Preparation method of 2-((4R, 6S)-6-chloromethyl-2-alkyl-1,3-dioxane -4-yl)acetic acid

A technology of dioxane and chloromethyl is applied in the field of synthesis of statin hypolipidemic drugs, can solve problems such as unfavorable large-scale industrial production, and achieve the effects of low cost, easy availability of raw materials and mild reaction conditions

Inactive Publication Date: 2013-07-31
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] Above-mentioned several methods are all unfavorable for large-scale industrialized production

Method used

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  • Preparation method of 2-((4R, 6S)-6-chloromethyl-2-alkyl-1,3-dioxane -4-yl)acetic acid
  • Preparation method of 2-((4R, 6S)-6-chloromethyl-2-alkyl-1,3-dioxane -4-yl)acetic acid
  • Preparation method of 2-((4R, 6S)-6-chloromethyl-2-alkyl-1,3-dioxane -4-yl)acetic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Will ( S )-7-Chloro-6-hydroxyhept-3-vin-2-one (1.82 g) was dissolved in dichloromethane (50 ml), and fresh acetaldehyde (2 ml) and nitric acid pentahydrate were added under stirring at room temperature Bismuth (0.5 g), stirred at room temperature in the dark for 4 d, after the reaction was completed, washed with water, dried the organic phase with anhydrous sodium sulfate, concentrated to obtain a yellow oily liquid 1-((4 R ,6 S )-6chloromethyl-2-methyl-1,3-dioxan-4-yl)propan-2-one (2.00 g, 97%) = 4.8 o ( c 1.0, CHCl 3 );

[0045] 1 H NMR (400MHz, CDCl 3 ): δ 4.69 (q, J=4.8Hz, 1H) 4.05 (m, 1H) 3.81 (m, 1H) 3.49 (dd, J =11.2, 5.6Hz, 1H) 3.40 (dd, J =11.6, 5.2Hz, 1H) 2.73 (dd, J =16.4, 6.8Hz, 1H) 2.45 (dd, J =16.4, 5.2Hz, 1H) 2.13 (s, 3H) 1.68 (d, J =12.8Hz, 1H) 1.34~1.23 (m, 4H).

Embodiment 2

[0047] Will ( S )-7-Chloro-6-hydroxyhept-3-vin-2-one (1.82 g) was dissolved in 1,2-dichloroethane (50 ml), and propionaldehyde (1.5 g) and Bismuth nitrate pentahydrate (0.5 g), stirred at room temperature in the dark for 3 days, after the reaction was completed, washed with water, the organic phase was dried with anhydrous sodium sulfate, concentrated to obtain a yellow oily liquid 1-((4 R ,6 S )-6chloromethyl-2-ethyl-1,3-dioxan-4-yl)propan-2-one (2.07 g, 94%) = 4.3 o ( c 1.0, CHCl 3 ).

Embodiment 3

[0049] Will ( S )-7-Chloro-6-hydroxyhept-3-vin-2-one (1.82 g) was dissolved in dichloromethane (50 ml), and freshly prepared acetaldehyde (4 ml) and pentahydrate were added under stirring at 0°C Bismuth nitrate (1 g), stirred in the dark at 0°C for 7 days, after the reaction was completed, washed with water, dried the organic phase with anhydrous sodium sulfate, concentrated to obtain a yellow oily liquid 1-((4 R ,6 S )-6chloromethyl-2-ethyl-1,3-dioxan-4-yl)propan-2-one (1.96 g, 95%) = 4.7 o ( c 1.0, CHCl 3 ).

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Abstract

The invention belongs to the technical field of chemical synthesis, and concretely relates to a p reparation method of 2-((4R, 6S)-6-chloromethyl-2-alkyl-1,3-dioxane-4-yl)acetic acid. The compound is a key intermediate for preparing statin hypolipemic drugs. According to the method, (S)-7-chloro-6-hydroxyheptyl-3-vinyl-2-one is used as raw materials, 1-(6-chloromethyl-2-alkyl-1,3-dioxane-4-yl)propyl-2-one is obtained through addition, and the 2-((4R, 6S)-6-chloromethyl-2-alkyl-1,3-dioxane-4-yl)acetic acid (I) is obtained through a haloform reaction. The method is mild in condition, simple to operate and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, in particular to a method for the preparation of 2-((4R,6S)-6-chloromethyl-2-alkyl-1,3-dioxane-4-yl)acetic acid method, the compound can be used as an important chiral intermediate for the synthesis of statin hypolipidemic drugs. Background technique [0002] 2-((4 R ,6 S )-6-chloromethyl-2-alkyl-1,3-dioxane-4-yl)acetic acid is a chemical synthesis intermediate, which can be used in the synthesis of statins for hypolipidemic drugs. Its structural formula is shown in the following formula (I). [0003] [0004] In the formula; R is C 1 -C 4 alkyl. [0005] Chinese patents CN101613341 and CN102180862 etc. reported that (S)-4-chloro-3-hydroxybutyronitrile and tert-butyl bromoacetate were reacted by Blaise and then methoxy diethyl boron was used as chiral control reagent by sodium borohydride Reduction, and finally prepare 2-((4 R ,6 S )-6-chloromethyl-2,2-dimethyl-1,3-dioxane-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D319/06
Inventor 陈芬儿熊方均李杰胡乐萌陈文学何秋琴
Owner FUDAN UNIV
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