Novel method for efficiently synthesizing Kukoamine B and Kukoamine D and derivatives thereof

Abstract

The invention relates to the field of organic synthetic chemistry, in particular to a novel method for efficiently synthesizing Kukoamine B, Kukoamine D and derivatives thereof. According to the method disclosed by the invention, tert-butyl (4-aminobutyl) carbamate is taken as an initial raw material, and the tert-butyl (4-aminobutyl) carbamate is prepared through a Michael addition reaction, an N-alkylation reaction, a cyano group reduction amidation'one-pot method ', a hydrolysis reaction, Boc removal and other reactions. Kukoamine B, Kukoamine D and derivatives thereof are synthesized through simple steps, the reaction cost is reduced, particularly, in-situ reduction of cyano groups is realized by innovatively adopting a catalyst to cooperate with a sodium borohydride system in the reaction, and amide is generated by further coupling with prefabricated activated ester without post-treatment, so that a two-step one-pot continuous reaction system is successfully constructed. According to the process, safe operation under the normal pressure condition is achieved, the reaction safety is improved, and the good yield is achieved.

Description

Technical Field

[0001] The present invention relates to the field of organic synthetic chemistry, and in particular to a novel method for efficiently synthesizing Kukoamine B and Kukoamine D and derivatives thereof. Background Art

[0002] Kukoamine B, Kukoamine D and N 1 ,N 4 ,N 12 -tris(dihydrocaffeoyl)spermine is a natural alkaloid extracted from the root bark of the traditional medicinal plant Lycium chinense. Modern pharmacological research has found that these compounds exhibit significant biological activities due to their unique molecular structure, including potent antioxidant, anti-inflammatory, and neuroprotective effects. They also have potential therapeutic value in improving cognitive dysfunction and alleviating neurodegenerative diseases, and have become active lead compounds that have attracted much attention in the field of neurological drug research and development. However, the current approaches to obtaining these compounds face bottlenecks: traditional plant extraction methods are limited by the low content of active ingredients in the root bark of Lycium chinense, making large-scale production difficult; existing chemical synthesis methods have problems such as cumbersome steps, harsh reaction conditions, low yields, and complex by-products, which restrict their large-scale preparation and application development.

[0003] Therefore, it is necessary to find a method for preparing Kukoamine B, Kukoamine D and their derivatives with simple operation, mild reaction conditions, high yield and few by-products, which is suitable for industrial production. Summary of the Invention

[0004] To overcome the shortcomings of the prior art, the present invention provides a method for preparing Kukoamine B, Kukoamine D, and their derivatives with simple procedures, mild reaction conditions, high yields, and suitability for industrial production. This method employs a modular synthesis strategy and uses green chemistry methods to precisely control key reaction sites, successfully establishing an efficient system for preparing the target products.

[0005] The present invention is achieved through the following technical solutions:

[0006] The invention provides a method for synthesizing Kukoamine B, Kukoamine D and derivatives thereof. The method uses tert-butyl (4-aminobutyl) carbamate as a starting material and prepares the Kukoamine B, Kukoamine D and derivatives thereof through Michael addition reaction, N-alkylation reaction, cyano group reduction amidation (one-pot method), hydrolysis reaction, Boc removal and other reactions.

[0007]

[0008] The general structural formula of Kukoamine B, Kukoamine D and their derivatives are as follows:

[0009]

[0010]

[0011] in,

[0012] R1 is Cbz, H;

[0013] R2 is C1-C4 alkoxy, OH, H;

[0014] R3 is C1-C4 alkoxy, OH, H;

[0015] R4 is CN, CH2NH2;

[0016] Furthermore,

[0017] R2 and R3 are both C1-C4 alkoxy or both OH.

[0018] The reaction process of Kukoamine B, Kukoamine D and their derivatives is as follows:

[0019]

[0020]

[0021] Wherein, R2 and R3 are as described above.

[0022] Furthermore, the Kukoamine B, Kukoamine D and their derivatives are compounds with the following structures:

[0023]

[0024]

[0025] Specifically, the reaction flow of the synthesis method of Kukoamine B of the present invention is as follows:

[0026]

[0027] The synthetic method specifically comprises the following steps:

[0028] (I) tert-Butyl (4-aminobutyl) carbamate 1 undergoes Michael addition reaction with acrylonitrile in an organic solvent to produce compound 2;

[0029] (II) Compound 2 is reacted with benzyl chloroformate in an organic solvent to obtain compound 3;

[0030] (III) Compound 3 is first reduced to its cyano group using sodium borohydride in the presence of a catalyst, and then reacts with 2,5-dioxopyrrolidin-1-yl 3-(3,4-dimethoxyphenyl)propionate under alkaline conditions of N,N-diisopropylethylamine to produce compound 4;

[0031] (IV) Compound 4 reacts in a hydrochloric acid dioxane solution or a trifluoroacetic acid solution to produce compound 5;

[0032] (V) Compound 5 reacts with acrylonitrile under alkaline conditions to produce compound 6;

[0033] (VI) Compound 6 undergoes amidation reaction with 3-(3,4-dimethoxyphenyl)propionic acid in an organic solvent in the presence of HATU and N,N-diisopropylethylamine to obtain compound 7;

[0034] (VII) Compound 7 is subjected to a cyano reduction reaction using sodium borohydride in the presence of a catalyst to produce compound 8;

[0035] (IX) Compound 8 reacts with boron tribromide to obtain compound Kukoamine B.

[0036] In the step (I), the organic solvent is: methanol, ethanol, dichloromethane or anhydrous tetrahydrofuran; preferably methanol;

[0037] In the step (I), the molar ratio of tert-butyl (4-aminobutyl) carbamate to acrylonitrile is 1:1-1:1.5;

[0038] In the step (II), the organic solvent is: methanol, ethanol, dichloromethane or anhydrous tetrahydrofuran; preferably anhydrous tetrahydrofuran;

[0039] In the step (II), the molar ratio of compound 2 to benzyl chloroformate is 1:1-1:2;

[0040] In the step (III), the catalyst is nickel chloride (NiCl2), nickel bromide trihydrate (NiBr2·3H2O), cobalt chloride hexahydrate (CoCl2·6H2O), nickel chloride hexahydrate (NiCl2·6H2O), preferably nickel chloride hexahydrate; sodium borohydride is the reducing agent;

[0041] In the step (III), the molar ratio of the catalyst to sodium borohydride is 1:4-1:50, preferably 1:4-1:10;

[0042] The molar ratio of compound 3 to the catalyst is 1:1-1:6, preferably 1:1-1:1.5;

[0043] In the step (III), the reaction occurs at room temperature, normal pressure and nitrogen atmosphere;

[0044] The molar ratio of compound 3, N,N-diisopropylethylamine, and 2,5-dioxopyrrolidin-1-yl 3-(3,4-dimethoxyphenyl)propionate is 1:1-2:1-2.5;

[0045] The 2,5-dioxopyrrolidin-1-yl 3-(3,4-dimethoxyphenyl) propionate (AE) has the structural formula:

[0046]

[0047] The 2,5-dioxopyrrolidin-1-yl 3-(3,4-dimethoxyphenyl) propionate is prepared by the following method:

[0048] Oxalyl chloride and N,N-dimethylformamide are added to a dichloromethane solution of 3-(3,4-dimethoxyphenyl)propionic acid to react to obtain an acetyl chloride intermediate. This intermediate is dissolved in tetrahydrofuran and 1-hydroxypyrrolidine-2,5-dione and triethylamine are added to react to obtain the product.

