CN111943879A - A kind of (3S, 4R) 3-amino-4 (methoxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester and its synthesis method - Google Patents

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a tert-butyl (3S,4R)3-amino-4-(methoxymethyl)pyrrolidine-1-formate and a synthesis method thereof. (E) 4-methoxybut-2-enoate is a raw material, and (3S, 4R) 3-amino-4- is prepared through five-step reaction of active hydrogen protection, sulfonylation, substitution, amidation and dehydration reaction (Methoxymethyl)pyrrolidine-1-tert-butyl formate, the synthesis method of the invention has the characteristics of simple process, low cost and high efficiency, and is suitable for industrial promotion.

Description

A kind of (3S, 4R) 3-amino-4 (methoxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester and its synthetic method

technical field

The invention belongs to the technical field of organic synthesis, in particular to a tert-butyl (3S,4R)3-amino-4-(methoxymethyl)pyrrolidine-1-carboxylate and a synthesis method thereof.

Background technique

Pyrrole derivatives are an important class of nitrogen heterocyclic compounds that widely exist in nature and often have important physiological and pharmacological activities. For example, pyrrole derivatives are important pharmaceutical intermediates, especially some chiral pyrrole derivatives, which are widely used as synthetic modules for various drugs. In addition, as an intermediate of fine chemical products, pyrrole is widely used in catalysts, medicines, pesticides and other fields. Therefore, the synthesis of pyrrole derivatives is of great significance.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a compound that can be used as a pharmaceutical intermediate, namely (3S,4R) 3-amino-4-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester, and to provide its chemical resolve resolution.

For achieving the above object, technical scheme of the present invention is as follows:

The present invention provides a compound, the compound is (3S, 4R) 3-amino-4-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester, and the molecular structure is shown in formula I:

The present invention also provides a kind of synthetic method of the above-mentioned compound, it is characterized in that, comprises the following steps:

S1. Dissolve (E) 4-methoxybut-2-enoate in a solvent, add N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl (base) methylamine, cool down to below 20 °C, slowly add a dichloromethane solution containing trifluoroacetic acid dropwise, react at room temperature, add dichloromethane to the reaction solution after the reaction, wash with saturated sodium bicarbonate, and then Dry with anhydrous sodium sulfate and concentrate to obtain (3S,4R)-1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester;

S2. Dissolve (3S, 4R)-1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester obtained in step S1 in a solvent, then add concentrated hydrochloric acid, and add under nitrogen protection The catalyst Pd(OH) ₂ /C is subjected to hydrogenation reaction at 10-35°C. After the reaction, the reaction solution is filtered to remove the catalyst Pd(OH) ₂ /C, and the filtrate obtained by filtration is spin-dried to obtain (3S , 4R)-4-(methoxymethyl)pyrrolidine-3-carboxylate ethyl ester hydrochloride;

S3. (3S, 4R)-4-(methoxymethyl)-pyrrolidine-3-carboxylate ethyl ester hydrochloride obtained in step S2 is added to dichloromethane, and then triethylamine and sodium bicarbonate are added , then add the dichloromethane solution containing (Boc) ₂ O, slowly warm up to room temperature, react, after the reaction is completed, the reaction solution is cooled to room temperature, the reaction solution is layered, the water layer is taken, extracted with dichloromethane, and washed with citric acid 3 times , washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate obtained by filtration was concentrated to dryness to obtain a crude product, which was passed through a column to obtain (3S,4S)-1-tert-butyl 3-ethyl 4- (Methoxymethyl)pyrrolidine-1,3 dicarboxylate;

S4. Dissolve (3S,4S)-1-tert-butyl 3-ethyl 4-(methoxymethyl)pyrrolidine-1,3 dicarboxylate obtained in step S3 in toluene, add benzyl alcohol and trisodium Ethanolamine, the temperature is controlled below 20 ℃, diphenyl azide phosphoric acid is added dropwise, stirred at room temperature, and the temperature is raised to 85-105 ℃ to carry out the reaction, after the reaction is completed, the reaction solution is concentrated and dissolved in ethyl acetate, and then washed with water. Washed with saturated aqueous sodium bicarbonate solution, concentrated, mixed with samples, and passed through column to obtain (3S,4R) tert-butyl 3-(benzyloxycarbonyl)-4(methoxymethyl)pyrrolidine-1-carboxylate;

