Preparation method of aliskiren intermediate

An inert gas, straight-chain technology, applied in the field of preparation of aliskiren intermediates, can solve the problems of complicated post-processing operations, unfavorable large-scale production, low reaction yield, etc., and achieves improved efficiency, improved yield, and wide application. Foreground effect

Active Publication Date: 2012-10-31
SHANGHAI INST OF PHARMA IND +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The technical problem to be solved by the present invention is to overcome the low reaction yield and post-treatment operation that exist in the synthetic method of the existing Alikren intermediate (2S)-bromomethyl-3-methyl-butylbenzyl ether. Complicate...

Method used

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  • Preparation method of aliskiren intermediate
  • Preparation method of aliskiren intermediate
  • Preparation method of aliskiren intermediate

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Embodiment 1

[0041] The preparation of embodiment 1 compound IVa

[0042]

[0043] Under nitrogen protection, compound IIIa (40.0 g, 153.2 mmol) was dissolved in 500 ml of anhydrous CH 2 Cl 2 , cooled to 0°C, dropwise added TiCl 4 (18ml, 163.8mmol), dropwise, the solution was yellow, stirred for 5min; dropwise added N, N-diisopropylethylamine (30ml, 174mmol), dropwise, the reaction solution turned black, stirred for 1 hour; dropwise Compound II a (44ml, 316.8mmol) was reacted at 0°C for 20 hours after dropping, and the reaction solution gradually turned yellow. Add 200ml saturated NH 4 Cl aqueous solution and 320ml water, stir, separate liquid, use CH for water phase 2 Cl 2 (70ml×2) extraction, combined organic phase, washed with water and saturated brine successively, anhydrous MgSO 4 dry. Filtration and concentration under reduced pressure gave an oil (50.2 g, 85.8%), which was recrystallized from n-hexane and petroleum ether to give 46.9 g of a white solid with a yield of 80.1...

Embodiment 2

[0049] The preparation of embodiment 2 compound IVa

[0050]

[0051] Under nitrogen protection, compound IIIa (40.0g, 153.2mmol) was dissolved in 500ml anhydrous tetrahydrofuran, cooled to 0°C, and TiCl was added dropwise 4 (18ml, 163.8mmol), dropwise, the solution was yellow, stirred for 5min; dropwise added N, N-diisopropylethylamine (30ml, 174mmol), dropwise, the reaction solution turned black, stirred for 1 hour; dropwise Compound IIa (44ml, 316.8mmol) was reacted at 0°C for 20 hours after dropping, and the reaction solution gradually turned yellow. Add 200ml saturated NH 4 Cl aqueous solution and 320ml water, stirred, separated, the aqueous phase was extracted with ethyl acetate (70ml×2), the organic phases were combined, washed with water and saturated brine successively, anhydrous MgSO 4 dry. Filtrate and concentrate under reduced pressure to obtain an oil, which was recrystallized from n-hexane and petroleum ether to obtain 44.1 g of a white solid with a yield o...

Embodiment 3

[0052] The preparation of embodiment 3 compound IVa

[0053]

[0054] Under nitrogen protection, compound IIIa (40.0g, 153.2mmol) was dissolved in 500ml of anhydrous dimethyl sulfoxide, cooled to 0°C, and TiCl was added dropwise 4 (18ml, 163.8mmol), dropwise, the solution was yellow, stirred for 5min; dropwise added N, N-diisopropylethylamine (30ml, 174mmol), dropwise, the reaction solution turned black, stirred for 1 hour; dropwise Compound IIa (32ml, 229.8mmol) was reacted at 0°C for 20 hours after dropping, and the reaction solution gradually turned yellow. Add 200ml saturated NH 4 The reaction was quenched by aqueous Cl solution, the solvent was spun off under reduced pressure, 320ml of water was added to the residue, extracted with ethyl acetate (70ml×3), the organic phases were combined, washed with water and saturated brine successively, and anhydrous MgSO 4 dry. Filtrate and concentrate under reduced pressure to obtain an oil, which was recrystallized from n-hexa...

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Abstract

The invention discloses a preparation method of an aliskiren intermediate shown as a formula IV. The method comprises the following step of: reacting a compound II with a compound III under the protection of an inert gas in a dry organic solvent under the actions of titanium tetrachloride and dry DIPEA (Diisopropylethylamine), wherein Z is Cl, Br or I; R1, R2 and R5 independently refer to H, straight chain or branch chain alkyl with 1-3 carbon atoms, straight chain or branch chain alkoxyl with 1-3 carbon atoms, straight chain or branch chain alkyl with 1-3 carbon atoms which is substituted by straight chain or branch chain alkoxyl with 1-3 carbon atoms, or alkoxyl with 1-6 carbon atoms which is substituted by alkoxyl with 1-6 carbon atoms; R3 is straight chain or branch chain alkyl with 1-4 carbon atoms; R4 is benzyl or benzyl with a substituent on a benzene ring; and R6 is O, S or HN. According to the method, the reaction yield is increased on a large scale, the reaction cost is reduced, and the reaction efficiency is increased. The method is suitable for large-scale industrial production, and has a wide application prospect.

Description

technical field [0001] The invention relates to a method for preparing an Aliskiren intermediate. Background technique [0002] Cardiovascular disease, including high blood pressure, ranks first among the diseases that cause death in the world. At present, the incidence of hypertensive diseases in my country is about 23.3%, and the number of patients has exceeded 160 million, and it is increasing year by year. There are about 3.5 million new hypertensive patients every year. Every year, cardiovascular and cerebrovascular diseases caused by hypertension More than 2.6 million people died from the disease. According to statistics, the drugs currently used to treat hypertension can only control the condition of 25% of hypertensive patients. Therefore, many pharmaceutical companies and scientific research institutes at home and abroad are competing to research and develop drugs that can effectively prevent and treat cardiovascular diseases such as hypertension. [0003] [0...

Claims

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Application Information

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IPC IPC(8): C07D263/26C07C43/174C07C41/22
Inventor 龙青朱雪焱俞雄袁哲东王胡博
Owner SHANGHAI INST OF PHARMA IND
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