A kind of preparation method of spermidine

Abstract

The invention discloses a method for preparing spermidine. The method comprises the following steps: dissolving oxalyl chloride and a base in a first solvent, slowly adding 4-bromo-1-butylamine hydrobromic acid, and reacting to obtain 2-((4-bromobutyl)amino)-2-oxoacetyl chloride; adding a base to the reaction solvent of the obtained 2-((4-bromobutyl)amino)-2-oxoacetyl chloride, and slowly adding 3-bromo-1-propylamine hydrobromic acid to obtain N 1 ‑(4‑Bromobutyl)‑N 2 ‑(3‑bromopropyl)oxalamide; 1 ‑(4‑Bromobutyl)‑N 2 ‑(3‑bromopropyl)oxalamide, benzylamine and a base are added to a second solvent to react to obtain 8‑benzyl‑1,4,8‑triazacyclododecane‑2,3‑dione; 8‑benzyl‑1,4,8‑triazacyclododecane‑2,3‑dione is added to an acid for hydrolysis to obtain N 1 ‑(3‑Aminopropyl)‑N 1 Benzylbutane-1,4-diamine; N 1 ‑(3‑Aminopropyl)‑N 1 Benzylbutane-1,4-diamine is added to Raney nickel / methanol, and hydrogen is passed through the reaction to obtain crude spermidine, which is then distilled to obtain pure spermidine. The preparation method of the present invention is easy to operate and safe, easy to industrial-scale production, and has a high conversion rate of spermidine and high product purity.

Description

Technical Field

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

[0002] Spermidine, a low-molecular-weight aliphatic carbide containing three amine groups, is a naturally occurring polyamine found in all organisms. As an important raw material for pharmaceutical synthesis, it is widely used in the synthesis of pharmaceutical intermediates. Spermidine participates in numerous biological processes within the body, such as regulating cell proliferation, cell aging, organ development, immunity, and cancer, among other physiological and pathological processes. Recent studies have demonstrated that spermidine plays a crucial role in regulating processes such as synaptic plasticity, oxidative stress, and autophagy in the nervous system.

[0003] Currently, spermidine is synthesized primarily using 1,4-butanediamine and acrylonitrile as raw materials. This involves an addition reaction followed by cyanidation reduction of the cyano group to produce spermidine. While this synthesis method requires only two steps and is relatively short, it suffers from two drawbacks: First, the large excess of 1,4-butanediamine is difficult to remove; and second, the addition reaction of acrylonitrile and 1,4-butanediamine produces a high concentration of impurities with physical and chemical properties similar to those of spermidine, making purification difficult and hindering industrial production and broader applications. Summary of the Invention

[0004] The object of the present invention is to provide a method for preparing spermidine to solve the problems raised in the above background technology.

[0005] To achieve the above object, the technical solution adopted by the present invention is: a method for preparing spermidine, comprising the following steps:

[0006] S1) dissolving oxalyl chloride and a base in a first solvent, and slowly adding 4-bromo-1-butylamine hydrobromide to react to produce 2-((4-bromobutyl)amino)-2-oxoacetyl chloride;

[0007] S2) adding a base to the prepared 2-((4-bromobutyl)amino)-2-oxoacetyl chloride reaction solvent, slowly adding 3-bromo-1-propylamine hydrobromic acid to prepare N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxalamide;

[0008] S3) N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxalamide, benzylamine and a base are added to a second solvent to react to prepare 8-benzyl-1,4,8-triazacyclododecane-2,3-dione;

[0009] S4) 8-benzyl-1,4,8-triazacyclododecane-2,3-dione was added to an acid for hydrolysis to obtain N 1 -(3-aminopropyl)-N 1 -benzylbutane-1,4-diamine;

[0010] S5) N 1 -(3-aminopropyl)-N 1 -Benzylbutane-1,4-diamine was added to Raney nickel / methanol and hydrogen was introduced to react to obtain crude spermidine, which was then distilled to obtain pure spermidine.

[0011] As a further optimization, the molar ratio of oxalyl chloride to 4-bromo-1-butylamine hydrobromide in S1 is (1-1.2):1.

