WO2016074324A1 - Preparation method of 2-((4r, 6s)-6-bromomethyl-2, 2-dimethyl-1, 3-dioxane-4-yl)acetate - Google Patents

Abstract

Provided is a preparation method of 2-((4R, 6S)-6-bromomethyl-2, 2-dimethyl-1, 3-dioxane-4-yl)acetate (I). Such compound is a key chiral intermediate in preparing a statins lipid-lowering drugs. The method comprises: carrying out a bromination cyclization reaction on 3-((substituted oxyformyl)oxy)-5-hexenoate (II) with a bromination reagent in an organic solvent in the presence of an inorganic base to obtain 2-((4R, 6S)-6-bromomethyl-2-oxo-1, 3-dioxane-4-yl)acetate (III), and then carrying out a ketalation reaction with a ketalation reagent in the presence of a protonic acid to obtain the 2-((4R, 6S)-6-bromomethyl-2, 2-dimethyl-1, 3-dioxane-4-yl)acetate (I). The method has readily available raw material, mild conditions, simple operation and low cost, thus facilitating industrial production.

Description

Preparation method of 2-((4R,6S)-6-bromomethyl-2,2-dimethyl-1,3-dioxohex-4-yl)acetate Technical field

The invention belongs to the technical field of chemical synthesis and relates to a 2-((4R,6S)-6-bromomethyl-2,2-dimethyl-1,3-dioxohex-4-yl)acetate. The preparation method can be used as an important drug to synthesize a chiral intermediate for the synthesis of statin hypolipidemic drugs.

Background technique

2-((4R,6S)-6-Bromomethyl-2,2-dimethyl-1,3-dioxohex-4-yl)acetate is a chemical synthesis intermediate that can be used in statins Synthesis of lipid-lowering drugs. Its structural formula is shown in the following figure (I).

Wherein R is C ₁ -C ₈ alkyl or cycloalkyl, monosubstituted or polysubstituted aryl or aralkyl.

U.S. Patent No. 5,228,313 discloses the use of methyl (S)-4-bromo-3-hydroxybutanoate as a starting material for Claisen condensation with tert-butyl acetate and diastereomeric selection with diethylmethoxyboron/borohydride. Preparation of tert-butyl 2-((4R,6S)-6-bromomethyl-2,2-dimethyl-1,3-dioxacyclo-4-yl)acetate by sexual reduction and ketalization (I) Methods.

However, the first two steps of the method are carried out under low temperature (-78 ° C) and anhydrous anaerobic conditions, the reaction conditions are harsh, and the expensive flammable and explosive diethyl methoxy boron is used in the reduction reaction. Industrial production is inconvenient.

Chinese patent CN103614430 and the Chinese Journal of Pharmaceutical Industry 2013, 44(10): 975-977 report another case of methyl (S)-4-bromo-3-hydroxybutanoate as raw material and tert-butyl acetate. Claisen condensation, bio-reduction and ketalization to prepare 2-((4R,6S)-6-bromomethyl-2,2-dimethyl-1,3-dioxohex-4-yl)acetate The method of butyl ester (I).

This method uses Candida Magnotiae IF0705 as a reducing agent to reduce the carbonyl group of the Claisen condensation product, but this species has no commercial source.

Both of the above methods are not conducive to large-scale industrial production.

Summary of the invention

To overcome the deficiencies of the prior art, the present invention provides a 2-((4R,6S)-6-bromomethyl-2,2-dimethyl-1,3-dioxohex-4-yl) Efficient preparation method of acetate (I), suitable for industrial production.

The synthetic route is shown below:

Wherein R, R' are the same or different C ₁ -C ₈ alkyl or cycloalkyl, monosubstituted or polysubstituted aryl or aralkyl.

The specific steps are as follows: 3-((substituted oxycarbonyl)oxy)-5-hexenoic acid ester (II) is brominated by a bromination reagent in an organic solvent in the presence of an inorganic base to obtain 2-( (4R,6S)-6-Bromomethyl-2-oxo-1,3-dioxacyclo-4-yl)acetate (III). Compound (III) is ketalized with a ketalization reagent under the presence of a protonic acid to obtain 2-((4R,6S)-6-bromomethyl-2,2-dimethyl-1,3- Dioxetane-4-yl)acetate (I).

