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Preparation method of esomeprazole magnesium

A technology of esomeprazole magnesium and compounds, which is applied in the field of medicinal chemistry, can solve the problems of unfavorable large-scale industrial production, low resolution yield, high production cost, etc., and achieve easy industrial production, good reproducibility, and stable form Effect

Inactive Publication Date: 2014-07-23
北京华禧联合科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The enantiomeric purity of the product obtained by this method is acceptable (ee value is 99.8%), but the resolution yield is low (38%), the product loss is large, the production cost is high, and it is not conducive to large-scale industrial production.

Method used

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  • Preparation method of esomeprazole magnesium
  • Preparation method of esomeprazole magnesium
  • Preparation method of esomeprazole magnesium

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preparation example Construction

[0025] The invention provides a kind of preparation method of esomeprazole magnesium, comprising:

[0026] A, 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride, inorganic base and 2-mercapto-5 methoxy-benzimidazole react in ethanol to obtain the compound with (I ) compounds with structure

[0027]

[0028] b. React the compound with the structure of formula (I) with catalyst, chiral ligand (+)-l-tartrate-di-tert-butyl ester, organic base, water and oxidant in an organic solvent to obtain the compound with structure (II) ,

[0029]

[0030] c. reacting the compound having the structure of formula (II) with the inorganic sodium salt in an organic solvent to obtain esomeprazole sodium salt.

[0031] In the present invention, 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and 2-mercapto-5methoxy-benzimidazole are first dissolved in ethanol, and then an inorganic base is added to reflux After 3-6 hours, the compound having the structure of formula (I...

Embodiment 1-1

[0039] Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-lH-benzimidazole

[0040] 2-Chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride (50g, 225mmol), sodium carbonate (53g, 495mmol) and 2-mercapto-5-methoxy Base-benzimidazole (40g, 225 mmol) was added in a three-necked flask (1000 ml), and absolute ethanol (400 ml) was measured by a graduated cylinder, heated to reflux, stirred for 4 hours, and monitored by TLC at the end of the reaction (developing agent was acetic acid Ethyl ester) after the reaction is complete, stop the heating, cool down to room temperature naturally, add diatomaceous earth (15g), remove the insoluble matter by suction filtration under reduced pressure, collect the filtrate, and spin evaporate under reduced pressure to obtain an oily substance, which is recrystallized with toluene to obtain a white powdery solid (67.6g).

[0041] The purity of the compound with the structure of formula (I) measured by HPLC is 99.8%

Embodiment 1-2

[0043] Preparation of esomeprazole

[0044] Add the compound of formula (I) obtained above (67.6g, 205mmol) into a three-necked flask, measure toluene (500ml) into the three-necked flask, heat up to 80°C, heat and stir to dissolve, then cool down to 50°C, Add (+)-l-tartrate-di-tert-butyl ester (21.5g, 82mmol), tetraisopropyl titanate (11.6g, 41mmol) was added, and pure water (0.36g, 20.5mmol) was added dropwise ), keep the reaction temperature at about 50°C, stir for 1 hour, then cool down to 30-35°C, add N,N-diisopropylethylamine (15.9g, 123mmol) dropwise, after the drop, add isopropyl Hydrogen peroxide (44.6g, 205mmol) was added dropwise to the reaction system, and the reaction temperature was maintained at 30-35°C during the dropwise addition. Aqueous sodium hydroxide solution (250ml) was quenched, separated and purified to give the compound of formula (II) (29.7g).

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Abstract

The invention discloses a preparation and refinement method of esomeprazole magnesium. The preparation and refinement method comprises the following steps: condensing 2-chloromethyl-3, 5-dimethyl-4-methoxyl pyridine hydrochloride and 2-sulfydryl-5-methoxy-benzimidazole serving as starting materials, carrying out improved sharpless asymmetric oxidation so as to prepare esomeprazole sodium, then carrying out salt displacement so as to prepare esomeprazole magnesium, and finally refining to obtain high-purity esomeprazole magnesium. The preparation method is mild in reaction conditions, simple to operate, good in repeatability and high in yield and facilitates industrial production. The chromatographic purity of esomeprazole magnesium prepared by the method is above 99.8%; the optical purity of esomeprazole magnesium reaches above 99.6%; esomeprazole magnesium is stable in morphology and can meet medicinal requirements.

Description

Technical field: [0001] The invention relates to the technical field of medicinal chemistry, in particular to a magnesium salt of esomeprazole and a preparation method thereof technical background: [0002] Esomeprazole is the S-isomer of omeprazole, and its chemical name is (S)-5-methoxy-2-[[4-methoxy-3,5- Dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole, whose molecular formula is C 17 h 19 N 3 o 3 S. Esomeprazole is a new generation isomeric proton pump inhibitor (PPI), which is the drug of choice for the treatment of peptic ulcer, gastroesophageal reflux disease (GERD), duodenal ulcer and other diseases. [0003] Esomeprazole magnesium is a sustained-control oral preparation, which is sold in the US market under the trade name NEXIUM. There are two specifications of its sustained-release capsules, 20mg and 40mg respectively. Each specification contains The main component is esomeprazole magnesium trihydrate, which is 22.3 mg and 44.5 mg respectively according t...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 谭祖磊魏爱伟毕华
Owner 北京华禧联合科技发展有限公司
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