catalyst, an oxidant with 1.3 to 1.5 times molar equivalent relative to prochiral compound lansoprazole thioether is used for selective catalytic oxidation to obtain the (R)-lansoprazole. The method has the advantages of being economic, environmentally friendly, high efficiency, high in optical purity and high in chemical purity of products, and is a method 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 dexlansoprazole with anti-peptic ulcer activity by enantioselective catalytic oxidation. Background technique [0002] Dexlansoprazole (dexlansoprazole) is the dextrorotatory form of lansoprazole, the chemical name is (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy) -2-pyridyl]methyl]sulfinyl]-1H-benzimidazole, its structure is shown in formula (I): [0003] [0004] Dexlansoprazole controlled-release capsules are produced by Takeda Pharmaceutical North America, and were approved by the US FDA in 2009. Dexlansoprazole Controlled-Release Capsules is the first PPI designed to provide dual controlled-release (DDR) in 2 doses, once daily for the treatment of patients with non-erosive gastroesophageal reflux disease (GERD) Heartburn, erosive esophagitis and maintenance treatment of erosive esophagus have a good market prospect. [...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 李文华秦继红
Owner SHANGHAI HUILUN BIOLOGICAL TECH CO LTD
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