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Preparation method of esomeprazole and preparation method of esomeprazole salt

A technology of esomeprazole salt and lutidine hydrochloride, applied in the field of medicine, can solve the problems of high price of the resolving agent, difficult to realize industrialized production, low selectivity and the like, and achieves reduction of impurity nitrogen oxides and The production of sulfone, easy industrial production, the effect of improving yield and purity

Active Publication Date: 2013-03-27
SHANDONG UNIV +1
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Problems solved by technology

[0004] At present, esomeprazole salt is mainly obtained by esomeprazole salification, therefore, the preparation method of esomeprazole not only affects the yield and the purity of esomeprazole, but also affects the yield and purity of esomeprazole salt. yield and purity
The preparation methods of esomeprazole include: racemic body omeprazole resolution method, omeprazole sulfide asymmetric catalytic oxidation method and biochemical oxidation method, but because racemic body omeprazole The resolution method will waste half of the omeprazole, causing environmental pollution and economic loss, and the price of the optically active resolution agent is also relatively expensive, so the large-scale use of this resolution method in industry is limited; biochemical Due to the complicated operation and low selectivity of the oxidation method, its application is also limited; the common method for preparing esomeprazole is the asymmetric catalytic oxidation method of omeprazole sulfide, for example: International Patent Application WO96 / 02535 Disclosed is a method for obtaining S-omeprazole by oxidizing omeprazole sulfide with hydrogen peroxide derivatives in the presence of chiral bidentate ligand diethyl tartrate, titanium metal complex and alkali; Patent application WO03 / 089408 describes the oxidation of omeprazole thioether in the presence of a base under the catalysis of chiral monodentate (S)-(+)-mandelic acid ester complexes with titanium or vanadium to obtain L-oxime The method of meprazole
However, a large amount of impurity nitrogen oxides and sulfones are easily produced in the above-mentioned preparation process, which affects the yield and purity of esomeprazole and its salts, making it difficult to realize industrial production

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  • Preparation method of esomeprazole and preparation method of esomeprazole salt
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preparation example Construction

[0036] The invention provides a kind of preparation method of esomeprazole salt, comprising:

[0037] a, 2-chloromethyl-4-nitro-3,5-lutidine hydrochloride, inorganic base and 5-methoxy-2-mercaptobenzimidazole are reacted in water to obtain formula (I) structural compounds,

[0038] Formula (I);

[0039] b. Reacting the compound having the structure of formula (I), a chiral inducer, a catalyst, water and an oxidizing agent in an organic solvent to obtain a compound having the structure of formula (II),

[0040] Formula (II);

[0041] c. reacting the compound having the structure of formula (II) and methoxide in an organic solvent to obtain esomeprazole salt, and the methoxide is sodium methoxide or potassium methoxide.

[0042] The present invention reacts 2-chloromethyl-4-nitro-3,5-lutidine hydrochloride, inorganic base and 5-methoxy-2-mercaptobenzimidazole in water to obtain ) structure, the molar ratio of the 2-chloromethyl-4-nitro-3,5-lutidine hydrochloride to the 5...

Embodiment 1

[0069] (S)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole sodium (Esso Meprazole sodium) preparation

[0070] Add 23.7 g (100 mmol) of 2-chloromethyl-4-nitro-3,5-lutidine hydrochloride into 95 ml of water, heat up to 40°C, stir to dissolve and set aside; Take 100 ml of tap water and pour it into a 500 ml three-neck bottle, add 8.8 g (220 mmol) of caustic soda, and then add 19.8 g (110 mmol) of 5-methoxy-2-mercaptobenzimidazole into the above dilute alkaline water and stir Make it dissolve, then control the temperature at 35~40°C, slowly drop 2-chloromethyl-4-nitro-3,5-lutidine hydrochloride solution into the reaction solution over 3 hours, and add Afterwards, continue to react at 35~40°C for 3 hours, and determine the end point of the reaction by TLC (developing agent is V 甲苯 :V 乙酸乙酯 :V 甲醇 =5:2:1), after the reaction was completed, filter, wash and dry to obtain 34.1 grams of the compound with the structure of formula (I).

[0071] The pu...

Embodiment 2

[0081] (S)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole potassium (Esso Meprazole potassium) preparation

[0082] Add 23.7 g (100 mmol) of 2-chloromethyl-4-nitro-3,5-lutidine hydrochloride into 95 ml of water, heat up to 40°C, stir to dissolve and set aside; Take 100 ml of tap water and pour it into a 500 ml three-neck bottle, add 8.8 g (220 mmol) of caustic soda, and then add 19.8 g (110 mmol) of 5-methoxy-2-mercaptobenzimidazole into the above dilute alkaline water and stir Make it dissolve, then control the temperature at 35~40°C, slowly drop 2-chloromethyl-4-nitro-3,5-lutidine hydrochloride aqueous solution into the reaction solution over 3 hours, add After completion, continue to react at 35~40°C for 3 hours, and determine the end point of the reaction by TLC (developing agent is V 甲苯 :V 乙酸乙酯 :V 甲醇 =5:2:1), after the reaction was completed, filter, wash and dry to obtain 34.2 grams of the compound with the structure of formula (I). ...

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Abstract

The invention adopts 2-chloromethyl-4-nitryl-3, 5-dimethyl pyridine hydrochloride and 5-methoxyl-2-mercapto benzimidazole as starting materials to prepare esomeprazole salt by condensation, asymmetric oxidation and methoxidation. A preparation method has the advantages that the repeatability is good, the operation is simple, and the industrial production is easy; and the preparation conditions are moderate, the generation of impurities such as nitric oxide and sulphone is reduced in the preparation process, and the yield and the purity of the esomeprazole salt are increased.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of esomeprazole and esomeprazole salt. Background technique [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, the molecular formula is: C 17 h 19 N 3 o 3 S. Esomeprazole is an isomeric proton pump inhibitor, and proton pump inhibitors (PPIs) are the drugs of choice for the treatment of acid-related diseases such as peptic ulcer and gastroesophageal reflux disease. [0003] Esomeprazole salt is obtained through the modification of esomeprazole salt. Esomeprazole salt can reduce the irritation to the body, and has good solubility in the body, and improves bioavailability, so that it can To produce more ideal pharmacological effects, common esomeprazole salts mainly include esomeprazole sodium, esomeprazole potassium, and esomeprazole magnes...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 宋伟国褚亚飞高东圣董良军杨磊王伟田梅吕伟香刘东
Owner SHANDONG UNIV
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