[0049] wherein the molar ratio of 3-(3,4-dimethoxyphenyl)propionic acid to oxalyl chloride is 1:1-1:2;

[0050] The molar ratio of the 3-(3,4-dimethoxyphenyl)propionic acid to 1-hydroxypyrrolidine-2,5-dione is 1:1-1:1.5.

[0051] In the step (IV), the reaction solvent is dichloromethane.

[0052] In the step (V), the base is triethylamine;

[0053] The molar ratio of compound 5 to acrylonitrile is 1:1-1:1.5, and the molar ratio of compound 5 to triethylamine is 1:2-1:4.

[0054] In the step (VI), the organic solvent is DMF;

[0055] In the step (VI), the molar ratio of compound 6, 3-(3,4-dimethoxyphenyl)propionic acid, HATU and N,N-diisopropylethylamine is 1:1-1.5:1-1.5:1-1.5, preferably 1:1.5:1.5:1.5.

[0056] In the step (VII), the catalyst is nickel chloride (NiCl2), nickel bromide trihydrate (NiBr2·3H2O), cobalt chloride hexahydrate (CoCl2·6H2O), nickel chloride hexahydrate (NiCl2·6H2O), preferably nickel chloride hexahydrate; sodium borohydride is the reducing agent;

[0057] The molar ratio of the catalyst to sodium borohydride is 1:4-1:50, preferably 1:40-1:50;

[0058] The molar ratio of the catalyst to compound 7 is 1:1-1:6, preferably 1:4-1:6.

[0059] In the step (IX), the molar ratio of compound 8 to boron tribromide is 1:6-10.

[0060] The present invention also provides a method for synthesizing Kukoamine D, and the reaction process is as follows:

[0061]

[0062] The synthetic method specifically comprises the following steps:

[0063] (I) tert-Butyl (4-aminobutyl) carbamate 1 undergoes Michael addition reaction with acrylonitrile in an organic solvent to produce compound 2;

[0064] (II) Compound 2 reacts with 3-(3,4-dimethoxyphenyl)propionic acid in an organic solvent in the presence of HATU and N,N-diisopropylethylamine to obtain compound 9;

[0065] (III) Compound 9 is first reduced to its cyano group using sodium borohydride in the presence of a catalyst, and then reacts with 2,5-dioxopyrrolidin-1-yl 3-(3,4-dimethoxyphenyl)propionate under alkaline conditions of N,N-diisopropylethylamine to produce compound 10;

[0066] (IV) Compound 10 reacts in a hydrochloric acid dioxane solution or a trifluoroacetic acid solution to produce compound 11;

[0067] (V) Compound 11 reacts with acrylonitrile in the presence of N,N-diisopropylethylamine to produce compound 12;

[0068] (VI) Compound 12 reacts with benzyl chloroformate in the presence of N,N-diisopropylethylamine to produce compound 13;

[0069] (VII) Compound 13 is subjected to cyanide reduction reaction using sodium borohydride in the presence of a catalyst to produce compound 14;

[0070] (IX) Compound 14 reacts with boron tribromide to obtain compound Kukoamine D.

[0071] In the step (I), the organic solvent is: methanol, ethanol, dichloromethane or anhydrous tetrahydrofuran; preferably methanol;

[0072] In the step (I), the molar ratio of tert-butyl (4-aminobutyl) carbamate to acrylonitrile is 1:1-1:1.5.

[0073] In the step (II), the molar ratio of compound 2, 3-(3,4-dimethoxyphenyl)propionic acid, HATU and N,N-diisopropylethylamine is 1:1-1.5:1-1.5:1-2, preferably 1:1.05-1.1:1.05-1.1:2.

[0074] In the step (II), the organic solvent is DMF.

[0075] In the step (III), the reaction occurs at room temperature, normal pressure and nitrogen atmosphere;

[0076] The molar ratio of compound 9, N,N-diisopropylethylamine, and 2,5-dioxopyrrolidin-1-yl 3-(3,4-dimethoxyphenyl)propionate is 1:1-2:1-2.5;

[0077] The catalyst is nickel chloride (NiCl2), nickel bromide trihydrate (NiBr2·3H2O), cobalt chloride hexahydrate (CoCl2·6H2O), nickel chloride hexahydrate (NiCl2·6H2O), preferably nickel chloride hexahydrate; sodium borohydride is the reducing agent;

[0078] The molar ratio of the catalyst to sodium borohydride is 1:4-1:50, preferably 1:4-1:10;

[0079] The molar ratio of compound 9 to the catalyst is 1:1-1:6, preferably 1:1-1:1.5;

[0080] In the step (IV), the reaction solvent is dichloromethane.

[0081] In the step (V), the molar ratio of compound 11 to acrylonitrile is 1:1-1:1.5;

[0082] In the step (VI), the molar ratio of compound 12 to benzyl chloroformate is 1:1-2; the reaction solvent is anhydrous tetrahydrofuran, and the reaction temperature is room temperature.

[0083] In the step (VII), the catalyst is nickel chloride (NiCl2), nickel bromide trihydrate (NiBr2·3H2O), cobalt chloride hexahydrate (CoCl2·6H2O), nickel chloride hexahydrate (NiCl2·6H2O), preferably nickel chloride hexahydrate; sodium borohydride is the reducing agent;

[0084] The ratio of catalyst to sodium borohydride is 1:4-1:50, preferably 1:4-1:10;

[0085] The molar ratio of compound 13 to the catalyst is 1:1-1:6, preferably 1:1-1:1.5;

[0086] The reaction occurs at room temperature and pressure under nitrogen atmosphere.

[0087] In the step (IX), the molar ratio of compound 14 to boron tribromide is 1:6-10.

[0088] The present invention also provides derivatives N 1 ,N 4 ,N 12 -The synthesis method of tri(dihydrocaffeoyl)spermine, its reaction process is as follows:

[0089]

[0090] The synthetic method specifically comprises the following steps:

[0091] (1) Compound 13 is reduced to its cyano group using sodium borohydride in the presence of a catalyst, and then reacts with 2,5-dioxopyrrolidin-1-yl 3-(3,4-dimethoxyphenyl)propionate in the presence of N,N-diisopropylethylamine to produce compound 15;

[0092] (2) Compound 15 reacts with boron tribromide to obtain compound N 1 ,N 4 ,N 12 -Tri(dihydrocaffeoyl)spermine.

