CN104230932B - Matrine derivative and preparation method and application - Google Patents

Matrine derivative and preparation method and application Download PDF

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CN104230932B
CN104230932B CN201310244092.3A CN201310244092A CN104230932B CN 104230932 B CN104230932 B CN 104230932B CN 201310244092 A CN201310244092 A CN 201310244092A CN 104230932 B CN104230932 B CN 104230932B
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CN104230932A (en
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钟俊
王国成
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Jiangsu Tasly Diyi Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings

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Abstract

The present invention relates to matrine derivative and preparation method and application, and in particular to new kuh-seng alkaloid class compound of the class with following general structure and preparation method thereof, and application of these compounds in antineoplastic is prepared.

Description

Matrine derivative and preparation method and application
Technical field
Present invention design pharmaceutical technology field, and in particular to the new matrine derivative of a class, and preparation method, and Application of these compounds in antineoplastic is prepared.
Technical background
Kuh-seng alkaloid it is common as：Matrine, oxymatrine, sophocarpine, Sophoridine etc. are the unique quinolines of a class In western pyridine Alkaloid, be widely present in legume kuh-seng, Sophora alopecuroide and root of subprostrate sophora, be the master of this several conventional Chinese herbal medicine Want active ingredient（Active ingredient of autonomic drug handbook [M] Beijing is compiled in station by Chinese herbal medicine information center of State Pharmaceutical Administration：The people defend Raw publishing house, 1986,700.）.Kuh-seng alkaloid has extensive antibacterial, anti-inflammatory, antiallergy, antitumor, anti-arrhythmia cordis, disappeared The effects such as swollen diuresis, immune collection biological regulation, clinically by substantial amounts of application, with boundless application prospect （Chen Weizhong, Zhu Muliang, Zhang Xingrong Chinese Journal of New Drugs and Clinical Remedies [J], 2000,19 (15)：410）.Alkaloid of sophora flavescens ait is to more Plant experimental tumor inhibited, and mostly transplanted solid tumor.They have direct lethal effect to cancer cell, and They have toxicity low, the advantage of unrestraint marrow and body's immunity（Chen B H,Zhou Y H,Qian W B.Study on anti-tumor mechanisms of matrine[J].Zhejiang J Integr Tradit Chin West Med（Zhejiang combination of Chinese tradiational and Western medicine magazine）, 2010,20 (8)：524-526.）.
Matrine (matrine), structure is as follows：
Matrine is through ethanol by legume kuh-seng Sophora flavescens Ait dry root, plant, fruit Extract what is be made Deng organic solvent, matrine sterling is white powder.It has the duplication for suppressing hepatitis B HbeAg, Shang You Anticancer and antiarrhythmic effect.
On anticancer aspect, existing Matrine Sodium Chloride Injections launch, its indication is:Antitumor auxiliary is used Medicine.For preventing tumour patient to occur dyscrasia, improve tumour patient life quality.Specification:100ml:Matrine 80mg and chlorine Change sodium 0.9g usage and dosages:Drip-feed.1 times a day, each 100ml（1 bag）.The instillation time should not be less than 40 minutes.
Because the curative effect of existing matrine is still unsatisfactory, to improve the antitumor curative effect index of existing matrine, Its side effect is reduced, while the problem of solving in pharmaceutical preparation, such as water solubility problems, stability problem etc. needs to find in items More superior matrine medicine in index, is that this present invention is transformed the structure of matrine, is found surprisingly that The more superior matrine derivative on antitumous effect and in other indexs.
The content of the invention
The technical problem to be solved in the present invention is to provide it is a kind of can be used for prepare antineoplastic matrine derivative and Its preparation method.
Matrine derivative of the present invention, its structure is as follows：
Present invention also offers the preparation method of above-claimed cpd, this method uses following reaction scheme：
Route 1：
Route 2：
It is related to each compound, specifically includes following technical scheme：：
（1）TSM-9 preparation：
By matrine and mass ratio 1：10~40 halogenating agent mixing, is heated to 40 DEG C~100 DEG C, reacts 12~48h, system It is standby to obtain TSM-9；
Wherein, halogenating agent is selected from：Thionyl chloride, POCl3, phosphorus trichloride or phosphorus pentachloride.
（2）TSM-5 or TSM-6 preparation：
TSS-9 is dissolved in mass ratio 1：In 10~40 solvent, the catalyst of TSS-9 mass 1%~10% is added, in hydrogen Atmospheric pressure reacts 12~48h under 0.1MPa~10MPa, to be heated to 40 DEG C~100 DEG C, and catalytic hydrogenation prepares TSM-5 And TSM-6；
Wherein,
Solvent is selected from：One or more in methanol, ethanol, isopropanol, acetone, tetrahydrofuran or dioxane；Catalysis Agent is selected from：Palladium carbon, palladium dydroxide or Renney Ni.
（3）TSM-7 or TSM-8 preparation：
TSM-5 or TSM-6 are dissolved in mass ratio 1：In 10~30 solvent, mass ratio 1 is added：1~5 acetylation examination Agent, is heated to 40 DEG C~140 DEG C, reacts 12~48h, prepares TSM-7 or TSM-8；Wherein,
Solvent is selected from：Methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dimethylformamide, dimethyl acetamide, two One or more in methyl sulfoxide or hexamethyl phosphoramide；
Acetylation reagent is selected from：Ammonium acetate, lithium acetate, sodium acetate, potassium acetate, acetic acid rubidium or cesium acetate.
