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Method for preparing high-purity esomeprazole

A technology for esomeprazole salt and benzimidazole, which is applied in the field of synthesis and purification of esomeprazole salt, can solve the problems of increasing the difficulty of operation, unsuitable for industrial production, and high reaction temperature, and achieves improved drug efficacy and safety, reduce the difficulty of operation, reduce the effect of impurity content

Active Publication Date: 2012-07-18
NANJING YOUKE BIOLOGICAL MEDICAL RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

HOLT ROBERT et al. disclosed in WO9617076 and WO9617077 the preparation of esomeprazole by using microorganisms to selectively oxidize prochiral sulfides and selectively reduce racemic sulfone compounds. However, due to the poor stability of microorganisms, the product purification is difficult. And the yield is low, so it is not suitable for industrial production
[0008] (2), chromatographic resolution method, that is, the use of chromatography to split omeprazole to obtain esomeprazole, but this method is more common in small-scale preparations in laboratories because of its high cost and low yield. There is no report on large-scale industrial production
E. M. Larsen et al. disclose a method for preparing esomeprazole by an improved sharpless asymmetric oxidation method in WO9602535, but in this preparation method, it is necessary to repeatedly adjust the pH value, which increases the difficulty of operation; and the reaction The higher temperature (above 80°C) leads to higher impurity content in the product; at the same time, the e.e. value of the product obtained by this method can reach 87%, but the yield is only 40%: these defects make this method not suitable for industrial production

Method used

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  • Method for preparing high-purity esomeprazole
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  • Method for preparing high-purity esomeprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1 Esomeprazole ( )Synthesis

[0034]

[0035] Weighing type Add 180g (1mol) of the compound shown, add 540mL of methanol, and stir to obtain a suspension solution; weigh 100g (2.5mol) of NaOH and dissolve it in 100mL of water, add 200mL of methanol to obtain a mixed solution, slowly add to the methanol suspension of the above-mentioned imidazole In the solution, maintain the reaction temperature at about 50°C, and start to add slowly The methanol solution of the compound [Formula Compound 221g (1mol): Methanol 700mL]. After the dropwise addition, keep the temperature for 0.5-1h, monitor by TLC (petroleum ether: ethyl acetate = 1:3 as the developing agent), the reaction is complete, and the reaction is ended. After extraction, suction filtration and vacuum drying, 243g of formula The indicated compound has an HPLC purity of 99.76%, m.p.: 119-120°C.

[0036] Under the protection of nitrogen, take the formula obtained in the previous step 229g...

Embodiment 2

[0038] The preparation of embodiment 2 esomeprazole sodium

[0039] Dissolve 35.0g of esomeprazole in 40mL of methanol, stir until dissolved and clear, and dissolve 5.0g of sodium hydroxide in 5.5mL of water, cool down to below room temperature, then dilute with 5.5mL of methanol, and add dropwise to the reaction solution , stirred at 45°C for 0.5h, then heated to 55°C for 1h. Concentrate, repeatedly add water with anhydrous isopropanol (25 mL×2), concentrate until viscous, add 7 mL ether and stir evenly, after standing still, a large amount of solid precipitates, pour 20 mL ether to dilute, and centrifuge to obtain 36.5 g Crude esomeprazole sodium.

[0040] Dissolve the crude esomeprazole sodium prepared in the previous step in 40mL of absolute ethanol in batches, control the system at about 35°C, and basically dissolve (slightly mixed); filter the above solution with a Buchner funnel containing activated carbon cake to obtain clarification yellow liquid. When the oil in...

Embodiment 3

[0047] The preparation of embodiment 3 esomeprazole sodium

[0048] Dissolve 35.0g of esomeprazole in 40mL of methanol, stir until dissolved and clear, and dissolve 5.0g of sodium hydroxide in 5.5mL of water, cool down to below room temperature, then dilute with 5.5mL of methanol, and add dropwise to the reaction solution , stirred at 45°C for 0.5h, then heated to 50°C for 1h. Concentrate, repeatedly add water with anhydrous isopropanol (25 mL×2), concentrate to a viscous substance, add 7 mL petroleum ether and stir evenly, after standing still, a large amount of solid precipitates, pour 20 mL petroleum ether to dilute, and centrifuge to obtain 35.7g crude esomeprazole sodium.

[0049] Dissolve the crude esomeprazole sodium prepared in the previous step in batches in 40mL of methanol, control the system at about 35°C, and basically dissolve (slightly mixed); filter the above solution with a Buchner funnel containing activated carbon cake to obtain a clear yellow liquid . ...

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Abstract

The invention discloses a method for synthesizing and refining salt of esomeprazole. According to the method, 2-sulfydryl-5-methoxyl-1H-benzimidazole is used as an initiative raw material for reaction, and a reaction condition is optimized, so that reaction is performed under a mild condition, and the content of impurities in the product is reduced effectively. After the synthesized product is refined further, the purity and enantiomer excess of the product are over 99 percent, so that the effect and safety of administration are improved.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a method for synthesizing and refining esomeprazole salt. Background technique [0002] Omeprazole (Omeprazole) is the first proton pump inhibitor (PPI) developed by AstraZeneca in Sweden that can effectively inhibit gastric acid secretion. ＋ / K ＋ -ATPase), first listed in Sweden in 1988, entered the U.S. market in 1989, the trade name is Losec MUPS, and its indications are gastric ulcer, duodenal ulcer, reflux esophagitis, Zhuo-Ellison syndrome ( Zollinger-ellsion) syndrome. Patent EP0005129 first disclosed the chemical structure and preparation method of omeprazole, and patent EP0124495 disclosed its metal salt. P. L. Lindberg et al. disclosed in US5877192 that omeprazole has two isomers, dextrorotatory (R-) and left-rotary (S-), among which the efficacy of the S-isomer is significantly better than that of R - Omeprazole. [0003] S-omeprazole, also known as Esomeprazol...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 闵涛车晓明晁阳叶海姚洛芫赵翠
Owner NANJING YOUKE BIOLOGICAL MEDICAL RES
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