[0093] As described above,

[0094] In the step (1), the molar ratio of compound 13, N,N-diisopropylethylamine, and 2,5-dioxopyrrolidin-1-yl 3-(3,4-dimethoxyphenyl)propionate is 1:30-40:1-2.5;

[0095] The catalyst is nickel chloride (NiCl2), nickel bromide trihydrate (NiBr2·3H2O), cobalt chloride hexahydrate (CoCl2·6H2O), nickel chloride hexahydrate (NiCl2·6H2O), preferably nickel chloride hexahydrate, and sodium borohydride is the reducing agent;

[0096] The molar ratio of the catalyst to sodium borohydride is 1:4-1:50, preferably 1:4-1:10;

[0097] The molar ratio of compound 13 to the catalyst is 1:1-1:6, preferably 1:1-1:1.5.

[0098] In the step (2), the molar ratio of compound 15 to boron tribromide is 1:6-10.

[0099] The present invention also provides intermediates for preparing Kukoamine B and Kukoamine D and their derivatives, the structures of which are as follows:

[0100]

[0101]

[0102] Wherein, R2 is C1-C4 alkoxy, OH, H; R3 is C1-C4 alkoxy, OH, H;

[0103] Specifically, the structure of the intermediate compound is:

[0104]

[0105]

[0106] The present invention provides a novel method for synthesizing Kukoamine B, Kukoamine D, and their derivatives using economically available raw materials through simple steps, reducing reaction costs. In particular, the method innovatively utilizes a catalyst in conjunction with a sodium borohydride system to achieve in-situ reduction of the cyano group, eliminating the need for post-treatment for further coupling with a preformed activated ester to form an amide. This successfully establishes a "two-step, one-pot" continuous reaction system. This process enables safe operation under atmospheric pressure, improving reaction safety while also achieving good yields. Furthermore, the active esters used are prepared by efficient esterification of methoxydihydrocaffeic acid. This method not only achieves high yields but also effectively avoids the cumbersome step of freshly prepared acyl chlorides in traditional methods, further optimizing the synthesis process. The yields of Kukoamine B, Kukoamine D, and their derivatives produced by the present invention are all at least 20-30%. The method not only enables the efficient preparation of natural active polyamine compounds but also provides a scalable technical platform for their large-scale production, possessing significant industrial application value. DETAILED DESCRIPTION

[0107] Example 1 Synthesis of 2,5-dioxopyrrolidin-1-yl-3-(3,4-dimethoxyphenyl)propionate (AE)

[0108]

[0109] At 0 ° C, oxalyl chloride (15.24 g, 120 mmol) and dimethylformamide (DMF, 18 drops) were added to a solution of 3-(3,4-dimethoxyphenyl)propionic acid (A, 16.82 g, 80 mmol) in dichloromethane (280 mL), followed by stirring at 0 ° C for 3 hours. The reaction system was then warmed to room temperature, stirred for 3 hours, and the dichloromethane was removed by concentration to obtain an acetyl chloride intermediate. The crude intermediate was dissolved in tetrahydrofuran (THF, 160 mL) and cooled to 0 ° C, followed by the addition of 1-hydroxypyrrolidine-2,5-dione (10.12 g, 88 mmol) and triethylamine (TEA, 22.4 mL, 160 mmol) at 0 ° C. The reaction mixture was then warmed to room temperature, stirred overnight, and THF was removed by concentration to obtain a residue. The residue was treated with H2O (35 mL) and saturated NaHCO3 solution (90 mL) while stirring to produce a precipitate. The precipitate was collected by filtration and dried in air to give the target compound AE (24.23 g, 99%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ6.92(d,J=2.1Hz,1H),6.85(d,J=8.1Hz,1H),6.80(d,J=8.4Hz,1 H),3.75(s,3H),3.72(s,3H),2.98(t,J=7.4Hz,2H),2.89(t,J=7.4Hz,2H),2.82(s,4H).

[0110] Example 2 Synthesis of kukoamine B

[0111]

[0112] Reagents and conditions: (I) acrylonitrile, methanol, overnight, 99.8%; (II) triethylamine, benzyl chloroformate, tetrahydrofuran, 0°C to room temperature, overnight, 85%; (III) nickel chloride hexahydrate, sodium borohydride, methanol, 0°C, N,N-diisopropylethylamine, AE, room temperature, overnight, 74.6%; (IV) trifluoroacetic acid, dichloromethane, 0°C, 1 hour; room temperature, 4 hours, 99.9%; ( V) triethylamine, acrylonitrile, methanol, room temperature, overnight, 99.8%; (VI) 3-(3,4-dimethoxyphenyl)propionic acid, N,N-diisopropylethylamine, HATU, N,N-dimethylformamide, 0°C to room temperature, overnight, 73%; (VII) nickel chloride hexahydrate, sodium borohydride, methanol, 0°C, 99.7%; (IX) boron tribromide, dichloromethane, 0°C to room temperature, overnight, 73%. Step 1: Synthesis of tert-butyl (4-((2-cyanoethyl)amino)butyl)carbamate (2)

[0113]

[0114] Acrylonitrile (2.14 g, 40.4 mmol) was added to a solution of tert-butyl (4-aminobutyl) carbamate 1 (7.53 g, 40 mmol) in methanol (100 mL), and then stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated to give a colorless oily compound 2 (9.65 g, 99.8%). 1 H NMR (400MHz, CDCl3): δ1.43 (s, 9H), 1.48-1.55 (m, 4H), 2.51 (t, J = 6.6Hz, 2H), 2.66(t,J=6.4Hz,2H),2.91(t,J=6.6Hz,2H),3.08-3.15(m,2H),4.80(s,1H). 13 C NMR (CDCl3, 100MHz): δ18.96,27.50,28.02,28.69,40.60,45.27,48.97,79.31,118.98,156.29.LC-MS[M+H] + m / z 242.2 (calcd for C 12 H 23 N3O2, 241.18);

[0115] Step 2: Synthesis of benzyl (4-((tert-butyloxycarbonyl)amino)butyl)(2-cyanoethyl)carbamate (3)

[0116]

[0117] Triethylamine (TEA, 8.3 mL, 60 mmol) was added to a solution of compound 2 (7.2 g, 30 mmol) in anhydrous tetrahydrofuran (THF, 50 mL), and the mixture was cooled to 0°C. Benzyl chloroformate (CbzCl, 6.4 mL, 45 mmol) was added at 0°C, and then stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated to remove tetrahydrofuran. The residue was diluted with ethyl acetate (30 mL) and washed with 1N hydrochloric acid solution (10 mL x 3) and saturated brine (10 mL), then dried over anhydrous sodium sulfate and concentrated to obtain a small amount of solid. After adding n-hexane and cold methyl tert-butyl ether, a large amount of white solid precipitated from the system, and finally compound 3 (9.54 g, 85%) was obtained by filtration as a white solid. Mp: 61–62°C, 1 H NMR (400MHz, DMSO-d6): δ1.25-1.35(m,2H),1.37(s,9H),1.42-1.50(m,2H),2.74(t,J=6.6Hz,2H),2 .83-2.98(m,2H),3.19-3.29(m,2H),3.45-3.53(m,2H),5.09(s,2H),7.30-7.41(m,5H).LC-MS[M+H] + m / z 376.2 (calcdfor C 20 H 29 N3O4,375.22).

