A preparation method of spermidine

Abstract

The present invention provides a method for preparing spermidine, which relates to the technical field of organic synthesis. The method for preparing spermidine comprises: condensing 3-chloropropylamine hydrochloride and triphenylmethane to obtain 3-chloro-N-tritylpropylamine; condensing 3-chloro-N-tritylpropylamine and 1,4-butanediamine to obtain N 1 ‑(3‑(tritylamino)propyl)butane‑1,4‑diamine; N 1 The trityl group is removed from 1,4-(3-(tritylamino)propyl)butane to obtain spermidine hydrochloride; and spermidine hydrochloride is liberated in the presence of a base to obtain spermidine. The preparation method of the present invention can achieve a high yield and purity in a relatively short reaction period, avoids the problems of a high proportion of by-products, high purification difficulty, and residual solvent, improves the reaction efficiency, and has mild reaction conditions, simple production equipment, and is more energy-saving and environmentally friendly while being convenient for industrialized amplification production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, in particular to a method for preparing spermidine. Background Art

[0002] Spermidine is an aliphatic polyamine compound widely distributed throughout the body. It is biosynthesized from putrescine (butanediamine) and adenosylmethionine. Spermidine inhibits neuronal synthases and binds to and precipitates DNA. It is also used to purify DNA-binding proteins and stimulate T4 polynucleotide kinase activity. Spermidine was first isolated from semen and discovered, but it is actually a widespread substance in the body. Whole grains, kelp, mushrooms, beans, and whole cereals are all rich sources of this substance.

[0003] The uses of spermidine are as follows: (1) Boar sperm cryopreservation: Studies have shown that adding spermidine to boar sperm cryopreservation fluid can enhance the preservation efficacy of boar semen, improve the quality and activity of boar sperm, and prolong the in vitro storage life of boar sperm. (2) Anti-aging: Spermidine has excellent antioxidant properties and can scavenge free radicals in the body to prevent cell damage. (3) Enhance muscle mass: Studies have shown that spermidine can increase the muscle alanine content in muscle, thereby increasing the oxygen content of muscle and delaying the occurrence of muscle fatigue. (4) Regulate and protect nerves: Spermidine has antioxidant and anti-inflammatory effects on neurodegeneration, can improve learning and memory, protect nerve cells, and prevent Alzheimer's disease. (5) Anti-cancer: Many studies have shown that spermidine supplementation can reduce the occurrence of tumors in mice, such as reducing the incidence of visible skin tumors in elderly female mice and slowing the growth of colorectal tumors in mice; other studies have found that spermidine can enhance anti-tumor immune responses. (6) Protect cardiovascular disease: Spermidine can improve blood pressure and reduce the incidence and mortality of cardiovascular disease.

[0004] CN102659605A discloses a method for synthesizing spermidine, the main technical features of which are: first, preparing Cbz-monoprotected 1,4-butanediamine, then subjecting it to an addition reaction with acrylonitrile, and finally reducing the cyano group in the addition product and removing the Cbz protection, to obtain spermidine through a five-step reaction.

[0005] CN109096122A discloses a method for preparing spermidine by reacting aminopropanol and butyrolactone as raw materials, followed by reduction, amino protection and other steps.

[0006] CN115872898A discloses a method in which 1,4-butanediamine and acrylonitrile are reacted as raw materials under solvent-free conditions, the obtained product is directly subjected to hydrogenation reduction reaction, and spermidine is obtained through distillation.

[0007] The currently reported preparation processes generally have the following problems: (1) multiple synthesis steps, complicated post-reaction treatment, and low yield; (2) cumbersome process operations, which are not conducive to industrial scale-up production; (3) the use of hydrogenation reduction process, which has certain safety hazards; (4) the metal catalyst is expensive, the production cost is high, and the recovery and reuse of precious metal catalysts need to be considered. (5) Side reactions are relatively obvious, and there are many by-products, which are difficult to separate and purify.

[0008] In view of this, the present invention is proposed. Summary of the Invention

[0009] The present invention aims to provide a method for preparing spermidine, which is intended to simplify the process, reduce production costs, and improve product purity and yield.

[0010] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are adopted:

[0011] In a first aspect, the present invention provides a method for preparing spermidine, comprising:

[0012] (1) condensing 3-chloropropylamine hydrochloride and triphenylmethane to obtain 3-chloro-N-tritylpropylamine;

[0013] (2) 3-Chloro-N-tritylpropylamine and 1,4-butanediamine were subjected to condensation reaction to obtain N 1 -(3-(tritylamino)propyl)butane-1,4-diamine;

[0014] (3) N 1 -(3-(tritylamino)propyl)butane-1,4-diamine removes the trityl group to obtain spermidine hydrochloride;

[0015] (4) Spermidine hydrochloride is liberated in the presence of a base to obtain spermidine.

[0016] Preferably, in step (1), the molar ratio of 3-chloropropylamine hydrochloride to triphenylmethane is 1:(0.8-1.2).

[0017] Preferably, in step (1), the condensation reaction is carried out in a solvent.

[0018] Preferably, in step (1), the solvent comprises any one or a combination of at least two of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile or dimethyl sulfoxide, preferably dichloromethane.

[0019] Preferably, in step (1), the condensation reaction is carried out in the presence of an acid binding agent.

[0020] Preferably, in step (1), the acid binding agent comprises triethylamine, potassium carbonate or cesium carbonate or any one or a combination of at least two thereof, preferably triethylamine.

[0021] Preferably, in step (1), the molar ratio of 3-chloropropylamine hydrochloride, triphenylmethane and acid binding agent is 1:(0.8-1.2):(1-3).

[0022] Preferably, in step (1), the specific steps of the condensation reaction are:

[0023] 3-chloropropylamine hydrochloride, an acid-binding agent, and a solvent are mixed and stirred to obtain a raw material solution 1; triphenylmethane chloride is dissolved in the solvent to obtain a raw material solution 2; and the raw material solution 2 is dropwise added to the raw material solution 1 to carry out a condensation reaction to obtain a reaction solution containing 3-chloro-N-tritylpropylamine.

[0024] Preferably, the temperature of the dropwise added raw material liquid 2 is below 5°C.

[0025] Preferably, the condensation reaction is: first reacting at below 5°C for 1 to 12 hours, and then reacting at 5 to 35°C for 12 to 24 hours.

[0026] Preferably, in step (1), the condensation reaction further includes the following post-treatment steps:

[0027] The reaction solution containing 3-chloro-N-tritylpropylamine is filtered, extracted, washed, dried, concentrated and recrystallized in sequence to obtain 3-chloro-N-tritylpropylamine.

[0028] Preferably, in step (1), the condensation reaction further includes the following post-treatment steps:

[0029] The reaction solution containing 3-chloro-N-tritylpropylamine is filtered, the filtrate is collected, washed with water, and the organic phase is collected and dried. The crude product is concentrated to obtain a crude product, which is recrystallized in an organic solvent to obtain 3-chloro-N-tritylpropylamine.

[0030] Preferably, in step (1), the organic solvent for recrystallization is toluene and / or ethyl acetate.

[0031] Preferably, in step (1), the molar ratio of 3-chloro-N-tritylpropylamine to 1,4-butanediamine is 1:(1-10).

[0032] Preferably, in step (2), the condensation reaction is carried out in a solvent.

[0033] Preferably, in step (2), the solvent comprises any one or a combination of at least two of N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dimethyl sulfoxide or 1,3-dimethyl-2-imidazolidinone, preferably N,N-dimethylformamide.

