Synthesis process of spermidine

Abstract

The invention provides a synthesis process of spermidine. Comprising the following steps: reacting 1, 4-butanediamine with benzyl chloroformate to obtain mono-protected butanediamine; under the catalysis of aluminum oxide, reacting mono-protected butanediamine with acrylonitrile to obtain a compound 3; under the action of a catalyst, the compound 3 is subjected to hydrogenation reduction and deprotection reaction, and a target product is obtained. The method disclosed by the invention is relatively short in synthesis step, high in yield and high in product purity. In the third step of the method, purification is not needed, and the purity of the obtained spermidine reaches 98% or above. The method disclosed by the invention is easy and safe to operate and easy for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a process for efficiently synthesizing spermidine under low cost and mild reaction conditions. Background Art

[0002] Spermidine is an important physiologically active substance in animal and plant cells. It plays a wide range of biological roles in the body, including stimulating growth, anti-oxidation, anti-tumor, delaying aging and alleviating memory impairment. Studies have shown that the biological effects of spermidine cover almost the entire process from animal embryos to aging and death of the body, regulating activities such as cell proliferation, differentiation, apoptosis, signal transduction and gene expression, and can control cancer progression, resist aging, improve cognitive function, protect the cardiovascular system, affect immune function, improve metabolic syndrome symptoms, promote hair follicle growth, etc. In addition, the level of spermidine in animals will gradually decrease with age, while spermidine supplemented in food can be better absorbed by the intestines, and its expression level can be detected in the blood and related tissues. Due to its extremely low cytotoxicity and cytoprotective effects, the use of spermidine as a dietary supplement has received more and more attention.

[0003] The preparation methods of spermidine include extraction method, synthetase method, microbial fermentation method and chemical synthesis method. Due to the low content of spermidine in animals, plants or microorganisms, the extraction efficiency is often relatively low; the synthetase method and microbial fermentation method also face the problems of complex enzyme preparation, low yield and difficult extraction. The main chemical synthesis methods are as follows: CN109096122B reports that 3-aminopropanol and butyrolactone are used as raw materials, the ring is opened to obtain amide, and then lithium aluminum tetrahydride is used for reduction to obtain a dihydroxy compound, and then the amino group is protected by Boc, Mitsunobu reaction, and the hydroxyl group is replaced with phthalimide group, and finally deprotected to obtain spermidine hydrochloride. This method has a long route and uses relatively high-cost steps such as lithium aluminum tetrahydride and Mitsunobu reaction, which is not suitable for industrial production. The reaction formula is as follows:

[0004]

[0005] CN102659605B reacts an intermediate prepared by phenol and benzyl chloroformate with 1,4-diaminodiamine to obtain monoprotected diaminodiamine, which is then reacted with acrylonitrile, and then hydrogenated and deprotected to obtain spermidine. This method has a relatively long route, a long reaction time, a complicated operation, a large amount of reagent consumption, a lot of three wastes generated, and a low efficiency. The reaction formula is as follows:

[0006]

[0007] CN111302953B reports that protected aminobutanol and mono-protected propylenediamine are used as raw materials, docked by Mitsunobu reaction, and a spliced ​​intermediate is obtained, and finally two protecting groups are removed to obtain spermidine trihydrochloride. The route of this method is relatively simple, but the triphenylphosphine used in the Mitsunobu reaction is difficult to remove, and the amount of three wastes is large. The reaction formula is as follows:

[0008]

[0009] CN113548971B reported that 3-phthalimide propionaldehyde (V) and N-tert-butyloxycarbonyl-1,4-butanediamine (IV) were used as raw materials, and the intermediate N-tert-butyloxycarbonyl-4-(3-phthalimide propylamino)butylamine (III) was obtained by reductive amination reaction. The intermediate (III) was deprotected to obtain spermidine trihydrochloride (II), and spermidine trihydrochloride (II) can be freed to obtain spermidine (I). The method uses the controlled reagent hydrazine hydrate, and gas is generated during the reaction, which is highly dangerous, and the process of obtaining spermidine by reduced pressure distillation is prone to polymerization reaction. The reaction formula is as follows:

