Preparation method for 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate

Patent metadata

Field	Value
Publication number	US-10214506-B2
Application number	US-201815871049-A
Country	US
Kind code	B2
Filing date	Jan 14, 2018
Priority date	May 25, 2017
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

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 CO 2 . 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.

First claim

What is claimed is:

1. A preparation method for 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate, characterized in that
a chemical formula of the 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate (I) is

wherein R is alkyl or cycloalkyl having 1 to 8 carbon atoms, or mono- or poly-substituted aryl or aralkyl, wherein 2((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)acetate (I) is prepared by bromination and cyclization of 3-((substituted oxycarbonyl)oxy)-5-hexenoate as raw material with hypochlorite sad bromide in an organic solvent in presence of CO 2 , according to following reaction route:

wherein R and R′ are same or different alkyl or cycloalkyl having 1 to 8 carbon atoms, or mono- or poly-substituted aryl or aralkyl;
M is alkali metal, alkaline earth metal or ammonium cation; wherein
the hypochlorite is selected from one or more of ethyl hypochlorite, isopropyl hypochlorite and tert-butyl hypochlorite;
the bromide is selected from one or more of potassium bromide, sodium bromide and ammonium bromide; and
the organic solvent is selected from one or more of ethyl acetate, dichloromethane, tetrahydrofuran, methanol, acetic acid, N,N-dimethyl formamide, acetone and acetonitrile.

2. The preparation method according to claim 1 , wherein
a mole ratio of the 3-((substituted oxycarbonyl)oxy)-5-hexenoate (II) to the hypochlorite to the bromide is 1:(1-5):(1-5);
a reaction temperature is −60° C. to 50° C.; and
a reaction time is 10 mins to 180 mins.

3. The preparation method according to claim 1 , wherein
the hypochlorite is tert-butyl hypochlorite;
the bromide is potassium bromide; and
the organic solvent is dichloromethane.

4. The preparation method according to claim 2 , wherein
the hypochlorite is tert-butyl hypochlorite;
the bromide is potassium bromide; and
the organic solvent is dichloromethane.

5. The preparation method according to claim 2 , wherein
a mole ratio of the 3-((substituted oxycarbonyl)oxy)-5-hexenoate (II) to the hypochlorite to the bromide is 1:(1.5-2.5):(1.5-2.5);
a reaction temperature is −40° C. to 25° C.; and
a reaction time is 30 mins to 60 mins.

6. The preparation method according to claim 1 , wherein
the CO 2 is under a pressure of 0.1 MPa to 1 MPa.

Assignees

• Univ Fudan

Inventors

• Chen Fener
• Huang Guanxin
• Meng Ge
• Liu Minjie
• Wu Yan
• Cheng Dang
• Huang Zedu
• Peng Haihui
• Xiong Fangjun

Classifications

• C07B41/12

  of carboxylic acid ester groups · CPC title

• C07B47/00

  Formation or introduction of functional groups not provided for in groups C07B39/00 - C07B45/00 · CPC title

• C07D319/06 Primary

  not condensed with other rings · CPC title