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Preparation method of Vonoprazan fumarate

A technology of fumaric acid and dicarbonic acid, which is applied in the field of preparation of vonolax fumarate, can solve the problems of weakened safety, unfavorable industrialized large-scale production, impurity I and impurity II cannot be removed, and the like. effect, improved efficacy and safety, simple starting material

Pending Publication Date: 2022-05-27
日照正济药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] This route removes the impurity III in the reaction process by adding Boc to protect the amino group, and the purity is improved, but the impurity I and impurity II cannot be removed, and the sodium-hydrogen high-risk reagent is used in the sulfonylation reaction, and the safety is greatly weakened. Not conducive to large-scale industrial production

Method used

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  • Preparation method of Vonoprazan fumarate
  • Preparation method of Vonoprazan fumarate
  • Preparation method of Vonoprazan fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Preparation of compound 3

[0041]

[0042] 530.00g of acetonitrile, 200.00g of compound 1, 25.83g of DMAP, 117.67g of triethylamine were successively added to the 500ml reaction flask, the stirring was turned on, the temperature was controlled between 15 and 35°C, and 206.52g of compound 2 was added dropwise. The dropwise addition was completed in about 30min; at 15-35°C, the reaction was incubated for 1-3h; then, the reaction solution was added to 1000.00 g of water with a temperature of 5-15°C, stirred for 1-2 hours, filtered, and the filter cake was rinsed with water. , dried at 50°C to obtain 321.27g of brown solid, HPLC purity: 99.5%, yield 92%.

[0043] Preparation of compound 4

[0044]

[0045] Between 10 and 20°C, add 433.97g of 13% methylamine methanol solution, 400.00g of methanol and 200.00g of compound 3 into the reaction flask in turn, keep stirring for 1 to 2h; between -15 to 0°C , add 11.45g of sodium borohydride in batches, keep stirring for 1h...

Embodiment 2

[0057] Preparation of compound 3

[0058] Add 530.00g of tetrahydrofuran, 200.00g of compound 1, 25.83g of DMAP, and 150.29g of DIPEA into the 500ml reaction flask in turn, turn on stirring, control the temperature between 15 and 35°C, and add 206.52g of compound 2 dropwise for about 30 minutes. The left and right dropwise addition is completed; at 15-35 ℃, the reaction is incubated for 1-3 hours; then the reaction solution is added to 1000.00 g of water with a temperature of 5-15 ℃, stirred for 1-2 hours at the temperature, filtered, and the filter cake is rinsed with water and placed in After drying at 50°C, 320.22 g of a brown solid was obtained. The HPLC purity was 99.3%, and the yield was 91.7%.

[0059] Preparation of compound 4

[0060] Between 10 and 20°C, add 433.97g of 13% methylamine ethanol solution, 400.00g of ethanol and 200.00g of compound 3 into the reaction flask in turn, keep stirring for 1 to 2h; between -15 to 0°C , add 513.28g of sodium borohydride aceta...

Embodiment 3

[0069] Preparation of compound 3

[0070] 530.00g of methylene chloride, 200.00g of compound 1, 25.83g of DMAP, 123.26g of sodium carbonate were successively added to the 500ml reaction flask, stirring was turned on, the temperature was controlled between 15 and 35°C, and 206.52g of compound 2 was added dropwise. , the dropwise addition was completed in about 30min; at 15-35 ℃, the reaction was incubated for 1-3 hours; then the reaction solution was added to 1000.00 g of water with a temperature of 5-15 ℃, stirred for 1-2 hours, filtered, and the filter cake was rinsed with water After that, it was dried at 50° C. to obtain 319.27 g of brown solid, HPLC purity: 99.3%, yield 91.5%.

[0071] Preparation of compound 4

[0072] Between 10 and 20°C, add 433.97g of 13% methylamine methanol solution, 400.00g of tetrahydrofuran and 200.00g of compound 3 into the reaction flask in sequence, and keep stirring for 1 to 2h; at -15 to 0°C , add 26.63 g of sodium cyanoborohydride in batch...

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Abstract

The invention provides a preparation method of Vonoprazan fumarate, and belongs to the field of medicine synthesis. According to the synthesis process route disclosed by the invention, the compounds which are easy to obtain in the market and low in price are used as raw materials, the reaction conditions are mild, the selectivity is high, the used reagents are few, the post-treatment is simple, the high-purity and high-yield product can be stably obtained, and the Vonoprasone fumarate is stably supplied.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a preparation method of vonorasan fumarate. Background technique [0002] Gastric acid-related diseases (ARDs) are a class of upper gastrointestinal diseases in which gastric acid is closely related to the pathogenesis, including gastroesophageal reflux disease, dyspepsia, gastrointestinal ulcers, gastritis, duodenitis, and some anti-inflammatory drugs. of digestive tract diseases. The incidence of ARDs is increasing year by year worldwide. In China, ARDs have become one of the major diseases, seriously affecting the quality of life of patients and bringing a large economic burden to patients. In clinical practice, homogeneous proton pump inhibitors (PPIs) have been widely used in the treatment of ARDs and are the main therapeutic drugs for human diseases. [0003] Vonolaxan fumarate acts as a potassium ion competitive blocker, and the in vitro activity expe...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07C57/15C07C51/41
CPCC07D401/12C07C51/412Y02P20/55
Inventor 王晓飞罗林王怀秋潘天龙
Owner 日照正济药业有限公司
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