[0118] Step 3: Synthesis of benzyl(4-((tert-butyloxycarbonyl)amino)butyl)(3-(3-(3,4-dimethoxyphenyl)propionamido)propyl)carbamate (4)

[0119]

[0120] At 0 ° C and under a nitrogen atmosphere, nickel chloride hexahydrate (NiCl2·6H2O, 6.28 g, 26.4 mmol) was added to a methanol (200 mL) solution of compound 3 (9.04 g, 24 mmol), followed by the addition of sodium borohydride (NaBH4, 4.56 g, 120 mmol) in batches. The reaction was monitored by thin layer chromatography (TLC) and liquid chromatography-mass spectrometry (LCMS) until completion, and N, N-diisopropylethylamine (DIPEA, 8 mL, 48 mmol) and compound AE (11.04 g, 36 mmol) were added and stirred at room temperature overnight. The reaction solution was filtered and concentrated to remove methanol to obtain a residue, which was purified by column chromatography to obtain compound 4 (10.23 g, 74.6%) as a yellow oil. 1H NMR (400MHz, DMSO-d6): δ1.27-1.35(2H,m),1.37(9H,s),1.41-1.51(2H, m),1.52-1.71(2H,m),2.27-2.39(2H,m),2.67-2.79(2H,m),2.85-2.96( 2H,m),2.98-3.07(2H,m),3.11-3.23(4H,m),3.70(3H,s),3.72(3H,s),5 .06(2H,s),6.65-6.84(4H,m),7.26-7.40(5H,m),7.78(t,J=5.6Hz,2H). 13 C NMR (CDCl3, 100MHz): δ25.66,27.36,27.55,28.43,31.44,35.45,38.82,39.99,43.72,46.31,46.96,55.79,55.90,67.22,79.19 ,111.11,111.64,120.22,127.78,128.15,128.58,128.76,133.59,136.57,147.26,148.74,156.01,156.96,172.25; LC-MS[M+H] + m / z 572.3 (calcd for C 31 H 45 N3O7,571.33).

[0121] By changing the catalyst nickel chloride hexahydrate to NiCl2, NiBr2·3H2O, CoCl2·6H2O, and changing the amount of catalyst, sodium borohydride, and DIPEA, compound 4 was obtained with different yields. The results are shown in Table 1:

[0122] Table 1 Effects of different catalysts and the amount of catalyst, NaBH4 and base on the yield of compound 4

[0123]

[0124]

[0125] The results showed that the yields of compound 4 exceeded 30% when NiCl2, NiBr2, CoCl2·6H2O, and NiCl2·6H2O were used as catalysts, the molar ratio of catalyst to sodium borohydride was 1:4-1:50, the molar ratio of compound 3 to AE was 1:1-1:2, the molar ratio of compound 3 to catalyst was 1:0.2-1:1.1, and the molar ratio of compound 3 to DIPEA was 1:1-1:3. When NiCl2·6H2O was used as the catalyst, the molar ratio of NiCl2·6H2O to sodium borohydride was 1:4-1:50, the molar ratio of compound 3 to DIPEA was 1:1.5-3.0, the molar ratio of compound 3 to AE was 1:1-1:2, and the molar ratio of compound 3 to catalyst was 1:0.2-1.1, the yield of compound 4 exceeded 50%. When the molar ratio of NiCl2·6H2O to sodium borohydride is 1:4-1:10, especially 1:4-1:5, the molar ratio of compound 3 to AE is 1:1.5-1:2, and the molar ratio of compound 3 to DIPEA is 1:2.0-3.0, the yield of compound 4 can reach about 75% or more.

[0126] Step 4: Synthesis of benzyl(4-aminobutyl)(3-(3-(3,4-dimethoxyphenyl)propionamido)propyl)carbamate (5)

[0127]

[0128] Trifluoroacetic acid (8.3 mL, 112 mmol) was added to a solution of compound 4 (9.14 g, 16 mmol) in dichloromethane (50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, then at room temperature for 4 hours, and concentrated to give the crude product, compound 5 (9.2 g, 99.9%), as a trifluoroacetate salt, as a yellow oil. 1 H NMR (400MHz, DMSO-d6): δ1.42-1.56(4H,m),1.57-1.67(2H,m),2.27-2.38(2H,m),2.69-2.84(4H,m),2.98-3.08(2H,m),3.13- 3.24(4H,m),3.70(3H,s),3.71(3H,s),5.06(2H,s),6.66-6.84(3H,m),7.28-7.40(5H,m),7.74(2H,s),7.81(t,J=5.6Hz,1H). 13C NMR(DMSO-d6,100MHz): δ24.80,25.07,31.22,36.64,37.79,46.72,55.35,55.81,55.98,66.54,112.3 2,112.63,114.80,117.70,120.39,127.78,128.21,128.88,134.26,137.50,147.51,155.75,171.84; 19 F NMR(376MHz,CDCl3)δ-74.74.LC-MS[M+H] + m / z 472.2 (calcd for C 26 H 37 N3O5,471.22).

[0129] Step 5: Synthesis of benzyl(4-((2-cyanoethyl)amino)butyl)(3-(3-(3,4-dimethoxyphenyl)propionamido)propyl)carbamate (6)

[0130]

[0131] Acrylonitrile (0.7 g, 13.2 mmol) and triethylamine (TEA, 4.7 mL, 36 mmol) were added to a solution of compound 5 (6.83 g, 12 mmol) in methanol (MeOH, 35 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour and then at room temperature overnight. After completion of the reaction, the mixture was concentrated to give compound 6 (6.3 g, 99.8%) as a yellow oil. 1 HNMR (400MHz, DMSO-d6): δ1.39-1.53(4H,m),1.55-1.66(2H,m),2.27-2.36(2H,m),2.62-2.80(6H,m),2.87-3.06(4H,m) ,3.11-3.23(4H,m),3.70(3H,s),3.71(3H,s),5.06(2H,s),6.65-6.84(3H,m),7.27-7.39(5H,m),7.80(t,J=5.75Hz,1H). 13C NMR (100MHz, DMSO-d6): δ25.26,26.19,28.42,29.12,31.23,36.64,37.81,43.94,47.84,55.37,55.83,55.99,66.50,1 12.32,112.64,119.47,120.39,127.80,128.19,128.90,134.29,137.50,147.50,149.03,155.72,171.81; LC-MS[M+H] + m / z 525.3 (calcd for C 29 H 40 N4O5,524.30).