The starting material compound (II) of the present invention can be prepared by referring to the world patent WO2003053950 or the Chinese patent CN101735272. The inorganic base used in the preparation of the compound (III) from the compound (II) is an alkali metal or alkaline earth metal hydroxide, carbonate, phosphate or C ₁ -C ₄ alkoxylate such as potassium carbonate or potassium phosphate. Sodium ethoxide, etc.; the brominated reagent used is bromine, N-bromoacetamide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, N,N -dibromobenzenesulfonamide; the organic solvent used is a halogenated or polyhalogenated alkane such as dichloromethane, chloroform, a monosubstituted or polysubstituted aromatic hydrocarbon such as toluene, chlorobenzene, a symmetric, asymmetric ether or a cyclic ether such as diethyl ether. Methyl tert-butyl ether, tetrahydrofuran, acetonitrile, or a mixed solvent of the above solvents, which are inexpensive and readily available. In the reaction, the molar ratio of the compound (II), the bromine reagent and the base is 1:1 to 5:1 to 5, the reaction temperature is -80 to 0 ° C, and the reaction time can be smoothly carried out when the reaction time is 10 to 120 minutes. The compound (III) obtained by the reaction was used in the next step without isolation and purification.

The protic acid used in the preparation of the compound (I) from the compound (III) in the present invention is hydrogen chloride, sulfuric acid, C ₁ -C ₆ alkylsulfonic acid, monosubstituted or polysubstituted arylsulfonic acid or camphorsulfonic acid. The ketalization reagent used is acetone, 2,2-dimethylpropane or a mixture of the two in any ratio. The compound (III), the protic acid and the ketalization test have a molar ratio of 1:0.01 to 1:5 to 500, and are reacted at 0 to 50 ° C for 6 to 72 hours to obtain the compound (I).

The best conditions in the present invention are:

When the compound (III) is produced from the compound (II), the solvent used is dichloromethane, the base is potassium carbonate, and the bromine reagent is bromine. The molar ratio of the compound (II), the inorganic base and the bromine reagent is 1:1.5 to 2.5:1.5 to 2.5, the reaction temperature is -40 to -20 ° C, and the reaction time is 30 to 60 minutes.

When the compound (I) is produced from the compound (III), the acid used is p-toluenesulfonic acid or methanesulfonic acid; and the ketalization reagent used is acetone. The molar ratio of the compound (III), the acid and the ketalizing agent is from 1:0.5 to 1:20 to 100, the reaction temperature is from 25 to 35 ° C, and the reaction time is from 24 to 48 hours.

The invention has the characteristics of easy availability of raw materials, mild reaction conditions, simple operation and high product purity, and is suitable for industrial production.

detailed description

The following examples better illustrate the present invention. However, the invention is not limited to the following embodiments.

Example 1

Methyl 3-((tert-butoxycarbonyl)oxy)-5-hexenoate (1.22 g) was dissolved in dichloromethane (20 mL), potassium carbonate (1.38 g) was added, and the mixture was stirred at -40 °C Add bromine (1.6g), dilute, stir for 45 minutes, complete the reaction, add 10% sodium sulfite solution (10mL), extract the reaction with dichloromethane, combine the organic phase, wash with saturated sodium bicarbonate solution, anhydrous sulfuric acid Sodium is dried, concentrated, A crude product of methyl 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxacyclo-4-yl)acetate as a pale yellow oil was obtained.

The oil and acetone (10 g) were placed in a reaction flask, p-toluenesulfonic acid monohydrate (0.90 g) was added, and the mixture was stirred at 25 ° C for 36 hours. After completion of the reaction, saturated sodium hydrogencarbonate solution (10 mL) was added and concentrated. The acetone was extracted with ethyl acetate. The organic layer was combined, washed with 10% sodium sulfite solution and brine, and dried over anhydrous sodium sulfate to give a yellow oil 2-((4R,6S)-6-bromo Methyl 2-oxo-1,3-dioxacyclo-4-yl)acetate (1.16 g, 82%).