[0010]

[0011] CN116283604A reports that oxalyl chloride and alkali are dissolved in a first solvent, 4-bromo-1-butylamine hydrobromic acid is slowly added, and 2-((4-bromobutyl)amino)-2-oxoacetyl chloride is prepared by reaction; alkali is added to the prepared 2-((4-bromobutyl)amino)-2-oxoacetyl chloride reaction solvent, and 3-bromo-1-propylamine hydrobromic acid is slowly added to prepare N1-(4-bromobutyl)-N2-(3-bromopropyl)oxalamide; N1-(4-bromobutyl)-N2-(3-bromopropyl)oxalamide is prepared. 1-(3-aminopropyl)-N1-benzylbutane-1,4-diamine; 2-(3-aminopropyl)-N1-benzylbutane-1,4-diamine is added to Raney nickel / methanol, and hydrogen is passed through the reaction to obtain crude spermidine, which is then distilled to obtain pure spermidine. This method has a long route, a low yield, and high energy consumption. The reaction formula is as follows:

[0012]

[0013] CN 113735716 B reports that 4-dimethylaminopyridine is used as a catalyst, 2-pyrrolidone and di-tert-butyl dicarbonate react in an organic solvent to obtain 1-(tert-butoxycarbonyl)-2-pyrrolidone; the obtained 1-(tert-butoxycarbonyl)-2-pyrrolidone is dissolved in a solvent, added to a 1,3-propylenediamine solution, stirred to react until the reaction is completed, and after post-treatment, [3-(3-amino-propylcarbamoyl)propyl]-tert-butyl carbamate is obtained; after reduction with a reducing agent, [4-(3-amino-propylamino)butyl]-tert-butyl carbamate is obtained after post-treatment; and hydrochloric acid is then added to react and deprotect the group to obtain spermidine. The method has a relatively long route and a large amount of three wastes. The reaction formula is as follows:

[0014]

[0015] US2023219881A1 reported that 1,4-diaminobutane and acrylonitrile were used as raw materials, and after Boc protection of the last amino group, a cyano intermediate was obtained by Michael addition reaction, and then the cyano group was hydrogenated and reduced to obtain spermidine hydrochloride. This method has a relatively long route, a low conversion rate, and a large amount of diaminobutane residue is difficult to remove. The quality of the obtained spermidine is not high, which is not conducive to industrial production. The reaction formula is as follows:

[0016]

[0017] In view of the problems that the existing process for synthesizing spermidine has a long synthesis route, requires the use of relatively dangerous reducing agents such as lithium aluminum hydroxide or controlled reagents such as hydrazine hydrate, is difficult to purify, has a low reaction yield, and the prepared products are mostly spermidine hydrochloride, the present invention provides a new process for synthesizing spermidine. Summary of the invention

[0018] The invention aims at the deficiencies of the prior art and provides a synthesis process of spermidine. The synthesis process is simple and efficient, low in cost and high in product purity.

[0019] The synthesis process of spermidine provided by the present invention comprises the following steps:

[0020] 1) reacting 1,4-butanediamine with benzyl chloroformate (Cl-Cbz) to obtain mono-protected butanediamine;

[0021] 2) reacting the mono-protected butanediamine with acrylonitrile under the catalysis of aluminum oxide to obtain compound 3;

[0022]

[0023] 3) Under the action of a catalyst, compound 3 undergoes hydrogenation reduction and deprotection reaction to obtain the target product.

[0024] The catalyst is one of Pd / C, Pd(OAc)2, NH3·H2O, or Pd / C, Ni, LiOH, or Raney nickel, Pd / C, NH3·H2O.

