CN107522766A

CN107522766A - One kind has ursolic acid quinolyl hydrazide derivatives of antitumor activity and its preparation method and application

Info

Publication number: CN107522766A
Application number: CN201710718110.5A
Authority: CN
Inventors: 谷文; 金晓燕; 陶徐兵; 陈浩; 耿艺; 王石发
Original assignee: Nanjing Forestry University
Current assignee: Nanjing Forestry University
Priority date: 2017-08-21
Filing date: 2017-08-21
Publication date: 2017-12-29
Anticipated expiration: 2037-08-21
Also published as: CN107522766B

Abstract

Disclose a kind of ursolic acid quinoline hydrazide derivative with antitumor activity and its preparation method and application.A kind of the ursolic acid quinoline hydrazides class Hete rocyclic derivatives and its pharmaceutically acceptable salt with structure shown in formula I of the present invention：Wherein, I a：R₁=H R₂=CH₃；I‑b：R₁=OMe R₂=CH₃；I‑c：R₁=F R₂=CH₃；I‑d：R₁=Cl R₂=CH₃；I‑e：R₁=H R₂=n C₄H₉；I‑f：R₁=OMe R₂=n C₄H₉；I‑g：R₁=F R₂=n C₄H₉；I‑h：R₁=Cl R₂=n C₄H₉A kind of ursolic acid quinoline hydrazides class Hete rocyclic derivatives and its pharmaceutically acceptable salt involved in the present invention have significant antitumor activity, pharmacological experiment shows, the ursolic acid quinoline hydrazide derivative of the present invention has significant inhibitory action to human breast cancer cell MDA MB 231, human cervical carcinoma cell HeLa and human liver cancer cell SMMC 7721, and hypotoxicity is shown to the normal liver epithelial cell QSG 7701 of people, the potentiality with developing anti-tumor medicaments.

Description

One kind has ursolic acid quinolyl hydrazide derivatives and its preparation side of antitumor activity Method and application

Technical field

The present invention relates to organic synthesis and medicinal chemistry art, and in particular to one kind has the ursolic acid quinoline of antitumor activity Quinoline hydrazides class Hete rocyclic derivatives and its preparation method and application.

Background technology

Malignancy Tumor is serious threat human health and the disease of social development.According to the newest system of the World Health Organization Count, the whole world every year has 8,800,000 people to die from cancer, account for the whole world every year total toll about 1/6, and Chinese malignant tumour Number of the infected accounts for the 21.8% of the whole world.Three big means of oncotherapy are respectively operative treatment, radiotherapy (abbreviation radiotherapy) With chemotherapy (abbreviation chemotherapy).Wherein chemotherapy uses DNA synthetic inhibitors or thin as a kind of conventional treatments Born of the same parents divide the cellulotoxic preparation of inhibitor etc to suppress tumour cell, but simultaneously, these preparations can also kill normal propagation Faster cell, cause the symptoms such as infection, bleeding.Therefore, selectivity is developed compared with, the tumor suppression that security is good, curative effect is high Medicine is the important directions of modern tumor disease research.

Ursolic acid (ursolic acid, UA) also known as ursolic acid, malol, are Ursane pentacyclic triterpenoids. Ursolic acid is widely distributed in plant, is distributed in the various plants such as tea tree, fruit tree, medicinal plant, herb plant and paulownia, according to Statistics, the isolated ursolic acid in existing 34 section, the 108 kinds of plants of nature, thus be a kind of aboundresources, have exploitation latent The active components of plants of power.Ursolic acid has anticancer, anti-inflammatory, anti-oxidant, anti-diabetic, antiviral, liver protection and strengthen immunity Etc. multiple biological activities.Wherein, its antitumaous effect has obtained increasing concern.The mechanism of anticancer action of ursolic acid includes Many aspects, such as CDCC, inducing cell necrosis and apoptosis, epidermal growth factor receptor kinase inhibitory action, DNA polymerizations Enzyme and topoisomerase enzyme inhibition and Antineoplastic angiogenesis effect etc..But because the bioavilability of ursolic acid is relatively low, one Determine to limit its application clinically in degree.Therefore need to improve the anti-of ursolic acid by the method for modifying for chemical structure Cancer activity and bioavilability.The research both at home and abroad on the structure derivatization of ursolic acid is concentrated mainly on three sites at present： (1) C-28 positions carboxyl；(2) A rings C-3 positions hydroxyl；(3) C rings double bond.But the current report on ursolic acid Hete rocyclic derivatives both at home and abroad Road is still considerably less.

Quinolines refer to quinoline and its homologue, are a kind of important nitrogen-containing heterocycle compounds, such chemical combination Thing has the bioactivity such as good antibacterial, antitumor, is one of newtype drug and the focus of pesticide research exploitation.Protected in medical treatment Strong aspect quinolines are widely used in the treatment and prevention of the diseases such as malaria, ulcer, cancer, inhibition of HIV and schizophrenia. Quinoline is a ring core with stronger pharmacological activity, can show to resist after introducing quinoline ring in the molecule of some compounds Bacterium, anti-inflammatory analgesic, antitumor and viral isoreactivity.Hydrazide kind compound is a kind of nitrogenous heteroatomic compound, and many contains The compound of hydrazides group has the bioactivity such as antiviral, anti-inflammatory, anticancer, is a very important drug effect in medicament research and development Group.Therefore the quinoline ring with different substituents is introduced on black bearberry acid molecule A rings, carrying out structural modification to its carboxyl introduces acyl Diazanyl simultaneously carries out biological activity test, and the acquisition preferably new ursolic acid quinoline hydrazide derivative of bioactivity will have important Chemistry and biology meaning.

The content of the invention

In order to overcome above-mentioned weak point of the prior art, it is an object of the invention to provide a kind of antitumor activity is higher Ursolic acid quinoline hydrazides class Hete rocyclic derivatives with antitumor activity and its preparation method and application.

In order to realize above-mentioned technical purpose, the technical solution adopted by the present invention it is as follows：One kind of the present invention has anti-swollen The ursolic acid quinoline hydrazide derivative and its pharmaceutically acceptable salt of tumor activity：

Wherein, I-a：R₁=H R₂=CH₃；I-b：R₁=OMe R₂=CH₃；I-c：R₁=F R₂=CH₃；I-d：R₁=Cl R₂=CH₃；

I-e：R₁=H R₂=n-C₄H₉；I-f：R₁=OMe R₂=n-C₄H₉；I-g：R₁=F R₂=n-C₄H₉；I-h：R₁= Cl R₂=n-C₄H₉。

Described one kind of the present invention has the preparation method of the ursolic acid quinoline hydrazide derivative of antitumor activity, bag Include following steps：

(1) ursolic acid obtains 3- oxidation ursolic acid by Jones reagent oxidation reaction, has structure shown in formula II：

；

(2) o-nitrobenzaldehyde of different substituents reduces in the presence of Fe/HCl and obtains corresponding o-amino benzoyl Aldehyde, 3- aoxidize ursolic acid to the o-Aminobenzaldehyde of different substituents the condensation reaction under alkalescence condition nitrogen atmosphere obtain it is corresponding The ursolic acid quinoline containing different substituents, there is structure shown in general formula III：

Wherein, III-a：R₁=H；III-b：R₁=OMe；III-c：R₁=F；III-d：R₁=Cl；

(3) the ursolic acid quinoline of different substituents obtains the acyl chlorides of corresponding ursolic acid quinoline in the presence of thionyl chloride Change compound, there is structure shown in formula IV：

Wherein, IV-a：R₁=H；IV-b：R₁=OM_e；IV-c：R₁=F；IV-d：R₁=Cl；

(4) the chloride compound of the ursolic acid quinoline of different substituents is reacted with acethydrazide and valeric acid hydrazine in alkalescence condition The hydrazide derivatives of corresponding ursolic acid quinoline are obtained, there is structure shown in formula I：

Further, in step (1), 3- oxidation ursolic acid II synthesis

Add ursolic acid and acetone in 500mL round-bottomed flask, after stirring and dissolving in frozen water stirring reaction 15min, After Jones reagent is slowly added dropwise and is warmed to room temperature stirring reaction 5h, isopropanol stirring reaction 30min is added, reaction filters off after terminating Precipitation collects filtrate, and the white needles that the chartreuse thick solid that filtrate decompression is concentrated to give is obtained with recrystallizing methanol are brilliant Body, 3- oxidation ursolic acid II is made；The molal volume ratio of the ursolic acid and acetone is 0.0184mol/L；The acetone, Jones The volume ratio of reagent and isopropanol is 250: 1.9: 90；

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-a synthesis

2- nitrobenzaldehydes are stirred in ethanol, acetic acid, distilled water and are to slowly warm up to 50 DEG C, are added also after being completely dissolved Former iron powder and 600 μ L concentrated hydrochloric acids, continue to be heated to 85 DEG C of back flow reaction 1h, mixed liquor is filtered and is washed with water after stopping reaction Filter residue, merging filtrate, 3 collection organic phases are extracted with dichloromethane, it is each to wash 3 times, saturated sodium bicarbonate solution and strong brine To wash and once removed water afterwards with anhydrous sodium sulfate, it is 2- aminobenzaldehyde crude products that the removing organic solvent that is concentrated under reduced pressure, which obtains yellow solid, It is directly used in the unsubstituted ursolic acid quinoline of synthesis；The mol ratio of the 2- nitrobenzaldehydes and reduced iron powder is 1:10；The second Alcohol, acetic acid, the volume ratio of distilled water are 2:2:1；The 2- nitrobenzaldehydes rub with the cumulative volume of ethanol, acetic acid and distilled water Your volume is 0.15mol/L；The volume ratio 0.6 of the concentrated hydrochloric acid and the cumulative volume of ethanol, acetic acid and distilled water：20；

The ethanol solution that 3- in 50mL three neck round bottom flask is aoxidized to ursolic acid II and 2- aminobenzaldehyde is protected in nitrogen Under 2.4mL saturation potassium hydroxide-ethanol solution, 85 DEG C of back flow reaction 24h is added dropwise, reaction pours into reaction solution after terminating In mixture of ice and water, after ice-out with dichloromethane extract 3 times collection organic phases, washing 3 times, saturated sodium bicarbonate solution and Strong brine is respectively washed once to be removed water with anhydrous sodium sulfate afterwards, and the removing organic solvent that is concentrated under reduced pressure obtains yellow solid, with silicagel column pair It is isolated and purified, and solvent selects petroleum ether acetone system, and the volume ratio of the petroleum ether and acetone is 150:1, it is made pure Compound ursolic acid quinolines Hete rocyclic derivatives III-a；

The mol ratio of the 3- oxidation ursolic acid and the ethanol solution of 2- aminobenzaldehydes is 2：3；The 3- aoxidizes black bearberry The mass volume ratio of acid and saturation potassium hydroxide-ethanol solution is 0.35g/mL；

In step (3), ursolic acid quinoline chloride compound IV-a synthesis

Compound III-a 5mL benzene is dissolved, thionyl chloride is then slowly added dropwise, it is anti-to be to slowly warm up to 80 DEG C of backflows Should about 4h, stop the benzene in reaction solution and thionyl chloride are steamed to obtain to the compound IV-a of pale-yellow solid after reaction and be used for Subsequent reactions；The mol ratio of the compound III-a and thionyl chloride, benzene is 0.15:3:56；