[0132] Step 6: Synthesis of benzyl(4-(N-(2-cyanoethyl)-3-(3,4-dimethoxyphenyl)propionamido)butyl)(3-(3-(3,4-dimethoxyphenyl)propionamido)propyl)carbamate (7)

[0133]

[0134] 3-(3,4-Dimethoxyphenyl)propionic acid (3.04 g, 14.5 mmol), HATU (5.5 g, 14.5 mmol) and N,N-diisopropylethylamine (DIPEA, 3.3 mL, 14.5 mmol) were dissolved in N,N-dimethylformamide (DMF, 15 mL) at 0°C. After 20 minutes, a solution of compound 6 (5.06 g, 9.67 mmol) in DMF (10 mL) was added dropwise. The reaction mixture was stirred at 0°C for 0.5 hours and then stirred at room temperature overnight. After the reaction was completed, water (20 mL) was added to the suspension and extracted with ethyl acetate (15 mL×3). The organic phase was washed with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography to give the target compound 7 (5.06 g, 73%) as a yellow oil. 1H NMR (400MHz, DMSO-d6): δ1.31-1.47(4H,m),1.53-1.64(2H,m),2.26-2.38(2H,m), 2.53-2.80(8H,m),2.98-3.07(2H,m),3.11-3.21(4H,m),3.22-3.32(2H,m),3.42-3 .58(2H,m),3.69(3H,s),3.70(3H,s),3.71(3H,s),3.73(3H,s),5.04(1H,s),5.07( 1H,s),6.65-6.75(2H,m),6.76-6.86(4H,m),7.26-7.39(5H,m),7.74-7.80(1H,m). 13 C NMR (100MHz, DMSO-d6): δ16.09,26.03,30.92,31.02,31.23,34.54,34.64,36.65,37.82,41. 84,42.80,44.72,46.74,47.72,55.37,55.81,55.83,55.97,56.03,66.49,112.31,112.36,1 12.63,112.85,112.92,119.60,120.38,120.56,120.61,127.79,128.18,128.86,134.25,13 4.32,137.60,147.52,147.57,149.05,149.10,155.72,171.77,171.82,172.14; LC-MS[M+Na] + m / z 739.5 (calcd for C 40 H 52 N4O8,716.38).

[0135] Step 7: Synthesis of N-(3-aminopropyl)-3-(3,4-dihydroxyphenyl)-N-(4-((3-(3-(3,4-dihydroxyphenyl)propionamido)propyl)amino)butyl)propionamide (8)

[0136]

[0137] At 0°C under a nitrogen atmosphere, nickel chloride hexahydrate (NiCl2·6H2O, 0.155 g, 0.65 mmol) was added to a solution of compound 7 (2.36 g, 3.3 mmol) in methanol (15 mL), followed by the addition of sodium borohydride (NaBH4, 1 g, 26.4 mmol) in portions. The reaction was monitored by thin layer chromatography (TLC) and liquid chromatography-mass spectrometry (LCMS) until completion, and the methanol was concentrated to obtain a crude product, compound 8 (2.4 g, 99.7%), as a yellow oil. 1 H NMR (400MHz, DMSO-d6): δ1.28-1.48(m,4H),1.52-1.66(m,2H),1.67-1.85(m,2H),2.28-2. 40(m,2H),2.51-2.63(m,2H),2.63-2.86(m,6H),2.96-3.08(m,2H),3.09-3.24(m,6H),3.25 -3.39(m,2H),3.69(s,3H),3.70(s,3H),3.71(s,3H),3.73(s,3H),5.05(s,1H),5.07(s,1H ),6.63-6.76(m,2H),6.76-6.89(m,4H),7.23-7.42(m,5H),7.88-7.96(m,1H),8.48(s,1H). 13 C NMR (100MHz, DMSO-d6): δ25.04,26.50,27.86,31.07,31.25,34.54,36.66,36.84,36 .97,37.80,42.65,44.82,46.80,47.32,55.80,55.85,55.96,56.01,66.49,112.31, 112.34,112.63,112.82,120.39,120.57,127.79,128.17,128.83,128.85,134.29,1 34.33,137.60,147.51,147.56,149.05,149.09,155.72,171.49,171.86.LC-MS[M+H] + m / z 721.5 (calcd for C 40 H 56 N4O8,720.41).

[0138] Step 8: Synthesis of benzyl(4-(N-(3-aminopropyl)-3-(3,4-dimethoxyphenyl)propionamido)butyl)(3-(3-(3,4-dimethoxyphenyl)propionamido)propyl)carbamate (kukoamine B)

[0139]

[0140] Boron tribromide (BBr3, 1.95 mL, 16.5 mmol) was slowly added to a solution of compound 8 (1.4 g, 2 mmol) in dichloromethane (12 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was concentrated to obtain a residue, which was purified by Biotage C18 (60 g) column chromatography to afford Kukoamine B (0.89 g, 73%) with a purity of 98% (as determined by liquid chromatography) as a white, foamy solid in the form of its hydrobromide salt. 1 H NMR (400MHz, DMSO-d6): δ1.38-1.64(m,4H),1.65-1.87(m,4H),2.31(t,J=7.7Hz 2H),2.52-2.58(m,2H),2.58-2.69(m,4H),2.70-2.95(m,6H),3.11(q,J=6.7Hz,2H),3.18-3.28(m,2H),3.29-3.40(m,2H),6 .38-6.50(m,2H),6.55-6.68(m,4H),7.77(s,1H),7.82(s,1H),8.03(t,J=5.9Hz,1H),8.43(s,2H),8.65(s,2H).LC-MS[M+H] + m / z 531.0 (calcd for C 28 H 42 N4O6,530.31).

[0141] Example 3 Synthesis of kukoamine D

[0142]

[0143] Reagents and conditions: (I) Acrylonitrile, methanol, overnight, 99.8%; (II) N,N-diisopropylethylamine, HATU, 3-(3,4-dimethoxyphenyl)propionic acid, 0°C, 0.5 hours, room temperature, overnight, 99.8%; (III) NiCl2·6H2O, sodium borohydride, methanol, 0°C, N,N-diisopropylethylamine, room temperature, overnight, 78%; (IV) Hydrogen chloride, CH2Cl2, 0℃, 4 hours; room temperature, 1 hour, 99.8%; (V) N,N-diisopropylethylamine, acrylonitrile, methanol, room temperature, overnight, 71%; (VI) N,N-diisopropylethylamine, CbzCl, 0℃ to room temperature, overnight, 75%; (VII) NiCl2·6H2O, sodium borohydride, methanol, 0℃; 91% (IX) BBr3, CH2Cl2, 0℃ to room temperature, overnight, 86.4%.

[0144] Step 1: Synthesis of tert-butyl (4-((2-cyanoethyl)amino)butyl)carbamate (2)

[0145] Same as step 1 in Example 2.

[0146] Step 2: Synthesis of tert-butyl (4-(N-(2-cyanoethyl)-3-(3,4-dimethoxyphenyl)propionamido)butyl)carbamate (9)

[0147]

[0148] N,N-diisopropylethylamine (13.24 mL, 78 mmol) and HATU (16.30 g, 42.9 mmol) were added to a solution of 3-(3,4-dimethoxyphenyl)propionic acid (8.6 g, 41 mmol) in anhydrous DMF (80 mL). After stirring at 0°C for 20 minutes, compound 2 (9.4 g, 39 mmol) was dissolved in 10 mL of DMF and slowly added dropwise. The reaction mixture was stirred at 0°C for 0.5 hours, then gradually warmed to room temperature and stirred overnight. The mixture was concentrated and diluted with water (100 mL), extracted with ethyl acetate (2 x 120 mL), washed three times with water (30 mL x 3), and washed with saturated brine (40 mL). The organic phase was dried over anhydrous sodium sulfate and filtered to obtain crude compound 9 (17.6 g, 99.8%) as a yellow oil. 1H NMR (400MHz, DMSO-d6): δ1.23-1.34(m,2H),1.36(s,9H),1.39-1.52(m,2H) ),2.58(t,J=7.4Hz,1H),2.64-2.70(m,2H),2.71-2.80(m,3H),2.86-2.97( m,2H),3.21-3.30(m,2H),3.48(t,J=6.7Hz,1H),3.55(t,J=6.7Hz,1H),3. 70(s,3H),3.73(s,3H),6.67-6.75(m,1H),6.79-6.86(m,2H).LC-MS[M+Na] + m / z456.2 (calcd for C 23 H 35 N3O5,433.26).

