CN111943879A - (3S, 4R) 3-amino-4 (methoxymethyl) pyrrolidine-1-tert-butyl formate and synthetic method thereof - Google Patents
(3S, 4R) 3-amino-4 (methoxymethyl) pyrrolidine-1-tert-butyl formate and synthetic method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of organic synthesis, and discloses (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-tert-butyl formate and a synthesis method thereof, wherein the method provided by the invention takes (E) 4-methoxybutyl-2-gadoleic acid ester as a raw material, and prepares the (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-tert-butyl formate through five steps of reaction of active hydrogen protection, sulfonylation, substitution, amidation and dehydration.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-tert-butyl formate and a synthesis method thereof.
Background
Pyrrole derivatives are an important class of nitrogen heterocyclic compounds, widely exist in the whole natural world, 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, pyrrole is used as an intermediate of fine chemical products, and has wide application in the fields of catalysts, medicines, pesticides and the like. The synthesis of pyrrole derivatives is therefore of great importance.
Disclosure of Invention
The invention aims to provide a compound which can be used as a medical intermediate, namely (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-tert-butyl formate, and a chemical synthesis method thereof.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the invention provides a compound which is (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-tert-butyl formate, and the molecular structure of the compound is shown as a formula I:
the invention also provides a synthesis method of the compound, which is characterized by comprising the following steps:
s1, dissolving (E) 4-methoxybutyl-2-enoate in a solvent, adding N- (methoxymethyl) (phenyl) -N- ((trimethylsilyl) methyl) methylamine, cooling to below 20 ℃, slowly dropwise adding a dichloromethane solution containing trifluoroacetic acid, reacting at room temperature, adding dichloromethane into a reaction solution after the reaction is finished, washing with saturated sodium bicarbonate, drying with anhydrous sodium sulfate, and concentrating to obtain (3S, 4R) -1-benzyl-4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester;
s2, dissolving the (3S, 4R) -1-benzyl-4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester obtained in the step S1 in a solvent, adding concentrated hydrochloric acid, and adding a catalyst Pd (OH) under the protection of nitrogen2/C, hydrogenation reaction is carried out at the temperature of 10-35 ℃, and after the reaction is finished, reaction liquid is filtered to remove the catalyst Pd (OH)2/C, spin-drying the filtrate obtained by filtering to obtain(3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester hydrochloride;
s3, adding the (3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester hydrochloride obtained in the step S2 into dichloromethane, adding triethylamine and sodium bicarbonate, and adding a solution containing (Boc)2Slowly heating a dichloromethane solution of O to room temperature, reacting, cooling a reaction solution to room temperature after the reaction is finished, layering the reaction solution, taking a water layer, extracting dichloromethane, washing with citric acid for 3 times, washing with saturated saline solution for 3 times, drying with anhydrous sodium sulfate, filtering, concentrating a filtrate obtained by filtering to dryness to obtain a crude product, and passing through a column to obtain (3S, 4S) -1-tert-butyl 3-ethyl 4- (methoxymethyl) pyrrolidine-1, 3-dicarboxylic ester;
s4, dissolving the (3S, 4S) -1-tert-butyl 3-ethyl 4- (methoxymethyl) pyrrolidine-1, 3 dicarboxylic ester obtained in the step S3 in toluene, adding benzyl alcohol and triethanolamine, controlling the temperature to be below 20 ℃, dropwise adding diphenylphosphoryl azide, stirring at room temperature, heating to 85-105 ℃ for reaction, concentrating and dissolving the reaction solution in ethyl acetate after the reaction is finished, washing with water and a saturated sodium bicarbonate aqueous solution, concentrating, mixing the sample, and passing through a column to obtain (3S, 4R)3- (benzyloxycarbonyl) -4 (methoxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester;
s5, dissolving the tert-butyl (3S, 4R)3- (benzyloxycarbonyl) -4 (methoxymethyl) pyrrolidine-1-carboxylate obtained in the step S4 in a solvent, adding wet Pd/C with the Pd content of 5 wt% under the protection of nitrogen, stirring, carrying out hydrogenation reaction at 10-35 ℃, filtering the reaction solution after the reaction is finished, adding methyl tert-butyl ether after the filtrate obtained by filtering is dried, dropwise adding ethyl hydrochloride at 0-10 ℃, adjusting the pH to 9-10, stirring, filtering, and drying the filter cake obtained by filtering to obtain the tert-butyl (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-carboxylate.