In step (4), ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-a synthesis

Gained ursolic acid quinoline chloride compound IV-a is dissolved in 5mL ether, 0 DEG C is cooled to, by acethydrazide, triethylamine It is dissolved in 2mL dichloromethane and is added dropwise in reaction vessel, is slowly increased to that reaction 6h is stirred at room temperature, reaction will be anti-after terminating Answer liquid to pour into mixture of ice and water, extract 3 collection organic phases with dichloromethane after ice-out, wash 3 times, unsaturated carbonate hydrogen Sodium solution and strong brine are respectively washed once to be removed water with anhydrous sodium sulfate afterwards, and the removing organic solvent that is concentrated under reduced pressure obtains yellow solid, uses Silicagel column isolates and purifies to it, and solvent selects petroleum ether acetone system, and the volume ratio of the petroleum ether and acetone is 30:1, Pure compound ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-a is made；The IV-a, acethydrazide and triethylamine, ether, dichloromethane The mol ratio of alkane is 0.15:0.225:0.3:48:76；

Further, in step (1), 3- oxidation ursolic acid II synthesis

Add ursolic acid and acetone in 500mL round-bottomed flask, after stirring and dissolving in frozen water stirring reaction 15min, After 1.872mL Jones reagent is slowly added dropwise and is warmed to room temperature stirring reaction 5h, isopropanol stirring reaction 30min, reaction are added Precipitation is filtered off after end and collects filtrate, what the chartreuse thick solid that filtrate decompression is concentrated to give was obtained with recrystallizing methanol White needle-like crystals, 3- oxidation ursolic acid II is made；The molal volume ratio of the ursolic acid and acetone is 0.0184mol/L；Institute The volume ratio for stating acetone, Jones reagent and isopropanol is 250：1.9：90；

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-a synthesis

The mass ratio of the 3- oxidation ursolic acid and the ethanol solution of 2- aminobenzaldehydes is 2：3；The 3- aoxidizes black bearberry The mass volume ratio of acid and saturation potassium hydroxide-ethanol solution is 0.35g/mL；

In step (3), ursolic acid quinoline chloride compound IV-a synthesis

In step (4), ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-e synthesis

Gained compound IV-a is dissolved in 5mL ether, is cooled to 0 DEG C, and valeric acid hydrazine, triethylamine are dissolved in 2mL dichloromethane In alkane and it is added dropwise in reaction vessel, is slowly increased to that reaction 6h is stirred at room temperature, reaction solution is poured into frozen water after terminating and mixed by reaction In compound, 3 collection organic phases are extracted with dichloromethane after ice-out, washing 3 times, saturated sodium bicarbonate solution and strong brine Respectively wash and once removed water afterwards with anhydrous sodium sulfate, the removing organic solvent that is concentrated under reduced pressure obtains yellow solid, and it is carried out with silicagel column Isolate and purify, solvent selects petroleum ether acetone system, and the volume ratio of the petroleum ether and acetone is 80:1, pure compound bear is made Tartaric acid quinoline hydrazides class Hete rocyclic derivatives I-e；The IV-a, the mol ratio of valeric acid hydrazine and triethylamine, ether, dichloromethane are 0.15:0.225:0.3:48:76。

Further, in step (1), 3- oxidation ursolic acid II synthesis

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-b synthesis

5- hydroxyl -2- nitrobenzaldehydes, methyl iodide, potassium carbonate and N, the N- diformazan added in 50mL round-bottomed flask Base formamide, reaction 8h is stirred at room temperature, reaction pours into reaction solution in mixture of ice and water after terminating, with two after ice-out Chloromethanes extracts 3 collection organic phases, and washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once use anhydrous slufuric acid afterwards Sodium removes water, and it is 5- methoxyl group -2- nitrobenzaldehydes 100% that the removing organic solvent that is concentrated under reduced pressure, which obtains yellow solid,；The 5- hydroxyls The mol ratio of base -2- nitrobenzaldehydes, methyl iodide and potassium carbonate is 4:6:6；Methyl iodide and N, N- the dimethyl formyl The volume ratio of amine is 0.4：10；

5- methoxyl group -2- nitrobenzaldehydes are stirred in ethanol, acetic acid, distilled water and are to slowly warm up to 50 DEG C, it is completely molten Reduced iron powder and 600 μ L concentrated hydrochloric acids are added after solution, continues to be heated to 85 DEG C of back flow reaction 1h, filters mixed liquor after stopping reaction And filter residue is washed with water, merging filtrate, 3 collection organic phases are extracted with dichloromethane, wash 3 times, saturated sodium bicarbonate solution Respectively wash with strong brine and once removed water afterwards with anhydrous sodium sulfate, it is 5- methoxies that the removing organic solvent that is concentrated under reduced pressure, which obtains yellow solid, Base -2- aminobenzaldehyde crude products are directly used in synthesizing methoxy ursolic acid quinoline；5- methoxyl groups -2- the nitrobenzaldehydes and second Alcohol, acetic acid, the mass volume ratio of cumulative volume of distilled water are 0.02g/mL；The ethanol, acetic acid, the volume ratio of distilled water are 2: 2:1；The mol ratio of the 5- methoxyl groups -2- nitrobenzaldehydes and reduced iron powder is 1:10；The ethanol, acetic acid, distilled water The volume ratio of cumulative volume and concentrated hydrochloric acid is 175：6；

By 0.445g (1mmol) 3- oxidation ursolic acid II and 0.225g (1.5mmol) in 50mL three neck round bottom flask 2mL saturation potassium hydroxide-ethanol solution is added dropwise in the ethanol solution of 5- methoxyl group -2- aminobenzaldehydes under nitrogen protection, 85 DEG C of back flow reaction 24h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 are extracted with dichloromethane after ice-out Secondary collection organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, depressurized Concentration removes organic solvent and obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, The volume ratio of the petroleum ether and acetone is 100:1, pure compound ursolic acid quinolines Hete rocyclic derivatives III-b is made；It is described It is 2 that 3-, which aoxidizes ursolic acid and the mol ratio of the ethanol solution of 5- methoxyl group -2- aminobenzaldehydes,：3；3- oxidation ursolic acid with The mass volume ratio of saturation potassium hydroxide-ethanol solution is 0.22g/mL；

In step (3), ursolic acid quinoline chloride compound IV-b synthesis

0.085g (0.15mmol) compound III-b 5mL benzene is dissolved, 200 μ L (3mmol) are then slowly added dropwise Thionyl chloride, 80 DEG C of back flow reaction about 4h are to slowly warm up to, steam the benzene in reaction solution and thionyl chloride after stopping reaction Compound IV-b to pale-yellow solid is used for subsequent reactions；The compound III-b and thionyl chloride, benzene mol ratio is 0.15:3:56；

In step (4), ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-b synthesis

Gained compound IV-b is dissolved in 5mL ether, is cooled to 0 DEG C, by 17.1mg (0.225mmol) acethydrazide, 45 μ L (0.3mmol) triethylamine is dissolved in 2mL dichloromethane and is added dropwise in reaction vessel, is slowly increased to be stirred at room temperature instead 6h, reaction is answered to pour into reaction solution in mixture of ice and water after terminating, it is organic with dichloromethane 3 collections of extraction after ice-out Phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and the removing that is concentrated under reduced pressure has Solvent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the petroleum ether Volume ratio with acetone is 30:1, pure compound ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-b is made；The IV-b, acetyl The mol ratio of hydrazine and triethylamine, ether, dichloromethane is 0.15:0.225:0.3:48:76；

Further, in step (1), 3- oxidation ursolic acid II synthesis

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-b synthesis

0.668g (4mmol) 5- hydroxyl -2- nitrobenzaldehydes, 400 μ L (6mmol) are added in 50mL round-bottomed flask Methyl iodide, 0.832g (6mmol) potassium carbonate and 10mL DMF, be stirred at room temperature reaction 8h, Reaction pours into reaction solution in mixture of ice and water after terminating, and 3 collection organic phases, washing are extracted with dichloromethane after ice-out 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed once to be removed water with anhydrous sodium sulfate afterwards, and the removing organic solvent that is concentrated under reduced pressure obtains It is 5- methoxyl group -2- nitrobenzaldehydes (0.52g, 100%) to yellow solid；5- hydroxyls -2- the nitrobenzaldehydes, iodate first The mol ratio of alkane and potassium carbonate is 4:6:6；The volume ratio of the methyl iodide and N,N-dimethylformamide is 0.4：10；

By 0.36g (2mmol) 5- methoxyl group -2- nitrobenzaldehydes in ethanol, acetic acid, distilled water (2:2:1,17.5mL) Middle stirring is to slowly warm up to 50 DEG C, and 1.12g (20mmol) reduced iron powders and 600 μ L concentrated hydrochloric acids are added after being completely dissolved, and continues to add Mixed liquor is filtered to 85 DEG C of back flow reaction 1h and filter residue is washed with water, merging filtrate, extracted with dichloromethane by heat after stopping reaction Take 3 collection organic phases, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are subtracted It is that 5- methoxyl group -2- aminobenzaldehydes crude products (0.24g) are directly used in synthesis that pressure concentration, which removes organic solvent and obtains yellow solid, Methoxyl group ursolic acid quinoline；5- methoxyl groups -2- the nitrobenzaldehydes and ethanol, acetic acid, distilled water cumulative volume mass body Product ratio is 0.02g/mL；The ethanol, acetic acid, the volume ratio of distilled water are 2:2:1；5- methoxyl groups -2- the nitrobenzaldehydes Mol ratio with reduced iron powder is 1:10；The ethanol, acetic acid, the volume ratio of the cumulative volume of distilled water and concentrated hydrochloric acid are 175：6；

In step (3), ursolic acid quinoline chloride compound IV-b synthesis

In step (4), ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-f synthesis

Gained compound IV-b is dissolved in 5mL ether, is cooled to 0 DEG C, by 25.0mg (0.225mmol) valeric acid hydrazine, 45 μ L (0.3mmol) triethylamine is dissolved in 2mL dichloromethane and is added dropwise in reaction vessel, is slowly increased to be stirred at room temperature instead 6h, reaction is answered to pour into reaction solution in mixture of ice and water after terminating, it is organic with dichloromethane 3 collections of extraction after ice-out Phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and the removing that is concentrated under reduced pressure has Solvent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the petroleum ether Volume ratio with acetone is 50:1, pure compound ursolic acid quinolines Hete rocyclic derivatives I-f is made；The IV-b, valeric acid hydrazine with Triethylamine, ether, the mol ratio of dichloromethane are 0.15:0.225:0.3:48:76.

