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Preparation method of esomeprazole trihydrate

A technology for esomeprazole magnesium trihydrate and esomeprazole sodium is applied in the field of preparation of esomeprazole magnesium trihydrate, and can solve the problem of being unsuitable for industrial scale production, excessive residual solvent and high cost The problem is to achieve the effect of improving chemical purity and optical purity, product content and product yield.

Active Publication Date: 2014-03-26
CHENGDU YILUKANG MEDICAL TECH & SERVICE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are following problems in the inclusion resolution method: (1) in order to obtain esomeprazole of high optical purity, it is necessary to use excess (S)-binaphthol relative to omeprazole, and this reagent is expensive, and the cost is relatively high. (2) Benzene solvents are used in the resolution process, which is highly toxic and the residual solvent exceeds the standard; (3) The optical purity of the SS clathrate is low, and its enantiomeric excess value is about 90%. Someprazole is further purified, and the operation is complicated, the loss is large, and the yield is low
Step 2 first generates the method for potassium salt and filters again, causes the yield of final product to be lower, is not suitable for industrial scale production

Method used

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  • Preparation method of esomeprazole trihydrate
  • Preparation method of esomeprazole trihydrate
  • Preparation method of esomeprazole trihydrate

Examples

Experimental program
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Embodiment 1

[0046] Embodiment 1 This embodiment is the preparation embodiment of esomeprazole magnesium trihydrate

[0047] Step (1) preparation of intermediate 1

[0048] Add 150ml of absolute ethanol and 3.0g of sodium hydroxide into a 250ml three-necked flask, heat and stir at 25-30°C for 2 hours, and then add 20.0g of omeprazole. Add 4.1 g of disodium hydrogen phosphate, continue stirring for 1 hour, transfer the reaction solution into a 250 ml single-necked bottle, evaporate to dryness in a water bath at 35-40 °C under reduced pressure, add 200 ml of acetone to the residue, stir and analyze at 10-15 °C crystal. After filtration, the filter cake was dried under reduced pressure at 35-40°C to obtain intermediate 1 with a yield of 98%, a purity of 99.914%, and a pH value of 10.8. The molar ratio of disodium hydrogen phosphate to omeprazole is 1:2.

[0049] Step (2) preparation of intermediate 2

[0050] Intermediate 1 prepared in step (1) was added with 12 g of titanium isopropoxide...

Embodiment 2

[0058] Embodiment 2 This embodiment is the preparation embodiment of esomeprazole magnesium trihydrate

[0059] Step (1) preparation of intermediate 1

[0060] Add 150ml of absolute ethanol and 3.0g of sodium hydroxide into a 250ml three-necked flask, heat and stir at 25-30°C for 3 hours, and then add 20g of omeprazole. Add 8.2 g of disodium hydrogen phosphate, continue to stir for 1.5 hours, transfer the reaction solution into a 250 ml single-necked bottle, evaporate to dryness under reduced pressure in a water bath at 35 to 40 ° C, add 200 ml of acetone to the residue and stir at 10 to 15 ° C to analyze crystal. After filtration, the filter cake was dried under reduced pressure at 35-40°C to obtain Intermediate 1 with a yield of 97%, a purity of 99.89%, and a pH value of Intermediate 1 of 10.7. The molar ratio of disodium hydrogen phosphate to omeprazole is 1:1.

[0061] Step (2) preparation of intermediate 2

[0062] With embodiment 1.

[0063] Step (3): Preparation of...

Embodiment 3

[0069] Embodiment 3 This embodiment is the preparation embodiment of esomeprazole magnesium trihydrate

[0070] Step (1) preparation of intermediate 1

[0071] With embodiment 1.

[0072] Step (2) preparation of intermediate 2

[0073] With embodiment 1.

[0074] Step (3): Preparation of Intermediate 3

[0075] With embodiment 1.

[0076] Step (4): Preparation of Intermediate 4

[0077] Add 3.5g of sodium hydroxide and 200ml of ethyl acetate to 324.2g of the intermediate obtained in step (3), stir for 2 hours with 200ml of purified water, separate layers, acidify the alkaline aqueous layer, extract with ethyl acetate, dry, evaporate under reduced pressure The crude product of intermediate 4 esomeprazole was dried; the molar ratio of sodium hydroxide to intermediate 3 was 6:1; the yield of intermediate 4 was 97%, and the HPLC purity was 99.811%.

[0078] Step (5): Add 7.74g of esomeprazole, 0.89g of sodium hydroxide, and 50ml of absolute ethanol prepared in step (4) into ...

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Abstract

The invention relates to the field of medicinal chemistry, in particular to a preparation method of esomeprazole trihydrate. The preparation method of esomeprazole trihydrate comprises the steps as follows: omeprazole is taken as an original raw material and subjected to complexation, separation, hydrolysis and salifying thato obtain the esomeprazole trihydrate. With the adoption of the preparation method, the yield and the purity of esomeprazole trihydrate can be remarkably improved, further, the reaction steps are simple, the environment protection is realized, the cost is controllable, and accordingly, the preparation method is suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a preparation method of esomeprazole magnesium trihydrate. Background technique [0002] Omeprazole, the chemical name is 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl-1H-benzimidazole. Omeprazole is a proton pump inhibitor that effectively inhibits gastric acid secretion and is used as an antiulcer drug. Omeprazole is a chiral compound in which the sulfur atom is the stereogenic center. Omeprazole is thus a racemic mixture of its two single enantiomers, the R- and S-enantiomers of omeprazole. [0003] The chemical name of esomeprazole is: S-5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl-1H- Sodium benzimidazole, the compound is the S-isomer of omeprazole. The structure of esomeprazole is as follows: [0004] [0005] Esomeprazole has been reported to have improved pharmacokinetic properties and improved therapeutic effects suc...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 李文军陶长戈向玲骆均勇彭超
Owner CHENGDU YILUKANG MEDICAL TECH & SERVICE
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