[0149] Step 3: Synthesis of tert-butyl (4-(3-(3,4-dimethoxyphenyl)-N-(3-(3-(3,4-dimethoxyphenyl)propionamido)propyl)propionamido)butyl)carbamate (10)

[0150]

[0151] NiCl2·6H2O (8.33 g, 35 mmol) was added to a solution of compound 9 (15.16 g, 35 mmol) in methanol (100 mL). Sodium borohydride (9.31 g, 245 mmol) was added portionwise at 0°C under a nitrogen atmosphere. The reaction was monitored by TLC and LCMS. After completion, N,N-diisopropylethylamine (DIPEA, 11.9 mL, 70 mmol) and compound AE (14.95 g, 49 mmol) were added, followed by stirring at room temperature overnight. The reaction solution was filtered and concentrated to remove methanol to obtain a residue, which was purified by column chromatography to obtain compound 10 (17.18 g, 78%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6): δ1.22-1.35(m,4H),1.36(s,9H),1.49-1.63(m,2H),2.25-2.38(m,2H),2.52-2.60(m,2H),2.64-2.81(m,4H),2.8 4-2.93(m,2H),2.94-3.06(m,2H),3.11-3.22(m,4H),3.70(s,6H),3.72(s,6H),6.64-6.72(m,2H),6.75-6.83(m,4H),7.70-7.84(m,1H). 13C NMR(DMSO-d6,100MHz): δ24.73,25.86,26.78,28.23,28.26,30.64,30.7 7,34.18,35.97,36.27,37.35,37.40,44.79,46.93,55.34,55.36,55.49 ,55.93,77.39,111.79,111.83,111.88,112.14,112.36,119.86,120.07 ,133.76, 133.94,147.02,148.56,155.61,170.81,171.21; LC-MS[M+Na] + m / z 652.4 (calcd for C 34 H 51 N3O8,629.37).

[0152] Step 4: Synthesis of N-(4-aminobutyl)-3-(3,4-dimethoxyphenyl)-N-(3-(3-(3,4-dimethoxyphenyl)propionamido)propyl)propionamide hydrochloride (11)

[0153]

[0154] Hydrogen chloride (4.0 M in 1,4-dioxane, 10 mL, 40.5 mmol) was added to compound 10 (14.75 g,

[0155] The reaction mixture was stirred at 0°C for 4 hours, then gradually warmed to room temperature and stirred for 1 hour. The dichloromethane was removed by concentration and replaced with dichloromethane several times to remove the residual dioxane solvent, yielding compound 11 (19.2 g, 99.8%) as a white foamy solid. 1 H NMR (400MHz, DMSO-d6): δ1.32-1.53(m,4H),1.54-1.67(m,2H),2.27-2.39(m,2H),2.54-2.63(m,2H),2.67-2.82(m,5H),2.93-3.09(m,

[0156] 2H),3.15-3.27(m,3H),3.53-3.62(m,2H),3.71(s,12H),6.63-6.92(m,6H),7.85(s,1H),7.94(s,

[0157] 2H). 13C NMR(DMSO-d6,100MHz): δ24.35,24.42,25.57,30.62,30.78,34.17,36.00,37.34,38.53,43.05,44.23,46.74,55.38,55. 42,55.52,55.58,111.87,112.17,112.45,119.90,120.06,133.78,133.96,147.03,148.56,171.07,171.48; LC-MS[M+H] + m / z 530.3 (calcd for C 29 H 43 N3O6,529.32).

[0158] Step 5: Synthesis of N-(4-((2-cyanoethyl)amino)butyl)-3-(3,4-dimethoxyphenyl)-N-(3-(3-(3,4-dimethoxyphenyl)propionamido)propyl)propionamide (12)

[0159]

[0160] N,N-diisopropylethylamine (DIPEA, 3 mL, 17.7 mmol) and acrylonitrile (0.31 g, 5.9 mmol) were added to a solution of compound 11 (3.42 g, 5.9 mmol) in methanol (20 mL), and then stirred at room temperature overnight. The methanol was concentrated to remove the residue, which was dissolved in ethyl acetate (20 mL) and washed with hydrochloric acid solution (2 M; 10 mL × 2). The hydrochloric acid solution was collected and neutralized with saturated sodium bicarbonate solution to pH = 8, then extracted with chloroform (15 mL × 2) and washed with water (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 12 (2.43 g, 71%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6): δ1.25-1.38(m,2H),1.38-1.48(m,2H),1.50-1.63(m,2H),2.26-2.37(m,2H),2.42-2.49(m,4H),2.68-2.79(m,6H),2.9 5-3.07(m,2H),3.13-3.24(4H,m),3.69(s,3H),3.70(s,3H),3.71(s,3H ),3.72(s,3H),6.63-6.75(m,2H),6.76-6.87(m,4H),7.68-7.85(m,1H). 13CNMR(DMSO-d6,100MHz): δ17.75,25.17,26.52,26.77,30.65,30.77,34.16,36.29,37.34,44.70,44.86,48.06,48.26,55.36,55.39, 55.51,55.55,111.85,111.90,112.20,112.44,119.98,119.91,120.07,133.83,133.97,147.06,148.59,171.07,171.43; LC-MS[M+H] + m / z 583.4 (calcd for C 32 H 46 N4O6,582.34).

[0161] Step 6: Synthesis of benzyl(3-aminopropyl)(5-(3-(3,4-dimethoxyphenyl)-N-(3-(3-(3,4-dimethoxyphenyl)propionamido)propyl)propionamido)pentyl)carbamate (13)

[0162]

[0163] N,N-Diisopropylethylamine (DIPEA, 1.36 mL, 8 mmol) was added to a solution of compound 12 (2.33 g, 4 mmol) in anhydrous tetrahydrofuran (THF, 10 mL) and cooled to 0°C. Benzyl chloroformate (CbzCl, 1.03 g, 6 mmol) was added at 0°C, and the mixture was stirred at room temperature overnight. The tetrahydrofuran was removed by concentration to obtain a residue, which was purified by column chromatography to obtain compound 13 (2.16 g, 75%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6): δ1.31-1.48(m,4H),1.49-1.66(m,2H),2.27-2.39(m,2H) ,2.51-2.58(m,2H),2.66-2.83(m,6H),2.93-3.07(m,2H),3.08-3.23(m,4H),3.2 3-3.31(m,2H),3.43-3.53(m,2H),3.69(s,6H),3.72(s,6H),5.07(s,1H),5.09(s ,1H),6.63-6.74(m,2H),6.75-6.87(m,4H),7.25-7.47(m,5H),7.71-7.86(m,1H). 13C NMR(CDCl3,DMSO-d6): δ16.80,24.49,27.66,30.60,30.79,34.17,36.00,36.29,37.42 ,42.95,44.77,46.55,46.90,55.34,55.42,55.49,55.52,66.45,111.81,111.86,112. 16,112.40,119.05,119.88,119.91,120.05,120.09,127.53,127.85,128.38,128.40, 133.78,133.83,133.96,136.71,147.04,148.58,155.29,170.91,171.24; LC-MS[M+H] + m / z717.3 (calcd for C 40 H 52 N4O8,716.38).

