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Preparation method of R-lipoic acid cholinesterase halide

A lipoic acid choline and halide technology, which is applied in the field of pharmaceutical chemical synthesis, can solve problems such as preparation conditions and operations that are not given, and achieve the effects of safe use, simplified operation, and reasonable reaction route

Inactive Publication Date: 2017-08-25
SUZHOU FUSHILAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] but did not give the preparation conditions and operations

Method used

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  • Preparation method of R-lipoic acid cholinesterase halide
  • Preparation method of R-lipoic acid cholinesterase halide
  • Preparation method of R-lipoic acid cholinesterase halide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Preparation of R-lipoic acid-2-chloroethyl ester:

[0031] Method A): Add R-lipoic acid (10.0g, 48.5mmol) and dichloromethane (200mL) into the reaction flask, stir to dissolve, add N,N'-dicyclohexylcarbodiimide (12.0g, 58.2mmol ) and 4-dimethylaminopyridine (1.2g, 9.7mmol), cooled in an ice bath, 2-chloroethanol (8.8g, 109.1mmol) was added dropwise, and the reaction mixture was reacted at 35°C for 18h. Post-treatment and purification, the crude product was recrystallized with a mixed solvent of ethyl acetate and n-hexane to obtain R-lipoic acid-2-chloroethyl ester, a light yellow solid (12.0g), with a yield of 92%, and the reaction formula was:

[0032]

[0033] (2) Preparation of R-lipoic acid choline ester chloride:

[0034] R-lipoic acid-2-chloroethyl ester (12.0g, 44.6mmol) and toluene (200mL) were added to the reaction flask, stirred and dissolved, cooled in an ice bath, trimethylamine aqueous solution (7.5mL, 16.9M, 126.8mmol) was added dropwise, The reac...

Embodiment 2

[0037] (1) Preparation of R-lipoic acid-2-bromoethyl ester:

[0038] Method A): Add R-lipoic acid (12.0g, 58.2mmol) and acetonitrile (250mL) into a reaction flask, stir to dissolve, add N,N'-carbonyldiimidazole (10.4g, 64.0mmol) and 2,6-bis Pyridine (0.6g, 5.8mmol) was cooled in an ice bath, 2-bromoethanol (21.8g, 174.5mmol) was added dropwise, and the reaction mixture was reacted at 20°C for 24h. After treatment and purification, the crude product was recrystallized with a mixed solvent of ethyl acetate and n-hexane to obtain R-lipoic acid-2-bromoethyl ester, a light yellow solid (15.7g), with a yield of 86%. The reaction formula is:

[0039]

[0040](2) Preparation of R-lipoic acid choline ester bromide:

[0041] R-lipoic acid-2-bromoethyl ester (15.5g, 49.5mmol) and acetonitrile (200mL) were added to the reaction flask, stirred to dissolve, cooled in an ice bath, and trimethylamine aqueous solution (6.5mL, 16.9M, 109.9mmol) was added dropwise, The reaction mixture was ...

Embodiment 3

[0044] (1) Preparation of R-lipoic acid-2-iodoethyl ester:

[0045] Method A): Add R-lipoic acid (15.0g, 72.7mmol) and methyl tert-butyl ether (300mL) into the reaction flask, stir to dissolve, add N,N'-diisopropylcarbodiimide (11.9 g, 94.5mmol) and pyridine (1.7g, 21.8mmol), cooled in an ice bath, 2-iodoethanol (18.8g, 109.1mmol) was added dropwise, and the reaction mixture was reacted at 50°C for 12h. After treatment and purification, the crude product was recrystallized with a mixed solvent of ethyl acetate and n-hexane to obtain R-lipoic acid-2-iodoethyl ester, a light yellow solid (23.0g), with a yield of 88%, and the reaction formula was:

[0046]

[0047] (2) Preparation of R-lipoic acid choline ester iodide:

[0048] Add R-lipoic acid-2-iodoethyl ester (23.0g, 63.8mmol) and N,N-dimethylformamide (250mL) into the reaction flask, stir to dissolve, cool in an ice bath, add trimethylamine aqueous solution (6.0mL , 16.9M, 101.4mmol), the reaction mixture was reacted at...

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Abstract

The invention provides a preparation method of an R-lipoic acid cholinesterase halide and belongs to the technical field of medicinal chemical synthesis. R-lipoic acid-2-halogen ethyl ester I and trimethylamine react in a solvent to generate quaternary ammonium salt, so that an R-lipoic acid cholinesterase halide II is obtained. Impurities during reaction are fewer, and operations such as aftertreatment and purification are simplified; raw materials and the used reagent are easy to get and safe to use, and a reaction route is reasonable, so that the preparation method is applicable to industrial enlarged production; and no pollutant is produced in a preparation process, so that the green environmental protection effect is realized.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of R-lipoic acid choline ester halide. Background technique [0002] Lipoic acid (α-Lipoic acid) is a biologically active natural product that was first isolated from pig liver by Reed in 1951. Lipoic acid contains a chiral center. Studies have shown that the two enantiomers of lipoic acid, the R-enantiomer has biological activity, while the S-enantiomer is basically inactive and non-toxic. Lipoic acid has been widely used in the field of clinical medicine in Europe and America, such as liver disease, senile dementia, cataract, heart disease, diabetes, AIDS, psoriasis, eczema, Parkinson's disease, rheumatism, heart disease, neurological disease, subacute necrosis It is known as "universal antioxidant" for the treatment of diseases such as encephalopathy, radiation injury, and heavy metal poisoning. With the in-depth res...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D339/04
CPCC07B2200/07C07D339/04
Inventor 莫国宁
Owner SUZHOU FUSHILAI PHARMA CO LTD
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