Preparation method of spermidine

Abstract

The invention provides a preparation method of spermidine, and relates to the technical field of organic synthesis. The preparation method of the spermidine comprises the following steps: carrying out condensation reaction on 3-chloropropylamine hydrochloride and triphenylchloromethane to obtain 3-chloro-N-triphenylmethyl propylamine; the preparation method comprises the following steps: carrying out condensation reaction on 3-chloro-N-triphenylmethyl propylamine and 1, 4-butanediamine to obtain N1-(3-(triphenylmethyl amino) propyl) butane-1, 4-diamine; the preparation method comprises the following steps: removing triphenylmethyl from N1-(3-(triphenylmethyl amino) propyl) butane-1, 4-diamine to obtain spermidine hydrochloride; the spermidine hydrochloride is dissociated in the presence of alkali to obtain spermidine. According to the preparation method disclosed by the invention, relatively high yield and purity can be achieved in a relatively short reaction period, the problems of high by-product proportion, high purification difficulty, solvent residue and the like are avoided, the reaction efficiency is improved, the reaction conditions are mild, the required production equipment is simple, and the preparation method is more energy-saving and environment-friendly while being convenient for industrial large-scale production.

Description

Technical Field

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

[0002] Spermidine is an aliphatic polyamine compound that is widely distributed in organisms. It is biosynthesized from putrescine (butanediamine) and adenosylmethionine. Spermidine can inhibit neuronal synthases, bind to and precipitate DNA; it can also be used to purify DNA-binding proteins and stimulate T4 polynucleotide kinase activity. Spermidine was first discovered by separating it from semen, but in fact it is a substance that is widely present in organisms. Whole wheat foods, kelp, mushrooms, beans and whole grains are rich in this ingredient.

[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 extend the in vitro storage life of boar sperm. (2) Anti-aging: Spermidine has excellent antioxidant properties and can remove free radicals in the body to avoid cell damage. (3) Enhance muscle quality: Studies have shown that spermidine can increase the content of muscle alanine 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 supplementing with spermidine 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 response. (6) Protect cardiovascular system: 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: firstly, preparing Cbz-monoprotected 1,4-butanediamine, then subjecting it to an addition reaction with acrylonitrile, finally reducing the cyano group in the addition product, removing the Cbz protection, and obtaining 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 preparation processes reported so far generally have the following problems: (1) There are many synthesis steps, complicated post-reaction treatment, and low yield; (2) The process operation is cumbersome and not conducive to industrial scale-up production; (3) The use of hydrogenation reduction process 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) The side reactions are relatively obvious, the by-products are relatively large, and the separation and purification are difficult.

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

[0009] The object of the present invention is to provide a method for preparing spermidine, which aims to simplify the process flow, 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 particularly adopted:

[0011] In a first aspect, the present invention provides a method for preparing spermidine, the 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 are 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 of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile or dimethyl sulfoxide, or a combination of at least two thereof, 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 added dropwise 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 solution 2 is below 5°C.

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

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

[0029] The reaction solution containing 3-chloro-N-tritylpropylamine is filtered, the filtrate is collected, the organic phase is collected and dried after washing with water, and concentrated to obtain a crude product, and the crude product 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 of N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dimethyl sulfoxide or 1,3-dimethyl-2-imidazolidinone, or a combination of at least two thereof, 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 a 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 step: 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 comprises the following post-treatment steps:

[0042] 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, and then dried. After concentration, 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 1-10M, preferably 6M.

[0046] Preferably, in step (3), the N 1 The molar ratio of -(3-(tritylamino)propyl)butane-1,4-diamine to 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 time is 3 to 24 hours.

[0048] Preferably, in step (3), the removal of the trityl group further comprises 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 comprises 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 the 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 thereof.

[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 dissociation temperature is 25 to 80° C., and the dissociation time is 3 to 12 hours.

[0063] Preferably, in step (4), the freeing step further comprises the following post-treatment steps:

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

[0065] Preferably, in step (4), the freeing step further comprises the following post-treatment steps:

[0066] The reaction solution containing spermidine is filtered and eluted with ethanol, and 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 the volatile solvent 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 great difficulty in purification, improves the 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 implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0071] Figure 1 The hydrogen nuclear magnetic resonance spectrum of the spermidine hydrochloride product obtained in Example 1 is shown in FIG. 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 case of any potential ambiguity, the definitions provided herein take precedence over any dictionary or external definitions. In this application, unless otherwise stated, the use of "or" means "and / or". In addition, the use of the term "including" and other forms is non-limiting.

