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Preparation method of 2-((4r,6s)6 bromomethyl 2-oxo-1,3-dioxane-4-yl)acetate

A technology of dioxane and bromomethyl, applied in the field of chemical synthesis, can solve the problems of high cost, complicated synthesis of substituted oxyformyl protecting groups, poor atom economy and the like

Active Publication Date: 2020-10-30
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] This method avoids the formation of dibromo by-products and has certain technical advantages, but the main defect of this method is that the synthesis of the substituted oxoformyl protecting group in its starting material is cumbersome, the molecular weight of the protecting group is relatively large, and it can be removed after the reaction. Become waste, high cost, poor atom economy

Method used

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  • Preparation method of 2-((4r,6s)6 bromomethyl 2-oxo-1,3-dioxane-4-yl)acetate
  • Preparation method of 2-((4r,6s)6 bromomethyl 2-oxo-1,3-dioxane-4-yl)acetate
  • Preparation method of 2-((4r,6s)6 bromomethyl 2-oxo-1,3-dioxane-4-yl)acetate

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Experimental program
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Effect test

Embodiment 1

[0026] will( R ) Tert-butyl-3-hydroxy-5-hexenoate (1.86 g), potassium bromide (2.38 g) and dichloromethane (20 mL) are placed in an autoclave and filled with CO 2 (0.5 MPa) gas, add tert-butyl hypochlorite (1.63 g) dropwise under stirring at -20℃, after dripping, keep stirring for 60 minutes, after the reaction is complete, add 10% sodium sulfite solution (15 mL), and use two Extract with methyl chloride, combine the organic phases, wash with saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, and concentrate to obtain a light yellow solid crude product. The crude product was washed with petroleum ether (25 mL) to obtain a white powdery solid 2-((4 R , 6 S ) Tert-Butyl-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate (2.62 g, 85%).

Embodiment 2

[0028] ( R )-3-Hydroxy-5-hexenoic acid methyl ester (1.44 g), potassium bromide (2.38 g) and acetonitrile (20 mL) were placed in an autoclave and filled with CO 2 (2MPa) gas, add tert-butyl hypochlorite (2.17 g) dropwise with stirring at 0℃, after dripping, keep stirring for 30 minutes, after the reaction is completed, add 10% sodium sulfite solution (15 mL), and use ethyl acetate for the reaction solution Extract, combine the organic phases, wash with saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, concentrate, and wash the remaining oil with petroleum ether (25 mL) to obtain a pale yellow oil 2-((4 R , 6 S ) Methyl-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate (2.09 g, 75%).

Embodiment 3

[0030] will( R ) Tert-Butyl-3-hydroxy-5-hexenoate (1.86 g) was dissolved in dichloromethane (20 mL), sodium bromide (2.06 g) was added, and CO was introduced 2 (0.1 MPa) gas, add isopropyl hypochlorite (1.90 g) dropwise with stirring at 25°C. After dripping, keep stirring for 45 minutes, after the reaction is completed, add 10% sodium sulfite solution (15 mL), and use dichloride for the reaction solution Methane extraction, combined organic phases, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to obtain a light yellow solid crude product. The crude product was washed with petroleum ether (25 mL) to obtain a white powdery solid 2-((4 R , 6 S ) Tert-Butyl-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate (2.47 g, 80%).

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Abstract

The present disclosure belongs to the technical field of organic synthesis and particularly relates to a preparation method for 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate. The 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate is a key chiral intermediate for preparation of statin antilipemic agents. In the present disclosure, the 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate is obtained by bromination and cyclization of 3-((substituted oxycarbonyl)oxy)-5-hexenoate as raw material with hypochlorite and bromide in an organic solvent in the presence of CO2. The method of the present disclosure has the advantages of readily available raw material, mild reaction conditions, easy operation, low cost, excellent atomic economy and less by-products, and is applicable to industrial production.

Description

Technical field [0001] The present invention belongs to the technical field of chemical synthesis, and specifically relates to a 2-((4 R , 6 S ) Preparation method of 6-bromomethyl-2-oxo-1,3-dioxane-4-yl) acetate. Background technique [0002] 2-((4 R , 6 S )-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate is a chemical synthesis intermediate, which can be used in the synthesis of statins for lowering blood lipids. Its structural formula is shown in (I): [0003] [0004] In the formula, R is C 1 -C 8 Alkyl or cycloalkyl, mono- or multi-substituted aryl or aralkyl. [0005] The Chinese patent (CN104356109) discloses that 3-((substituted oxyformyl)oxy)-5-hexenoate is used as a raw material, and a bromocyclization reaction is carried out under the action of a bromine reagent and a base to prepare 2-((4 R , 6 S ) The method of 6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate (I). [0006] [0007] This method not only produces about 80% of the target product (I), but also generates about 20% o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D319/06
CPCC07D319/06C07B41/12C07B47/00
Inventor 陈芬儿黄关欣黄则度彭海辉熊方均
Owner FUDAN UNIV
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