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

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.sub.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.

Claims

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 ##STR00005## 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.sub.2, according to following reaction route: ##STR00006## 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.sub.2 is under a pressure of 0.1 MPa to 1 MPa.

Description

DETAILED DESCRIPTION OF THE DISCLOSURE

(1) The present disclosure will be further described by embodiments. But the present disclosure is not limited thereto.

Embodiment 1

(2) (R)-3-hydroxy-5-tert-butyl hexenoate (1.86 g), potassium bromide (2.38 g) and dichloromethane (20 mL) were placed in an autoclave; CO.sub.2 (0.5 MPa) was filled; tert-butyl hypochlorite (1.63 g) as added dropwise while stirring the mixture at 20 C.; at the end of dropwise addition of tert-butyl hypochlorite, the mixture was stirred for 60 mins while being kept at a certain temperature; at the end of reaction, 10% sodium sulfite solution (15 mL) was added in the mixture; the reaction liquid was extracted with dichloromethane; and the organic phase was collected, washed with saturated sodium bicarbonate solution, dried with 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-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl) tert-butyl acetate (2.62 g, 85%).

Embodiment 2

(3) (R)-3-hydroxy-5-methyl hexenoate (1.44 g), potassium bromide (2.38 g) and acetonitrile (20 mL) were placed in an autoclave; CO.sub.2 (2 MPa) was filled; tert-butyl hypochlorite (2.17 g) was added dropwise while stirring the mixture at 0 C.; at the end of dropwise addition of tert-butyl hypochlorite, the mixture was stirred for 30 mins while being kept at a certain temperature; at the end of reaction, 10% sodium sulfite solution (15 mL) was added in the mixture; the reaction liquid was extracted with ethyl acetate; the organic phase was collected, washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, and concentrated; and the residual oily matter was washed with petroleum ether (25 mL) to obtain a light yellow oily matter 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl)methyl acetate (2.09 g, 75%).

Embodiment 3

(4) (R)-3-hydroxy-5-tert-butyl hexenoate (1.86 g) was dissolved in dichloromethane (20 mL), and added with sodium bromide (2.06 g); CO.sub.2 (0.1 MPa) was filled; isopropyl hypochlorite (1.90 g) was added dropwise while stirring the mixture at 25 C.; at the end of dropwise addition of isopropyl hypochlorite, the mixture was stirred for 45 mins while being kept at a certain temperature; at the end of reaction, 10% sodium sulfite solution (15 mL) was added in the mixture; the reaction liquid was extracted with dichloromethane; and the organic phase was collected, washed with saturated sodium bicarbonate solution, dried with 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-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl) tert-butyl acetate (2.47 g, 80%).

Embodiment 4

(5) (R)-3-hydroxy-5-tert-butyl) hexenoate (1.86 g) was dissolved in tetrahydrofuran (20 mL), and added with ammonium bromide (1.50 g); CO.sub.2 (0.1 MPa) was filled; tert-butyl hypochlorite (3.24 g) was added dropwise while stirring the mixture at 0 C.; at the end of dropwise addition of tert-butyl hypochlorite, the mixture was stirred for 90 mins while being kept at a certain temperature; at the end of reaction, 10% sodium sulfite solution (15 mL) was added in the mixture; the reaction liquid was extracted with ethyl acetate; and the organic phase was collected, washed with saturated sodium bicarbonate solution, dried with 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-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxane-4-yl) tert-butyl acetate (2.13 g, 69%).