[0025] The operation of step 1) of the above method is: dissolving 1,4-butanediamine in an organic solvent, stirring at a certain temperature, then dissolving benzyl chloroformate (Cl-Cbz) in an organic solvent, slowly adding it dropwise to the reaction system, stirring and reacting for a certain period of time, adjusting the pH to acidic, adding water for extraction, retaining the aqueous phase, further adjusting the pH of the aqueous phase to alkaline, adding an organic solvent for extraction, drying with anhydrous sodium sulfate, and purifying by ammonia column chromatography to obtain mono-protected butanediamine (compound 2);

[0026] Wherein, the organic solvent is one of dichloromethane, dichloroethane and chloroform;

[0027] The molar ratio of 1,4-butanediamine and Cl-Cbz is 1:(0.8-3);

[0028] The reaction temperature may be -20 to 10°C, and the reaction time may be 10 to 30 hours; preferably, the reaction temperature is 0°C, and the reaction time is 24 hours;

[0029] The acidic pH value is 1 to 4, and the alkaline pH value is 10 to 12.

[0030] The operation of step 2) of the above method is: taking mono-protected butanediamine and dissolving it in an organic solvent, adding acrylonitrile and aluminum oxide, stirring the reaction system at a certain temperature for a certain time, filtering after the reaction, and purifying by silica gel column chromatography to obtain compound 3;

[0031] Wherein, the organic solvent is one of acetonitrile, tetrahydrofuran, DMF and DMSO;

[0032] The molar ratio of compound 2, acrylonitrile and aluminum oxide can be 1:(2-4):(1-3) in sequence;

[0033] The reaction temperature is 50-120°C, and the reaction time is 10-15h. Preferably, the reaction temperature is 80°C, and the reaction time is 12h.

[0034] The operation of step 3) of the above method is: dissolving compound 3 in an organic solvent, adding a catalyst, placing the mixture in a sealed reactor, introducing hydrogen into the reactor, heating the reactor for a certain period of time, filtering the reaction after the reaction is completed, and spinning the filtrate to obtain the target product (spermidine);

[0035] Wherein, the organic solvent is one of methanol, ethanol, acetone and ethyl acetate;

[0036] The mass ratio of Pd / C (Pd content 10%), Pd(OAc)2, and NH3·H2O is 1:(2-10):(10-20), or the mass ratio of Pd / C (Pd content 10%), Ni, and LiOH is 1:(2-4):(2-4), or the mass ratio of Raney nickel (nickel content 40%), Pd / C (Pd content 10%), and NH3·H2O is 1:(0.2-0.4):(5-20);

[0037] The molar ratio of compound 3 to Pd / C (in terms of Pd) is (1-30):1, the pressure of hydrogen in the reactor is 1.1-2.2 MPa, the reaction temperature is 50-80° C., and the reaction time is 6-12 h.

[0038] Preferably, in step (3), the hydrogen pressure in the reactor is 1.5 MPa, the reaction temperature is 60° C., and the reaction time is 8 h.

[0039] Compared with the prior art, the synthesis process of the present invention has the following characteristics:

[0040] 1) The method of the present invention has short synthesis steps, high yield and high product purity.

[0041] 2) The third step of the method of the present invention does not require purification, and the purity of the obtained spermidine is more than 98%.

[0042] 3) The method of the present invention is easy and safe to operate and is easy to be produced on an industrial scale. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 The present invention is a process flow chart for synthesizing spermidine.

[0044] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of compound 2 prepared in Example 1 of the present invention.

[0045] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of compound 3 prepared in Example 1 of the present invention.

[0046] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of compound 4 prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0047] The present invention is further described in detail below in conjunction with specific embodiments, and the examples provided are only for illustrating the present invention, rather than for limiting the scope of the present invention. The examples provided below can be used as a guide for further improvements by those of ordinary skill in the art, and do not constitute a limitation of the present invention in any way.

[0048] The experimental methods in the following examples, unless otherwise specified, are all conventional methods, and are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. The materials, reagents, etc. used in the following examples, unless otherwise specified, can all be obtained from commercial channels.

