CN106831397A - A kind of anthraquinone analog compound and preparation method thereof and medical application - Google Patents

A kind of anthraquinone analog compound and preparation method thereof and medical application Download PDF

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CN106831397A
CN106831397A CN201611138847.1A CN201611138847A CN106831397A CN 106831397 A CN106831397 A CN 106831397A CN 201611138847 A CN201611138847 A CN 201611138847A CN 106831397 A CN106831397 A CN 106831397A
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anthraquinone analog
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anthraquinone
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李玉新
鲍永利
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Northeastern University China
Northeast Normal University
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    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
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    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
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Abstract

A kind of anthraquinone analog compound of the present invention and preparation method thereof and medical application, with M-phthalic acid cheap and easy to get as initiation material, it is condensed by the intermediate and the methoxy benzoyl chloride of 2 bromine 5 obtained by bromo, hydrolysis, esterification, condensation product obtains target product 1 by hydrolysis, cyclization, debrominate reduction, the anthraquinone of 5 dihydroxy, 3 carboxyl 9,10.Reaction raw materials of the present invention are cheap and easy to get, and cost is relatively low, simple to operate, and yield is high.Antitumor activity result shows, artificial synthesized 1, the anthraquinone of 5 dihydroxy, 3 carboxyl 9,10 has preferable antitumor activity.

Description

A kind of anthraquinone analog compound and preparation method thereof and medical application
Technical field
The present invention relates to a kind of anthraquinone analog compound, while providing its preparation method and medical application, belong to medical system Standby technical field.
Background technology
In recent years, malignant tumour, cranial vascular disease and the big chronic disease of heart disease three have turned into national life and health most It is big to threaten.Wherein malignant tumour has turned into the number one killer of human health.Chemotherapy is the side of conventional treatment tumour Method, but because the toxic and side effect of medicine can often cause a series of adverse reaction.Therefore the efficient, anticarcinogen of low toxicity is searched out Thing turns into the focus of people's research.
The content of the invention
It is an object of the invention to provide a kind of anthraquinone analog compound（It is named as：1,5- dihydroxy -3- carboxyl -9,10- anthracenes Quinone）For first from natural plants Juglans mandshurica（Juglans mandshuricaMaxim）In the noval chemical compound that extracts, the change Compound has preferable antitumor activity, can be used to prepare antineoplastic.
Another object of the present invention is to provide a kind of synthetic method of anthraquinone analog compound, reaction raw materials are cheap and easy to get, Cost is relatively low, simple to operate, and yield is high.
A kind of anthraquinone analog compound of the present invention（It is named as：1,5- dihydroxy -3- carboxyl -9,10- anthraquinones）, it is special It is general structure as follows to levy；
Molecular formula is：C15H8O6, molecular weight is 284.
The reaction equation of the synthetic method of anthraquinone analog compound of the present invention is as follows：
A kind of anthraquinone analog compound of the invention（It is named as：1,5- dihydroxy -3- carboxyl -9,10- anthraquinones）Synthetic method, its Comprise the following steps：
A () is with M-phthalic acid（II）It is initiation material, the concentrated sulfuric acid makees solvent, with N-bromosuccinimide（NBS）Reaction, Obtain midbody compound（III）.Compound（III）, with sodium hydrate aqueous solution effect, cuprous oxide is raw as catalyst Into midbody compound（IV）.N-bromosuccinimide（NBS）With M-phthalic acid（III）Mol ratio be 1.0, reaction temperature It is 60 DEG C to spend, and the reaction time is 6 h；NaOH and compound（IV）Mol ratio be 5.0, cuprous oxide is catalytic amount, instead Should be heated in 130 DEG C of oil bath, reflux time is in 20 h-25 h；