Example 2

Methyl 3-((tert-butoxycarbonyl)oxy)-5-hexenoate (1.22 g) was dissolved in dichloromethane (20 mL), potassium phosphate (1.60 g) was added and stirred at -20 ° C Add bromine (1.60g), drip, stir for 1 hour, complete the reaction, add 10% sodium sulfite solution (10mL), extract the reaction with dichloromethane, combine the organic phase, wash with saturated sodium bicarbonate solution, anhydrous sulfuric acid The sodium was dried and concentrated to give EtOAc (EtOAc:EtOAc.

The oil and 2,2-dimethoxypropane (15 g) were placed in a reaction flask, methanesulfonic acid (0.40 g) was added, and stirred at 25 ° C for 40 hours. After completion of the reaction, saturated sodium bicarbonate solution (10 mL) was added. The 2,2-dimethoxypropane is concentrated under reduced pressure, and the residue is evaporated to ethyl acetate. Methyl ((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxacyclo-4-yl)acetate (0.80 g, 57%).

Example 3

3-((tert-Butoxycarbonyl)oxy)-5-hexenoic acid tert-butyl ester (1.43g) was dissolved in acetonitrile (20mL), sodium carbonate (1.00g) was added, and the mixture was stirred at -40 °C Add N-bromosuccinimide (1.78g), drip, stir for 1 hour, complete the reaction, add 10% sodium sulfite solution (10mL), extract the reaction with dichloromethane, combine the organic phase, saturated hydrogen carbonate The sodium solution was washed with anhydrous sodium sulfate and concentrated to give a pale yellow oil (2-(((())))) Crude product of tert-butyl acetate.

The oil and acetone (20 g) were placed in a reaction flask, and camphorsulfonic acid (1.50 g) was added thereto, and the mixture was stirred at 35 ° C for 24 hours. After completion of the reaction, saturated sodium hydrogencarbonate solution (10 mL) was added, and acetone was concentrated under reduced pressure. Extract with ethyl acetate, combine the organic phases, and sequentially use 10% sodium sulfite solution and satiety Washed with brine and dried over anhydrous sodium sulfate to give a white oil (2-((4,6,6,6)-6-bromomethyl-2-oxo-1,3-dihexacyclo-4-yl)acetate Butyl ester (1.14 g, 71%).

Example 4

3-((Benzyloxycarbonyl)oxy)-5-hexenoic acid tert-butyl ester (1.60g) was dissolved in toluene (20mL), potassium carbonate (1.38g) was added, and bromine was added dropwise with stirring at -60 °C After the completion of the reaction, the mixture was stirred for 1.5 hours. After the reaction was completed, a 10% sodium sulfite solution (10 mL) was added, and the reaction mixture was extracted with toluene. The organic phase was combined, washed with saturated sodium hydrogen A crude yellow oil of 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dioxacyclo-4-yl)acetic acid tert-butyl ester was obtained.

The oil and acetone (20 g) were placed in a reaction flask, p-toluenesulfonic acid monohydrate (0.50 g) was added, and the mixture was stirred at 25 ° C for 48 hours. After completion of the reaction, saturated sodium hydrogen carbonate solution (10 mL) was added and concentrated. The acetone was extracted with ethyl acetate. The organic layer was combined, washed with 10% sodium sulfite solution and brine, and dried over anhydrous sodium sulfate to give a yellow oil 2-((4R,6S)-6-bromo tert-Butyl benzyl-2-oxo-1,3-dioxacyclo-4-yl)acetate (1.02 g, 63%).

Example 5

Methyl 3-((tert-butoxycarbonyl)oxy)-5-hexenoate (1.22 g) was dissolved in tetrahydrofuran (20 mL), potassium carbonate (1.38 g) was added, and bromine was added dropwise with stirring at -40 °C After the completion of the reaction, the mixture was stirred for 45 minutes. After the reaction was completed, a 10% sodium sulfite solution (10 mL) was added, and the reaction mixture was extracted with dichloromethane. The organic phase was combined, washed with saturated sodium hydrogen carbonate and dried over anhydrous sodium sulfate. Concentration gave a crude product of methyl 2-((4R,6S)-6-bromomethyl-2-oxo-1,3-dihexacyclo-4-yl)acetate as a pale yellow oil.

