Preparation method for intermediate 3-isopropylfuranone derivatives of blood-pressure-reducing medicine aliskiren

A technology of propylfuranone and an intermediate, which is applied in the field of pharmaceutical preparation, can solve the problems of complex synthesis and long steps of the intermediate compound V-3, and achieves the effects of low cost, simple operation and easy availability of raw materials

Inactive Publication Date: 2014-08-13
CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method step is longer, also needs to use Grignard reagent equally, and the synthesis of intermediate formula compound V-3 is also more complicated

Method used

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  • Preparation method for intermediate 3-isopropylfuranone derivatives of blood-pressure-reducing medicine aliskiren
  • Preparation method for intermediate 3-isopropylfuranone derivatives of blood-pressure-reducing medicine aliskiren
  • Preparation method for intermediate 3-isopropylfuranone derivatives of blood-pressure-reducing medicine aliskiren

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Embodiment 1

[0054] In order to fully illustrate the essence of the patent of the present invention, preparation ideas and ideas, verify the preparation method described in the present invention in the following examples, these examples are only for illustration and special case representative, should not be interpreted or understood as protection of the present invention limit. Embodiment 1: the preparation of intermediate:

[0055] Step 1: Preparation of (2S, 4S)-2-amino-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanoic acid (II) :

[0056] according to Helv. Chim. Acta , 2003, 86, synthesized by the method of 2848-2868.

example 2

[0058] The second step: (2S, 4S)-2-((N,N-dibenzyl)amino)-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)- The preparation of 5-methylhexanoic acid benzyl ester (III):

[0059]

[0060] Add (2S, 4S)-2-amino-4-(4-methoxy-3-(3-methoxypropoxy) successively to a 500mL three-necked round-bottomed flask equipped with a spherical condenser, mechanical stirring and a thermometer ) benzyl)-5-methylhexanoic acid (formula compound II) (19.0g, 53.8mmol), potassium carbonate (35g, 253.6mmol), ethanol 300mL, water 100m, benzyl chloride (27.0g, 213.3mmol), Stir and heat to reflux, react for 8 hours, and TLC detects that the reaction raw materials are completely reacted. Ethanol was evaporated under reduced pressure at 50°C, excess benzyl chloride was evaporated under reduced pressure at 90°C, 100 mL of deionized water was added, ethyl acetate (100 mL×3) was added for extraction, and the combined organic phases were sequentially washed with deionized water (100 mL) and saturated salt Washed with...

example 3

[0063] The third step: (3S, 5S)-1-chloro-3-((N,N-dibenzyl)amino)-5-(4-methoxy-3-(3'-methoxypropoxy) ) benzyl)-6-methyl-2-heptanone (formula compound IV) preparation:

[0064]

[0065] Under nitrogen protection, add 9.0 g (2S, 4S)-2-((N, N'-dibenzyl)amino)-4-(4-methoxy-3- (3-methoxypropoxy)benzyl)-5-methylhexanoic acid benzyl ester (compound of formula III) (9.0g14.4mmol), bromochloromethane (8.2g63.6mmol) and 90mlTHF, dry ice / acetone cooling To -78°C, n-butyllithium (45ml2.5mol / L112.5mmol) was slowly added dropwise, and reacted for 4 hours, and the reaction raw materials were detected by HPLC to complete the reaction. Add saturated ammonium chloride aqueous solution (80ml) to quench the reaction, recover the solvent under reduced pressure, add dichloromethane (150ml×3) for extraction, wash with saturated brine, recover the solvent under reduced pressure, and the resulting residue is purified by a short silica gel column and concentrated to obtain Compound represented by f...

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Abstract

The invention relates to a preparation method for intermediates 3-isopropylfuranone derivatives of a blood-pressure-reducing medicine aliskiren, and belongs to the technical field of medicine preparation methods. The method is characterized by comprising: taking (2S,4S)-2-amino-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylcaproic acid (compound II) as a raw material, and performing amino protection to obtain a compound III; reacting the compound III with bromochloromethane to obtain a compound IV; performing reduction and ring-closing reaction on the compound IV to obtain a compound VI; reacting the compound VI with diethyl malonate to obtain a compound VII; reacting the compound VII with a 2-halopropane to obtain a compound VIII; and performing decarboxylation on the compound VIII to obtain a compound IX. The method has the advantages of raw material easy availability, operation simpleness, method reliability, low cost, easy industrialization and the like.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation methods, and in particular relates to a new method for preparing aliskiren intermediate furanone. Background technique [0002] The chemical name of Aliskiren is: (2S, 4S, 5S, 7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl Base-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide (CAS NO: 173334-57-1), the chemical structure is as shown in formula I Show. [0003] [0004] Aliskiren, a new antihypertensive drug, is a second-generation renin inhibitor developed by Novartis that acts on the renin-angiotensin-aldosterone system (RAS). Novartis has obtained the world patent of aliskiren (WO2007048027) in April 2007, and protected its novel antihypertensive therapeutic effect. Aliskiren (Tekturna) is listed in the United States. It is estimated that the sales of Aliskiren will reach 2.1 billion US dollars by 2015, and it is expected to become another "blockbu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/33
CPCY02P20/55C07D307/33
Inventor 王立新徐小英许景刚秦斌田芳贺光云
Owner CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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