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Method for preparing (S)-pantoprazole in high-enantioselectivity way

A technology of pantoprazole and pantoprazole sulfide, which is applied in the field of highly enantioselective preparation of pantoprazole, can solve the problems of cumbersome and troublesome, insufficient chiral purity, cumbersome separation operation, etc.

Active Publication Date: 2012-07-25
GUANGDONG HUANAN PHARMACEUTICAL GROUP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In the above-mentioned open patent of preparing pantoprazole single enantiomer, mainly contain following three kinds of methods: the one, adopt the method for chiral resolution reagent to resolve racemic pantoprazole, and in the resolution process Separation operation is quite loaded down with trivial details, and raw material utilization rate is low (as WO91 / 12221, WO94 / 27988 and WO92 / 08716); The 2nd, adopt the method of biochemistry, use biological enzyme to oxidize pantoprazole sulfide or to pantoprazole The azole sulfone is reduced to obtain the single enantiomer of pantoprazole, but this method requires special experimental equipment and experimental methods, which is relatively too loaded down with trivial details and troubles (such as WO96 / 17076 and WO96 / 17077); the third is to adopt asymmetric Oxidation method, use chiral prosthetic group or catalyzer to prepare the single enantiomer of pantoprazole, this method is convenient and easy (as CN1157614A and CN1717402) with respect to former two
But this method also has obvious defective at present: 1) need a large amount of special organic bases; This has increased the complexity of cost and operation
2) The chiral purity of (S)-pantoprazole obtained is not high enough

Method used

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  • Method for preparing (S)-pantoprazole in high-enantioselectivity way
  • Method for preparing (S)-pantoprazole in high-enantioselectivity way
  • Method for preparing (S)-pantoprazole in high-enantioselectivity way

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Experimental program
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Effect test

Embodiment 1

[0033] Dissolve (1R,2S)-1-amino-2-indanol 0.01mol in 20ml acetonitrile, add Ti(OiPr) under stirring 4(0.005mol), cooled to 15 ° C, stirred for 15 minutes, then added pantoprazole sulfide (0.01mol), then slowly added dropwise cumene hydroperoxide 0.0232mol, continued to react for 3 hours, added to the reaction system 20ml of toluene, stirred for 10min, then added 12.5% ​​ammonia water (50ml×3) and stirred for 20min each, separated the layers, combined the ammonia water layer, then adjusted the pH to 7.5-8 with glacial acetic acid in an ice-water bath, and then added ethyl acetate (50ml × 3) extraction, combined organic layers, then distilled off ethyl acetate, the obtained (S)-pantoprazole free body was dissolved with 3ml of ethyl acetate, then added dropwise with 3ml petroleum ether and stirred, filtered, below 40°C After vacuum drying, 2.40 g of (S)-pantoprazole was obtained after purification. Yield: 62.66%; Ee (%): 100%; see relevant graph Figure 1 to Figure 5 .

[0034...

Embodiment 2

[0036] (1R,2S)-1-Amino-2-indanol 0.005mol was dissolved in 20ml of dichloromethane, and Ti(OiPr) was added under stirring 4 (0.005mol), cooled to -12 ℃, stirred for 15 minutes, then added pantoprazole sulfide (0.01mol), then slowly added dropwise cumene hydroperoxide 0.01mol, continued to react for 20 hours, and added to the reaction system Add 20ml of toluene, stir for 10min, then add 12.5% ​​ammonia water (50ml×3) and stir for 20min each, separate the layers, combine the ammonia water layer, then adjust the pH to 7.5-8 with glacial acetic acid in an ice-water bath, and then use ethyl acetate ( 50ml×3) extraction, combined organic layers, then evaporated ethyl acetate, the obtained (S)-pantoprazole free body was dissolved with 3ml of ethyl acetate, then added dropwise with 3ml of petroleum ether and stirred, filtered, 40°C Following vacuum drying, 1.43 g of (S)-pantoprazole was obtained after purification. Yield: 37.33%; Ee(%): 45.86%.

Embodiment 3

[0038] (1R,2S)-1-Amino-2-indanol 0.0067mol was dissolved in 20ml of dichloromethane, and Ti(OiPr) was added under stirring 4 (0.005mol), cooled to 0 ℃, stirred for 15 minutes, then added pantoprazole sulfide (0.01mol), then slowly added dropwise cumene hydroperoxide 0.015mol, continued to react for 11 hours, added to the reaction system 20ml of toluene, stirred for 10min, then added 12.5% ​​ammonia water (50ml×3) and stirred for 20min each, separated the layers, combined the ammonia water layer, then adjusted the pH to 7.5-8 with glacial acetic acid in an ice-water bath, and then added ethyl acetate (50ml × 3) extraction, combined organic layers, then distilled off ethyl acetate, the obtained (S)-pantoprazole free body was dissolved with 3ml of ethyl acetate, then added dropwise with 3ml petroleum ether and stirred, filtered, below 40°C After vacuum drying, 1.54 g of (S)-pantoprazole was obtained after purification. Yield: 40.21%; Ee(%): 53.27%.

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Abstract

The invention relates to the field of medicinal chemistry, in particular to a method for preparing (S)-pantoprazole in a high-enantioselectivity way. The method is characterized in that any organic alkali is not added under the condition of chiral reagent existence, and oxidants are used for directly oxidizing 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)-methyl]-sulfenyl]-1H-benzimidazole. The ee value of the (S)-pantoprazole obtained by using the method provided by the invention can reach 100 percent.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for preparing (S)-pantoprazole with high enantioselectivity. Background technique [0002] Compound (S)-pantoprazole, (S)-5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H - Benzimidazoles and pharmaceutically acceptable salts thereof are described in CN1822835A. Pantoprazole is a proton pump inhibitor that inhibits the final step of gastric acid production by covalently binding to two sites of the H+-K+-ATPase system of gastric parietal cells in a dose-dependent manner and makes both basal and stimulated states gastric acid secretion is inhibited. S-pantoprazole sodium can be studied as a proton pump inhibitor like esomeprazole for the treatment of diseases related to gastric acid secretion disorders such as: gastroesophageal reflux, gastritis, acute gastric mucosal lesions, gastric ulcer, compound acute gastric ulcer, duodenitis, duodenal ulcer an...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 龙超峰任请谢称石朱雄朱永洋
Owner GUANGDONG HUANAN PHARMACEUTICAL GROUP CO LTD
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