INTERMEDIATE OF POLYAMINE DERIVATIVE, PREPARATION METHOD THEREFOR, AND USE THEREOF

Abstract

An intermediate of a polyamine derivative, a preparation method therefor, and a use thereof. The intermediate is easy to prepare and high in purity; and when the intermediate is used for preparing the polyamine derivative, the obtained product is high in purity, the operation is simple and convenient, the purity and yield of the polyamine derivative are improved, the purification operation for the product is simplified, and the industrial production of the polyamine derivative and a medicinal salt thereof can be improved. Further provided is a preparation method for the polyamine derivative, the operation thereof is simple and convenient, and the purity of the obtained product is high. The method has a very good application prospect in the field of chemical medicines.

Claims

1.-10. (canceled)

11. A compound, having a structure of formula I: ##STR00040## wherein m.sub.1 is selected from an integer of 1-6; R.sup.1 and R.sup.2 are independently selected from: OH and alkoxy; G is selected from O and S; R.sup.3 is selected from: ##STR00041## wherein m.sub.2 is selected from an integer of 1-6, and R.sup.4 and R.sup.5 are independently selected from alkyl.

12. The compound according to claim 11, wherein the compound has the following structure: ##STR00042##

13. The compound according to claim 11, wherein R.sup.4 and R.sup.5 are independently selected from C.sub.1-C.sub.6 alkyl.

14. The compound according to claim 11, wherein R.sup.3 is selected from: ##STR00043##

15. The compound according to claim 11, wherein the compound has the following structure: ##STR00044##

16. A preparation method for the compound according to claim 11, comprising a step of reacting a compound of formula II with R.sup.3-G-H, wherein the compound of formula II has the following structure: ##STR00045## wherein Z is halogen.

17. The preparation method according to claim 16, wherein the reaction is carried out in a solvent, wherein the solvent is selected from: dichloromethane, chloroform, ethyl acetate, n-hexane, cyclohexane, and methyl tert-butyl ether.

18. The preparation method according to claim 16, wherein the reaction system further comprises an acid scavenger.

19. The preparation method according to claim 16, wherein the reaction is carried out at a temperature of 15 to 35 C.

20. Use of the compound according to claim 11 in the preparation of a polyamine derivative or a pharmaceutically acceptable salt thereof, wherein the polyamine derivative has the following structure: ##STR00046## wherein R.sub.1-R.sub.10 are independently selected from: H, OH, alkoxy, aryloxy, and aralkoxy; R.sub.11 is H or ##STR00047## R.sub.12 is H or ##STR00048## R.sub.13 is CH.sub.2NH.sub.2; n.sub.1-n.sub.7 are independently selected from an integer of 0-10; and n is 0 or 1.

21. A preparation method for a compound of formula III, wherein the compound of formula III has the following structure: ##STR00049## wherein R.sub.1-R.sub.10 are independently selected from: H, OH, alkoxy, aryloxy, and aralkoxy; R.sub.11 is H, an amino protecting group, or ##STR00050## wherein R.sub.11 is CN, CH.sub.2NH.sub.2, or CH.sub.2NHR.sub.11, and R.sub.11 is an amino protecting group; R.sub.12 is H, an amino protecting group, or ##STR00051## wherein R.sub.12 is CN, CH.sub.2NH.sub.2, or CH.sub.2NHR.sub.12, and R.sub.12 is an amino protecting group; R.sub.13 is CN, CH.sub.2NH.sub.2, or CH.sub.2NHR.sub.13, and R.sub.13 is an amino protecting group; n.sub.1-n.sub.7 are independently selected from an integer of 0-10; and n is 0 or 1; the preparation method comprises a step (a) of reacting a compound of formula IV with a compound of formula V and/or a compound of formula VI: ##STR00052## wherein R.sub.11a is H, an amino protecting group, or ##STR00053## R.sub.12a is H, an amino protecting group, or ##STR00054## X and Y are independently selected from O and S; R.sub.14 and R.sub.15 are independently selected from ##STR00055## wherein n.sub.8 is an integer of 1-6, and R.sub.16 and R.sub.17 are independently selected from alkyl; and n.sub.1-n.sub.7, n, and R.sub.1-R.sub.10 are as defined as in the compound of formula III; optionally, the preparation method further comprises step (b): reducing the reaction product of step (a).