（4）TSM-1 or TSM-2 preparation：
TSM-7 or TSM-8 are dissolved in mass ratio 1：In 10~30 solvent, TSM-7 or TSM-8 mass 1%~5% is added Alkali, react at room temperature 12~48h, prepare TSM-1 or TSM-2；
Wherein,
Solvent is selected from：One or more in water, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran or dioxane；
Alkali is selected from：Sodium methoxide, caustic alcohol, sodium hydroxide or potassium hydroxide.
（5）TSM-3 or TSM-4 preparation：
It is 1 that TSM-1 or TSM-2 are dissolved in into mass ratio：In 10~30 solvent, ice-water bath is cooled to 0 DEG C~10 DEG C, addition TSM-1 or TSM-2 mass ratioes are 1：1~5 times amount fluorination reagent, natural 12~48h of temperature reaction, prepare TSM-4 or TSM-3。
Wherein,
Solvent is selected from：One or more in dichloromethane, chloroform, 1,2- dichloroethanes；
Fluorination reagent is selected from：DAST or Deoxofluor.
（6）TSM-10 preparation：
TSM-9 is dissolved in mass ratio 1：In 10~30 solvents, mass ratio 1 is added：0.5~2 alkali and 1：0.25~1 chlorine Change lithium, be heated to 80~150 DEG C, react 12~48h, prepare TSM-10；
Wherein,
Solvent is selected from：Toluene, dimethylbenzene, dioxane, dimethylformamide, dimethyl acetamide, dimethyl sulfoxide (DMSO) or One or more in hexamethyl phosphoramide；
Alkali is selected from：Lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate or cesium carbonate.
（7）TSM-11 preparation：
It is 1 that TSM-10 is dissolved in into mass ratio：In 10~30 morpholine, 80 DEG C~120 DEG C are heated to, 12~48h, system is reacted It is standby to obtain TSM-11.
（8）TSM-12 preparation：
It is 1 that TSM-11 is dissolved in into mass ratio：In 10~30 solvent, TSM-11 mass ratioes 1 are added：1~5 trifluoroacetic acid Acid anhydride and 1：1~5 alkali, reacts at room temperature 12~48h, prepares TSM-12；
Wherein,
Solvent is selected from：One or more in dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes；
Alkali is selected from：Potassium carbonate, sodium carbonate, triethylamine, diisopropyl ethyl amine, pyridine or DMAP.（9） TSM-13 preparation：
It is 1 that TSM-12 is dissolved in into mass ratio：In 10~30 solvent, it is 1 to add TSM-12 mass ratioes：1~5 acid, room Temperature 6~24h of reaction, prepares TSM-13；
Wherein,
Solvent is selected from：One or more in methanol, ethanol, tetrahydrofuran or dioxane；
Acid is selected from：Trifluoroacetic acid, hydrochloric acid or sulfuric acid.
（10）TSM-14 preparation：
It is 1 that TSM-13 is dissolved in into mass ratio：In 10~30 solvent, it is 1 to add TSM-13 mass ratioes：1~10 hydration Hydrazine and 1：1~10 acid, is heated to 60 DEG C~100 DEG C, reacts 12~48h, prepares TSM-14；Wherein,
Solvent is selected from：One or more in benzene, toluene, tetrahydrofuran or dioxane；
Acid is selected from：Trifluoroacetic acid, hydrochloric acid, sulfuric acid or p-methyl benzenesulfonic acid.
Present invention additionally comprises application of the matrine derivative in antineoplastic is prepared.It is preferred that, it is described swollen Knurl is brain colloid, glioma, liver cancer, lung cancer, colon cancer, thin stomach cancer, cervical carcinoma or melanoma.
Present invention additionally comprises, the pharmaceutical composition containing matrine derivative of the present invention, described pharmaceutical composition is with this hair The pharmaceutical preparations composition that bright matrine derivative is prepared into as active constituents of medicine.It is of the invention according to clinical needs In pharmaceutical composition, can also include can be with the matrine derivative compatibility of the present invention other drugs, preferred antineoplastic Thing.
The pharmaceutical preparations composition of the present invention, can contain pharmaceutically acceptable carrier as needed, wherein the present invention Matrine derivative as active constituents of medicine, its in the formulation shared percentage by weight can be 0.1-99.9%, remaining is medicine The acceptable carrier of thing.The pharmaceutical preparations composition of the present invention, exists, the unit dosage form refers in a unit Every of the unit, such as tablet of preparation, every capsule of capsule, every bottle of oral liquid, every bag of granule, every of injection Deng.
The pharmaceutical preparations composition of the present invention can be any pharmaceutically useful formulation, and these formulations include：Tablet, sugar coated tablet Agent, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, mouth containing agent, granule, electuary, Pill, powder, paste, sublimed preparation, supensoid agent, pulvis, solution, injection, suppository, ointment, emplastrum, creme, spray, Drops, patch, pill, freeze-dried powder and related sustained-release preparation, embedding medium etc..
