Preparation method of (R)-(+)-lipoic acid

A technology of lipoic acid and ethyl dichlorooctanoate, which is applied in the field of preparation of R-lipoic acid, can solve the problems of inability to meet industrialized scale-up production, does not conform to green technology, and high waste discharge, and can meet the requirements of industrial scale-up production and process steps. The effect of reducing and reducing waste discharge

Inactive Publication Date: 2016-04-27
SUZHOU FUSHILAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The methods for preparing R-lipoic acid in the prior art, including the three methods mentioned above, all have high cost, low yield and large raw material consumption, which

Method used

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  • Preparation method of (R)-(+)-lipoic acid
  • Preparation method of (R)-(+)-lipoic acid
  • Preparation method of (R)-(+)-lipoic acid

Examples

Experimental program
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Embodiment 1

[0035] A) Preparation of cyclization solution: put (S)-6,8-dichlorooctanoic acid ethyl ester and sulfur into a reaction vessel equipped with a stirring device, heat up to 70°C, and add dropwise an 8% sodium sulfide aqueous solution Carry out the cyclization reaction, the time of the cyclization reaction is 5 hours, the molar ratio of (S)-6,8-dichlorooctanoic acid ethyl ester, sulfur and sodium sulfide aqueous solution is 1:1.7:1, keep the temperature at 70°C for 2h, After the cyclization reaction is completed, use an organic solvent, that is, extract with toluene, and concentrate to obtain a cyclization liquid;

[0036] B) Preparation of hydrolyzate: the cyclization solution obtained by step A) is put into a reaction vessel equipped with a stirring device and added with a mass percent concentration of 4% sodium hydroxide solution for hydrolysis reaction, and the cyclization solution and mass percent concentration are The molar ratio of the 4% sodium hydroxide solution is 1:1.5...

Embodiment 2

[0040] A) Preparation of cyclization solution: put (S)-6,8-dichlorooctanoic acid ethyl ester and sulfur into a reaction vessel equipped with a stirring device, heat up to 80°C, and add dropwise an aqueous sodium sulfide solution with a concentration of 20% by mass Carry out cyclization reaction, the time of cyclization reaction is 0.5 hours, the molar ratio of (S)-6,8-dichlorooctanoic acid ethyl ester, sulfur and sodium sulfide aqueous solution is 1:1.5:1, keep warm at 80°C for 1.5h , the cyclization reaction is completed, and the organic solvent is used to extract with ethyl acetate, and concentrated to obtain the cyclization liquid;

[0041] B) Preparation of hydrolyzate: the cyclization solution obtained by step A) is dropped into a reaction vessel equipped with a stirring device and added with a concentration of 3% potassium hydroxide for hydrolysis reaction, and the cyclization solution and mass percent concentration are The molar ratio of the 3% potassium hydroxide solut...

Embodiment 3

[0045] A) Preparation of cyclization solution: put (S)-6,8-dichlorooctanoic acid ethyl ester and sulfur into a reaction vessel equipped with a stirring device, heat up to 90°C, and add dropwise an aqueous sodium sulfide solution with a concentration of 12% by mass Carry out the cyclization reaction, the time of the cyclization reaction is 3 hours, the molar ratio of (S)-6,8-dichlorooctanoic acid ethyl ester, sulfur and sodium sulfide aqueous solution is 1:2:1.5, keep the temperature at 90°C for 1h, After the cyclization reaction is completed, use an organic solvent, that is, extract with cyclohexane, and concentrate to obtain a cyclization liquid;

[0046] B) Preparation of hydrolyzate: put the cyclization solution obtained by step A) into a reaction vessel equipped with a stirring device and add a sodium carbonate solution with a mass percent concentration of 8% to carry out the hydrolysis reaction, and the cyclization solution and mass percent concentration are 8% The molar ...

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Abstract

The invention discloses a preparation method of (R)-(+)-lipoic acid and belongs to the field of organic and medicinal chemistry. The preparation method comprises the following steps: (S)-ethyl 6,8-dichloro caprylate and sulfur are fed into a reaction container equipped with a stirring device, the mixture is heated, an aqueous sodium sulphide solution is added dropwise for a cyclization reaction, heat is preserved, then extraction and concentration are performed, and a cyclization liquid is obtained; the cyclization liquid is fed into the reaction container, an alkaline solution is added, a hydrolysis reaction is performed, and a hydrolysate is obtained through cooling; an organic solvent is added to the hydrolysate, pH is regulated with acid, extraction is performed, an organic layer obtained through extraction is washed to be neutral, then an organic solvent is removed through pressure reduction, a primary product is obtained, a mixed solvent is added to the primary product, the mixture is heated and dissolved, a filter aid is added, stirring and adsorption are performed, filtering is performed, a faint yellow liquid is obtained and cooled, crystals are precipitated, and a finished product is obtained. The steps are reduced, and the preparation efficiency is high; raw material consumption is reduced, the optical rotation of (R)-(+)-lipoic acid reaches 117-118 degrees, the ee value is 99.0%-99.5%, the content is higher than 99%, and waste emission is reduced.

Description

technical field [0001] The invention belongs to the field of organic medicinal chemistry, and in particular relates to a preparation method of R-lipoic acid. Background technique [0002] The aforementioned R-lipoic acid, also known as D-lipoic acid, is a white or light yellow odorless powder or crystal. Optical rotation +120°, Solubility: Insoluble in water, but soluble in benzene, ethanol, chloroform, lipids, etc. The English names of R-lipoic acid are: (R)-(+)-Lipoicacid, (R)-(+)-Thiocticacid and (R)-(+)-1,2Dithiolane-3-pentanoic acid; the chemical name is: ( R)-(+)-1,2-dithiolanyl-3-pentanoic acid and (R)-(+)-5-(1',2'-dithianolyl-3'-)- Valeric acid. [0003] Lipoic acid is a biologically active natural product. In 1951, Raed et al. reported that a crystalline cofactor of a growth-promoting enzyme was isolated from treated insoluble liver tissue residues. Because of its high fat solubility and acidity (pka=4.7), this compound was named sulfur bitter. [0004] R-lipo...

Claims

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Application Information

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IPC IPC(8): C07D339/04
CPCC07D339/04C07B2200/07
Inventor 丁建飞
Owner SUZHOU FUSHILAI PHARMA CO LTD
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