B compound that () is obtained by step (a)（IV）, there is esterification generation compound with ethanol（V）, reaction sulfuric acid Make catalyst, reaction is heated in 100 DEG C of oil bath, and the time of back flow reaction is about 36 h.Compound（V）, with dichloromethane Make solvent, DMAP (DMAP) makees catalyst, with dimethyl dicarbonate butyl ester（B℃2O）Reaction generation intermediate（VI）, Dimethyl dicarbonate butyl ester（B℃2O）With compound（V）Mol ratio be 1.2-1.5, reaction carry out at room temperature；
(c) m-methoxybenzoic acid（VII）, make solvent condition in glacial acetic acid, with bromine reacting generating compound（VIII）, its Middle bromine and m-methoxybenzoic acid（VII）Mol ratio be 1.2, the temperature of reaction is 110 DEG C, and the reaction time is 10 h. Compound（VIII）React generation chloride compounds under reflux conditions with thionyl chloride（IX）, wherein add one to drip DMF urging Agent；
D intermediate that () is obtained by step (b)（VI）, first with organic base TMPMgBr.LiCl is acted on, then with compound acyl chlorides （IX）Reaction generation important intermediate（X）, wherein chloride compounds（IX）With compound（VI）Mol ratio is 2.0, double salt CuCl2LiCl and compound（VI）Mol ratio be 0.2, reaction solvent used is THF；
E compound that () is obtained by step (d)（X）, with lithium hydroxide effect, hydrolysis generation compound（XI）, reaction is used Solvent is methanol/water (3:1), lithium hydroxide and compound（X）Mol ratio be 10.0, reaction temperature be 80 DEG C；
F compound that () is obtained by step (h)（XI）, under the melting salt action of alchlor/sodium chloride, cyclization, dehydration life Into compound（XII）, the wherein mol ratio of alchlor/sodium chloride is 2.0, and the temperature of reaction is 155-160 DEG C, reaction Time is 10 h；
G compound that () is obtained by step (f)（XII）, solvent is made in HMPA (HMPA), reacted with sodium methoxide, Obtain compound（I）, wherein sodium methoxide and compound（XII）Mol ratio be 10.0, the temperature of reaction is 100 DEG C, reaction Time is 8 h.
The positive effect of the present invention is：
A kind of new compound is provided, with antitumor activity, can be used to prepare antineoplastic.Synthesis technique of the present invention it is anti- Answer raw material cheap and easy to get, cost is relatively low, it is simple to operate, the advantages of yield is more satisfactory.
Purposes of the anthraquinone analog compound of the present invention in oncotherapy is proved in the following manner：
The antitumor activity carried out using MTT methods.Each tumour cell is inoculated with respectively in 96 orifice plates, and cell density is 5 ×104Individual/ml；Next day add, concentration be respectively 100 μ g/ml, 10 μ g/ml, the compound of 1 μ g/ml carried out with DMSO it is dilute Release, while setting DMSO control groups, every group sets 3 multiple holes, and administration volume is 100 μ l/ holes；Cell is containing 5% CO237 DEG C of incubators After continuing to cultivate 44h, 20 μ l MTT are added per hole（5mg/ml）, continue to cultivate 4h；Supernatant is abandoned in suction, and 100 μ l DMSO are added per hole, On ELIASA, 600s, the OD values at detection 570nm are vibrated；Independent experiment in triplicate more than.Result shows, institute of the present invention Mention to various tumor cell strains, including human liver cancer cell HepG2, human colon cancer cell HCT-8 cells, human lung carcinoma cell A549 has different degrees of inhibited proliferation, and to normal cell L0 under respective concentration2Influence it is smaller, show one In Dingan County's gamut, there is inhibited proliferation to the tumour cell of in vitro culture, as a result see table 1 in embodiment.
Specific embodiment：
With reference to specific embodiment, the present invention is further illustrated, is only section Example of the invention, not Do any formal limitation to the present invention, it is every above-described embodiment to be made according to technical spirit of the invention any simply repair Change or prepare anthraquinone analog compound and its derivative, equivalent variations and modification using this method, belong to the technology of the present invention side In the range of case.