In step (1), 3- oxidation ursolic acid II synthesis

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-c synthesis

By the fluoro- 2- nitrobenzaldehydes of 0.51g (3mmol) 5- in ethanol, acetic acid, distilled water (2:2:1,20mL) stirred in 50 DEG C are to slowly warm up to, 1.68g (30mmol) reduced iron powders and 600 μ L concentrated hydrochloric acids are added after being completely dissolved, continue to be heated to 85 DEG C back flow reaction 1h, mixed liquor is filtered after stopping reaction and filter residue is washed with water, merging filtrate, with dichloromethane extraction 3 times Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and decompression is dense It is that the fluoro- 2- aminobenzaldehydes crude products (0.43g) of 5- are directly used in synthesizing fluoro black bearberry that contracting, which removes organic solvent and obtains yellow solid, Sour quinoline；The mol ratio of the fluoro- 2- nitrobenzaldehydes of the 5- and reduced iron powder is 1:10；The ethanol, acetic acid, the body of distilled water Product is than being 2:2:1；The molal volume of the fluoro- 2- nitrobenzaldehydes of 5- and the cumulative volume of ethanol, acetic acid and distilled water is 0.15mol/L；The volume ratio 0.6 of the concentrated hydrochloric acid and the cumulative volume of ethanol, acetic acid and distilled water：20；

By 0.67g (1.5mmol) 3- oxidation ursolic acid II and 0.35g (2.5mmol) in 50mL three neck round bottom flask The ethanol solution of the fluoro- 2- aminobenzaldehydes of 5- is added dropwise 2mL saturation potassium hydroxide-ethanol solution under nitrogen protection, 85 DEG C Back flow reaction 24h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 150:1, pure compound ursolic acid quinolines Hete rocyclic derivatives III-c is made；The 3- oxygen The mol ratio for changing ursolic acid and the ethanol solution of the fluoro- 2- aminobenzaldehydes of 5- is 3：5；The 3- oxidation ursolic acid and saturation hydrogen-oxygen The mass volume ratio for changing potassium ethanol solution is 0.34g/mL；

In step (3), ursolic acid quinoline chloride compound IV-c synthesis

0.084g (0.15mmol) compound III-c 5mL benzene is dissolved, 200 μ L (3mmol) are then slowly added dropwise Thionyl chloride, 80 DEG C of back flow reaction about 4h are to slowly warm up to, steam the benzene in reaction solution and thionyl chloride after stopping reaction Compound IV-c to pale-yellow solid is used for subsequent reactions；The compound III-c and thionyl chloride, benzene mol ratio is 0.15:3:56；

In step (4), ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-c synthesis

Gained compound IV-c is dissolved in 5mL ether, is cooled to 0 DEG C, by 17.1mg (0.225mmol) acethydrazide, 45 μ L (0.3mmol) triethylamine is dissolved in 2mL dichloromethane and is added dropwise in reaction vessel, is slowly increased to be stirred at room temperature instead 6h, reaction is answered to pour into reaction solution in mixture of ice and water after terminating, it is organic with dichloromethane 3 collections of extraction after ice-out Phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and the removing that is concentrated under reduced pressure has Solvent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the petroleum ether Volume ratio with acetone is 30:1, pure compound ursolic acid quinolines Hete rocyclic derivatives I-c is made；The IV-c, acethydrazide with Triethylamine, ether, the mol ratio of dichloromethane are 0.15:0.225:0.3:48:76；

Further, in step (1), 3- oxidation ursolic acid II synthesis

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-c synthesis

By 0.67g (1.5mmol) 3- oxidation ursolic acid II and 0.35g (2.5mmol) in 50mL three neck round bottom flask The ethanol solution of the fluoro- 2- aminobenzaldehydes of 5- is added dropwise 2mL saturation potassium hydroxide-ethanol solution under nitrogen protection, 85 DEG C Back flow reaction 24h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 150:1, pure compound III-c is made；The 3- oxidation ursolic acid and the fluoro- 2- aminobenzenes of 5- The mol ratio of the ethanol solution of formaldehyde is 3：5；The quality volume of the 3- oxidation ursolic acid and saturation potassium hydroxide-ethanol solution Than for 0.34g/mL；

In step (3), ursolic acid quinoline chloride compound IV-c synthesis

In step (4), ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-g synthesis

Gained compound IV-c is dissolved in 5mL ether, is cooled to 0 DEG C, by 25.0mg (0.225mmol) valeric acid hydrazine, 45 μ L (0.3mmol) triethylamine is dissolved in 2mL dichloromethane and is added dropwise in reaction vessel, is slowly increased to be stirred at room temperature instead 6h, reaction is answered to pour into reaction solution in mixture of ice and water after terminating, it is organic with dichloromethane 3 collections of extraction after ice-out Phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and the removing that is concentrated under reduced pressure has Solvent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the petroleum ether Volume ratio with acetone is 80:1, pure compound ursolic acid quinolines Hete rocyclic derivatives I-g is made；The IV-c, valeric acid hydrazine with Triethylamine, ether, the mol ratio of dichloromethane are 0.15:0.225:0.3:48:76.

In step (1), 3- oxidation ursolic acid II synthesis

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-d synthesis

By the chloro- 2- nitrobenzaldehydes of 0.55g (3mmol) 5- in ethanol, acetic acid, distilled water (2:2:1,20mL) stirred in 50 DEG C are to slowly warm up to, 1.68g (30mmol) reduced iron powders and 600 μ L concentrated hydrochloric acids are added after being completely dissolved, continue to be heated to 85 DEG C back flow reaction 1h, mixed liquor is filtered after stopping reaction and filter residue is washed with water, merging filtrate, with dichloromethane extraction 3 times Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and decompression is dense It is that the chloro- 2- aminobenzaldehydes crude products (0.45g) of 5- are directly used in synthesis chloro black bearberry that contracting, which removes organic solvent and obtains yellow solid, Sour quinoline；The mol ratio of the chloro- 2- nitrobenzaldehydes of the 5- and reduced iron powder is 1:10；The ethanol, acetic acid, the body of distilled water Product is than being 2:2:1；The molal volume of the chloro- 2- nitrobenzaldehydes of 5- and the cumulative volume of ethanol, acetic acid and distilled water is 0.15mol/L；The volume ratio 0.6 of the concentrated hydrochloric acid and the cumulative volume of ethanol, acetic acid and distilled water：20；

By 0.67g (1.5mmol) 3- oxidation ursolic acid II and 0.38g (2.5mmol) in 50mL three neck round bottom flask The ethanol solution of the chloro- 2- aminobenzaldehydes of 5- is added dropwise 2mL saturation potassium hydroxide-ethanol solution under nitrogen protection, 85 DEG C Back flow reaction 24h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 150:1, pure compound III-d is made；The 3- oxidation ursolic acid and the chloro- 2- aminobenzenes of 5- The mol ratio of the ethanol solution of formaldehyde is 3：5；The quality volume of the 3- oxidation ursolic acid and saturation potassium hydroxide-ethanol solution Than for 0.34g/mL；

In step (3), ursolic acid quinoline chloride compound IV-d synthesis

0.086g (0.15mmol) compound III-d 5mL benzene is dissolved, 200 μ L (3mmol) are then slowly added dropwise Thionyl chloride, 80 DEG C of back flow reaction about 4h are to slowly warm up to, steam the benzene in reaction solution and thionyl chloride after stopping reaction Compound IV-d to pale-yellow solid is used for subsequent reactions；The compound III-d and thionyl chloride, benzene mol ratio is 0.15:3:56；

In step (4), ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-d synthesis

Gained compound IV-d is dissolved in 5mL ether, is cooled to 0 DEG C, by 17.1mg (0.225mmol) acethydrazide, 45 μ L (0.3mmol) triethylamine is dissolved in 2mL dichloromethane and is added dropwise in reaction vessel, is slowly increased to be stirred at room temperature instead 6h, reaction is answered to pour into reaction solution in mixture of ice and water after terminating, it is organic with dichloromethane 3 collections of extraction after ice-out Phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and the removing that is concentrated under reduced pressure has Solvent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the petroleum ether Volume ratio with acetone is 30:1, pure compound ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-d is made；The IV-d, acetyl The mol ratio of hydrazine and triethylamine, ether, dichloromethane is 0.15:0.225:0.3:48:76；

Further, in step (1), 3- oxidation ursolic acid II synthesis

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-d synthesis

By 0.67g (1.5mmol) 3- oxidation ursolic acid II and 0.38g (2.5mmol) in 50mL three neck round bottom flask The ethanol solution of the chloro- 2- aminobenzaldehydes of 5- is added dropwise 2mL saturation potassium hydroxide-ethanol solution under nitrogen protection, 85 DEG C Back flow reaction 24h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 150:1, pure compound ursolic acid quinolines Hete rocyclic derivatives III-d is made；The 3- oxygen The mol ratio for changing ursolic acid and the ethanol solution of the chloro- 2- aminobenzaldehydes of 5- is 3：5；The 3- oxidation ursolic acid and saturation hydrogen-oxygen The mass volume ratio for changing potassium ethanol solution is 0.34g/mL；

In step (3), ursolic acid quinoline chloride compound IV-d synthesis

0.086g (0.15mmol) compound III-d 5mL benzene is dissolved, 200 μ L (3mmol) are then slowly added dropwise Thionyl chloride, 80 DEG C of back flow reaction about 4h are to slowly warm up to, steam the benzene in reaction solution and thionyl chloride after stopping reaction Compound IV-d to pale-yellow solid is used for subsequent reactions；The compound III-d and thionyl chloride, the mol ratio of benzene For 0.15:3:56；

In step (4), ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-h synthesis

Gained compound IV-d is dissolved in 5mL ether, is cooled to 0 DEG C, by 25.0mg (0.225mmol) valeric acid hydrazine, 45 μ L (0.3mmol) triethylamine is dissolved in 2mL dichloromethane and is added dropwise in reaction vessel, is slowly increased to be stirred at room temperature instead 6h, reaction is answered to pour into reaction solution in mixture of ice and water after terminating, it is organic with dichloromethane 3 collections of extraction after ice-out Phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and the removing that is concentrated under reduced pressure has Solvent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the petroleum ether Volume ratio with acetone is 80:1, pure compound ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-h is made；The IV-d, valeric acid The mol ratio of hydrazine and triethylamine, ether, dichloromethane is 0.15:0.225:0.3:48:76.

Ursolic acid quinoline hydrazides class Hete rocyclic derivatives of the present invention with structure shown in Formulas I and its it can pharmaceutically connect Application of the salt received in tumor is prepared.

Further, the tumour is human breast cancer cell MDA-MB-231, human cervical carcinoma cell HeLa or human liver cancer Any one in cell SMMC-7721.

Beneficial effect：The present invention has antitumor activity, and pharmacological experiment shows, ursolic acid quinolines of the invention derive Thing has significant suppression to human breast cancer cell MDA-MB-231, human cervical carcinoma cell HeLa and human liver cancer cells Hep G2 Make and use, and hypotoxicity is shown to the normal liver epithelial cell QSG-7701 of people.

The present invention is to be oxidized to after carbonyl and carry the adjacent ammonia of different substituents by the C-3 positions hydroxyl on ursolic acid A rings Benzaldehyde condensation introduces the quinoline heterocycle with different substituents and obtains corresponding ursolic acid quinoline, the black bearberry of different substituents The C-28 positions carboxyl of the ursolic acid parent of sour quinoline obtains corresponding ursolic acid quinolines heterocycle with acethydrazide or valeric acid hydrazine reaction Derivative.The structure of the analog derivative is more novel, has no report both at home and abroad.Value with developing anti-tumor medicaments.

Embodiment

The present invention is further illustrated by the following examples.It should be understood that these embodiments are the explainations of the present invention And citing, the scope of the present invention is not limited in any form.

The invention provides a kind of ursolic acid quinoline hydrazides class Hete rocyclic derivatives and its pharmacy with structure shown in formula I Upper acceptable salt：

A kind of ursolic acid quinoline hydrazide derivative with antitumor activity of the present invention and preparation method thereof and Using comprising the following steps：

(1) ursolic acid has structure shown in formula II by Jones reagent oxidation reaction 3- oxidation ursolic acid：

Wherein, III-a：R₁=H；III-b：R₁=OMe；III-c：R₁=F；III-d：R₁=Cl

Wherein, IV-a：R₁=H；IV-b：R₁=OM_e；IV-c：R₁=F；IV-d：R₁=Cl

I-e：R₁=H R₂=n-C₄H₉；I-f：R₁=OMe R₂=n-C₄H₉；I-g：R₁=F R₂=n-C₄H₉；I-h：R₁= Cl R₂=n-C₄H₉

The tumour is human breast cancer cell MDA-MB-231, human cervical carcinoma cell HeLa or human liver cancer cell SMMC- Any one in 7721, the normal cell are behaved normal liver epithelial cell QSG-7701.

Embodiment 1

3- oxidation ursolic acid II synthesis

2g (4.6mmol) ursolic acid and 250mL acetone are added in 500mL round-bottomed flask, after stirring and dissolving Stirring reaction 15min in frozen water, after 1.872mL Jones reagent is slowly added dropwise and is warmed to room temperature stirring reaction 5h, add 90mL Isopropanol stirring reaction 30min, reaction filter off precipitation after terminating and collect filtrate, and the chartreuse that filtrate decompression is concentrated to give is sticky The white needle-like crystals that shape solid is obtained with recrystallizing methanol are 3- oxidation ursolic acid II (1.2g, 65.6%).