[0034] Preferably, in step (2), the condensation reaction is carried out in the presence of an acid binding agent.

[0035] Preferably, in step (2), the acid binding agent comprises triethylamine, potassium carbonate or cesium carbonate or any one or a combination of at least two thereof, preferably triethylamine.

[0036] Preferably, in step (2), the molar ratio of 3-chloro-N-tritylpropylamine, 1,4-butanediamine and acid binding agent is 1:(1-10)(1-3).

[0037] Preferably, in step (2), the specific steps of the condensation reaction are:

[0038] 3-Chloro-N-tritylpropylamine, 1,4-butanediamine, an acid-binding agent and a solvent are mixed and stirred to carry out a condensation reaction to obtain N-containing 1 -(3-(tritylamino)propyl)butane-1,4-diamine reaction solution.

[0039] Preferably, in step (2), the temperature of the condensation reaction is 20 to 120° C., and the time of the condensation reaction is 3 to 24 hours.

[0040] Preferably, in step (2), the condensation reaction further comprises the following post-treatment steps: 1 The reaction solution of -(3-(tritylamino)propyl)butane-1,4-diamine was extracted, washed, dried and concentrated in sequence to obtain N 1 -(3-(tritylamino)propyl)butane-1,4-diamine.

[0041] Preferably, in step (2), the condensation reaction further includes the following post-treatment steps:

[0042] Containing N 1 The reaction solution of -(3-(tritylamino)propyl)butane-1,4-diamine was added with an extractant for extraction, and the organic phase was collected, washed with water, and dried, and concentrated to obtain N 1 -(3-(tritylamino)propyl)butane-1,4-diamine.

[0043] Preferably, in step (2), the extractant comprises water and ethyl acetate.

[0044] Preferably, in step (3), the removal of the trityl group is carried out in dilute hydrochloric acid.

[0045] Preferably, in step (3), the concentration of the dilute hydrochloric acid is 1 to 10 M, preferably 6 M.

[0046] Preferably, in step (3), the N 1 The molar ratio of -(3-(tritylamino)propyl)butane-1,4-diamine and hydrochloric acid is 1:(1 to 10).

[0047] Preferably, in step (3), the reaction temperature for removing the trityl group is 20 to 80° C., and the reaction time is 3 to 24 hours.

[0048] Preferably, in step (3), the removal of the trityl group further includes the following post-treatment steps:

[0049] The reaction solution containing spermidine hydrochloride is filtered, washed, concentrated and recrystallized in sequence to obtain spermidine hydrochloride.

[0050] Preferably, in step (3), the removal of the trityl group further includes the following post-treatment steps:

[0051] The reaction solution containing spermidine hydrochloride is filtered, the aqueous phase is washed with ethyl acetate, the aqueous phase is collected and concentrated to obtain a crude product, the crude product is recrystallized in an organic solvent, the product is precipitated and then filtered, the filter residue is rinsed with acetone, the solid is collected and dried to obtain spermidine hydrochloride.

[0052] Preferably, in step (3), the recrystallization solvent is a mixed solvent of ethanol and water.

[0053] Preferably, in step (3), in the recrystallization solvent, the volume ratio of water to ethanol is (1-5):(5-95).

[0054] Preferably, in step (3), the temperature of the acetone used for elution is below 5°C; the amount of acetone used is 5 to 10 times the mass of the filter residue; and the number of elutions is 3 to 5 times.

[0055] Preferably, in step (3), the temperature for drying after collecting the solid is 40 to 60° C., and the drying time is 2 to 12 hours.

[0056] Preferably, in step (4), the base comprises an organic base and / or an inorganic base.

[0057] Preferably, the organic base comprises triethylamine.

[0058] Preferably, the inorganic base includes any one of sodium hydroxide, potassium carbonate or cesium carbonate, or a combination of at least two of them.

[0059] Preferably, in step (4), the freeing is carried out in a solvent.

[0060] Preferably, in step (4), the solvent comprises any one of methanol, ethanol, isopropanol or dichloromethane, or a combination of at least two thereof, preferably ethanol.

[0061] Preferably, in step (4), the molar ratio of spermidine hydrochloride to base is 1:(1-5).

[0062] Preferably, in step (4), the temperature for the dissociation is 25 to 80° C., and the time for the dissociation is 3 to 12 hours.

[0063] Preferably, in step (4), the following post-treatment steps are further included after the release:

[0064] The reaction solution containing spermidine is filtered and concentrated in sequence to obtain spermidine.

[0065] Preferably, in step (4), the following post-treatment steps are further included after the release:

[0066] The reaction solution containing spermidine is filtered and eluted with ethanol. The filtrate is collected and concentrated to obtain spermidine.

[0067] Compared with the prior art, the present invention has the following beneficial effects:

[0068] (1) The method for preparing spermidine of the present invention uses 3-chloropropylamine hydrochloride, triphenylmethane and 1,4-butanediamine as reaction raw materials. By optimizing the reaction temperature, time, feed ratio and experimental scheme, a higher yield and purity can be achieved in a shorter reaction cycle. At the same time, the limitation of the reaction temperature by volatile solvents is avoided, thereby improving the reaction rate.

[0069] (2) The method for preparing spermidine of the present invention also avoids the problem of high proportion of by-products and difficulty in purification, improves reaction efficiency, mild reaction conditions, simple production equipment, and is convenient for industrial scale-up production while being more energy-saving and environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0071] Figure 1 The figure is the hydrogen nuclear magnetic resonance spectrum of the spermidine hydrochloride product obtained in Example 1. DETAILED DESCRIPTION

[0072] Unless otherwise defined herein, scientific and technical terms used in conjunction with the present invention shall have the meanings commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear; however, in the event of any potential ambiguity, the definitions provided herein take precedence over any dictionary or external definitions. In this application, the use of "or" means "and / or" unless otherwise stated. In addition, the use of the term "including" and other forms is non-limiting.

[0073] It should be noted that the following description sets forth specific details to facilitate a full understanding of the present invention. However, the present invention can be implemented in a variety of other ways than those described herein, and those skilled in the art may make similar generalizations without departing from the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0074] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0075] In a first aspect, the present invention provides a method for preparing spermidine, comprising:

[0076] (1) 3-chloropropylamine hydrochloride and triphenylmethane are subjected to a condensation reaction to obtain 3-chloro-N-tritylpropylamine; the reaction formula is as follows:

[0077]

[0078] (2) 3-Chloro-N-tritylpropylamine and 1,4-butanediamine were subjected to condensation reaction to obtain N 1 -(3-(tritylamino)propyl)butane-1,4-diamine; the reaction formula is as follows:

[0079]

[0080] (3) N 1 -(3-(tritylamino)propyl)butane-1,4-diamine removes the trityl group to obtain spermidine hydrochloride; the reaction formula is as follows:

[0081]

[0082] (4) Spermidine hydrochloride is liberated in the presence of a base to obtain spermidine; the reaction formula is shown below:

[0083]

[0084] In the present invention, 3-chloropropylamine hydrochloride, triphenylmethane and 1,4-butanediamine are used as reaction raw materials, and a four-step reaction is carried out to prepare spermidine simply and efficiently. The reaction products of each step can be purified by simple recrystallization, and a product with high purity can be obtained efficiently. Furthermore, the present invention can achieve a higher yield and purity in a shorter reaction cycle by optimizing the reaction temperature, time, feed ratio and experimental scheme, while also avoiding the problems of a high proportion of by-products and difficulty in purification, improving the reaction efficiency, avoiding the problem of solvent residue, and the reaction conditions are mild, the required production equipment is simple, and it is convenient for industrial scale-up production while being more energy-saving and environmentally friendly.