[0012] As a further optimization, the base in S1 is one or more of triethylamine, trimethylamine or N,N-diisopropylethylamine, preferably triethylamine, and the molar ratio of triethylamine to 4-bromo-1-butylamine hydrobromide is (2-2.5):1, and 2:1 can be selected.

[0013] As a further optimization, the first solvent in S1 is one or more of dichloromethane, dichloroethane, tetrahydrofuran or DMF, preferably dichloromethane, and the weight ratio of dichloromethane to 4-bromo-1-butylamine hydrobromic acid is (1-10):1, and 10:1 can be selected.

[0014] As a further optimization, the base in S2 is one or more of triethylamine, trimethylamine or N,N-diisopropylethylamine, preferably triethylamine, and the molar ratio of triethylamine to 3-bromo-1-propylamine hydrobromide is (2-2.5):1, and 2:1 can be selected.

[0015] As a further optimization, the molar ratio of 3-bromo-1-propylamine hydrobromide to oxalyl chloride in S2 is (1-1.2):1.

[0016] As a further optimization, the benzylamine in S3 was combined with N 1 -(4-Bromobutyl)-N 2 The molar ratio of -(3-bromopropyl)oxamide is (0.9-1):1, and 1:1 can be selected.

[0017] As a further optimization, the base in S3 is one or more of triethylamine, potassium carbonate or sodium carbonate, preferably potassium carbonate or sodium carbonate, which 1 -(4-Bromobutyl)-N 2 The molar ratio of -(3-bromopropyl)oxamide is (2-3):1, and can be selected as 1.2:1.

[0018] As a further optimization, the second solvent in S3 is one or more of dichloromethane, dichloroethane, tetrahydrofuran, dioxane or toluene, preferably dichloromethane, which is 1 -(4-Bromobutyl)-N 2 The weight ratio of -(3-bromopropyl)oxamide is (5-10):1, and 10:1 can be selected.

[0019] As a further optimization, the acid in S4 is a 10% aqueous solution of hydrochloric acid or sulfuric acid, and the mass ratio of hydrochloric acid or sulfuric acid to 8-benzyl-1,4,8-triazacyclododecane-2,3-dione is (8-10):1, preferably 10:1.

[0020] As a further optimization, Raney nickel in S5 and N 1 -(3-aminopropyl)-N 1 The mass ratio of benzylbutane-1,4-diamine is (0.1-0.3):1, preferably 0.2:1.

[0021] As a further optimization, methanol in S5 was mixed with N 1 -(3-aminopropyl)-N 1 The mass ratio of benzylbutane-1,4-diamine is (6-10):1, preferably 6:1.

[0022] The preparation process of the present invention is as follows:

[0023]

[0024] Compared with the prior art, the beneficial effects of the present invention are embodied in:

[0025] 1. The preparation method of the present invention is easy to operate, safe to operate, and easy to be produced on an industrial scale;

[0026] 2. The raw materials used in the present invention are low in cost and environmentally friendly and pollution-free;

[0027] 3. The conversion rate of spermidine prepared by the present invention is high, the product and impurities are easily separated, and the product purity is high. DETAILED DESCRIPTION

[0028] The following are specific embodiments of the present invention, which further describe the technical solutions of the present invention, but the present invention is not limited to these embodiments.

[0029] Example 1

[0030] A method for preparing spermidine comprises the following steps:

[0031] S1) 139.7 g of oxalyl chloride and 202.4 g of triethylamine were dissolved in 2.3 kg of dichloromethane, the temperature was controlled at 0°C, and 233 g of 4-bromo-1-butylamine hydrobromide was slowly added. The reaction was incubated for 2 h after addition and the reaction was detected to be complete;

[0032] S2) 202 g of triethylamine was added to the 2-((4-bromobutyl)amino)-2-oxoacetyl chloride reaction solvent prepared in S1, the temperature was controlled at 0°C, and 265 g of 3-bromo-1-propylamine hydrobromic acid was slowly added. After the addition was complete, the temperature was raised to 25°C, and the reaction was allowed to proceed for 2 h. The reaction was detected to be complete, and the triethylamine salt was filtered to remove the triethylamine salt. Water was added, the layers were separated, and the mixture was washed once with 10% citric acid, the layers were separated, the mixture was washed once with water, and the mixture was dried and evaporated to dryness to obtain 320 g of N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxalamide;