Embodiment 2

The synthesis of ursolic acid quinolines Hete rocyclic derivatives (III-a)

By 0.45g (3mmol) 2- nitrobenzaldehydes in ethanol, acetic acid, distilled water (2:2:1,20mL) stirring is slow in 50 DEG C are warming up to, 1.68g (30mmol) reduced iron powders and 600 μ L concentrated hydrochloric acids are added after being completely dissolved, continues to be heated to 85 DEG C times Stream reaction 1h, mixed liquor is filtered and filter residue is washed with water after stopping reaction, merging filtrate, and 3 collections are extracted with dichloromethane Organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, be concentrated under reduced pressure and remove Go organic solvent to obtain yellow solid and be directly used in the unsubstituted ursolic acid quinoline of synthesis for 2- aminobenzaldehydes crude product (0.41g).

By 0.78g (1.8mmol) 3- oxidation ursolic acid II and 0.41g (2.7mmol) in 50mL three neck round bottom flask 2.4mL saturation potassium hydroxide-ethanol solution is added dropwise in the ethanol solution of 2- aminobenzaldehydes under nitrogen protection, and 85 DEG C are returned Stream reaction 24h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 collections are extracted with dichloromethane after ice-out Organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, be concentrated under reduced pressure and remove Go organic solvent to obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, the stone The volume ratio of oily ether and acetone is 150:1, pure compound III-a (0.71g, 68%) is made.

M.p.243-245℃；¹H NMR(500MHz,CDCl₃):δ 0.90 (s, 3H), 0.96 (s, 3H), 0.95 (d, J= 5.80Hz, 3H), 1.15 (s, 3H), 1.27 (d, J=7.75Hz, 3H), 1.28-1.38 (m, 3H), 1.40 (s, 3H), 1.43 (s, 3H), 1.49-1.76 (m, 12H), 1.92-2.28 (m, 5H), 2.58 (d, J=15.30Hz, 1H), 2.96 (d, J=15.70Hz, 1H), 5.35 (s, 1H), 7.40 (t, J=7.30Hz, 1H), 7.58 (t, J=7.15Hz, 1H), 7.67 (d, J=9.60Hz, 1H), 7.68 (s, 1H), 7.99 (d, J=8.35Hz, 1H)；IR(KBr,cm^-1):2924,2854,1695,1607,1454, 1378,1087,1041,1015,973；ESI-MS:m/z[M+H]⁺:540.39；Anal.Calcd.for C₃₇H₄₉NO₂:C 82.33,H 9.15,N 2.59；found:C 82.29,H 9.17,N 2.61.

Embodiment 3

The synthesis of ursolic acid quinolines Hete rocyclic derivatives (III-b)

0.668g (4mmol) 5- hydroxyl -2- nitrobenzaldehydes, 400 μ L (6mmol) are added in 50mL round-bottomed flask Methyl iodide, 0.832g (6mmol) potassium carbonate and 10mL DMF, be stirred at room temperature reaction 8h, Reaction pours into reaction solution in mixture of ice and water after terminating, and 3 collection organic phases, washing are extracted with dichloromethane after ice-out 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed once to be removed water with anhydrous sodium sulfate afterwards, and the removing organic solvent that is concentrated under reduced pressure obtains It is 5- methoxyl group -2- nitrobenzaldehydes (0.52g, 100%) to yellow solid.

By 0.36g (2mmol) 5- methoxyl group -2- nitrobenzaldehydes in ethanol, acetic acid, distilled water (2:2:1,17.5mL) Middle stirring is to slowly warm up to 50 DEG C, and 1.12g (20mmol) reduced iron powders and 600 μ L concentrated hydrochloric acids are added after being completely dissolved, and continues to add Mixed liquor is filtered to 85 DEG C of back flow reaction 1h and filter residue is washed with water, merging filtrate, extracted with dichloromethane by heat after stopping reaction Take 3 collection organic phases, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are subtracted It is that 5- methoxyl group -2- aminobenzaldehydes crude products (0.24g) are directly used in synthesis that pressure concentration, which removes organic solvent and obtains yellow solid, Methoxyl group ursolic acid quinoline.

By 0.445g (1mmol) 3- oxidation ursolic acid II and 0.225g (1.5mmol) in 50mL three neck round bottom flask 2mL saturation potassium hydroxide-ethanol solution is added dropwise in the ethanol solution of 5- methoxyl group -2- aminobenzaldehydes under nitrogen protection, 85 DEG C of back flow reaction 24h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 are extracted with dichloromethane after ice-out Secondary collection organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, depressurized Concentration removes organic solvent and obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, The volume ratio of the petroleum ether and acetone is 100:1, pure compound III-b (0.43g, 70%) is made.

M.p.255-258℃；¹H NMR(300MHz,CDCl₃):δ 0.88 (s, 3H), 0.92 (s, 3H), 0.95 (d, J= 6.75Hz, 3H), 1.15 (s, 3H), 1.27 (d, J=6.55Hz, 3H), 1.28-1.38 (m, 3H), 1.40 (s, 3H), 1.43 (s, 3H), 1.49-1.76 (m, 12H), 1.92-2.28 (m, 5H), 2.56 (d, J=15.03Hz, 1H), 2.93 (d, J=15.18Hz, 1H),3.90(s,3H,OCH₃), 5.36 (s, 1H), 6.96 (s, 1H), 7.25 (d, J=7.65Hz, 1H), 7.60 (s, 1H), 7.91 (d, J=8.80Hz, 1H)；IR(KBr,cm^-1):2926,2857,1728,1693,1457,1385,1314,1277, 1078,1030,972；ESI-MS:m/z[M+H]⁺:570.40；Anal.Calcd.for C₃₈H₅₁NO₃:C 80.10,H 9.02,N 2.46；found:C 80.13,H 9.04,N 2.59.

Embodiment 4

The synthesis of ursolic acid quinolines Hete rocyclic derivatives (III-c)

By the fluoro- 2- nitrobenzaldehydes of 0.51g (3mmol) 5- in ethanol, acetic acid, distilled water (2:2:1,20mL) stirred in 50 DEG C are to slowly warm up to, 1.68g (30mmol) reduced iron powders and 600 μ L concentrated hydrochloric acids are added after being completely dissolved, continue to be heated to 85 DEG C back flow reaction 1h, mixed liquor is filtered after stopping reaction and filter residue is washed with water, merging filtrate, with dichloromethane extraction 3 times Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and decompression is dense It is that the fluoro- 2- aminobenzaldehydes crude products (0.43g) of 5- are directly used in synthesizing fluoro black bearberry that contracting, which removes organic solvent and obtains yellow solid, Sour quinoline.

By 0.67g (1.5mmol) 3- oxidation ursolic acid II and 0.35g (2.5mmol) in 50mL three neck round bottom flask The ethanol solution of the fluoro- 2- aminobenzaldehydes of 5- is added dropwise 2mL saturation potassium hydroxide-ethanol solution under nitrogen protection, 85 DEG C Back flow reaction 24h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 150:1, pure compound III-c (0.51g, 62%) is made.

M.p.235-237℃；¹H NMR(300MHz,CDCl₃):δ 0.88 (s, 3H), 0.91 (s, 3H), 0.93 (d, J= 6.20Hz, 3H), 1.14 (s, 3H), 1.26 (d, J=6.40Hz, 3H), 1.28-1.38 (m, 3H), 1.36 (s, 3H), 1.40 (s, 3H), 1.49-1.76 (m, 11H), 1.92-2.28 (m, 6H), 2.57 (d, J=15.51Hz, 1H), 2.94 (d, J=15.66Hz, 1H), 5.33 (s, 1H), 7.27 (d, J=8.50Hz, 1H), 7.37 (t, J=8.50Hz, 1H), 7.62 (s, 1H), 7.97 (dd, J =8.91,5.61Hz, 1H)；IR(KBr,cm^-1):2959,2925,2855,1695,1492,1457,1378,1213,1147, 1077,968,829；ESI-MS:m/z[M+H]⁺:558.38；Anal.Calcd.for C₃₇H₄₈FNO₂:C 79.67,H 8.67,N 2.51；found:C 79.68,H 8.65,N 2.53.

Embodiment 5

The synthesis of ursolic acid quinolines Hete rocyclic derivatives (III-d)

By the chloro- 2- nitrobenzaldehydes of 0.55g (3mmol) 5- in ethanol, acetic acid, distilled water (2:2:1,20mL) stirred in 50 DEG C are to slowly warm up to, 1.68g (30mmol) reduced iron powders and 600 μ L concentrated hydrochloric acids are added after being completely dissolved, continue to be heated to 85 DEG C back flow reaction 1h, mixed liquor is filtered after stopping reaction and filter residue is washed with water, merging filtrate, with dichloromethane extraction 3 times Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and decompression is dense It is that the chloro- 2- aminobenzaldehydes crude products (0.45g) of 5- are directly used in synthesis chloro black bearberry that contracting, which removes organic solvent and obtains yellow solid, Sour quinoline.

By 0.67g (1.5mmol) 3- oxidation ursolic acid II and 0.38g (2.5mmol) in 50mL three neck round bottom flask The ethanol solution of the chloro- 2- aminobenzaldehydes of 5- is added dropwise 2mL saturation potassium hydroxide-ethanol solution under nitrogen protection, 85 DEG C Back flow reaction 24h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 150:1, pure compound III-d (0.58g, 64%) is made.

M.p.247-249℃；¹H NMR(300MHz,CDCl₃):δ 0.89 (s, 3H), 0.91 (s, 3H), 0.96 (d, J= 6.40Hz, 3H), 0.98 (s, 3H), 1.26 (d, J=6.40Hz, 3H), 1.28-1.38 (m, 3H), 1.36 (s, 3H), 1.40 (s, 3H), 1.49-1.76 (m, 12H), 1.92-2.28 (m, 5H), 2.57 (d, J=14.94Hz, 1H), 2.95 (d, J=15.75Hz, 1H), 5.35 (s, 1H), 7.51 (d, J=8.88Hz, 1H), 7.59 (s, 1H), 7.65 (s, 1H), 7.92 (d, J=8.94Hz, 1H)；IR(KBr,cm^-1):2924,2855,1695,1480,1404,1379,1262,1183,1070,967,920,828；ESI- MS:m/z[M+H]⁺:574.35；Anal.Calcd.for C₃₇H₄₈ClNO₂:C 77.39,H 8.43,N 2.44；found:C 77.40,H 8.45,N 2.47.

Embodiment 6

The synthesis of ursolic acid quinoline chloride compound (IV-a)

0.081g (0.15mmol) compound III-a 5mL benzene is dissolved, 200 μ L (3mmol) are then slowly added dropwise Thionyl chloride, 80 DEG C of back flow reaction about 4h are to slowly warm up to, steam the benzene in reaction solution and thionyl chloride after stopping reaction Compound IV-a to pale-yellow solid is used for subsequent reactions

Embodiment 7

The synthesis of ursolic acid quinoline chloride compound (IV-b)

0.085g (0.15mmol) compound III-b 5mL benzene is dissolved, 200 μ L (3mmol) are then slowly added dropwise Thionyl chloride, 80 DEG C of back flow reaction about 4h are to slowly warm up to, steam the benzene in reaction solution and thionyl chloride after stopping reaction Compound IV-b to pale-yellow solid is used for subsequent reactions.

Embodiment 8

The synthesis of ursolic acid quinoline chloride compound (IV-c)

0.084g (0.15mmol) compound III-c 5mL benzene is dissolved, 200 μ L (3mmol) are then slowly added dropwise Thionyl chloride, 80 DEG C of back flow reaction about 4h are to slowly warm up to, steam the benzene in reaction solution and thionyl chloride after stopping reaction Compound IV-c to pale-yellow solid is used for subsequent reactions.

