A benzimidazole alkyl bromide salt-zhimu saponin element derivative, and a preparation method and application thereof

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a benzimidazole alkyl bromide salt-anemarrhena saponin aglycone derivative, a preparation method and application thereof. The benzimidazole alkyl bromide salt-anemarrhena saponin aglycone derivative provided by the application has a structure shown in formula 1 or formula 2. The application combines an anemarrhena saponin aglycone skeleton and a benzimidazole skeleton, and the obtained benzimidazole alkyl bromide salt-anemarrhena saponin aglycone derivative with the structure shown in formula 1 or formula 2 has significant antitumor activity. The antitumor growth inhibition activity of the benzimidazole alkyl bromide salt-anemarrhena saponin aglycone derivative provided by the application is better than that of cisplatin (DDP), an anticancer drug.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and particularly relates to a benzimidazole alkyl bromide salt- zhimu sapogenin derivative, a preparation method and application thereof. BACKGROUND

[0002] So far, cancer is still one of the main causes of human death, and conquering cancer cells has been a hot issue of research at home and abroad. Chemotherapy is a main method for treating malignant tumors in the whole body, but it will damage other cells while fighting tumor cells. Therefore, it is urgent to seek an efficient anti-tumor drug for the treatment of anti-tumor.

[0003] As one of the most representative drugs in the field of chemotherapy drugs, platinum drugs play an irreplaceable role in the clinical treatment of various cancers. The mechanism of action of platinum anti-tumor compounds on cancer cells can be summarized as follows: after the platinum anti-tumor compound is injected into the cell, it is hydrolyzed in the cytoplasm, reacts with water to form a positively charged hydrate, enters the nucleus under the action of electrostatic attraction, and forms a complex with DNA, thereby hindering the replication and transcription of DNA, and leading to cell apoptosis.

[0004] However, due to the insufficient tumor inhibition effect of platinum drugs on cancer cells, the dosage of platinum drugs is large, and the toxic side effects on normal cells are serious. SUMMARY

[0005] The purpose of the present application is to provide a benzimidazole alkyl bromide salt-zhimu sapogenin derivative, a preparation method and application thereof. The benzimidazole alkyl bromide salt-zhimu sapogenin derivative provided by the present application has significant anti-tumor activity, and the inhibition activity on tumor growth is better than that of the anticancer drug cisplatin (DDP).

[0006] In order to achieve the above purpose, the present application provides the following technical scheme:

[0007] The present application provides a benzimidazole alkyl bromide salt-zhimu sapogenin derivative, which has the structure of formula 1 or

[0008] Formula 2:

[0009]

[0010] In formula 1 or formula 2, R 2 is 4-bromobenzoylmethyl, 2-naphthoylmethyl, 2-naphthyl, 4-methoxybenzoylmethyl, 4-bromobenzyl, 4-methylbenzyl or 2-bromobenzyl.

[0011] The present application provides a preparation method of the benzimidazole alkyl bromide salt-zhimu sapogenin derivative described in the above technical scheme, which comprises the following steps:

[0012] mixing 2-methylbenzimidazolyl-panaxadiol of structure shown in formula 3 or 5,6-dimethylbenzimidazolyl-panaxadiol of structure shown in formula 4, a brominating reagent and an organic solvent to carry out a salt formation reaction, to obtain benzimidazolyl bromide-panaxadiol derivative of structure shown in formula 1 or formula 2; the brominating reagent is R 2 -Br;

[0013]

[0014] Preferably, the preparation method of 2-methylbenzimidazolyl-panaxadiol of structure shown in formula 3 or 5,6-dimethylbenzimidazolyl-panaxadiol of structure shown in formula 4 comprises the following steps:

[0015] mixing panaxadiol, an organic base, methylsulfonyl chloride and an organic solvent to carry out a sulfonylation reaction, to obtain MsO-panaxadiol of structure shown in formula 5;

[0016]

[0017] mixing 2-methylbenzimidazol or 5,6-dimethylbenzimidazol, the MsO-panaxadiol, an alkali metal carbonate and an organic solvent to carry out an imidazole ring reaction, to obtain 2-methylbenzimidazolyl-panaxadiol of structure shown in formula 3 or 5,6-dimethylbenzimidazolyl-panaxadiol of structure shown in formula 4.

[0018] Preferably, the molar ratio of 2-methylbenzimidazolyl-panaxadiol of structure shown in formula 3 or 5,6-dimethylbenzimidazolyl-panaxadiol of structure shown in formula 4 to the brominating reagent is 1:(1-2).

[0019] Preferably, the salt formation reaction is carried out under refluxing conditions, and the holding time of the salt formation reaction is 24-48h.

[0020] Preferably, the organic base is triethylamine; and the molar ratio of the panaxadiol, the organic base and the methylsulfonyl chloride is 1:3:1.5.

[0021] Preferably, the temperature of the formylation reaction is room temperature, and the time of the formylation reaction is 2h.

[0022] Preferably, the alkali metal carbonate comprises cesium carbonate and / or sodium carbonate.

[0023] The molar ratio of the 2-methylbenzimidazol or 5,6-dimethylbenzimidazol, the MsO-panaxadiol and the alkali metal carbonate is 2:1:3.

[0024] Preferably, the imidazole ring reaction is carried out in a protective gas, the imidazole ring reaction is carried out under refluxing conditions, and the holding time of the imidazole ring reaction is 12-24 hours.

[0025] The application provides application of the benzimidazole alkyl bromide salt-anemarrhena sapogenin derivative in preparation of an antitumor drug.

[0026] The application provides a benzimidazole alkyl bromide salt-anemarrhena sapogenin derivative with a structure shown in formula 1 or formula 2. The benzimidazole alkyl bromide salt-anemarrhena sapogenin derivative provided by the application has a significantly antitumor activity, and the tumor growth inhibition activity of the benzimidazole alkyl bromide salt-anemarrhena sapogenin derivative provided by the application is better than that of cisplatin (DDP) which is an anticancer drug. According to the results of the examples, the benzimidazole alkyl bromide salt-anemarrhena sapogenin derivative with the structure shown in formula 1 or formula 2 is screened for cytotoxic activity on five cell strains of leukemia (K562), hepatoma (SMMC-7721), lung cancer (A-549), breast cancer (MCF-7) and human normal breast epithelial cells (MCF10A) according to the MTS method, the benzimidazole alkyl bromide salt-anemarrhena sapogenin derivative provided by the application has a significantly in-vitro tumor growth inhibition activity on four human cancer cell strains (leukemia, hepatoma, lung cancer and breast cancer), and the in-vitro tumor growth inhibition activity of the 14 compounds is better than that of cisplatin (DDP) which is an anticancer drug. Especially, the in-vitro antitumor cytotoxic activity of the compound with the structure shown in formula 2-6 and the compound with the structure shown in formula 2-7 on K562, SMMC-7721, A-549 and MCF-7 cell strains is 13.2 times, 23.6 times, 12.8 times, 80.8 times and 13.2 times, 9.5 times, 14.0 times, 77.8 times of that of DDP respectively. The compound has very good activity and selectivity on breast cancer cells. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 The application provides a preparation flowchart of the benzimidazole alkyl bromide salt-anemarrhena sapogenin derivative. DETAILED DESCRIPTION

[0028] The application provides a benzimidazole alkyl bromide salt-anemarrhena sapogenin derivative with a structure shown in formula 1 or formula 2.