[0033] S3) 320g N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxamide, 99.6 g benzylamine, 154 g potassium carbonate and 3.2 kg dichloromethane, reflux reaction for 8 hours, check the completion of the reaction, filter the salt, wash the filtrate with water, dry, and concentrate to obtain 242 g 8-benzyl-1,4,8-triazacyclododecane-2,3-dione;

[0034] S4) 242g 8-benzyl-1,4,8-triazacyclododecane-2,3-dione is added to 2.4kg

[0035] The mixture was refluxed in 10% hydrochloric acid for 10 h, and then 10 g of activated carbon was added and refluxed for 2 h. The mixture was filtered, and the pH was adjusted to 9 by adding sodium hydroxide. The mixture was extracted with DCM, washed with water, dried, and concentrated to obtain 157 g of N 1 -(3-aminopropyl)-N 1 -benzylbutane-1,4-diamine;

[0036] S5) 157 g N was added to a 2 L autoclave. 1 -(3-aminopropyl)-N 1 -benzylbutane-1,4-diamine, 30g Raney nickel and 1kg methanol, hydrogen pressure 2.0MPa, react at 60℃ for 24h, filter the reaction liquid, concentrate to dryness to obtain the crude product, and distill to obtain 81.3g of colorless and transparent spermidine.

[0037] The purity measured by gas chromatography was 99.9%.

[0038] Example 2

[0039] A method for preparing spermidine comprises the following steps:

[0040] S1) 139.7 g of oxalyl chloride and 202.4 g of triethylamine were dissolved in 2.3 kg of dichloromethane, the temperature was controlled at 0°C, and 233 g of 4-bromo-1-butylamine hydrobromide was slowly added. The reaction was incubated for 2 h after addition and the reaction was detected to be complete;

[0041] S2) 202 g of triethylamine was added to the 2-((4-bromobutyl)amino)-2-oxoacetyl chloride reaction solvent prepared in S1, the temperature was controlled at 0°C, and 265 g of 3-bromo-1-propylamine hydrobromic acid was slowly added. After the addition was complete, the temperature was raised to 25°C and the reaction was allowed to proceed for 2 h. The reaction was detected to be complete, the triethylamine salt was filtered to remove the triethylamine salt, water was added, the layers were separated, and the mixture was washed once with 10% citric acid, the layers were separated, the mixture was washed once with water, and the mixture was dried and evaporated to dryness to obtain 325 g of N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxalamide;

[0042] S3) 325g N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxamide, 101.1 g benzylamine, 156.4 g potassium carbonate and 3.2 kg dichloromethane, reflux reaction for 8 h, check the completion of the reaction, filter the salt, wash the filtrate with water, dry, and concentrate to obtain 247 g 8-benzyl-1,4,8-triazacyclododecane-2,3-dione;

[0043] S4) 247 g of 8-benzyl-1,4,8-triazacyclododecane-2,3-dione was added to 2.4 kg of 10% sulfuric acid, refluxed for 10 h, and then 10 g of activated carbon was added and refluxed for 2 h, filtered, and sodium hydroxide was added to adjust the pH to 9, extracted with DCM, washed with water, dried, and concentrated to obtain 161.6 g of N 1 -(3-aminopropyl)-N 1 -benzylbutane-1,4-diamine;

[0044] S5) 161.6 g of N was added to a 2 L autoclave. 1 -(3-aminopropyl)-N 1 -benzylbutane-1,4-diamine, 30g Raney nickel and 1kg methanol, hydrogen pressure 2.0MPa, react at 60℃ for 24h, filter the reaction liquid, concentrate to dryness to obtain the crude product, and distill to obtain 85g of colorless and transparent spermidine.

[0045] The purity measured by gas chromatography was 99.8%.