[0085] As an optional embodiment of the present invention, in step (1), the molar ratio of 3-chloropropylamine hydrochloride to triphenylmethane is 1:(0.8-1.2), for example, it can be 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1, 1:1.05, 1:1.05, 1:1, 1:1.15, 1:1.2, etc., preferably 1:1.

[0086] As an optional embodiment of the present invention, in step (1), the condensation reaction is carried out in a solvent.

[0087] As an optional embodiment of the present invention, in step (1), the solvent includes any one or a combination of at least two of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile or dimethyl sulfoxide, preferably dichloromethane.

[0088] It should be noted that the present invention optimizes the selection of the reaction solvent and the molar ratio of 3-chloropropylamine hydrochloride and triphenylmethane. If the reaction solvent is selected outside the above range, the reaction will not proceed or the yield will be significantly reduced.

[0089] As an optional embodiment of the present invention, in step (1), the condensation reaction is carried out in the presence of an acid binding agent.

[0090] As an optional embodiment of the present invention, in step (1), the acid binding agent includes triethylamine, potassium carbonate or cesium carbonate or any one or a combination of at least two thereof, preferably triethylamine.

[0091] As an optional embodiment of the present invention, in step (1), the molar ratio of the 3-chloropropylamine hydrochloride, triphenylmethane and acid binding agent is 1: (0.8-1.2): (1-3), for example, it can be 1:0.8:1, 1:0.85:1, 1:0.9:1, 1:0.95:1, 1:1:1, 1:1.05:1, 1:1.05:1, 1:1:1, 1:1.15:1, 1:1.2:1, 1:0.8:2, 1:0.85:2, 1:0.9:2, 1:0.95:2, 1:1:2, 1:1.05:2, 1:1.05:2, 1:1:2, 1:1.15:2, 1:1.2:2, 1:0.8:3, 1:0.85:3, 1:0.9:3, 1:0.95:3, 1:1:3, 1:1.05:3, 1:1.05:3, 1:1:3, 1:1.15:3, 1:1.2:3, etc., can also be any value between the above adjacent values, preferably 1:1:1, 1:1:2 or 1:1:3. The purity and yield of 3-chloro-N-tritylpropylamine prepared within this range are higher.

[0092] As an optional embodiment of the present invention, in step (1), the specific steps of the condensation reaction are:

[0093] 3-chloropropylamine hydrochloride, an acid-binding agent, and a solvent are mixed and stirred to obtain a raw material solution 1; triphenylmethane chloride is dissolved in the solvent to obtain a raw material solution 2; and the raw material solution 2 is dropwise added to the raw material solution 1 to carry out a condensation reaction to obtain a reaction solution containing 3-chloro-N-tritylpropylamine.

[0094] As an optional embodiment of the present invention, in step (1), the temperature of the dropwise added raw material liquid 2 is below 5°C, for example, it can be 5°C, 4°C, 3°C, 2°C, 1°C, 0°C, -1°C, -2°C, -3°C, -4°C, -5°C, etc.

[0095] As an optional embodiment of the present invention, in step (1), the condensation reaction is:

[0096] The reaction is first carried out at a temperature below 5°C (for example, 5°C, 4°C, 3°C, 2°C, 1°C, 0°C, -1°C, -2°C, -3°C, -4°C, -5°C, etc.) for 1 to 12 h (for example, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, etc.), and then at a temperature between 5 and 35°C (for example, 5°C, 6°C, 8°C, 10°C, 12°C, 14°C, 16°C, 18°C, 20°C, 22°C, 24°C, 25°C, 26°C, 28°C, 30°C, 32°C, 34°C, 35°C, etc.) for 12 to 24 h (for example, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h, etc.). The condensation reaction in step (1) is carried out within the above-mentioned temperature and time range to prepare 3-chloro-N-tritylpropylamine with higher purity and yield.

[0097] As an optional embodiment of the present invention, in step (1), the condensation reaction further includes the following post-treatment steps:

[0098] The reaction solution containing 3-chloro-N-tritylpropylamine is filtered, extracted, washed, dried, concentrated and recrystallized in sequence to obtain 3-chloro-N-tritylpropylamine.

[0099] As an optional embodiment of the present invention, in step (1), the condensation reaction further includes the following post-treatment steps:

[0100] The reaction solution containing 3-chloro-N-tritylpropylamine is filtered, the filtrate is collected, washed with water, and the organic phase is collected and dried. The crude product is concentrated to obtain a crude product, which is recrystallized in an organic solvent to obtain 3-chloro-N-tritylpropylamine.

[0101] As an optional embodiment of the present invention, in step (1), the organic solvent for recrystallization is toluene and / or ethyl acetate.

[0102] As an optional embodiment of the present invention, in step (2), the molar ratio of 3-chloro-N-tritylpropylamine and 1,4-butanediamine is 1:(1-10), for example, it can be 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, etc., preferably 1:(4-6), and more preferably 1:5.

[0103] In the present invention, the raw materials of step (2) are condensed with 3-chloro-N-tritylpropylamine and 1,4-butanediamine to synthesize N 1-(3-(tritylamino)propyl)butane-1,4-diamine. This step not only reduces the introduction of other impurities, but also eliminates the limitation of volatile solvents on the reaction temperature. Furthermore, the molar ratio of 3-chloro-N-tritylpropylamine and 1,4-butanediamine is limited to the above range. The amount of 1,4-butanediamine used is to enable the complete reaction of 3A and minimize the production of bilateral condensation byproducts, preferably 1:5, to improve the utilization of raw materials while ensuring the yield and purity of the product.

[0104] As an optional embodiment of the present invention, in step (2), the condensation reaction is carried out in a solvent.

[0105] As an optional embodiment of the present invention, in step (2), the solvent includes any one or a combination of at least two of N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dimethyl sulfoxide or 1,3-dimethyl-2-imidazolidinone, preferably N,N-dimethylformamide.

[0106] As an optional embodiment of the present invention, in step (2), the condensation reaction is carried out in the presence of an acid binding agent.

[0107] As an optional embodiment of the present invention, in step (2), the acid binding agent includes triethylamine, potassium carbonate or cesium carbonate or any one or a combination of at least two thereof, preferably triethylamine.

[0108] As an optional embodiment of the present invention, in step (2), the molar ratio of the 3-chloro-N-tritylpropylamine, 1,4-butanediamine and the acid binding agent is 1:(1-10)(1-3), for example, it can be 1:1:1, 1:2:1, 1:3:1, 1:4:1, 1:5:1, 1:6:1, 1:7:1, 1:8:1, 1:9:1, 1:10:1, 1:1:2, 1:2:2, 1:3:2, 1:4:2, 1:5:2, 1:6:2, 1:7:2, 1:8:2, 1:9:2, 1:10:2, 1:1:3, 1:2:3, 1:3:3, 1:4:3, 1:5:3, 1:6:3, 1:7:3, 1:8:3, 1:9:3, 1:10:3, etc.

[0109] As an optional embodiment of the present invention, in step (2), the specific steps of the condensation reaction are:

[0110] 3-Chloro-N-tritylpropylamine, 1,4-butanediamine, an acid-binding agent and a solvent are mixed and stirred to carry out a condensation reaction to obtain N-containing 1 -(3-(tritylamino)propyl)butane-1,4-diamine reaction solution.