Embodiment 1
Step 1：The preparation of 5- bromines M-phthalic acid (III)
M-phthalic acid (II) (5 g, 60 mmol) is dissolved in the concentrated sulfuric acid at room temperature（30 mL）In, high-temperature is risen to 60 DEG C. Then to NBS (10.6 g, 60 mmol) is added in solution in three batches, 3 g are added per half an hour.TLC tracking reactions, treat original After material has reacted, reaction solution pours into ice（200 g）In, there is white solid to separate out.Filtering, filter cake water (100 mL) and petroleum ether (50 mL) is washed 3 times.Rotary Evaporators solvent evaporated is used, white solid 5- bromines M-phthalic acid (III) 13.2 g, yield is obtained It is 90%, is directly used in next step.Fusing point：277-278 °C；Literature value：275-277℃（J. Org. Chem. 2007, 72, 5867-5869）；
Step 2：The preparation of 5- Hydroxy M Phthalic Acids (IV)
To in the 250 mL round-bottomed flasks equipped with magnetic stir bar, 5- bromines M-phthalic acid (20 g, 80 mmol), water are added （64 mL）And NaOH (16 g, 400 mmol).Again to the cuprous oxide (0.5 that catalytic amount is added in this mixed solution g).Then 130 DEG C are warmed up to, flow back about 20 h.TLC tracking reactions, after reaction completely.Reaction solution is transferred to a dropping liquid leakage In bucket, it is slowly dropped to and fills 15% HCl（82 mL）250 mL round-bottomed flasks in, it is stirring while adding, there is white solid to analyse Go out.Mixed liquor is increased to 60-70 DEG C, stirs 1 h.Room temperature is cooled to, is filtered, filter cake water（200 mL）Wash 3 times.After drying, Obtain the g of white solid 12.8, yield 86%.Product is directly used in next step reaction.Fusing point：284-285 °C；Literature value：284- 285 °C (Chem. Ber.1880, 13, 493) ；
Step 3：The preparation of 5- Hydroxy M Phthalic Acids diethylester (V)
To addition 5- Hydroxy M Phthalic Acids (IV) in the 500 mL round-bottomed flasks equipped with reflux condensing tube and magnetic stir bar （10 g, 55 mmol）, add absolute ethyl alcohol（150 mL）It is completely dissolved it.Then to the concentrated sulfuric acid is added dropwise in flask（5 mL）, reaction solution backflow 36 h, TLC detection reaction is completely.Reaction solution is cooled to room temperature, and ethanol vacuum distillation is removed.Then Add 5% sodium bicarbonate solution（100 mL）, ethyl acetate（3 × 100 mL）Extraction, organic phase uses saturated aqueous common salt again（2 × 100 mL）Washing.Organic phase is merged, and solvent is boiled off with decompression after anhydrous sodium sulfate drying, obtains white solid 10.9 G, yield is 84%.The product of gained is directly reacted with next step.Fusing point：104-105 DEG C, literature value：104.7-105.1 °C （J. Am. Chem. S℃. 1998,120, 7328-7336）；
Step 4：The preparation of 5- tertiary butyloxycarbonyls Epoxide carbonyl ester dimethyl isophthalate (VI)
To in the 500 mL round-bottomed flasks equipped with magnetic stir bar, 5- Hydroxy M Phthalic Acids diethylester (V) are added（14 g, 60 mmol）, dichloromethane（200 mL）, after stirring and dissolving, it is cooled to 0 DEG C.Be subsequently adding DMAP (368 mg, 3 mmol) and Di-tert-butyl dicarbonate (17.9 g, 82 mmol), is stirred at room temperature 3 h, and TLC detection reactions are complete.It is full to being added in reaction solution Reaction is quenched, dichloromethane with ammonium chloride solution (150 mL)（3 × 100 mL）Extraction, organic phase is dry with anhydrous sodium sulfate After dry, solvent is boiled off.Obtain crude yellow solid.With recrystallizing methanol, there is crystal to separate out.Filtering, filter cake petroleum ether washes 3 It is secondary, obtain the g of white solid 13.3, yield 68%.Fusing point：71-72℃.
Hydrogen is composed1H-NMR (400 MHz, CDCl3): δ 8.57 (s, 1H, ArH), 8.04 (s, 2H, ArH), 4.43 (q, J = 7.2 Hz, 4H), 1.59 (s, 9H), 1.43 (t, J = 7.2 Hz, 6H).
Step 5：The bromo- 5- methoxy benzoic acids of 2-（VIII）Preparation
To m-methoxybenzoic acid (10 g, 55 mmol) is added in the 250 mL round-bottomed flasks equipped with magnetic agitation, add Acetic acid（20 mL）It is completely dissolved it.By bromine（3.4 mL）Water（10 mL）Solution is slowly added in flask, Ran Houzai Add water（60 mL）, mixed-liquor return 10 h, TLC detection reaction is completely.Reaction solution is cooled to room temperature, filtering, filter cake water Wash twice, obtain the crude product of white.Crude product acetic acid and water are recrystallized to give the g of sterling 10.9 of white, yield 72%.Fusing point： 155-157℃；Literature value：154-157℃(Tetrahedron1963, 19, 1001-1010)。
Step 6：The bromo- 5- methoxy benzoyl chlorides of 2-（IX）Preparation
To in the 100 mL round-bottomed flasks equipped with reflux condensing tube and magnetic stir bar, the bromo- 5- methoxy benzoic acids of 2- are added（5 g, 21.7 mmol）, thionyl chloride（10 mL）, one drop DMF.After the h of mixed-liquor return 8, reaction is complete.Air-distillation is reacted Liquid, excessive thionyl chloride is removed, and products obtained therefrom is directly used in next step reaction.