[0046] Example 3

[0047] A method for preparing spermidine comprises the following steps:

[0048] S1) 139.7 g of oxalyl chloride and 202.4 g of triethylamine were dissolved in 2.3 kg of dichloromethane, the temperature was controlled at 0°C, and 233 g of 4-bromo-1-butylamine hydrobromide was slowly added. The reaction was incubated for 2 h after addition and the reaction was detected to be complete;

[0049] S2) 202 g of triethylamine was added to the 2-((4-bromobutyl)amino)-2-oxoacetyl chloride reaction solvent prepared in S1, the temperature was controlled at 0°C, and 265 g of 3-bromo-1-propylamine hydrobromic acid was slowly added. After the addition was complete, the temperature was raised to 25°C and the reaction was allowed to proceed for 2 h. The reaction was detected to be complete, the triethylamine salt was filtered to remove the salt, water was added, the layers were separated, and the mixture was washed once with 10% citric acid, the layers were separated, the mixture was washed once with water, and the mixture was dried and evaporated to dryness to obtain 313 g of N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxalamide;

[0050] S3) 313g N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxamide, 97.4 g benzylamine, 115.6 g sodium carbonate and 3.2 kg dichloromethane, reflux reaction for 8 hours, detect the completion of the reaction, filter the salt, wash the filtrate with water, dry, and concentrate to obtain 237.5 g 8-benzyl-1,4,8-triazacyclododecane-2,3-dione;

[0051] S4) 237.5 g of 8-benzyl-1,4,8-triazacyclododecane-2,3-dione was added to 2.4 kg of 10% hydrochloric acid, refluxed for 10 h, then 10 g of activated carbon was added and refluxed for 2 h, filtered, and sodium hydroxide was added to adjust the pH to 9, extracted with DCM, washed with water, dried, and concentrated to obtain 152.4 g of N 1 -(3-aminopropyl)-N 1 -benzylbutane-1,4-diamine;

[0052] S5) 152.4 g of N was added to a 2 L autoclave. 1 -(3-aminopropyl)-N 1 -benzylbutane-1,4-diamine, 30g Raney nickel and 1kg methanol, hydrogen pressure 2.0MPa, react at 60℃ for 24h, filter the reaction liquid, concentrate to dryness to obtain the crude product, and distill to obtain 79.3g of colorless and transparent spermidine.

[0053] The purity measured by gas chromatography was GC99.9%.

[0054] Example 4

[0055] A method for preparing spermidine comprises the following steps:

[0056] S1) 139.7 g of oxalyl chloride and 202.4 g of triethylamine were dissolved in 2.3 kg of dichloromethane, the temperature was controlled at 0°C, and 233 g of 4-bromo-1-butylamine hydrobromide was slowly added. The reaction was incubated for 2 h after addition and the reaction was detected to be complete;

[0057] S2) 202 g of triethylamine was added to the 2-((4-bromobutyl)amino)-2-oxoacetyl chloride reaction solvent prepared in S1, the temperature was controlled at 0°C, and 265 g of 3-bromo-1-propylamine hydrobromic acid was slowly added. After the addition was complete, the temperature was raised to 25°C and the reaction was allowed to proceed for 2 h. The reaction was detected to be complete, the triethylamine salt was filtered to remove the triethylamine salt, water was added, the layers were separated, and the mixture was washed once with 10% citric acid, the layers were separated, the mixture was washed once with water, and the mixture was dried and evaporated to dryness to obtain 317 g of N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxalamide;

[0058] S3) 317g N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxamide, 98.6 g benzylamine, 117.1 g sodium carbonate and 3.2 kg dichloromethane, reflux reaction for 8 hours, detect the completion of the reaction, filter the salt, wash the filtrate with water, dry, and concentrate to obtain 241.3 g 8-benzyl-1,4,8-triazacyclododecane-2,3-dione;

[0059] S4) 241.3 g of 8-benzyl-1,4,8-triazacyclododecane-2,3-dione was added to 2.4 kg of 10% hydrochloric acid, refluxed for 10 h, then 10 g of activated carbon was added and refluxed for 2 h, filtered, and sodium hydroxide was added to adjust the pH to 9, extracted with DCM, washed with water, dried, and concentrated to obtain 154.8 g of N 1 -(3-aminopropyl)-N 1 -benzylbutane-1,4-diamine;

[0060] S5) 154.8 g of N was added to a 2 L autoclave. 1 -(3-aminopropyl)-N 1 -benzylbutane-1,4-diamine, 30g Raney nickel and 1kg methanol, hydrogen pressure 2.0MPa, react at 60℃ for 24h, filter the reaction liquid, concentrate to dryness to obtain the crude product, and distill to obtain 81.5g of colorless and transparent spermidine.

