Preparation method of chiral 2-aminomethyl tetrahydrofuran

Abstract

The invention provides a preparation method of chiral 2-aminomethyl tetrahydrofuran. The preparation method comprises the following steps: (1) reacting chiral epoxy chloropropane with 2-chloroethyl magnesium bromide to generate chiral 1, 5-dichloro-2-pentanol; (2) carrying out intramolecular cyclization reaction on the chiral 1, 5-dichloro-2-pentanol in the presence of an alkaline substance to generate chiral 5-chloro-1, 2-epoxy pentane; (3) enabling the chiral 5-chloro-1, 2-epoxypentane to react with dibenzylamine to generate chiral 1-dibenzylamino-5-chloro-2-pentanol; (4) carrying out intramolecular cyclization reaction on the chiral 1-dibenzylamino-5-chloro-2-pentanol in the presence of an alkaline substance to generate chiral 2-benzylaminomethyl tetrahydrofuran; and (5) carrying out ahydrogenation reaction on the chiral 2-benzylaminomethyl tetrahydrofuran under the action of a palladium catalyst to generate the product chiral 2-aminomethyl tetrahydrofuran. The synthetic method isshort in route, low in production cost, less in three wastes and suitable for industrial production.

Description

technical field

[0001] The invention belongs to the field of compound synthesis, and relates to a preparation method of chiral 2-aminomethyltetrahydrofuran, in particular to a preparation method of chiral optically pure 2-aminomethyltetrahydrofuran suitable for industrial production. Background technique

[0002] Chiral 2-aminomethyltetrahydrofuran, commonly known as chiral tetrahydrofurfurylamine, is an essential substance for organisms to synthesize chlorophyll, heme, cytochrome, and vitamin B2. In recent years, chiral 2-aminomethyltetrahydrofuran has attracted increasing attention as a new type of photodynamic compound, and has begun to play an important role in the fields of medicine, agriculture, and liquid crystal materials. Chiral 2-aminomethyltetrahydrofuran is an endogenous substance in organisms, and it is mainly used in photodynamic therapy in the medical field. It is a second-generation photodynamic drug that has just been developed in recent years. Compared wit...

Examples

Embodiment 1

[0061] The preparation of embodiment 1 (S)-2-aminomethyltetrahydrofuran

[0062] (1) First, 2-chloroethylmagnesium bromide. Mix 1-bromo-2-chloroethane (177.5 g, 1.25 mol) with 500 mL of tetrahydrofuran to obtain a 1-bromo-2-chloroethane tetrahydrofuran solution, which is set aside. Under the protection of nitrogen, 29.16g (1.2mol) of magnesium bars, 300mL of tetrahydrofuran, and 0.2g of iodine were sequentially added, and 20mL of the above-prepared 1-bromo-2-chloroethane tetrahydrofuran solution was added dropwise. Heat slowly to reflux. When the reaction color became lighter and faded away, the remaining 1-bromo-2-chloroethane tetrahydrofuran solution was added dropwise. After dropping, continue to reflux for 2h. After cooling to 25°C, the obtained 2-chloroethylmagnesium bromide was protected under nitrogen for later use.

[0063] Stir and mix (S)-epichlorohydrin (92.5g, 1mol) with 500mL of anhydrous tetrahydrofuran, cool to -50°C, add the above-prepared 2-chloroethylmagn...

Embodiment 2

[0069] The preparation of embodiment 2 (R)-2-aminomethyltetrahydrofuran

[0070] (1) The preparation method of 2-chloroethylmagnesium bromide is the same as in Example 1.

[0071] Stir and mix (R)-epichlorohydrin (101.8 g, 1.1 mol) and 500 mL of anhydrous tetrahydrofuran, cool to -65° C., and add the above-prepared 2-chloroethylmagnesium bromide dropwise. Control the rate of addition so that the reaction temperature is not higher than -55°C. After dropping, control the temperature in the range of -65~-55°C for 1.5h. Turn off the freezer and let it warm up to 25°C naturally. Then 400 g of saturated ammonium chloride aqueous solution was added dropwise. Stir at room temperature for 1 h, and extract the reaction solution 3 times with 500 mL of ethyl acetate each time. Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to remove the solvent, and distill under high vacuum to obtain 118.92g (R)-1,5-dichloro-2-pentanol as a light yello...

technical field

[0001] The invention belongs to the field of compound synthesis, and relates to a preparation method of chiral 2-aminomethyltetrahydrofuran, in particular to a preparation method of chiral optically pure 2-aminomethyltetrahydrofuran suitable for industrial production. Background technique

[0002] Chiral 2-aminomethyltetrahydrofuran, commonly known as chiral tetrahydrofurfurylamine, is an essential substance for organisms to synthesize chlorophyll, heme, cytochrome, and vitamin B2. In recent years, chiral 2-aminomethyltetrahydrofuran has attracted increasing attention as a new type of photodynamic compound, and has begun to play an important role in the fields of medicine, agriculture, and liquid crystal materials. Chiral 2-aminomethyltetrahydrofuran is an endogenous substance in organisms, and it is mainly used in photodynamic therapy in the medical field. It is a second-generation photodynamic drug that has just been developed in recent years. Compared wit...

Examples

Embodiment 1

[0061] The preparation of embodiment 1 (S)-2-aminomethyltetrahydrofuran

[0062] (1) First, 2-chloroethylmagnesium bromide. Mix 1-bromo-2-chloroethane (177.5 g, 1.25 mol) with 500 mL of tetrahydrofuran to obtain a 1-bromo-2-chloroethane tetrahydrofuran solution, which is set aside. Under the protection of nitrogen, 29.16g (1.2mol) of magnesium bars, 300mL of tetrahydrofuran, and 0.2g of iodine were sequentially added, and 20mL of the above-prepared 1-bromo-2-chloroethane tetrahydrofuran solution was added dropwise. Heat slowly to reflux. When the reaction color became lighter and faded away, the remaining 1-bromo-2-chloroethane tetrahydrofuran solution was added dropwise. After dropping, continue to reflux for 2h. After cooling to 25°C, the obtained 2-chloroethylmagnesium bromide was protected under nitrogen for later use.

[0063] Stir and mix (S)-epichlorohydrin (92.5g, 1mol) with 500mL of anhydrous tetrahydrofuran, cool to -50°C, add the above-prepared 2-chloroethylmagn...

Embodiment 2

[0069] The preparation of embodiment 2 (R)-2-aminomethyltetrahydrofuran

[0070] (1) The preparation method of 2-chloroethylmagnesium bromide is the same as in Example 1.

[0071] Stir and mix (R)-epichlorohydrin (101.8 g, 1.1 mol) and 500 mL of anhydrous tetrahydrofuran, cool to -65° C., and add the above-prepared 2-chloroethylmagnesium bromide dropwise. Control the rate of addition so that the reaction temperature is not higher than -55°C. After dropping, control the temperature in the range of -65~-55°C for 1.5h. Turn off the freezer and let it warm up to 25°C naturally. Then 400 g of saturated ammonium chloride aqueous solution was added dropwise. Stir at room temperature for 1 h, and extract the reaction solution 3 times with 500 mL of ethyl acetate each time. Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to remove the solvent, and distill under high vacuum to obtain 118.92g (R)-1,5-dichloro-2-pentanol as a light yello...

Images