S5. Dissolve (3S, 4R) 3-(benzyloxycarbonyl)-4(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in step S4 in a solvent, under nitrogen protection, add Pd The wet Pd/C with a content of 5 wt% is stirred, and the hydrogenation reaction is carried out under the condition of 10-35 ° C. After the reaction, the reaction solution is filtered, and the filtrate obtained by filtration is spin-dried and then added with methyl tertiary butyl ether. Under the condition of 0～10℃, add hydrochloric ether dropwise, adjust pH=9～10, filter after stirring, and dry the filter cake obtained by filtration to obtain (3S,4R)3-amino-4-(methoxymethyl) ) tert-butyl pyrrolidine-1-carboxylate.

Preferably, the solvent is one of tetrahydrofuran, dichloromethane and chloroform.

Preferably, the reaction time of step S1 is 12h.

Preferably, the time of the hydrogenation reaction in step S2 is 12h, and the concentration of the concentrated hydrochloric acid is 12mol/L.

Preferably, the reaction time of step S3 is 12h, the (3S,4R)-4-(methoxymethyl)pyrrolidine-3-carboxylate ethyl ester hydrochloride, triethylamine and (Boc) _The molar ratio of 2O is 1:1:1.

Preferably, the reaction time of step S4 is 12h.

Preferably, the time of the hydrogenation reaction in step S5 is 12h.

The beneficial effects of the present invention are as follows: the present invention uses (E) 4-methoxybut-2-enoate and N-methoxymethyl-N-(trimethylsilane) benzylamine as raw materials, (3S,4R)3-amino-4-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester was prepared in five steps of hydrogen protection, sulfonylation, substitution, amidation and dehydration. The synthesis method of the invention has the advantages of simple process, low cost and high efficiency, and provides a solid foundation for mass production and subsequent research of such compound materials.

Specific implementation method

In the following specific embodiments, the specific embodiments of the present invention are described in detail. These specific embodiments are only for description and are not used to limit the scope or implementation principles of the present invention. The protection scope of the present invention is subject to the claims, including obvious changes or changes made on this basis.

Example 1

Synthesis of S1, (3S,4R)-1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester:

In a 500 mL four-necked flask, 61.7 g of (E) 4-methoxybut-2-enoate was dissolved in 100 mL of dichloromethane, and 20.97 g of N-(methoxy) was added under mechanical stirring. Methyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine, cooled to 20°C, slowly added dropwise 70mL of a dichloromethane solution containing trifluoroacetic acid (this solution was composed of 20mL of trifluoroacetic acid). Fluoroacetic acid and 50 mL of dichloromethane), after the dropwise addition, the reaction was naturally raised to room temperature for 12 h, and the completion of the reaction was monitored by TLC. Washed once with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, concentrated to obtain 105 g of ethyl (3S,4R)-1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylate, obtained The rate is 89%.

Synthesis of S2, (3S,4R)-4-(methoxymethyl)pyrrolidine-3-carboxylate ethyl ester hydrochloride:

In a 500mL four-necked flask, dissolve 102g of (3S,4R)-1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester obtained in step S1 in 350mL of ethanol, Then 30 mL of concentrated hydrochloric acid was added, 7 g of catalyst Pd(OH) ₂ /C was added under nitrogen protection, and the hydrogenation reaction was carried out at 25 °C overnight. The reaction was completed by thin-layer chromatography. After the reaction, the reaction solution was filtered to The catalyst Pd(OH) ₂ /C was removed, and the filtrate obtained by filtration was spin-dried to obtain 83 g of (3S,4R)-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester hydrochloride, Yield 99%.

Synthesis of S3, (3S,4R)-1-benzyl 3-ethyl 4-(methoxymethyl)pyrrolidine-1,3-dicarboxylate:

In a 500mL reaction flask, take 78g of (3S,4R)-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester hydrochloride obtained in step S2, add 35.4g of triethylamine and 21.8g of sodium bicarbonate, and then 200 mL of a dichloromethane solution containing 72 g of (Boc) ₂ O was added, and the temperature was slowly raised to room temperature for 12 h. The raw materials were analyzed by thin-layer chromatography for complete reaction, the reaction solution was layered, the water layer was taken, and extracted with dichloromethane 3 times (the volume of ethyl acetate used for each extraction was 500 mL, and the organic phase was collected at the end of each extraction), and citric acid was used. Wash 3 times (the volume of citric acid used for each extraction is 500mL, and the organic phase is collected at the end of each extraction), and washed 3 times with saturated brine (the volume of saturated brine used for each extraction is 500mL, and the volume of each extraction is 500mL. Collect the organic phase), combine the organic phases obtained by 3 extractions and dry with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain a crude product, which is passed through a column to obtain 77g of (3S, 4R)-1-benzyl 3-ethyl 4 -(Methoxymethyl)pyrrolidine-1,3-dicarboxylate in 76.8% yield.

