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Preparation method of Aliskiren

A compound and selected technology, applied in the field of medicine and chemical industry, can solve the problems of complicated operation, high cost of raw materials, low conversion rate, etc.

Active Publication Date: 2012-10-24
ZHEJIANG APELOA JIAYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Aiming at the defects of high raw material cost, cumbersome operation, low yield, low conversion rate, and low equipment utilization rate in the process of preparing Alikren in the prior art, it is urgent to provide a raw material that is easy to obtain, easy to operate, and high in yield, suitable for The method for the preparation of Aliklen in industrialized production

Method used

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  • Preparation method of Aliskiren
  • Preparation method of Aliskiren
  • Preparation method of Aliskiren

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] {(1S,3S)-3-[4-methoxy-3-(3-methoxypropoxy)benzoyl]-1-[(2S,4S)-4-isopropyl-5- Preparation of tert-butyl oxytetrahydrofuran-2-yl]-4-methylpentyl}carbamate (Compound II)

[0079] Add 80g of 4-methoxy-3-(3-methoxypropoxy)-bromobenzene and 0.6L THF into a 2L single-necked flask, stir and cool down to -60°C, and add 120mL of 2.5M n-butyllithium dropwise. After the dropwise addition, (3S,5S)-1-tert-butoxycarbonyl-3-isopropyl-5-((2S,4S)-4-isopropyl-5-oxo- Tetrahydro-furan-2-yl)-pyrrolidin-2-one (compound I) (90 g dissolved in 0.4 L THF), the dropwise addition was completed in 40 min. Stir the reaction at -50°C to -60°C for 1 hour, spot the plate, and monitor the end point of the reaction by TLC. After the reaction was completed, 240 mL of 2N hydrochloric acid was added to quench the reaction at low temperature, and then gradually warmed to room temperature.

[0080] The resulting reaction solution was concentrated to obtain a yellow viscous liquid. 600 mL of water and 1500 ...

Embodiment 2

[0092] Preparation of compound II

[0093] Add 80g of 4-methoxy-3-(3-methoxypropoxy)-bromobenzene and 0.6LTHF into a 2L single-necked flask, stir and cool down to -70℃~-80℃, add dropwise 120mL of 2.5M n-butyl base lithium. After the dropwise addition, (3S,5S)-1-tert-butoxycarbonyl-3-isopropyl-5-((2S,4S)-4-isopropyl-5-oxo- Tetrahydro-furan-2-yl)-pyrrolidin-2-one (90g dissolved in 0.4L THF), the dropwise addition was completed in 40min. Stir the reaction at -70~-80°C for 1 hour, spot the plate, and monitor the end point of the reaction by TLC. After the reaction was completed, 200 mL of 2N hydrochloric acid was added to quench the reaction at low temperature, and then gradually warmed to room temperature.

[0094] The resulting reaction solution was concentrated to obtain a yellow viscous liquid. 600 mL of water and 1500 mL of ethyl acetate were added thereto and stirred, the layers were separated, and the organic phase was concentrated to obtain viscous crude compound II. ...

Embodiment 3

[0104] Preparation of compound II

[0105] Add 80g of 4-methoxy-3-(3-methoxypropoxy)-bromobenzene, 0.6LTH F into a 2L single-necked flask, stir and cool down to -10~-20℃, add 1M isopropyl bromide dropwise Magnesium chloride 300mL. After the dropwise addition, (3S,5S)-1-tert-butoxycarbonyl-3-isopropyl-5-((2S,4S)-4-isopropyl-5-oxo- Tetrahydro-furan-2-yl)-pyrrolidin-2-one (90g dissolved in 0.4L THF), the dropwise addition was completed in 40min. Stir the reaction at -10 to -20°C for 1 hour, spot the plate, and monitor the end point of the reaction by TLC. After the reaction was completed, 200 mL of 2N hydrochloric acid was added to quench the reaction at low temperature, and then gradually warmed to room temperature.

[0106] The resulting reaction solution was concentrated to obtain a yellow viscous liquid. 600 mL of water and 1500 mL of ethyl acetate were added thereto and stirred, the layers were separated, and the organic phase was concentrated to obtain viscous crude com...

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Abstract

The invention discloses a preparation method of the Aliskiren. The method includes that (3S,5S)-3-isopropyl-5-((2S,4S)-4-isopropyl-5-oxo-tetrahydrofuran-2-yl)-pyrrolidine-2-ketone (compound I) protected by amino serves as an initial material, subjecting the initial material to addition through 4-methoxy-3-(3-methoxy-propoxy)-bromobenzene and metal reagents, hydrogenation reduction, acid catalysis cyclization, 3-Amino-2,2-dimethylpropionamide aminolysis, reduction ring-opening and deprotection, and obtaining the Aliskiren. The preparation method of the Aliskiren has the advantages that raw materials are easy to obtain, the operation is simple and convenient, the production cost is low, the conversion rate is high, the device utilization rate is high, and the method is environment friendly and suitable for industrial production.

Description

technical field [0001] The invention relates to the synthesis of an antihypertensive drug, in particular to a preparation method of Alikren, which belongs to the field of medicine and chemical industry. Background technique [0002] Aliskiren (trade name Tekturna) is a new type of antihypertensive drug that directly inhibits renin, and was approved by the US Food and Drug Administration (FDA) in 2007. Studies have shown that Alikren, whether used alone or in combination with other antihypertensive drugs, can significantly reduce blood pressure in hypertensive patients. [0003] [0004] Alikren is the first drug with a new pharmacological mechanism of action introduced in the field of hypertension treatment in the world for more than ten years. It not only has a significant therapeutic effect, but also creates a new direction for the treatment of hypertension. With the extensive attention of pharmaceutical companies and research institutions, many process routes have bee...

Claims

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Application Information

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IPC IPC(8): C07C237/20C07C231/12
Inventor 庄程翰章丽周敦峰周雄飞王小波吴瑜亮张拥军张兴贤
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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