[0164] Step 7: Synthesis of benzyl(3-aminopropyl)[4-(3-(3,4-dimethoxyphenyl)-N-[3-(3-(3,4-dimethoxyphenyl)propionamido]propyl)propionamido)butyl]carbamate (14)

[0165]

[0166] NiCl2·6H2O (0.68 g, 2.64 mmol) was added to a methanol solution (10 mL) of compound 13 (1.72 g, 2.4 mmol) at 0°C under a nitrogen atmosphere, followed by the addition of sodium borohydride (NaBH4, 0.91 g, 24 mmol) in portions. After the reaction was completed as monitored by TLC and LCMS, the reaction solution was concentrated to remove methanol to obtain a residue, which was purified by flash preparative chromatography (Biotage) to obtain the formate salt form of compound 14 (1.67 g, 91% yield). 1H NMR (400MHz, DMSO-d6): δ1.28-1.47(m,4H),1.47-1.61(m,2H),1.64-1.92(m,2H),2.26 -2.38(m,2H),2.43-2.50(m,2H),2.62-2.81(m,6H),2.94-3.06(m,2H),3.07-3.23(m,6 H),3.23-3.35(m,2H),3.67(s,3H),3.69(s,3H),3.71(s,3H),3.72(s,3H),5.06(d,J=1 1.0Hz,2H),6.63-6.73(m,2H),6.74-6.88(m,4H),7.25-7.42(m,5H),7.78-7.98(m,1H). 13 C NMR(CDCl3,DMSO-d6): δ24.57,27.64,30.58,30.76,34.10,35.98,36.28,3 7.39,43.00,44.82,46.93,55.33,55.36,55.48,55.53,66.10,111.80,111 .85,112.13,112.38,119.86,120.04,127.39,127.73,128.37,128.39,133 .77,133.91,137.03,147.02,148.56,155.30,170.88,171.43; LC-MS[M+H] + m / z 721.3 (calcd for C 40 H 56 N4O8,720.41).

[0167] Step 8: Synthesis of N-(4-((3-aminopropyl)amino)butyl)-3-(3,4-dihydroxyphenyl)-N-(3-(3-(3,4-dihydroxyphenyl)propionamido)propyl)propionamide (kukoamine D)

[0168]

[0169] BBr (1.61 mL, 16.5 mmol) was slowly added dropwise to a dichloromethane solution (CH Cl, 10 mL) of compound 14 (1.19 g, 1.65 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature (RT) and stirred overnight. The reaction mixture was then cooled to 0°C and quenched with pre-cooled methanol (15 mL) dropwise. The mixture was stirred at room temperature for 30 minutes and concentrated to obtain a residue. The residue was purified on a Biotage C18 column (60 g) to obtain the target product, Kukoamine D bromate (0.87 g, 86.4% yield), with a purity of 98% (determined by liquid chromatography) as a white powder. 1 H NMR (400MHz, DMSO-d6): δ1.41-1.65(m,6H),1.82-1.99(m,2H),2.21-2.32(m,2H),2.41-2.49(m,2H),2.56-2.68(m,4H),2.74-2.9 7(m,6H),2.97-3.07(m,2H),3.10-3.27(m,4H),6.37-6.48(m,2H),6.54-6.66(m,4H),7.80(t,J=5.6Hz,1H),7.87(t,J=5.5Hz,1H). 13 C NMR(DMSO-d6,100MHz): δ24.00,25.84,27.65,30.42,31.60,34.30,36.05,36.40,37.50,43.10,44.13,44.91,46.79,115. 41,115.66,115.84,115.87,118.71,118.83,132.11,132.18,143.27,143.32,144.95,144.99,171.21,171.58.LC-MS[M+H] + m / z 531.3 (calcd for C 28 H 42 N4O6,530.31).

[0170] Example 4 N 1 ,N 4 ,N 12 -Synthesis of tri(dihydrocaffeoyl)spermine

[0171] Step 1: Synthesis of benzyl[4-(3-(3,4-dimethoxyphenyl)-N-[3-(3-(3,4-dimethoxyphenyl)propionamido]propyl)propionamido)butyl][3-(3-(3,4-dimethoxyphenyl)propionamido)propyl]carbamate (15)

[0172]

[0173] Nickel chloride hexahydrate (NiCl2·6H2O, 0.48 g, 2 mmol) was added to a methanol solution (20 mL) of compound 13 (1.43 g, 2 mmol) at 0°C under a nitrogen atmosphere, followed by the addition of sodium borohydride (NaBH4, 0.46 g, 12 mmol) in portions. After the reaction was completed as monitored by TLC and LCMS, N,N-diisopropylethylamine (DIPEA, 11.9 mL, 70 mmol) and compound AE (0.92 g, 3 mmol) were added to the system and stirred at room temperature overnight. The reaction solution was concentrated to remove methanol to obtain a residue, which was purified by column chromatography to obtain the target product, compound 15 (1.09 g, 60% yield), as a foamy solid. 1 H NMR (400MHz, DMSO-d6): δ1.28-1.43(m,4H),1.48-1.64(m,4H),2.21-2.39(m,4H),2. 42-2.49(m,2H),2.64-2.81(m,6H),2.92-3.06(m,4H),3.07-3.24(m,8H),3(2H,m),3. 11-3.22(4H,m),3.68(s,6H),3.70(s,6H),3.71(s,6H),5.03(s,1H),5.05(s,1H),6.5 6(s,2H),6.61-6.74(m,3H),6.74-6.86(m,6H),7.23-7.40(m,5H),7.71-7.89(m,2H). 13 C NMR(DMSO-d6,100MHz): δ24.58,27.66,28.73,30.60,30.76,34.14 36.00,36.18,37.36,37.41,42.98,44.80,46.93,54.91,55.35,55.51,65.99,111.82,111.85,112.15,112.39,119.88,119.91, 120.05,127.32,128.37,128.40,133.77,133.82,133.95,137.12,147.04,148.57,155.24,170.90,171.33,171.44; LC-MS[M+Na] + m / z 935.5 (calcd for C 51 H 68 N4O 11 ,912.49).

