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Novel butyrolactone derivative synthesizing method

A technology of butyrolactone and derivatives, which is applied in the field of new synthesis of butyrolactone derivatives, can solve problems such as difficulty in maintaining extremely high chiral purity, and achieve good stereoselectivity, reduce production costs, and low cost

Inactive Publication Date: 2018-03-23
安徽华胜医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] As another example, the document Hughes, G. et al., J.Am.Chem.Soc.2003, 125, 11253-11258 reported that n-valeraldehyde was used as a raw material, through cyclization, reduction, and finally through asymmetric reduction to obtain the above-mentioned butyrol Ester derivatives, where expensive chiral catalysts and ligands are used and it is difficult to maintain very high chiral purity

Method used

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  • Novel butyrolactone derivative synthesizing method
  • Novel butyrolactone derivative synthesizing method
  • Novel butyrolactone derivative synthesizing method

Examples

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Embodiment 1

[0033] Synthesis of the compound shown in embodiment 1 formula (III)

[0034] Dissolve diisopropylamine (6.1 g, 3 equivalents) in 30 mL of ether, cool to -78°C, add 40 mL of n-butyl lithium in n-hexane (1.6M n-hexane solution, 3.2 equivalents), and at this temperature After stirring for 30 minutes, add (-)-spartenine (3.2 equivalents), then stir at this temperature for 30 minutes, add 20 mL of valeric acid ether solution (2.0 g valeric acid, 1 equivalent) represented by formula (II) , then stirred at -40°C for 1 hour, then cooled to -78°C, added 20 mL of bromoacetonitrile in ether (2.4 g bromoacetonitrile, 1 equivalent), stirred at -78°C for 2 hours, and then heated to 0 ℃, drop 50mL saturated ammonium chloride aqueous solution to terminate the reaction, wash with 75mL water, 75mL saturated brine successively, dry, spin to dry the solvent, and after column chromatography, obtain the compound shown in formula (III) (yield 56 %, e.r. value is 98:2, e.r. refers to the ratio of t...

Embodiment 2

[0035] Synthesis of the compound shown in embodiment 2 formula (III)

[0036] Dissolve diisopropylamine (6.1 g, 3 equivalents) in 30 mL of ether, cool to -78°C, add 40 mL of n-butyl lithium in n-hexane (1.6M n-hexane solution, 3.2 equivalents), and at this temperature After stirring for 30 min, add the compound (3.2 equivalents) shown in formula (VI) again, then stir at this temperature for 30 min, add 20 mL of valeric acid ether solution (2.0 g valeric acid, 1 equivalent) shown in formula (II) , then stirred at -40°C for 1 hour, then cooled to -78°C, added 20 mL of bromoacetonitrile in ether (2.4 g bromoacetonitrile, 1 equivalent), stirred at -78°C for 2 hours, and then heated to 0 ℃, drop 50mL of saturated ammonium chloride aqueous solution to terminate the reaction, wash with 75mL of water, 75mL of saturated brine successively, dry, spin to dry the solvent, and after column chromatography, obtain the compound shown in formula (III) (yield 49 %, e.r. value is 96:4, e.r. ref...

Embodiment 3

[0039] The compound represented by formula (III) prepared in Example 1 (10 g, 1 equivalent) was dissolved in 200 mL of tetrahydrofuran and cooled to 0° C., and 280 mL of tetrahydrofuran borane complex (1M tetrahydrofuran, 4 equivalents) was added, 20 to 30 After stirring overnight at ℃, 100 mL of 1N (mol / L) hydrochloric acid aqueous solution was added dropwise, stirred for 1 hour, diluted with 500 mL of methyl tert-butyl ether, washed successively with 250 mL of 1N aqueous hydrochloric acid solution, 250 mL of saturated aqueous sodium bicarbonate solution, and 250 mL of saturated brine. After drying and spin-drying the solvent, the compound represented by formula (IV) was obtained (7.7 g, yield 85%). high resolution mass spectrometry (ESI + ): The theoretical value of C7H14NO+ is 128.1070, and the measured value is 128.1063.

[0040] Suspend the compound (20.3g, 1 equivalent) represented by formula (IV) in a mixture of 30mL ethanol and 10mL water, add NaOH (3g), reflux for 20...

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Abstract

The invention discloses a novel butyrolactone derivative synthesizing method. The method comprises the following steps: (1) pentanoic acid shown in a formula (II) reacts with bromoacetonitrile after achiral lithiation reaction, and a compound shown in a formula (III) is obtained; (2) a carboxyl group of the compound shown in the formula (III) is reduced by borane, and a compound shown in the formula (IV) is obtained; (3) a cyano group of the compound represented in the formula (IV) is hydrolyzed under the basic condition, a carboxylic acid derivative represented in the formula (V) is obtainedand subjected to a dehydration cyclization reaction, and the butyrolactone derivative represented in the formula (I) is obtained. The method has the advantages that the synthesis cost of raw materialpentanoic acid is low, only four steps are needed, the stereoselectivity is good, and accordingly, the production cost can be obviously reduced. The synthesis route is shown in the description.

Description

technical field [0001] The invention relates to the technical field of organic compound synthesis, and more specifically relates to a novel method for synthesizing butyrolactone derivatives. Background technique [0002] The butyrolactone derivative represented by the following formula (I) is a key intermediate in the synthesis of the novel antiepileptic drug Brivaracetam. [0003] [0004] At present, many documents have reported the synthesis method of the above-mentioned butyrolactone derivatives. For example, the following synthesis method has been reported in the patent document WO2016 / 191435, wherein R-epichlorohydrin is used as raw material, and diethyl malonate Ester condensation, reaction with ethyl magnesium bromide, and finally decarboxylation to obtain the key intermediate butyrolactone derivatives, but the cost is relatively expensive. [0005] [0006] As another example, the document Hughes, G. et al., J.Am.Chem.Soc.2003, 125, 11253-11258 reported that ...

Claims

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Application Information

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IPC IPC(8): C07D307/33C07D207/27
CPCC07D307/33C07D207/27
Inventor 钱祝进许良志胡志刚何大荣杜小鹏何勇刘庄子
Owner 安徽华胜医药科技有限公司
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