[0061] The purity measured by gas chromatography was GC99.9%.

[0062] The preparation method of the present invention has the advantages of simple process, easy operation, environmental protection, no pollution, low cost, safe operation, easy industrial-scale production, high conversion rate, easy separation of product and impurities, and high product purity.

[0063] The specific embodiments described herein are merely illustrative of the spirit of the present invention. Persons skilled in the art may make various modifications, additions, or substitutions to the described specific embodiments without departing from the spirit of the present invention or exceeding the scope of the appended claims.

Claims

1. A method for preparing spermidine, characterized in that: The steps include: S1) dissolving oxalyl chloride and a base in a first solvent, slowly adding 4-bromo-1-butylamine hydrobromic acid, and reacting to obtain 2-((4-bromobutyl)amino)-2-oxoacetyl chloride, wherein the base is triethylamine, and the molar ratio of triethylamine to 4-bromo-1-butylamine hydrobromic acid is 2-2.5:1; S2) adding a base to the obtained 2-((4-bromobutyl)amino)-2-oxoacetyl chloride reaction solvent, and slowly adding 3-bromo-1-propylamine hydrobromic acid to obtain N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxalamide, wherein the base is triethylamine, and the molar ratio of triethylamine to 3-bromo-1-propylamine hydrobromic acid is 2-2.5:1; S3) N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxalamide, benzylamine and a base are added to a second solvent to react to obtain 8-benzyl-1,4,8-triazacyclododecane-2,3-dione, wherein the base is potassium carbonate or sodium carbonate, which reacts with N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxalamide has a molar ratio of 2-3:1; S4) 8-benzyl-1,4,8-triazacyclododecane-2,3-dione is added to an acid for hydrolysis to obtain N 1 -(3-aminopropyl)-N 1 -benzylbutane-1,4-diamine; S5) N 1 -(3-aminopropyl)-N 1 -Benzylbutane-1,4-diamine is added to Raney nickel / methanol, and hydrogen is passed through the reaction to obtain crude spermidine, which is then distilled to obtain pure spermidine.

2. The method for preparing spermidine according to claim 1, characterized in that: The molar ratio of oxalyl chloride to 4-bromo-1-butylamine hydrobromic acid in S1 is 1-1.2:

1.

3. The method for preparing spermidine according to claim 1, characterized in that: The first solvent in S1 is one or more of dichloromethane, dichloroethane, tetrahydrofuran or DMF, and the weight ratio of the first solvent to 4-bromo-1-butylamine hydrobromic acid is 1-10:

1.

4. The method for preparing spermidine according to claim 1, characterized in that: The molar ratio of 3-bromo-1-propylamine hydrobromic acid to oxalyl chloride in S2 is 1-1.2:

1.

5. The method for preparing spermidine according to claim 1, characterized in that: Benzylamine in S3 and N 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxalamide has a molar ratio of 0.9-1:

1.

6. The method for preparing spermidine according to claim 1, characterized in that: The second solvent in S3 is one or more of dichloromethane, dichloroethane, tetrahydrofuran, dioxane or toluene, which is 1 -(4-Bromobutyl)-N 2 -(3-bromopropyl)oxalamide, the weight ratio is 5-10:

1.

7. The method for preparing spermidine according to claim 1, characterized in that: The acid in S4 is a 10% aqueous solution of hydrochloric acid or sulfuric acid, and the mass ratio of hydrochloric acid or sulfuric acid to 8-benzyl-1,4,8-triazacyclododecane-2,3-dione is 8-10:

1.

8. The method for preparing spermidine according to claim 1, characterized in that: Raney nickel and N in S5 1 -(3-aminopropyl)-N 1 -benzylbutane-1,4-diamine has a mass ratio of 0.1-0.3:1; methanol and N 1 -(3-aminopropyl)-N 1 -benzylbutane-1,4-diamine has a mass ratio of 6-10:1.

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