Synthesizing method of butyrolactone derivative

A synthesis method and derivative technology, applied in the field of synthesis of butyrolactone derivatives, can solve problems such as difficulty in maintaining extremely high chiral purity, and achieve the effects of good regioselectivity, simple steps, and low cost

Inactive Publication Date: 2018-02-06
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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  • Synthesizing method of butyrolactone derivative
  • Synthesizing method of butyrolactone derivative
  • Synthesizing method of butyrolactone derivative

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Experimental program
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Embodiment 1

[0026] The preparation of (R)-2-propyl-oxirane shown in embodiment 1 formula (II)

[0027] The synthetic route is as follows:

[0028]

[0029] Add R-epichlorohydrin (4.0g, 43.2mmol), cuprous cyanide (387mg, 4.32mmol) and tetrahydrofuran (50mL) into the three-necked flask, cool to -78°C under stirring, and add 1mol / L ethyl bromide dropwise Magnesium chloride in tetrahydrofuran (21.6 mL, 64.9 mmol). The temperature of the reaction solution was slowly raised to -20°C, and 100 mL of saturated ammonium chloride aqueous solution was added dropwise. After the dropwise addition, the layers were allowed to stand and the water phase was extracted with methyl tert-butyl ether (50 mL×3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain a yellow oil. The above yellow oil was dissolved in 50 mL of ether, powdered sodium hydroxide (9.4 g, 235 mmol) was added, vigorously stirred at room temperature for...

Embodiment 2

[0030] The preparation of embodiment 2 organozinc compounds

[0031] In a reaction flask, after zinc powder (15.1 g, 231 mmol) was mixed with 90 mL of toluene, trimethylchlorosilane (TMSCl) (3.7 mL, 29 mmol) was added under nitrogen protection, and the mixture was heated at 60° C. for 20 minutes, Then ethyl bromoacetate (213 mmol) was added dropwise, and the temperature was controlled at 60° C., heated at this temperature for 30 minutes, cooled to 20-30° C., and supernatant A was obtained after filtration, which was an organozinc compound.

Embodiment 3

[0032] The preparation of embodiment 3 organozinc compounds

[0033] In the reaction flask, after mixing zinc powder (174mmol) with 80mL toluene, trimethylchlorosilane (TMSCl) (3.7mL, 29mmol) was added under nitrogen protection, the mixture was heated at 50°C for 10 minutes, and then added dropwise Ethyl bromoacetate (145 mmol), and the temperature was controlled at 50°C, heated at this temperature for 20 minutes, cooled to 20-30°C, filtered to obtain the supernatant A, which was the organozinc compound.

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Abstract

The invention discloses a synthesizing method of a butyrolactone derivative. The synthesizing method comprises the following steps of (1) activating (R)-2-propyl-ethylene oxide shown in a formula (II)by a titanium reagent, and performing addition reaction by an organic zinc compound, so as to obtain a compound shown in a formula (III); (2) performing molecular lactone exchange reaction on the compound shown in the formula (III) under the acid condition, so as to obtain the butyrolactone derivative shown in a formula (I). The synthesizing method has the advantages that the synthesizing steps are simple, the production cost is low, the selectivity of areas is strong, and the yield rate is high; the synthesizing route is shown in the description.

Description

technical field [0001] The invention relates to the technical field of organic compound synthesis, more specifically to a 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 n-valeraldehyde wa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/33C07D207/27
Inventor 杜小鹏许良志胡志刚何大荣钱祝进何勇刘庄子
Owner 安徽华胜医药科技有限公司
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