Synthesis of S4, (3S, 4R) 3-(benzyloxycarbonyl)-4-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester:

In a 500mL four-necked flask, take 28.7g of (3S,4R)-1-benzyl 3-ethyl 4-(methoxymethyl)pyrrolidine-1,3-dicarboxylate obtained in step S3 and dissolve it in In 250 mL of toluene, 23.8 g of benzyl alcohol and 14.9 g of triethanolamine were added, the temperature was controlled below 20 °C, 37 g of diphenylphosphonium azide was added dropwise, stirred at room temperature for 0.5 h, heated to 95 ° C, and reacted for 12 h, monitored by TLC The reaction was complete, after the reaction was completed, the reaction solution was concentrated and dissolved in 200 mL of ethyl acetate, washed with water again, washed with saturated aqueous sodium bicarbonate solution, concentrated, mixed with samples, and passed through the column to obtain 21.8 g of (3S, 4R) 3-(benzyl) Oxycarbonyl)-4-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in 60% yield.

Synthesis of S5, (3S,4R) 3-amino-4-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester:

In a 250mL four-necked flask, take 18g of (3S,4R)3-(benzyloxycarbonyl)-4-(methoxymethyl)pyrrolidine-1-carboxylate tert-butyl ester obtained in step S4 and dissolve it in 100mL of In methanol, under nitrogen protection, 1 g of wet Pd/C with a Pd content of 5 wt% was added and stirred, and the hydrogenation reaction was carried out at 25 ° C for 12 h. The reaction was completed by thin-layer chromatography. After the reaction, the reaction solution was filtered. The filtrate obtained by filtration was spin-dried, and then 300 mL of methyl tert-butyl ether was added. The temperature was controlled at about 0 °C, and diethyl ether hydrochloride was added dropwise to control pH=9-10. After stirring for 1 hour, the filter cake was dried. 8.3 g of (3S,4R) tert-butyl 3-amino-4-(methoxymethyl)pyrrolidine-1-carboxylate were obtained in 72% yield.

Example 2

Synthesis of S1, (3S,4R)-1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester:

In a 500 mL four-necked flask, 61.7 g of (E) 4-methoxybut-2-enoate was dissolved in 100 mL of dichloromethane, and 20.9 g of N-(methoxy) was added under mechanical stirring. Methyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine, cooled to 0 °C, slowly added 70 mL of a dichloromethane solution containing trifluoroacetic acid (this solution was composed of 20 mL of trifluoroacetic acid). acetic acid and 50 mL of dichloromethane), after the dropwise addition, the reaction was naturally raised to room temperature for 12 h, and the completion of the reaction was monitored by TLC. It was washed once with sodium bicarbonate, dried with anhydrous sodium sulfate, and concentrated to obtain 103 g of ethyl (3S,4R)-1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylate, yield was 88.5%.

Synthesis of S2, (3S,4R)-4-(methoxymethyl)pyrrolidine-3-carboxylate ethyl ester hydrochloride:

In a 500mL four-necked flask, dissolve 102g of (3S,4R)-1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester obtained in step S1 in 350mL of ethanol, Then 30 mL of concentrated hydrochloric acid was added, 7 g of catalyst Pd(OH) ₂ /C was added under nitrogen protection, and the hydrogenation reaction was carried out at 10 °C overnight. The reaction was completed by thin-layer chromatography. After the reaction, the reaction solution was filtered to The catalyst Pd(OH) ₂ /C was removed, and the filtrate obtained by filtration was spin-dried to obtain 83 g of (3S,4R)-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester hydrochloride, Yield 99%.