22. The preparation method according to claim 21, wherein R.sub.16 and R.sub.11 are independently selected from C.sub.1-C.sub.6 alkyl.

23. The preparation method according to claim 21, wherein R.sub.14 and R.sub.15 are independently selected from: ##STR00056##

24. The preparation method according to claim 21, wherein the reaction is carried out in a solvent, wherein the solvent is selected from: ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, toluene, xylene, chlorobenzene, and dioxane.

25. The preparation method according to claim 24, wherein the solvent is ethyl acetate, toluene, or dioxane.

26. The preparation method according to claim 21, wherein the reaction is carried out at a temperature of 50 to 70 C.

27. The preparation method according to claim 21, wherein the compound of formula IV has the following structure: ##STR00057## wherein R.sub.11 and R.sub.12 are independently selected from an amino protecting group.

28. The preparation method according to claim 21, wherein R.sub.2, R.sub.3, R.sub.7, and R.sub.8 are independently selected from: H, OH, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.12 aryloxy, and C.sub.7-C.sub.12 aralkoxy.

29. The preparation method according to claim 21, wherein R.sub.11 is ##STR00058## R.sub.12 is H, and R.sub.13 is CH.sub.2NH.sub.2, and the preparation method further comprises step (c): subjecting the reduced product of step (b) to an amino deprotection treatment.

30. The preparation method according to claim 21, wherein the compound of formula III has the following structure: ##STR00059##

Description

BRIEF DESCRIPTION OF THE DRAWING

[0118] FIG. 1 shows a nuclear magnetic resonance hydrogen spectrum of compound 1a prepared in the example of the present invention. Instrument model: Bruker avance 400 (400 MHz) nuclear magnetic resonance spectrometer; test condition: 400 MHz; solvent: deuterated chloroform.

DETAILED DESCRIPTION OF THE INVENTION

[0119] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention relates.

[0120] The amino protecting group involved in the present invention may be any suitable known amino protecting group, such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methanesulfonyl (Ms), or p-toluenesulfonyl (Ts), particularly Boc.

[0121] The inert gas involved in the present invention refers to a gas that does not participate in the reaction, and may include nitrogen and the like in addition to rare gases such as helium, neon, argon, krypton, and xenon, depending on the specific reaction conditions.

[0122] The term alkyl refers to a hydrocarbyl group that is linear or branched and that does not contain unsaturated bonds, and that is linked to the rest of the molecule via a single bond. The alkyl used herein generally contains 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, and preferably contains 1 to 6 carbon atoms (i.e., C.sub.1-C.sub.6 alkyl). Examples of alkyl 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, and the like.

[0123] The term alkoxy refers to a substituent formed from a hydroxy group by substituting the hydrogen atom with alkyl. The alkoxy used herein generally contains 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, and preferably contains 1 to 6 carbon atoms (i.e., C.sub.1-C.sub.6 alkoxy). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. The substituent formed from a hydroxy group by substituting the hydrogen atom with aryl is aryloxy, and the aryloxy used herein generally contains 6 to 18 (e.g., 6, 8, 10, 12, 14, 16, or 18) carbon atoms, and preferably contains 6 to 12 carbon atoms (i.e., C.sub.6-C.sub.12 aryloxy). Examples of the aryloxy include, but are not limited to, phenoxy. The substituent formed from an alkoxy group by substituting the hydrogen atom of a hydroxy group with aralkyl is aralkoxy, and the aralkoxy used herein generally contains 7 to 18 (e.g., 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) carbon atoms, and preferably contains 7 to 12 carbon atoms (i.e., C.sub.7-C.sub.12 aralkoxy). Examples of aralkoxy include, but are not limited to, benzyloxy.