[0111] As an optional embodiment of the present invention, in step (2), the temperature of the condensation reaction is 20-120°C, for example, it can be 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, etc., and the time of the condensation reaction is 3-24h, for example, it can be 3h, 4h, 6h, 8h, 10h, 12h, 14h, 16h, 18h, 20h, 22h, 24h, etc.

[0112] As an optional embodiment of the present invention, in step (2), the condensation reaction further includes the following post-treatment steps:

[0113] Containing N 1 The reaction solution of -(3-(tritylamino)propyl)butane-1,4-diamine was extracted, washed, dried and concentrated in sequence to obtain N 1 -(3-(tritylamino)propyl)butane-1,4-diamine.

[0114] As an optional embodiment of the present invention, in step (2), the condensation reaction further includes the following post-treatment steps: 1 The reaction solution of -(3-(tritylamino)propyl)butane-1,4-diamine was added with an extractant for extraction, and the organic phase was collected, washed with water, and dried, and concentrated to obtain N 1 -(3-(tritylamino)propyl)butane-1,4-diamine.

[0115] As an optional embodiment of the present invention, in step (2), the extractant includes water and ethyl acetate.

[0116] As an optional embodiment of the present invention, in step (3), the removal of the trityl group is carried out in dilute hydrochloric acid.

[0117] As an optional embodiment of the present invention, in step (3), the concentration of the dilute hydrochloric acid is 1 to 10 M, for example, it can be 1 M, 2 M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9 M, 10 M, etc., preferably 6 M.

[0118] As an optional embodiment of the present invention, in step (3), the N 1 The molar ratio of -(3-(tritylamino)propyl)butane-1,4-diamine and hydrochloric acid is 1:(1-10), for example, it can be 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, etc., preferably 1:(4-6), and more preferably 1:6.

[0119] In the present invention, in step (3), the amount of hydrochloric acid used is sufficient to complete the reaction of 3B, preferably 1:(4-6), more preferably 1:6, which improves the efficiency of the reaction while avoiding the use of excessive acid and ensures the purity of the product for easy post-processing.

[0120] As an optional embodiment of the present invention, in step (3), the reaction temperature for removing the trityl group is 20-80°C, for example, 20h, 25h, 30h, 35h, 40h, 45h, 50h, 55h, 60h, 65h, 70h, 75h, 80h, etc., and the time is 3-24h, for example, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 14h, 16h, 18h, 20h, 22h, 24h, etc.

[0121] As an optional embodiment of the present invention, in step (3), the removal of the trityl group further includes the following post-treatment steps:

[0122] The reaction solution containing spermidine hydrochloride is filtered, washed, concentrated and recrystallized in sequence to obtain spermidine hydrochloride.

[0123] As an optional embodiment of the present invention, in step (3), the removal of the trityl group further includes the following post-treatment steps:

[0124] The reaction solution containing spermidine hydrochloride is filtered, the aqueous phase is washed with ethyl acetate, the aqueous phase is collected and concentrated to obtain a crude product, the crude product is recrystallized in an organic solvent, the product is precipitated and then filtered, the filter residue is rinsed with acetone, the solid is collected and dried to obtain spermidine hydrochloride.

[0125] As an optional embodiment of the present invention, in step (3), the recrystallization solvent is a mixed solvent of ethanol and water.

[0126] In the present invention, in order to achieve a better recrystallization effect, distilled water relative to the recrystallization solvent can be added during the recrystallization process to obtain a product with higher purity and a higher recrystallization yield.

[0127] As an optional embodiment of the present invention, in step (3), in the recrystallization solvent, the volume ratio of water to ethanol is (1-5): (5-95);

[0128] Here, “1-5” can be, for example, 1, 2, 3, 4, 5, etc.;

[0129] Here, “5-95” can be, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, etc.

[0130] As an optional embodiment of the present invention, in step (3), the temperature of the acetone used for elution is below 5°C, for example, it can be 5°C, 4°C, 3°C, 2°C, 1°C, 0°C, -1°C, -2°C, -3°C, -4°C, -5°C, etc.; the amount of acetone used is 5 to 10 times the mass of the filter residue, for example, it can be 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, etc.; the number of elutions is 3 to 5 times, for example, it can be 3 times, 4 times, or 5 times.

[0131] As an optional embodiment of the present invention, in step (3), the drying temperature after collecting the solid is 40-60°C, for example, 40°C, 45°C, 50°C, 55°C, 60°C, etc., and the drying time is 2-12h, for example, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, etc., preferably 6-8h.

[0132] As an optional embodiment of the present invention, in step (3), the drying after collecting the solid is vacuum drying.

[0133] As an optional embodiment of the present invention, in step (4), the base includes an organic base and / or an inorganic base.

[0134] As an optional embodiment of the present invention, in step (4), the organic base includes triethylamine.

[0135] As an optional embodiment of the present invention, in step (4), the inorganic base includes any one of sodium hydroxide, potassium carbonate or cesium carbonate, or a combination of at least two of them.

[0136] As an optional embodiment of the present invention, in step (4), the freeing is carried out in a solvent.

[0137] As an optional embodiment of the present invention, in step (4), the solvent includes any one of methanol, ethanol, isopropanol or dichloromethane, or a combination of at least two thereof, preferably ethanol.

[0138] As an optional embodiment of the present invention, in step (4), the molar ratio of spermidine hydrochloride to base is 1:(1-5), for example, it can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, etc., preferably 1:(3-4), and more preferably 1:3.5.

[0139] As an optional embodiment of the present invention, in step (4), the free temperature is 25-80°C, for example, it can be 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, etc., and the free time is 3-12h, for example, it can be 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, etc.

[0140] As an optional embodiment of the present invention, in step (4), the freeing step further includes the following post-treatment steps:

[0141] The reaction solution containing spermidine is filtered and concentrated in sequence to obtain spermidine.

[0142] As an optional embodiment of the present invention, in step (4), the freeing step further includes the following post-treatment steps:

[0143] The reaction solution containing spermidine is filtered and eluted with ethanol. The filtrate is collected and concentrated to obtain spermidine.

[0144] As an optional embodiment of the present invention, the method for preparing spermidine comprises the following steps:

[0145] (1) 3-chloropropylamine hydrochloride, an acid-binding agent, and a solvent are mixed and stirred to obtain a raw material solution 1; triphenylmethane is dissolved in a solvent to obtain a raw material solution 2; the raw material solution 2 is added dropwise to the raw material solution 1, and the mixture is reacted at a temperature below 5° C. for 1 to 12 hours, and then at a temperature of 5 to 35° C. for 12 to 24 hours to obtain a reaction solution containing 3-chloro-N-tritylpropylamine; the reaction solution containing 3-chloro-N-tritylpropylamine is filtered, extracted, washed, dried, concentrated, and recrystallized in sequence to obtain 3-chloro-N-tritylpropylamine.

[0146] (2) 3-chloro-N-tritylpropylamine, 1,4-butanediamine, an acid-binding agent and a solvent are mixed and stirred, and condensed at 20-120°C for 3-24 hours to obtain N-containing 1 -(3-(tritylamino)propyl)butane-1,4-diamine reaction solution; 1 The reaction solution of -(3-(tritylamino)propyl)butane-1,4-diamine was extracted, washed, dried and concentrated in sequence to obtain N 1 -(3-(tritylamino)propyl)butane-1,4-diamine.

[0147] (3) Toward N 1dilute hydrochloric acid is added to 1,4-(3-(tritylamino)propyl)butane-1,4-diamine, and the mixture is stirred and reacted at 20-80° C. for 3-24 hours to obtain a reaction solution containing spermidine hydrochloride; the reaction solution containing spermidine hydrochloride is filtered, washed, concentrated and recrystallized in sequence to obtain spermidine hydrochloride.