The pharmaceutical composition of the present invention, its preparation being administered orally can contain conventional excipient, such as adhesive, filling Agent, diluent, tablet agent, lubricant, disintegrant, colouring agent, flavor enhancement and wetting agent, can be coated to tablet if necessary.
Applicable filler includes cellulose, mannitol, lactose and other similar fillers.Suitable disintegrant bag Include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycollate.Suitable lubricant includes, for example firmly Fatty acid magnesium.Suitable pharmaceutically acceptable wetting agent includes lauryl sodium sulfate.
It can be filled by mixing, the conventional method such as tabletting prepares solid oral composition.Work can be made by carrying out mixing repeatedly Property material be distributed in entirely using a large amount of fillers those compositions in.
The form of oral liquid for example can be aqueous or oily suspensions, solution, emulsion, syrup or elixir, Or can be a kind of dry products that can be compounded before use with water or other suitable carriers.This liquid preparation can contain Conventional additive, such as suspending agent, such as sorbierite, syrup, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl are fine Dimension element, aluminium stearate gel or hydrogenated edible fats, emulsifying agent, such as lecithin, anhydro sorbitol monooleate or Arab Glue；Non-aqueous carrier（They can include edible oil）, such as apricot kernel oil, fractionated coconut oil, the oiliness of the ester of such as glycerine Ester, propane diols or ethanol；Preservative, such as para hydroxybenzene methyl esters or propylparaben or sorbic acid, and if need Will, conventional flavouring agent or colouring agent can be contained.
For injection, the fluid unit dosage form of preparation contains the active material and sterile carrier of the present invention.According to carrier And concentration, this compound can be suspended or be dissolved.The preparation of solution is dissolved in a kind of load typically by by active material In body, sterilization is filtered before a kind of suitable bottle or ampoule is loaded into, is then sealed.For example a kind of local anaesthesia of auxiliary material Agent, preservative and buffer can also be dissolved in this carrier., can be after bottle be loaded by this in order to improve its stability Composition frost is planted, and under vacuo removes water.
The pharmaceutical composition of the present invention, suitable pharmaceutically acceptable load is optionally added when being prepared into medicament Body, the pharmaceutically acceptable carrier is selected from：Mannitol, sorbierite, sodium pyrosulfite, sodium hydrogensulfite, sodium thiosulfate, salt Sour cysteine, TGA, methionine, injection Vitamin B_6 DTA disodiums, Ethylenediaminetetraacetic Acid Calcium Salt, carbonate, the acetic acid of monovalence alkali metal Salt, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, wheat Bud sugar, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and its Derivative, alginates, gelatin, polyvinylpyrrolidone, glycerine, POLYSORBATE 80, agar, calcium carbonate, calcium bicarbonate, surface-active Agent, polyethylene glycol, cyclodextrin, beta-schardinger dextrin, phospholipid material, kaolin, talcum powder, calcium stearate, magnesium stearate etc..
The preparation of the present invention determines usage and dosage according to the situation of patient when in use, can often taken three times per day, each 1-20 Agent, such as：1-20 bags or grain or piece or branch, every dose of 1mg-1000mg.
Beneficial effects of the present invention are further illustrated below by way of experiment.
Pharmacological evaluation
Derivative is tested to SHG-44 with mtt assay（Human glioma cell）, U251（Human glioma cell）, HepG2 (human liver cancer cell), A549（Human lung adenocarcinoma cell）, HCT-8（Human colon cancer cell）, BGC823（Gastric carcinoma cells）, MS751（Human cervical carcinoma cell）, WM-266-4（Human melanoma cell）Anti tumor activity in vitro.Collect well-grown swollen Oncocyte, 1.0~1.5 × 10 are configured to DMEM the and RPMI1640 culture mediums containing 10% calf serum respectively4/ mL cells hang Liquid, in being inoculated with 96 well culture plates, per the μ l of hole 100, puts 37 DEG C, 5%CO2Dosing after culture 24h in incubator, experiment sets blank pair According to given the test agent sets 3 concentration, per 3 parallel holes of concentration, puts 37 DEG C, 5%CO2Culture 4 days in incubator.Nutrient solution is discarded, often Hole adds MTT solution（0.4mg/mL, serum-free RPMI1640 are prepared）100 μ l, 37 DEG C of incubation 4h.Abandoning supernatant, adds per hole Enter DMSO150 μ l, dissolve after Fomazan particles, gentle agitation, with 550 type ELIASAs in Detection wavelength 540nm, reference wavelength OD values are determined under 405nm, and calculate cell inhibitory rate.Experimental result such as following table：
（1）Derivatives antitumor activity under 100 μ g/mL concentration
a:Derivatives concentration is 100 μ g/mL；b:5-FU concentration is 1 μ g/mL
（2）Inhibitory activity of the derivative to stomach cancer cell BGC823 under various concentrations
a:5-FU concentration is 10 μ g/mL
The Pharmacological experiment result shows that：The serial kuh-seng alkaloid derivative of synthesis has antitumor activity effect, with hardship It is comparison medicine to join alkali or Sophoridine, in the case of being administered simultaneously with the TSM series compounds of synthesis, by contrasting their suppression Rate discovery, compound TSM-1, TSM-4, TSM-5, TSM-6, TSM-7, TSM-8, TSM-9, TSM-10, TSM-11, TSM-12, TSM-13, TSM-14 antitumor activity are better than comparison medicine.