Preferably, the solvent is one of tetrahydrofuran, dichloromethane and chloroform.
Preferably, the reaction time of step S1 is 12 h.
Preferably, the hydrogenation reaction time in the step S2 is 12h, and the concentration of the concentrated hydrochloric acid is 12 mol/L.
Preferably, the reaction time of step S3 is 12h, and the (3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester hydrochloride, triethylamine and (Boc)2The molar ratio of O is 1:1: 1.
Preferably, the reaction time of step S4 is 12 h.
Preferably, the time of the hydrogenation reaction in the step S5 is 12 h.
The invention has the beneficial effects that: the invention takes (E) 4-methoxybutyl-2-enoate and N-methoxymethyl-N- (trimethylsilane) benzylamine as raw materials, and prepares (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-tert-butyl formate through five steps of reactions including active hydrogen protection, sulfonylation, substitution, amidation and dehydration. The synthetic method has the advantages of simple process, low cost and high efficiency, and provides a solid foundation for mass production and subsequent research of the compound materials.
Detailed description of the invention
The following detailed description will provide specific embodiments of the present invention. These embodiments are merely illustrative and not intended to limit the scope or the principles of the invention, which is defined by the claims and includes obvious modifications and variations based thereon.
Example 1
Synthesis of S1, ethyl (3S, 4R) -1-benzyl-4- (methoxymethyl) pyrrolidine-3-carboxylate:
in a 500mL four-necked flask, 61.7g of (E) 4-methoxybut-2-enoic acid ester is dissolved in 100mL of dichloromethane, 20.97g of N- (methoxymethyl) (phenyl) -N- ((trimethylsilyl) methyl) methylamine is added with mechanical stirring, the temperature is reduced to 20 ℃, 70mL of a dichloromethane solution containing trifluoroacetic acid (the solution is prepared from 20mL of trifluoroacetic acid and 50mL of dichloromethane), the solution naturally rises to room temperature after completion of the dropwise addition, the reaction is monitored by TLC for completion, the reaction solution is poured into a separating funnel after completion of the reaction, 1L of dichloromethane is then added, the mixture is washed once with saturated sodium bicarbonate, the mixture is dried with anhydrous sodium sulfate, and 105g of (3S, 4R) -1-benzyl-4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester is obtained after concentration, the yield thereof was found to be 89%.
Synthesis of S2, (3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester hydrochloride:
in a 500mL four-necked flask, 102g of (3S, 4R) -1-benzyl-4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester obtained in step S1 was dissolved in 350mL of ethanol, 30mL of concentrated hydrochloric acid was added, and 7g of a catalyst Pd (OH) was added under nitrogen protection2The hydrogenation reaction is carried out overnight at the temperature of 25 ℃, the reaction is completely analyzed by thin layer chromatography, and after the reaction is finished, the reaction liquid is filtered to remove the catalyst Pd (OH)2The filtrate obtained by filtration was dried by spinning to obtain 83g of ethyl (3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylate hydrochloride in a yield of 99%.
Synthesis of S3, (3S, 4R) -1-benzyl 3-ethyl 4- (methoxymethyl) pyrrolidine-1, 3-dicarboxylate:
in a 500mL reaction flask, 78g of ethyl (3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylate hydrochloride obtained in step S2 was taken, 35.4g of triethylamine and 21.8g of sodium hydrogencarbonate were added, and a solution containing 72g of (Boc) was further added2O in 200mL of dichloromethane was slowly warmed to room temperature, and reacted for 12 h. Analyzing the raw materials to completely react by thin layer chromatography, demixing reaction liquid, taking a water layer, extracting for 3 times by using dichloromethane (the volume of ethyl acetate adopted in each extraction is 500mL, and the organic phase is collected at the end of each extraction), washing for 3 times by using citric acid (the volume of citric acid adopted in each extraction is 500mL, and the organic phase is collected at the end of each extraction), washing for 3 times by using saturated saline solution (the volume of saturated saline solution adopted in each extraction is 500mL, and the organic phase is collected at the end of each extraction), combining the organic phases obtained in the 3 times of extraction, drying by using anhydrous sodium sulfate, filtering, concentrating to dryness to obtain a crude product, and passing through a column to obtain 77g of (3S, 4R) -1-benzyl 3-ethyl 4- (methoxymethyl) pyrrolidine-1, 3-dicarboxylic ester, wherein the yield is 76.8%.
