Synthesis process of racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride

Abstract

The invention relates to the technical field of research and development of chemical drugs, and discloses a synthesis process for improving the purity of racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride serving as a racemic medical intermediate, namely a racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride synthesis process adopting hydrogen peroxide as an oxidizing agent. And the whole device has multiple beneficial effects. The process can obtain the product with the purity of more than or equal to 98% to meet the medical requirements; the hydrogen peroxide is used to realize environmental protection and reduce pollution; reaction steps are optimized, conditions are mild, cost and energy consumption are reduced, the yield reaches about 70%, synthesis time is shortened to about 7-8 days, and benefits are improved. The effects of the steps are remarkable, the initial raw materials are prepared to construct a molecular skeleton, amino is introduced for precise conversion, the oxidation reaction is green and good in selectivity, a key structure is formed in the esterification reaction, a crude product is obtained through the salification reaction, recrystallization is performed for primary purification, column chromatography can be selected for further purification to reach the high standard, and a high-quality scheme is provided for synthesis of medical intermediates.

Description

Technical Field

[0001] The invention relates to the technical field of chemical drug research and development, and specifically to a synthesis process for improving the purity of racemic pharmaceutical intermediate racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride (abbreviated as: racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride). Background Art

[0002] Racemic (2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride is an important pharmaceutical intermediate, which is widely used in the preparation of anti-tumor drugs. Its preparation involves the racemization method of chiral amines, which is usually prepared by using a metal catalyst to prepare a catalyst fixed bed, and is obtained by reaction under the conditions of 150-270°C and 0.1-10MPa. This method requires a relatively large initial equipment investment, and is not applicable to thermally unstable compounds, and has certain limitations in actual production applications. Therefore, the development of this project has broad market prospects. Summary of the invention

[0003] In view of the deficiencies of the prior art, the present invention provides a synthesis process for improving the purity of racemic pharmaceutical intermediate racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride.

[0004] To achieve the above object, the present invention provides the following technical solution: a synthesis process for improving the purity of racemic pharmaceutical intermediate racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride, (i) Preparation of starting materials: select compounds containing furan rings (such as 2,5-dihydrofuran), halogenated alkanes (such as methyl bromide), amine compounds (such as ammonia or a suitable amine salt), catalysts (such as specific metal complexes), hydrogen peroxide (aqueous solution with a mass fraction of 30%), and other necessary organic solvents (such as dichloromethane, ethanol, etc.) and inorganic reagents (such as sodium hydroxide, hydrochloric acid, etc.), and prepare intermediate product 1; (ii) introducing an amino functional group: reacting the intermediate product 1 with an amine compound to introduce an amino functional group, thereby obtaining an intermediate product 2 containing an amino group; (iii) Oxidation reaction: using hydrogen peroxide as an oxidant, the intermediate product 2 is subjected to an oxidation reaction to oxidize a specific functional group into the structure required by the target product; (iv) Esterification reaction: the oxidized intermediate product 3 is reacted with methanol under the action of an acidic catalyst to undergo an esterification reaction to form an ester group; (V) Salt-forming reaction: Racemic (2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester reacts with hydrochloric acid to form hydrochloride.

[0005] Preferably, 2,5-dihydrofuran (100 g, 1.2 mol) is added to 500 mL of dry dichloromethane, stirred evenly, and methyl bromide (120 g, 1.4 mol) and an appropriate amount of a metal complex catalyst (such as 5 g of a palladium complex) are slowly added dropwise under ice bath cooling. After the addition is complete, the reaction is stirred at room temperature for 6-8 hours, and the reaction progress is monitored by gas chromatography (GC) to ensure that the reaction is complete. After the reaction is completed, the reaction solution is washed with 5% sodium hydroxide solution (2×100 mL) and saturated brine (100 mL) in sequence, the organic phase is dried with anhydrous sodium sulfate, filtered, and dichloromethane is removed by reduced pressure distillation to obtain an intermediate product 1 as a colorless oily liquid.

[0006] Preferably, the intermediate product 1 (80 g, hypothetical amount) obtained above is dissolved in 300 mL of ethanol, ammonia (excessive) is introduced, and the reaction is carried out in a high-pressure reactor at 80-90° C. and 2-3 MPa for 12-14 hours. After the reaction is completed, the reaction is cooled to room temperature, and the excess ammonia and ethanol are removed by vacuum distillation to obtain an intermediate product 2 containing an amino group as a light yellow solid.

