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Synthetic method for mainly intermediate compounds of anti-hypertensive drug aliskiren

A synthesis method and compound technology are applied in the field of main intermediates of hypertensive drug aliskiren, and can solve the problems of high cost, high use price, cumbersome steps and the like

Inactive Publication Date: 2008-10-15
CHONGQING NANSONG CHEMI TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] Synthetic route 3: using another chiral inducer, using expensive LDA and iodoisopropane, and the raw material 1 is also difficult to buy directly, and it takes several steps to synthesize, the steps are cumbersome, and the cost is also high

Method used

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  • Synthetic method for mainly intermediate compounds of anti-hypertensive drug aliskiren
  • Synthetic method for mainly intermediate compounds of anti-hypertensive drug aliskiren
  • Synthetic method for mainly intermediate compounds of anti-hypertensive drug aliskiren

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Synthesis of (2R)-3-methyl-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-1-butanol:

[0028] The first step: the synthesis of 4-methoxy-3-(3-methoxypropoxy)benzaldehyde

[0029] Add 600ml acetone, 152g 3-hydroxyl-4-methoxybenzaldehyde, 153g 3-methoxybromopropane, 120g anhydrous sodium carbonate in the reactor, stir, heat and reflux reaction for 6-8 hours, distill and reclaim the solvent, Add 300ml of ethyl acetate to dissolve the distillation residue, wash with 100ml of 10% aqueous sodium hydroxide solution and 100ml of water, dry with anhydrous sodium sulfate, and recover the solvent by distillation to obtain 4-methoxy-3-(3- Methoxypropoxy)benzaldehyde (yield 87%). Elemental analysis and spectroscopic data indicated that the product was the above compound:

[0030] 1 H NMR (CDCl 3 , 400MHz, TMS) δ: 9.75(s, 1H), 7.35-7.38(m, 2H), 6.89(d, 1H, J=8.0Hz), 4.09(t, 2H, J=6.6Hz), 3.86(s , 3H), 3.49(t, 2H, J=6.2Hz), 3.27(s, 3H), 2.05(m, 2H)ppm; 13 C NMR (CDCl 3 , 100MHz, TMS)...

Embodiment 2

[0043] Synthesis of (2R)-3-methyl-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-1-butanol:

[0044] The first step: the synthesis of 4-methoxy-3-(3-methoxypropoxy)benzaldehyde

[0045] Add 600ml of absolute ethanol, 152g of 3-hydroxy-4-methoxybenzaldehyde, 184g of 3-methoxybromopropane, and 120g of anhydrous potassium carbonate into the reactor, stir, heat and reflux for 6-8 hours, and recover by distillation Solvent, the distillation residue was dissolved in 300ml of ethyl acetate, washed with 100ml of 10% aqueous sodium hydroxide solution and 100ml of water, dried with anhydrous sodium sulfate, and recovered by distillation to obtain 4-methoxy-3-( 3-methoxypropoxy)benzaldehyde (90% yield). Elemental analysis and spectroscopic data indicated that the product was the above compound:

[0046] 1 H NMR (CDCl 3 , 400MHz, TMS) δ: 9.75(s, 1H), 7.35-7.38(m, 2H), 6.89(d, 1H, J=8.0Hz), 4.09(t, 2H, J=6.6Hz), 3.86(s , 3H), 3.49(t, 2H, J=6.2Hz), 3.27(s, 3H), 2.05(m, 2H)ppm; 13 C NMR (CDC...

Embodiment 3

[0059] Synthesis of (2R)-3-methyl-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-1-butanol:

[0060] The first step: the synthesis of 4-methoxy-3-(3-methoxypropoxy)benzaldehyde

[0061] Add 600ml acetonitrile, 152g 3-hydroxyl-4-methoxybenzaldehyde, 168g 3-methoxybromopropane, 120g anhydrous potassium carbonate in the reactor, stir, heat and reflux for 6-8 hours, and recycle the solvent. Add 300ml of ethyl acetate to dissolve the distillation residue, wash with 100ml of 10% aqueous sodium hydroxide solution and 100ml of water, dry with anhydrous sodium sulfate, and recover the solvent by distillation to obtain 4-methoxy-3-(3- Methoxypropoxy)benzaldehyde (95% yield). Elemental analysis and spectroscopic data indicated that the product was the above compound:

[0062] 1 H NMR (CDCl 3 , 400MHz, TMS) δ: 9.75(s, 1H), 7.35-7.38(m, 2H), 6.89(d, 1H, J=8.0Hz), 4.09(t, 2H, J=6.6Hz), 3.86(s , 3H), 3.49(t, 2H, J=6.2Hz), 3.27(s, 3H), 2.05(m, 2H)ppm; 13 C NMR (CDCl 3 , 100MHz, TMS) δ: 190.2...

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Abstract

The invention provides a novel synthetic method for the main intermediate compound-(2R)-3-methy-2-(4 -methoxy-3-(3-methoxy-C) benzyl)-1-butyl alcohol of hypertension drug Aliskiren. The invention adopts the method with the steps that firstly the raw material of 3-hydroxy-4-methoxy benzaldehyde is etherified by 3-methoxy bromopropane (mol ratio of 1:1 to 1.2), and then is condensed with isopentyl aldehyde (in mol ratio of 1:1 to 1.3); catalytic hydrogenation is performed to the condensation product; then the main intermediate compound of the hypertension drug Aliskiren is obtained through resolution. The method has the advantages that the raw material and the reagent are easy to be obtained, the cost is low, the synthetic process is short, and only three steps are required to prepare the raceme of the main intermediate compound of the Aliskiren; when the enzyme method is utilized to perform the resolution of the raceme, the main intermediate compound-(2R)-3-methy-2-(4-methoxy-3-(3-methoxy-C) benzyl)-1-butyl alcohol of the hypertension drug Aliskiren can be obtained.

Description

Technical field: [0001] The present invention relates to a main intermediate of the hypertensive drug Aliskiren and a new synthesis method. Background technique: [0002] Aliskiren (Aliskiren, CAS: 173334-57-1) is a new molecular entity and is the first drug for the treatment of hypertension approved by the US FDA to directly inhibit the renal enzyme renin that causes blood pressure to increase. It is predicted that by 2015 Aliskiren sales will reach 2.1 billion US dollars. [0003] Aliskiren Tablets (trade name: Tekturna): dosage form: film-coated tablet; 150, 300mg; development company: Novartis; approved marketing time: 2007-03-06; indication: for the treatment of hypertension, can be used alone Use or in combination with other antihypertensive drugs. [0004] The Chinese chemical name of Aliskiren is: (αS, γS, δS, ζS)-δ-amino-nitrogen-(3-amino-2,2-dimethyl-3-oxypropyl)-γ-hydroxyl-4 -Methoxy-3-(3-methoxypropoxy)-α, ζ-bis(1-methylethyl)phenyloctylamide; the English chem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C43/23C07C41/26C07C41/18C12P41/00
Inventor 衡林森夏仕文何从林
Owner CHONGQING NANSONG CHEMI TECH
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