Step 7：4-（The bromo- 5- methoxybenzoyls bases of 2-）-5-（Tertiary fourth carbonyloxy group carbonyl ester）Dimethyl isophthalate Base（X）Preparation
（1）Prepare TMPMgBrLiCl
Magnesium chips (1.07 g, 44 mmol) and anhydrous Lithium chloride (1.7 g, 40 mmol) are placed in a drying full of nitrogen 250 mL there-necked flasks in, add anhydrous THF (10 mL).In 30 DEG C of THF by isopropyl bromide (40 mmol, 3.78 mL) (10 mL) solution is added drop-wise in reaction bulb.Trigger after reaction a few minutes.After dripping, mixed liquor is stirred at room temperature 12 h.
i-The titration of PrMgBrLiCl concentration：
To equipped with magnetic stir bar and rubber stopper, menthol is added in the round-bottomed flask full of dry 50 mL of nitrogen（2 mmol, 312 mg）, 1,10- phenanthroline (4 mg).With syringe by rubber stopper to adding dry tetrahydrofuran in device （15 mL）, solution is stirred at room temperature.The grignard reagent of about 2 mL is taken to being dropwise added dropwise in flask with syringe, Zhi Daorong Liquid is changed into purple, and does not disappear for a long time.The mL of volume 1.5 of titration grignard reagent used is write down, grignard reagent is calculatedi- The concentration of PrMgBrLiCl is 1.33 mmol/mL.
Then 2,2,6,6- tetramethyl piperidines (TMPH) (1.05 eq, 30.7 mmol, 4.9 mL) are slowly added dropwise, are added dropwise After finishing, reaction solution stirs about 10 h at this temperature, remaining to only a small amount of magnesium.Obtained reagent puts into next at once Step reaction is used.
（2）Prepare CuCl2LiCl
To equipped with magnetic stir bar, full of addition anhydrous Lithium chloride (1.7 g, 40 mmol) in the dry round-bottomed flask of nitrogen, Vacuumized with oil pump, be heated to 130 DEG C of h of drying 1.Then room temperature is cooled under the protection of nitrogen, is rapidly added CuCl (1.98 g, 20 mmol, 99% Cu).Reaction system is replaced as nitrogen, 130 DEG C of 5 h of vacuum drying are raised to.It is cooled to room Temperature, anhydrous THF (20 mL) is added with syringe.Reaction unit is wrapped up with black plastic bag, is stirred under the conditions of room temperature lucifuge About 6 h.Obtain the suspension CuCl2LiCl (1 M/L in THF) of yellow green.Obtained reagent puts into reaction at once Use.
（3）Compound（X）Synthesis
To equipped with magnetic stir bar, full of adding compound in the dry 250 mL there-necked flasks of nitrogen（VI） (3.5 g, 10.0 Mmol), anhydrous THF (20 mL), stirs at 0 DEG C, is completely dissolved it.Then TMPMgBrLiCl (1.2 is dropwise added dropwise Eq, 15 mL), stir 3 h.Reaction solution is reduced to 40 DEG C, CuCl2LiCl (2 mL, 0.2 equiv., 1.00 are added M in THF), stir 10 min.