Embodiment 9

The synthesis of ursolic acid quinoline chloride compound (IV-d)

0.086g (0.15mmol) compound III-d 5mL benzene is dissolved, 200 μ L (3mmol) are then slowly added dropwise Thionyl chloride, 80 DEG C of back flow reaction about 4h are to slowly warm up to, steam the benzene in reaction solution and thionyl chloride after stopping reaction Compound IV-d to pale-yellow solid is used for subsequent reactions.

Embodiment 10

The synthesis of ursolic acid quinoline hydrazides class Hete rocyclic derivatives (I-a)

The gained compound IV-a of embodiment 6 is dissolved in 5mL ether, 0 DEG C is cooled to, by 17.1mg (0.225mmol) second Hydrazides, 45 μ L (0.3mmol) triethylamine are dissolved in 2mL dichloromethane and are added dropwise in reaction vessel, are slowly increased to room Warm stirring reaction 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 30:1, pure compound I-a (0.076g, 84.1%) is made.

M.p.267-269℃；¹H NMR(500MHz,CDCl₃):δ 0.83 (s, 3H), 0.87 (s, 3H), 0.93 (d, J= 6.40Hz, 3H), 0.98 (d, J=5.05Hz, 3H), 1.18 (s, 3H), 1.42 (s, 3H), 1.44 (s, 3H), 1.50-1.94 (m, 15H), 2.03 (s, 3H), 2.06-2.37 (m, 4H), 2.59 (d, J=15.45Hz, 1H), 2.96 (d, J=15.35Hz, 1H), 5.60 (s, 1H), 7.41 (t, J=7.55Hz, 3H), 7.58 (t, J=7.65Hz, 1H), 7.69 (d, J=8.50Hz, 1H), 7.70 (s, 1H), 8.00 (d, J=8.50Hz, 1H), 8.77 (d, J=7.10Hz, 1H, NH), 8.95 (d, J=7.15Hz, 1H, NH)；IR(KBr,cm^-1):3251,2953,2924,2854,1618,1492,1458,1378,1081,968,759；ESI-MS: m/z[M+H]⁺:596.43；Anal.Calcd.for C₃₉H₅₃N₃O₂:C 78.61,H 8.97,N 7.05,found:C 78.60, H 8.98,N 7.08.

Embodiment 11

The synthesis of ursolic acid quinoline hydrazides class Hete rocyclic derivatives (I-b)

The gained compound IV-b of embodiment 7 is dissolved in 5mL ether, 0 DEG C is cooled to, by 17.1mg (0.225mmol) second Hydrazides, 45 μ L (0.3mmol) triethylamine are dissolved in 2mL dichloromethane and are added dropwise in reaction vessel, are slowly increased to room Warm stirring reaction 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 30:1, pure compound I-b (0.043g, 57.6%) is made.

M.p.290-293℃；¹H NMR(500MHz,CDCl₃):δ 0.83 (s, 3H), 0.87 (s, 3H), 0.92 (d, J= 7.25Hz, 3H), 0.97 (d, J=7.50Hz, 3H), 1.18 (s, 3H), 1.39 (s, 3H), 1.42 (s, 3H), 1.47-1.93 (m, 15H), 2.03 (s, 3H), 2.05-2.18 (m, 4H), 2.57 (d, J=15.10Hz, 1H), 2.92 (d, J=15.30Hz, 1H), 3.91(s,3H,OCH₃), 5.59 (s, 1H), 6.96 (d, J=2.55Hz, 1H), 7.25 (d, J=7.65Hz, 1H), 7.60 (s, 1H), 7.91 (d, J=8.80Hz, 1H), 8.78 (m, 1H, NH), 8.94 (m, 1H, NH)；IR(KBr,cm^-1):3249,2953, 2925,2855,1621,1492,1457,1378,1222,1080,1030,828,668；ESI-MS:m/z[M+H]⁺:626.44； Anal.Calcd.for C₄₀H₅₅N₃O₃:C 76.76,H 8.86,N 6.71,found:C 76.73,H 8.88,N 6.75.

Embodiment 12

The synthesis of ursolic acid quinoline hydrazides class Hete rocyclic derivatives (I-c)

The gained compound IV-c of embodiment 8 is dissolved in 5mL ether, 0 DEG C is cooled to, by 17.1mg (0.225mmol) second Hydrazides, 45 μ L (0.3mmol) triethylamine are dissolved in 2mL dichloromethane and are added dropwise in reaction vessel, are slowly increased to room Warm stirring reaction 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 30:1, pure compound I-c (0.071g, 88.4%) is made.

M.p.274-278℃；¹H NMR(500MHz,CDCl₃):δ 0.83 (s, 3H), 0.89 (s, 3H), 0.93 (d, J= 6.40Hz, 3H), 0.97 (d, J=6.25Hz, 3H), 1.18 (s, 3H), 1.40 (s, 3H), 1.43 (s, 3H), 1.45-1.93 (m, 15H), 2.04 (s, 3H), 2.06-2.19 (m, 4H), 2.57 (d, J=15.45Hz, 1H), 2.95 (d, J=15.50Hz, 1H), 5.69 (s, 1H), 7.29 (dd, J=9.05,2.65Hz, 1H), 7.35 (dt, J=8.95,2.90Hz, 1H), 7.64 (s, 1H), 7.98 (dd, J=9.15,5.40Hz, 1H), 8.89 (d, J=7.00Hz, 1H, NH), 8.96 (d, J=7.00Hz, 1H, NH)；IR (KBr,cm^-1):3230,2952,2925,2855,1616,1492,1456,1378,1212,1148,1077,969,829,802； ESI-MS:m/z[M+H]⁺:614.42；Anal.Calcd.for C₃₉H₅₂FN₃O₂:C 76.31,H 8.54,N 6.85,found: C 76.30,H 8.55,N 6.87.

Embodiment 13

The synthesis of ursolic acid quinoline hydrazides class Hete rocyclic derivatives (I-d)

The gained compound IV-d of embodiment 9 is dissolved in 5mL ether, 0 DEG C is cooled to, by 17.1mg (0.225mmol) second Hydrazides, 45 μ L (0.3mmol) triethylamine are dissolved in 2mL dichloromethane and are added dropwise in reaction vessel, are slowly increased to room Warm stirring reaction 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 30:1, pure compound I-d (0.078g, 74.3%) is made.

M.p.270-273℃；¹H NMR(300MHz,CDCl₃):δ 0.83 (s, 3H), 0.88 (s, 3H), 0.93 (d, J= 6.33Hz, 3H), 0.98 (d, J=6.78Hz, 3H), 1.18 (s, 3H), 1.40 (s, 3H), 1.42 (s, 3H), 1.54-1.95 (m, 15H), 2.03 (s, 3H), 2.08-2.23 (m, 4H), 2.58 (d, J=15.84Hz, 1H), 2.95 (d, J=15.69Hz, 1H), 5.60 (s, 1H), 7.51 (d, J=8.91Hz, 1H), 7.61 (s, 1H), 7.67 (s, 1H), 7.79 (d, J=7.50Hz, 2H), 7.92 (d, J=9.00Hz, 1H), 8.65 (bis, 1H, NH), 8.95 (bis, 1H, NH)；IR(KBr,cm^-1):3234,2949, 2924,2855,1616,1479,1456,1378,1184,1070,968,919,828,753；ESI-MS:m/z[M+H]⁺: 630.38；Anal.Calcd.for C₃₉H₅₂ClN₃O₂:C 74.32,H 8.32,N 6.67,found:C 74.37,H 8.30,N 6.65.

Embodiment 14

The synthesis of ursolic acid quinoline hydrazides class Hete rocyclic derivatives (I-e)

The gained compound IV-a of embodiment 6 is dissolved in 5mL ether, is cooled to 0 DEG C, by the penta of 25.0mg (0.225mmol) Sour hydrazine, 45 μ L (0.3mmol) triethylamine are dissolved in 2mL dichloromethane and are added dropwise in reaction vessel, are slowly increased to room Warm stirring reaction 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 80:1, pure compound I-e (0.056g, 70.2%) is made.

M.p.278-281℃；¹H NMR(500MHz,CDCl₃):δ 0.81 (s, 3H), 0.87 (s, 3H), 0.94 (d, J= 6.40Hz, 3H), 0.97 (d, J=7.40Hz, 3H), 1.18 (s, 3H), 1.42 (s, 3H), 1.44 (s, 3H), 1.49-1.78 (m, 18H), 1.92-2.20 (m, 8H), 2.23 (t, J=7.45Hz, 2H), 2.59 (d, J=15.50Hz, 1H), 2.96 (d, J= 15.30Hz, 1H), 5.62 (s, 1H), 7.41 (t, J=7.45Hz, 1H), 7.58 (t, J=7.65Hz, 1H), 7.68 (d, J= 8.55Hz, 1H), 7.70 (s, 1H), 7.99 (d, J=8.45Hz, 1H), 8.71 (d, J=7.35Hz, 1H, NH), 9.06 (d, J= 7.40Hz,1H,NH)；IR(KBr,cm^-1):3223,2954,2924,2855,1615,1492,1457,1378,1190,1075, 969,753；ESI-MS:m/z[M+H]⁺:638.48；Anal.Calcd.for C₄₂H₅₉N₃O₂:C 79.08,H 9.32,N 6.59,found:C 79.12,H 9.33,N 6.57.

Embodiment 15

The synthesis of ursolic acid quinoline hydrazides class Hete rocyclic derivatives (I-f)

The gained compound IV-b of embodiment 7 is dissolved in 5mL ether, is cooled to 0 DEG C, by the penta of 25.0mg (0.225mmol) Sour hydrazine, 45 μ L (0.3mmol) triethylamine are dissolved in 2mL dichloromethane and are added dropwise in reaction vessel, are slowly increased to room Warm stirring reaction 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 50:1, pure compound I-f (0.051g, 46.4%) is made.

M.p.282-285℃；¹H NMR(500MHz,CDCl₃):δ 0.81 (s, 3H), 0.89 (s, 3H), 0.94 (d, J= 6.45Hz, 3H), 0.98 (d, J=6.40Hz, 3H), 1.18 (s, 3H), 1.39 (s, 3H), 1.42 (s, 3H), 1.47-1.76 (m, 18H), 1.91-2.10 (m, 4H), 2.18-2.25 (m, 4H), 2.56 (d, J=15.70Hz, 1H), 2.92 (d, J=16.20Hz, 1H),3.90(s,3H,OCH₃), 5.61 (s, 1H), 6.96 (s, 1H), 7.24 (d, J=8.95Hz, 1H), 7.59 (s, 1H), 7.88 (d, J=9.20Hz, 1H), 8.71 (d, J=7.60Hz, 1H, NH), 9.07 (d, J=7.30Hz, 1H, NH)；IR(KBr, cm^-1):3226,2954,2924,2854,1618,1492,1459,1379,1222,1080,1032,964,829,805；ESI- MS:m/z[M+H]⁺:668.48；Anal.Calcd.for C₄₃H₆₁N₃O:C 81.21,H 9.67,N 6.61,found:C 81.24,H 9.65,N 6.62.

Embodiment 16

The synthesis of ursolic acid quinoline hydrazides class Hete rocyclic derivatives (I-g)

The gained compound IV-c of embodiment 8 is dissolved in 5mL ether, is cooled to 0 DEG C, by the penta of 25.0mg (0.225mmol) Sour hydrazine, 45 μ L (0.3mmol) triethylamine are dissolved in 2mL dichloromethane and are added dropwise in reaction vessel, are slowly increased to room Warm stirring reaction 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 80:1, pure compound I-g (0.083g, 7.2%) is made.