The present invention's is the provision of a kind of antineoplastic being expected to as high-efficiency low-toxicity, to more than numerous cancer patients one Plant the selection for the treatment of.
Embodiment：
With reference to embodiment, the invention will be further described, and preparation method is as follows：
The compound TSM-9 of embodiment 1 preparation
5g matrines are added in 500mL four-neck flasks, 200g thionyl chlorides heat 24h in 80 DEG C.Naturally cool to room Temperature, reaction solution is poured into 1L frozen water, is stirred continuously, and pH=7 is neutralized to 6N sodium hydroxide solution, with 500mL × 3CH2Cl2Extraction, anhydrous Na2SO4Dry.Suction filtration, concentrates filtrate, through silica gel column chromatography（V(PE):V(EA)=1:1）Purifying, can obtain Compound TSM-94.3g, yield 67%.Compound TSM-9MS:m/z339[M+Na]+；1H NMR(CDCl3):δ3.54-3.47 (m,2H),3.28-3.21(dd,1H),2.89-2.86(m,1H),2.85-2.75(m,2H),2.66-2.59(m,1H),2.27- 2.17(m,2H),2.15-2.08(m,1H),2.01-1.79(m,6H),1.74-1.59(m,2H),1.58-1.45(m,3H), 1.13-1.02(m,1H).
The compound TSM-9 of embodiment 2 preparation
5g matrines are added in 500mL four-neck flasks, 50g POCl3s heat 16h in 100 DEG C.Naturally cool to room Temperature, reaction solution is poured into 1L frozen water, is stirred continuously, and pH=7 is neutralized to 6N sodium hydroxide solution, with 500mL × 3CH2Cl2Extraction, anhydrous Na2SO4Dry.Suction filtration, concentrates filtrate, through silica gel column chromatography（V(PE):V(EA)=1:1）Purifying, can obtain Compound TSM-95.5g, yield 85%.Compound TSM-9MS:m/z339[M+Na]+；1H NMR(CDCl3):δ3.54-3.47 (m,2H),3.28-3.21(dd,1H),2.89-2.86(m,1H),2.85-2.75(m,2H),2.66-2.59(m,1H),2.27- 2.17(m,2H),2.15-2.08(m,1H),2.01-1.79(m,6H),1.74-1.59(m,2H),1.58-1.45(m,3H), 1.13-1.02(m,1H).
Embodiment 3 compound TSM-5 and TSM-6 preparation
5g TSM-9 are dissolved in 100g absolute ethyl alcohols, 200mg palladium-carbon catalysts are added, pressed in Hydrogen Vapor Pressure for 1.0MPa Under power, 80 DEG C of reaction 24h are heated, stops reaction, is filtered to remove palladium carbon.Filtrate is concentrated, through silica gel column chromatography（V(PE):V(EA)=2: 1）Purifying, can respectively obtain compound TSM-51.7g and TSM-62.2g, total recovery 88%.Compound TSM-5MS:m/z305[M +Na]+；1H NMR(CDCl3):δ4.58-4.47(m,2H),3.68-3.61(t,1H),3.59-3.47(m,2H),3.19-3.17 (d, 1H), 2.71-2.66 (m, 2H), 2.36-2.24 (m, 4H), 2.15-2.11 (m, 4H), 1.97-1.62 (m, 7H) compounds TSM-6MS:m/z305[M+Na]+；1H NMR(CDCl3):δ4.39-4.32(m,2H),4.00-3.95(m,1H),3.19-3.13 (t,1H),2.86-2.78(dd,2H),2.36-2.26(m,2H),2.13(bs,1H),2.06-1.93(m,3H),1.89-1.86 (m,1H),1.74-1.38(m,10H).
Embodiment 4 compound TSM-5 and TSM-6 preparation
5g TSM-9 are dissolved in 60g dioxane, 80mg Renney Ni catalyst is added, is in Hydrogen Vapor Pressure Under 10MPa pressure, 90 DEG C of reaction 48h are heated, stops reaction, is filtered to remove palladium carbon.Filtrate is concentrated, through silica gel column chromatography（V(PE): V(EA)=2:1）Purifying, can respectively obtain compound TSM-51.3g and TSM-61.8g, total recovery 88%.Compound TSM-5MS: m/z305[M+Na]+；1H NMR(CDCl3):δ4.58-4.47(m,2H),3.68-3.61(t,1H),3.59-3.47(m,2H), 3.19-3.17(d,1H),2.71-2.66(m,2H),2.36-2.24(m,4H),2.15-2.11(m,4H),1.97-1.62(m, 7H) compounds TSM-6MS:m/z305[M+Na]+；1H NMR(CDCl3):δ4.39-4.32(m,2H),4.00-3.95(m, 1H),3.19-3.13(t,1H),2.86-2.78(dd,2H),2.36-2.26(m,2H),2.13(bs,1H),2.06-1.93(m, 3H),1.89-1.86(m,1H),1.74-1.38(m,10H).
