Intermediates of polyamine derivatives, their preparation methods and uses

Abstract

An intermediate for polyamine derivatives, its preparation method, and its uses are disclosed. This intermediate is easy to prepare, has high purity, and when used in the preparation of polyamine derivatives, yields products with high purity. The process is simple, which is beneficial for improving the purity and yield of polyamine derivatives, simplifying product purification procedures, and thus improving the industrial production of polyamine derivatives and their pharmaceutical salts. A method for preparing polyamine derivatives is also provided, which is simple to operate and yields products with high purity. The above method has very promising applications in the chemical and pharmaceutical fields.

Description

Technical Field

[0001] This invention relates to the field of chemical and pharmaceutical technology, specifically to an intermediate of a polyamine derivative, its preparation method, and its uses. Background Technology

[0002] Systemic inflammatory response syndrome (SIRS) and autoimmune disorders, such as sepsis and autoimmune diseases, are two types of diseases caused by an excessive immune response of the body. Currently, there are still no effective treatments, making targeted prevention and treatment a focus of clinical attention. Sepsis, in particular, refers to systemic inflammatory response syndrome (SIRS) caused by infection. Septic shock is a severe stage of sepsis and is one of the leading causes of death in ICU patients.

[0003] Studies show that the mechanism of sepsis involves pathogen-associated molecular patterns (PAMPs) released by pathogens such as bacteria, viruses, and fungi being recognized by pattern recognition receptors (PRRs) of the host's innate immune system. This mediates the activation of inflammatory cells, thereby triggering a systemic excessive inflammatory response. Epidemiological surveys show that the PAMP molecules that cause sepsis mainly include bacterial lipopolysaccharide (LPS), bacterial genomic DNA (CpG DNA), peptidoglycan (PGN), lipoteichoic acid (LTA), viral RNA, and yeast polysaccharides.

[0004] Chinese invention patent CN105348137B discloses a pharmaceutical salt of a polyamine derivative, its preparation method and uses. This pharmaceutical salt of a polyamine derivative can be used to prepare drugs for treating sepsis. However, the purity of intermediates and final products is not considered in its preparation process, and its preparation process needs further improvement.

[0005] Therefore, it is essential to develop a method suitable for industrial application that can produce high-purity polyamine derivatives and their intermediates. Summary of the Invention

[0006] To overcome the shortcomings of the prior art, the present invention provides a method for preparing polyamine derivatives and their intermediates, and their uses.

[0007] In a first aspect of the present invention, a compound of formula I is provided having the following structure:

[0008]

[0009] in,

[0010] m1 is selected from integers from 1 to 6 (e.g., 1, 2, 3, 4, 5, 6);

[0011] R 1 and R 2 Independently selected from: OH, alkoxy;

[0012] G is selected from O and S;

[0013] R 3 Selected from: Where m2 is selected from integers from 1 to 6 (e.g., 1, 2, 3, 4, 5, 6), R 4 and R 5 It is independently selected from alkyl groups.

[0014] Specifically, m1 is selected from integers from 1 to 3, such as 1, 2, 3, and especially 2.

[0015] Specifically, m2 is selected from integers from 1 to 3, such as 1, 2, 3, especially 2.

[0016] Specifically, R 1 R 2 Independently selected from: OH, C1-C6 alkoxy groups; more specifically, R 1 R 2 Independently selected from: OH, C1-C3 alkoxy groups; more specifically, R 1 R 2 Independently selected from: OH, methoxy, ethoxy.

[0017] Specifically, the compound shown in Formula I can have the following structure:

[0018] Specifically, R 4 and R 5 It is independently selected from C1-C6 alkyl groups, especially C1-C3 alkyl groups, such as methyl, ethyl, and n-propyl.

[0019] In some embodiments of the present invention, R 3 Selected from:

[0020] In some embodiments of the present invention, the compound represented by Formula I has the following structure:

[0021]

[0022] In a second aspect of the invention, a method for preparing a compound of formula I is provided, comprising a compound of formula II and R. 3-GH undergoes the reaction process.

