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

Abstract

Disclosed are an intermediate of a polyamine derivative pharmaceutical salt, a preparation method therefor, and use thereof. The intermediate compound has the following structure: (I), which can be used to prepare a polyamine derivative and a pharmaceutical salt thereof, and has very good application prospects in the field of chemical medicine.

##STR00001##

Claims

1.-10. (canceled)

11. A compound having the following structure: ##STR00023## wherein, R.sub.1-R.sub.10 are independently selected from: H, OH, alkoxy, aryloxy, and aralkoxy; R.sub.11 is R.sub.3 or ##STR00024## n.sub.1-n.sub.6 are independently selected from an integer of 0-10; R.sub.1 is X.sub.1R.sub.1, wherein X.sub.1 is C(O)O or S(O).sub.2, and R.sub.1 is selected from: alkyl, alkenyl, aralkyl, and aryl; R.sub.2 is X.sub.2R.sub.2, wherein X.sub.2 is C(O)O or S(O).sub.2, and R.sub.2 is selected from: alkyl, alkenyl, aralkyl, and aryl; and R.sub.3 is X.sub.3R.sub.3, wherein X.sub.3 is C(O)O or S(O).sub.2, and R.sub.3 is selected from: alkyl, alkenyl, aralkyl, and aryl.

12. The compound according to claim 11 having the following structure: ##STR00025##

13. The compound according to claim 11, 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.

14. The compound according to claim 11, wherein R.sub.2, R.sub.3, R.sub.7, and R.sub.8 are independently selected from: H, OH, and C.sub.1-C.sub.6 alkoxy.

15. The compound according to claim 11, wherein R.sub.1, R.sub.2, and R.sub.3 are independently selected from: C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.6-C.sub.12 aryl, and C.sub.7-C.sub.12 aralkyl.

16. The compound according to claim 11, wherein R.sub.1, R.sub.2, and R.sub.3 are independently selected from: methyl, ethyl, tert-butyl, p-methylphenyl, allyl, and fluorenylmethyl.

17. The compound according to claim 11, wherein R.sub.1, R.sub.2, and R.sub.3 are independently selected from: tert-butoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, fluorenylmethoxycarbonyl, p-toluenesulfonyl, and mesyl.

18. A preparation method for the compound according to claim 11, wherein the compound is prepared from a compound of formula V having the following structure: ##STR00026## wherein R.sub.12 is R.sub.3 or ##STR00027##

19. The preparation method according to claim 18, comprising mixing the compound of formula V with R.sub.13-R.sub.2 and/or R.sub.13-R.sub.3, alcohol, and a catalyst, and reacting, wherein R.sub.13 is a leaving group.

20. The preparation method according to claim 19, wherein the alcohol is selected from: ethanol, isopropanol, or tert-butanol.

21. The preparation method according to claim 19, wherein the catalyst is Raney Ni or palladium on carbon.

22. The preparation method according to claim 19, wherein the reaction is performed at a temperature of 40-50 C.

23. The preparation method according to claim 19, wherein the reaction is performed under pressure of 1.0-2.0 MPa.

24. The preparation method according to claim 19, wherein the preparation method further comprises a purification step by column chromatography, wherein an eluent for the column chromatography is a mixture of acetone and n-heptane.

25. A preparation method for a polyamine derivative or a pharmaceutically acceptable salt thereof, comprising the following reaction scheme, wherein the polyamine derivative has a structure of formula VI: ##STR00028## wherein, R.sub.1-R.sub.10 are independently selected from: H, OH, alkoxy, aryloxy, and aralkoxy; R.sub.11 is R.sub.3 or ##STR00029## R.sub.14 is H or ##STR00030## n.sub.1-n.sub.6 are independently selected from an integer of 0-10; R.sub.1 is X.sub.1R.sub.1, wherein X.sub.1 is C(O)O or S(O).sub.2, and R.sub.1 is selected from: alkyl, alkenyl, aralkyl, and aryl; R.sub.2 is X.sub.2R.sub.2, wherein X.sub.2 is C(O)O or S(O).sub.2, and R.sub.2 is selected from: alkyl, alkenyl, aralkyl, and aryl; R.sub.3 is X.sub.3R.sub.3, wherein X.sub.3 is C(O)O or S(O).sub.2, and R.sub.3 is selected from: alkyl, alkenyl, aralkyl, and aryl; and the step of preparing a compound of formula VI from a compound of formula I comprises mixing the compound of formula I with a solvent, slowly adding a removal reagent, and performing a reaction.