[0029] The application provides a benzimidazole alkyl bromide salt-anemarrhena sapogenin derivative with a structure shown in formula 1 or formula 2.

[0030]

[0031] In formula 1 or formula 2, R 24-bromobenzoylmethyl, 2-naphthoylmethyl, 2-naphthyl, 4-methoxybenzoylmethyl, 4-bromobenzyl, 4-methylbenzyl or 2-bromobenzyl.

[0032] In the present application, the benzimidazolidinyl bromide-anthraquinone derivative shown in formula 1 is a 2-methylbenzimidazolidinyl bromide-anthraquinone derivative, and is specifically preferably a structure shown in formula 1-1 to formula 1-7:

[0033]

[0034]

[0035] In the present application, the benzimidazolidinyl bromide-anthraquinone derivative shown in formula 2 is a 5,6-dimethylbenzimidazolidinyl bromide-anthraquinone derivative, and is specifically preferably a structure shown in formula 2-1 to formula 2-7:

[0036]

[0037]

[0038] The present application provides a preparation method of the benzimidazolidinyl bromide-anthraquinone derivative described in the above technical solution, which comprises the following steps:

[0039] The 2-methylbenzimidazolidinyl-anthraquinone shown in formula 3 or the 5,6-dimethylbenzimidazolidinyl-anthraquinone shown in formula 4, a brominating reagent and an organic solvent (hereinafter referred to as a first organic solvent) are mixed (hereinafter referred to as a first mixing) to perform a salt formation reaction, so as to obtain the benzimidazolidinyl bromide-anthraquinone derivative shown in formula 1 or formula 2; the brominating reagent is R 2 -Br;

[0040]

[0041] In the present application, all the preparation raw materials / components are commercially available products well known to those skilled in the art, unless otherwise specified.

[0042] In the present application, the preparation method of the 2-methylbenzimidazolidinyl-anthraquinone shown in formula 3 or the 5,6-dimethylbenzimidazolidinyl-anthraquinone shown in formula 4 preferably comprises the following steps:

[0043] The anthraquinone, an organic base, methylsulfonyl chloride and an organic solvent (hereinafter referred to as a second organic solvent) are mixed (hereinafter referred to as a second mixing) to perform a sulfonylation reaction, so as to obtain the MsO-anthraquinone shown in formula 5;

[0044]

[0045] The imidazole ring reaction is carried out by mixing 2-methylbenzimidazole or 5,6-dimethylbenzimidazole, the MsO-anemoside aglycone, an alkali metal carbonate and an organic solvent (hereinafter referred to as a third organic solvent) (hereinafter referred to as a third mixing) to obtain 2-methylbenzimidazole alkyl-anemoside aglycone of the structure shown in formula 3 or 5,6-dimethylbenzimidazole alkyl-anemoside aglycone of the structure shown in formula 4.

[0046] The sulfonating reaction is carried out by second mixing the anemoside aglycone, an organic base, methylsulfonyl chloride and a second organic solvent to obtain the MsO-anemoside aglycone of the structure shown in formula 5.

[0047] In the present application, the anemoside aglycone has the structure shown in formula 6:

[0048]

[0049] In the present application, the CAS number of the anemoside aglycone is: 126-19-2.

[0050] In the present application, the organic base is preferably triethylamine.

[0051] In the present application, the second organic solvent is preferably dichloromethane.

[0052] In the present application, the molar ratio of the anemoside aglycone, the organic base and the methylsulfonyl chloride is preferably 1:3:1.5.

[0053] In the present application, the ratio of the volume of the second organic solvent to the total mass of the anemoside aglycone, the organic base and the methylsulfonyl chloride is preferably 40 mL:1 g.

[0054] In the present application, the first mixing preferably includes the following sequence: dissolving the anemoside aglycone in a second organic solvent to obtain an anemoside aglycone solution; mixing the anemoside aglycone solution and an organic base to obtain a mixed solution; adding the methylsulfonyl chloride to the mixed solution under the condition of an ice water bath.

[0055] In the present application, the temperature of the xanthation reaction is preferably room temperature, and the time of the xanthation reaction is preferably 2 h. In the present application, the sulfonating reaction is preferably carried out under the condition of stirring.

[0056] In the present application, the sulfurylation reaction is followed by obtaining a sulfurylation reaction solution, and the sulfurylation reaction solution is preferably subjected to post-treatment to obtain MsO-Notoginsenosidic Acid shown in the structure of Formula 5. In the present application, the post-treatment preferably comprises the following steps: quenching the reaction by mixing the sulfurylation reaction solution with water to obtain an aqueous phase; mixing the aqueous phase with an organic extractant to perform extraction, and combining the extracted phases to obtain an extracted organic phase; and sequentially performing washing, drying, solvent removal, and column chromatography separation on the extracted organic phase to obtain MsO-Notoginsenosidic Acid shown in the structure of Formula 5. In the present application, the volume ratio of the amount of water used to the volume of the second organic solvent during the quenching reaction is preferably 5:4. The organic extractant is preferably dichloromethane, and the number of times of extraction is preferably 3, and the volume ratio of the organic extractant to the second organic solvent used each time is preferably 5:4. The washing is preferably saturated brine washing, and the volume ratio of the saturated brine to the second organic solvent is preferably 5:4. The drying reagent is preferably anhydrous Na2SO4. The specific implementation of the solvent removal is preferably reduced pressure distillation. The column chromatography separation is preferably silica gel column chromatography separation.

[0057] After obtaining the MsO-Notoginsenosidic Acid, 2-methylbenzimidazole or 5,6-dimethylbenzimidazole, the MsO-Notoginsenosidic Acid, an alkali metal carbonate, and a third organic solvent are mixed to perform imidazole ring reaction to obtain 2-methylbenzimidazole alkyl-Notoginsenosidic Acid shown in the structure of Formula 3 or 5,6-dimethylbenzimidazole alkyl-Notoginsenosidic Acid shown in the structure of Formula 4.

[0058] The alkali metal carbonate preferably comprises cesium carbonate and / or sodium carbonate.

[0059] In the present application, the third organic solvent is preferably toluene.

[0060] In the present application, the molar ratio of the 2-methylbenzimidazole or 5,6-dimethylbenzimidazole, the MsO-Notoginsenosidic Acid, and the alkali metal carbonate is 2:1:3.

[0061] In the present application, the volume ratio of the third organic solvent to the total mass of the 2-methylbenzimidazole or 5,6-dimethylbenzimidazole, the MsO-Notoginsenosidic Acid, and the alkali metal carbonate is preferably 40 mL:1 g.