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

[0074] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0075] In a first aspect, the present invention provides a method for preparing spermidine, the 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 are 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) freeing spermidine hydrochloride in the presence of a base to obtain spermidine; the reaction formula is as follows:

[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 high proportion of by-products and great 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 more energy-saving and environmentally friendly while being convenient for industrialized amplification.

[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 of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile or dimethyl sulfoxide, or a combination of at least two thereof, 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 beyond the above range, the reaction cannot proceed or the yield is 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 added dropwise 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] First, react at below 5°C (for example, it may be 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, it may be 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 react at 5 to 35°C (for example, it may be 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, it may be 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 step (1) performs the condensation reaction 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, the organic phase is collected and dried after washing with water, and concentrated to obtain a crude product, and the crude product 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 to 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-diamine 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 the reaction temperature by the volatile solvent. Further, the molar ratio of the 3-chloro-N-tritylpropylamine and 1,4-butanediamine is limited to the above range, and the amount of 1,4-butanediamine is such that the reaction of 3A is complete and the generation of by-products of bilateral condensation is avoided to the greatest extent, preferably 1:5, so as to improve the utilization rate of the raw materials and ensure 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 of N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dimethyl sulfoxide or 1,3-dimethyl-2-imidazolidinone, or a combination of at least two thereof, 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 a 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] 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.

[0114] As an optional embodiment of the present invention, in step (2), the condensation reaction further comprises the following post-treatment step: 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 then dried. After concentration, 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 10M, for example, it can be 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, 10M, etc., preferably 6M.

[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 to 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, it can be 20h, 25h, 30h, 35h, 40h, 45h, 50h, 55h, 60h, 65h, 70h, 75h, 80h, etc., and the time is 3-24h, for example, it can be 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 comprises 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 comprises 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 the acetone 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, 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, it can be 40°C, 45°C, 50°C, 55°C, 60°C, etc., and the drying time is 2-12h, for example, it can be 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, and 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 chloride is dissolved in the solvent to obtain a raw material solution 2; the raw material solution 2 is added dropwise to the raw material solution 1, and the reaction is first carried out 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 to 120° C. for 3 to 24 hours to obtain a 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) Towards N 1-(3-(tritylamino)propyl)butane-1,4-diamine is added with dilute hydrochloric acid, and the mixture is stirred at 20-80° C. for reaction 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) mixing spermidine hydrochloride, a base and a solvent to obtain a reaction solution containing spermidine; filtering and concentrating the reaction solution containing spermidine 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 are prepared according to existing methods or directly purchased from the market.

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

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

[0153] Example 1

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

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

[0156] Accurately weigh 3-chloropropylamine hydrochloride (192.3mmol) and triethylamine (384.6mmol) and add them to a 1L round-bottom flask, add 200mL of dichloromethane and stir at 0°C; immediately dissolve triphenylmethane (192.3mmol) in 200mL of dichloromethane, slowly dropwise add into the reaction flask, keep stirring at 0°C for 2h, then return to room temperature and continue stirring for 12h; after the reaction is completed, filter, collect the filtrate and wash with clean water (2×100mL), 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, filter and collect the precipitated white solid product, and dry at 80°C to obtain 51g 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 into 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, extract the aqueous phase with ethyl acetate (50 mL × 3), wash the combined organic phases with saturated brine (200 mL × 3), collect the organic phases, add anhydrous sodium sulfate, dry and concentrate to obtain the crude product of 3B.