[0007] Preferably, in a 500mL three-necked flask, the intermediate product 2 (50g, hypothetical amount) is dissolved in 200mL of dichloromethane, and a 30% mass fraction of hydrogen peroxide aqueous solution (30mL, excess) is slowly added under stirring, and an appropriate amount of alkaline catalyst (such as sodium carbonate, 5g) is added. The reaction temperature is controlled at 30-40°C during the dropwise addition. After the dropwise addition is completed, the reaction is continued to stir at this temperature for 6-8 hours. After the reaction is completed, an appropriate amount of sodium sulfite solution (mass fraction of 10%) is added to remove excess hydrogen peroxide and stirred for 30 minutes. The reaction solution is transferred to a separatory funnel, separated, the organic phase is dried with anhydrous sodium sulfate, filtered, and dichloromethane is removed by vacuum distillation to obtain the oxidized intermediate product 3 as a white solid.

[0008] Preferably, the intermediate product 3 (30 g, hypothetical amount) is added to 200 mL of methanol, an appropriate amount of concentrated sulfuric acid (2 mL) is added as a catalyst, and the reaction is carried out under reflux conditions for 8-10 hours. After the reaction is completed, it is cooled to room temperature, the reaction solution is poured into ice water, the pH is adjusted to 7-8 with sodium carbonate solution, and extracted with dichloromethane (3×100 mL). The organic phases are combined, dried with anhydrous sodium sulfate, filtered, and dichloromethane is removed by vacuum distillation to obtain racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester as a colorless oily liquid.

[0009] Preferably, the racemic (2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester (20 g, hypothetical amount) obtained above is dissolved in 100 mL of anhydrous ether, and dry hydrogen chloride gas is slowly introduced under stirring until the reaction is complete (judged by pH test paper or other detection methods). A white solid gradually precipitates, and stirring is continued for 1-2 hours to allow the reaction to proceed fully. Filter, wash the solid with a small amount of cold anhydrous ether, and dry to obtain a crude product of racemic (2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride.

[0010] Preferably, the target product is purified: Recrystallization: Dissolve the crude racemic (2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride (10 g, hypothetical amount) in an appropriate amount of ethanol-water mixed solvent (ethanol: water = 3:1), heat to 60-70°C, and stir to completely dissolve. Then slowly cool to room temperature, and then put in a refrigerator (0-5°C) for overnight, and a large amount of crystals precipitate. Collect the crystals by filtration, wash with a small amount of cold ethanol-water mixed solvent (ethanol: water = 1:1), and dry to obtain racemic (2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride with high purity. Preferably, if the purity of the product after recrystallization still does not meet the requirements, column chromatography can be used for further purification. With silica gel as the stationary phase, a suitable eluent (such as a mixed solvent of ethyl acetate-methanol-water, the ratio is adjusted according to the actual situation) is selected, and the recrystallized product is loaded for column chromatography separation. The eluate containing the target product is collected, and the solvent is removed by reduced pressure distillation to obtain high-purity racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride, and the purity can reach more than 98% by high performance liquid chromatography (HPLC) detection.

[0011] Compared with the prior art, the present invention provides a synthesis process for improving the purity of racemic pharmaceutical intermediate racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride, which has the following beneficial effects: 1. The synthesis process for improving the purity of racemic pharmaceutical intermediate racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride can finally obtain racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride with a purity of ≥98% through optimized synthesis route and purification steps, which meets the strict requirements of the pharmaceutical field for high-purity intermediates and provides a reliable basis for subsequent drug synthesis. Hydrogen peroxide is used as an oxidant, and the by-product after the reaction is mainly water, which significantly reduces the generation of hazardous waste. At the same time, the use of traditional strong oxidizing reagents is reduced, the pollution to the environment is reduced, and it is in line with the concept of green chemistry. The reaction steps are reduced compared with traditional processes, and the reaction is carried out under mild conditions, which reduces energy consumption and the need for special equipment. At the same time, the yield is improved to about 70%, which reduces production costs and improves economic benefits. The synthesis time is shortened compared with the traditional process, from about 10-12 days to about 7-8 days, which improves production efficiency.