[0062] In the present application, the third mixing preferably comprises the following steps: dissolving the MsO-Notoginsenosidic Acid in a third organic solvent to obtain a MsO-Notoginsenosidic Acid solution; and sequentially adding an alkali metal carbonate and 2-methylbenzimidazole or 5,6-dimethylbenzimidazole to the MsO-Notoginsenosidic Acid solution.

[0063] In the present application, the imidazole ring-closing reaction is carried out in a protective gas, preferably nitrogen. The imidazole ring-closing reaction is carried out under reflux, and the holding time of the imidazole ring-closing reaction is preferably 12-24 h. The imidazole ring-closing reaction is carried out under stirring.

[0064] In the present application, the imidazole ring-closing reaction is followed by obtaining a ring-closing reaction liquid, and the ring-closing reaction liquid is preferably subjected to post-treatment to obtain the 2-methylbenzimidazolidinyl-oridonide of the structure shown in Formula 3 or the 5,6-dimethylbenzimidazolidinyl-oridonide of the structure shown in Formula 4. In the present application, the post-treatment preferably comprises the following steps: sequentially cooling the ring-closing reaction liquid to room temperature, removing the solvent by distillation under reduced pressure, adding water to separate an organic phase to obtain an aqueous phase; mixing the aqueous phase and an organic extractant to perform extraction, and combining the extracted phases to obtain an extracted organic phase; sequentially performing washing, drying, solvent removal and column chromatography separation on the extracted organic phase to obtain the MsO-oridonide of the structure shown in Formula 5. In the present application, the quenching reaction is carried out with a ratio of the amount of water to the volume of the second organic solvent preferably being 5:4. The organic extractant is preferably dichloromethane, and the number of extraction times is preferably 3, and the volume ratio of the organic extractant to the third organic solvent used each time is preferably 5:4. The washing is preferably washing with saturated brine, and the volume ratio of the saturated brine to the second organic solvent is preferably 5:4. The drying reagent is preferably anhydrous Na2SO4. The specific embodiment of the removal of the solvent is preferably distillation under reduced pressure. The column chromatography separation is preferably silica gel column chromatography separation.

[0065] In the present application, the first organic solvent is preferably acetone.

[0066] The brominating reagent is preferably 4-bromobenzoylmethyl bromide, 2-bromo-2-acetylnaphthalene, 2-naphthylmethyl bromide, 4-methoxybenzoylmethyl bromide, 4-bromobenzyl bromide, 4-methylbenzyl bromide or 2-bromobenzyl bromide;

[0067] In the present application, the molar ratio of the 2-methylbenzimidazolidinyl-oridonide of the structure shown in Formula 3 or the 5,6-dimethylbenzimidazolidinyl-oridonide of the structure shown in Formula 4 to the brominating reagent is 1:(1-2), and more preferably 1:2.

[0068] In the present application, the volume ratio of the first organic solvent to the total mass of the 2-methylbenzimidazolidinyl-oridonide of the structure shown in Formula 3 or the 5,6-dimethylbenzimidazolidinyl-oridonide of the structure shown in Formula 4 and the brominating reagent is preferably 80 mL:1 g.

[0069] In the present application, the salt formation reaction is carried out under reflux, and the holding time of the salt formation reaction is preferably 24-48 h.

[0070] In the present invention, after the salt-forming reaction, a salt-forming reaction liquid is obtained. In the present invention, the salt-forming reaction liquid is preferably post-treated to obtain the benzimidazolyl bromide-timosaponin derivative having the structure shown in Formula 1 or Formula 2. In the present invention, the post-treatment preferably comprises the following steps: cooling the salt-forming reaction liquid to room temperature, allowing a solid precipitate to separate, and performing solid-liquid separation to obtain a solid product; and sequentially washing and drying the solid product to obtain the benzimidazolyl bromide-timosaponin derivative having the structure shown in Formula 1 or Formula 2. In the present invention, the solid-liquid separation is preferably filtration. The washing solvent is preferably ethyl acetate.

[0071] The present invention provides the use of the benzimidazolyl bromide-timosaponin derivative described in the above technical solution or the benzimidazolyl bromide-timosaponin derivative prepared by the preparation method described in the above technical solution in the preparation of anti-tumor drugs.

[0072] In the present invention, the anti-tumor drug preferably comprises the benzimidazolyl bromide-timosaponin derivative described in the above technical solution and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0073] In the present invention, the anti-tumor drug is preferably a drug for treating leukemia, a drug for treating liver cancer, a drug for treating lung cancer or a drug for treating breast cancer.

[0074] In order to further illustrate the present invention, the technical solution provided by the present invention is described in detail below with reference to the accompanying drawings and embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0075] Example 13 α-(2-methylbenzimidazole)-anemasaponin

[0076] According to the flow chart of Example 1:

[0077] The sapogenin of Anemarrhena asphodeloides ( Figure 1 a1) in was dissolved in dichloromethane, triethylamine was added, and methylsulfonyl chloride was slowly added under ice bath for 5 minutes, in a molar ratio of timosaponin / triethylamine / methylsulfonyl chloride = 1 / 3 / 1.5, and the amount of dichloromethane was 40 mL / g raw material (total mass of timosaponin, triethylamine and methylsulfonyl chloride). After the reaction system was stirred at room temperature for 2 hours, water (50 mL) was added to quench the reaction, and the aqueous phase was extracted with dichloromethane (50 mL × 3 times). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and the solvent was distilled off under reduced pressure. After silica gel column chromatography, 3β-MsO-timosaponin ( Figure 1 a2 in );

[0078]

[0079] 3β-MsO-timosaponin of structure shown in Formula 5 was dissolved in a toluene solution, cesium carbonate and 2-methylbenzimidazole were added, and the molar ratio of 3β-MsO-timosaponin of structure shown in Formula 5 / cesium carbonate / 2-methylbenzimidazole was 1 / 3 / 2, and the amount of toluene was 40mL / g raw material (total mass of 3β-MsO-timosaponin of structure shown in Formula 5, cesium carbonate and 2-methylbenzimidazole). After heating under reflux and stirring for 12 hours under nitrogen protection, the mixture was cooled to room temperature; the solvent was removed by distillation under reduced pressure, water (50mL) was added, the organic phase was separated, the aqueous phase was extracted with dichloromethane (50mL×3 times), the organic phases were combined, washed with saturated brine (50mL), dried over anhydrous Na2SO4, filtered, the solvent was removed by distillation under reduced pressure, and silica gel column chromatography was performed to obtain 3α-2-methylbenzimidazolidine alkyl-timosaponin of structure shown in Formula 3 ( Figure 1 a3 in );

[0080]

[0081] 3α-2-methylbenzimidazolidine alkyl bromide-animathyrogenin as shown in formula 3 is white powder with a yield of 41%;

[0082] 1 H NMR(400MHz,Chloroform-d)δ7.63–7.61(m,1H),7.42–7.37(m,1H),7.17–7.12(m,2 H),4.43–4.38(m,1H),4.22–4.13(m,1H),3.90(dd,J=11.2,2.8Hz,1H),3.25(d,J=11 .2Hz,1H),2.68–2.62(m,1H),2.55(d,J=1.2Hz,3H),2.29–2.18(m,1H),1.99–1.73(m ,8H),1.64–1.20(m,17H),1.03–1.00(m,6H),0.96(d,J=6.4Hz,3H),0.74(s,3H)ppm.