26. The preparation method according to claim 25, wherein the removal reagent is a solution of hydrogen chloride in an organic solvent.

27. The preparation method according to claim 26, wherein the organic solvent is selected from: ethyl acetate, cyclopentyl methyl ether, isopropyl acetate, methyl tert-butyl ether, methyl acetate, and propyl acetate.

28. The preparation method according to claim 25, wherein the reaction is performed at a temperature of 0-25 C.

29. The preparation method according to claim 25, wherein the preparation method further comprises a salt formation step by reacting the polyamine derivative with an acid; the salt formation step comprises slowly adding a solution of an acid in an organic solvent to a solution of the polyamine derivative and performing a reaction.

30. The preparation method according to claim 29, wherein the acid is selected from: hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, oxalic acid, malonic acid, succinic acid, benzoic acid, trifluoroacetic acid, maleic acid, fumaric acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluene sulfonic acid; and the step of slowly adding a solution of an acid in an organic solvent is performed at a temperature of 0-15 C.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0100] FIG. 1 shows the results of nuclear magnetic resonance hydrogen spectrum for compound 2a. Instrument model: Bruker avance 400 (400 MHz) nuclear magnetic resonance spectrometer; test condition: 400 MHz; solvent: deuterated chloroform.

[0101] FIG. 2 shows the results of mass spectrum for compound 2a. Instrument model: Agilent Technologies 6530 Accurate-Mass Q-TOF LC/MS; test condition: ESI, fragmentor voltage: 175V, collision energy: 0.

DETAILED DESCRIPTION

[0102] 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.

[0103] The term alkyl refers to linear or branched hydrocarbyl that does not contain unsaturated bonds and that is attached to the rest of the molecule via a single bond. The alkyl as used herein generally contains 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, preferably 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. If alkyl is substituted with aryl, it is correspondingly aralkyl (e.g., C.sub.7-C.sub.18 aralkyl, e.g., C.sub.7-C.sub.15 aralkyl or C.sub.7-C.sub.12 aralkyl; e.g., (C.sub.1-C.sub.6 alkylene)-(C.sub.6-C.sub.12 aryl) or (C.sub.1-C.sub.3 alkylene)-phenyl), such as benzyl, benzhydryl, or phenethyl.

[0104] The term alkenyl refers to linear or branched hydrocarbyl that contains at least two carbon atoms and at least one unsaturated bond and that is attached to the rest of the molecule via a single bond. Alkenyl as used herein generally contains 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, preferably 2 to 6 carbon atoms (i.e., C.sub.2-C.sub.6 alkenyl). Examples of alkenyl include, but are not limited to, ethenyl, 1-methyl-ethenyl, 1-propenyl, 2-propenyl, 3-propenyl (also referred to as allyl), butenyl, or the like.

[0105] The term alkoxy refers to a substituent formed from hydroxyl by substituting the hydrogen atom with alkyl. The alkoxy as used herein generally contains 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, preferably 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. A substituent formed from hydroxyl 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, preferably 6 to 12 carbon atoms (i.e., C.sub.6-C.sub.12 aryloxy). Examples of aryloxy include, but are not limited to, phenoxy. A substituent formed from hydroxyl in alkoxy by substituting the hydrogen atom 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, preferably 7 to 12 carbon atoms (i.e., C.sub.7-C.sub.12 aralkoxy). Examples of aralkoxy include, but are not limited to, benzyloxy.

[0106] The term aryl refers to a functional group or substituent derived from a simple aromatic ring, including monocyclic aryl groups and/or fused aryl groups, such as monocyclic or bicyclic aryl groups containing 1-3 rings and having 6-18 (e.g., 6, 8, 10, 12, 14, 16, or 18) carbon ring atoms. Aryl as used herein is generally monocyclic or bicyclic aryl containing 1-2 rings and having 6-12 carbon ring atoms (i.e., C.sub.6-12 aryl), wherein H on the carbon atoms may be substituted, for example, with alkyl, halogen, and other groups. Examples of aryl include, but are not limited to, phenyl, p-methylphenyl, naphthyl, biphenyl, indenyl, and the like.

[0107] The term halogen refers to bromine, chlorine, iodine, or fluorine.