[0023]

[0024] Where Z is a halogen, especially chlorine; and m1 and R 1 -R 2 As defined in the compound shown in Formula I above;

[0025] The R 3 In -GH, G and R 3 As defined in the compound shown in Formula I above.

[0026] Specifically, the reaction is carried out under a protective gas, which can be an inert gas, such as nitrogen or argon, preferably nitrogen.

[0027] Specifically, the reaction temperature is between 15 and 35°C (e.g., 15, 16, 18, 20, 22, 24, 25, 26, 28, 30, 32, 34, 35°C), especially 20-30°C.

[0028] Specifically, the reaction time can be 1-6 hours (e.g., 1, 2, 3, 4, 5, 6 hours), especially 2-4 hours.

[0029] Specifically, the reaction is carried out in a solvent selected from: dichloromethane, chloroform, ethyl acetate, n-hexane, cyclohexane, methyl tert-butyl ether, especially dichloromethane.

[0030] Specifically, the reaction system also includes an acid-binding agent, such as an organic weak base or an inorganic weak base, which can be selected from pyridine, triethylamine, N,N-diisopropylethylamine, alkali metal acetate (such as sodium acetate) and / or alkali metal carbonate (such as sodium carbonate, potassium carbonate), preferably triethylamine.

[0031] Specifically, the preparation method also includes a step of purifying the reaction product.

[0032] Specifically, the purification steps include one or more of the following: washing, concentration, crystallization, filtration, and drying.

[0033] Specifically, the preparation method includes: under a protective gas, R... 3 -GH is mixed with a solvent, and an acid-binding agent is added dropwise. During the dropwise addition, the compound shown in Formula II is added, and the reaction proceeds.

[0034] After the reaction is complete, the reaction product is purified.

[0035] Specifically, the acid-binding agent is added dropwise at -10 to 10°C (e.g., -10, -8, -6, -5, -4, -2, 0, 2, 4, 5, 6, 8, 10°C), especially at -5 to 5°C.

[0036] In a third aspect of the invention, a method for preparing the compound represented by Formula III is provided.

[0037]

[0038] in,

[0039] R1-R 10 Independently selected from: H, OH, alkoxy, aryloxy, arylalkoxy;

[0040] R 11 H, amino protecting group or Among them, R 11 'For -CN, -CH2-NH2 or -CH2-NH-R 11 "R" 11 " is an amino protecting group;

[0041] R 12 H, amino protecting group or Among them, R 12 'For -CN, -CH2-NH2 or -CH2-NH-R 12 "R" 12 " is an amino protecting group;

[0042] R 13 -CN, -CH2-NH2 or -CH2-NH-R 13 ', R 13 ' is an amino protecting group;

[0043] n1-n7 are independently selected from integers from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10);

[0044] n' is 0 or 1;

[0045] The preparation method includes step (a): reacting the compound shown in formula IV with the compound shown in formula V and / or the compound shown in formula VI.

[0046]

[0047] Among them, R 11a H, amino protecting group or

[0048] R 12a H, amino protecting group or

[0049] X and Y are independently selected from O and S;

[0050] R 14 and R 15 Selected independently Where n8 is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, 6), R 16 and R 17 Independently selected from alkyl groups;

[0051] And n1-n7, n' and R1-R 10 As defined in the compound shown in Formula III.

[0052] Specifically, n8 is an integer from 1 to 3, such as 1, 2, or 3, especially 2.

[0053] Specifically, R 16 and R 17 It is independently selected from C1-C6 alkyl groups, especially C1-C3 alkyl groups, such as methyl, ethyl, and n-propyl.

[0054] In some embodiments of the present invention, R 14 and R 15 Selected independently from:

[0055] In some embodiments of the present invention, R 11a for

[0056] In some embodiments of the present invention, R 12a It is an amino protecting group.

