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Preparation method for esomeprazole magnesium trihydrate

A technology for esomeprazole magnesium trihydrate and esomeprazole, which is applied in the field of pharmaceutical preparation, can solve the problems of long production cycle, difficulty in reaching quality standards for final products, and difficulty in drying, etc. Stereoselective and specific effects

Active Publication Date: 2014-05-14
珠海润都制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Since esomeprazole magnesium trihydrate contains three waters of crystallization, if the final product is refined and purified with a solvent, the water of crystallization will be easily separated. Prazole or esomeprazole potassium is purified, otherwise the final product is difficult to reach the quality standard
However, due to the poor stability of the intermediate esomeprazole, it is very easy to decompose; and the intermediate esomeprazole potassium is very easy to absorb moisture and is not easy to dry. Therefore, the method of separating and purifying the intermediate has caused the preparation process Problems such as cumbersome, difficult, long production cycle and low product yield

Method used

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  • Preparation method for esomeprazole magnesium trihydrate
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  • Preparation method for esomeprazole magnesium trihydrate

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Embodiment one: the preparation of esomeprazole magnesium trihydrate

[0039] Add 62g (0.188mol) omeprazole sulfide, 20g (0.097mol) D-diethyl tartrate, 21g (0.074mol) tetraisopropyl titanate, 220g n-butyl acetate, 0.4g water into 500mL three-neck In the bottle, heat up to 50°C, stir and react for 1.5 hours; cool down to 10°C, add 2.0g benzyltriethylammonium chloride (TEBA), 240g sodium hypochlorite solution (available chlorine content is 4% to 5%), and control the temperature The reaction was carried out at 10°C for 3 hours. The reaction is monitored by high-performance liquid chromatography, and when the omeprazole sulfide content is below 1%, the reaction is stopped to obtain esomeprazole. Subsequently, add 700g mass concentration to reaction system and be that the sodium hydroxide aqueous solution of 12.5% ​​extracts, and esomeprazole forms esomeprazole sodium and is dissolved in alkali water layer; Discard n-butyl acetate layer, collects alkali water layer, add 22...

Embodiment 2

[0041] Embodiment two: the preparation of esomeprazole magnesium trihydrate

[0042] Add 80g (0.243mol) omeprazole sulfide, 28.4g (0.139mol) D-diethyl tartrate, 41.4g (0.146mol) tetraisopropyl titanate, 320g n-pentyl acetate, 0.7g water into 500mL In the three-necked flask, heat up to 50°C, stir and react for 1.5 hours; cool down to 10°C, add 1.0g benzyltriethylammonium chloride (TEBA), 320g sodium hypochlorite solution (available chlorine content is 4% to 5%), The temperature was controlled and reacted at 9°C for 4 hours. The reaction is monitored by high-performance liquid chromatography, and when the omeprazole sulfide content is below 1%, the reaction is stopped to obtain esomeprazole. Subsequently, add 850g mass concentration to reaction system and be that the aqueous sodium hydroxide solution of 12.5% ​​extracts, and esomeprazole forms esomeprazole sodium and is dissolved in alkaline water layer; Discards n-pentyl acetate layer, collects alkaline water layer, add 320g ...

Embodiment 3

[0044] Embodiment three: the preparation of esomeprazole magnesium trihydrate

[0045] Get the n-butyl acetate layer discarded after the completion of the reaction of Example 1, wash 3 times with 200g water, wash the n-butyl acetate layer to neutrality, then add anhydrous sodium sulfate and molecular sieves to dry, and n-butyl acetate The moisture content of ester layer is controlled below 0.08%, obtains the n-butyl acetate that reclaims.

[0046] Add 100g (0.304mol) omeprazole sulfide, 50g (0.176mol) tetraisopropyl titanate, 0.5g water and recovered n-butyl acetate (containing catalyst D-diethyl tartrate) into a 500mL three-necked flask In the medium, heat up to 50°C, stir and react for 1.5 hours; cool down to 5°C, add 1.0g benzyltriethylammonium chloride (TEBA), 380g sodium hypochlorite solution (available chlorine content is 4% to 5%), and control the temperature at React at 8°C for 4 hours. The reaction is monitored by high-performance liquid chromatography, and when the...

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Abstract

The invention discloses a preparation method for esomeprazole magnesium trihydrate, and the preparation method comprises the following steps: 1) taking omeprazole sulfide, then adding a chiral ligand, a catalyst and an organic solvent, heating and mixing for reaction, so as to form a chiral omeprazole sulfide compound; 2) adding an inorganic oxidant for oxidation reaction, and oxidizing omeprazole sulfide into esomeprazole; 3) adding inorganic base aqueous solution, extracting so as to enable the esomeprazole, obtained in the step 2), to form an esomeprazole inorganic salt, and dissolving the esomeprazole inorganic salt into the inorganic base aqueous solution layer; 4) adding inorganic magnesium salt into the inorganic base aqueous solution layer, stirring for reaction, and then carrying out centrifugation and drying, thus obtaining the esomeprazole magnesium trihydrate. The preparation method has the advantages of being high in product purity, high in yield, simple in technique, high-efficiency, environment-friendly, low in cost and the like.

Description

technical field [0001] The invention relates to a preparation method of medicine, in particular to a preparation method of esomeprazole magnesium trihydrate. Background technique [0002] Esomeprazole, chemical name: bis-S-5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl] Sulfinyl}-1H-benzimidazole, molecular formula C 17 h 19 N 3 o 3 S (shown in formula I below), the molecular weight is 345.42. Esomeprazole is the L-isomer of Omeprazole, that is, the (S)-isomer. It is the world's first isomer proton pump inhibitor (I-PPI), because it has more High bioavailability, longer time of intragastric pH>4, low dosage and significant curative effect, so it has wider clinical application prospects. [0003] (Formula I) [0004] At present, the preparation methods of esomeprazole mainly include the following types: (1) racemate resolution method, by introducing a chiral group into the omeprazole molecule, the original racemate produces stereoisometry structure, after...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 李红钊姜春来祝家健周爱新
Owner 珠海润都制药股份有限公司
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