[0108] The term systemic inflammatory response syndrome or SIRS refers to a response related to at least two of the following criteria: temperature>38 C. or <36 C., heart rate >90/min, respiratory rate>20/min or paCO.sub.2<32 milliliters of mercury (mmHg), leukocyte count>1210.sup.9/L or <410.sup.9/L, or immature leukocyte more than 10% (Bone R C; Balk R A; Cerra F B., et al., Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine[J]. Chest, 1992, 101(6):1644-1655.). SIRS may be caused by infection or trauma of any other type, particularly of the burn, surgery, or injury type. Sepsis, severe sepsis, and septic shock all correspond to SIRS caused by infection. In a patient in the state of sepsis (sepsis, severe sepsis, and septic shock), who presents SIRS as a result of infection, the infection that causes SIRS may arise from a number of sources, particularly from bacterial, viral, or fungal sources.

[0109] The term autoimmune disease refers to a disorder resulting from an autoimmune response. An autoimmune disease is the result of inappropriate and excessive responses to self-antigens. Autoimmune diseases include, but are not limited to: one or more of organ-specific autoimmune disease, systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, and ulcerative colitis.

[0110] The disclosures of the various publications, patents, and published patent specifications cited herein are hereby incorporated by reference in their entireties.

[0111] 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.

PREPARATION AND PURIFICATION OF COMPOUNDS

Example 1

##STR00015##

[0112] Compound 1, di-tert-butyl dicarbonate (Boc.sub.2O or BOC.sub.2O), ethanol, and Raney Ni were added to an autoclave. The mixture was reacted under stirring at 45 C., 1.0-2.0 MPa for 48 h. The mixture was concentrated to dryness under reduced pressure to give a crude product of Compound 2a (72.2% purity, 100.8% yield).

[0113] The crude product of Compound 2a was purified by column chromatography (200-300 mesh silica gel chromatographic column), and eluted with acetone:n-heptane=1:2 (v/v) to give Compound 2a (96.2% purity, 56.4% overall yield).

Example 2

##STR00016##

[0114] Compound 1, diethyl pyrocarbonate, isopropanol, and Raney Ni were added to an autoclave. The mixture was reacted under stirring at 40 C., 1.0-2.0 MPa for 48 h. The mixture was concentrated to dryness under reduced pressure to give a crude product of Compound 2b (69.8% purity, 99.4% yield).

[0115] The crude product of Compound 2b was purified by column chromatography (200-300 mesh silica gel chromatographic column), and eluted with acetone:n-heptane=1:2 (v/v) to give Compound 2b (93.8% purity, 55.1% overall yield).

Example 3

##STR00017##

[0116] Compound 1, diethyl pyrocarbonate, tert-butanol, and Raney Ni were added to an autoclave. The mixture was reacted under stirring at 50 C., 1.0-2.0 MPa for 48 h. The mixture was concentrated to dryness under reduced pressure to give a crude product of Compound 2c (68.7% purity, 100.2% yield).

[0117] The crude product of Compound 2c was purified by column chromatography (200-300 mesh silica gel chromatographic column), and eluted with acetone:n-heptane=1:2 (v/v) to give Compound 2c (91.1% purity, 53.5% overall yield).

Example 4

##STR00018##

[0118] Compound 1, N-(9-fluorenylmethoxycarbonyloxy) succinimide (Fmoc-OSU), ethanol, and Raney Ni were added to an autoclave. The mixture was reacted under stirring at 45 C., 1.0-2.0 MPa for 48 h. The mixture was concentrated to dryness under reduced pressure to give a crude product of Compound 2d (16.8% purity, 39.0% yield).

Comparative Example 1

##STR00019##

[0119] Compound 1, ethanol, and Raney Ni were added to an autoclave. The mixture was reacted under stirring at 45 C., 1.0-2.0 MPa for 48 h. The mixture was concentrated to dryness under reduced pressure to give a crude product of Compound 5 (69.2% purity, 65.9% yield).

[0120] The first purification method: the crude product of Compound 5 was purified by column chromatography (200-300 mesh silica gel chromatographic column), and eluted with acetone:n-heptane=4:1 (v/v) to give Compound 5 (72.4% purity, 30.5% overall yield). After trying purification by column chromatography, the purity and yield were still very low.

[0121] The second purification method: the crude product of Compound 5 was added to dichloromethane (DCM). The mixture was stirred until the solid was dissolved to give a clear solution. With the temperature controlled at 0-10 C., the solution was extracted with 1 M hydrochloric acid twice. The aqueous phases were combined, adjusted with 1 M sodium hydroxide to above pH 10, and extracted with DCM three times. The extract was washed with 10% sodium chloride twice and concentrated to dryness. The operations described above were repeated 3 times to give Compound 5 (96.1% purity, 6.4% yield). This purification method had a certain impurity removal effect, but there was a serious emulsification phenomenon in the alkali extraction process, and the process was complex, so that the method is not beneficial to scale-up production.