Embodiment 5 compound TSM-7 and TSM-8 preparation
By 2g TSM-5（TSM-6）It is dissolved in 50g dimethylformamides, cesium acetate 5g is added, in 100 DEG C of heating responses 24h.Reaction solution is poured into 200ml water, with 100mL × 3CH2Cl2Extraction, anhydrous Na2SO4Dry.Suction filtration, concentrates filtrate, warp Silica gel column chromatography（V(PE):V(EA)=1:3）Purifying, can obtain compound TSM-71.8g yields 82%（TSM-8）.Compound TSM- 7MS:m/z329[M+Na]+；1H NMR(CDCl3):δ4.83-4.61(m,2H),4.13-4.09(m,1H),3.82-3.75(m, 1H),3.68-3.62(m,2H),3.28-3.26(d,2H),2.69-2.66(m,2H),2.41-2.25(m,8H),2.13-2.11 (m, 3H), 1.91-1.58 (m, 7H) compounds TSM-8MS:m/z329[M+Na]+；1H NMR(CDCl3):δ4.41-4.34(m, 1H),4.22-4.16(m,2H),3.75(s,1H),3.25-3.19(m,1H),2.95-2.88(m,2H),2.33-2.27(m, 3H),2.26-1.96(m,6H),1.85-1.68(m,5H),1.64-1.42(m,5H).
Embodiment 6 compound TSM-7 and TSM-8 preparation
By 2g TSM-5（TSM-6）It is dissolved in 20g isopropanols, ammonium acetate 2g is added, in 80 DEG C of heating response 48h.Will be anti- Liquid is answered to pour into 200ml water, with 100mL × 3CH2Cl2Extraction, anhydrous Na2SO4Dry.Suction filtration, concentrates filtrate, through silica gel column layer Analysis（V(PE):V(EA)=1:3）Purifying, can obtain compound TSM-71.8g yields 82%（TSM-8）.Compound TSM-7MS:m/ z329[M+Na]+；1HNMR(CDCl3):δ4.83-4.61(m,2H),4.13-4.09(m,1H),3.82-3.75(m,1H), 3.68-3.62(m,2H),3.28-3.26(d,2H),2.69-2.66(m,2H),2.41-2.25(m,8H),2.13-2.11(m, 3H), 1.91-1.58 (m, 7H) compounds TSM-8MS:m/z329[M+Na]+；1H NMR(CDCl3):δ4.41-4.34(m, 1H),4.22-4.16(m,2H),3.75(s,1H),3.25-3.19(m,1H),2.95-2.88(m,2H),2.33-2.27(m, 3H),2.26-1.96(m,6H),1.85-1.68(m,5H),1.64-1.42(m,5H).
Embodiment 7 compound TSM-1 and TSM-2 preparation
By 200mg TSM-7（TSM-8）It is dissolved in 6g methanol, adds 5mg sodium methoxides, in room temperature reaction 12h, concentration filter Liquid, through silica gel column chromatography（V(PE):V(EA)=1:6）Purifying, can obtain compound TSM-1150mg yields 88%（TSM-2）.Chemical combination Thing TSM-1MS:m/z287[M+Na]+；1H NMR(CDCl3):δ4.53-4.40(m,2H),3.93-3.89(m,1H),3.71- 3.64(t,1H),3.58-3.51(m,2H),3.18-3.16(d,2H),2.68(bs,2H),2.37-2.25(m,5H),2.11- 2.07 (m, 3H), 1.89-1.59 (m, 7H) compounds TSM-2MS:m/z287[M+Na]+；1H NMR(CDCl3):δ4.20- 4.15(dd,1H),4.04-3.97(m,2H),3.73(s,1H),3.20-3.13(t,1H),2.85-2.78(m,2H),2.19 (bs,1H),2.11-1.88(m,6H),1.80-1.66(m,5H),1.60-1.39(m,5H).
Embodiment 8 compound TSM-1 and TSM-2 preparation
By 200mg TSM-7（TSM-8）It is dissolved in 2g dioxane, adds 5g water, 10mg sodium hydroxides, in room temperature reaction 24h, concentrates filtrate, through silica gel column chromatography（V(PE):V(EA)=1:6）Purifying, can obtain compound TSM-1123mg yields 72% （TSM-2）.Compound TSM-1MS:m/z287[M+Na]+；1H NMR(CDCl3):δ4.53-4.40(m,2H),3.93-3.89 (m,1H),3.71-3.64(t,1H), 3.58-3.51(m,2H),3.18-3.16(d,2H),2.68(bs,2H),2.37-2.25 (m, 5H), 2.11-2.07 (m, 3H), 1.89-1.59 (m, 7H) compounds TSM-2MS:m/z287[M+Na]+；1H NMR (CDCl3):δ4.20-4.15(dd,1H),4.04-3.97(m,2H),3.73(s,1H),3.20-3.13(t,1H),2.85- 2.78(m,2H),2.19(bs,1H),2.11-1.88(m,6H),1.80-1.66(m,5H),1.60-1.39(m,5H).
