Preparation method of (S)-3-hydroxytetrahydrofuran and (R)-3-hydroxytetrahydrofuran

Abstract

The invention discloses a preparation method of (S)-3-hydroxytetrahydrofuran and (R)-3-hydroxytetrahydrofuran, relating to the technical field of preparation of five-element heterocyclic compounds containing one oxygen atom as the only heterocyclic atom. The method comprises the following steps: by using (S)-carnitine or (R)-carnitine as the initial raw material, carrying out reduction reaction in a reducer and an organic solvent to obtain (S) or (R)-2,4-dihydroxy-N,N,N-trimethyl butyl amine alkali; adding a hydrogen chloride organic solvent solution into an organic solvent to perform salification reaction to obtain (S) or (R)-2,4-dihydroxy-N,N,N-trimethyl butyl amine hydrochloride; and finally, adding alkali into a polar solvent, heating, and carrying out cyclization reaction to obtain the (S) or (R)-3-hydroxytetrahydrofuran. The method has the advantages of low cost, simple technique, high yield, cheap and accessible raw materials, short reaction steps, short period and low pollution, and is suitable for industrial production.

Description

technical field

[0001] The invention relates to the technical field of preparation of five-membered heterocyclic compounds containing one oxygen atom as the only heterocyclic atom. Background technique

[0002] Regarding the synthesis of (S)-3-hydroxytetrahydrofuran, there have been some relevant reports in China recently. Most of the current chemical synthesis methods use (S)-4-chloro-3-hydroxybutyric acid ethyl ester as raw material. Finally, the target product is synthesized by removing the hydrogen chloride ring under acidic conditions. Although the synthesis steps of this method are short, the required raw materials are expensive and the cost is high, so it is difficult to realize industrialization.

[0003] Chemical. Research and Application.Vol.21, No.7.July.2009 reported that L-malic acid was used as the starting material to generate (S)-dimethyl malate through methyl esterification with thionyl chloride / methanol , and then reduced with sodium borohydride / sodium car...

Examples

Embodiment 1

[0022] (1) Preparation of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine base

[0023] Add 30g (0.186mol) (S)-carnitine to a four-necked flask equipped with a thermometer, stirring, and an external bath, and then add 300ml of tetrahydrofuran. 0.28mol) (1.5eq) sodium borohydride, after adding, return to room temperature for reaction, after the reaction, add 16.8g of water to quench the reaction, evaporate THF and water under reduced pressure, then add 300ml of ethyl acetate, stir, and filter with suction , The purity of the product in the filtrate: 75.8%, the filtrate is directly used for the next step of salt formation.

[0024] (2) Preparation of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine hydrochloride

[0025] Put the ethyl acetate solution of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine base prepared above in a four-necked flask, and slowly add hydrogen chloride (0.242mol ) (1.3eq) of ethyl acetate solution, the ice-water bath controlled the temperature not to exceed 40°C, ...

Embodiment 2

[0030] (1) Preparation of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine base

[0031] Add 30g (0.186mol) (S)-carnitine to a four-necked flask equipped with a thermometer, stirring, and an external bath, and then add 300ml of tetrahydrofuran. 0.558mol) (3eq) sodium borohydride, after adding, return to room temperature for reaction, after the reaction, add 16.8g of water to quench the reaction, evaporate THF and water under reduced pressure, then add 300ml of ethyl acetate, stir, and suction filter, Product purity in the filtrate: 74.1%, and the filtrate is directly used for the next step of salt formation.

[0032] (2) Preparation of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine hydrochloride

[0033] Put the ethyl acetate solution of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine base prepared above in a four-necked flask, and slowly add hydrogen chloride (0.242mol ) (1.3eq) of ethyl acetate solution, the ice-water bath controlled the temperature not to exceed 40°C, after dripping...

Embodiment 3

[0038] (1) Preparation of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine base

[0039] Add 30g (0.186mol) (S)-carnitine to a four-necked flask equipped with a thermometer, stirring, and an external bath, and then add 300ml of tetrahydrofuran. 0.465mol) (2.5eq) sodium borohydride, after adding, return to room temperature for reaction, after the reaction, add 16.8g of water to quench the reaction, evaporate THF and water under reduced pressure, then add 300ml of ethyl acetate, stir, and filter with suction , The purity of the product in the filtrate: 74.5%, the filtrate is directly used for the next step of salt formation.