Comparative Example 2

[0122] The reaction scheme is as shown in Comparative Example 1.

[0123] Compound 1, a saturated solution of ammonia in methanol, and Raney Ni were added to an autoclave. The mixture was reacted under stirring at 45 C., 1.0-2.0 MPa for 48 h. The mixture was concentrated to dryness under reduced pressure to give a crude product of Compound 5 (18.5% purity, 44.3% yield).

Boc(tert-butoxycarbonyl) Removal and Salt Formation

Example 5

##STR00020##

[0124] 15 g of Compound 2a obtained by purification in Example 1 was added to a three-necked flask. 150.0 g of dichloromethane was added. The system was stirred until the solid was dissolved to give a clear solution. With the temperature controlled at 10 C., 78.3 g of 15% ethyl acetate hydrogen chloride (EA HCl) was slowly added. The mixture was reacted under stirring for 2 h. 75.0 g of water was added to the reaction solution, and stirred for quenching. The mixture was left to stand for liquid separation. The lower organic phase was discarded. The upper aqueous phase was adjusted to pH 12-14 with 4 M sodium hydroxide, and extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a solution of Compound 3 in dichloromethane with a purity of 98.2%.

##STR00021##

[0125] The solution of Compound 3 in dichloromethane obtained in the previous step was added to a 250 mL three-neck flask, and the solution was cooled to 0 C. 4 M ethyl acetate solution of hydrochloric acid was slowly added. The mixture was reacted under stirring for 3-5 h with the temperature controlled at 0-10 C. 30 g of methanol was added to the reaction flask with the temperature controlled at 20-30 C. The mixture was stirred and concentrated under reduced pressure at a temperature below 30 C. 60 g of ethyl acetate was added to the concentrate. The mixture was concentrated under reduced pressure at a temperature below 30 C. The filter cake was rinsed with ethyl acetate, and dried under vacuum to give an off-white solid with a yield of 85.3% and a purity of 92.5%.

Example 6

##STR00022##

[0126] 15 g of Compound 2a obtained by purification in Example 1 was added to a three-necked flask. 150.0 g of dichloromethane was added. The system was stirred until the solid was dissolved to give a clear solution. With temperature controlled at 0 C., 78.3 g of 15% cyclopentyl methyl ether hydrogen chloride (CPME.Math.HCl) was slowly added. The mixture was reacted under stirring for 2 h. 75.0 g of water was added to the reaction solution, and stirred for quenching. The mixture was left to stand for liquid separation. The lower organic phase was discarded. The upper aqueous phase was adjusted to pH 12-14 with 4 M sodium hydroxide, and extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a solution of Compound 3 in dichloromethane with a purity of 98.0%.

[0127] 60 g of the solution of Compound 3 in dichloromethane obtained in the previous step was added to a 250 mL three-neck flask, and the solution was cooled to 10 C. 0.5 M ethyl acetate solution of oxalic acid was slowly added. The mixture was reacted under stirring for 3-5 h with the temperature controlled at 0-10 C. 30 g of methanol was added to the reaction flask with the temperature controlled at 20-30 C. The mixture was stirred and concentrated under reduced pressure at a temperature below 30 C. 60 g of ethyl acetate was added to the concentrate. The mixture was concentrated under reduced pressure at a temperature below 30 C. The filter cake was rinsed with ethyl acetate, and dried under vacuum to give a light yellow solid with a yield of 79.9% and a purity of 87.6%.

[0128] In the above Example:

[0129] The results of nuclear magnetic resonance hydrogen spectrum and mass spectrum for Compound 2a are shown in FIGS. 1 and 2, respectively.

[0130] Conclusion: Compound 2a has a molecular formula of C.sub.49H.sub.79N.sub.5O.sub.12 with an average molecular weight of 930.19. In the ESI+mode high resolution mass spectrum of the test sample, there is a peak with m/z=930.5985, which is an M+H excimer ion peak. The data of high-resolution mass spectrum and nuclear magnetic resonance hydrogen spectrum show that the relative molecular mass detected for the test sample is consistent with the relative molecular mass of compound 2a, which matches the structures.

[0131] The above description is only for the purpose of illustrating the preferred examples 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.

[0132] The foregoing examples and methods described herein may vary based on the abilities, experience, and preferences of those skilled in the art.

[0133] 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.