[0148] (4) Spermidine hydrochloride, a base, and a solvent are mixed and stirred to obtain a reaction solution containing spermidine; and the reaction solution containing spermidine is filtered and concentrated in sequence to obtain spermidine.

[0149] In the present invention, the preparation process provided by the embodiment of the present invention realizes process simplification, meets the requirements of energy conservation and environmental protection, greatly reduces production costs, and increases economic benefits. Overall, the preparation method provided by the embodiment of the present invention has the advantages of short reaction cycle and high yield of product spermidine.

[0150] The present invention is further described below by way of examples. Unless otherwise specified, the materials in the examples were prepared according to existing methods or directly purchased from the market.

[0151] In the following examples and comparative examples, the high performance liquid chromatography (HPLC) test was performed using a Shimadzu LC-2030 high performance liquid chromatograph, a UV-visible detector, and a Durashell C18 (L) column (250 × 4.6 mm id; particle size, 5 μm). The column temperature was 25° C., the detector wavelength was 240 nm, the mobile phase ratio was acetonitrile:methanol = 75:25, and the mobile phase flow rate was 1.5 mL / min.

[0152] In the following examples and comparative examples, equiv. represents molar equivalent, and room temperature represents 25 to 30°C.

[0153] Example 1

[0154] This embodiment provides a method for preparing spermidine, which comprises the following steps:

[0155] (1) Preparation of 3-chloro-N-tritylpropylamine (3A)

[0156] Accurately weigh 3-chloropropylamine hydrochloride (192.3 mmol) and triethylamine (384.6 mmol) and add them to a 1 L round-bottom flask, add 200 mL of dichloromethane and stir at 0°C; then dissolve triphenylmethane (192.3 mmol) in 200 mL of dichloromethane and slowly add it dropwise into the reaction flask, maintain stirring at 0°C for 2 h, then return to room temperature and continue stirring for 12 h; after the reaction is completed, filter and collect the filtrate, wash it with clean water (2×100 mL), combine the organic phases, add anhydrous sodium sulfate, dry it, and concentrate to obtain a crude product; the crude product is placed in toluene and recrystallized at 110°C, and the precipitated white solid product is collected by filtration and dried at 80°C to obtain 51 g of pure 3A with a yield of 79%.

[0157] (2) Preparation of N 1 -(3-(Tritylamino)propyl)butane-1,4-diamine (3B)

[0158] Accurately weigh 3A (148.8 mmol), 1,4-butanediamine (744.3 mmol) and triethylamine (148.8 mmol) and add them to a 1 L round-bottom flask. Add 200 mL of N,N-dimethylformamide and stir at 80 °C for 8 h. After the reaction is completed, cool to room temperature, add 200 mL of water and stir evenly. The aqueous phase is extracted with ethyl acetate (50 mL × 3), and the combined organic phases are washed with saturated brine (200 mL × 3). The organic phases are collected, added with anhydrous sodium sulfate, dried, and concentrated to obtain the crude product 3B.

[0159] (3) Preparation of spermidine hydrochloride

[0160] Dilute hydrochloric acid (140 mL, 6 M) was added to a reaction flask containing 3B (139.3 mmol) and stirred at room temperature for 12 h. After the reaction was completed, the reaction was filtered, the filter cake was rinsed with water, the filtrate was collected and washed with ethyl acetate (30 mL × 3), and the aqueous phase was collected and concentrated to obtain a crude product of spermidine hydrochloride; the crude product of spermidine hydrochloride was placed in ethanol at 80 ° C for recrystallization, and the precipitated white solid product was collected by filtration and rinsed with acetone (20 mL × 3). After washing, the solid was dried in vacuo at 50 ° C to obtain 28 g of the product spermidine hydrochloride, and the total yield of the two steps was 68%.

[0161] (4) Preparation of spermidine

[0162] Accurately weigh spermidine hydrochloride (98.2 mmol) and sodium hydroxide (294.6 mmol) and add them to a 1 L round-bottom flask, add 500 mL of ethanol and stir at 25 ° C for 6 h; after the reaction is completed, filter and rinse with ethanol (20 mL × 3), collect the filtrate and concentrate to obtain 14 g of spermidine product with a yield of 98% and a purity of 99.3%. (Among them, Figure 1 (This is the H NMR spectrum of the spermidine hydrochloride product obtained in Example 1).

[0163] Example 2

[0164] This embodiment provides a method for preparing spermidine, which comprises the following steps:

[0165] (1) Preparation of 3-chloro-N-tritylpropylamine (3A)

[0166] Accurately weigh 3-chloropropylamine hydrochloride (961.5 mmol) and triethylamine (2.88 mol) and add them to a 3 L round-bottom flask, add 1000 mL of dichloromethane and mechanically stir at 0°C; then dissolve triphenylmethane (961.5 mmol) in 1000 mL of chloromethane and slowly add it dropwise into the reaction flask, maintain stirring at 0°C for 2 h, then return to room temperature and continue stirring for 16 h; after completion of the reaction, filter, collect the filtrate, wash with clean water (2×500 mL), combine the organic phases, add anhydrous sodium sulfate, dry, and concentrate to obtain a crude product; the crude product is placed in toluene and recrystallized at 110°C, and the precipitated white solid product is collected by filtration and dried at 80°C to obtain 263 g of pure 3A with a yield of 81%.

[0167] (2) Preparation of N 1 -(3-(Tritylamino)propyl)butane-1,4-diamine (3B)

[0168] Accurately weigh 3A (595.5 mmol), 1,4-butanediamine (2.98 mol) and triethylamine (595.5 mmol) were added to a 5 L round-bottom flask. 200 mL of N,N-dimethylformamide was added and mechanically stirred at 80 °C for 12 h. After the reaction was completed, the temperature was lowered to room temperature. 800 mL of water was added and stirred uniformly. The aqueous phase was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (500 mL × 3). The organic phases were collected, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product 3B.

[0169] (3) Preparation of spermidine hydrochloride

[0170] Dilute hydrochloric acid (540 mL, 6 M) was added to a reaction flask containing 3B (541.8 mmol) and stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was filtered, the filter cake was rinsed with water, the filtrate was collected and washed with ethyl acetate (120 mL × 3), and the aqueous phase was collected and concentrated to obtain a crude product of spermidine hydrochloride; the crude product of spermidine hydrochloride was placed in ethanol at 80 ° C for recrystallization, and the precipitated white solid product was collected by filtration and rinsed with acetone (60 mL × 3). After washing, the solid was dried in vacuo at 50 ° C to obtain 126 g of the product spermidine hydrochloride, and the total yield of the two steps was 76%.

[0171] (4) Preparation of spermidine

[0172] Accurately weigh spermidine hydrochloride (490.9 mmol) and sodium hydroxide (1.47 mol) were added to a 2 L round-bottom flask, and 1 L of ethanol was added and stirred at 25 ° C for 8 h. After the reaction was completed, the mixture was filtered and rinsed with ethanol (50 mL × 3). The filtrate was collected and concentrated to obtain 68 g of spermidine product with a yield of 95% and a purity of 99.5%.

