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Preparation and analysis methods of benzimidazole derivative

A technology of benzimidazole and its derivatives, which is applied in the field of preparation of pharmaceutical compounds, and can solve problems such as environmental pollution and potential safety hazards

Active Publication Date: 2019-02-05
WUHAN LL SCI & TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, the column chromatography purification process requires the use of a large amount of silica gel, quartz sand, and organic solvents, which will generate a large amount of solid or liquid waste, pollute the environment, and pose a great safety hazard.
Moreover, the impurity content of purified products in the prior art still needs to be improved to improve the safety and reliability of pharmaceutical compounds

Method used

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  • Preparation and analysis methods of benzimidazole derivative
  • Preparation and analysis methods of benzimidazole derivative
  • Preparation and analysis methods of benzimidazole derivative

Examples

Experimental program
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Effect test

preparation example 1

[0116] According to the method before the column chromatography described in Example 13 of patent application 201410010180.1, 10 kg of the pure compound of the following formula 4-1 was dissolved in 200 L of DMF, and 21.2 kg of azilsartan and 25 kg of cesium carbonate were added under stirring, and then the temperature was raised to 40°C, keep this temperature for 24 hours. TLC monitors the reaction and shows that the compound of formula 4-1 has almost reacted completely. The temperature of the reaction solution is lowered to room temperature, and 1000L of water is added, extracted with ethyl acetate (200L*3), and the combined organic phases are washed with saturated aqueous sodium chloride (100L*2 ), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain a 20kg mixture, which is an oil containing a compound of formula 5 and its rearrangement impurity compound 5-1, wherein the content of the rearrangement impurity compound 5-1 is detecte...

Embodiment 1

[0119] 1) Add 40 L of butanol to about 10 kg of the crude oil of the compound of formula 5, heat up to 80° C. to dissolve, cool to room temperature and crystallize overnight. Filtrate, collect the solid, rinse the filter cake with 2.0L butanol, and dry under reduced pressure to obtain 9.5 kg of the product, with a yield of 95.0% (calculated based on the crude oil of the compound of formula 5), ​​and a product purity of 87.0%;

[0120] 2) Add 18.4L of tert-butylketone to 9.5kg of solid compound of formula 5 after recrystallization in the previous step, beat at room temperature for 2h, filter, and dry under reduced pressure to obtain 8.64kg of product with a purity of 99.2% and a yield of 90.9%, in which the content of rearranged impurities 0.42%, less than 0.50%.

Embodiment 2

[0122] 1) Add 52L of ethanol with a mass percentage of 75% to about 13kg of the crude oil of the compound of formula 5, and heat up to 60°C for 2 hours to dissolve. Slowly cool down to room temperature to crystallize overnight. Filter to collect the solid, rinse the filter cake with 2L of 75% ethanol, and dry under reduced pressure to obtain 11.1 kg of the product, with a yield of 85.4% (calculated based on the crude oil of the compound of formula 5), ​​and a product purity of 87.6%.

[0123] 2) Add 110L of methyl isobutyl ketone to the solid 11.1Kg of the compound of formula 5 after recrystallization in the previous step, heat to 80°C to completely dissolve, cool to room temperature for crystallization overnight, filter, and dry under reduced pressure to obtain 9.6 kg of the compound of formula 5 , the purity is 99.4%, the yield is 86.5%, and the rearrangement impurity content is 0.38%, less than 0.50%.

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Abstract

The invention belongs to the field of preparation methods of drug compounds and particularly relates to preparation and analysis methods of a benzimidazole derivative. The preparation method comprisesthe steps of recrystallizing a mixture containing a compound represented by a formula I shown in the description with a solvent, carrying out pulping, carrying out filtering, and carrying out drying,thereby obtaining the product. According to the methods, the preparation process is simple in operation; compared with the prior art, the methods have the advantages that the operation cycle is short, the cost is low, the product yield is high, the discharge of waste gases, waste water and waste residues is low, the obtained compound is relatively high in purity, and the content of a rearrangement product is low. The purification process provided by the invention solves the technical problem of the existing column chromatography that amplified large-batch purification cannot be achieved and meets the requirements on industrial production.

Description

technical field [0001] The invention belongs to the field of preparation methods of pharmaceutical compounds, and in particular relates to preparation and analysis methods of benzimidazole derivatives. Background technique [0002] Hypertension (Hypertension) is the most common cardiovascular disease, and it is also a major risk factor leading to increased morbidity and mortality of congestive heart failure, stroke, coronary heart disease, renal failure, and aortic aneurysm. Antihypertensive drugs play a key role in the treatment and prevention of hypertensive diseases. With the deepening understanding of the pathogenesis of hypertension, many antihypertensive drugs with better efficacy, such as diuretics, β-blockers, calcium channel antagonists, angiotensin converting enzyme inhibitors (ACEI, Puryl class), angiotensin II AT1 receptor blockers (ARB, sartan class), have been continuously discovered and successfully applied in clinic. The development of angiotensin II AT1 re...

Claims

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Application Information

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IPC IPC(8): C07D413/14G01N30/02G01N30/34
CPCC07D413/14G01N30/02G01N30/34C07D403/14C07D413/10C07D493/04C07D498/18
Inventor 雷四军方详冯伟陈永凯王朝东
Owner WUHAN LL SCI & TECH DEV
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