[0057] Specifically, the above reaction is carried out under a protective gas, which can be an inert gas, such as nitrogen or argon, preferably nitrogen.

[0058] Specifically, the temperature of the above reaction is 50-70℃ (e.g., 50, 52, 54, 55, 56, 58, 60, 62, 64, 65, 66, 68, 70℃), especially 55-65℃.

[0059] Specifically, the reaction time is 6-60 hours (e.g., 6, 12, 24, 30, 36, 40, 42, 48, 54, 60 hours), especially 40-48 hours.

[0060] Specifically, the above reaction is carried out in a solvent, which can be selected from: ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, toluene, xylene, chlorobenzene, dioxane, etc. In particular, the solvent is ethyl acetate, toluene or dioxane, preferably ethyl acetate.

[0061] Specifically, the preparation method also includes a step of purifying the reaction product.

[0062] Specifically, the purification step may include washing the reaction product, and the washing solvent may be water.

[0063] Specifically, the purification step may also include concentrating the washed reaction product.

[0064] More specifically, the preparation method includes: mixing the compound shown in Formula IV with a reaction solvent under a protective gas, heating, adding the compound shown in Formula V and / or the compound shown in Formula VI, and reacting;

[0065] After the reaction is complete, the reaction product is purified.

[0066] Specifically, n1 is an integer from 1 to 5, such as an integer from 1 to 3, such as 2.

[0067] Specifically, n2 is an integer from 0 to 5, such as an integer from 1 to 3, such as 2.

[0068] Specifically, n3 is an integer from 0 to 5, such as an integer from 1 to 3, such as 2.

[0069] Specifically, n4 is an integer from 1 to 5, such as an integer from 1 to 3, such as 2.

[0070] Specifically, n5 is an integer from 0 to 5, such as an integer from 1 to 3, such as 2.

[0071] Specifically, n6 is an integer from 0 to 5, such as an integer from 1 to 3, such as 2.

[0072] Specifically, n7 is an integer from 0 to 5, such as an integer from 1 to 3, such as 2.

[0073] In some embodiments of the present invention, n' is 1.

[0074] Specifically, the compound shown in Formula IV has the following structure:

[0075]

[0076]

[0077] Among them, R 11 "' and R 12 "Independently selected from amino protecting groups. Specifically, the compound shown in Formula V has the following structure:"

[0078]

[0079] Specifically, the compound shown in Formula VI has the following structure:

[0080]

[0081]

[0082] Specifically, R1 is H.

[0083] Specifically, R4 is H.

[0084] Specifically, R5 is H.

[0085] Specifically, R6 is H.

[0086] Specifically, R9 is H.

[0087] Specifically, R 10 For H.

[0088] Specifically, R2, R3, R7, and R8 are independently selected from: H, OH, alkoxy, aryloxy, and arylalkoxy; more specifically, R2, R3, R7, and R8 are independently selected from: H, OH, C1-C6 alkoxy, C6-C 12 Aryloxy group, C7-C 12 Arylalkoxy; more specifically, R2, R3, R7, R8 are independently selected from: H, OH, C1-C6 alkoxy; even more specifically, R2, R3, R7, R8 are independently selected from: OH, methoxy, ethoxy.

[0089] Specifically, R2 and R3 are the same, and / or R7 and R8 are the same; preferably, R2, R3, R7, and R8 are all the same.

[0090] In some embodiments of the present invention, the compound shown in Formula V has the same structure as the compound shown in Formula VI.

[0091] In some embodiments of the present invention, the preparation method includes the step of reacting the compound shown in Formula IV with the compound shown in Formula V, wherein the compound shown in Formula IV has the structure shown in Formula IV-1, and the compound shown in Formula V has the structure of V-1, V-2, or V-3.

[0092] In some embodiments of the present invention, in formula III, R 11 for R 12 R is an amino protecting group. 13 The preparation method further includes step (b): reducing the reaction product of step (a).

[0093] Specifically, the reduction reaction system also includes solvents, such as alcohols, for example ethanol, isopropanol, tert-butanol, and especially ethanol.