Embodiment 9 compound TSM-3 and TSM-4 preparation
0.9g TSM-2 are added in the mono- neck bottles of 50mL（TSM-1）, 30g CH2Cl2, ice bath is cooled to 0 DEG C.Add 1g Deoxo-fluor, is warmed to room temperature reaction naturally, and TLC detection raw material reactions are complete.20mL water is added, with 20mL × 3CH2Cl2Extraction Take, anhydrous Na2SO4Dry.Suction filtration, concentrates filtrate, through silica gel column chromatography（V(PE):V(EA)=2:1）Purifying, can obtain compound TSM- 30.4g yield 44%（TSM-4）.Compound TSM-3MS:m/z289[M+Na]+；1H NMR(CDCl3):δ4.93-4.78(dt, 1H),4.28-4.23(dd,1H),4.08-4.06(m,1H),3.45-3.43(m,1H),3.28-3.21(m,3H),2.93- 2.88(m,2H),2.24-2.20(m,2H),1.93-1.83(m,4H),1.79-1.55(m,8H).19F NMR(CDCl3):δ- 186.0. compound TSM-4MS:m/z289[M+Na]+；1H NMR(CDCl3):δ5.17-5.05(dt,1H),4.71(s,1H), 4.31-4.26(dd,1H),3.70-3.67(m,1H),3.53(bs,1H),3,37-3.31(m,2H),3.02-2.99(m,2H), 2.20-2.00(m,6H),1.82-1.89(m,8H).19F NMR(CDCl3):δ-196.6.
Embodiment 10 compound TSM-3 and TSM-4 preparation
0.9g TSM-2 are added in the mono- neck bottles of 50mL（TSM-1）, 10g1,2- dichloroethanes, ice bath is cooled to 0 DEG C.Plus Enter 2g DAST, reaction is warmed to room temperature naturally, TLC detection raw material reactions are complete.20mL water is added, with 20mL × 3CH2Cl2Extraction, Anhydrous Na2SO4Dry.Suction filtration, concentrates filtrate, through silica gel column chromatography（V(PE):V(EA)=2:1）Purifying, can obtain compound TSM- 30.55g yield 60%（TSM-4）.Compound TSM-3MS:m/z289[M+Na]+；1H NMR(CDCl3):δ4.93-4.78(dt, 1H),4.28-4.23(dd,1H),4.08-4.06(m,1H),3.45-3.43(m,1H),3.28-3.21(m,3H),2.93- 2.88(m,2H),2.24-2.20(m,2H),1.93-1.83(m,4H),1.79-1.55(m,8H).19F NMR(CDCl3):δ- 186.0. compound TSM-4MS:m/z289[M+Na]+；1H NMR(CDCl3):δ5.17-5.05(dt,1H),4.71(s,1H), 4.31-4.26(dd,1H),3.70-3.67(m,1H),3.53(bs,1H),3,37-3.31(m,2H),3.02-2.99(m,2H), 2.20-2.00(m,6H),1.82-1.89(m,8H).19F NMR(CDCl3):δ-196.6.
The compound TSM-10 of embodiment 11 preparation
200mg TSM-9,5g dimethylformamides, 100mg lithium carbonates and 50mg lithium chlorides are added in the mono- neck bottles of 50mL, Keep 80 DEG C of reaction 8h.50mL water is added, with 50mL × 3CH2Cl2Extraction, anhydrous Na2SO4Dry.Suction filtration, concentrates filtrate, warp Silica gel column chromatography（V(PE):V(EA)=1:1）Purifying, can obtain compound TSM-10168mg yields 94%.Compound TSM-10MS:m/ z303[M+Na]+；1H NMR(CDCl3):δ3.67-3.60(m,1H),3.23-3.17(dd,1H),2.91-2.88(m,1H), 2.83-2.77(m,1H),2.66-2.59(m,1H),2.28-2.12(m,3H),2.07-1.74(m,6H),1.73-1.46(m, 5H),1.18-1.07(m,1H).
The compound TSM-10 of embodiment 12 preparation
200mg TSM-9,3g dimethylbenzene, 200mg lithium carbonates and 100mg lithium chlorides are added in the mono- neck bottles of 50mL, is kept 100 DEG C of reaction 48h.50mL water is added, with 50mL × 3CH2Cl2Extraction, anhydrous Na2SO4Dry.Suction filtration, concentrates filtrate, through silicon Plastic column chromatography（V(PE):V(EA)=1:1）Purifying, can obtain compound TSM-10152mg yields 85%.Compound TSM-10MS:m/ z303[M+Na]+；1H NMR(CDCl3):δ3.67-3.60(m,1H),3.23-3.17(dd,1H),2.91-2.88(m,1H), 2.83-2.77(m,1H),2.66-2.59(m,1H),2.28-2.12(m,3H),2.07-1.74(m,6H),1.73-1.46(m, 5H),1.18-1.07(m,1H).
The compound TSM-11 of embodiment 13 preparation
5.4g TSM-10 are added in the mono- neck bottles of 500mL, 150g morpholines are added, 80 DEG C of 24h of heating stop reaction, added 500mL dichloromethane, with the 3N salt acid elutions of 250mL × 3, organic phase anhydrous Na2SO4Dry.Suction filtration, concentrates filtrate, through silicon Plastic column chromatography（V(PE):V(EA)=1:4）Purifying, can obtain compound TSM-113.7g yields 69%, compound TSM-11MS:m/z332 [M+1]+；1H NMR(CDCl3):δ5.48(dd,1H),4.19(dd,1H),3.88-3.80(m,4H),3.20(t,1H),3.03- 2.94(m,2H),2.79-2.74(m,2H),2.66-2.59(m,1H),2.23-2.16(m,2H),2.00(brs,3H),1.87- 1.69(m,7H),1.61-1.44(m,5H).