[0083] 13C NMR (100 MHz, CDC13) δ 150.0, 132.9, 120.7, 120.5, 118.3, 109.9, 108.7, 79.9, 64.1, 61.1, 56.0, 55.8, 42.3, 41.2, 40.8, 39.7, 39.5, 35.8, 34.5, 33.9, 30.8, 30.2, 26.1, 25.9, 25.8, 25.0, 24.8, 24.7, 22.6, 19.7, 15.5, 15.1, 14.0, 13.4 ppm.

[0084] Example 2 3α-(2-methylbenzimidazole-3-(2-naphthoylmethyl) bromide salt)-chimusanol

[0085] According to the flow chart of Example 1: 3α-2-methylbenzimidazole alkyl bromide salt-chimusanol of the structure shown in Formula 3 was dissolved in acetone solvent, 2-bromo-2-acetylnaphthalene was added with stirring, the amount was 2-bromo-2-acetylnaphthalene / 3α-2-methylbenzimidazole alkyl bromide salt of the structure shown in Formula 3 = 1 / 2, the amount of acetone was 80 mL / g of raw material (total mass of 3α-2-methylbenzimidazole alkyl bromide salt of the structure shown in Formula 3 and 2-bromo-2-acetylnaphthalene), the reaction was stirred and refluxed for 24 hours, cooled to room temperature, a solid precipitate was precipitated, filtered, the precipitate was washed with ethyl acetate (20 mL) several times, dried, to prepare 3α-2-methylbenzimidazole alkyl bromide salt-chimusanol derivative of the structure shown in Formula 1-1;

[0086]

[0087] 3α-2-methylbenzimidazole alkyl bromide salt-chimusanol derivative of the structure shown in Formula 1-1 was a white powder, with a yield of 77%;

[0088] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.10 - 8.03 (m, 4H), 7.79 - 7.71 (m, 3H), 7.64 (t, J = 8.0 Hz, 1H), 6.59 (s, 2H), 4.83 (d, J = 12.9 Hz, 1H), 4.35 (q, J = 6.8 Hz, 1H), 3.81 (d, J = 8.4 Hz, 1H), 3.24 (d, J = 10.8 Hz, 1H), 2.97 (s, 3H), 2.68 - 2.59 (m, 1H), 2.35 - 2.25 (m, 1H), 2.03 - 1.62 (m, 15H), 1.44 - 1.18 (m, 10H), 1.07 - 1.01 (m, 6H), 0.98 (d, J = 6.0 Hz, 3H), 0.77 (s, 3H) ppm.

[0089] 13 C NMR (100 MHz, DMSO-d6) δ 191.6, 153.3, 136.1, 132.5, 131.9, 130.2, 129.1, 128.4, 127.9, 126.9, 126.5, 124.0, 114.7, 114.0, 109.4, 80.9, 64.8, 62.4, 59.5, 55.9, 52.4, 42.5, 42.1, 41.2, 40.8, 36.0, 35.6, 34.9, 31.9, 30.7, 27.0, 26.8, 26.1, 25.9, 25.2, 23.7, 20.8, 16.7, 16.4, 15.0, 11.7 ppm.

[0090] Example 3 3a-(2-methylbenzimidazole-3-(4-bromobenzoylmethyl) bromide salt)-chimusanol

[0091] According to the flow chart of Example 1: basically the same as the preparation method of Example 2, except that 2-bromo-2-acetylnaphthalene in Example 2 is replaced by 4-bromobenzoylmethyl bromide, to prepare 3a-2-methylbenzimidazole alkyl bromide salt-chimusanol derivative shown in structure 1-2;

[0092]

[0093] White powder, yield 75%;

[0094] 1H NMR (400 MHz, DMSO-d6) δ 8.14 - 7.97 (m, 4H), 7.92 (d, J = 8.0 Hz, 2H), 7.72 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 6.43 (s, 2H), 4.82 (s, 1H), 4.35 (d, J = 6.8 Hz, 1H), 3.81 (d, J = 9.6 Hz, 1H), 3.24 (d, J = 10.4 Hz, 1H), 2.92 (s, 3H), 2.62 (q, J = 12.4 Hz, 1H), 2.33 - 2.21 (m, 1H), 2.04 - 1.21 (m, 25H), 1.09 - 0.87 (m, 9H), 0.77 (s, 3H) ppm.

[0095] 13 C NMR (100 MHz, DMSO-d6) δ 190.5, 152.6, 132.7, 131.9, 131.9, 130.6, 126.3, 125.8, 114.1, 113.5, 108.8, 80.3, 64.2, 61.8, 58.9, 55.3, 51.7, 42.0, 41.5, 40.6, 40.1, 35.4, 35.0, 34.3, 31.3, 30.1, 26.4, 26.2, 25.5, 25.3, 24.6, 23.1, 20.2, 16.1, 15.8, 14.4, 11.1 ppm.

[0096] Example 4 3a-(2-methylbenzimidazole-3-(2-naphthylmethyl) bromide salt)-chimusanol

[0097] According to the flow chart of Example 1: basically the same as the preparation method of Example 2, the difference is that 2-bromo-2-acetylnaphthalene in Example 2 is replaced by 2-naphthylmethyl bromide, to prepare 3a-2-methylbenzimidazole alkyl bromide salt-chimusanol derivative shown in structure 1-3;

[0098]

[0099] White solid, yield 80%;

[0100] 1H NMR (400 MHz, DMSO-d6) δ 8.02 (dd, J = 8.4, 3.2 Hz, 2H), 7.97 - 7.90 (m, 4H), 7.71 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.56 - 7.53 (m, 2H), 7.49 (dd, J = 8.4, 1.6 Hz, 1H), 5.98 (s, 2H), 4.84 - 4.76 (m, 1H), 4.39 - 4.31 (m, 1H), 3.81 (d, J = 8.4 Hz, 1H), 3.24 (d, J = 10.8 Hz, 1H), 3.09 (s, 3H), 2.65 - 2.54 (m, 1H), 2.29 - 2.20 (m, 1H), 1.97 - 1.72 (m, 11H), 1.67 - 1.59 (m, 3H), 1.53 - 1.23 (m, 11H), 1.03 (d, J = 8.0 Hz, 6H), 0.98 (d, J = 6.4 Hz, 3H), 0.77 (s, 3H) ppm.

