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Novel preparation method of esprazole magnesium trihydrate and intermediate thereof

A technology of esomeprazole and omeprazole sulfide, which is applied in the field of chemical drug synthesis and can solve problems such as toxicity, acetonitrile is volatile, and environmental pollution

Active Publication Date: 2019-06-21
浙江康德药业集团股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disclosed a kind of preparation method of esomeprazole magnesium as CN104803978A, wherein the required temperature control range of each step is from-20 degree centigrade to reflux temperature, under the situation of mass production, there is difficulty in the control of its reaction process, it is difficult to obtain as its The purity yield of data record; CN104447699A also discloses a kind of preparation method of esomeprazole magnesium trihydrate, and its required maximum reaction temperature needs to reach 70 degrees Celsius, and the required temperature control range is at 0-70 degrees Celsius Between, there is also difficulty in the control of the reaction process; and acetonitrile is added in the refining and purification of the intermediate potassium salt, and heated to 60-65 degrees Celsius and stirred for 2.5 hours, but acetonitrile is volatile, toxic, and flammable, and there are potential safety hazards
According to the disclosure of this patent application, 4L of acetonitrile is required for the preparation of 0.8 kg of esomeprazole potassium; if this ratio is used for mass production, a large amount of acetonitrile will be consumed in the production process; in addition, some steps of the method require up to 70 degrees Celsius It can be expected that potential safety hazards will easily escalate, and it will pollute the environment and pose a threat to the health of personnel in the production environment.

Method used

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  • Novel preparation method of esprazole magnesium trihydrate and intermediate thereof
  • Novel preparation method of esprazole magnesium trihydrate and intermediate thereof
  • Novel preparation method of esprazole magnesium trihydrate and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Embodiment 1. condensation reaction, prepares the preparation of omeprazole sulfide (intermediate 1)

[0073] Reaction equation:

[0074]

[0075] (1) Add 102.0kg of 95% ethanol to a 200L reactor, add 6.2kg of medicinal sodium hydroxide under nitrogen protection, and stir to dissolve. Control the temperature of the reaction solution at 15-25°C, add 11.9kg of 2-mercapto-5-methoxybenzimidazole, 15.0kg of Ogilvy chloride (67.87mol) and 0.3kg of potassium iodide in sequence, and slowly raise the temperature to 50°C-55°C ℃, keep warm for 30 minutes;

[0076] (wherein the mol ratio of 2-mercapto-5-methoxybenzimidazole, Ogilvy chloride, sodium hydroxide and potassium iodide is 1:1.02:2.27:0.027; 95% ethanol consumption is 7 times quality of Ogilvy chloride, Or 2-mercapto-5-methoxybenzimidazole 8.8 times the mass).

[0077] (2) Sampling is monitored by TLC method (developing agent ethyl acetate: n-hexane = 1:1) 2-mercapto-5-methoxybenzimidazole spots disappear, the reacti...

Embodiment 2

[0080] Embodiment 2. chiral oxidation reaction prepares esomeprazole

[0081] Reaction equation:

[0082]

[0083] (1) Add 87.7kg of toluene (the amount of toluene is 4 times the mass of omeprazole sulfide) to 21.62kg of intermediate I (containing 64.54mol omeprazole sulfide) obtained in Example 1, and heat up to 50°C After stirring and dissolving completely, transfer it to a 500L reactor, and turn on the nitrogen protection.

[0084] (2) Heat up to 50±3°C, add 169g of purified water and 5.47kg of D-diethyl tartrate, keep warm for 20 minutes, slowly add isopropyl titanate toluene solution dropwise (5.79kg of isopropyl titanate dissolved in 7.4kg Toluene), maintain the temperature of the reaction solution at 50±3°C and stir for 50min to 60min. Wherein, the molar ratio of water, D-diethyl tartrate, isopropyl titanate and omeprazole sulfide is 0.14:0.4:0.3:1.

[0085] (3) Cool down to 15-20°C, and add 2.66kg of triethylamine. Continue to cool down, slowly add cumene hydrop...

Embodiment 3

[0087] Embodiment 3. becomes potassium salt reaction

[0088] Reaction equation:

[0089]

[0090] (1) The esomeprazole reaction liquid of embodiment 2 gained is cooled to below 10 ℃, slowly adds potassium hydroxide methanol solution (5.92kg potassium hydroxide is dissolved in 40kg methanol), separates out solid;

[0091] (2) Heat up to 25-30°C and stir to react for 2 hours. Filtration, the filter cake was beaten with a mixed solution of 14.6kg toluene and 14.6kg methanol for 30 minutes, and filtered;

[0092] (3) The filter cake was dried under reduced pressure at 40~45°C to obtain 21.5kg with a purity of 97.216% (see figure 2 ) crude esomeprazole potassium (intermediate 2, containing 20.90 g of esomeprazole potassium, molecular weight 384, ie 54.427 mol), was sampled and submitted for inspection, and entered the refining process in line with the quality control standard of intermediate 2. If unqualified, rework is carried out until it meets the quality control standar...

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Abstract

The invention relates to a novel preparation method of esprazole magnesium trihydrate and an intermediate thereof, and belongs to a pharmaceutical technology. The preparation method comprises the following steps: (1) performing condensation reaction to prepare omeprazole sulfide; and (2) performing chiral oxidation reaction to prepare esprazole, performing potassium salt forming reaction to prepare esprazole potassium, and performing ion exchange reaction to obtain the esprazole magnesium trihydrate. The method is high in product yield, high in product purity, mild and safe in reaction condition, low in energy consumption, easy to control and suitable for industrial mass production.

Description

technical field [0001] The invention relates to chemical medicine synthesis technology, in particular to a new preparation method of esomeprazole magnesium trihydrate and its intermediate. Background technique [0002] Esomeprazole magnesium trihydrate, chemical name: bis-S-5-methoxy-2{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl ]sulfinyl}-1H-benzimidazole magnesium trihydrate. Molecular formula is C 34 h 36 MgN 6 o 6 S 2 ·3H 2 O, molecular weight 767.1, indication for gastroesophageal reflux disease, combined with appropriate antibiotics can eradicate Helicobacter pylori. Because of its good medicinal performance and convenient route of administration, it is favored in clinical use. [0003] The synthetic route generally includes the ion exchange reaction between the intermediate esomeprazole sodium salt or potassium salt and magnesium salt; the purity and yield of the finished product depend on the reaction conditions used in the synthetic route, the reagents used an...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 胡增仁郑璐邵良碧于庆明毛辉
Owner 浙江康德药业集团股份有限公司
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