[0159] (3) Preparation of spermidine hydrochloride

[0160] Dilute hydrochloric acid (140 mL, 6 M) was added to a reaction bottle containing 3B (139.3 mmol), and the mixture was stirred at room temperature for 12 h. After the reaction was completed, the mixture was filtered, and the filter cake was rinsed with water. The filtrate was collected and washed with ethyl acetate (30 mL × 3). 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 the rinsing was completed, 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 (98.2mmol) and sodium hydroxide (294.6mmol) and add them to a 1L round-bottom flask, add 500mL of ethanol and stir at 25°C for 6h; after the reaction is completed, filter and rinse with ethanol (20mL×3), collect and concentrate the filtrate to obtain 14g of spermidine product, with a yield of 98% and a purity of 99.3%. (Among them, Figure 1 : 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, and the method for preparing spermidine comprises the following steps:

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

[0166] Accurately weigh 3-chloropropylamine hydrochloride (961.5mmol) and triethylamine (2.88mol) and add them to a 3L round-bottom flask, add 1000mL of dichloromethane and stir mechanically at 0°C; immediately dissolve triphenylmethane (961.5mmol) in 1000mL of chloromethane, slowly dropwise add it into the reaction bottle, keep stirring at 0°C for 2h, then return to room temperature and continue stirring for 16h; after the reaction is completed, filter, collect the filtrate and wash it with clean water (2×500mL), 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, filter and collect the precipitated white solid product, and dry it at 80°C to obtain 263g 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) and add them into a 5 L round-bottom flask, add 200 mL of N,N-dimethylformamide and mechanically stir at 80 °C for 12 h. After the reaction is completed, cool to room temperature, add 800 mL of water and stir evenly, extract the aqueous phase with ethyl acetate (200 mL×3), wash the combined organic phases with saturated brine (500 mL×3), collect the organic phases, add anhydrous sodium sulfate, dry and concentrate to obtain the crude product of 3B.

[0169] (3) Preparation of spermidine hydrochloride

[0170] Dilute hydrochloric acid (540 mL, 6 M) was added to a reaction bottle containing 3B (541.8 mmol) and stirred at room temperature for 16 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 (120 mL × 3), 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, the precipitated white solid product was collected by filtration, and washed with acetone (60m × 3). After the washing was completed, 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) and add them into a 2 L round-bottom flask, add 1 L of ethanol and stir at 25 ° C for 8 h; after the reaction is completed, filter and rinse with ethanol (50 mL × 3), collect and concentrate the filtrate 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, and the method for preparing spermidine comprises the following steps:

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

[0176] Accurately weigh 3-chloropropylamine hydrochloride (192.3mmol) and triethylamine (384.6mmol) and add them to a 1L round-bottom flask, add 200mL of tetrahydrofuran and stir at 0°C; immediately dissolve triphenylmethane (192.3mmol) in 200mL of tetrahydrofuran, slowly drop into the reaction bottle, keep stirring at 0°C for 2h, then return to room temperature and continue stirring for 12h. After the reaction is completed, filter, collect the filtrate and wash it with clean water (2×100mL), combine the organic phases, add anhydrous sodium sulfate, dry and concentrate to obtain a crude product; place the crude product in ethyl acetate at 80°C for recrystallization, filter and collect the precipitated white solid product, and dry at 80°C to obtain 48g of 3A pure product 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 into 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, extract the aqueous phase with ethyl acetate (50 mL×3), wash the combined organic phases with saturated brine (200 mL×3), collect the organic phases, add anhydrous sodium sulfate, dry, and concentrate to obtain the crude product of 3B.

[0179] (3) Preparation of spermidine hydrochloride

[0180] Dilute hydrochloric acid (90 mL, 6 M) was added to the reaction bottle containing 3B (134.7 mmol) and stirred at room temperature for 24 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), the aqueous phase was collected and concentrated to obtain the crude product of spermidine hydrochloride; the crude product of spermidine hydrochloride was placed in ethanol at 80 ° C for recrystallization, the precipitated white solid product was collected by filtration, and acetone (20 mL × 3) was rinsed. After the rinsing was completed, 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) and add them into a 1 L round-bottom flask, add 500 mL of dichloromethane and stir at 25 ° C for 12 h; after the reaction is completed, filter and rinse with dichloromethane (20 mL×3), collect and concentrate the filtrate 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, and the method for preparing spermidine comprises the following steps:

