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A kind of preparation method of atorvastatin chain measurement intermediate

A technology of reaction time and organic solvents, applied in the direction of organic chemistry, can solve the problems of unsuitable industrial production, limited industrial application, and inability to recycle, and achieve the effect of mild reaction conditions and easy operation

Active Publication Date: 2019-07-05
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The tryptophan-boron derivative chiral catalyst used in this route has no commercial source, is difficult to prepare, and cannot be recycled, which limits the industrial application of this route
[0010] Therefore, none of the above methods is suitable for industrial production

Method used

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  • A kind of preparation method of atorvastatin chain measurement intermediate
  • A kind of preparation method of atorvastatin chain measurement intermediate
  • A kind of preparation method of atorvastatin chain measurement intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1, tert-butyl ( R )-1-benzyloxyhex-5-en-3-yl carbonate (III) preparation

[0050] Will( R )-1-benzyloxyhex-5-enol (II) (100g, 485mmol), dichloromethane (500mL), zinc acetate (9g, 4.9mmol) and di-tert-butyl dicarbonate (127g, 582mmol) In the reaction flask, heat and stir to reflux for 12 hours. After the reaction is complete, cool to room temperature and filter. After the filtrate is concentrated in solvent, it is distilled under reduced pressure to obtain light yellow oily liquid (III) (134 g, 91%).

Embodiment 2

[0051] Embodiment 2, tert-butyl ( R )-1-benzyloxyhex-5-en-3-yl carbonate (III) preparation

[0052] Will( R )-1-benzyloxyhex-5-enol (200g, 0.97mol), toluene (1L), zinc acetate (18g, 9.8mmol) and di-tert-butyl dicarbonate (233g, 1.07mol) in a reaction flask , heated and stirred at 80°C for 6h, after the reaction was completed, cooled to room temperature, filtered, and the filtrate concentrated the solvent and distilled under reduced pressure to obtain a light yellow oily liquid (III) (279g, 94%).

Embodiment 3

[0053] Embodiment 3, (4 S ,6 S )-4-(2-benzyloxyethyl)-6-bromomethyl-2-oxo-1,3-dioxane (IV) preparation

[0054] Compound (III) (50g, 163mmol), potassium carbonate (34g, 244mmol) and dichloromethane (500mL) were placed in a dry reaction flask, and bromine (31g, 196mmol) was added dropwise at -40°C with stirring. After dropping within 0.5h, keep stirring for 1h, after the reaction is completed, quench with 5% sodium bisulfite solution, separate layers, extract the water phase with dichloromethane, combine several layers, wash with water, dry over anhydrous sodium sulfate, and filter , the filtrate was concentrated to give colorless oily liquid (IV) (52.6g, 98%).

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Abstract

The invention belongs to the technical field of organic chemistry and concretely relates to a preparation method of an atorvastatin measuring chain intermediate 2-((4R, 6S))-6-(2-(benzyloxy)ethyl)-2, 2-dimethyl-1, 3-dioxane-4-yl)ethylamine (I). The preparation method comprises that, through tert-butoxycarbonylation, intramolecular bromination cyclization, acetonide protection, acetylation, hydrolysis and oxidation, an aldehyde is prepared from (R)-1-benzyloxy-hex-5-en-3-ol (II) prepared from D-aspartic acid by tert-butoxycarbonylation, and through a Henry reaction, acetylation and reduction, the desired compound 2-((4R, 6S))-6-(2-(benzyloxy)ethyl)-2, 2-dimethyl-1, 3-dioxane-4-yl)ethylamine (I) is prepared from the aldehyde and nitromethane. The preparation method utilizes easily available raw materials, is carried out under mild reaction conditions, can be simply operated and is convenient to use in industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and in particular relates to an atorvastatin chain measurement intermediate--2-((4 R ,6 S )-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxane-4-yl)ethanamine (I). Background technique [0002] 2-((4 R ,6 S )-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxane-4-yl)ethylamine (I) is a synthetic hypolipidemic drug Atorval An important intermediate of statin calcium. Its structure is as follows: [0003] [0004] In 2010, M E. Maier et al. (Tetrahedron, 2010, 66:9738-9744) reported the synthesis method of compound (I) for the first time, and the synthesis route is as follows: [0005] [0006] This method uses the complex of chiral phosphorus ligand and metal iridium twice to catalyze the asymmetric allylation of the aldehyde group to extend the side chain and build the stereocenter. The chiral phosphorus ligand and iridium used in this route are very expensive. And it is difficult ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D319/06
CPCC07D319/06
Inventor 陈芬儿吴妍刘敏杰王海峰颜琳洁韩胜
Owner FUDAN UNIV
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