[0101] 13 C NMR (100 MHz, DMSO-d6) δ 133.2, 133.0, 132.3, 132.1, 130.1, 129.2, 128.3, 128.1, 127.1, 127.1, 126.8, 126.7, 126.4, 125.6, 114.8, 114.1, 109.4, 80.9, 64.8, 62.3, 59.4, 55.9, 48.8, 42.5, 42.1, 41.2, 40.7, 36.0, 35.6, 34.9, 31.9, 30.6, 27.0, 26.9, 26.8, 26.1, 25.9, 25.2, 23.7, 20.8, 16.6, 16.4, 15.0, 12.1 ppm.

[0102] Example 5 3a-(2-methylbenzimidazole-3-(4-methoxybenzoylmethyl) bromo salt)-chikusetsu saponin aglycone

[0103] According to the flow chart of Example 1: substantially the same as the preparation method of Example 2, except that 2-bromo-2-acetylnaphthalene in Example 2 is replaced by 4-methoxybenzoylmethyl bromide, to prepare 3a-2-methylbenzimidazole alkyl bromide-chikusetsu saponin aglycone derivative shown in the structure of Formula 1-4;

[0104]

[0105] White powder, yield 73%;

[0106] 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 8.4 Hz, 2H), 7.72 (t, J = 8.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.40 (s, 2H), 4.82 (t, J = 13.2 Hz, 1H), 4.43 - 4.27 (m, 1H), 3.91 (s, 3H), 3.81 (d, J = 8.4 Hz, 1H), 3.24 (d, J = 10.8 Hz, 1H), 2.91 (s, 3H), 2.67 - 2.55 (m, 1H), 2.34 - 2.21 (m, 1H), 2.02 - 1.58 (m, 14H), 1.54 - 1.14 (m, 11H), 1.12 - 0.90 (m, 9H), 0.77 (s, 3H) ppm.

[0107] 13 C NMR (100 MHz, DMSO-d6) δ 189.2, 164.3, 152.6, 131.9, 131.1, 129.2, 126.5, 126.3, 125.8, 114.1, 113.4, 108.8, 80.3, 64.2, 61.8, 58.9, 55.8, 55.3, 51.4, 42.0, 41.5, 40.6, 40.1, 35.4, 35.0, 34.3, 31.3, 30.1, 26.4, 26.2, 25.5, 25.3, 24.6, 23.1, 20.2, 16.1, 15.8, 14.4, 11.1 ppm.

[0108] Example 6 3a-(2-methylbenzimidazole-3-(4-bromobenzyl) bromide salt)-chimusanol

[0109] According to the flow chart of Example 1: basically the same as the preparation method of Example 2, except that 2-bromo-2-acetylnaphthalene in Example 2 is replaced by 4-bromobenzyl bromide, to prepare 3a-2-methylbenzimidazole alkyl bromide salt-chimusanol derivative shown in the structure of formula 1-5;

[0110]

[0111] White powder, yield 83%;

[0112] 1H NMR (400 MHz, DMSO-d6) δ 7.97 (dd, J = 17.4, 8.4 Hz, 2H), 7.71 (t, J = 7.4 Hz, 1H), 7.65 - 7.57 (m, 3H), 7.34 (d, J = 8.4 Hz, 2H), 5.80 (s, 2H), 4.74 (t, J = 11.6 Hz, 2H), 4.39 - 4.31 (m, 1H), 3.81 (dd, J = 10.8, 2.8 Hz, 1H), 3.24 (d, J = 10.8 Hz, 1H), 3.01 (s, 3H), 2.56 (d, J = 12.4 Hz, 1H), 2.29 - 2.15 (m, 1H), 1.99 - 1.55 (m, 15H), 1.52 - 1.22 (m, 10H), 1.06 - 0.96 (m, 9H), 0.77 (s, 3H) ppm.

[0113] 13 C NMR (100 MHz, DMSO-d6) δ 152.4, 132.3, 130.1, 126.9, 126.5, 114.8, 114.0, 109.4, 80.9, 64.8, 62.3, 59.4, 55.9, 47.9, 42.5, 42.1, 40.7, 36.0, 35.6, 34.9, 31.9, 30.5, 27.0, 26.9, 26.8 26.1, 25.9, 25.1, 23.6, 20.8, 16.7, 16.4, 15.0, 12.0 ppm.

[0114] Example 7 3a-(2-methylbenzimidazole-3-(4-methylbenzyl) bromide salt)-chimusanol

[0115] According to the flow chart of Example 1: substantially the same as the preparation method of Example 2, except that 2-bromo-2-acetylnaphthalene in Example 2 is replaced by 4-methylbenzyl bromide, to prepare 3a-2-methylbenzimidazole alkyl bromide salt-chimusanol derivative shown in the structure of formula 1-6;

[0116]

[0117] White powder, yield 80%;

[0118] 1H NMR (400 MHz, DMSO-d6) δ 8.00 - 7.96 (m, 2H), 7.70 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 5.76 (s, 2H), 4.79 - 4.73 (m, 1H), 4.37 - 4.32 (m, 1H), 3.81 (d, J = 8.4 Hz, 1H), 3.24 (d, J = 10.8 Hz, 1H), 3.03 (s, 3H), 2.56 (d, J = 12.4 Hz, 1H), 2.28 (s, 3H), 2.26 - 2.15 (m, 1H), 1.99 - 1.56 (m, 14H), 1.51 - 1.16 (m, 11H), 1.09 - 1.02 (m, 6H), 0.98 (d, J = 6.0 Hz, 3H), 0.76 (s, 3H) ppm.

[0119] 13 C NMR (100 MHz, DMSO-d6) δ 152.2, 138.2, 131.7, 130.0, 127.9, 126.8, 126.4, 114.7, 114.1, 109.4, 80.9, 64.8, 62.3, 59.4, 55.9, 48.4, 42.5, 42.1, 41.2, 40.7, 36.0, 35.6, 34.9, 31.9, 30.5, 26.9, 26.9, 26.8, 26.0, 25.9, 25.1, 23.6, 21.1, 20.7, 16.7, 16.4, 15.0, 12.0 ppm.

[0120] Example 8 3a-(2-methylbenzimidazole-3-(2-bromobenzyl) bromide salt)-chimusanol

[0121] According to the flow chart of Example 1: substantially the same as the preparation method of Example 2, except that 2-bromo-2-acetylnaphthalene in Example 2 is replaced by 2-bromobenzyl bromide, to prepare 3a-2-methylbenzimidazole alkyl bromide salt-chimusanol derivative shown in the structure of formula 1-7;

[0122]

[0123] White powder, yield 98%;

[0124] 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 8.4 Hz, 1H), 7.79 - 7.70 (m, 3H), 7.60 (t, J = 8.0 Hz, 1H), 7.35 - 7.33 (m, 2H), 7.01 - 6.97 (m, 1H), 5.82 (s, 2H), 4.81 (s, 1H), 4.39 - 4.31 (m, 1H), 3.81 (d, J = 8.4 Hz, 1H), 3.24 (d, J = 11.2 Hz, 1H), 2.98 (s, 3H), 2.65 - 2.55 (m, 1H), 2.30 - 2.19 (m, 1H), 2.00 - 1.60 (m, 15H), 1.53 - 1.26 (m, 10H), 1.04 - 0.97 (m, 9H), 0.77 (s, 3H) ppm.