Synthesis of S3, (3S,4R)-1-benzyl 3-ethyl 4-(methoxymethyl)pyrrolidine-1,3-dicarboxylate:

In a 500mL reaction flask, take 78g of (3S,4R)-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester hydrochloride obtained in step S2, add 35.4g of triethylamine and 21.8g of sodium bicarbonate, and then 200 mL of a dichloromethane solution containing 72 g of (Boc) ₂ O was added, and the temperature was slowly raised to room temperature for 12 h. The raw materials were analyzed by thin-layer chromatography for complete reaction, the reaction solution was layered, the water layer was taken, and extracted with dichloromethane 3 times (the volume of ethyl acetate used for each extraction was 500 mL, and the organic phase was collected at the end of each extraction), and citric acid was used. Wash 3 times (the volume of citric acid used for each extraction is 500 mL, and the organic phase is collected at the end of each extraction), and washed 3 times with saturated brine (the volume of saturated brine used for each extraction is 500 mL, and the volume of each extraction is 500 mL). Collect the organic phase), combine the organic phases obtained by 3 extractions and dry with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain a crude product, which is passed through a column to obtain 77g of (3S, 4R)-1-benzyl 3-ethyl 4 -(Methoxymethyl)pyrrolidine-1,3-dicarboxylate in 76.8% yield.

Synthesis of S4, (3S, 4R) 3-(benzyloxycarbonyl)-4-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester:

In a 500mL four-necked flask, take 28.7g of (3S,4R)-1-benzyl 3-ethyl 4-(methoxymethyl)pyrrolidine-1,3-dicarboxylate obtained in step S3 and dissolve it in In 250 mL of toluene, 23.8 g of benzyl alcohol and 14.9 g of triethanolamine were added, the temperature was controlled below 20 °C, 37 g of diphenylphosphoryl azide was added dropwise, stirred at room temperature for 0.5 h, heated to 85 °C, and reacted for 12 h, monitored by TLC The reaction was complete, after the reaction was completed, the reaction solution was concentrated and dissolved in 200 mL of ethyl acetate, washed once with water, washed with saturated aqueous sodium bicarbonate solution, concentrated, mixed with samples, and passed through the column to obtain 18.2 g of (3S, 4R) 3-(benzyl) Oxycarbonyl)-4-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in 50% yield.

Synthesis of S5, (3S,4R) 3-amino-4-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester:

In a 250mL four-necked flask, take 18g of (3S,4R)3-(benzyloxycarbonyl)-4-(methoxymethyl)pyrrolidine-1-carboxylate tert-butyl ester obtained in step S4 and dissolve it in 100mL of In ethanol, under nitrogen protection, 1 g of wet Pd/C with a Pd content of 5 wt% was added and stirred, and the hydrogenation reaction was carried out at 15 ° C for 12 h. The reaction was completed by thin-layer chromatography. After the reaction, the reaction solution was filtered. The filtrate obtained by filtration was spin-dried, and then 300 mL of methyl tert-butyl ether was added. The temperature was controlled at about 0 °C, and diethyl ether hydrochloride was added dropwise to control pH=9-10. After stirring for 1 hour, the filter cake was dried. 8.4 g of (3S,4R) tert-butyl 3-amino-4-(methoxymethyl)pyrrolidine-1-carboxylate were obtained in 73% yield.

Example 3

Synthesis of S1, (3S,4R)-1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester:

In a 500 mL four-necked flask, 61.7 g of (E) 4-methoxybut-2-enoate was dissolved in 100 mL of dichloromethane, and 20.97 g of N-(methoxy) was added under mechanical stirring. Methyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine, cooled to 10 °C, slowly added 70 mL of a dichloromethane solution containing trifluoroacetic acid (the solution was composed of 20 mL of trifluoroacetic acid). acetic acid and 50 mL of dichloromethane), after the dropwise addition, the reaction was naturally raised to room temperature for 12 h, and the completion of the reaction was monitored by TLC. Washed once with sodium bicarbonate, then dried with anhydrous sodium sulfate, and concentrated to obtain 106 g of (3S,4R)-1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester, the yield is 90%.

Synthesis of S2, (3S,4R)-4-(methoxymethyl)pyrrolidine-3-carboxylate ethyl ester hydrochloride:

In a 500mL four-necked flask, dissolve 102g of (3S,4R)-1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester obtained in step S1 in 350mL of ethanol, Then 30 mL of concentrated hydrochloric acid was added, 7 g of catalyst Pd(OH) ₂ /C was added under nitrogen protection, and the hydrogenation reaction was carried out at 35 ° C overnight. The reaction was completed by thin-layer chromatography. After the reaction, the reaction solution was filtered to The catalyst Pd(OH) ₂ /C was removed, and the filtrate obtained by filtration was spin-dried to obtain 83 g of (3S,4R)-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester hydrochloride, Yield 99%.