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

[0186] Accurately weigh 3-chloropropylamine hydrochloride (192.3mmol) and triethylamine (490.8mmol) and add them to a 1L round-bottom flask, add 200mL of dichloromethane and stir at 0°C. Then dissolve triphenylmethane (192.3mmol) in 200mL of dichloromethane and slowly drop it into the reaction bottle, keep stirring at 0°C for 2h, then return to room temperature and continue stirring for 12h. After the reaction is completed, filter, collect the filtrate and wash it with clean water (2×100mL), combine the organic phases, add anhydrous sodium sulfate, dry and concentrate to obtain a crude product. Recrystallize from toluene at 110°C, filter and collect the precipitated white solid product, and dry it at 80°C to obtain 46g of 3A pure product 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 1L round-bottom flask, add 200 mL of N,N-dimethylformamide and stir at 80°C for 6 h. After the reaction is completed, cool to room temperature, add 200 mL of water and stir evenly, extract the aqueous phase with ethyl acetate (50 mL × 3), wash the combined organic phases with saturated brine (200 mL × 3), collect the organic phases, add anhydrous sodium sulfate, dry and concentrate to obtain the crude product 3B.

[0189] (3) Preparation of spermidine hydrochloride

[0190] Add dilute hydrochloric acid (142 mL, 6 M) to the reaction bottle containing 3B (141.9 mmol) and stir at room temperature for 24 h. After the reaction is completed, filter and rinse the filter cake with water. Collect the filtrate and wash it with ethyl acetate (30 mL × 3). Collect the aqueous phase and concentrate it to obtain the crude product of spermidine hydrochloride. Recrystallize it from ethanol at 80 ° C, filter and collect the precipitated white solid product, rinse it with acetone (20 mL × 3), and after rinsing, dry the solid at 50 ° C in vacuum to obtain 32 g of the product spermidine hydrochloride, with a total yield of 77% in two steps.

[0191] (4) Preparation of spermidine

[0192] Accurately weigh spermidine hydrochloride (98.2 mmol) and potassium hydroxide (294.6 mmol) and add them to a 1L round-bottom flask, add 500 mL of ethanol and stir at 25°C for 12 h. After the reaction is completed, filter and rinse with acetone (20 mL×3). After collecting and concentrating the filtrate, 16 g of spermidine product can be obtained, with a yield of 94% and a purity of 99.5%.

[0193] Example 5

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

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

[0196] Accurately weigh 3-chloropropylamine hydrochloride (192.3mmol) and triethylamine (384.6mmol) and add them to a 1L round-bottom flask, add 200mL of dichloromethane and stir at 0°C; immediately dissolve triphenylmethane (192.3mmol) in 200mL of dichloromethane, slowly dropwise add into the reaction flask, keep stirring at 0°C for 2h, then return to room temperature and continue stirring for 12h; after the reaction is completed, filter, collect the filtrate and wash with clean water (2×100mL), 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, filter and collect the precipitated white solid product, and dry at 80°C to obtain 52g 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 1L round-bottom flask, add 200 mL of N,N-dimethylformamide and stir at 80°C for 12 h. After the reaction is completed, cool to room temperature, add 200 mL of water and stir evenly, extract the aqueous phase with ethyl acetate (50 mL × 3), combine the organic phases and wash with saturated brine (200 mL × 3), collect the organic phases, add anhydrous sodium sulfate, dry and concentrate to obtain the crude product 3B.

[0199] (3) Preparation of spermidine hydrochloride

[0200] Add dilute hydrochloric acid (114 mL, 6 M) to the reaction bottle containing 3B (136.8 mmol) and stir at 50 ° C for 3 h. After the reaction is completed, cool to room temperature, filter, rinse the filter cake with water, collect the filtrate and wash it with ethyl acetate (30 mL × 3), collect the aqueous phase and concentrate to obtain the crude product of spermidine hydrochloride. Recrystallize from ethanol at 80 ° C, filter and collect the precipitated white solid product, rinse with acetone (20 mL × 3), and after the washing is completed, the solid is vacuum dried at 50 ° C to obtain 26 g of the product spermidine hydrochloride, and the total yield of the two steps is 63%.