[0125] 13 C NMR (100 MHz, DMSO-d6) δ 153.0, 133.7, 133.3, 130.8, 128.9, 128.8, 126.9, 126.6, 114.9, 113.8, 109.4, 80.9, 64.8, 62.3, 59.6, 55.9, 49.3, 42.5, 42.1, 41.2, 40.7, 36.0, 35.6, 34.9, 31.9, 30.6, 27.0, 26.9, 26.8, 26.1, 25.9, 25.2, 23.7, 20.8, 16.7, 16.4, 15.0, 12.1 ppm.

[0126] Example 9 3a-(5,6-dimethylbenzimidazole)-jionoside

[0127] According to the flow chart of Example 1:

[0128] 3β-MsO-jionoside shown in the structure of Formula 5 was prepared according to the preparation method of Example 1;

[0129] 3β-MsO-anemarrhena sapogenin of the structure shown in Formula 5 was dissolved in a toluene solution, and cesium carbonate and 5,6-dimethylbenzimidazole were added in a molar ratio of 3β-MsO-anemarrhena sapogenin of the structure shown in Formula 5 / cesium carbonate / 5,6-dimethylbenzimidazole = 1 / 3 / 2, and the amount of toluene was 40 mL / g raw material (total mass of 3β-MsO-anemarrhena sapogenin of the structure shown in Formula 5, cesium carbonate and 5,6-dimethylbenzimidazole). The mixture was heated under reflux and stirred for 12 hours under the protection of gas, and then cooled to room temperature; the solvent was distilled off under reduced pressure, water (50 mL) was added, the organic phase was separated, the aqueous phase was extracted with dichloromethane (50 mL × 3 times), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and the solvent was distilled off under reduced pressure. After silica gel column chromatography, 3α-2-5,6-dimethylbenzimidazolidine-anemarrhena sapogenin ( Figure 1 a4 in the );

[0130]

[0131] White powder, yield 46%;

[0132] 1 H NMR(400MHz,Chloroform-d)δ7.86(s,1H),7.49(s,1H),7.10(s,1H),4.40–4.33(m,1 H),4.18–4.09(m,1H),3.89(dd,J=10.8,2.8Hz,1H),3.24(d,J=11.2Hz,1H),2.31(d, J=9.6Hz,7H),2.01–1.66(m,12H),1.64–1.54(m,3H),1.45–1.27(m,6H),1.25–1.22( m,1H),1.21–1.14(m,4H),1.02–0.99(m,6H),0.94(d,J=6.8Hz,3H),0.72(s,3H)ppm.

[0133] 13 C NMR (100MHz, DMSO-d6) δ138.4,119.3,109.2,108.7,79.9,64.1,61.1,55.4,55.1,42.0,41.2,40.1,39.7,39 .2,35.3,34.5,34.1,32.6,30.8,26.6,26.1,26.0,25.7,25.0,24.8,22.6,19.7,19.2,15.5,15.0,13.3ppm.

[0134] Example 10 3α-(5,6-dimethylbenzimidazole-3-(2-naphthalenecarbonylmethyl) bromide)- jionoside base

[0135] According to the flow chart of Example 1: 3α-2-5,6-dimethylbenzimidazolealkyl- jionoside base of structure shown in formula 4 was dissolved in acetone solvent, 2-bromo-2- acetonaphthalene was added under stirring, the amount was 3α-2-5,6-dimethylbenzimidazolealkyl- jionoside base / 2-bromo-2-acetonaphthalene = 1 / 2 (molar ratio), the amount of acetone was 80 mL / g of raw material (total mass of 3α-2-5,6-dimethylbenzimidazolealkyl-jionoside base and 2-bromo-2-acetonaphthalene), the reaction was stirred and refluxed for 24 hours, cooled to room temperature, a solid precipitate was separated out, filtered, the precipitate was washed with ethyl acetate (20 mL) for several times, dried, to prepare 3α-5,6-dimethylbenzimidazolealkyl bromide-jionoside base derivative of structure shown in formula 2-1;

[0136]

[0137] White powder, yield 98%;

[0138] 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.95 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.12 - 8.07 (t, J = 6.8 Hz, 2H), 8.02 (s, 1H), 7.91 (s, 1H), 7.79 - 7.70 (m, 2H), 6.47 (s, 2H), 4.85 - 4.79 (t, J = 12.4 Hz, 1H), 4.30 - 4.25 (m, 1H), 3.76 (d, J = 10.4 Hz, 1H), 3.20 (d, J = 10.8 Hz, 1H), 2.42 (m, 7H), 1.98 - 1.61 (m, 15H), 1.44 - 1.15 (m, 11H), 1.03 - 0.99 (m, 6H), 0.92 (d, J = 6.8 Hz, 3H), 0.74 (s, 3H) ppm.

[0139] 13C NMR (100 MHz, DMSO-d6) δ 191.7, 141.3, 132.5, 131.5, 131.3, 130.2, 129.9, 129.5, 129.3, 128.4, 127.9, 123.8, 113.9, 113.8, 109.4, 80.9, 64.8, 62.5, 57.6, 56.0, 53.5, 42.4, 42.1, 35.7, 35.5, 35.0, 32.9, 31.9, 27.5, 26.9, 26.6, 26.0, 25.9, 23.6, 20.8, 20.4, 16.6, 16.4, 14.9 ppm.

[0140] Example 11 3a-(5,6-dimethylbenzimidazole-3-(4-bromobenzoylmethyl) bromide salt)-chimeroside aglycone

[0141] According to the flow chart of Example 1: substantially the same as the preparation method of Example 10, except that 2-bromo-2-acetylnaphthalene in Example 10 is replaced by 4-bromobenzoylmethyl bromide, to prepare 3a-5,6-dimethylbenzimidazole alkyl bromide salt-chimeroside aglycone derivative shown in formula 2-2;

[0142]

[0143] White powder, yield 71 %;

[0144] 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.93 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.78 (s, 1H), 6.23 (s, 2H), 4.76 - 4.68 (m, 1H), 4.24 - 4.18 (m, 1H), 3.70 (d, J = 8.4 Hz, 1H), 3.14 (d, J = 10.8 Hz, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 2.28 - 2.21 (m, 1H), 1.89 - 1.54 (m, 15H), 1.37 - 1.08 (m, 11H), 0.94 (m, 6H), 0.86 (d, J = 7.2 Hz, 3H), 0.67 (s, 3H) ppm.

[0145] 13C NMR (100 MHz, DMSO-d6) δ 191.1, 141.1, 136.7, 132.7, 130.8, 130.8, 129.4, 113.9, 113.8, 109.4, 80.9, 64.8, 62.5, 57.6, 56.0, 53.5, 42.4, 42.1, 35.7, 35.5, 35.0, 32.9, 31.9, 27.5, 26.9, 26.5, 26.0, 25.9, 23.6, 20.8, 20.5, 16.6, 16.4, 15.0 ppm.

