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Aliskiren intermediate and preparation method thereof

A technology for intermediates and compounds, applied in the field of pharmaceutical synthesis, can solve the problems of polluted environment, complicated process, low yield, etc., and achieve the effects of stable yield, reduced difficulty, and reduced production cost

Active Publication Date: 2011-11-16
CHONGQING QIANTAI BIOLOGICAL MEDICINE
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] The purpose of the present invention is to solve the shortcomings of complex process, low yield, high cost, and environmental pollution in the existing Alikren preparation process. In order to achieve the above-mentioned purpose, the present invention provides a new Alikren intermediate and a preparation method, There are also methods for the preparation of Alikren using these intermediates

Method used

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  • Aliskiren intermediate and preparation method thereof
  • Aliskiren intermediate and preparation method thereof
  • Aliskiren intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1 Synthesis of 4-methoxy-3-(3-methoxypropoxy)phenylboronic acid (formula III)

[0043]

[0044] Under nitrogen protection, add 100g (363.45mol) of 4-bromo-1-methoxyl-2-(3-methoxypropoxy)benzene (formula 1) successively to a 1L three-necked flask [according to Helvetica Chimica Acta-Vol.86 (2003), prepared by the method disclosed in P2848-2870] and 500ml of tetrahydrofuran (THF), cooled to -78°C after stirring and dissolving, then slowly added dropwise 110ml of 2.5M (545.18mmol ) of n-butyllithium (n-BuLi), control the reaction temperature below -70°C, and continue to stir for 1 hour after the dropwise addition, and the reaction solution is a white turbid solution at this time. 68.35g (726.9mmol) triisopropyl borate [B(i-PrO) 3] was slowly added dropwise to the reaction solution, and the reaction temperature was controlled to be lower than -70°C. The reaction solution was gradually clarified and stirred for 15 minutes. TLC [ethyl acetate (EA): petroleum ethe...

Embodiment 4

[0063] Synthesis of Example 4 Aliskiren (Aliskiren)

[0064]

Embodiment 2

[0065] use Example 2 or Example 3 The obtained product is prepared according to the method disclosed in CN101273012A or CN101016253A to prepare Aliskiren.

[0066] 1 HNMR(d 6 -DMSO, 400MHz) δ: 7.49 (1H, t), 7.14 (1H, s), 6.80 (4H, m), 6.69 (1H, d), 6.36 (1H, s), 3.97 (2H, t), 3.71 (3H,s), 3.46(2H,m), 3.28(2H,m), 3.24(3H,s), 3.10(2H,dd), 2.53(1H,m), 2.46(1H,d), 2.35( 1H,dd), 2.24(1H,t), 1.93(2H,p), 1.77(1H,s), 1.64(3H,m), 1.26(3H,m), 1.04(6H,s), 0.85(6H , dd), 0.79 (6H, m).

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PUM

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Abstract

The invention mainly relates to an aliskiren intermediate shown in formula I or II, and a method for synthesizing other intermediates close to aliskiren by utilizing the intermediate through Suzuki coupling reaction. By using Suzuki coupling reaction of the intermediate to synthesize sequent substances, the reaction difficulty can be greatly reduced and the product yield is stabilized at 70% or above, thus meeting the needs of large-scale industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to Alikren intermediates and preparation methods of these intermediates. Background technique [0002] Aliskiren (a) is a renin inhibitor that acts on the renin-angiotensin-aldosterone system (RAS), and is the first hypertension treatment approved by the US FDA to directly inhibit the renal enzyme renin that causes blood pressure to increase medicine. In May 2007, FDA approved Alikren hemifumarate for marketing. [0003] Alikren's chemical name is (2S, 4S, 5S, 7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[ 4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide, CAS No.: 173334-57-1, the chemical structure is shown in formula a: [0004] [0005] CH19940001169 (same family CN117960A) first announced the chemical structure and preparation method of Alikren; US7132569, WO0208172, US5559111, US5606078, CN101016253, WO2007045421, CN101774986 and other patents s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02C07D307/33
CPCY02P20/55
Inventor 袁建栋黄仰青池建文
Owner CHONGQING QIANTAI BIOLOGICAL MEDICINE
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