The compound TSM-11 of embodiment 14 preparation
5.4g TSM-10 are added in the mono- neck bottles of 500mL, 60g morpholines are added, 120 DEG C of 48h of heating stop reaction, added 500mL dichloromethane, with the 3N salt acid elutions of 250mL × 3, organic phase anhydrous Na2SO4Dry.Suction filtration, concentrates filtrate, through silicon Plastic column chromatography（V(PE):V(EA)=1:4）Purifying, can obtain compound TSM-114.4g yields 82%, compound TSM-11MS:m/z332 [M+1]+；1H NMR(CDCl3):δ5.48(dd,1H),4.19(dd,1H),3.88-3.80(m,4H),3.20(t,1H),3.03- 2.94(m,2H),2.79-2.74(m,2H),2.66-2.59(m,1H),2.23-2.16(m,2H),2.00(brs,3H),1.87- 1.69(m,7H),1.61-1.44(m,5H).
The compound TSM-12 of embodiment 15 preparation
1g TSM-11,30g dichloromethane, 4g TFAAs, 5g triethylamines, in room temperature are added in the mono- neck bottles of 100mL React 24h.200mL dichloromethane is added, is washed with the 3N salt acid elutions of 250mL × 3, then with the saturated sodium bicarbonate of 250mL × 3 Wash, organic phase anhydrous Na2SO4Dry.Suction filtration, concentrates filtrate, through silica gel column chromatography（V(PE):V(EA)=1:2）Purifying, must can change Compound TSM-120.9g yields 70%.Compound TSM-12MS:m/z428[M+1]+；1H NMR(CDCl3):δ4.44-4.10(m, 1H),3.96-3.93(m,3H),3.82-3.57(m,1H),3.48-3.39(m,3H),3.24-3.22(m,3H),3.18-3.05 (m,1H),3.02-2.60(m,3H),2.53-2.16(m,2H),2.01-1.42(m,9H),1.32-1.17(m,1H).
The compound TSM-12 of embodiment 16 preparation
Addition 1g TSM-11,10g1, the 2- dichloroethanes in the mono- neck bottles of 100mL, 2g TFAAs, 3g triethylamines, in React at room temperature 14h.200mL dichloromethane is added, with the 3N salt acid elutions of 250mL × 3, then with the unsaturated carbonate hydrogen of 250mL × 3 Sodium is washed, organic phase anhydrous Na2SO4Dry.Suction filtration, concentrates filtrate, through silica gel column chromatography（V(PE):V(EA)=1:2）Purifying, can Obtain compound TSM-120.7g yields 54%.Compound TSM-12MS:m/z428[M+1]+；1H NMR(CDCl3):δ4.44- 4.10(m,1H),3.96-3.93(m,3H),3.82-3.57(m,1H),3.48-3.39(m,3H),3.24-3.22(m,3H), 3.18-3.05(m,1H),3.02-2.60(m,3H),2.53-2.16(m,2H),2.01-1.42(m,9H),1.32-1.17(m, 1H).
The compound TSM-13 of embodiment 17 preparation
200mg TSM-12 are added in 100mL round-bottomed flasks, 6g dichloromethane is added, 0.3g trifluoroacetic acids, room temperature is stirred 24h is mixed, stops reaction.200mL dichloromethane is added, is washed with the saturated sodium bicarbonate of 250mL × 3, organic phase is with anhydrous Na2SO4Dry.Suction filtration, concentrates filtrate, through silica gel column chromatography（V(PE):V(EA)=1:2）Purifying, can obtain compound TSM-13150mg Yield 89%.Compound TSM-13MS:m/z359[M+1]+；1H NMR(CDCl3):δ3.87(s,1H),3.28-2.23(m, 1H),2.88-2.81(m,2H),2.74-2.67(m,1H),2.40-2.34(m,1H),2.19-2.15(m,1H),2.04(s, 1H),1.95-1.83(m,2H),1.71-1.63(m,6H),1.50-1.37(m,3H),1.28-1.25(m,1H),1.12-1.04 (m,1H).
The compound TSM-13 of embodiment 18 preparation
200mg TSM-12 are added in 100mL round-bottomed flasks, 3g tetrahydrofurans are added, 0.8g concentrated hydrochloric acids are stirred at room temperature 6h, stops reaction.200mL dichloromethane is added, is washed with the saturated sodium bicarbonate of 250mL × 3, organic phase anhydrous Na2SO4 Dry.Suction filtration, concentrates filtrate, through silica gel column chromatography（V(PE):V(EA)=1:2）Purifying, can obtain compound TSM-13126mg yields 75%.Compound TSM-13MS:m/z359[M+1]+；1H NMR(CDCl3):δ3.87(s,1H),3.28-2.23(m,1H), 2.88-2.81(m,2H),2.74-2.67(m,1H),2.40-2.34(m,1H),2.19-2.15(m,1H),2.04(s,1H), 1.95-1.83(m,2H),1.71-1.63(m,6H),1.50-1.37(m,3H),1.28-1.25(m,1H),1.12-1.04(m, 1H).