[0012] 2. The synthesis process for improving the purity of the racemic pharmaceutical intermediate racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride uses 2,5-dihydrofuran and methyl bromide as raw materials, reacts under the action of a metal complex catalyst, and successfully constructs the basic molecular skeleton required for subsequent reactions, laying the foundation for the introduction of other functional groups. By precisely controlling the reaction conditions, this step has high selectivity, can effectively reduce the occurrence of side reactions, and improve the purity and yield of the intermediate 1. The yield can reach a certain level, providing high-quality raw materials for subsequent reactions.

[0013] 3. The synthesis process for improving the purity of the racemic pharmaceutical intermediate racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride is to react the intermediate product 1 with ammonia under high pressure and specific temperature conditions, successfully introduce the amino functional group, and obtain the intermediate product 2. This step accurately realizes the transformation of the functional group and provides the key structure for the synthesis of the target product. Moderate reaction yield: The reaction is carried out under optimized conditions, and the yield is relatively considerable, which ensures that there is sufficient raw material supply for subsequent reactions, and the product purity also meets the requirements of subsequent reactions.

[0014] 4. The synthesis process for improving the purity of the racemic pharmaceutical intermediate racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride uses hydrogen peroxide as an oxidant to carry out an oxidation reaction on the intermediate product 2 at a mild temperature and in the presence of an alkaline catalyst. This process not only achieves the oxidation conversion of the target functional group, but also avoids the environmental pollution problem caused by the use of traditional strong oxidizing agents. The selective oxidation of hydrogen peroxide enables the reaction to proceed in the direction of the target product, reduces the occurrence of side reactions, improves the purity of the intermediate product 3, provides purer raw materials for subsequent reactions, and helps to improve the purity of the final product.

[0015] 5. The synthesis process for improving the purity of the racemic pharmaceutical intermediate racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride successfully introduces an ester group through an esterification reaction with methanol under the catalysis of concentrated sulfuric acid to form racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester. This step is the key to constructing the complete structure of the target product and prepares for the subsequent salt-forming reaction. Under reflux conditions, the reaction can proceed smoothly with a high yield (assuming about 80%) and a good product purity, providing sufficient and qualified raw materials for the subsequent salt-forming reaction. DETAILED DESCRIPTION

[0016] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0017] A synthetic process for improving the purity of racemic pharmaceutical intermediate racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride. (I) Preparation of starting materials: Select compounds containing furan rings: 2,5-dihydrofuran, etc.), halogenated alkanes (such as methyl bromide), amine compounds (such as ammonia or suitable amine salts), catalysts (such as specific metal complexes), hydrogen peroxide (30% by mass aqueous solution) and other necessary organic solvents (such as dichloromethane, ethanol, etc.) and inorganic reagents (such as sodium hydroxide, hydrochloric acid, etc.), and prepare intermediate product 1; add 2,5-dihydrofuran (100g, 1.2mol) to 500mL dry dichloromethane, stir evenly, and slowly add methyl bromide (120g, 1.4mol) and an appropriate amount of metal complex catalyst (such as 5g of a certain palladium complex) under ice bath cooling. After the addition is completed, stir the reaction at room temperature for 6-8 hours, and monitor the reaction progress by gas chromatography (GC) to ensure that the reaction is complete. After the reaction was completed, the reaction solution was washed with 5% sodium hydroxide solution (2×100 mL) and saturated brine (100 mL) in sequence, the organic phase was dried over anhydrous sodium sulfate, filtered, and dichloromethane was removed by distillation under reduced pressure to obtain intermediate product 1 as a colorless oily liquid.

[0018] (ii) Introduction of amino functional groups: reacting the intermediate product 1 with an amine compound to introduce an amino functional group to obtain an intermediate product 2 containing an amino group; dissolving the intermediate product 1 obtained above (80 g, hypothetical amount) in 300 mL of ethanol, introducing ammonia (excessive), and reacting in a high-pressure reactor at 80-90°C and 2-3 MPa for 12-14 hours. After the reaction is completed, cool to room temperature, and remove excess ammonia and ethanol by vacuum distillation to obtain an intermediate product 2 containing an amino group as a light yellow solid.