[0146] Example 12 3a-(5,6-dimethylbenzimidazole-3-(2-naphthylmethyl) bromide salt)-chimusanol

[0147] Following the flow chart of Example 1: essentially the same as the preparation method of Example 10, except that 2-bromo-2-acetylnaphthalene in Example 10 is replaced by 2-naphthylmethyl bromide, to prepare 3a-5,6-dimethylbenzimidazole alkyl bromide salt-chimusanol derivative shown in the structure of Formula 1-3;

[0148]

[0149] White solid, yield 73%;

[0150] 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.05 (s, 1H), 8.01 - 7.90 (m, 4H), 7.73 (s, 1H), 7.62 - 7.51 (m, 3H), 5.88 (s, 2H), 4.80 - 4.67 (m, 1H), 4.37 - 4.25 (m, 1H), 3.22 (d, J = 10.8 Hz, 1H), 2.36 (d, J = 22.8 Hz, 7H), 2.03 - 1.61 (m, 15H), 1.46 - 1.16 (m, 11H), 1.02 (m, 6H), 0.95 (d, J = 6.8 Hz, 3H), 0.75 (s, 3H) ppm.

[0151] 13C NMR (100 MHz, DMSO-d6) δ 140.5, 133.2, 132.3, 129.8, 129.2, 128.4, 128.2, 127.3, 127.2, 127.1, 125.7, 114.0, 113.7, 109.4, 80.9, 64.8, 62.5, 57.8, 56.0, 50.5, 42.5, 42.1, 40.7, 35.7, 35.6, 35.1, 32.8, 31.9, 27.4, 27.0, 26.9, 26.6, 26.0, 25.9, 23.6, 20.8, 20.5, 20.4, 16.6, 16.4, 15.0 ppm.

[0152] Example 13 3a-(5,6-dimethylbenzimidazole-3-(4-methoxybenzoylmethyl) bromo salt)-chimeroside aglycone

[0153] Following the flow chart of Example 1: essentially the same as the preparation method of Example 10, except that 2-bromo-2-acetylnaphthalene in Example 10 is replaced by 4-methoxybenzoylmethyl bromide, to prepare 3a-5,6-dimethylbenzimidazole alkyl bromide-chimeroside aglycone derivative shown in the structure of Formula 1-4;

[0154]

[0155] White powder, yield 99%;

[0156] 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.11 (d, J = 9.2 Hz, 2H), 8.00 (s, 1H), 7.83 (s, 1H), 7.20 (d, J = 9.2 Hz, 2H), 6.26 (s, 2H), 4.83 - 4.75 (m, 1H), 4.31 - 4.25 (m, 1H), 3.91 (s, 3H), 3.77 (m, 1H), 3.21 (d, J = 10.8 Hz, 1H), 2.41 (m, 7H), 1.99 - 1.60 (m, 15H), 1.44 - 1.13 (m, 11H), 1.01 (m, 6H), 0.93 (d, J = 6.8 Hz, 3H), 0.74 (s, 3H) ppm.

[0157] 13C NMR (100 MHz, DMSO-d6) δ 189.9, 164.7, 141.2, 137.0, 136.6, 131.3, 129.4, 114.9, 113.8, 113.8, 109.4, 80.9, 64.8, 62.5, 57.6, 56.3, 56.0, 53.1, 42.4, 42.1, 35.7, 35.5, 35.0, 32.9, 31.9, 27.5, 26.9, 26.5, 26.0, 25.9, 23.6, 20.8, 20.4, 16.6, 16.4, 14.9 ppm.

[0158] Example 14 3a-(5,6-dimethylbenzimidazole-3-(4-bromobenzyl) bromide salt)-chimeroside aglycone

[0159] Following the flow chart of Example 1: essentially the same as the preparation method of Example 10, except that 2-bromo-2-acetylnaphthalene in Example 10 is replaced by 4-bromobenzyl bromide, to prepare 3a-5,6-dimethylbenzimidazole aglycone bromide salt-chimeroside aglycone derivative shown in the structure of Formula 1-5;

[0160]

[0161] White powder, yield 75%;

[0162] 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (d, J = 4.0 Hz, 1H), 7.96 (s, 1H), 7.68 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 5.70 (s, 2H), 4.74 - 4.67 (m, 1H), 4.33 - 4.28 (m, 1H), 3.79 (d, J = 8.4 Hz, 1H), 3.22 (d, J = 10.4 Hz, 1H), 2.38 (d, J = 15.6 Hz, 7H), 1.97 - 1.63 (m, 15H), 1.45 - 1.15 (m, 11H), 1.01 (d, J = 6.8 Hz, 6H), 0.95 (d, J = 6.8 Hz, 3H), 0.75 (s, 3H) ppm.

[0163] 13C NMR (100 MHz, DMSO-d6) δ 140.4, 137.0, 136.8, 134.2, 132.3, 130.6, 114.1, 113.6, 109.4, 80.9, 64.8, 62.5, 57.8, 56.0, 49.6, 42.5, 42.1, 35.7, 35.6, 35.1, 32.8, 31.9, 27.4, 27.0, 26.9, 26.6, 26.0, 25.9, 23.6, 20.8, 20.5, 20.4, 16.6, 16.4, 15.0 ppm.

[0164] Example 15 3a-(5,6-dimethylbenzimidazol-3-(4-methylbenzyl) bromide salt)-chimeroside

[0165] According to the flow chart of Example 1: substantially the same as the preparation method of Example 10, except that 2-bromo-2-acetylnaphthalene in Example 10 is replaced by 4-methylbenzyl bromide, to prepare

[0166] 3a-5,6-dimethylbenzimidazole alkyl bromide salt-chimeroside derivative of the structure shown in formula 1-6;

[0167]

[0168] White powder, yield 96%;

[0169] 1 H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 5.65 (s, 2H), 4.76 - 4.65 (t, J = 11.6 Hz, 1H), 4.36 - 4.26 (dd, J = 14.8, 7.6 Hz, 1H), 3.79 (dd, J = 11.2, 2.8 Hz, 1H), 3.22 (d, J = 11.2 Hz, 1H), 2.37 (d, J = 15.2 Hz, 7H), 2.28 (s, 3H), 1.98 - 1.60 (m, 15H), 1.46 - 1.16 (m, 11H), 1.01 (d, J = 6.4 Hz, 6H), 0.95 (d, J = 6.8 Hz, 3H), 0.75 (s, 3H) ppm.

[0170] 13C NMR (100 MHz, DMSO-d6) δ 140.2, 136.8, 131.8, 129.9, 129.7, 128.4, 114.0, 113.7, 109.4, 80.9, 64.8, 62.5, 57.7, 56.0, 50.2, 42.5, 42.1, 35.7, 35.6, 35.1, 32.9, 31.9, 27.5, 27.0, 26.9, 26.6, 26.1, 25.9, 23.6, 21.2, 20.8, 20.5, 20.4, 16.6, 16.4, 15.0 ppm.