The compound TSM-14 of embodiment 19 preparation
The addition 500mg TSM-13 in 100mL round-bottomed flasks, addition 15g toluene, hydrazine hydrate 2g, trifluoroacetic acid 0.5g, 24h is heated to reflux, 200mL ethyl acetate is added, is washed with the saturated sodium bicarbonate of 100mL × 3, organic phase anhydrous Na2SO4 Dry.Suction filtration, concentrates filtrate, through silica gel column chromatography（V(PE):V(EA)=1:2）Purifying, can obtain compound TSM-14350mg yields 71%.Compound TSM-14MS:m/z355[M+1]+；1H NMR(CDCl3):δ4.41-4.32(m,2H),3.41-3.34(t, 1H),3.24-3.18(dd,1H),2.92-2.83(m,3H),2.20-2.18(m,1H),2.05-1.86(m,4H),1.82- 1.77(m,2H),1.73-1.67(m,3H),1.62-1.55(m,1H),1.50-1.44(m,2H).
The compound TSM-14 of embodiment 20 preparation
The addition 500mg TSM-13 in 100mL round-bottomed flasks, addition 5g dioxane, hydrazine hydrate 5g, concentrated hydrochloric acid 5g, plus Heat backflow 48h, adds 200mL ethyl acetate, is washed with the saturated sodium bicarbonate of 100mL × 3, organic phase anhydrous Na2SO4It is dry It is dry.Suction filtration, concentrates filtrate, through silica gel column chromatography（V(PE):V(EA)=1:2）Purifying, can obtain compound TSM-14409mg yields 83%.Compound TSM-14MS:m/z355[M+1]+；1H NMR(CDCl3):δ4.41-4.32(m,2H),3.41-3.34(t, 1H),3.24-3.18(dd,1H),2.92-2.83(m,3H),2.20-2.18(m,1H),2.05-1.86(m,4H),1.82- 1.77(m,2H),1.73-1.67(m,3H),1.62-1.55(m,1H),1.50-1.44(m,2H)。

Claims (5)

1. a kind of matrine derivative, it is characterised in that the compound has following structure：
2. the preparation method of matrine derivative described in claim 1, it is characterised in that comprise the following steps：
Step (1)
By matrine and mass ratio 1：10~40 halogenating agent mixing, is heated to 40 DEG C~100 DEG C, reacts 12~48h, be prepared into To TSM-9；
Wherein, halogenating agent is selected from：Thionyl chloride, POCl3, phosphorus trichloride or phosphorus pentachloride；
Step (2)
TSM-9 is dissolved in mass ratio 1：In 10~30 solvents, mass ratio 1 is added：0.5~2 alkali and 1：0.25~1 chlorination Lithium, is heated to 80~150 DEG C, reacts 12~48h, prepares TSM-10；
Wherein,
Solvent is selected from：Toluene, dimethylbenzene, dioxane, dimethylformamide, dimethyl acetamide, dimethyl sulfoxide (DMSO) or pregnancy One or more in base phosphamide；
Alkali is selected from：Lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate or cesium carbonate；
Step (3)
It is 1 that TSM-10 is dissolved in into mass ratio：In 10~30 morpholine, 80 DEG C~120 DEG C are heated to, 12~48h is reacted, is prepared into To TSM-11.
3. the preparation method of matrine derivative described in claim 1, it is characterised in that comprise the following steps
It is 1 that TSM-11 is dissolved in into mass ratio：In 10~30 solvent, TSM-11 mass ratioes 1 are added：1~5 TFAA and 1：1~5 alkali, reacts at room temperature 12~48h, prepares TSM-12；
Wherein,
Solvent is selected from：One or more in dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes；
Alkali is selected from：Potassium carbonate, sodium carbonate, triethylamine, diisopropyl ethyl amine, pyridine or DMAP.
4. the preparation method of matrine derivative described in claim 1, it is characterised in that comprise the following steps：
It is 1 that TSM-12 is dissolved in into mass ratio：In 10~30 solvent, it is 1 to add TSM-12 mass ratioes：1~5 acid, room temperature is anti- 6~24h is answered, TSM-13 is prepared；
Wherein,
Solvent is selected from：One or more in methanol, ethanol, tetrahydrofuran or dioxane；
Acid is selected from：Trifluoroacetic acid, hydrochloric acid or sulfuric acid；
It is 1 that TSM-13 is dissolved in into mass ratio：In 10~30 solvent, it is 1 to add TSM-13 mass ratioes：1~10 hydrazine hydrate and 1：1~10 acid, is heated to 60 DEG C~100 DEG C, reacts 12~48h, prepares TSM-14；Wherein,
Solvent is selected from：One or more in benzene, toluene, tetrahydrofuran or dioxane；
Acid is selected from：Trifluoroacetic acid, hydrochloric acid, sulfuric acid or p-methyl benzenesulfonic acid.
5. application of the matrine derivative described in claim 1 in antineoplastic is prepared, the tumour is glioma, god Through glioma, liver cancer, lung cancer, colon cancer, thin stomach cancer, cervical carcinoma or melanoma.
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