M.p.289-291℃；¹H NMR(500MHz,CDCl₃):δ 0.81 (s, 3H), 0.88 (s, 3H), 0.93 (d, J= 6.40Hz, 3H), 0.97 (d, J=6.55Hz, 3H), 1.18 (s, 3H), 1.40 (s, 3H), 1.42 (s, 3H), 1.45-1.78 (m, 18H), 1.92-2.19 (m, 8H), 2.23 (t, J=7.45Hz, 2H), 2.57 (d, J=15.50Hz, 1H), 2.95 (d, J= 15.55Hz, 1H), 5.61 (s, 1H), 7.29 (dd, J=9.00,2.35Hz, 1H), 7.35 (dt, J=8.55,2.35Hz, 1H), 7.64 (s, 1H), 7.98 (dd, J=9.05,5.45Hz, 1H), 8.73 (d, J=7.25Hz, 1H, NH), 9.06 (d, J= 7.35Hz,1H,NH)；IR(KBr,cm^-1):3238,2954,2925,2870,1614,1493,1456,1378,1286,1213, 1148,1077,969,829,801；ESI-MS:m/z[M+H]⁺:656.47；Anal.Calcd.for C₄₂H₅₈FN₃O₂:C 76.91,H 8.91,N 6.41,found:C 76.86,H 8.92,N 6.45.

Embodiment 17

The synthesis of ursolic acid quinoline hydrazides class Hete rocyclic derivatives (I-h)

The gained compound IV-d of embodiment 9 is dissolved in 5mL ether, is cooled to 0 DEG C, by the penta of 25.0mg (0.225mmol) Sour hydrazine, 45 μ L (0.3mmol) triethylamine are dissolved in 2mL dichloromethane and are added dropwise in reaction vessel, are slowly increased to room Warm stirring reaction 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 80:1, pure compound I-h (0.084g, 70.4%) is made.

M.p.303-307℃；¹H NMR(500MHz,CDCl₃):δ 0.82 (s, 3H), 0.88 (s, 3H), 0.91 (d, J= 7.35Hz, 3H), 0.94 (d, J=6.25Hz, 3H), 1.22 (s, 3H), 1.38 (s, 3H), 1.41 (s, 3H), 1.49-1.79 (m, 19H), 1.93 (m, 1H), 2.08 (m, 2H), 2.19 (m, 2H), 2.24 (m, 2H), 2.58 (d, J=15.20Hz, 1H), 2.96 (d, J=15.30Hz, 1H), 5.62 (s, 1H), 7.52 (d, J=9.00,1H), 7.62 (s, 1H), 7.67 (s, 1H), 7.93 (d, J=7.90Hz, 1H), 8.76 (d, J=6.60Hz, 1H, NH), 9.07 (d, J=6.90Hz, 1H, NH)；IR(KBr,cm^-1): 3230,2953,2925,2869,1614,1479,1457,1379,1183,1069,965,918,828；ESI-MS:m/z[M+H ]⁺:672.43；Anal.Calcd.for C₄₂H₅₈ClN₃O₂:C 75.02,H 8.69,N 6.25,found:C 75.00,H 8.73,N 6.24.

Experiment 1

Anti tumor activity in vitro screens

Screening cell line is：Human breast cancer cell MDA-MB-231, human cervical carcinoma cell HeLa, human liver cancer cell The SMMC-7721 and normal liver epithelial cell QSG-7701 of people.

Experimental method：

Take the logarithm growth period cell in good condition, Trypsin Induced, be made 5 × 10⁴Cell/mL suspension.Will be thin Born of the same parents' suspension moves into 96 well culture plates, per the μ L of hole 100, puts 37 DEG C, 5%CO₂Under the conditions of cultivate 24h.

Tested derivative is configured to certain density mother liquor with DMSO, then will be spread out with DMEM culture mediums or 1640 culture mediums Biological mother liquor is diluted to the dilution of different activities.Old culture medium is removed, adds the drug containing serum-free DMEM of various concentrations Culture medium or 1640 culture mediums, per the μ L of hole 100.Separately set blank control group and positive control Etoposide (VP-16) control group.Medicine After thing effect 72h, the μ L of MTT solution (5mg/mL) 10 are added in every hole, continue to incubate 4h.

Supernatant in each hole is sucked, the μ L of DMSO 100 are added per hole, 5min is vibrated, crystal is fully dissolved, ELIASA The absorbance value (OD values) in each hole at 540nm is determined, calculates the proliferation inhibition rate of cell：Inhibiting rate (%)=(1- medication groups are put down Equal OD values/blank control group mean OD value) × 100%.Data processing is carried out using SPSS16.0 softwares and calculates cancer cell increasing Half-inhibition concentration (the IC grown₅₀), it the results are shown in Table 1.Table 1 be ursolic acid quinoline hydrazides class Hete rocyclic derivatives to MDA-MB-231, The in-vitro multiplication inhibitory action result of HeLa and SMMC-7721 cells.

Table 1

^aNT：Do not test

As shown in table 1, synthesized ursolic acid quinoline hydrazides class Hete rocyclic derivatives these three tumour cells are respectively provided with compared with Strong inhibitory action, wherein compound I-a, I-b, I-c, I-d have stronger inhibitory action to MDA-MB-231 cells, are better than Positive control Etoposide, wherein compound I-d are most strong to the inhibitory activity of MDA-MB-231 cells, IC₅₀For 0.12 ± 0.01 μ mol/L；Compound I-a, I-b, I-c, I-d exhibit improvements over the inhibitory action of Etoposide, wherein compound to HeLa cells I-d is optimal to the inhibitory action of HeLa cells, IC₅₀For 0.08 ± 0.01 μm of ol/L；Compound I-a, I-b, I-c, I-d couple SMMC-7721 cells have stronger inhibited proliferation, wherein inhibited proliferations of the compound I-d to SMMC-7721 cells Most preferably, IC₅₀For 0.34 ± 0.03 μm of ol/L；In synthesized ursolic acid quinoline hydrazide derivative, compound I-a, I-b, I- C, I-d shows hypotoxicity, IC to normal cell QSG-7701 cells₅₀>40 μm of ol/L, wherein increasing to three kinds of tumour cells Grow ICs of the most strong compound I-d of inhibitory action to QSG-7701 cells₅₀For 43.76 ± 1.73 μm of ol/L, it is to normal cell Cytotoxicity be significantly lower than to the cytotoxicity of tumour cell.Result above shows such compound for breast cancer, uterine neck Cancer and liver cancer cells have significant inhibitory action, have the potentiality of exploitation cancer therapy drug.

General principle, principal character and the advantages of the present invention of the present invention has been shown and described above.The technology of the industry Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the simply explanation described in above-described embodiment and specification is originally The principle of invention, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, the present invention Claimed scope is by appended claims, specification and its equivalent thereof.

Claims

1. one kind has the ursolic acid quinoline hydrazide derivative and its pharmaceutically acceptable salt of antitumor activity：

Wherein, I-a：R₁=H R₂=CH₃；I-b：R₁=OMe R₂=CH₃；I-c：R₁=F R₂=CH₃；I-d：R₁=Cl R₂= CH₃；

I-e：R₁=H R₂=n-C₄H₉；I-f：R₁=OMe R₂=n-C₄H₉；I-g：R₁=F R₂=n-C₄H₉；I-h：R₁=Cl R₂ =n-C₄H₉。

2. one kind described in claim 1 has the preparation method of the ursolic acid quinoline hydrazide derivative of antitumor activity, its It is characterised by comprising the following steps：

；

(2) o-nitrobenzaldehyde of different substituents reduces in the presence of Fe/HCl and obtains corresponding o-Aminobenzaldehyde, 3- Aoxidizing ursolic acid, the condensation reaction under alkalescence condition nitrogen atmosphere obtains corresponding contain with the o-Aminobenzaldehyde of different substituents There is the ursolic acid quinoline of different substituents, there is structure shown in general formula III：

(3) the ursolic acid quinoline of different substituents obtains the chloride of corresponding ursolic acid quinoline in the presence of thionyl chloride Compound, there is structure shown in formula IV：

Wherein, IV-a：R₁=H；IV-b：R₁=OMe；IV-c：R₁=F；IV-d：R₁=Cl；

(4) the chloride compound of the ursolic acid quinoline of different substituents reacts to obtain with acethydrazide and valeric acid hydrazine in alkalescence condition The hydrazide derivatives of corresponding ursolic acid quinoline, have structure shown in formula I：

I-e：R₁=H R₂=n-C₄H₉；I-f：R₁=OMe R₂=n-C₄H₉；I-g：R₁=FR₂=n-C₄H₉；I-h：R₁=Cl R₂ =n-C₄H₉。

3. the preparation side of a kind of ursolic acid quinoline hydrazide derivative with antitumor activity according to claim 2 Method, it is characterised in that：

In step (1), 3- oxidation ursolic acid II synthesis

Add ursolic acid and acetone in 500mL round-bottomed flask, after stirring and dissolving in frozen water stirring reaction 15min, slowly After Jones reagent is added dropwise and is warmed to room temperature stirring reaction 5h, isopropanol stirring reaction 30min is added, reaction filters off precipitation after terminating Collection filtrate, the white needle-like crystals that the chartreuse thick solid that filtrate decompression is concentrated to give is obtained with recrystallizing methanol, 3- oxidation ursolic acid II is made；The molal volume ratio of the ursolic acid and acetone is 0.0184mol/L；The acetone, Qiong Sishi The volume ratio of agent and isopropanol is 250：1.9：90；

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-a synthesis

2- nitrobenzaldehydes are stirred in ethanol, acetic acid, distilled water and are to slowly warm up to 50 DEG C, reduced iron is added after being completely dissolved Powder and 600 μ L concentrated hydrochloric acids, continue to be heated to 85 DEG C of back flow reaction 1h, mixed liquor is filtered after stopping reaction and filter is washed with water Slag, merging filtrate, 3 collection organic phases are extracted with dichloromethane, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed Once removed water afterwards with anhydrous sodium sulfate, it is 2- aminobenzaldehyde crude products that the removing organic solvent that is concentrated under reduced pressure, which obtains yellow solid, directly Connect for synthesizing unsubstituted ursolic acid quinoline；The mol ratio of the 2- nitrobenzaldehydes and reduced iron powder is 1:10；The ethanol, Acetic acid, the volume ratio of distilled water are 2:2:1；Mole of the 2- nitrobenzaldehydes and the cumulative volume of ethanol, acetic acid and distilled water Volume is 0.15mol/L；The volume ratio 0.6 of the concentrated hydrochloric acid and the cumulative volume of ethanol, acetic acid and distilled water：20；

By in 50mL three neck round bottom flask 3- aoxidize ursolic acid II and 2- aminobenzaldehyde ethanol solution under nitrogen protection by 2.4mL saturation potassium hydroxide-ethanol solution is added dropwise to, 85 DEG C of back flow reaction 24h, reacts and reaction solution is poured into frozen water after terminating In mixture, 3 collection organic phases are extracted with dichloromethane after ice-out, washing 3 times, saturated sodium bicarbonate solution and dense salt Water is respectively washed once to be removed water with anhydrous sodium sulfate afterwards, and the removing organic solvent that is concentrated under reduced pressure obtains yellow solid, and it is entered with silicagel column Row isolates and purifies, and solvent selects petroleum ether acetone system, and the volume ratio of the petroleum ether and acetone is 150:1, purifying is made and closes Thing ursolic acid quinolines Hete rocyclic derivatives III-a；

The mol ratio of the 3- oxidation ursolic acid and the ethanol solution of 2- aminobenzaldehydes is 2：3；3- oxidation ursolic acid with The mass volume ratio of saturation potassium hydroxide-ethanol solution is 0.35g/mL；

In step (3), ursolic acid quinoline chloride compound IV-a synthesis

Compound III-a 5mL benzene is dissolved, thionyl chloride is then slowly added dropwise, is to slowly warm up to 80 DEG C of back flow reactions about 4h, the compound IV-a for stopping steaming to obtain by the benzene in reaction solution and thionyl chloride after reacting pale-yellow solid are used for subsequently Reaction；The mol ratio of the compound III-a and thionyl chloride, benzene is 0.15:3:56；

Gained ursolic acid quinoline chloride compound IV-a is dissolved in 5mL ether, is cooled to 0 DEG C, acethydrazide, triethylamine are dissolved in In 2mL dichloromethane and it is added dropwise in reaction vessel, is slowly increased to that reaction 6h is stirred at room temperature, reacts reaction solution after terminating Pour into mixture of ice and water, after ice-out with dichloromethane extract 3 times collection organic phases, washing 3 times, saturated sodium bicarbonate it is molten Liquid and strong brine are respectively washed once to be removed water with anhydrous sodium sulfate afterwards, and the removing organic solvent that is concentrated under reduced pressure obtains yellow solid, uses silica gel Post isolates and purifies to it, and solvent selects petroleum ether acetone system, and the volume ratio of the petroleum ether and acetone is 30:1, it is made Pure compound ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-a；The IV-a, acethydrazide and triethylamine, ether, dichloromethane Mol ratio is 0.15:0.225:0.3:48:76.