[0049] The specifications and sources of the reagents used in the following examples are as follows:

[0050] 1,4-Butanediamine, Cl-Cbz, acrylonitrile, acetonitrile, aluminum oxide, Raney nickel (nickel content 40%), Pd / C (Pd content 10%), Pd(OAc)2, hydrogen, ammonia, dichloromethane, methanol, hydrochloric acid, and sodium hydroxide were all purchased from Shanghai Sinopharm Chemical Reagent Co., Ltd. and were all analytical grade reagents.

[0051] Embodiment 1,

[0052] Reference Figure 1 The process flow diagram shown is for the synthesis of spermidine.

[0053] (1) Compound 120.0 g was dissolved in 200 mL of dichloromethane and stirred at 0°C. Then, Cl-Cbz raw material (38.0 g) was dissolved in 200 mL of dichloromethane and slowly added dropwise at 0°C. The reaction system was stirred at 0°C for 24 h. After the reaction was completed, the pH was adjusted to acidic (pH=2-3), water was added for extraction 3 times, the aqueous phase was retained, the pH of the aqueous phase was further adjusted to alkaline (pH=11-12), dichloromethane was added for extraction, dried over anhydrous sodium sulfate, and purified by column chromatography with dichloromethane, methanol, and aqueous ammonia to finally obtain compound 230.0 g with a yield of 60%.

[0054] (2) 29.0 g of the compound was dissolved in 60 mL of DMF, 5.9 g of acrylonitrile and 8.7 g of aluminum oxide were added, and the reaction system was stirred at 120° C. for 8 h. After the reaction was completed, the mixture was filtered, and silica gel was added and purified by column chromatography with dichloromethane and methanol to finally obtain 37.3 g of the compound with a yield of 65%.

[0055] (3) 34.0 g of the compound was dissolved in 60 mg of methanol, and Raney nickel (2.5 g), Pd / C (800 mg), and NH3·H2O (15.0 mL) were added as catalysts. The mixture was placed in a sealed reactor, and hydrogen (1.5 MPa) was introduced into the reactor. The reaction was heated at 65°C for 12 h. After the reaction was completed, the filtrate was filtered and the filtrate was dried to obtain 41.8 g of the product. The yield was 85% and the product purity was 98%.

[0056] Embodiment 2,

[0057] (1) Compound 120.0 g was dissolved in 200 mL of dichloromethane and stirred at 0°C. Then, the Cl-Cbz raw material (38.0 g) was dissolved in 200 mL of dichloromethane and slowly added dropwise at 5°C. The reaction system was stirred at 5°C for 24 h. After the reaction was completed, the pH was adjusted to acidic (pH=2-3), water was added for extraction 3 times, the aqueous phase was retained, the pH of the aqueous phase was further adjusted to alkaline (pH=11-12), dichloromethane was added for extraction, dried over anhydrous sodium sulfate, and purified by column chromatography with dichloromethane, methanol, and aqueous ammonia to finally obtain compound 231 g with a yield of 62%.

[0058] (2) 29.0 g of the compound was dissolved in 60 mL of acetonitrile, 5.9 g of acrylonitrile and 8.7 g of aluminum oxide were added, and the reaction system was stirred at 90° C. for 12 h. After the reaction was completed, the mixture was filtered, and silica gel was added and purified by column chromatography with dichloromethane and methanol to finally obtain 37.4 g of the compound with a yield of 66%.

[0059] (3) 34.0 g of compound was dissolved in 60 mg of methanol, Pd(OAc)2 (5.0 g), Pd / C (800 mg), and NH3·H2O (15.0 mL) were added as catalysts, and the mixture was sealed in a reaction kettle. Hydrogen (1.5 MPa) was introduced into the reaction kettle, and the mixture was heated at 65°C for 12 h. After the reaction was completed, the mixture was filtered and the filtrate was dried to obtain 41.9 g of the product with a yield of 90% and a purity of 97%.