[0019] (III) Oxidation reaction: Use hydrogen peroxide as an oxidant to carry out oxidation reaction on intermediate product 2, and oxidize specific functional groups to the structure required by the target product; In a 500mL three-necked flask, dissolve intermediate product 2 (50g, assumed amount) in 200mL dichloromethane, slowly drip a 30% mass fraction of hydrogen peroxide aqueous solution (30mL, excess) under stirring, and add an appropriate amount of alkaline catalyst (such as sodium carbonate, 5g). During the dripping process, control the reaction temperature at 30-40℃. After the dripping is completed, continue to stir the reaction at this temperature for 6-8 hours. After the reaction is completed, add an appropriate amount of sodium sulfite solution (mass fraction of 10%) to remove excess hydrogen peroxide, and stir for 30 minutes. Transfer the reaction solution to a separatory funnel, separate the layers, dry the organic phase with anhydrous sodium sulfate, filter, and remove dichloromethane by reduced pressure distillation to obtain the oxidized intermediate product 3 as a white solid.

[0020] (IV) Esterification reaction: The oxidized intermediate product 3 reacts with methanol under the action of an acidic catalyst to form an ester group; the intermediate product 3 (30 g, assumed amount) is added to 200 mL of methanol, and an appropriate amount of concentrated sulfuric acid (2 mL) is added as a catalyst, and the reaction is carried out under reflux conditions for 8-10 hours. After the reaction is completed, it is cooled to room temperature, the reaction solution is poured into ice water, the pH is adjusted to 7-8 with sodium carbonate solution, and extracted with dichloromethane (3×100 mL). The organic phases are combined, dried with anhydrous sodium sulfate, filtered, and dichloromethane is removed by vacuum distillation to obtain racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester as a colorless oily liquid.

[0021] (V) Salt-forming reaction: Racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester reacts with hydrochloric acid to form hydrochloride. The racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester (20 g, hypothetical amount) obtained above is dissolved in 100 mL of anhydrous ether, and dry hydrogen chloride gas is slowly introduced under stirring until the reaction is complete (judged by pH test paper or other detection methods). A white solid gradually precipitates, and stirring is continued for 1-2 hours to allow the reaction to proceed fully. Filter, wash the solid with a small amount of cold anhydrous ether, and dry to obtain the crude product of racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride.

[0022] Purification treatment: Recrystallization: Dissolve the crude product of racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride (10g, assumed amount) in an appropriate amount of ethanol-water mixed solvent (ethanol: water = 3:1), heat to 60-70°C, and stir to completely dissolve. Then slowly cool to room temperature, and then put it in a refrigerator (0-5°C) for overnight, and a large amount of crystals will precipitate. Collect the crystals by filtration, wash with a small amount of cold ethanol-water mixed solvent (ethanol: water = 1:1), and dry to obtain racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride with high purity.

[0023] If the purity of the product after recrystallization still does not meet the requirements, column chromatography can be used for further purification. With silica gel as the stationary phase, select a suitable eluent (such as a mixed solvent of ethyl acetate-methanol-water, the ratio is adjusted according to the actual situation), and load the recrystallized product for column chromatography separation. Collect the eluate containing the target product, and remove the solvent by vacuum distillation to obtain high-purity racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride. The purity can reach more than 98% by high-performance liquid chromatography (HPLC). Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A process for synthesizing racemic (2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride, characterized in that: (I) Preparation of starting materials: selecting compounds containing furan rings: 2,5-dihydrofuran, etc., halogenated alkanes: methyl bromide, amine compounds: ammonia or suitable amine salts, catalysts: metal complexes, hydrogen peroxide and other necessary organic solvents: dichloromethane, ethanol; inorganic reagents: sodium hydroxide, hydrochloric acid, and preparing intermediate product 1; (ii) introducing an amino functional group: reacting the intermediate product 1 with an amine compound to introduce an amino functional group, thereby obtaining an intermediate product 2 containing an amino group; (iii) Oxidation reaction: using hydrogen peroxide as an oxidant, the intermediate product 2 is subjected to an oxidation reaction to oxidize a specific functional group into the structure required by the target product; (iv) Esterification reaction: the oxidized intermediate product 3 is reacted with methanol under the action of an acidic catalyst to undergo an esterification reaction to form an ester group; (V) Salt-forming reaction: Racemic (2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester reacts with hydrochloric acid to form hydrochloride.

