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Preparation method of atorvastatin measuring chain intermediate

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

Active Publication Date: 2017-03-15
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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  • Preparation method of atorvastatin measuring chain intermediate
  • Preparation method of atorvastatin measuring chain intermediate
  • Preparation method of atorvastatin measuring chain 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) (100 g, 485 mmol), dichloromethane (500 mL), zinc acetate (9 g, 4.9 mmol) and di-tert-butyl dicarbonate (127 g, 582 mmol) were placed In the reaction flask, heat and stir to reflux for 12 h, after the reaction is completed, cool to room temperature, filter, and concentrate the filtrate with solvent, and then distill under reduced pressure to obtain a pale 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) were placed in a reaction flask , heated and stirred at 80 °C for 6 h, the reaction was completed, cooled to room temperature, filtered, the filtrate was concentrated to solvent, and then distilled under reduced pressure to obtain a pale yellow oily liquid (III) (279 g, 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) (50 g, 163 mmol), potassium carbonate (34 g, 244 mmol) and dichloromethane (500 mL) were placed in a dry reaction flask, and bromine (31 g, 196 mmol) was added dropwise at -40°C with stirring. The dripping was completed within 0.5 h, and the mixture was kept under stirring for 1 h. After the reaction was completed, it was quenched with 5% sodium bisulfite solution, and the layers were separated. The aqueous phase was extracted with dichloromethane, and several layers were combined, washed with water, dried over anhydrous sodium sulfate, and filtered. , the filtrate was concentrated to give a 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 a kind of atorvastatin chain measuring intermediate--2-((4 R ,6 S )-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)ethanamine (I). Background technique [0002] 2-((4 R ,6 S )-6-(2-(benzyloxy)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)ethanamine (I) is a synthetic hypolipidemic drug Atova. Important intermediate of statin calcium. Its structure is as follows: [0003] [0004] In 2010, M E. Maier et al. (Tetrahedron, 2010, 66: 9738-9744) first reported the synthetic method of compound (I), and its synthetic route is as follows: [0005] [0006] In this method, the complex of chiral phosphorus ligand and metal iridium is used twice to catalyze the asymmetric allylation of aldehyde groups to extend the side chain and build the stereocenter. Both the chiral phosphorus ligand and iridium used in this route are very expensive. And it is difficult to r...

Claims

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Application Information

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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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