[0094] Specifically, the reduction reaction system also includes catalysts, such as Raney Ni and palladium on carbon.

[0095] In other embodiments of the present invention, in formula III, R 11 for R12 For H, R 13 The preparation method further includes step (c): deprotecting the reduction product from step (b) with amino groups.

[0096] In some embodiments of the present invention, the above preparation method includes the step of reacting the compound of formula IV with the compound of formula V, wherein the compound of formula IV has the structure shown in formula IV-1, and the compound of formula V is selected from the following structures:

[0097] The compound shown in Formula I has the following structure: It can be prepared by further reduction. Further deprotection preparation

[0098] In a fourth aspect of the invention, the use of the compound described in the first aspect in the preparation of polyamine derivatives or pharmaceutical salts thereof is provided.

[0099] Specifically, the polyamine derivative has the following structure:

[0100]

[0101] in,

[0102] R1-R 10 Independently selected from: H, OH, alkoxy, aryloxy, arylalkoxy;

[0103] R 11 For H or

[0104] R 12 For H or

[0105] R 13 It is -CH2-NH2;

[0106] n1-n7 are independently selected from integers from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10);

[0107] n' is 0 or 1.

[0108] Specifically, n1 is an integer from 1 to 5, such as an integer from 1 to 3, such as 2.

[0109] Specifically, n2 is an integer from 0 to 5, such as an integer from 1 to 3, such as 2.

[0110] Specifically, n3 is an integer from 0 to 5, such as an integer from 1 to 3, such as 2.

[0111] Specifically, n4 is an integer from 1 to 5, such as an integer from 1 to 3, such as 2.

[0112] Specifically, n5 is an integer from 0 to 5, such as an integer from 1 to 3, such as 2.

[0113] Specifically, n6 is an integer from 0 to 5, such as an integer from 1 to 3, such as 2.

[0114] Specifically, n7 is an integer from 0 to 5, such as an integer from 1 to 3, such as 2.

[0115] In some embodiments of the present invention, n' is 1.

[0116] Specifically, R1 is H.

[0117] Specifically, R4 is H.

[0118] Specifically, R5 is H.

[0119] Specifically, R6 is H.

[0120] Specifically, R9 is H.

[0121] Specifically, R 10 For H.

[0122] Specifically, R2, R3, R7, and R8 are independently selected from: H, OH, alkoxy, aryloxy, and arylalkoxy; more specifically, R2, R3, R7, and R8 are independently selected from: H, OH, C1-C6 alkoxy, C6-C 12 Aryloxy group, C7-C 12 Arylalkoxy; more specifically, R2, R3, R7, R8 are independently selected from: H, OH, C1-C6 alkoxy; even more specifically, R2, R3, R7, R8 are independently selected from: OH, methoxy, ethoxy.

[0123] Specifically, R2 and R3 are the same, and / or R7 and R8 are the same; preferably, R2, R3, R7, and R8 are all the same, for example, all of them are methoxy groups.

[0124] In some embodiments of the present invention, R 11 for R 12 For H.

[0125] In one embodiment of the present invention, the polyamine derivative has the following structure:

[0126]

[0127] In a fifth aspect of the invention, the use of the compounds described in the first aspect in the preparation of medicaments that antagonize bacterial lipopolysaccharide (LPS), bacterial genomic DNA (CpG DNA), peptidoglycan (PGN), lipoteichoic acid (LTA), viral RNA, and yeast polysaccharides is provided.

[0128] In a sixth aspect of the invention, the use of the compound described in the first aspect in the preparation of a medicament for treating sepsis is provided.