The oil and acetone (10 g) were placed in a reaction flask, p-toluenesulfonic acid monohydrate (0.90 g) was added, and the mixture was stirred under reflux at 56 ° C for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, and saturated sodium hydrogen carbonate solution (10 mL) was added. The acetone is concentrated under reduced pressure, and the residue is evaporated to ethyl acetate. EtOAc (EtOAc) Methyl-6-bromomethyl-2-oxo-1,3-dioxacyclo-4-yl)acetate (1.04 g, 74%).

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that the above teachings of the present invention have been read. A person skilled in the art can make various changes or modifications to the invention, and the equivalents are also within the scope defined by the appended claims.

Claims (7)

Preparation method of 2-((4R,6S)-6-bromomethyl-2,2-dimethyl-1,3-dioxohex-4-yl)acetate (I),

Wherein R is C ₁ -C ₈ alkyl or cycloalkyl, monosubstituted or polysubstituted aryl or aralkyl; Characterized in that 3-((substituted oxycarbonyl)oxy)-5-hexenoic acid ester (II) is brominated by a bromination reagent in an organic solvent in the presence of an inorganic base to give 2-(( 4R,6S)-6-bromomethyl-2-oxo-1,3-dioxacyclo-4-yl)acetate (III), which is then reduced with a ketalizing agent in the presence of a protic acid The ketonization reaction gives 2-((4R,6S)-6-bromomethyl-2,2-dimethyl-1,3-dioxohex-4-yl)acetate (I)

Wherein R, R' are the same or different C ₁ -C ₈ alkyl or cycloalkyl, monosubstituted or polysubstituted aryl or aralkyl; The specific preparation conditions are: (1) The inorganic base used in the preparation of the compound (III) from the compound (II) is an alkali metal or alkaline earth metal hydroxide, carbonate, phosphate or C ₁ -C ₄ alkoxylate; (2) The bromination reagent used in the preparation of the compound (III) from the compound (II) is bromine, N-bromoacetamide, N-bromosuccinimide, 1,3-dibromo-5,5. - dimethylhydantoin, N,N-dibromobenzenesulfonamide; (3) The organic solvent used in the preparation of the compound (III) from the compound (II) is a halogenated or polyhalogenated alkane, a monosubstituted or polysubstituted aromatic hydrocarbon, a symmetric or asymmetric ether or a cyclic ether, acetonitrile or a mixture of the above solvents. Solvent (4) The protic acid used in the preparation of the compound (I) from the compound (III) is hydrogen chloride, sulfuric acid, C ₁ -C ₆ alkylsulfonic acid, monosubstituted or polysubstituted arylsulfonic acid or camphorsulfonic acid; (5) The ketalization reagent used in the preparation of the compound (I) from the compound (III) is acetone, 2,2-Dimethoxypropane or a mixture of the two in any ratio. The preparation method according to claim 1, wherein the molar ratio of the compound (II), the inorganic base to the bromine reagent is 1:1 to 5:1 to 5, the reaction temperature is -80 to 0 ° C, and the reaction time is 10 to 120. minute. The preparation method according to claim 1, wherein the molar ratio of the compound (III), the protonic acid and the ketalizing agent is 1:0.01 to 1:5 to 500, the reaction temperature is 0 to 100 ° C, and the reaction time is 6 to 72. hour. The method of claim 1 wherein the inorganic base used is potassium carbonate; the bromine reagent is bromine; and the solvent is dichloromethane. The method according to claim 2, wherein the molar ratio of the compound (II), the inorganic base and the bromine reagent is preferably 1:1.5 to 2.5:1.5 to 2.5, the reaction temperature is -40 to -20 ° C, and the reaction time is 30 °. 60 minutes. The method of claim 1 wherein the protonic acid used is preferably p-toluenesulfonic acid or methanesulfonic acid; the ketalizing agent used is acetone. The method according to claim 3, wherein the molar ratio of the compound (III), the protonic acid and the ketalizing agent is preferably 1:0.5 to 1:20 to 50, the reaction temperature is 25 to 35 ° C, and the reaction time is 24 to 48. hour.