[0040] (2) Preparation of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine hydrochloride

[0041] Put the ethyl acetate solution of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine base prepared above in a four-necked flask, and slowly add hydrogen chloride (0.205mol ) (1.1eq) of ethyl acetate solution, the temperature in an ice-water bath should not exceed 40°C, afte...

technical field

[0001] The invention relates to the technical field of preparation of five-membered heterocyclic compounds containing one oxygen atom as the only heterocyclic atom. Background technique

[0002] Regarding the synthesis of (S)-3-hydroxytetrahydrofuran, there have been some relevant reports in China recently. Most of the current chemical synthesis methods use (S)-4-chloro-3-hydroxybutyric acid ethyl ester as raw material. Finally, the target product is synthesized by removing the hydrogen chloride ring under acidic conditions. Although the synthesis steps of this method are short, the required raw materials are expensive and the cost is high, so it is difficult to realize industrialization.

[0003] Chemical. Research and Application.Vol.21, No.7.July.2009 reported that L-malic acid was used as the starting material to generate (S)-dimethyl malate through methyl esterification with thionyl chloride / methanol , and then reduced with sodium borohydride / sodium car...

Examples

Embodiment 1

[0022] (1) Preparation of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine base

[0023] Add 30g (0.186mol) (S)-carnitine to a four-necked flask equipped with a thermometer, stirring, and an external bath, and then add 300ml of tetrahydrofuran. 0.28mol) (1.5eq) sodium borohydride, after adding, return to room temperature for reaction, after the reaction, add 16.8g of water to quench the reaction, evaporate THF and water under reduced pressure, then add 300ml of ethyl acetate, stir, and filter with suction , The purity of the product in the filtrate: 75.8%, the filtrate is directly used for the next step of salt formation.

[0024] (2) Preparation of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine hydrochloride

[0025] Put the ethyl acetate solution of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine base prepared above in a four-necked flask, and slowly add hydrogen chloride (0.242mol ) (1.3eq) of ethyl acetate solution, the ice-water bath controlled the temperature not to exceed 40°C, ...

Embodiment 2

[0030] (1) Preparation of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine base

[0031] Add 30g (0.186mol) (S)-carnitine to a four-necked flask equipped with a thermometer, stirring, and an external bath, and then add 300ml of tetrahydrofuran. 0.558mol) (3eq) sodium borohydride, after adding, return to room temperature for reaction, after the reaction, add 16.8g of water to quench the reaction, evaporate THF and water under reduced pressure, then add 300ml of ethyl acetate, stir, and suction filter, Product purity in the filtrate: 74.1%, and the filtrate is directly used for the next step of salt formation.

[0032] (2) Preparation of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine hydrochloride

[0033] Put the ethyl acetate solution of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine base prepared above in a four-necked flask, and slowly add hydrogen chloride (0.242mol ) (1.3eq) of ethyl acetate solution, the ice-water bath controlled the temperature not to exceed 40°C, after dripping...

Embodiment 3

[0038] (1) Preparation of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine base

[0039] Add 30g (0.186mol) (S)-carnitine to a four-necked flask equipped with a thermometer, stirring, and an external bath, and then add 300ml of tetrahydrofuran. 0.465mol) (2.5eq) sodium borohydride, after adding, return to room temperature for reaction, after the reaction, add 16.8g of water to quench the reaction, evaporate THF and water under reduced pressure, then add 300ml of ethyl acetate, stir, and filter with suction , The purity of the product in the filtrate: 74.5%, the filtrate is directly used for the next step of salt formation.

[0040] (2) Preparation of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine hydrochloride

[0041] Put the ethyl acetate solution of (S)-2,4-dihydroxy-N,N,N-trimethylbutylamine base prepared above in a four-necked flask, and slowly add hydrogen chloride (0.205mol ) (1.1eq) of ethyl acetate solution, the temperature in an ice-water bath should not exceed 40°C, afte...

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