[0129] This invention provides an intermediate for polyamine derivatives, its preparation method, and its uses. This intermediate is easy to prepare, has high purity, and when used in the preparation of polyamine derivatives, it helps improve product purity and yield. The operation is simple, which is beneficial for improving the purity and yield of polyamine derivatives, simplifying product purification operations, and thus improving the industrial production of polyamine derivatives and their pharmaceutical salts. This invention also provides a method for preparing polyamine derivatives, which is simple to operate and yields products with high purity, showing great promise for application in the chemical and pharmaceutical fields. Attached Figure Description

[0130] Figure 1 The image shows the 1H NMR spectrum of compound 1a prepared in this embodiment of the invention. Instrument model: Brukeravance 400 (400MHz) NMR spectrometer; test conditions: 400MHz; solvent: deuterated chloroform. Detailed Implementation

[0131] Unless otherwise defined, all scientific and technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0132] The amino protecting group involved in this invention can be any suitable known amino protecting group, such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methanesulfonyl (Ms), p-toluenesulfonyl (Ts), etc., especially Boc.

[0133] The inert gas involved in this invention refers to a gas that does not participate in the reaction. In addition to rare gases such as helium, neon, argon, krypton, and xenon, it may also include nitrogen, depending on the reaction conditions.

[0134] The term "alkyl" refers to a straight-chain or branched hydrocarbon group that does not contain unsaturated bonds and is connected to the rest of the molecule by a single bond. Alkyl groups as used herein typically contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, preferably 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc.

[0135] The term "alkoxy" refers to a substituent formed when a hydrogen atom in a hydroxyl group is replaced by an alkyl group. Alkoxy groups as used herein typically contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, preferably 1 to 6 carbon atoms (i.e., C1-C6 alkoxy groups). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc. A substituent formed when a hydrogen atom in a hydroxyl group is replaced by an aryl group is an aryloxy group. Aaryloxy groups as used herein typically contain 6 to 18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon atoms, preferably 6 to 12 carbon atoms (i.e., C6-C6 alkoxy groups). 12 Aryloxy groups. Examples of aryloxy groups include, but are not limited to, phenoxy groups. An arylalkoxy group is formed when the hydrogen atom of the hydroxyl group in an alkoxy group is replaced by an aryl alkyl group. The arylalkoxy groups used herein typically contain 7 to 18 (e.g., 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18) carbon atoms, preferably 7 to 12 carbon atoms (i.e., C7-C1). 12 Arylalkoxy groups. Examples of arylalkoxy groups include, but are not limited to, benzyloxy groups.

[0136] The term "halogen" refers to bromine, chlorine, iodine, or fluorine, preferably chlorine.

[0137] All publications, patents, and published patent specifications cited in this article are incorporated herein in their entirety through citation.

[0138] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0139] Example 1

[0140]

[0141] Under nitrogen protection, 798 g of dichloromethane and 90 g (0.78 mol) of NHS (nitrogen-hydroxysuccinimide) were added to a glass reactor. The mixture was stirred for 5-15 minutes, cooled to -5 to 5°C, and maintained at -5 to 5°C. 79.5 g of triethylamine was added dropwise. During the dropwise addition, the solid gradually dissolved. The temperature was maintained at -5 to 5°C, and compound 2 (3,4-dimethoxyphenylpropionyl chloride) (0.85 mol, 195.6 g) was added. White fumes were produced, and a solid precipitated. The temperature was slowly raised to 20-30°C and maintained at 20-30°C with stirring for 2-4 hours. The mixture was washed, concentrated, crystallized, filtered, and dried to obtain 199.5 g of solid, which is compound 1a, with a purity of 99.3%.

[0142] Compound 1a: Mass spectrum: m / z = 307.3, 1H NMR spectrum as shown below. Figure 1 As shown.

[0143] Example 2

[0144]

[0145] Under nitrogen protection, 798 g of dichloromethane and 92 g of 2-diethylaminoethanol (0.78 mol) were added to a glass reactor. The mixture was stirred for 5-15 minutes, cooled to -5 to 5°C, and maintained at -5 to 5°C. 79.5 g of triethylamine was added dropwise. During the dropwise addition, the solid gradually dissolved. The temperature was maintained at -5 to 5°C, and 0.85 mol (195.6 g) of 3,4-dimethoxyphenylpropionyl chloride was added. White fumes were produced, and a solid precipitated. The temperature was slowly raised to 20-30°C and maintained at 20-30°C with stirring for 2-4 hours. The mixture was washed, concentrated, crystallized, filtered, and dried to obtain 170.2 g of solid, which is compound 1b, with a purity of 96.2%.