Synthesis of S4, (3S, 4R)3- (benzyloxycarbonyl) -4- (methoxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester:
28.7g of (3S, 4R) -1-benzyl 3-ethyl 4- (methoxymethyl) pyrrolidine-1, 3-dicarboxylic acid ester obtained in step S3 was taken in a 500mL four-necked flask, and dissolved in 250mL of toluene, followed by addition of 23.8g of benzyl alcohol and 14.9g of triethanolamine, the temperature was controlled to 20 ℃ or lower, 37g of diphenylphosphorylazide was added dropwise, the mixture was stirred at room temperature for 0.5 hour, the temperature was raised to 95 ℃ and the reaction was carried out for 12 hours, the reaction mixture was concentrated and dissolved in 200mL of ethyl acetate after completion of the reaction, washed with water, washed once with saturated aqueous sodium bicarbonate solution, concentrated, sampled and subjected to column chromatography to obtain 21.8g of tert-butyl (3S, 4R)3- (benzyloxycarbonyl) -4- (methoxymethyl) pyrrolidine-1-carboxylate with a yield of 60%.
Synthesis of S5, (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester:
dissolving 18g of tert-butyl (3S, 4R)3- (benzyloxycarbonyl) -4- (methoxymethyl) pyrrolidine-1-carboxylate obtained in step S4 in 100mL of methanol in a 250mL four-necked flask, adding 1g of wet Pd/C with a Pd content of 5 wt% under nitrogen protection, stirring, carrying out hydrogenation reaction at 25 ℃ for 12h, analyzing by thin layer chromatography for completion of the reaction, filtering the reaction solution after completion of the reaction, drying the filtered filtrate, adding 300mL of methyl tert-butyl ether, adding dropwise ethyl hydrochloride at about 0 ℃, controlling the pH to 9-10, stirring for 1h, filtering, drying the filtered cake to obtain 8.3g of tert-butyl (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-carboxylate, the yield was 72%.
Example 2
Synthesis of S1, ethyl (3S, 4R) -1-benzyl-4- (methoxymethyl) pyrrolidine-3-carboxylate:
in a 500mL four-necked flask, 61.7g of (E) 4-methoxybut-2-enoic acid ester is dissolved in 100mL of dichloromethane, 20.9g of N- (methoxymethyl) (phenyl) -N- ((trimethylsilyl) methyl) methylamine is added with mechanical stirring, the temperature is reduced to 0 ℃, 70mL of a dichloromethane solution containing trifluoroacetic acid (the solution is prepared from 20mL of trifluoroacetic acid and 50mL of dichloromethane), the solution naturally rises to room temperature after completion of the dropwise addition, the reaction is monitored by TLC for completion, the reaction solution is poured into a separating funnel after completion of the reaction, 1L of dichloromethane is then added, the mixture is washed once with saturated sodium bicarbonate and dried with anhydrous sodium sulfate, and 103g of (3S, 4R) -1-benzyl-4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester is obtained after concentration, the yield thereof was found to be 88.5%.
Synthesis of S2, (3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester hydrochloride:
in a 500mL four-necked flask, 102g of (3S, 4R) -1-benzyl-4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester obtained in step S1 was dissolved in 350mL of ethanol, 30mL of concentrated hydrochloric acid was added, and 7g of a catalyst Pd (OH) was added under nitrogen protection2The hydrogenation reaction is carried out overnight at the temperature of 10 ℃, the reaction is completely analyzed by thin layer chromatography, and after the reaction is finished, the reaction liquid is filtered to remove the catalyst Pd (OH)2The filtrate obtained by filtration was dried by spinning to obtain 83g of ethyl (3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylate hydrochloride in a yield of 99%.