[0201] (4) Preparation of spermidine

[0202] Accurately weigh spermidine hydrochloride (90.0 mmol) and sodium hydroxide (270.0 mmol) and add them into 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 and concentrate the filtrate 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 Embodiment 1 only in that, in 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 Embodiment 1;

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

[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, and the specific reaction process is as follows:

[0208]

[0209] The results showed that the intermediate product 3A' in the subsequent reaction had decreased crystallinity, low recrystallization yield, and difficult product purification. The final total yield of spermidine product was 25% and the purity was 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, and the specific reaction process is as follows:

[0212]

[0213] The results showed that the intermediate product 3A" in the subsequent reaction had decreased crystallinity, low recrystallization yield, and difficult 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: in step (1), an Fmoc protecting group is used instead of a trityl protecting group. The specific reaction process is as follows:

[0216]

[0217] The results showed that the protecting group could not be removed in the subsequent reaction under hydrochloric acid conditions, spermidine hydrochloride product could not be obtained, and 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 -(3-(tritylamino)propyl)butane-1,4-diamine (3B) is 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 -(3-(tritylamino)propyl)butane-1,4-diamine (3B) is 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 -(3-(tritylamino)propyl)butane-1,4-diamine (3B) is 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 is different from Example 3 only in that the volume of hydrochloric acid used in step (3) for preparing spermidine hydrochloride is 67 mL.

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

[0230] Comparative Example 8

[0231] This comparative example provides a method for preparing spermidine, which is different 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%, which was 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 is different from Example 1 only in that: in step (1), when preparing 3A, triphenylmethane raw material 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 reduced 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, first using 3-chloropropylamine hydrochloride, triethylamine and triphenylmethane as reaction raw materials to synthesize a product 3A with a trityl protecting group. Subsequently, 3A is condensed with 1,4-butanediamine, and the molar ratio of 1,4-butanediamine to 3A is optimized to obtain 3B with high purity in a simple and efficient manner. After the trityl protecting group of compound 3B is removed under the action of hydrochloric acid, spermidine hydrochloride can be obtained. Finally, spermidine hydrochloride can be freed under alkaline conditions to obtain a spermidine product with a high yield.

[0246] The preparation method of spermidine provided by the present invention has the following advantages: (1) triphenylmethane, 1,4-butanediamine and 3-chloropropylamine hydrochloride used are all cheap and readily available commercial raw materials, which reduces the cost of raw materials. (2) catalytic hydrogenation reduction process is avoided, and the reaction conditions are mild, and there is no need to consider the cost of precious metal catalysts. (3) The synthesis method has the advantages of 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 aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned 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) condensing 3-chloropropylamine hydrochloride and triphenylmethane to obtain 3-chloro-N-tritylpropylamine; (2) 3-chloro-N-tritylpropylamine and 1,4-diamine are subjected to condensation reaction to obtain N 1 -(3-(tritylamino)propyl)butane-1,4-diamine; (3) N 1 -(3-(tritylamino)propyl)butane-1,4-diamine removes the trityl group to obtain spermidine hydrochloride; (4) Spermidine hydrochloride is liberated in the presence of a base to obtain spermidine.

2. The method for preparing spermidine according to claim 1, characterized in that: In step (1), the molar ratio of 3-chloropropylamine hydrochloride to triphenylmethane is 1:(0.8-1.2); Preferably, in step (1), the condensation reaction is carried out in a solvent; Preferably, 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; Preferably, in step (1), the condensation reaction is carried out in the presence of an acid binding agent; Preferably, the acid binding agent comprises triethylamine, potassium carbonate or cesium carbonate or any one or a combination of at least two thereof, preferably triethylamine; Preferably, in step (1), the molar ratio of 3-chloropropylamine hydrochloride, triphenylmethane and acid binding agent is 1:(0.8-1.2):(1-3).

3. The method for preparing spermidine according to claim 1 or 2, characterized in that: In step (1), the specific steps of the condensation reaction are: 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; the raw material solution 2 is added dropwise to the raw material solution 1 to carry out a condensation reaction to obtain a reaction solution containing 3-chloro-N-tritylpropylamine; Preferably, the temperature of the dropwise added raw material solution 2 is below 5°C; Preferably, the condensation reaction is: first reacting at a temperature below 5°C for 1 to 12 hours, and then reacting at a temperature of 5 to 35°C for 12 to 24 hours.