[0060] Embodiment 3,

[0061] (1) Compound 120.0 g was dissolved in 200 mL of dichloromethane and stirred at 0°C. Then, Cl-Cbz raw material (38.0 g) was dissolved in 200 mL of dichloromethane and slowly added dropwise at -5°C. The reaction system was stirred at -5°C for 24 h. After the reaction was completed, the pH was adjusted to acidic (pH = 2-3), water was added for extraction 3 times, the aqueous phase was retained, the pH of the aqueous phase was further adjusted to alkaline (pH = 11-12), dichloromethane was added for extraction, dried over anhydrous sodium sulfate, and purified by column chromatography with dichloromethane, methanol, and aqueous ammonia to finally obtain compound 229.0 g with a yield of 58%.

[0062] (2) 29.0 g of the compound was dissolved in 60 mL of acetonitrile, 5.9 g of acrylonitrile and 8.7 g of aluminum oxide were added, and the reaction system was stirred at 90° C. for 12 h. After the reaction was completed, the mixture was filtered, and silica gel was added and purified by column chromatography with dichloromethane and methanol to finally obtain 37.4 g of the compound with a yield of 66%.

[0063] (3) 34.0 g of the compound was dissolved in 60 mg of methanol, and nickel (2.5 g), Pd / C (800 mg), and LiOH (2.5 g) were added as catalysts. The mixture was placed in a sealed reactor, and hydrogen (1.5 MPa) was introduced into the reactor. The reaction was heated at 65° C. for 12 h. After the reaction was completed, the filtrate was filtered and the filtrate was dried to obtain 41.8 g of the product. The yield was 85% and the product purity was 98.5%.

[0064] Comparative Example 1

[0065] (1) Compound 120.0 g was dissolved in 200 mL of dichloromethane and stirred at 0°C. Then, Cl-Cbz raw material (38.0 g) was dissolved in 200 mL of dichloromethane and slowly added dropwise at -5°C. The reaction system was stirred at -5°C for 24 h. After the reaction was completed, the pH was adjusted to acidic (pH = 2-3), water was added for extraction 3 times, the aqueous phase was retained, the pH of the aqueous phase was further adjusted to alkaline (pH = 11-12), dichloromethane was added for extraction, dried over anhydrous sodium sulfate, and purified by column chromatography with dichloromethane, methanol, and aqueous ammonia to finally obtain compound 229.0 g with a yield of 58%.

[0066] (2) 29.0 g of the compound was dissolved in 60 mL of acetonitrile, 5.9 g of acrylonitrile and 8.7 g of aluminum oxide were added, and the reaction system was stirred at 90° C. for 12 h. After the reaction was completed, the mixture was filtered, and silica gel was added and purified by column chromatography with dichloromethane and methanol to finally obtain 37.4 g of the compound with a yield of 66%.

[0067] (3) 34.0 g of the compound was dissolved in 60 mg of methanol, and Pd(OAc)2 (5.0 g) and NH3·H2O (15.0 mL) were added as catalysts. The mixture was placed in a sealed reactor, and hydrogen (1.5 MPa) was introduced into the reactor. The reaction was heated at 65°C for 12 h. After the reaction was completed, the filtrate was filtered and the filtrate was dried to obtain 40.1 g of the product (yield 5%).

[0068] The results showed that in step (3), the catalytic effect of the single catalyst [Pd(OAc)2 and NH3·H2O] was poor, and the yield of compound 4 was too low.

[0069] Comparative Example 2

[0070] (1) Compound 120.0 g was dissolved in 200 mL of dichloromethane and stirred at 0°C. Then, Cl-Cbz raw material (38.0 g) was dissolved in 200 mL of dichloromethane and slowly added dropwise at -5°C. The reaction system was stirred at -5°C for 24 h. After the reaction was completed, the pH was adjusted to acidic (pH = 2-3), water was added for extraction 3 times, the aqueous phase was retained, the pH of the aqueous phase was further adjusted to alkaline (pH = 11-12), dichloromethane was added for extraction, dried over anhydrous sodium sulfate, and purified by column chromatography with dichloromethane, methanol, and aqueous ammonia to finally obtain compound 229.0 g with a yield of 58%.