[0124] The term halogen refers to bromine, chlorine, iodine, or fluorine, preferably chlorine.

[0125] The disclosures of the various publications, patents, and published patent specifications cited herein are hereby incorporated by reference in their entireties.

[0126] The technical solutions of the present invention will be clearly and completely described below with reference to the examples of the present invention, and it is obvious that the described examples are only a part of the examples of the present invention but not all of them. Based on the examples of the present invention, all other examples obtained by those of ordinary skills in the art without creative work shall fall within the protection scope of the present invention.

Example 1

##STR00030##

[0127] Under nitrogen atmosphere, 798 g of dichloromethane was added into a glass reaction kettle, followed by the addition of 90 g (0.78 mol) of NHS (N-hydroxysuccinimide). The mixture was stirred for 5-15 min, cooled to 5 to 5 C., controlled at 5 to 5 C., and dropwise added with 79.5 g of triethylamine. During the dropwise addition, the solid was gradually dissolved to give a clear solution. Compound 2 (3,4-dimethoxyphenylpropionyl chloride) (0.85 mol, 195.6 g) was added with the temperature controlled at 5 to 5 C. A white mist was generated, and a solid was precipitated. The mixture was slowly heated to 20-30 C., stirred for reaction for 2-4 h with the temperature controlled at 20-30 C., washed, concentrated, crystallized, filtered, and dried to give 199.5 g of a solid, namely compound 1a with a purity of 99.3%.

[0128] Compound 1a: Mass spectrum: m/z=307.3, and nuclear magnetic resonance hydrogen spectrum as shown in FIG. 1.

Example 2

##STR00031##

[0129] Under nitrogen atmosphere, 798 g of dichloromethane was added into a glass reaction kettle, followed by the addition of 92 g of 2-diethylaminoethanol (0.78 mol). The mixture was stirred for 5-15 min, cooled to 5 to 5 C., controlled at 5 to 5 C., and dropwise added with 79.5 g of triethylamine. During the dropwise addition, the solid was gradually dissolved to give a clear solution. 3,4-dimethoxyphenylpropionyl chloride (0.85 mol, 195.6 g) was added with the temperature controlled at 5 to 5 C. A white mist was generated, and a solid was precipitated. The mixture was slowly heated to 20-30 C., stirred for reaction for 2-4 h with the temperature controlled at 20-30 C., washed, concentrated, crystallized, filtered, and dried to give 170.2 g of a solid, namely compound 1b with a purity of 96.2%.

Example 3

##STR00032##

[0130] Under nitrogen atmosphere, 798 g of dichloromethane was added into a glass reaction kettle, followed by the addition of 103.7 g of 2-diethylaminoethanethiol (0.78 mol). The mixture was stirred for 5-15 min, cooled to 5 to 5 C., controlled at 5 to 5 C., and dropwise added with 79.5 g of triethylamine. During the dropwise addition, the solid was gradually dissolved to give a clear solution. 3,4-dimethoxyphenylpropionyl chloride (0.85 mol, 195.6 g) was added with the temperature controlled at 5 to 5 C. A white mist was generated, and a solid was precipitated. The mixture was slowly heated to 20-30 C., stirred for reaction for 2-4 h with the temperature controlled at 20-30 C., washed, concentrated, crystallized, filtered, and dried to give 165.2 g of a solid, namely compound 1c with a purity of 94.3%.

Example 4

##STR00033##

[0131] Under nitrogen atmosphere, 60.9 g (0.18 mol) of compound 4 was added into a 1000 mL three-neck flask, followed by the addition of 265.6 g of ethyl acetate. The mixture was stirred for 5-15 min, heated to 55-65 C., controlled at 55-65 C., and added with 98.6 g (0.32 mol) of compound 1a. After the addition, the mixture was stirred for reaction for another 40-48 h with the temperature controlled at 55-65 C., washed with water, and concentrated to give 115 g of compound 5 with a purity of 79.29%.

