Method for preparing aliskiren intermediate

An intermediate and reaction technology, which is applied in the field of preparation of non-peptide renin inhibitor aliskiren intermediates, can solve the problems of multi-hazardous chemicals, low total yield of routes, many steps, etc., and achieves reasonable cost and high yield. High efficiency and easy operation

Inactive Publication Date: 2014-09-03
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This synthetic route has many steps, and the multi-step reaction needs to use column chromatography to purify the product, and many dangerous chemicals are used, the total yield of the route is low, and it is not suitable for large-scale production

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  • Method for preparing aliskiren intermediate

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preparation example Construction

[0032] The preparation method of a kind of Aliskiren intermediate of the present invention, the synthetic route of this intermediate is:

[0033] .

Embodiment 1

[0035] Including the following synthetic steps:

[0036] (1) Synthesis of intermediate 1: under anhydrous and oxygen-free conditions, put 140mL of n-butyl (3mol / L) lithium in 600mL of tetrahydrofuran, stir, cool down to -80°C, and add dropwise; dropwise, the reaction is 30 Minutes later, 400 mL of (S)-3-(3-methylbutyryl)-4-benzyl-2-oxazolidinone (164.9 g, 0.63 mol, 3.0 eq) in tetrahydrofuran and 200 mL of trans 1,4-Dibromobutene (45.0g, 0.21mol, 1.0eq) in tetrahydrofuran; after the addition, react at -30°C for 8 hours; TLC shows that the reaction of the raw materials is complete, and quench with saturated ammonium chloride solution. Add ethyl acetate (500mL×3) for extraction; the organic layer was washed with water (500mL×2) and saturated sodium chloride solution (500mL×2), dried over anhydrous sodium sulfate, filtered with suction, and evaporated to dryness under reduced pressure to obtain 104.5 g of Yellow product. Yield: 78%.

[0037] (2) Synthesis of Intermediate 2: Put...

Embodiment 2

[0044] Including the following synthetic steps:

[0045] (1) Synthesis of intermediate 1: under anhydrous and oxygen-free conditions, put 130mL sodium hexamethyldisilazide (2moL / L) in 300mL tetrahydrofuran, stir, cool down to -80°C, and add dropwise; After dropping, add 200mL (S)-3-(3-methylbutyryl)-4-benzyl-2-oxazolidinone (98.9g, 0.34mol, 3.0eq) of tetrahydrofuran dropwise after 30 minutes of reaction solution and 100mL trans-1,4-dibromobutene (27g, 0.13mol, 1.0eq) in tetrahydrofuran; after addition, react at -30°C for 8 hours; Quenched and extracted by adding ethyl acetate (300mL×3); the organic layer was washed with water (300mL×2) and saturated sodium chloride solution (300mL×2), dried over anhydrous sodium sulfate, filtered with suction, and evaporated to dryness under reduced pressure. 60.3 g of pale yellow product was obtained. Yield: 75%.

[0046] (2) Synthesis of intermediate 2: Put 54g of intermediate 1 (0.09mol, 1.0eq) in 350mL of tetrahydrofuran, stir, then add...

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Abstract

The invention discloses a method for preparing an aliskiren intermediate. The method comprises the following synthesis steps: (1) by adopting trans-1, 4-dibromo butene as a raw material, carrying out nucleophilic substitution with a chiral auxiliary agent under the action of strong alkali; (2) removing one molecule of S-benzyl oxazolidinone under the action of a bromo-reagent; (3) reacting with an azide reagent in the presence of a catalyst; (4) removing one molecule of S-benzyl oxazolidinone under the action of an alkali reagent to form a carboxylic acid compound; (5) reacting with a acyl chloride reagent and converting carboxylic acid into an anhydride compound under the action of the alkali reagent; (6) reducing ester group into alcoholic hydroxyl group under the action of a reducing reagent; (7) selectively oxidizing the alcoholic hydroxyl group into aldehyde under the action of an oxidizing agent to obtain the intermediate. The method disclosed by the invention has the beneficial effects that the process method is safe and reliable, high in yield, easy to operate and reasonable in cost and is more suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of an aliskiren intermediate, in particular to a preparation method of a non-peptide renin inhibitor aliskiren intermediate. Background technique [0002] Aliskiren (aliskiren) is a new non-peptide oral low molecular weight non-peptide renin inhibitor pioneered by Novartis Pharmaceuticals. Its trade name is Tekturna. Its 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. Its structural formula is: [0003] . [0004] The tablet exists in the form of hemifumarate, which is a new antihypertensive drug that molecularly simulates the active site of renin according to X-ray crystallography. It has a strong, stable and long-lasting antihypertensive effect, and can further protect target organs. Renin is a circulating enzyme that indirectly stimulates the release of adrenal aldosterone. When the secretion ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/33C07D413/06C07D263/26
CPCC07D307/33
Inventor 李泽标严军林燕峰刘明元
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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