Synthesis of S3, (3S,4R)-1-benzyl 3-ethyl 4-(methoxymethyl)pyrrolidine-1,3-dicarboxylate:

In a 500mL reaction flask, take 78g of (3S,4R)-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester hydrochloride obtained in step S2, add 35.4g of triethylamine and 21.8g of sodium bicarbonate, and then 200 mL of a dichloromethane solution containing 72 g of (Boc) ₂ O was added, and the temperature was slowly raised to room temperature for 12 h. The raw materials were analyzed by thin-layer chromatography for complete reaction, the reaction solution was layered, the water layer was taken, and extracted with dichloromethane 3 times (the volume of ethyl acetate used for each extraction was 500 mL, and the organic phase was collected after each extraction), and citric acid was used. Wash 3 times (the volume of citric acid used for each extraction is 500mL, and the organic phase is collected at the end of each extraction), and washed 3 times with saturated brine (the volume of saturated brine used for each extraction is 500mL, and the volume of each extraction is 500mL. Collect the organic phase), combine the organic phases obtained by 3 extractions and dry with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain a crude product, which is passed through a column to obtain 77g of (3S, 4R)-1-benzyl 3-ethyl 4 -(Methoxymethyl)pyrrolidine-1,3-dicarboxylate in 76.8% yield.

Synthesis of S4, (3S, 4R) 3-(benzyloxycarbonyl)-4-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester:

In a 500mL four-necked flask, take 28.7g of (3S,4R)-1-benzyl 3-ethyl 4-(methoxymethyl)pyrrolidine-1,3-dicarboxylate obtained in step S3 and dissolve it in In 250 mL of toluene, 23.8 g of benzyl alcohol and 14.9 g of triethanolamine were added, the temperature was controlled below 20 °C, 37 g of diphenylphosphonium azide was added dropwise, stirred at room temperature for 0.5 h, heated to 105 ° C, and reacted for 12 h, monitored by TLC The reaction was complete. After the reaction was completed, the reaction solution was concentrated and dissolved in 200 mL of ethyl acetate, washed with water, washed with saturated aqueous sodium bicarbonate solution, concentrated, mixed with samples, and passed through the column to obtain 22.9 g of (3S, 4R) 3-(benzyl) Oxycarbonyl)-4-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in 63% yield.

Synthesis of S5, (3S,4R) 3-amino-4-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester:

In a 250mL four-necked flask, take 18g of (3S,4R)3-(benzyloxycarbonyl)-4-(methoxymethyl)pyrrolidine-1-carboxylate tert-butyl ester obtained in step S4 and dissolve it in 100mL of In tetrahydrofuran, under nitrogen protection, 1 g of wet Pd/C with a Pd content of 5 wt% was added and stirred, and the hydrogenation reaction was carried out at 35 ° C for 12 h. The reaction was completed by thin layer chromatography. After the reaction, the reaction solution was filtered, The filtrate obtained by filtration was spin-dried, and then 300 mL of methyl tert-butyl ether was added. The temperature was controlled at about 0 °C, and diethyl ether hydrochloride was added dropwise to control pH=9-10. After stirring for 1 hour, the filter cake was dried. 7.9 g of (3S,4R) tert-butyl 3-amino-4-(methoxymethyl)pyrrolidine-1-carboxylate were obtained in 69% yield.

While the basic principles and main features and advantages of the present invention have been shown and described above, it will be apparent to those skilled in the art that the present invention is not limited to the details of the above-described exemplary embodiments, but without departing from the spirit or essential aspects of the present invention. In the case of the characteristic features, the present invention can be implemented in other specific forms. Therefore, the embodiments are to be regarded in all respects as illustrative and not restrictive, and the scope of the invention is to be defined by the appended claims rather than the foregoing description, which are therefore intended to fall within the scope of the claims. All changes within the meaning and scope of the equivalents of , are included in the present invention. Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, and substitutions can be made in these embodiments without departing from the principle and spirit of the invention and modifications, the scope of the present invention is defined by the appended claims and their equivalents.