4. the preparation side of a kind of ursolic acid quinoline hydrazide derivative with antitumor activity according to claim 2 Method, it is characterised in that：

In step (1), 3- oxidation ursolic acid II synthesis

Add ursolic acid and acetone in 500mL round-bottomed flask, after stirring and dissolving in frozen water stirring reaction 15min, slowly After 1.872mL Jones reagent is added dropwise and is warmed to room temperature stirring reaction 5h, isopropanol stirring reaction 30min is added, reaction terminates Precipitation is filtered off afterwards collects filtrate, the white that the chartreuse thick solid that filtrate decompression is concentrated to give is obtained with recrystallizing methanol Acicular crystal, 3- oxidation ursolic acid II is made；The molal volume ratio of the ursolic acid and acetone is 0.0184mol/L；Described third The volume ratio of ketone, Jones reagent and isopropanol is 250：1.9：90；

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-a synthesis

By in 50mL three neck round bottom flask 3- aoxidize ursolic acid II and 2- aminobenzaldehyde ethanol solution under nitrogen protection by 2.4mL saturation potassium hydroxide-ethanol solution is added dropwise to, 85 DEG C of back flow reaction 24h, reacts and reaction solution is poured into frozen water after terminating In mixture, 3 collection organic phases are extracted with dichloromethane after ice-out, washing 3 times, saturated sodium bicarbonate solution and dense salt Water is respectively washed once to be removed water with anhydrous sodium sulfate afterwards, and the removing organic solvent that is concentrated under reduced pressure obtains yellow solid, and it is entered with silicagel column Row isolates and purifies, and solvent selects petroleum ether acetone system, and the volume ratio of the petroleum ether and acetone is 150:1, purifying is made and closes Thing ursolic acid quinolines Hete rocyclic derivatives III-a；Mole of the 3- oxidation ursolic acid and the ethanol solution of 2- aminobenzaldehydes Than for 2：3；The mass volume ratio of the 3- oxidation ursolic acid and saturation potassium hydroxide-ethanol solution is 0.35g/mL；

In step (3), ursolic acid quinoline chloride compound IV-a synthesis

Gained compound IV-a is dissolved in 5mL ether, is cooled to 0 DEG C, and valeric acid hydrazine, triethylamine are dissolved in 2mL dichloromethane And be added dropwise in reaction vessel, it is slowly increased to that reaction 6h is stirred at room temperature, reacts and reaction solution is poured into mixture of ice and water after terminating In, extract 3 collection organic phases with dichloromethane after ice-out, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed Once removed water afterwards with anhydrous sodium sulfate, the removing organic solvent that is concentrated under reduced pressure obtains yellow solid, and it is separated with silicagel column Purifying, solvent select petroleum ether acetone system, and the volume ratio of the petroleum ether and acetone is 80:1, pure compound ursolic acid is made Quinoline hydrazides class Hete rocyclic derivatives I-e；The IV-a, the mol ratio of valeric acid hydrazine and triethylamine, ether, dichloromethane are 0.15: 0.225:0.3:48:76。

5. the preparation side of a kind of ursolic acid quinoline hydrazide derivative with antitumor activity according to claim 2 Method, it is characterised in that：

In step (1), 3- oxidation ursolic acid II synthesis

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-b synthesis

5- hydroxyl -2- nitrobenzaldehydes, methyl iodide, potassium carbonate and N, the N- dimethyl methyl added in 50mL round-bottomed flask Acid amides, reaction 8h is stirred at room temperature, reaction pours into reaction solution in mixture of ice and water after terminating, and dichloromethane is used after ice-out Alkane extracts 3 collection organic phases, and washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed afterwards with anhydrous sodium sulfate Water, it is 5- methoxyl group -2- nitrobenzaldehydes 100% that the removing organic solvent that is concentrated under reduced pressure, which obtains yellow solid,；5- hydroxyls-the 2- The mol ratio of nitrobenzaldehyde, methyl iodide and potassium carbonate is 4:6:6；The body of the methyl iodide and N,N-dimethylformamide Product is than being 0.4：10；

5- methoxyl group -2- nitrobenzaldehydes are stirred in ethanol, acetic acid, distilled water and are to slowly warm up to 50 DEG C, after being completely dissolved Reduced iron powder and 600 μ L concentrated hydrochloric acids are added, continue to be heated to 85 DEG C of back flow reaction 1h, stops filtering mixed liquor after reacting and is used in combination Water washing filter residue, merging filtrate, 3 collection organic phases are extracted with dichloromethane, washing 3 times, saturated sodium bicarbonate solution and dense Salt solution is respectively washed once to be removed water with anhydrous sodium sulfate afterwards, and it is 5- methoxyl groups -2- that the removing organic solvent that is concentrated under reduced pressure, which obtains yellow solid, Aminobenzaldehyde crude product is directly used in synthesizing methoxy ursolic acid quinoline；5- methoxyl groups -2- the nitrobenzaldehydes and ethanol, second The mass volume ratio of sour, distilled water cumulative volume is 0.02g/mL；The ethanol, acetic acid, the volume ratio of distilled water are 2:2:1； The mol ratio of the 5- methoxyl groups -2- nitrobenzaldehydes and reduced iron powder is 1:10；The ethanol, acetic acid, the totality of distilled water Product and the volume ratio of concentrated hydrochloric acid are 175：6；

By the 5- first of 0.445g (1mmol) 3- oxidation ursolic acid II and 0.225g (1.5mmol) in 50mL three neck round bottom flask The ethanol solution of epoxide -2- aminobenzaldehydes is added dropwise 2mL saturation potassium hydroxide-ethanol solution under nitrogen protection, 85 DEG C Back flow reaction 24h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 receipts are extracted with dichloromethane after ice-out Collect organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, are concentrated under reduced pressure Remove organic solvent and obtain yellow solid, it is isolated and purified with silicagel column, solvent selects petroleum ether acetone system, described The volume ratio of petroleum ether and acetone is 100:1, pure compound ursolic acid quinolines Hete rocyclic derivatives III-b is made；The 3- oxygen The mol ratio for changing ursolic acid and the ethanol solution of 5- methoxyl group -2- aminobenzaldehydes is 2：3；The 3- oxidation ursolic acid and saturation The mass volume ratio of potassium hydroxide-ethanol solution is 0.22g/mL；

In step (3), ursolic acid quinoline chloride compound IV-b synthesis

0.085g (0.15mmol) compound III-b 5mL benzene is dissolved, 200 μ L (3mmol) chlorinations are then slowly added dropwise Sulfoxide, is to slowly warm up to 80 DEG C of back flow reaction about 4h, stops after reaction steaming to obtain by the benzene in reaction solution and thionyl chloride shallow The compound IV-b of yellow solid is used for subsequent reactions；The compound III-b and thionyl chloride, benzene mol ratio is 0.15:3:56；

Gained compound IV-b is dissolved in 5mL ether, is cooled to 0 DEG C, by 17.1mg (0.225mmol) acethydrazide, 45 μ L The triethylamine of (0.3mmol) is dissolved in 2mL dichloromethane and is added dropwise in reaction vessel, is slowly increased to that reaction is stirred at room temperature 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 collection organic phases are extracted with dichloromethane after ice-out, Washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and being concentrated under reduced pressure, it is organic molten to remove Agent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the petroleum ether and third The volume ratio of ketone is 30:1, pure compound ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-b is made；The IV-b, acethydrazide with Triethylamine, ether, the mol ratio of dichloromethane are 0.15:0.225:0.3:48:76.

6. a kind of ursolic acid quinoline hydrazide derivative with antitumor activity according to claim 2 and its preparation side Method, it is characterised in that：

In step (1), 3- oxidation ursolic acid II synthesis

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-b synthesis

0.668g (4mmol) 5- hydroxyl -2- nitrobenzaldehydes, 400 μ L (6mmol) iodine is added in 50mL round-bottomed flask Change methane, 0.832g (6mmol) potassium carbonate and 10mL DMF, reaction 8h, reaction is stirred at room temperature Reaction solution is poured into mixture of ice and water after end, after ice-out with dichloromethane extract 3 times collection organic phases, washing 3 times, Saturated sodium bicarbonate solution and strong brine are respectively washed once to be removed water with anhydrous sodium sulfate afterwards, and the removing organic solvent that is concentrated under reduced pressure obtains Huang Color solid is 5- methoxyl group -2- nitrobenzaldehydes (0.52g, 100%)；5- hydroxyls -2- the nitrobenzaldehydes, methyl iodide with The mol ratio of potassium carbonate is 4:6:6；The volume ratio of the methyl iodide and N,N-dimethylformamide is 0.4：10；

By 0.36g (2mmol) 5- methoxyl group -2- nitrobenzaldehydes in ethanol, acetic acid, distilled water (2:2:1,17.5mL) stirred in Mix and be to slowly warm up to 50 DEG C, 1.12g (20mmol) reduced iron powders and 600 μ L concentrated hydrochloric acids are added after being completely dissolved, continue to be heated to 85 DEG C of back flow reaction 1h, mixed liquor is filtered after stopping reaction and filter residue is washed with water, merging filtrate, 3 are extracted with dichloromethane Secondary collection organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, depressurized It is that 5- methoxyl group -2- aminobenzaldehydes crude products (0.24g) are directly used in synthesis first that concentration, which removes organic solvent and obtains yellow solid, Epoxide ursolic acid quinoline；5- methoxyl groups -2- the nitrobenzaldehydes and ethanol, acetic acid, distilled water cumulative volume quality volume Than for 0.02g/mL；The ethanol, acetic acid, the volume ratio of distilled water are 2:2:1；5- methoxyl groups -2- the nitrobenzaldehydes with The mol ratio of reduced iron powder is 1:10；The ethanol, acetic acid, the volume ratio of the cumulative volume of distilled water and concentrated hydrochloric acid are 175：6；

In step (3), ursolic acid quinoline chloride compound IV-b synthesis

Gained compound IV-b is dissolved in 5mL ether, is cooled to 0 DEG C, by 25.0mg (0.225mmol) valeric acid hydrazine, 45 μ L The triethylamine of (0.3mmol) is dissolved in 2mL dichloromethane and is added dropwise in reaction vessel, is slowly increased to that reaction is stirred at room temperature 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 collection organic phases are extracted with dichloromethane after ice-out, Washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and being concentrated under reduced pressure, it is organic molten to remove Agent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the petroleum ether and third The volume ratio of ketone is 50:1, pure compound ursolic acid quinolines Hete rocyclic derivatives I-f is made；The IV-b, valeric acid hydrazine and three second Amine, ether, the mol ratio of dichloromethane are 0.15:0.225:0.3:48:76；