[0071] (2) 29.0 g of the compound was dissolved in 60 mL of acetonitrile, 5.9 g of acrylonitrile and 8.7 g of aluminum oxide were added, and the reaction system was stirred at 90° C. for 12 h. After the reaction was completed, the mixture was filtered, and silica gel was added and purified by column chromatography with dichloromethane and methanol to finally obtain 37.4 g of the compound with a yield of 66%.

[0072] (3) 34.0 g of the compound was dissolved in 60 mg of methanol, Pd / C (800 mg) was added as a catalyst, and the mixture was placed in a sealed reactor. Hydrogen (1.5 MPa) was introduced into the reactor, and the reaction was heated at 65° C. for 12 h. After the reaction was completed, the filtrate was filtered and the filtrate was dried to obtain 40.1 g of the product, with a yield of 5%.

[0073] The results show that in step (3), the catalytic effect of the single catalyst Pd / C is poor, and the yield of compound 4 is too low.

[0074] Comparative Example 3

[0075]

[0076] Compound 1 and compound 2 were dissolved in acetonitrile at a molar ratio of 1.1:1, and aluminum oxide (Al2O3) was used as a catalyst, and stirred at 70°C for 12 hours. After the reaction was completed, purification was attempted by distillation, crystallization, and gel chromatography.

[0077] The results showed that compound 3 could not be obtained by the above purification method because compound 3 and the by-product had extremely similar polarity and solubility in different solvents, and compound 3 was unstable at high temperature and easily formed polymers.

[0078] Comparative Example 4

[0079]

[0080] (1) Compound 1 and di-tert-butyl dicarbonate ((Boc)2O) were dissolved in 1,4-dioxane at a molar ratio of 1:3 and stirred at room temperature for 12 hours. After the reaction was completed, dichloromethane was added to dissolve and washed with water three times to obtain an organic phase, which was dried over anhydrous sodium sulfate and rotary evaporated to obtain compound 2 (yield: 63%, purity: 97%).

[0081] (2) Compound 2 and acrylamide were dissolved in acetonitrile at a molar ratio of 1:1.5, and Al2O3 was used as a catalyst. The mixture was stirred at 100°C for 12 hours. After the reaction, gel chromatography was performed, and the polarity of the eluent was dichloromethane: methanol: triethylamine = 150:10:1, and finally compound 3 was obtained (yield: 33%, purity: 87%).

[0082] (3) Compound 3 and trifluoroacetic acid (TFA) were dissolved in dichloromethane at a molar ratio of 1:3 and stirred at room temperature for 3 h. After the reaction, gel chromatography was performed and the polarity of the eluent was dichloromethane: methanol: triethylamine = 150:10:2 to finally obtain compound 4 (yield: 46%, purity: 69%).

[0083] (4) Compound 4 and lithium aluminum hydride (LiAlH4) were dissolved in tetrahydrofuran at a molar ratio of 1:5 and stirred at room temperature for 12 h. After the reaction was completed, water was added to quench the mixture and the filtrate was filtered out by suction. The solvent was removed by rotary evaporation and the mixture was redissolved in tetrahydrofuran. The filtrate was filtered out by suction and the compound 5 was obtained by rotary evaporation (yield: 42%, purity: 52%).

[0084] The total yield of four steps is 4%.

[0085] The results show that compared with Comparative Example 3, the raw material 1,4-butanediamine can be purified by gel chromatography after being protected by (Boc)2O and then reacting with acrylamide, but the reaction efficiency of compound 2 and acrylamide is extremely low, and there are many by-products in the synthesis process, which makes purification difficult, resulting in further reduction in the yield and purity of compound 4 and compound 5.

