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Preparation method of aliskiren intermediate

An intermediate and isopropyl technology, applied in the field of compound preparation, can solve the problems of long synthetic route, production cost and increase of three wastes

Active Publication Date: 2012-05-02
WUHAN WUYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] As can be seen from the above, this synthetic method still has many defects: the synthetic route is long; because the theoretical maximum yield of resolution is only 50%, the production cost and the three wastes are increased; when using butyl lithium, it needs to be cooled with dry ice, which will limit the future Therefore, it is beneficial for the industrial production of Aliskiren to find a more convenient synthetic method for (S)-2-isopropyl-4-oxobutanoic acid methyl ester (I)

Method used

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  • Preparation method of aliskiren intermediate

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Experimental program
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Embodiment 1

[0028] The synthesis of embodiment 1 compound (E)-3-methyl-1-nitrobutene-1

[0029] Add 18.3g (254mmol) of isobutyraldehyde, 15.5g (254mmol) of nitromethane and 50mL of methanol into a 250mL three-necked flask, slowly drop in sodium hydroxide aqueous solution (12.2g of sodium hydroxide dissolved in 12mL of water). Add 10mL of methanol after the addition, and continue to stir the reaction solution for one hour at 0°C, then add 100mL of water to the reaction solution until it becomes clear, and pour the reaction solution into aqueous hydrochloric acid (120mL concentrated hydrochloric acid is diluted with water to 300mL) and stir For 15 minutes, extract three times with dichloromethane, 50 mL each time, combine the organic phases, and wash with anhydrous Na 2 SO 4 Let dry for 2 hours. After filtration, the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (petroleum ether (60-90°C) / ethyl acetate 20:1 (v / v)) to obtain light yello...

Embodiment 2

[0030] The preparation of embodiment 2 (S)-4-methyl-3-(nitromethyl)pentanal

[0031] Add catalyst ((S)-diphenyltrimethylsilylmethyl-2-pyrrolidine, 0.65g, 2mmol) in a 25mL single-necked round bottom flask, (E)-3-methyl-1-nitrobutyl En-1 (2.3 g, 20 mmol) and 2 mL of 1,4-dioxane were kept at 4°C, acetaldehyde (8.8 g, 200 mmol) was added, and the mixture was sealed and stirred at room temperature for 18 hours. Then add 10mL1N hydrochloric acid, extract with ethyl acetate (50mL×3), combine the organic phases, wash with anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated under reduced pressure, and then subjected to silica gel column chromatography (n-hexane / ethyl acetate=20:1 (v / v)) to obtain (S)-4-methyl-3-( Nitromethyl)valeraldehyde 1.8g (11.4mmol), yield 57%.

Embodiment 3

[0032] The preparation of embodiment 3 (S)-2-isopropyl group-4-oxobutanoic acid

[0033] Add (S)-4-methyl-3-(nitromethyl)pentanal (0.6g, 3.8mmol), sodium nitrite (0.79g, 11.4mmol), glacial acetic acid (2.3 g, 38mmol) and 5mL dimethyl sulfoxide, kept the temperature at 35°C and stirred for 6 hours, followed by thin-plate chromatography. Then add 10mL1N hydrochloric acid to the reaction solution, extract with ethyl acetate (30mL×3), combine the organic phases, anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated under reduced pressure, and silica gel column chromatography (dichloromethane / methanol=20:1 (v / v)) gave yellow oil (S)-2-isopropyl-4-oxobutanoic acid 0.4g (2.84mmol), yield 76%.

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Abstract

The invention relates to a preparation method of a compound, more specifically to a preparation method of an important intermediate (S)-2-isopropyl-4-oxobutyric acid methyl ester for synthesis of aliskiren. The preparation method provided by the invention comprises the following steps of: using isobutyraldehyde and nitromethane as raw materials, performing a Henry reaction and an elimination reaction to obtain corresponding conjugated nitroolefin, performing a Michael addition reaction between conjugated nitroolefin and acetaldehyde in the presence of a chiral catalyst to obtain (S)-4-methyl-3-(nitro methyl)pentanal, oxidizing the intermediate to obtain (S)-2-isopropyl-4-oxobutanoic acid, followed by methyl esterification to obtain (S)-2-isopropyl-4-oxobutyric acid methyl ester. The preparation method provided by the invention requires no low temperature, metal organic reagents or chiral separation, has advantages of easily obtained and low-priced raw materials and reagents, few synthesis steps, mild reaction condition and high yield, and is more suitable for industrial production.

Description

technical field [0001] The invention relates to a method for preparing a compound, in particular to a method for preparing an important intermediate (S)-2-isopropyl-4-oxobutanoic acid methyl ester used for synthesizing aliskiren. Background technique [0002] Aliskiren (English Aliskiren) is a second-generation renin inhibitor. It is an antihypertensive drug developed by Swiss Novartis. It was approved for marketing in the United States and Europe in 2007. ) of the first rate-limiting step. All current research data show that Aliskiren antihypertensive therapy has good safety and effectiveness, few side effects, long half-life, and is convenient to take once a day. The structural formula of Aliskiren is as follows: [0003] [0004] There are many reports on the synthetic route of Aliskiren, which are fully discussed in the Chinese patent CN101284769A and the paper (Chinese Journal of Pharmaceutical Industry 2009, 40, 468). The chiral carbon part connected to the isopr...

Claims

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Application Information

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IPC IPC(8): C07C69/67C07C67/08
Inventor 杨尚金冯珂郭亚兵潘季红丁友友朱毅
Owner WUHAN WUYAO PHARMA
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