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Aliskiren intermediate, and preparation method and application thereof

An intermediate and reaction technology, applied in the field of organic pharmaceuticals, can solve the problems of many by-products, high cost, and long reaction time, and achieve the effects of easy preparation, high safety, and low cost

Inactive Publication Date: 2013-07-17
NANJING OCEAN PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] In order to overcome the defects of high cost, complex process route, many by-products and long reaction time in the existing synthesis process, the present invention provides a new Alikren intermediate and its preparation method, and further provides this new The application method of Aliklen intermediates in the formation of intermediates closer to Aliklen

Method used

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  • Aliskiren intermediate, and preparation method and application thereof
  • Aliskiren intermediate, and preparation method and application thereof
  • Aliskiren intermediate, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043]First, weigh 13.0 g (43.7 mmol) of the compound of formula (II-a), dissolve it in 100 ml of dichloromethane, add 9.2 g (56.8 mmol) of carbonyldiimidazole, stir at room temperature for 1 hour, and gradually add the compound of formula (I-A) 5.1 g (52.4 mmol), stirred overnight, the reaction equation is shown in Reaction Equation 6:

[0044] Reaction 6

[0045] ;

[0046] The reaction solution was washed with 1 mol / L NaOH solution, left to separate the liquids, the organic phase was taken, the water phase was extracted twice with dichloromethane, the dichloromethane extract was combined with the organic phase, and the solution was washed with anhydrous sodium sulfate It was dried, filtered to remove anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound of formula (III-Aa), which was purified by silica gel column chromatography to obtain 13.4 g of compound (III-Aa) with a purity of 98% and a yield of 90%.

Embodiment 2

[0048] First, weigh 13.0 g (43.7 mmol) of the compound of formula (II-a), dissolve it in 100 ml of dichloromethane, add 9.2 g (56.8 mmol) of carbonyldiimidazole, stir at room temperature for 1 hour, and gradually add the compound of formula (I-B) 7.3 g (52.4 mmol), stirred overnight, the reaction equation is shown in Reaction Equation 7:

[0049] Reaction 7

[0050]

[0051] The reaction solution was washed with 1 mol / L NaOH solution, left to separate the liquids, the organic phase was taken, the water phase was extracted twice with dichloromethane, the dichloromethane extract was combined with the organic phase, and the solution was washed with anhydrous sodium sulfate Drying, filtration to remove anhydrous sodium sulfate, concentration under reduced pressure to obtain the crude compound of formula (III-Ba), which was purified by silica gel column chromatography to obtain 14.4 g of compound (III-Aa) with a purity of 98% and a yield of 86%.

[0052]

Embodiment 3

[0054] First, weigh 7.8 g (26.2 mmol) of the compound of formula (II-a), dissolve it in 60 ml of dichloromethane, add 5.5 g (33.9 mmol) of carbonyldiimidazole, stir at room temperature for 1 hour, and gradually add the compound of formula (I-C) 6.3 g (31.4 mmol), stirred overnight, the reaction equation is shown in Reaction Equation 8:

[0055] Reaction 8

[0056]

[0057] The reaction solution was washed with 1 mol / L NaOH solution, left to separate the liquids, the organic phase was taken, the water phase was extracted twice with dichloromethane, the dichloromethane extract was combined with the organic phase, and the solution was washed with anhydrous sodium sulfate It was dried, filtered to remove anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound of formula (III-Ca), which was purified by silica gel column chromatography to obtain 9.7 g of (III-Ca) compound with a purity of 97% and a yield of 84%.

[0058]

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Abstract

The invention relates to the organic pharmaceutical field, and especially relates to a synthesized renin inhibitor aliskiren intermediate, a synthetic method thereof and an application method of the synthesized aliskiren intermediate in a further reaction for forming an intermediate closer to aliskiren. The new aliskiren intermediate, the preparation method thereof and the application method of the aliskiren intermediate in the formation of the intermediate closer to aliskiren are provided to overcome the defects comprising high cost, complex technological route, many byproducts, long reaction time and the like of current synthetic technologies. A purpose that the aliskiren intermediate has the advantages of easy preparation and purification, low cost, high safety and suitableness for the industrialized production is realized.

Description

technical field [0001] The present invention relates to the field of organic pharmacy, in particular to a synthetic intermediate of Alikren, a protease inhibitor of high blood pressure, and a synthesis method thereof, and the synthetic Alikren intermediate is formed closer to Alikren after further reaction. Methods of application of Lychren's intermediates. [0002] Background technique [0003] The prevalence of hypertension in the world is about 10%. There are 180 million hypertensive patients in my country, and 3.5 million new hypertensive patients are added every year. Hypertension is the most common cardiovascular disease in my country and one of the biggest epidemics. It not only has a high prevalence rate, but also often causes heart, brain, and kidney complications, and is one of the main risk factors for stroke and coronary heart disease. Studies have shown that Aliskiren can significantly reduce blood pressure in hypertensive patients. The new antihypertensive ...

Claims

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Application Information

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IPC IPC(8): C07D307/33C07D413/06
CPCY02P20/55
Inventor 陈本顺周长岳张兵
Owner NANJING OCEAN PHARMA TECH
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