[0146] Example 3

[0147]

[0148] Under nitrogen protection, 798 g of dichloromethane and 103.7 g of 2-diethylaminoethanethiol (0.78 mol) were added to a glass reactor. The mixture was stirred for 5-15 minutes, cooled to -5 to 5°C, and maintained at -5 to 5°C. 79.5 g of triethylamine was added dropwise. During the dropwise addition, the solid gradually dissolved. Maintaining the temperature at -5 to 5°C, 0.85 mol (195.6 g) of 3,4-dimethoxyphenylpropionyl chloride was added. White fumes were produced, and a solid precipitated. The temperature was slowly raised to 20-30°C and maintained at 20-30°C with stirring for 2-4 hours. The mixture was washed, concentrated, crystallized, filtered, and dried to obtain 165.2 g of solid, which is compound 1c, with a purity of 94.3%.

[0149] Example 4

[0150]

[0151] Under nitrogen protection, 60.9 g (0.18 mol) of compound 4 and 265.6 g of ethyl acetate were added to a 1000 ml three-necked flask. The mixture was stirred for 5-15 minutes, heated to 55-65 °C, and maintained at 55-65 °C. Then, 98.6 g (0.32 mol) of compound 1a was added to the three-necked flask. After the addition was complete, the temperature was maintained at 55-65 °C, and the reaction was continued with stirring for 40-48 hours. The mixture was washed with water and concentrated to obtain 5115 g of compound with a purity of 79.29%.

[0152] Example 5

[0153]

[0154] Under nitrogen protection, 60.9 g (0.18 mol) of compound 4 and 265.6 g of ethyl acetate were added to a 1000 ml three-necked flask. The mixture was stirred for 5-15 minutes, heated to 55-65 °C, and maintained at 55-65 °C. Then, 98.9 g (0.32 mol) of compound 1b was added to the three-necked flask. After the addition was complete, the temperature was maintained at 55-65 °C, and the reaction was continued with stirring for 40-48 hours. The mixture was washed with water and concentrated to obtain 5103 g of compound with a purity of 72.56%.

[0155] Example 6

[0156]

[0157] Under nitrogen protection, 60.9 g (0.18 mol) of compound 4 and 265.6 g of ethyl acetate were added to a 1000 ml three-necked flask. The mixture was stirred for 5-15 minutes, heated to 55-65 °C, and maintained at 55-65 °C. 104 g (0.32 mol) of compound 1c was then added to the three-necked flask. After the addition was complete, the temperature was maintained at 55-65 °C, and the reaction was continued with stirring for 40-48 hours. The mixture was washed with water and concentrated to obtain 596 g of compound with a purity of 70.89%.

[0158] Example 7

[0159]

[0160] Under nitrogen protection, 60.9 g (0.18 mol) of compound 4 and 266 g of toluene were added to a 1000 ml three-necked flask. The mixture was stirred for 5-15 minutes, heated to 55-65 °C, and maintained at 55-65 °C. Then, 98.6 g (0.32 mol) of compound 1a was added to the three-necked flask. After the addition was complete, the temperature was maintained at 55-65 °C, and the reaction was continued with stirring for 40-48 hours. The mixture was washed with water and concentrated to obtain 5100 g of compound with a purity of 62.46%.

[0161] Example 8

[0162]

[0163] Under nitrogen protection, 60.9 g (0.18 mol) of compound 4 and 266 g of dioxane were added to a 1000 ml three-necked flask. The mixture was stirred for 5-15 minutes, heated to 55-65 °C, and maintained at 55-65 °C. Then, 98.6 g (0.32 mol) of compound 1a was added to the three-necked flask. After the addition was complete, the temperature was maintained at 55-65 °C, and the reaction was continued with stirring for 40-48 hours. The mixture was washed with water and concentrated to obtain 598 g of compound with a purity of 59.38%.