Example 5

##STR00034##

[0132] Under nitrogen atmosphere, 60.9 g (0.18 mol) of compound 4 was added into a 1000 mL three-neck flask, followed by the addition of 265.6 g of ethyl acetate. The mixture was stirred for 5-15 min, heated to 55-65 C., controlled at 55-65 C., and added with 98.9 g (0.32 mol) of compound 1b. After the addition, the mixture was stirred for reaction for another 40-48 h with the temperature controlled at 55-65 C., washed with water, and concentrated to give 103 g of compound 5 with a purity of 72.56%.

Example 6

##STR00035##

[0133] Under nitrogen atmosphere, 60.9 g (0.18 mol) of compound 4 was added into a 1000 mL three-neck flask, followed by the addition of 265.6 g of ethyl acetate. The mixture was stirred for 5-15 min, heated to 55-65 C., controlled at 55-65 C., and added with 104 g (0.32 mol) of compound 1c. After the addition, the mixture was stirred for reaction for another 40-48 h with the temperature controlled at 55-65 C., washed with water, and concentrated to give 96 g of compound 5 with a purity of 70.89%.

Example 7

##STR00036##

[0134] Under nitrogen atmosphere, 60.9 g (0.18 mol) of compound 4 was added into a 1000 mL three-neck flask, followed by the addition of 266 g of toluene. The mixture was stirred for 5-15 min, heated to 55-65 C., controlled at 55-65 C., and added with 98.6 g (0.32 mol) of compound 1a. After the addition, the mixture was stirred for reaction for another 40-48 h with the temperature controlled at 55-65 C., washed with water, and concentrated to give 100 g of compound 5 with a purity of 62.46%.

Example 8

##STR00037##

[0135] Under nitrogen atmosphere, 60.9 g (0.18 mol) of compound 4 was added into a 1000 mL three-neck flask, followed by the addition of 266 g of dioxane. The mixture was stirred for 5-15 min, heated to 55-65 C., controlled at 55-65 C., and added with 98.6 g (0.32 mol) of compound 1a. After the addition, the mixture was stirred for reaction for another 40-48 h with the temperature controlled at 55-65 C., washed with water, and concentrated to give 98 g of compound 5 with a purity of 59.38%.

Comparative Example 1

##STR00038##

[0136] Under nitrogen atmosphere, 60.9 g (0.18 mol) of compound 4 was added into a 1000 mL three-neck flask, followed by the addition of 265.6 g of ethyl acetate. The mixture was stirred for 5-15 min, heated to 55-65 C., controlled at 55-65 C., and added with 72.8 g (0.32 mol) of compound 2. After the addition, the mixture was stirred for reaction for another 40-48 h with the temperature controlled at 55-65 C., washed with water, and concentrated to give 91 g of compound 5 with a purity of 45.71%.

Comparative Example 2

##STR00039##

[0137] 5.3 g of compound 4 was dissolved in 25 mL of dichloromethane, followed by the addition of 6 mL of triethylamine. 40 mL of a solution of compound 2 dissolved in dichloromethane (at a concentration of 10%) was dropwise added at 0 C. The mixture was allowed to react for 24 h, and concentrated to remove the organic solvent. The residue was extracted with diethyl ether, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to remove the solvent to give 7.8 g of compound 5 with a purity of 33.62%.

[0138] The above description is only for the purpose of illustrating the preferred embodiments of the present invention, and is not intended to limit the scope of the present invention. Any modifications, equivalents, and the like made without departing from the spirit and principle of the present invention shall fall in the protection scope of the present invention.

[0139] The foregoing examples and methods described herein may vary based on the abilities, experience, and preferences of those skilled in the art.

[0140] The certain order in which the steps of the method are listed in the present invention does not constitute any limitation on the order of the steps of the method.