[0086] The present invention has been described in detail above. For those skilled in the art, without departing from the purpose and scope of the present invention, and without the need to carry out unnecessary experimental conditions, the present invention can be implemented in a wide range under equivalent parameters, concentrations and conditions. Although the present invention provides specific embodiments, it should be understood that the present invention can be further improved. In a word, according to the principles of the present invention, the application is intended to include any changes, uses or improvements to the present invention, including departure from the disclosed scope in the application, and changes made with conventional techniques known in the art.

Claims

1. A method for synthesizing spermidine, comprising the steps of: 1) reacting 1,4-butanediamine with benzyl chloroformate to obtain mono-protected butanediamine; 2) reacting the mono-protected butanediamine with acrylonitrile under the catalysis of aluminum oxide to obtain compound 3; 3) Under the action of a catalyst, compound 3 undergoes hydrogenation reduction and deprotection reaction to obtain the target product. The catalyst is one of Pd / C, Pd(OAc)2, NH3·H2O, or Pd / C, Ni, LiOH, or Raney nickel, Pd / C, NH3·H2O.

2. The method according to claim 1, characterized in that The operation of step 1) is as follows: 1,4-butanediamine is dissolved in an organic solvent, stirred at a certain temperature, benzyl chloroformate (Cl-Cbz) raw material is dissolved in an organic solvent, slowly added dropwise to the reaction system, reacted for a certain period of time under stirring, the pH is adjusted to acidic, water is added for extraction, the aqueous phase is retained, the pH of the aqueous phase is further adjusted to alkaline, an organic solvent is added for extraction, dried over anhydrous sodium sulfate, and purified by ammonia column chromatography to obtain mono-protected butanediamine.

3. The method according to claim 2, characterized in that The organic solvent is one of dichloromethane, dichloroethane and chloroform; The molar ratio of 1,4-butanediamine and Cl-Cbz is 1:(0.8-3); The reaction temperature can be -20 to 10°C and the reaction time can be 10 to 30 hours; The acidic pH value is 1 to 4, and the alkaline pH value is 10 to 12.

4. The method according to claim 1, characterized in that: The operation of step 2) is as follows: mono-protected butanediamine is dissolved in an organic solvent, acrylonitrile and aluminum oxide are added, the reaction system is stirred at a certain temperature for a certain time, after the reaction is completed, the reaction is filtered, and the compound 3 is purified by silica gel column chromatography to obtain compound 3.

5. The method according to claim 4, characterized in that The organic solvent is one of acetonitrile, tetrahydrofuran, DMF and DMSO; The molar ratio of compound 2, acrylonitrile and aluminum oxide is 1:(2-4):(1-3); The reaction temperature is 50-120°C and the reaction time is 10-15h.

6. The method according to claim 1, characterized in that The operation of step 3) is as follows: dissolving compound 3 in an organic solvent, adding a catalyst, placing the mixture in a sealed reactor, introducing hydrogen into the reactor, heating the reactor for a certain period of time, filtering after the reaction, and spinning the filtrate to obtain the target product.

7. The method according to claim 6, characterized in that The organic solvent is one of ethanol, acetone and ethyl acetate; The mass ratio of Pd / C, Pd(OAc)2, and NH3·H2O is 1:(2-10):(10-20), or the mass ratio of Pd / C, Ni, and LiOH is 1:(2-4):(2-4), or the mass ratio of Raney nickel, Pd / C, and NH3·H2O is 1:(0.2-0.4):(5-20); The molar ratio of compound 3 to Pd / C is (1-30):1, the pressure of hydrogen in the reactor is 1.1-2.2 MPa, the reaction temperature is 50-80° C., and the reaction time is 6-12 h.

8. The method according to claim 7, characterized in that In the step (3), the pressure of hydrogen in the reactor is 1.5 MPa, the reaction temperature is 60° C., and the reaction time is 8 h.

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