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Method for synthesizing statins compounds

A technology of simvastatin and methylation, applied in the field of preparation of statin compounds

Inactive Publication Date: 2008-06-04
马群力 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above synthesis route is the main route of domestic and foreign production enterprises

Method used

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  • Method for synthesizing statins compounds
  • Method for synthesizing statins compounds
  • Method for synthesizing statins compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: the preparation of lovastatin amide

[0029] Weigh 25Kg of lovastatin, and then add 29Kg of n-butylamine, then stir and slowly raise the temperature to 80°C, reflux for 1 hour, depressurize n-butylamine, and obtain a reddish-brown intermediate.

Embodiment 2

[0030] Embodiment 2: Preparation of lovastatin amide disiloxane

[0031] Add 100Kg of DMF to lovastatin amide, stir to dissolve, slowly add 35Kg of protective group tert-butyldimethylchlorosilane, after the heat release stops, then raise the temperature to 85°C and keep it for 3 hours, add water and cyclohexane to extract and discard The water layer and the cyclohexane layer were recovered under reduced pressure to obtain a reddish-brown viscous liquid.

Embodiment 3

[0032] Embodiment 3: the preparation of simvastatin amide disiloxane

[0033] Add tetrahydrofuran 95L\tetrahydropyrrole 125L, add n-butyllithium tetrahydrofuran solution 100L (about 20%) dropwise at -15°C--30°C, keep warm for 30 minutes after dropping, add tetrahydrofuran at -15°C--30°C 215L into the lovastatin amide disiloxane solution, keep warm for 1-4 hours, add dropwise methyl chloride tetrahydrofuran saturated solution at -10-0°C, control the end point by HPLC, add water to terminate the reaction, and concentrate the post-treatment oil layer under reduced pressure to obtain a red liquid.

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Abstract

The invention relates to a novel synthesis method of statin compounds, in particular to a preparation method of methylation reaction of Simvastatin (2,2-dimethylbutyric acid-8-((4R, 6R)-6-(2-((1s, 2s, 6R, 8S, 8aR)-1,2,6,7,8,8-a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl)ethyl))tetrahydrochysene-4-hydroxy-2H-pyran-2-ketone ester) and analogues thereof. The method consists of the reaction of Lovastatin amido disiloxane and methylating agent.

Description

technical field [0001] The invention relates to a method for preparing statin compounds, in particular to a method for synthesizing simvastatin. In the process of preparing simvastatin, lovastatin is used as a raw material, and lovastatin is formed by ring opening under the action of primary or secondary amines Amide; then use tert-butyl dimethyl chlorosilane and other protective agents such as hexaalkyl disiloxane to protect the hydroxyl to obtain lovastatin amide disiloxane. The present invention is to use this as raw material methylation reaction to form Simvastatin A new preparation method of statin amide disiloxane and simvastatin amide disiloxane deprotection under acid catalysis, hydrolysis under alkaline conditions to form simvastatin acid, and finally ring-closing lactonization to form simvastatin. The chemical name of simvastatin is: 2,2-dimethylbutyric acid-8-{(4R,6R)-6-(2-[(1s,2s,6R,,8S,8aR)-1,2,6 ,7,8,-a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl]ethyl)}tetrahyd...

Claims

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Application Information

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IPC IPC(8): C07D309/30
Inventor 马群力马坚勇
Owner 马群力
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