Preparation method of esomeprazole magnesium

A technology of esomeprazole magnesium and magnesium methoxide, which is applied in organic chemistry and other fields, can solve the problems that the final product is difficult to meet the quality standard, is not easy to dry, and has poor stability, and achieves simple and feasible preparation operations, avoiding a large amount of heat release, pH The effect of value stabilization

Active Publication Date: 2015-07-29
AMICOGEN CHINA BIOPHARM CO LTD
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  • Abstract
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AI Technical Summary

Problems solved by technology

The market demand for esomeprazole magnesium is increasing day by day. The current production process with high cost, low yield and complex operation is not conducive to the large-scale promotion of this product after domestic production
[0007] CN2012100025368 discloses the synthetic method of esomeprazole salt, is to add the aqueous solution of magnesium chloride to the methanol solution of esomeprazole, needs distillation after reaction, complicated operation
[0008] CN2012105747727 discloses a kind of preparation method of esomeprazole and salt thereof, first prepare esomeprazole potassium or esomeprazole sodium by esomeprazole, then convert into esomeprazole magnesium, The process is cumbersome and the material loss is large
Existing preparation methods all need to first intermediate--esomeprazole or esomeprazole potassium is purified, otherwise the final product obtained 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 of esomeprazole magnesium
  • Preparation method of esomeprazole magnesium
  • Preparation method of esomeprazole magnesium

Examples

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Embodiment 1

[0028] 1) Disperse 100g of 5-methoxy-2-mercaptobenzimidazole in 500ml of dichloromethane, lower the temperature to 0~5℃, and add 44ml of 15wt% sodium hydroxide aqueous solution to the above system, and the addition is complete. Afterwards, control the temperature to 0~5℃, and continue to add dropwise a solution of 125g 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and 125ml water. After the addition is complete, The temperature was raised to reflux and reacted for 2 hours, then the temperature was lowered to 15°C, and the mixture was allowed to stand for liquid separation. 200ml of water was added to the dichloromethane phase, stirred for 15 minutes, and the dichloromethane phase was obtained by standing for liquid separation.

[0029] 2) Add 40g of titanium tetraisopropoxide and 60g of D-diethyl tartrate to the dichloromethane phase, heat up to reflux, react for 1h, cool to 15°C, add 20g of diisopropylethylamine, and control the temperature from -20 to -15 At ℃, ad...

Embodiment 2

[0032] 1) Disperse 50g of 5-methoxy-2-mercaptobenzimidazole in 200ml of n-hexane, lower the temperature to -5~0°C, and add 30g of 20wt% potassium hydroxide aqueous solution to the above system. Then, control the temperature to 0~5℃, add dropwise a solution of 70g 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and 100ml water under vigorous stirring, and the addition is complete Afterwards, the temperature was raised to reflux and reacted for 3 hours, and then the temperature was lowered to 25° C., and the mixture was allowed to stand for liquid separation. 200 ml of water was added to the n-hexane phase, stirred for 15 minutes, and then stood for liquid separation to obtain the n-hexane phase.

[0033] 2) Add 20.2g of titanium tetraisopropoxide and 29.8g of D-diethyl tartrate to the n-hexane phase, heat to reflux, react for 3h, cool to 20℃, add 7.5g of triethylamine, control the temperature at -20~-15℃ , The solution prepared by 87.6g 80wt% cumene hydroperoxide and 9...

Embodiment 3

[0036] 1) Disperse 100g of 5-methoxy-2-mercaptobenzimidazole in 500ml of dichloromethane, cool to 0~5℃, add dropwise 44g of 15wt% sodium hydroxide aqueous solution to the above system, and the addition is complete Then, control the temperature to 0~5℃, and continue to add dropwise a solution made of 140g 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and 150ml water. After the addition is complete, The temperature was raised to reflux and reacted for 2 hours, then the temperature was lowered to 15°C, and the mixture was allowed to stand for liquid separation. Add 200 ml of water to the organic phase, stir for 15 minutes, and stand for liquid separation to obtain the methylene chloride phase.

[0037] 2) Add 38.5g of titanium tetraisopropoxide and 62.3g of D-diethyl tartrate to the dichloromethane phase, increase the temperature to reflux, react for 1h, reduce the temperature to 20℃, add 15.2g of triethylamine, and control the temperature from -20~-15 At °C, a solutio...

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Abstract

The invention relates to the field of chemical synthesis, in particular to a novel synthesis process for active pharmaceutical ingredients of a PPI (proton pump inhibitor), and especially relates to a preparation method of esomeprazole magnesium. According to the method, 5-methoxy-2-mercaptobenzimidazole and 2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride are taken as the starting raw materials and subjected to condensation, asymmetric oxidation and salifying to prepare esomeprazole magnesium, a wet product is refined with water and methanol, an intermediate does not require crystallization, filtering and drying, the operation steps are simplified, the production cycle is shortened, material loss and energy consumption in a processing process are reduced, the yield is improved, and good economic benefits and social benefits are realized. The preparation method is good in repeatability and simple to operate, improves the yield and purity of esomeprazole magnesium and facilitates industrial production.

Description

Technical field [0001] The invention relates to the field of chemical synthesis, in particular to a new process for the synthesis of a proton pump inhibitor (PPI) raw material drug, and in particular to a preparation method of esomeprazole magnesium. Background technique [0002] Esomeprazole, namely esomeprazole, is the S-isomer of omeprazole, its chemical name is: (S)-5-methoxy-2-[[4-methoxy-3,5 -Dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, is the world’s first isomer proton pump inhibitor synthesized by AstraZeneca (Astra) in Sweden ( I-PPI), proton pump inhibitor (PPI) is the first choice for the treatment of peptic ulcer, gastroesophageal reflux disease (GERD), duodenal ulcer and other diseases. Esomeprazole magnesium is a slow-control oral preparation. It is sold under the name of NEXIUM in the US market. The esomeprazole magnesium enteric-coated tablets currently on the market in China were developed by the original manufacturer AstraZeneca in 2002. It was app...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 朱历宏杜希兵李建国徐兴鹏王玲
Owner AMICOGEN CHINA BIOPHARM CO LTD
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