2. The synthesis process of racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride according to claim 1, characterized in that: 2,5-Dihydrofuran (100 g, 1.2 mol) was added to 500 mL of dry dichloromethane and stirred evenly. Methyl bromide (120 g, 1.4 mol) and an appropriate amount of metal complex catalyst were slowly added dropwise under ice bath cooling. After the addition was completed, the reaction was stirred at room temperature for 6-8 hours. The reaction progress was monitored by gas chromatography to ensure that the reaction was complete. After the reaction was completed, the reaction solution was washed with 5% sodium hydroxide solution (2×100 mL) and saturated brine (100 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and dichloromethane was removed by reduced pressure distillation to obtain intermediate 1 as a colorless oily liquid.

3. The synthesis process of racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride according to claim 1, characterized in that: The intermediate product 1 (80 g) obtained above was dissolved in 300 mL of ethanol, and excess ammonia was introduced. The mixture was reacted in a high-pressure reactor at 80-90°C and 2-3 MPa for 12-14 hours. After the reaction was completed, the mixture was cooled to room temperature and the excess ammonia and ethanol were removed by distillation under reduced pressure to obtain an intermediate product 2 containing an amino group as a light yellow solid.

4. The synthesis process of racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride according to claim 1, characterized in that: In a 500mL three-necked flask, the intermediate product 2 (50g) was dissolved in 200mL of dichloromethane, and a 30% aqueous hydrogen peroxide solution (30mL, excess) was slowly added dropwise under stirring, and an appropriate amount of alkaline catalyst (5g) was added at the same time. The reaction temperature was controlled at 30-40°C during the addition. After the addition was completed, the reaction was continued to be stirred at this temperature for 6-8 hours. After the reaction was completed, an appropriate amount of sodium sulfite solution (mass fraction of 10%) was added to remove excess hydrogen peroxide. The reaction solution was stirred for 30 minutes, and the reaction solution was transferred to a separatory funnel. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dichloromethane was removed by vacuum distillation to obtain the oxidized intermediate product 3 as a white solid.

5. The synthesis process of racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride according to claim 1, characterized in that: The intermediate product 3 (30 g) was added to 200 mL of methanol, and an appropriate amount of concentrated sulfuric acid (2 mL) was added as a catalyst. The reaction was carried out under reflux conditions for 8-10 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into ice water, and the pH was adjusted to 7-8 with sodium carbonate solution. The solution was extracted with dichloromethane (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dichloromethane was removed by distillation under reduced pressure to obtain racemic (2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester as a colorless oily liquid.

6. The synthesis process of racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride according to claim 1, characterized in that: The above-obtained racemic (2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester (20 g) was dissolved in 100 mL of anhydrous ether, and dry hydrogen chloride gas was slowly introduced under stirring until the reaction was complete and a white solid gradually precipitated. Stirring was continued for 1-2 hours to allow the reaction to proceed fully, and the solid was filtered and washed with a small amount of cold anhydrous ether. After drying, the crude product of racemic (2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride was obtained.

7. The synthesis process of racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride according to claim 1, characterized in that: The method also includes the purification of the target product: recrystallization: dissolving the crude product (10 g) of racemic (2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride in an appropriate amount of ethanol-water mixed solvent, heating to 60-70°C, stirring to completely dissolve it, then slowly cooling to room temperature, and then refrigerating in a refrigerator (0-5°C) overnight, a large amount of crystals precipitate, collecting the crystals by filtration, washing with a small amount of cold ethanol-water mixed solvent, and drying to obtain racemic (2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride with high purity.

8. The synthesis process of racemic-(2R, 4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride according to claim 7, characterized in that: If the purity of the product after recrystallization still does not meet the requirements, it can be further purified by column chromatography, using silica gel as the stationary phase, selecting a suitable eluent, loading the recrystallized product for column chromatography separation, collecting the eluate containing the target product, and removing the solvent by reduced pressure distillation to obtain high-purity racemic-(2R,4R)-4-aminotetrahydrofuran-2-carboxylic acid methyl ester hydrochloride. The purity can reach more than 98% as detected by high performance liquid chromatography.