[0171] Example 16 3a-(5,6-dimethylbenzimidazole-3-(2-bromobenzyl) bromide salt)-chimeroside aglycone

[0172] Following the flow chart of Example 1: essentially the same as the preparation method of Example 10, except that 2-bromo-2-acetylnaphthalene in Example 10 is replaced by 2-bromobenzyl bromide, to prepare 3a-5,6-dimethylbenzimidazole aglycone bromide salt-chimeroside aglycone derivative shown in the structure of Formula 1-7;

[0173]

[0174] White powder, yield 97%;

[0175] 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.02 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.60 (s, 1H), 7.41 - 7.32 (m, 2H), 7.04 (d, J = 5.2 Hz, 1H), 5.79 (s, 2H), 7.41 - 7.32 (m, 2H), 4.80 - 4.73 (t, J = 12 Hz, 1H), 3.78 (d, J = 8.4 Hz, 1H), 3.22 (d, J = 10.8 Hz, 1H), 2.38 (d, J = 29.6 Hz, 7H), 1.96 - 1.62 (m, 15H), 1.44 - 1.14 (m, 11H), 1.01 (d, J = 8.0 Hz, 6H), 0.94 (d, J = 6.8 Hz, 3H), 0.75 (s, 3H) ppm.

[0176] 13C NMR (100 MHz, DMSO-d6) δ 141.3, 137.2, 136.9, 133.7, 133.6, 131.0, 129.3, 128.9, 122.6, 114.1, 113.6, 109.4, 80.9, 64.8, 62.5, 57.8, 56.0, 50.8, 42.48, 42.1, 40.7, 35.7, 35.5, 35.1, 32.8, 31.9, 27.4, 27.0, 26.9, 26.6, 26.0, 25.9, 23.6, 20.8, 20.5, 20.4, 16.6, 16.4, 15.0 ppm.

[0177] Test Example

[0178] In vitro anti-tumor cytotoxic activity experiment of the example compounds:

[0179] The 2-methylbenzimidazole alkyl bromide salt of the structure shown in formula 3 - timosaponin, the 2-methylbenzimidazole alkyl bromide salt of the structure shown in formula 1-1 ~ 1-7 - timosaponin, the 2-5,6-dimethylbenzimidazole alkyl - timosaponin of the structure shown in formula 4 and the 5,6-dimethylbenzimidazole alkyl bromide salt of the structure shown in formula 2-1 ~ 2-7 - timosaponin derivatives were screened for cytotoxic activity according to the MTS method on five cell strains of leukemia (K562), liver cancer (SMMC-7721), lung cancer (A-549), breast cancer (MCF-7) and human normal breast epithelial cells (MCF10A). The half lethal dose IC 50 The results of the determination of the half lethal dose IC50 of some compounds are compared with the commercially available anticancer drug cisplatin (DDP) in Table 1.

[0180] Table 1 Test results of in vitro anti-tumor cytotoxic activity experiment of the example compounds

[0181]

[0182]

[0183] The above data show that the compounds of formula 1-1 to 1-7 and formula 2-1 to 2-7 all have significant in vitro tumor growth inhibition activity on four human cancer cell lines (leukemia, liver cancer, lung cancer, breast cancer), and the in vitro tumor growth inhibition activity of the 16 compounds is better than that of the anticancer drug cisplatin (DDP). In particular, the compounds of formula 2-6 and formula 2-7 have in vitro anti-tumor cell toxicity activity on K562, SMMC-7721, A-549, and MCF-7 cell lines, which is 13.2 times, 23.6 times, 12.8 times, 80.8 times, and 13.2 times, 9.5 times, 14.0 times, 77.8 times that of DDP, respectively. They have very good activity and certain selectivity on breast cancer cells.

[0184] Although the above examples make a detailed description of the present application, it is only a part of the embodiments of the present application, not all the embodiments, and other embodiments can be obtained according to the present embodiments without creativity, which all belong to the protection scope of the present application.

Claims

1. A benzimidazolyl bromide-animathyrsapogenin derivative, characterized in that: It has the structure shown in formula 2: Formula 2; In formula 2, R 2 It is 4-methylbenzyl or 2-bromobenzyl.

2. The method for preparing the benzimidazolyl bromide-timosaponin derivative according to claim 1, wherein: The following steps are involved: The 5,6-dimethylbenzimidazolidine-anemasaponin of the structure shown in formula 4, a bromination reagent and an organic solvent are mixed to form a salt to obtain a benzimidazolidine-anemasaponin derivative of the structure shown in formula 2; the bromination reagent is R 2 -Br; Formula 4.

3. The preparation method according to claim 2, characterized in that The preparation method of 5,6-dimethylbenzimidazolidinyl-anemarrhena sapogenin of the structure shown in Formula 4 comprises the following steps: Mixing timosaponin, an organic base, methylsulfonyl chloride and an organic solvent to carry out a sulfonylation reaction to obtain MsO-timosaponin of the structure shown in Formula 5; Formula 5; 5,6-dimethylbenzimidazole, the MsO-timosaponin, an alkali metal carbonate and an organic solvent are mixed to carry out an imidazole cyclization reaction to obtain 5,6-dimethylbenzimidazolidine-timosaponin with a structure shown in formula 4.

4. The preparation method according to claim 2, characterized in that The molar ratio of 5,6-dimethylbenzimidazolidinyl-anemarrhena sapogenin of the structure shown in Formula 4 to the bromination reagent is 1:(1~2).

5. The preparation method according to claim 2 or 4, characterized in that The salt-forming reaction is carried out under reflux conditions, and the holding time of the salt-forming reaction is 24 to 48 hours.

6. The preparation method according to claim 3, characterized in that The organic base is triethylamine; the molar ratio of the timosaponin, the organic base and the methanesulfonyl chloride is 1:3:1.

5.

7. The preparation method according to claim 3 or 6, characterized in that The temperature of the sulfonylation reaction is room temperature, and the time of the sulfonylation reaction is 2 h.

8. The preparation method according to claim 3, characterized in that The alkali metal carbonate includes cesium carbonate and / or sodium carbonate; The molar ratio of the 5,6-dimethylbenzimidazole, the MsO-timosaponin and the alkali metal carbonate is 2:1:

3.

9. The preparation method according to claim 3 or 8, characterized in that The imidazole cyclization reaction is carried out in a protective gas atmosphere, the imidazole cyclization reaction is carried out under reflux conditions, and the insulation time of the imidazole cyclization reaction is 12 to 24 hours.

10. Use of the benzimidazolyl bromide-timosaponin derivative according to claim 1 or the benzimidazolyl bromide-timosaponin derivative prepared by the preparation method according to any one of claims 2 to 9 in the preparation of antitumor drugs.

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