Synthesis of S3, (3S, 4R) -1-benzyl 3-ethyl 4- (methoxymethyl) pyrrolidine-1, 3-dicarboxylate:
in a 500mL reaction flask, 78g of ethyl (3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylate hydrochloride obtained in step S2 was taken, 35.4g of triethylamine and 21.8g of sodium hydrogencarbonate were added, and a solution containing 72g of (Boc) was further added2O in 200mL of dichloromethane was slowly warmed to room temperature, and reacted for 12 h. Analyzing the raw materials to completely react by thin layer chromatography, demixing reaction liquid, taking a water layer, extracting for 3 times by using dichloromethane (the volume of ethyl acetate adopted in each extraction is 500mL, and the organic phase is collected at the end of each extraction), washing for 3 times by using citric acid (the volume of citric acid adopted in each extraction is 500mL, and the organic phase is collected at the end of each extraction), washing for 3 times by using saturated saline solution (the volume of saturated saline solution adopted in each extraction is 500mL, and the organic phase is collected at the end of each extraction), combining the organic phases obtained in the 3 times of extraction, drying by using anhydrous sodium sulfate, filtering, concentrating to dryness to obtain a crude product, and passing through a column to obtain 77g of (3S, 4R) -1-benzyl 3-ethyl 4- (methoxymethyl) pyrrolidine-1, 3-dicarboxylic ester, wherein the yield is 76.8%.
Synthesis of S4, (3S, 4R)3- (benzyloxycarbonyl) -4- (methoxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester:
28.7g of (3S, 4R) -1-benzyl 3-ethyl 4- (methoxymethyl) pyrrolidine-1, 3-dicarboxylic acid ester obtained in step S3 was taken in a 500mL four-necked flask, and dissolved in 250mL of toluene, followed by addition of 23.8g of benzyl alcohol and 14.9g of triethanolamine, the temperature was controlled to 20 ℃ or lower, 37g of diphenylphosphorylazide was added dropwise, the mixture was stirred at room temperature for 0.5 hour, the temperature was raised to 85 ℃ and the reaction was carried out for 12 hours, the reaction mixture was concentrated and dissolved in 200mL of ethyl acetate after completion of the reaction, washed with water, washed once with saturated aqueous sodium bicarbonate solution, concentrated, sampled and subjected to column chromatography to obtain 18.2g of tert-butyl (3S, 4R)3- (benzyloxycarbonyl) -4- (methoxymethyl) pyrrolidine-1-carboxylate with a yield of 50%.
Synthesis of S5, (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester:
dissolving 18g of tert-butyl (3S, 4R)3- (benzyloxycarbonyl) -4- (methoxymethyl) pyrrolidine-1-carboxylate obtained in step S4 in 100mL of ethanol in a 250mL four-necked flask, adding 1g of wet Pd/C with the Pd content of 5 wt% under nitrogen protection, stirring, carrying out hydrogenation reaction at 15 ℃ for 12h, analyzing by thin layer chromatography for completion of the reaction, filtering the reaction solution after completion of the reaction, drying the filtered filtrate, adding 300mL of methyl tert-butyl ether, dropwise adding ethyl hydrochloride at about 0 ℃, controlling the pH to 9-10, stirring for 1h, filtering, drying the filtered cake to obtain 8.4g of tert-butyl (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-carboxylate, the yield was 73%.
Example 3
Synthesis of S1, ethyl (3S, 4R) -1-benzyl-4- (methoxymethyl) pyrrolidine-3-carboxylate:
in a 500mL four-necked flask, 61.7g of (E) 4-methoxybut-2-enoic acid ester is dissolved in 100mL of dichloromethane, 20.97g of N- (methoxymethyl) (phenyl) -N- ((trimethylsilyl) methyl) methylamine is added with mechanical stirring, the temperature is reduced to 10 ℃, 70mL of a dichloromethane solution containing trifluoroacetic acid (the solution is prepared from 20mL of trifluoroacetic acid and 50mL of dichloromethane), the solution naturally rises to room temperature after completion of the dropwise addition, the reaction is monitored by TLC for completion, the reaction solution is poured into a separating funnel after completion of the reaction, 1L of dichloromethane is then added, the mixture is washed once with saturated sodium bicarbonate and dried with anhydrous sodium sulfate, 106g of (3S, 4R) -1-benzyl-4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester is obtained after concentration, the yield thereof was found to be 90%.