[0173] Example 3

[0174] This embodiment provides a method for preparing spermidine, which comprises the following steps:

[0175] (1) Preparation of 3-chloro-N-tritylpropylamine (3A)

[0176] Accurately weigh 3-chloropropylamine hydrochloride (192.3 mmol) and triethylamine (384.6 mmol) into a 1L round-bottom flask. Add 200 mL of tetrahydrofuran and stir at 0°C. Then, dissolve triphenylmethane (192.3 mmol) in 200 mL of tetrahydrofuran and slowly add it dropwise to the reaction flask. Stir at 0°C for 2 hours, then return to room temperature and continue stirring for 12 hours. After the reaction is complete, filter and collect the filtrate, wash with clean water (2 x 100 mL). Combine the organic phases, add anhydrous sodium sulfate, dry, and concentrate to obtain the crude product. Recrystallize the crude product in ethyl acetate at 80°C. Collect the precipitated white solid by filtration and dry at 80°C to obtain 48 g of pure 3A with a yield of 74%.

[0177] (2) Preparation of N 1 -(3-(Tritylamino)propyl)butane-1,4-diamine (3B)

[0178] Accurately weigh 3A (148.8 mmol), 1,4-butanediamine (744.3 mmol), and potassium carbonate (148.8 mmol) and add them to a 1 L round-bottom flask. Add 200 mL of N,N-dimethylformamide and stir at 80°C for 8 h. After the reaction is completed, cool to room temperature, add 200 mL of water and stir evenly. The aqueous phase is extracted with ethyl acetate (50 mL × 3), and the combined organic phases are washed with saturated brine (200 mL × 3). The organic phases are collected, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product 3B.

[0179] (3) Preparation of spermidine hydrochloride

[0180] Dilute hydrochloric acid (90 mL, 6 M) was added to a reaction flask containing 3B (134.7 mmol) and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was filtered, the filter cake was rinsed with water, the filtrate was collected and washed with ethyl acetate (30 mL × 3), and the aqueous phase was collected and concentrated to obtain a crude product of spermidine hydrochloride. The crude product of spermidine hydrochloride was placed in ethanol at 80 ° C for recrystallization, and the precipitated white solid product was collected by filtration and rinsed with acetone (20 mL × 3). After washing, the solid was dried in vacuo at 50 ° C to obtain 30 g of the product spermidine hydrochloride, and the total yield of the two steps was 70%.

[0181] (4) Preparation of spermidine

[0182] Accurately weigh spermidine hydrochloride (98.2 mmol) and triethylamine (343.7 mmol) were added to a 1 L round-bottom flask, and 500 mL of dichloromethane was added and stirred at 25°C for 12 h. After the reaction was completed, the mixture was filtered and washed with dichloromethane (20 mL × 3). The filtrate was collected and concentrated to obtain 16 g of spermidine product with a yield of 94% and a purity of 99.4%.

[0183] Example 4

[0184] This embodiment provides a method for preparing spermidine, which comprises the following steps:

[0185] (1) Preparation of 3-chloro-N-tritylpropylamine (3A)

[0186] Accurately weigh 3-chloropropylamine hydrochloride (192.3 mmol) and triethylamine (490.8 mmol) into a 1L round-bottom flask. Add 200 mL of dichloromethane and stir at 0°C. Next, dissolve triphenylmethane (192.3 mmol) in 200 mL of dichloromethane and slowly add it dropwise to the reaction flask. Stir at 0°C for 2 hours, then return to room temperature and continue stirring for 12 hours. After the reaction is complete, filter and collect the filtrate, wash with clean water (2 x 100 mL), combine the organic phases, add anhydrous sodium sulfate, dry, and concentrate to obtain the crude product. Recrystallize from toluene at 110°C, collect the precipitated white solid by filtration, and dry at 80°C to obtain 46 g of pure 3A, with a yield of 72%.

[0187] (2) Preparation of N 1 -(3-(Tritylamino)propyl)butane-1,4-diamine (3B)

[0188] Accurately weigh 3A (148.8 mmol), 1,4-butanediamine (1.49 mol), and triethylamine (148.8 mmol) into a 1-L round-bottom flask. Add 200 mL of N,N-dimethylformamide and stir at 80°C for 6 h. After the reaction is complete, cool to room temperature, add 200 mL of water and stir until uniform. The aqueous phase is extracted with ethyl acetate (50 mL x 3). The combined organic phases are washed with saturated brine (200 mL x 3). The organic phases are collected, dried over anhydrous sodium sulfate, and concentrated to yield crude 3B.

[0189] (3) Preparation of spermidine hydrochloride

[0190] To a reaction flask containing 3B (141.9 mmol) was added dilute hydrochloric acid (142 mL, 6 M) and stirred at room temperature for 24 h. After completion of the reaction, the mixture was filtered, the filter cake rinsed with water, and the filtrate was collected and washed with ethyl acetate (30 mL x 3). The aqueous phase was collected and concentrated to yield the crude product, spermidine hydrochloride. The product was recrystallized from ethanol at 80°C, and the precipitated white solid product was collected by filtration and rinsed with acetone (20 mL x 3). After rinsing, the solid was dried under vacuum at 50°C to yield 32 g of spermidine hydrochloride, with a total yield of 77% across the two steps.

[0191] (4) Preparation of spermidine

[0192] Accurately weigh spermidine hydrochloride (98.2 mmol) and potassium hydroxide (294.6 mmol) were added to a 1-liter round-bottom flask. 500 mL of ethanol was added and stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered and rinsed with acetone (20 mL x 3). The filtrate was collected and concentrated to yield 16 g of spermidine with a yield of 94% and a purity of 99.5%.

[0193] Example 5

[0194] This embodiment provides a method for preparing spermidine, which comprises the following steps:

[0195] (1) Preparation of 3-chloro-N-tritylpropylamine (3A)

[0196] Accurately weigh 3-chloropropylamine hydrochloride (192.3 mmol) and triethylamine (384.6 mmol) and add them to a 1 L round-bottom flask, add 200 mL of dichloromethane and stir at 0°C; immediately dissolve triphenylmethane (192.3 mmol) in 200 mL of dichloromethane and slowly add it dropwise into the reaction flask, maintain stirring at 0°C for 2 h, then return to room temperature and continue stirring for 12 h; after the reaction is completed, filter and collect the filtrate, wash with clean water (2×100 mL), combine the organic phases, add anhydrous sodium sulfate, dry and concentrate to obtain a crude product; place the crude product in toluene at 110°C for recrystallization, collect the precipitated white solid product by filtration, and dry at 80°C to obtain 52 g of pure 3A with a yield of 80%.

[0197] (2) Preparation of N 1 -(3-(Tritylamino)propyl)butane-1,4-diamine (3B)

[0198] Accurately weigh 3A (148.8 mmol), 1,4-butanediamine (744.0 mol), and cesium carbonate (148.8 mmol) into a 1-L round-bottom flask. Add 200 mL of N,N-dimethylformamide and stir at 80°C for 12 h. After the reaction is complete, cool to room temperature, add 200 mL of water, and stir thoroughly. The aqueous phase is extracted with ethyl acetate (50 mL x 3). The combined organic phases are washed with saturated brine (200 mL x 3). The organic phases are collected, dried over anhydrous sodium sulfate, and concentrated to yield crude 3B.

[0199] (3) Preparation of spermidine hydrochloride

[0200] To a reaction flask containing 3B (136.8 mmol) was added dilute hydrochloric acid (114 mL, 6 M) and stirred at 50°C for 3 h. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filter cake was rinsed with water. The filtrate was collected and washed with ethyl acetate (30 mL x 3). The aqueous phase was collected and concentrated to yield the crude product, spermidine hydrochloride. Recrystallization was performed from ethanol at 80°C, and the precipitated white solid product was collected by filtration and rinsed with acetone (20 mL x 3). After rinsing, the solid was dried under vacuum at 50°C to yield 26 g of spermidine hydrochloride, with a total yield of 63% across the two steps.