Claims (8)

1. a compound, it is characterized in that, described compound is (3S, 4R) 3-amino-4-(methoxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester, and molecular structure is as shown in formula I:

2. the synthetic method of compound as claimed in claim 1, is characterized in that, comprises the steps: S1. Dissolve (E) 4-methoxybut-2-enoate in a solvent, add N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl (base) methylamine, cool down to below 20 °C, slowly add a dichloromethane solution containing trifluoroacetic acid dropwise, react at room temperature, add dichloromethane to the reaction solution after the reaction, wash with saturated sodium bicarbonate, and then Dry with anhydrous sodium sulfate and concentrate to obtain (3S,4R)-1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester; S2. (3S,4R)-1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylic acid ethyl ester obtained in step S1 is dissolved in a solvent, then concentrated hydrochloric acid is added, and under nitrogen protection Catalyst Pd(OH) ₂ /C, carry out hydrogenation reaction at 10-35 ℃, after the reaction, filter the reaction solution to remove catalyst Pd(OH) ₂ /C, and spin the filtrate obtained by filtration to obtain (3S , 4R)-4-(methoxymethyl)pyrrolidine-3-carboxylate ethyl ester hydrochloride; S3. (3S, 4R)-4-(methoxymethyl)-pyrrolidine-3-carboxylate ethyl ester hydrochloride obtained in step S2 is added to dichloromethane, and then triethylamine and sodium bicarbonate are added , then add the dichloromethane solution containing (Boc) ₂ O, slowly warm up to room temperature, react, after the reaction is completed, the reaction solution is cooled to room temperature, the reaction solution is layered, the water layer is taken, extracted with dichloromethane, and washed with citric acid 3 times , washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate obtained by filtration was concentrated to dryness to obtain a crude product, which was passed through a column to obtain (3S,4S)-1-tert-butyl 3-ethyl 4- (Methoxymethyl)pyrrolidine-1,3 dicarboxylate; S4. Dissolve (3S,4S)-1-tert-butyl 3-ethyl 4-(methoxymethyl)pyrrolidine-1,3 dicarboxylate obtained in step S3 in toluene, add benzyl alcohol and trisodium Ethanolamine, the temperature is controlled below 20 ℃, diphenyl azide phosphoric acid is added dropwise, stirred at room temperature, and the temperature is raised to 85-105 ℃ to carry out the reaction, after the reaction is completed, the reaction solution is concentrated and dissolved in ethyl acetate, and then washed with water. Washed with saturated aqueous sodium bicarbonate solution, concentrated, mixed with samples, and passed through column to obtain (3S,4R) tert-butyl 3-(benzyloxycarbonyl)-4(methoxymethyl)pyrrolidine-1-carboxylate; S5. Dissolve (3S, 4R) 3-(benzyloxycarbonyl)-4(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in step S4 in a solvent, under nitrogen protection, add Pd The wet Pd/C with a content of 5 wt% is stirred, and the hydrogenation reaction is carried out under the condition of 10-35 ° C. After the reaction, the reaction solution is filtered, and the filtrate obtained by filtration is spin-dried and then added with methyl tertiary butyl ether. Under the condition of 0～10℃, add hydrochloric ether dropwise, adjust pH=9～10, filter after stirring, and dry the filter cake obtained by filtration to obtain (3S,4R)3-amino-4-(methoxymethyl) ) tert-butyl pyrrolidine-1-carboxylate. 3. synthetic method as claimed in claim 2 is characterized in that, described solvent is a kind of in tetrahydrofuran, methylene dichloride and chloroform. 4. synthetic method as claimed in claim 2 is characterized in that, the time of the described reaction of step S1 is 12h. 5. synthetic method as claimed in claim 2 is characterized in that, the time of hydrogenation reaction described in step S2 is 12h, and described concentrated hydrochloric acid concentration is 12mol/L. 6. synthetic method as claimed in claim 2 is characterized in that, the time of the described reaction of step S3 is 12h, described (3S, 4R)-4-(methoxymethyl) pyrrolidine-3-carboxylic acid The molar ratio of ethyl ester hydrochloride, triethylamine and (Boc)2O was ₁ :1:1. 7. The synthetic method of claim 2, wherein the reaction time of step S4 is 12h. 8. synthetic method as claimed in claim 2, is characterized in that, the time of hydrogenation reaction described in step S5 is 12h.