Synthesis of S2, (3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester hydrochloride:
in a 500mL four-necked flask, 102g of (3S, 4R) -1-benzyl-4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester obtained in step S1 was dissolved in 350mL of ethanol, 30mL of concentrated hydrochloric acid was added, and 7g of a catalyst Pd (OH) was added under nitrogen protection2The hydrogenation reaction is carried out overnight at the temperature of 35 ℃, the reaction is completely analyzed by thin layer chromatography, and after the reaction is finished, the reaction liquid is filtered to remove the catalyst Pd (OH)2The filtrate obtained by filtration was dried by spinning to obtain 83g of ethyl (3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylate hydrochloride in a yield of 99%.
Synthesis of S3, (3S, 4R) -1-benzyl 3-ethyl 4- (methoxymethyl) pyrrolidine-1, 3-dicarboxylate:
in a 500mL reaction flask, 78g of ethyl (3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylate hydrochloride obtained in step S2 was taken, 35.4g of triethylamine and 21.8g of sodium hydrogencarbonate were added, and a solution containing 72g of (Boc) was further added2O in 200mL of dichloromethane was slowly warmed to room temperature, and reacted for 12 h. Analyzing the raw materials to completely react by thin layer chromatography, demixing reaction liquid, taking a water layer, extracting for 3 times by using dichloromethane (the volume of ethyl acetate adopted in each extraction is 500mL, and the organic phase is collected at the end of each extraction), washing for 3 times by using citric acid (the volume of citric acid adopted in each extraction is 500mL, and the organic phase is collected at the end of each extraction), washing for 3 times by using saturated saline solution (the volume of saturated saline solution adopted in each extraction is 500mL, and the organic phase is collected at the end of each extraction), combining the organic phases obtained in the 3 times of extraction, drying by using anhydrous sodium sulfate, filtering, concentrating to dryness to obtain a crude product, and passing through a column to obtain 77g of (3S, 4R) -1-benzyl 3-ethyl 4- (methoxymethyl) pyrrolidine-1, 3-dicarboxylic ester, wherein the yield is 76.8%.
Synthesis of S4, (3S, 4R)3- (benzyloxycarbonyl) -4- (methoxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester:
28.7g of (3S, 4R) -1-benzyl 3-ethyl 4- (methoxymethyl) pyrrolidine-1, 3-dicarboxylic acid ester obtained in step S3 was taken in a 500mL four-necked flask, and dissolved in 250mL of toluene, followed by addition of 23.8g of benzyl alcohol and 14.9g of triethanolamine, the temperature was controlled to 20 ℃ or lower, 37g of diphenylphosphorylazide was added dropwise, the mixture was stirred at room temperature for 0.5 hour, the temperature was raised to 105 ℃ and the reaction was carried out for 12 hours, the reaction mixture was concentrated and dissolved in 200mL of ethyl acetate after the completion of the reaction, washed with water, washed once with saturated aqueous sodium bicarbonate solution, concentrated, sampled and subjected to column chromatography to obtain 22.9g of tert-butyl (3S, 4R)3- (benzyloxycarbonyl) -4- (methoxymethyl) pyrrolidine-1-carboxylate in a yield of 63%.
Synthesis of S5, (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester:
dissolving 18g of tert-butyl (3S, 4R)3- (benzyloxycarbonyl) -4- (methoxymethyl) pyrrolidine-1-carboxylate obtained in step S4 in 100mL of tetrahydrofuran, adding 1g of wet Pd/C with the Pd content of 5 wt% under nitrogen protection, stirring, carrying out hydrogenation reaction at 35 ℃ for 12h, analyzing the reaction completion by thin layer chromatography, filtering the reaction solution after the reaction is finished, adding 300mL of methyl tert-butyl ether after the filtrate obtained by filtration is dried, dropwise adding ethyl hydrochloride at about 0 ℃, controlling the pH to 9-10, stirring for 1h, filtering, drying the filter cake obtained by filtration to obtain 7.9g of tert-butyl (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-carboxylate, the yield was 69%.