4. The method for preparing spermidine according to claim 3, characterized in that: In step (1), the condensation reaction further includes the following post-treatment steps: The reaction solution containing 3-chloro-N-tritylpropylamine is filtered, extracted, washed, dried, concentrated and recrystallized in sequence to obtain 3-chloro-N-tritylpropylamine; Preferably, in step (1), the condensation reaction further comprises the following post-treatment steps: The reaction solution containing 3-chloro-N-tritylpropylamine is filtered, the filtrate is collected, the organic phase is collected and dried after washing with water, and concentrated to obtain a crude product, and the crude product is recrystallized in an organic solvent to obtain 3-chloro-N-tritylpropylamine; Preferably, the organic solvent for recrystallization is toluene and / or ethyl acetate.

5. The method for preparing spermidine according to claim 1, characterized in that: In step (2), the molar ratio of 3-chloro-N-tritylpropylamine to 1,4-butanediamine is 1:(1-10); Preferably, in step (2), the condensation reaction is carried out in a solvent; Preferably, 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; Preferably, in step (2), the condensation reaction is carried out in the presence of an acid binding agent; Preferably, the acid binding agent comprises triethylamine, potassium carbonate or cesium carbonate or any one or a combination of at least two thereof, preferably triethylamine; 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).

6. The method for preparing spermidine according to claim 1 or 5, characterized in that: In step (2), the specific steps of the condensation reaction are: 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 a N-containing 1 -(3-(tritylamino)propyl)butane-1,4-diamine reaction solution; Preferably, the temperature of the condensation reaction is 20 to 120° C., and the time of the condensation reaction is 3 to 24 hours; Preferably, in step (2), the condensation reaction further comprises the following post-treatment step: 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; Preferably, in step (2), the condensation reaction further comprises the following post-treatment step: 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 then dried. After concentration, N 1 -(3-(tritylamino)propyl)butane-1,4-diamine; Preferably, the extractant comprises water and ethyl acetate.

7. The method for preparing spermidine according to claim 1, characterized in that: In step (3), the removal of the trityl group is carried out in dilute hydrochloric acid; Preferably, the concentration of the dilute hydrochloric acid is 1 to 10 M, preferably 6 M; Preferably, the N 1 The molar ratio of -(3-(tritylamino)propyl)butane-1,4-diamine to hydrochloric acid is 1:(1 to 10).

8. The method for preparing spermidine according to claim 1 or 7, characterized in that: In step (3), the reaction temperature for removing the trityl group is 20 to 80° C. and the time is 3 to 24 hours; Preferably, in step (3), after removing the trityl group, the following post-treatment step is further included: filtering, washing, concentrating and recrystallizing the reaction solution containing spermidine hydrochloride in sequence to obtain spermidine hydrochloride; Preferably, in step (3), after the removal of the trityl group, the following post-treatment step is further included: filtering the reaction solution containing spermidine hydrochloride, washing the aqueous phase with ethyl acetate, collecting the aqueous phase and concentrating it to obtain a crude product, recrystallizing the crude product in an organic solvent, filtering after the product precipitates, eluting the filter residue with acetone, collecting the solid and drying it to obtain spermidine hydrochloride; Preferably, the recrystallization solvent is a mixed solvent of ethanol and water; Preferably, the volume ratio of water to ethanol is (1-5):(5-95); Preferably, the temperature of the acetone used for elution is below 5°C; the amount of the acetone used is 5 to 10 times the mass of the filter residue; the number of elutions is 3 to 5 times; Preferably, the drying temperature after collecting the solid is 40 to 60° C., and the drying time is 2 to 12 hours.

9. The method for preparing spermidine according to claim 1, characterized in that: In step (4), the base includes an organic base and / or an inorganic base; Preferably, the organic base comprises triethylamine; Preferably, the inorganic base comprises any one or a combination of at least two of sodium hydroxide, potassium carbonate or cesium carbonate; Preferably, in step (4), the dissociation is carried out in a solvent; 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; Preferably, in step (4), the molar ratio of spermidine hydrochloride to base is 1:(1-5).

10. The method for preparing spermidine according to claim 1 or 9, characterized in that: In step (4), the dissociation temperature is 25 to 80° C., and the dissociation time is 3 to 12 hours; Preferably, in step (4), the following post-treatment steps are further included after the release: filtering and concentrating the reaction solution containing spermidine in sequence to obtain spermidine; Preferably, in step (4), the following post-treatment step is further included after the release: filtering the reaction solution containing spermidine, eluting with ethanol, collecting the filtrate, and concentrating it to obtain spermidine.

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