[0201] (4) Preparation of spermidine

[0202] Accurately weigh spermidine hydrochloride (90.0 mmol) and sodium hydroxide (270.0 mmol) were added to a 1 L round-bottom flask, and 500 mL of ethanol was added and stirred at 25°C for 6 h. After the reaction was completed, the mixture was filtered and rinsed with ethanol (20 mL × 3). The filtrate was collected and concentrated to obtain 13 g of spermidine product with a yield of 98% and a purity of 99.5%.

[0203] Example 6

[0204] This embodiment provides a method for preparing spermidine, which differs from Example 1 only in that, during the post-treatment process of step (3), the crude spermidine hydrochloride product is placed in an ethanol aqueous solution (the volume ratio of ethanol to water is 95:5) and recrystallized at 80° C., and the other steps are completely consistent with Example 1;

[0205] After elution, the solid was dried in vacuo at 50° C. to obtain 31 g of spermidine hydrochloride. The total yield of the two steps was 75%.

[0206] Comparative Example 1

[0207] This comparative example provides a method for preparing spermidine, which differs from Example 1 only in that: in step (1), a Boc protecting group is used instead of a trityl protecting group. The specific reaction process is as follows:

[0208]

[0209] The results showed that the intermediate product 3A' in the subsequent reaction had decreased crystallinity, a low recrystallization yield, and was difficult to purify. The final spermidine product had a total yield of 25% and a purity of 93.8%.

[0210] Comparative Example 2

[0211] This comparative example provides a method for preparing spermidine, which differs from Example 1 only in that, in step (1), a Cbz protecting group is used instead of a trityl protecting group. The specific reaction process is as follows:

[0212]

[0213] The results showed that the intermediate product 3A" in the subsequent reaction had decreased crystallinity, a low recrystallization yield, and difficulty in product purification. The final total yield of spermidine product was 22% and the purity was 96.2%.

[0214] Comparative Example 3

[0215] This comparative example provides a method for preparing spermidine, which differs from Example 1 only in that an Fmoc protecting group is used in place of a trityl protecting group in step (1). The specific reaction process is as follows:

[0216]

[0217] The results showed that the protecting group could not be removed under hydrochloric acid conditions in the subsequent reaction, and spermidine hydrochloride product could not be obtained, so the reaction could not proceed.

[0218] Comparative Example 4

[0219] This comparative example provides a method for preparing spermidine, which differs from Example 1 only in that: Step (2) prepares N 1The molar ratio of the raw materials 3A and 1,4-butanediamine used in the preparation of 3-(tritylamino)propyl)butane-1,4-diamine (3B) was 1:1.

[0220] The results showed that the reaction proceeded very slowly, the raw material 3A could not be completely converted, and the by-product Increased, the target product 3B accounted for less than 60%.

[0221] Comparative Example 5

[0222] This comparative example provides a method for preparing spermidine, which differs from Example 1 only in that: Step (2) prepares N 1 The molar ratio of the raw materials 3A and 1,4-butanediamine used in the preparation of -(3-(tritylamino)propyl)butane-1,4-diamine (3B) was 1:2.

[0223] The results showed that the reaction proceeded slowly and the by-products The target product 3B accounts for less than 75%.

[0224] Comparative Example 6

[0225] This comparative example provides a method for preparing spermidine, which differs from Example 1 only in that: Step (2) prepares N 1 The molar ratio of the raw materials 3A and 1,4-butanediamine used in the preparation of 3-(tritylamino)propyl)butane-1,4-diamine (3B) was 1:4.

[0226] The results showed that the by-products The target product 3B accounts for about 80%.

[0227] Comparative Example 7

[0228] This comparative example provides a method for preparing spermidine, which differs from Example 3 only in that the volume of hydrochloric acid used in step (3) to prepare spermidine hydrochloride is 67 mL.

[0229] The results showed that the reaction proceeded slowly and the raw materials could not be completely converted, with a conversion rate of 75%.

[0230] Comparative Example 8

[0231] This comparative example provides a method for preparing spermidine, which differs from Example 3 only in that the reaction temperature for preparing spermidine hydrochloride in step (3) is 100°C.

[0232] The results showed that the reaction solution was dark at the end of the reaction, the product was dark in color, the yield of spermidine hydrochloride was 52%, and the purity was 82%, indicating a decrease in purity.

[0233] Comparative Example 9

[0234] This comparative example provides a method for preparing spermidine, which differs from Example 5 only in that: Step (1) prepares N 1 The reaction solvent for the reaction of -(3-(tritylamino)propyl)butane-1,4-diamine (3B) is acetonitrile.

[0235] The results showed that the reaction progress was extremely slow, the raw materials were almost not converted, and the reaction could not proceed effectively.

[0236] Comparative Example 10

[0237] This comparative example provides a method for preparing spermidine, which differs from Example 1 only in that the recrystallization solvent for preparing pure product 3A in step (1) is replaced with ethanol.

[0238] The results showed that the purity of 3A dropped to 82% after recrystallization.

[0239] Comparative Example 11

[0240] This comparative example provides a method for preparing spermidine, which differs from Example 1 only in that: in step (1), when preparing 3A, triphenylmethane is added dropwise at room temperature.

[0241] The results showed that the yield of 3-chloro-N-tritylpropylamine (3A) was 56% and the purity was 94.6%. The yield was significantly decreased and the side reactions increased.

[0242] Comparative Example 12

[0243] This comparative example provides a method for preparing spermidine, which differs from Example 1 only in that: Step (2) prepares N 1 The reaction temperature of -(3-(tritylamino)propyl)butane-1,4-diamine (3B) is room temperature.

[0244] The results showed that the reaction could not proceed and the raw material 3A was not converted.

[0245] In summary, the present invention provides a method for preparing spermidine. 3-Chloropropylamine hydrochloride, triethylamine, and triphenylmethane are first used as reaction materials to synthesize product 3A, which carries a trityl protecting group. Subsequently, 3A is condensed with 1,4-butanediamine. By optimizing the molar ratio of 1,4-butanediamine to 3A, 3B is obtained in a simple and efficient manner with high purity. The trityl protecting group of compound 3B is removed in the presence of hydrochloric acid to obtain spermidine hydrochloride. Finally, spermidine hydrochloride is released under alkaline conditions to obtain the spermidine product in a high yield.

[0246] The method for preparing spermidine provided by the present invention has the following advantages: (1) triphenylmethane, 1,4-butanediamine, and 3-chloropropylamine hydrochloride are all inexpensive and readily available commercial raw materials, thereby reducing raw material costs. (2) catalytic hydrogenation reduction is avoided, and the reaction conditions are mild, eliminating the need to consider the cost of precious metal catalysts. (3) The synthesis method has the advantages of a short reaction cycle and high product yield in each step.

