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Method for preparing aliskiren intermediate

An organic solvent and straight chain technology, which is applied in the field of preparation of Alikren intermediates, can solve the problems of low reaction yield, complicated post-treatment operation and high cost

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

AI Technical Summary

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. It is more complicated, the product loss is more, the cost is high, and it is not conducive to the defects of large-scale industrial production, but a preparation method of 3-hydroxypropyl benzyl ether derivatives is provided, and the compound can be conveniently prepared. Alikren intermediate (2S)-Bromomethyl-3-methyl-butylbenzyl ether and its derivatives

Method used

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  • Method for preparing aliskiren intermediate
  • Method for preparing aliskiren intermediate
  • Method for preparing aliskiren intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0054] The preparation of embodiment 1 compound IVa

[0055]

[0056] 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 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, 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

[0061] Example 2 Preparation of Compound Va

[0062]

[0063] Under nitrogen protection, compound IVa (46.7g, 122.3mmol) was dissolved in 500ml of THF and H with a volume ratio of 3:1 2 In the mixed solution of O, when cooled to 0°C in an ice-salt bath, 30% H 2 o 2 Aqueous solution (83.6ml, 819.4mmol), after dropping, add LiOH·H 2 O (10.3g, 244.6mmol), slowly rose to room temperature, and the reaction was complete in 6 hours. Cool to below 0°C, add dropwise Na 2 SO 3 (92.5g, 733.8mmol) aqueous solution, keep the system temperature below 10°C during the dropwise addition. Filter, and wash the filter residue with cold water until the pH of the filtrate is about 12. The filtrate was evaporated to remove THF under reduced pressure at about 40°C, and the remaining aqueous phase was washed with CH 2 Cl 2 (300ml×3) After washing, discard the organic phase, adjust the pH of the aqueous phase to about 2 with 4mol / L hydrochloric acid, and then use CH 2 Cl 2 (300ml×3) extrac...

Embodiment 3

[0066] The preparation of embodiment 3 compound VIa

[0067]

[0068] Under nitrogen protection, NaBH 4 (7.0g, 183.8mmol) was suspended in 70ml of anhydrous THF, placed in an ice bath and cooled to below 10°C, and 230ml of THF solution of compound Va (27.2g, 122.5mmol) was added dropwise, stirred until no bubbles were generated, and after 5min, Add BF dropwise at the same temperature 3 ·Et 2 O (19.4ml, 153.1mmol), after dropping, stirred at room temperature, followed by TLC, and the reaction was complete in 3 hours. Cool to 0°C, slowly pour the reaction solution into 300ml of ice water, stir for 1h, extract with ethyl acetate (300ml×3), combine the organic phases, wash with saturated brine, anhydrous Na 2 SO 4 dry. After filtering and concentrating under reduced pressure, 23.6 g of oil was obtained, the yield was 92.6%, and the HPLC purity was above 97%.

[0069] Its structural identification data are as follows:

[0070] 1 H NMR (400MHz, CDCl 3 ): δ7.25-7.4(m, 5H)...

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Abstract

The invention discloses a method for preparing an aliskiren intermediate which is shown as a formula V. The method comprises the following step of: performing a reducing reaction on a compound V and NaBH4 and / or KBH4 in the presence of a boron trifluoride ether complex, KHSO4 or an ethylene glycol diethyl ether.hydrochloric acid compound in an organic solvent, wherein R1 and R2 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; and R3 is straight chain or branch chain alkyl with 1-4 carbon atoms. An aliskiren intermediate, i.e., (2S)-bromomethyl-3-methyl-butyl benzyl oxide and a derivative thereof can be prepared conveniently from a 3-hydroxypropyl benzyl oxide derivative. The method has the advantages of high yield, easiness and convenience for operating, low cost and suitability for large-scale industrial production.

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): C07C43/178C07C41/26
Inventor 龙青朱雪焱俞雄袁哲东王胡博
Owner SHANGHAI INST OF PHARMA IND
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