[0174] Step 2: Synthesis of 3-(3,4-dihydroxyphenyl)-N-(3-(3-(3,4-dihydroxyphenyl)propionamido)propyl)-N-(4-((3-(3-(3,4-dihydroxyphenyl)propionamido)propyl)amino)butyl)propionamide

[0175]

[0176] BBr3 (1.61 mL, 16.5 mmol) was slowly added to a solution of compound 15 (1.19 g, 1.65 mmol) in CH2Cl2 (10 mL) at 0°C. The reaction mixture was warmed to room temperature (RT) and stirred overnight. After the reaction was completed, the solvent was concentrated to obtain a residue. The residue was purified by Biotage C18 (60 g) column chromatography to obtain compound N 1 ,N 4 ,N 12 -Tri(dihydrocaffeoyl)spermine (0.87 g, 76%), purity 97% (determined by liquid chromatography), white foamy solid. 1 H NMR (400MHz, DMSO-d6): δ1.39-1.53(m,4H),1.53-1.63(m,2H),1.63-1.76(m,2H),2 .20-2.36(m,4H),2.40-2.49(m,2H),2.56-2.70(m,6H),2.72-2.81(m,2H),2.82-2.9 1(m,2H),2.94-3.05(m,2H),3.06-3.14(m,2H),3.14-3.29(m,4H),6.36-6.49(m,3H) ,6.52-6.65(m,6H),7.76-7.91(m,1H),8.01(s,1H),8.28(s,2H),8.61-8.81(m,6H). 13 C NMR(DMSO-d6,100MHz): δ24.42,26.11,27.66,28.78,30.41,30.49,30.55,34.29,35.47,36.05,37.36,37.49,44.64,44.89,46.6 8,115.41,115.66,115.85,118.70,118.82,131.98,132.11,132.16,143.25,143.30,144.97,171.21,172.56,172.16.LC-MS[M+H] + m / z 695.3 (calcd for C 37 H 50 N4O9,694.36).

Claims

1. A method for synthesizing Kukoamine B and Kukoamine D and their derivatives, characterized in that: The general structural formula of Kukoamine B, Kukoamine D and their derivatives are as follows: in, R1 is Cbz, H; R2 is C1-C4 alkoxy, OH, H; R3 is C1-C4 alkoxy, OH, H; R4 is CN, CH2NH2; Furthermore, R2 and R3 are both C1-C4 alkoxy or both OH; The reaction process is as follows:

2. The method for synthesizing Kukoamine B and Kukoamine D and their derivatives according to claim 1, characterized in that: The process I comprises the following steps: (I) tert-Butyl (4-aminobutyl) carbamate 1 undergoes Michael addition reaction with acrylonitrile in an organic solvent to produce compound 2; (II) Compound 2 is reacted with benzyl chloroformate in an organic solvent to obtain compound 3; (III) Compound 3 is first reduced to its cyano group using sodium borohydride in the presence of a catalyst, and then reacts with 2,5-dioxopyrrolidin-1-yl 3-(3,4-dimethoxyphenyl)propionate under alkaline conditions of N,N-diisopropylethylamine to produce compound 4; (IV) Compound 4 reacts in a hydrochloric acid dioxane solution or a trifluoroacetic acid solution to produce compound 5; (V) Compound 5 reacts with acrylonitrile under alkaline conditions to produce compound 6; (VI) Compound 6 undergoes amidation reaction with 3-(3,4-dimethoxyphenyl)propionic acid in an organic solvent in the presence of HATU and N,N-diisopropylethylamine to obtain compound 7; (VII) Compound 7 is subjected to a cyano reduction reaction using sodium borohydride in the presence of a catalyst to produce compound 8; (IX) Compound 8 reacts with boron tribromide to obtain compound Kukoamine B; The process II comprises the following steps: (I) tert-Butyl (4-aminobutyl) carbamate 1 undergoes Michael addition reaction with acrylonitrile in an organic solvent to produce compound 2; (II) Compound 2 reacts with 3-(3,4-dimethoxyphenyl)propionic acid in an organic solvent in the presence of HATU and N,N-diisopropylethylamine to obtain compound 9; (III) Compound 9 is first reduced to its cyano group using sodium borohydride in the presence of a catalyst, and then reacts with 2,5-dioxopyrrolidin-1-yl 3-(3,4-dimethoxyphenyl)propionate in the presence of N,N-diisopropylethylamine to produce compound 10; (IV) Compound 10 reacts in a hydrochloric acid dioxane solution or a trifluoroacetic acid solution to produce compound 11; (V) Compound 11 reacts with acrylonitrile in the presence of N,N-diisopropylethylamine to produce compound 12; (VI) Compound 12 reacts with benzyl chloroformate in the presence of N,N-diisopropylethylamine to produce compound 13; (VII) Compound 13 is subjected to cyanide reduction reaction using sodium borohydride in the presence of a catalyst to produce compound 14; (IX) Compound 14 reacts with boron tribromide to obtain compound Kukoamine D; The process III comprises the following steps: (1) Compound 13 is reduced to its cyano group using sodium borohydride in the presence of a catalyst, and then reacts with 2,5-dioxopyrrolidin-1-yl 3-(3,4-dimethoxyphenyl)propionate in the presence of N,N-diisopropylethylamine to produce compound 15; (2) Compound 15 reacts with boron tribromide to obtain compound N 1 ,N 4 ,N 12 -Tri(dihydrocaffeoyl)spermine.

3. The method for synthesizing Kukoamine B and Kukoamine D and their derivatives according to claim 2, characterized in that: The structures of Kukoamine B and Kukoamine D and their derivatives are as follows:

4. The method for synthesizing Kukoamine B and Kukoamine D and their derivatives according to claim 3, characterized in that: The reaction process is:

5. The method for synthesizing Kukoamine B and Kukoamine D and their derivatives according to claim 1, 2 or 4, characterized in that: In step (III) or step (VII) of process I or II, or step (1) of process III, the catalyst is nickel chloride, nickel bromide trihydrate, cobalt chloride hexahydrate, or nickel chloride hexahydrate, preferably nickel chloride hexahydrate; sodium borohydride is the reducing agent; and the molar ratio of the catalyst to sodium borohydride is 1:4-1:

50.

6. The method for synthesizing Kukoamine B and Kukoamine D and their derivatives according to claim 5, characterized in that: In the process I or II, the molar ratio of compound 3 or compound 9 in step (III), compound 13 in step (VII) and the catalyst is 1:1-1:6; the molar ratio of the catalyst in step (VII) to compound 7 is 1:1-1:6; in the step (III) or step (VII), the molar ratio of compound 3 or compound 9, N,N-diisopropylethylamine, and 2,5-dioxopyrrolidin-1-yl 3-(3,4-dimethoxyphenyl)propionate is: 1:1-2:1-2.

5.

7. The method for synthesizing Kukoamine B and Kukoamine D and their derivatives according to claim 1, 2 or 4, characterized in that: In step (1) of process III, the molar ratio of compound 13, N,N-diisopropylethylamine, and 2,5-dioxopyrrolidin-1-yl 3-(3,4-dimethoxyphenyl)propionate is 1:30-40:1-2.5; and the molar ratio of compound 13 to nickel chloride hexahydrate is 1:1-1:

6.

8. Use of the synthesis method according to any one of claims 1 to 7 in the preparation of Kukoamine B and Kukoamine D and their derivatives.

9. The intermediates for preparing Kukoamine B and Kukoamine D and their derivatives as follows: in, R2 is C1-C4 alkoxy, OH, H; R3 is C1-C4 alkoxy, OH, H; preferably:

10. Use of the intermediate according to claim 9 in the preparation of Kukoamine B, Kukoamine D and their derivatives.

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