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Simvastatin ammonium salt intermediates and preparation methods thereof

An intermediate, inert gas technology, applied in the field of simvastatin ammonium salt intermediate and its preparation, can solve the problems of poor overall product quality, unsuitable for industrial production, difficult to remove by-products, etc. The effect of industrial application value

Inactive Publication Date: 2014-06-04
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is to overcome the existing method for synthesizing simvastatin, which easily generates difficult-to-remove by-products, makes the overall product poor in quality, and is not suitable for industrialized production, and provides a method that can avoid the above-mentioned problems, and A new method with simple operation and high industrial application value, as well as the intermediate used in the method and its preparation method

Method used

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  • Simvastatin ammonium salt intermediates and preparation methods thereof
  • Simvastatin ammonium salt intermediates and preparation methods thereof
  • Simvastatin ammonium salt intermediates and preparation methods thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Preparation of triol acid methyl orthoformate derivatives (I, R is methyl)

[0031]

[0032] Under nitrogen protection, suspend 2.0g (6.25mmol) of diol lactone in 20.0ml of toluene, add 0.2g (6.25mmol) of methanol and 0.12g (0.63mmol) of p-toluenesulfonic acid monohydrate, at room temperature (25℃ ) stirring reaction, HPLC detection until the amount of reactants and products constant (2.0h). After controlling the temperature in an ice bath at 0~5°C, slowly add 10.0ml of a toluene solution of trimethyl orthoformate dropwise, containing 2.7g (25.47mmol) of trimethyl orthoformate, after 1.0h the addition is complete, and continue to keep warm and stir. TLC detected that the reactant was consumed and the reaction was completed (2.0h). Then add 0.13g (1.29mmol) of triethylamine to neutralize the acid catalyst, wash the reaction solution with 2×10.0ml saturated NaCl solution, wash the organic layer with anhydrous MgSO 4 After drying, the solvent was distilled o...

Embodiment 2

[0042] Example 2 Preparation of triol acid methyl orthoformate derivatives (I, R is methyl)

[0043] Under the protection of nitrogen, suspend 2.0g (6.25mmol) of diol lactone in 20.0ml of benzene, add 0.4g (12.5mmol) of methanol and methanesulfonic acid (0.12g, 1.25mmol), and stir the reaction at room temperature (30°C) , HPLC detection until the amount of reactant and product is constant (2.0h). After controlling the temperature in an ice bath at 4~5°C, slowly add 10.0ml of a toluene solution of trimethyl orthoformate dropwise, containing 2.0g (18.75mmol) of trimethyl orthoformate, after 1.0h the addition is complete, and continue to insulate and stir. TLC detected that the reactant was consumed and the reaction was completed (1.0h). Then add 0.13g (1.29mmol) of triethylamine to neutralize the acid catalyst, wash the reaction solution with 2×10.0ml saturated NaCl solution, wash the organic layer with anhydrous MgSO 4 After drying, the solvent was distilled off under reduced...

Embodiment 3

[0044] Example 3 Preparation of triol acid methyl orthoformate derivatives (I, R is methyl)

[0045] Under the protection of nitrogen, suspend 2.0g (6.25mmol) of diol lactone in 20.0ml of toluene, add 0.2g (6.25mmol) of methanol and 0.14g (0.96mmol) of 25wt% hydrochloric acid methanol solution, and stir the reaction at 0°C, HPLC Detect the amount of reactants and products until constant (2.0h). After controlling the temperature in an ice bath at 0~1°C, slowly add 10.0ml of a toluene solution of trimethyl orthoformate dropwise, containing 3.3g (31.25mmol) of trimethyl orthoformate, after 1.0h the addition is complete, continue to insulate and stir, and detect the reaction by TLC After the substance is consumed, the reaction ends (1.0h). Then add 0.13g (1.29mmol) of triethylamine to neutralize the acid catalyst, wash the reaction solution with 2×10.0ml saturated NaCl solution, wash the organic layer with anhydrous MgSO 4 After drying, the solvent was distilled off under reduce...

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Abstract

The invention discloses simvastatin ammonium salt intermediates which are represented in the formula IV and the formula I and preparation methods of the intermediates represented by the formulas I and IV. The intermediate represented by the formula IV is prepared by reacting the intermediate represented by the formula I with 2,2-dimethyl butyryl chloride. The intermediate represented by the formula I is prepared by performing transesterification on glycol lactone represented by the formula II and ortho-formate represented by the formula III. R represents methyl or ethyl. According to the methods for preparing the simvastatin ammonium salt intermediates, the operation is easy, the conditions are mild, and the yield is relatively high.

Description

[0001] This application is an application number: CN200810037175.4, application date: May 9, 2008, and is a divisional application of the patent application titled "Simvastatin Ammonium Salt Synthesis Method, Intermediate Used and Preparation Method". technical field [0002] The invention relates to a simvastatin ammonium salt intermediate and a preparation method thereof. Background technique [0003] Simvastatin ammonium salt (VI) is a key intermediate for the preparation of blood lipid-lowering drug simvastatin (VII). Utilizing the different solubility of simvastatin ammonium salt and simvastatin acid in the aqueous phase and organic phase, the active ingredients are fully extracted into the organic phase, and then the process of ammonium salt crystallization is carried out, so that impurities are effectively separated and higher purity is obtained. The ammonium salt of simvastatin is then cyclized to prepare simvastatin, so that the quality of the final product simvasta...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D319/06
Inventor 卞红平周后元应瑞芬
Owner SHANGHAI INST OF PHARMA IND CO LTD