[0164] Comparative Example 1

[0165]

[0166] Under nitrogen protection, 60.9 g (0.18 mol) of compound 4 and 265.6 g of ethyl acetate were added to a 1000 ml three-necked flask. The mixture was stirred for 5-15 minutes, heated to 55-65 °C, and maintained at 55-65 °C. Then, 72.8 g (0.32 mol) of compound 2 was added to the three-necked flask. After the addition was complete, the temperature was maintained at 55-65 °C, and the reaction was continued with stirring for 40-48 hours. The mixture was washed with water and concentrated to obtain 591 g of compound with a purity of 45.71%.

[0167] Comparative Example 2

[0168]

[0169] 45.3 g of compound was dissolved in 25 ml of dichloromethane, 6 ml of triethylamine was added, and 40 ml of compound 2 (concentration of 10%) dissolved in dichloromethane was added dropwise at 0 °C. The reaction was carried out for 24 hours, the solvent was concentrated, extracted with diethyl ether, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 57.8 g of compound with a purity of 33.62%.

[0170] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

[0171] The foregoing embodiments and methods described in this invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0172] The fact that the steps of the method are listed in a certain order in this invention does not constitute any restriction on the order of the method steps.

Claims

1. A compound, characterized in that, The compound has the following structure: in, G is selected from O and S; R 3 for Where m2 is selected from integers from 1 to 6, and R 4 and R 5 It is independently selected from C1-C6 alkyl groups.

2. The compound according to claim 1, characterized in that, R 4 and R 5 It is independently selected from C1-C3 alkyl groups.

3. The compound according to claim 1, characterized in that, R 3 Selected from: , .

4. The compound according to claim 1, characterized in that, The compound has the following structure: ,or 。 5. A method for preparing the compound according to any one of claims 1-4, characterized in that, Including the compound shown in Formula II and The reaction proceeds, and the compound shown in Formula II has the following structure: （Ⅱ） Where Z represents a halogen.

6. The preparation method according to claim 5, characterized in that, The reaction is carried out in a solvent selected from: dichloromethane, chloroform, ethyl acetate, n-hexane, cyclohexane, and methyl tert-butyl ether.

7. The preparation method according to claim 5, characterized in that, The reaction system also includes an acid-binding agent.

8. The preparation method according to claim 5, characterized in that, The reaction temperature is between 15 and 35°C.

9. The use of the compound according to any one of claims 1-4 in the preparation of polyamine derivatives or their pharmaceutical salts, characterized in that, The polyamine derivative has the following structure: in, R1, R4, R5, R6, R9, R 10 For H; R2, R3, R7, and R8 are methoxy groups; R 11 For H or ; R 12 For H or ; R 13 It is -CH2-NH2; n1 is 2; n2 is an integer between 0 and 5; n3 is an integer between 0 and 5; n4 is 2; n5 is an integer between 0 and 5; n6 is an integer between 0 and 5; n7 is an integer between 0 and 5; n' is 0 or 1.

10. Compounds Its application in the preparation of polyamine derivatives or their pharmaceutical salts is characterized by, The polyamine derivative has the following structure: ； The preparation method of the polyamine derivative includes the following steps: (a) Under a protective atmosphere, the compound shown in Formula IV-1 is mixed with a reaction solvent, the temperature is raised, and the compound is added. The reaction yields the compound shown in Formula I; The reaction solvent is ethyl acetate; the reaction temperature is 50-70℃. (b) The reaction product of step (a) is reduced to obtain ； (c) The reduction product of step (b) is subjected to amino deprotection treatment to obtain the polyamine derivative; The compound shown in Formula IV-1 has the following structure: ； The compound represented by Formula I has the following structure: ； Among them, R 12 ''' is an amino protecting group.

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