[0247] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing spermidine, characterized in that: The preparation method of spermidine comprises: (1) 3-Chloropropylamine hydrochloride and triphenylmethane are subjected to condensation reaction to obtain 3-chloro- N -tritylpropylamine; In step (1), the specific steps of the condensation reaction are: mixing 3-chloropropylamine hydrochloride, an acid binding agent and a solvent to obtain a raw material solution 1; dissolving triphenylmethane chloride in a solvent to obtain a raw material solution 2; adding the raw material solution 2 dropwise to the raw material solution 1 to carry out a condensation reaction to obtain a 3-chloropropylamine hydrochloride. N -tritylpropylamine reaction solution; the temperature of the dropwise addition of the raw material solution 2 is below 5°C; the condensation reaction is: first reacting at below 5°C for 1 to 12 h, then reacting at 5 to 35°C for 12 to 24 h; (2) 3-chloro- N -Tritylpropylamine and 1,4-butanediamine are condensed to obtain N 1 -(3-(tritylamino)propyl)butane-1,4-diamine; In step (2), the specific steps of the condensation reaction are: 3-chloro- N -tritylpropylamine, 1,4-butanediamine, acid binding agent and solvent are mixed and stirred to carry out condensation reaction to obtain N 1 -(3-(tritylamino)propyl)butane-1,4-diamine reaction solution; the condensation reaction temperature is 20-120° C., and the condensation reaction time is 3-24 h; (3) N 1 -(3-(tritylamino)propyl)butane-1,4-diamine removes the trityl group to obtain spermidine hydrochloride; In step (3), the removal of the trityl group is carried out in dilute hydrochloric acid; the reaction temperature for the removal of the trityl group is 20-80°C and the time is 3-24 hours; (4) freeing spermidine hydrochloride in the presence of a base to obtain spermidine; In step (4), the base is selected from an organic base and / or an inorganic base; the organic base is selected from triethylamine; the inorganic base is selected from any one or a combination of at least two of sodium hydroxide, potassium carbonate or cesium carbonate; the dissociation is carried out in a solvent; the dissociation temperature is 25-80°C, and the dissociation time is 3-12 h.

2. The method for preparing spermidine according to claim 1, wherein In step (1), the solvent is selected from any one of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile or dimethyl sulfoxide, or a combination of at least two thereof.

3. The method for preparing spermidine according to claim 2, wherein In step (1), the solvent is dichloromethane.

4. The method for preparing spermidine according to claim 1, wherein In step (1), the acid binding agent is selected from triethylamine, potassium carbonate or cesium carbonate or any one or a combination of at least two thereof.

5. The method for preparing spermidine according to claim 4, wherein In step (1), the acid binding agent is triethylamine.

6. The method for preparing spermidine according to claim 1, wherein In step (1), the molar ratio of the 3-chloropropylamine hydrochloride, triphenylmethane and acid binding agent is 1:(0.8~1.2):(1~3).

7. The method for preparing spermidine according to claim 1, wherein In step (1), the condensation reaction further includes the following post-treatment steps: Containing 3-chloro- N The reaction solution of triphenylmethylpropylamine was filtered, extracted, washed, dried, concentrated and recrystallized in sequence to obtain 3-chloro- N -tritylpropylamine.

8. The method for preparing spermidine according to claim 7, wherein In step (1), the condensation reaction further includes the following post-treatment steps: Containing 3-chloro- N The reaction solution of triphenylmethylpropylamine was filtered, the filtrate was collected, washed with water, and the organic phase was collected and dried. After concentration, a crude product was obtained. The crude product was recrystallized in an organic solvent to obtain 3-chloro- N -tritylpropylamine.

9. The method for preparing spermidine according to claim 8, wherein The organic solvent for recrystallization is toluene and / or ethyl acetate.

10. The method for preparing spermidine according to claim 1, wherein In step (2), the solvent is selected from any one or a combination of at least two of N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dimethyl sulfoxide or 1,3-dimethyl-2-imidazolidinone.

11. The method for preparing spermidine according to claim 10, characterized in that: In step (2), the solvent is N,N-dimethylformamide.

12. The method for preparing spermidine according to claim 1, wherein In step (2), the acid binding agent is selected from triethylamine, potassium carbonate or cesium carbonate or any one thereof or a combination of at least two thereof.

13. The method for preparing spermidine according to claim 12, characterized in that: In step (2), the acid binding agent is triethylamine.

14. The method for preparing spermidine according to claim 1, wherein In step (2), the molar ratio of 3-chloro-N-tritylpropylamine, 1,4-butanediamine and acid binding agent is 1:(1~10)(1~3).

15. The method for preparing spermidine according to claim 1, wherein In step (2), the condensation reaction further includes the following post-treatment steps: will contain N 1 The reaction solution of -(3-(tritylamino)propyl)butane-1,4-diamine was extracted, washed, dried and concentrated in sequence to obtain N 1 -(3-(tritylamino)propyl)butane-1,4-diamine.

16. The method for preparing spermidine according to claim 15, characterized in that: In step (2), the condensation reaction further includes the following post-treatment steps: will contain N 1 The reaction solution of -(3-(tritylamino)propyl)butane-1,4-diamine was added with an extractant for extraction, and the organic phase was collected, washed with water, dried, and concentrated to obtain N 1 -(3-(tritylamino)propyl)butane-1,4-diamine.

17. The method for preparing spermidine according to claim 16, wherein In step (2), the extractant is selected from water and ethyl acetate.

18. The method for preparing spermidine according to claim 1, wherein In step (3), the concentration of the dilute hydrochloric acid is 1~10 M.

19. The method for preparing spermidine according to claim 18, wherein In step (3), the concentration of the dilute hydrochloric acid is 6 M.

20. The method for preparing spermidine according to claim 1, characterized in that: In step (3), the molar ratio of N1-(3-(tritylamino)propyl)butane-1,4-diamine to hydrochloric acid is 1:(1-10).

21. The method for preparing spermidine according to claim 1, characterized in that: In step (3), after removing the trityl group, the following post-treatment steps are also included: The reaction solution containing spermidine hydrochloride is filtered, washed, concentrated and recrystallized in sequence to obtain spermidine hydrochloride.

22. The method for preparing spermidine according to claim 21, characterized in that: In step (3), the removal of the trityl group further includes the following post-treatment steps: The reaction solution containing spermidine hydrochloride is filtered, the aqueous phase is washed with ethyl acetate, the aqueous phase is collected and concentrated to obtain a crude product, the crude product is recrystallized in an organic solvent, the product is precipitated and then filtered, the filter residue is rinsed with acetone, the solid is collected and dried to obtain spermidine hydrochloride.

23. The method for preparing spermidine according to claim 22, wherein: In step (3), the recrystallization solvent is a mixed solvent of ethanol and water; the volume ratio of water to ethanol is (1-5):(5-95).

24. The method for preparing spermidine according to claim 22, wherein In step (3), the temperature of the acetone used for elution is below 5°C; the amount of acetone used is 5 to 10 times the mass of the filter residue; and the number of elutions is 3 to 5 times.

25. The method for preparing spermidine according to claim 22, wherein In step (3), the temperature for drying after collecting the solid is 40-60° C., and the drying time is 2-12 h.

26. The method for preparing spermidine according to claim 1, characterized in that: In step (4), the solvent is selected from any one of methanol, ethanol, isopropanol or dichloromethane, or a combination of at least two thereof.

27. The method for preparing spermidine according to claim 26, characterized in that: In step (4), the solvent is ethanol.

28. The method for preparing spermidine according to claim 1, wherein In step (4), the molar ratio of spermidine hydrochloride to base is 1:(1-5).

29. The method for preparing spermidine according to claim 1, wherein In step (4), the following post-processing steps are also included after the release: The reaction solution containing spermidine is filtered and concentrated in sequence to obtain spermidine.

30. The method for preparing spermidine according to claim 29, wherein In step (4), the following post-processing steps are also included after the release: The reaction solution containing spermidine is filtered and eluted with ethanol. The filtrate is collected and concentrated to obtain spermidine.

Images