While there have been shown and described what are at present considered the fundamental principles and essential features of the invention and its advantages, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but is capable of other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (8)
1. A compound is (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester, and the molecular structure of the compound is shown as a formula I:
2. a method of synthesizing a compound according to claim 1, comprising the steps of:
s1, dissolving (E) 4-methoxybutyl-2-enoate in a solvent, adding N- (methoxymethyl) (phenyl) -N- ((trimethylsilyl) methyl) methylamine, cooling to below 20 ℃, slowly dropwise adding a dichloromethane solution containing trifluoroacetic acid, reacting at room temperature, adding dichloromethane into a reaction solution after the reaction is finished, washing with saturated sodium bicarbonate, drying with anhydrous sodium sulfate, and concentrating to obtain (3S, 4R) -1-benzyl-4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester;
s2, dissolving the (3S, 4R) -1-benzyl-4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester obtained in the step S1 in a solvent, adding concentrated hydrochloric acid, and adding a catalyst Pd (OH) under the protection of nitrogen2/C, hydrogenation reaction is carried out at the temperature of 10-35 ℃, and after the reaction is finished, reaction liquid is filtered to remove the catalyst Pd (OH)2The filtrate obtained by filtering is dried in a spinning way to obtain (3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester hydrochloride;
s3, adding the (3S, 4R) -4- (methoxymethyl) pyrrolidine-3-carboxylic acid ethyl ester hydrochloride obtained in the step S2 into dichloromethane, adding triethylamine and sodium bicarbonate, and adding a solution containing (Boc)2Slowly heating the dichloromethane solution of O to room temperature, reacting, cooling the reaction solution to room temperature after the reaction is finished, layering the reaction solution, taking a water layer, extracting dichloromethane, washing with citric acid for 3 times, washing with saturated saline solution for 3 times, and washing with anhydrous sulfuric acidDrying sodium, filtering, concentrating the filtrate to dryness to obtain crude product, and passing through a column to obtain (3S, 4S) -1-tert-butyl 3-ethyl 4- (methoxymethyl) pyrrolidine-1, 3-dicarboxylic acid ester;
s4, dissolving the (3S, 4S) -1-tert-butyl 3-ethyl 4- (methoxymethyl) pyrrolidine-1, 3 dicarboxylic ester obtained in the step S3 in toluene, adding benzyl alcohol and triethanolamine, controlling the temperature to be below 20 ℃, dropwise adding diphenylphosphoryl azide, stirring at room temperature, heating to 85-105 ℃ for reaction, concentrating and dissolving the reaction solution in ethyl acetate after the reaction is finished, washing with water and a saturated sodium bicarbonate aqueous solution, concentrating, mixing the sample, and passing through a column to obtain (3S, 4R)3- (benzyloxycarbonyl) -4 (methoxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester;
s5, dissolving the tert-butyl (3S, 4R)3- (benzyloxycarbonyl) -4 (methoxymethyl) pyrrolidine-1-carboxylate obtained in the step S4 in a solvent, adding wet Pd/C with the Pd content of 5 wt% under the protection of nitrogen, stirring, carrying out hydrogenation reaction at 10-35 ℃, filtering the reaction solution after the reaction is finished, adding methyl tert-butyl ether after the filtrate obtained by filtering is dried, dropwise adding ethyl hydrochloride at 0-10 ℃, adjusting the pH to 9-10, stirring, filtering, and drying the filter cake obtained by filtering to obtain the tert-butyl (3S, 4R) 3-amino-4- (methoxymethyl) pyrrolidine-1-carboxylate.
3. The method of synthesis according to claim 2, wherein the solvent is one of tetrahydrofuran, dichloromethane and chloroform.
4. The method of claim 2, wherein the reaction time of step S1 is 12 hours.
5. The synthesis method of claim 2, wherein the hydrogenation reaction time of step S2 is 12h, and the concentrated hydrochloric acid concentration is 12 mol/L.
6. The method of claim 2, wherein the reaction time of step S3 is 12h, and the reaction time is 3S, 4R) -4- (methyl)Oxymethyl) pyrrolidine-3-carboxylic acid ethyl ester hydrochloride, triethylamine and (Boc)2The molar ratio of O is 1:1: 1.
7. The method of claim 2, wherein the reaction time of step S4 is 12 hours.
8. The synthesis method of claim 2, wherein the hydrogenation reaction time of the step S5 is 12 h.
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