In step (1), 3- oxidation ursolic acid II synthesis

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-c synthesis

By the fluoro- 2- nitrobenzaldehydes of 0.51g (3mmol) 5- in ethanol, acetic acid, distilled water (2:2:1,20mL) stirring is slow in 50 DEG C are warming up to, 1.68g (30mmol) reduced iron powders and 600 μ L concentrated hydrochloric acids are added after being completely dissolved, continues to be heated to 85 DEG C times Stream reaction 1h, mixed liquor is filtered and filter residue is washed with water after stopping reaction, merging filtrate, and 3 collections are extracted with dichloromethane Organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, be concentrated under reduced pressure and remove Go organic solvent to obtain yellow solid and be directly used in synthesizing fluoro ursolic acid quinoline for the fluoro- 2- aminobenzaldehydes crude products (0.43g) of 5- Quinoline；The mol ratio of the fluoro- 2- nitrobenzaldehydes of the 5- and reduced iron powder is 1:10；The ethanol, acetic acid, the volume ratio of distilled water For 2:2:1；The molal volume of the fluoro- 2- nitrobenzaldehydes of 5- and the cumulative volume of ethanol, acetic acid and distilled water is 0.15mol/ L；The volume ratio 0.6 of the concentrated hydrochloric acid and the cumulative volume of ethanol, acetic acid and distilled water：20；

The 5- of 0.67g (1.5mmol) 3- oxidation ursolic acid II and 0.35g (2.5mmol) in 50mL three neck round bottom flask is fluoro- 2mL saturation potassium hydroxide-ethanol solution, 85 DEG C of backflows are added dropwise in the ethanol solution of 2- aminobenzaldehydes under nitrogen protection 24h is reacted, reaction pours into reaction solution in mixture of ice and water after terminating, and extracting 3 collections with dichloromethane after ice-out has Machine phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and be concentrated under reduced pressure removing Organic solvent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the oil The volume ratio of ether and acetone is 150:1, pure compound ursolic acid quinolines Hete rocyclic derivatives III-c is made；The 3- aoxidizes bear The mol ratio of tartaric acid and the ethanol solution of the fluoro- 2- aminobenzaldehydes of 5- is 3：5；The 3- oxidation ursolic acid and saturation potassium hydroxide The mass volume ratio of ethanol solution is 0.34g/mL；

In step (3), ursolic acid quinoline chloride compound IV-c synthesis

0.084g (0.15mmol) compound III-c 5mL benzene is dissolved, 200 μ L (3mmol) chlorinations are then slowly added dropwise Sulfoxide, is to slowly warm up to 80 DEG C of back flow reaction about 4h, stops after reaction steaming to obtain by the benzene in reaction solution and thionyl chloride shallow The compound IV-c of yellow solid is used for subsequent reactions；The compound III-c and thionyl chloride, benzene mol ratio is 0.15:3:56；

Gained compound IV-c is dissolved in 5mL ether, is cooled to 0 DEG C, by 17.1mg (0.225mmol) acethydrazide, 45 μ L The triethylamine of (0.3mmol) is dissolved in 2mL dichloromethane and is added dropwise in reaction vessel, is slowly increased to that reaction is stirred at room temperature 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 collection organic phases are extracted with dichloromethane after ice-out, Washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and being concentrated under reduced pressure, it is organic molten to remove Agent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the petroleum ether and third The volume ratio of ketone is 30:1, pure compound ursolic acid quinolines Hete rocyclic derivatives I-c is made；The IV-c, acethydrazide and three second Amine, ether, the mol ratio of dichloromethane are 0.15:0.225:0.3:48:76.

7. a kind of ursolic acid quinoline hydrazide derivative with antitumor activity according to claim 2 and its preparation side Method, it is characterised in that：

In step (1), 3- oxidation ursolic acid II synthesis

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-c synthesis

The 5- of 0.67g (1.5mmol) 3- oxidation ursolic acid II and 0.35g (2.5mmol) in 50mL three neck round bottom flask is fluoro- 2mL saturation potassium hydroxide-ethanol solution, 85 DEG C of backflows are added dropwise in the ethanol solution of 2- aminobenzaldehydes under nitrogen protection 24h is reacted, reaction pours into reaction solution in mixture of ice and water after terminating, and extracting 3 collections with dichloromethane after ice-out has Machine phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and be concentrated under reduced pressure removing Organic solvent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the oil The volume ratio of ether and acetone is 150:1, pure compound III-c is made；The 3- oxidation ursolic acid and the fluoro- 2- aminobenzaldehydes of 5- Ethanol solution mol ratio be 3：5；The mass volume ratio of the 3- oxidation ursolic acid and saturation potassium hydroxide-ethanol solution is 0.34g/mL；

In step (3), ursolic acid quinoline chloride compound IV-c synthesis

Gained compound IV-c is dissolved in 5mL ether, is cooled to 0 DEG C, by 25.0mg (0.225mmol) valeric acid hydrazine, 45 μ L The triethylamine of (0.3mmol) is dissolved in 2mL dichloromethane and is added dropwise in reaction vessel, is slowly increased to that reaction is stirred at room temperature 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 collection organic phases are extracted with dichloromethane after ice-out, Washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and being concentrated under reduced pressure, it is organic molten to remove Agent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the petroleum ether and third The volume ratio of ketone is 80:1, pure compound ursolic acid quinolines Hete rocyclic derivatives I-g is made；The IV-c, valeric acid hydrazine and three second Amine, ether, the mol ratio of dichloromethane are 0.15:0.225:0.3:48:76；

In step (1), 3- oxidation ursolic acid II synthesis

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-d synthesis

By the chloro- 2- nitrobenzaldehydes of 0.55g (3mmol) 5- in ethanol, acetic acid, distilled water (2:2:1,20mL) stirring is slow in 50 DEG C are warming up to, 1.68g (30mmol) reduced iron powders and 600 μ L concentrated hydrochloric acids are added after being completely dissolved, continues to be heated to 85 DEG C times Stream reaction 1h, mixed liquor is filtered and filter residue is washed with water after stopping reaction, merging filtrate, and 3 collections are extracted with dichloromethane Organic phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, be concentrated under reduced pressure and remove Go organic solvent to obtain yellow solid and be directly used in synthesis chloro ursolic acid quinoline for the chloro- 2- aminobenzaldehydes crude products (0.45g) of 5- Quinoline；The mol ratio of the chloro- 2- nitrobenzaldehydes of the 5- and reduced iron powder is 1:10；The ethanol, acetic acid, the volume ratio of distilled water For 2:2:1；The molal volume of the chloro- 2- nitrobenzaldehydes of 5- and the cumulative volume of ethanol, acetic acid and distilled water is 0.15mol/ L；The volume ratio 0.6 of the concentrated hydrochloric acid and the cumulative volume of ethanol, acetic acid and distilled water：20；

The 5- of 0.67g (1.5mmol) 3- oxidation ursolic acid II and 0.38g (2.5mmol) in 50mL three neck round bottom flask is chloro- 2mL saturation potassium hydroxide-ethanol solution, 85 DEG C of backflows are added dropwise in the ethanol solution of 2- aminobenzaldehydes under nitrogen protection 24h is reacted, reaction pours into reaction solution in mixture of ice and water after terminating, and extracting 3 collections with dichloromethane after ice-out has Machine phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and be concentrated under reduced pressure removing Organic solvent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the oil The volume ratio of ether and acetone is 150:1, pure compound III-d is made；The 3- oxidation ursolic acid and the chloro- 2- aminobenzaldehydes of 5- Ethanol solution mol ratio be 3：5；The mass volume ratio of the 3- oxidation ursolic acid and saturation potassium hydroxide-ethanol solution is 0.34g/mL；

In step (3), ursolic acid quinoline chloride compound IV-d synthesis

0.086g (0.15mmol) compound III-d 5mL benzene is dissolved, 200 μ L (3mmol) chlorinations are then slowly added dropwise Sulfoxide, is to slowly warm up to 80 DEG C of back flow reaction about 4h, stops after reaction steaming to obtain by the benzene in reaction solution and thionyl chloride shallow The compound IV-d of yellow solid is used for subsequent reactions；The compound III-d and thionyl chloride, benzene mol ratio is 0.15:3:56；

Gained compound IV-d is dissolved in 5mL ether, is cooled to 0 DEG C, by 17.1mg (0.225mmol) acethydrazide, 45 μ L The triethylamine of (0.3mmol) is dissolved in 2mL dichloromethane and is added dropwise in reaction vessel, is slowly increased to that reaction is stirred at room temperature 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 collection organic phases are extracted with dichloromethane after ice-out, Washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and being concentrated under reduced pressure, it is organic molten to remove Agent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the petroleum ether and third The volume ratio of ketone is 30:1, pure compound ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-d is made；The IV-d, acethydrazide with Triethylamine, ether, the mol ratio of dichloromethane are 0.15:0.225:0.3:48:76.

8. a kind of ursolic acid quinoline hydrazide derivative with antitumor activity according to claim 2 and its preparation side Method, it is characterised in that：

In step (1), 3- oxidation ursolic acid II synthesis

In step (2), ursolic acid quinolines Hete rocyclic derivatives III-d synthesis

The 5- of 0.67g (1.5mmol) 3- oxidation ursolic acid II and 0.38g (2.5mmol) in 50mL three neck round bottom flask is chloro- 2mL saturation potassium hydroxide-ethanol solution, 85 DEG C of backflows are added dropwise in the ethanol solution of 2- aminobenzaldehydes under nitrogen protection 24h is reacted, reaction pours into reaction solution in mixture of ice and water after terminating, and extracting 3 collections with dichloromethane after ice-out has Machine phase, washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and be concentrated under reduced pressure removing Organic solvent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the oil The volume ratio of ether and acetone is 150:1, pure compound ursolic acid quinolines Hete rocyclic derivatives III-d is made；The 3- aoxidizes bear The mol ratio of tartaric acid and the ethanol solution of the chloro- 2- aminobenzaldehydes of 5- is 3：5；The 3- oxidation ursolic acid and saturation potassium hydroxide The mass volume ratio of ethanol solution is 0.34g/mL；

In step (3), ursolic acid quinoline chloride compound IV-d synthesis

Gained compound IV-d is dissolved in 5mL ether, is cooled to 0 DEG C, by 25.0mg (0.225mmol) valeric acid hydrazine, 45 μ L The triethylamine of (0.3mmol) is dissolved in 2mL dichloromethane and is added dropwise in reaction vessel, is slowly increased to that reaction is stirred at room temperature 6h, reaction pour into reaction solution in mixture of ice and water after terminating, and 3 collection organic phases are extracted with dichloromethane after ice-out, Washing 3 times, saturated sodium bicarbonate solution and strong brine are respectively washed and once removed water afterwards with anhydrous sodium sulfate, and being concentrated under reduced pressure, it is organic molten to remove Agent obtains yellow solid, and it is isolated and purified with silicagel column, and solvent selects petroleum ether acetone system, the petroleum ether and third The volume ratio of ketone is 80:1, pure compound ursolic acid quinoline hydrazides class Hete rocyclic derivatives I-h is made；The IV-d, valeric acid hydrazine with Triethylamine, ether, the mol ratio of dichloromethane are 0.15:0.225:0.3:48:76.

9. ursolic acid quinoline hydrazides class Hete rocyclic derivatives with structure shown in Formulas I described in claim 1 and its pharmaceutically may be used Application of the salt of receiving in tumor is prepared.

10. application according to claim 9, it is characterised in that：The tumour is human breast cancer cell MDA-MB-231, people Any one in cervical cancer cell HeLa or human liver cancer cells Hep G2.