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Asymmetric oxidation method for dexlansoprazole

An asymmetric and oxidant technology, applied in the direction of asymmetric synthesis, organic chemical methods, chemical instruments and methods, etc., can solve the problems of cumbersome operation and unrecoverable solvents, so as to avoid excessive oxidation, simplify the post-reaction treatment process, and reduce costs Effect

Inactive Publication Date: 2015-05-13
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The method is cumbersome to operate and the solvent cannot be recovered

Method used

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  • Asymmetric oxidation method for dexlansoprazole
  • Asymmetric oxidation method for dexlansoprazole
  • Asymmetric oxidation method for dexlansoprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Post-reaction treatment of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H-benzimidazole

[0031] At 20°C, 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridine]methylsulfanyl-1H-benzimidazole (30g) / 300ml toluene (Industrial grade) into a dry and clean 1000ml four-necked round bottom flask. Add 25.3g of L-(+)-diethyl tartrate / 16.3g of tetraisopropyl titanate, 7.4g of N,N-diisopropylethylamine, and 21.0g of cumene hydroperoxide to react, and take samples to monitor the reaction. After completion of the reaction, add 96g of 30% Na in the system 2 S 2 o 3 The solution quenched the reaction. Separate the layers to obtain the toluene phase. At 15°C, extract with 10% diethylamine solution (285ml×3), combine the aqueous phase, add 22.5g of acetone to the aqueous phase, and stir for 15min. At 15°C, use 20% acetic acid solution to adjust the pH to about 7, and continue stirring for 2 h. Suction filtration and drying to obtain 2-[[3-methyl-4-(2,...

Embodiment 2

[0032] Example 2 Post-reaction treatment of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H-benzimidazole

[0033] At 20°C, 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridine]methylsulfanyl-1H-benzimidazole (30g) / 300ml toluene (Industrial grade) into a dry and clean 1000ml four-necked round bottom flask. Add 25.3g of L-(+)-diethyl tartrate / 16.3g of tetraisopropyl titanate, 7.4g of N,N-diisopropylethylamine, and 21.0g of cumene hydroperoxide to react, and take samples to monitor the reaction. After completion of the reaction, add 96g of 30% Na in the system 2 S 2 o 3 The solution quenched the reaction. Separate the layers to obtain the toluene phase. At 15°C, 30% diethylamine solution was used for extraction (285ml×3). Combine the water phases, add 22.5 g of acetone to the water phase, and stir for 15 min. At 15°C, adjust the pH to about 7 with 20% acetic acid solution. The reaction continued to stir for 2h. Suction filtration and drying to obtain ...

Embodiment 3

[0034] Example 3 Post-reaction treatment of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H-benzimidazole

[0035]At 20°C, 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridine]methylsulfanyl-1H-benzimidazole (30g) / 300ml toluene (Industrial grade) into a dry and clean 1000ml four-necked round bottom flask. Add 25.3g of L-(+)-diethyl tartrate / 16.3g of tetraisopropyl titanate, 7.4g of N,N-diisopropylethylamine, and 21.0g of cumene hydroperoxide to react, and take samples to monitor the reaction. After completion of the reaction, add 245g 20% ​​Na in the system 2 S 2 o 3 The solution quenched the reaction, and the layers were separated. The obtained toluene phase was separated and extracted with 8% diethylamine solution (470ml×3). Take the combined aqueous phase and measure it by HPLC. Add 37.5 g of acetone to the water phase, and after cooling the system to 15° C., add 20% acetic acid solution to adjust the pH to about 8, and continue stirring for 1 h. S...

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Abstract

The invention relates to an asymmetric oxidation method for dexlansoprazole. The invention provides a method for producing 2-[[3-methyl-4-(2,2,2-trifluoroethoxyl)pyridine-2-radical]methylsulfinyl]-1H-benzimidazole. The method comprises the step of: in an organic solvent, performing the oxidation reaction on 2-[3-methyl-4-(2,2,2-trifluoroethoxyl)-2-pyridine]methylsulfonyl-1H-benzimidazole and an oxidizing agent under the existence of an asymmetric induction effect catalyst and alkali. The method is characterized in that the quantity of the oxidizing agent is about 1.2-1.4 molar equivalents relative to the 2-[3-methyl-4-(2,2,2-trifluoroethoxyl)-2-pyridine]methylsulfonyl-1H-benzimidazole. According to the production method disclosed by the invention, by controlling the use quantity of the oxidizing agent, raw materials can be completely converted and over oxidation is also avoided, so that target optical rotation sulfoxide derivatives can be effectively and industrially prepared under high yield and in a large scale by the convenient method, meanwhile, quite high enantioselectivty is realized and the quantity of over oxidation byproducts is very small.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an improved asymmetric oxidation reaction of dexlansoprazole and a post-treatment method thereof. Background technique [0002] Dexlansoprazole, whose structure is shown in formula (I), is the new medicine that researches and develops and goes on the market for the treatment of esophagitis by Japanese Takeda Company. Takeda launched the drug in the United States in February 2009. The drug is an enantiomer of the proton pump inhibitor lansoprazole, also known as dexlansoprazole, and is used to treat heartburn and varying degrees of erosive esophagus associated with non-erosive gastroesophageal reflux disease inflammation. [0003] [0004] Patent WO4628098 discloses the preparation method of lansoprazole for the first time, and dexlansoprazole is its R-configuration; Synthetic method is as follows: [0005] [0006] Post-treatment of the oxidation reaction reported in t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07B53/00
CPCC07D401/12C07B53/00
Inventor 李奎左文果黄旺勇
Owner SUNSHINE LAKE PHARM CO LTD
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