Take one and be equipped with stirrer and rubber stopper, the round-bottomed flask of the dry nitrogen protections of 250 mL adds 2- with injection Bromo- 5- methoxy benzoyl chlorides（IX）（5.4 g, 20 mmoL）, tetrahydrofuran（30 mL）, -40 DEG C of stirrings are cooled to, to this Above-mentioned TMPMgBrLiCl mixed liquors are slowly added dropwise in reaction bulb, room temperature is then raised to, stirring 3-5 h, TLC detections are anti- Should be complete.Reaction is quenched, dichloromethane to saturated ammonium chloride solution (100 mL) is added in reaction solution（3 × 100 mL）Extraction Take, after organic phase anhydrous sodium sulfate drying, decompression evaporates solvent, obtains crude product.Gained crude product is purified through column chromatography for separation, uses second Acetoacetic ester/petroleum ether（1:10）Wash-out, obtains white crystalline Compound（X）3.4 g, yield 63%.Fusing point：128 -130℃；
Hydrogen is composed：1H-NMR (400 MHz, CDCl3): δ 8.59 (s, 1H, ArH), 8.08 (s, 1H, ArH), 7.58 (d, J = 8.0 Hz, 1H, ArH), 7.20 (d, J = 3.0 Hz, 1H, ArH), 6.92 (dd, J = 8.0 Hz, 3.0 Hz, 1H, ArH), 4.46 (q, J = 7.0 Hz, 2H), 4.26 (q, J = 7.0 Hz, 2H), 3.76 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H), 1.40 (s, 9H), 1.23 (t, J = 7.0 Hz, 3 H)；
Step 8：4-（The bromo- 5- methoxybenzoyls bases of 2-）- 5- Hydroxy M Phthalic Acids（XI）Preparation
To adding compound in the 250 mL round-bottomed flasks equipped with reflux condensing tube and magnetic stir bar（X）(1..50 g, 2.7 Mmol), methanol/water (60 mL/20 mL), containing a lithium hydroxide for the crystallization water (3.0 g, 70 mmol).Reaction is increased to 80 DEG C of stirring 12 h, TLC detection reactions are complete.Room temperature is cooled to, to watery hydrochloric acid is added in reaction solution, pH is transferred to less than 2.Second Acetoacetic ester（3 × 100 mL）Extraction, organic phase is washed once with saturated aqueous common salt (100 mL) again.Organic phase is combined, After anhydrous sodium sulfate drying, decompression evaporates solvent, obtains the g of white solid 1.06, yield 100%.Fusing point：249 -251℃；
Hydrogen composes result：1H-NMR (400 MHz, DMSO-d6): δ 13.34 (br s, 2H), 10.53 (s, 1H), 7.96 (s, 1H, ArH), 7.65 (m, 2H, ArH), 7.08 (m, 2H, ArH), 3.72 (s, 3H)；
Step 9：Bromo- 4,8- dihydroxy -9 of 5-, 10- anthraquinone -2- carboxyl anthraquinones（XII）Preparation
Condenser pipe is equipped with to one, 100 mL of nitrogen protection add anhydrous Aluminum chloride in drying round-bottomed flask（8.4 g, 63 mmol）, anhydrous sodium chloride（1.8 g, 31.2 g）, mixture is heated to 150 °C in stirring condition.When mixture is changed into liquid When, add compound（XI）（0.8 g, 2.0 mmol）.Reactant mixture stirs 8 h at 155-160 °C.It is cold after reaction completely But to room temperature, 100 mL water are added, ultrasound is completely dissolved solid, uses ethyl acetate（4×100 mL）, organic phase uses water again（3 ×100 mL）Wash away impurity.Organic phase is combined, after anhydrous sodium sulfate drying, decompression evaporates solvent, obtains yellow solid 725 mg, products obtained therefrom directly carries out next step reaction without purifying；
Hydrogen composes result：1H-NMR (400 MHz, DMSO-d6):δ 13.81 (br s, 1H, ArCOOH), 12.99 (s, 1H, ArOH), 12.14 (s, 1H, ArOH), 8.12 (s, 1H, ArH), 8.03 (d, J = 9.0 Hz, 1H, ArH), 7.76 (s, 1H, ArH), 7.31 (d, J= 9.0 Hz, 1H, ArH)；
Step 10：A kind of anthraquinone analog compound（It is named as：1,5- dihydroxy -3- carboxyl -9,10- anthraquinones）（I）Preparation
Stirrer is equipped with to one, bromo- 4,8- dihydroxy -9 of addition 5- in 50 mL round-bottomed flasks of reflux condensing tube, 10- anthraquinones - 2- carboxyl anthraquinones（XII）（217 mg, .6 mmol）, the hexamethylphosphoric acid triamide (6.0 mL) for newly steaming again, freshly prepd methyl alcohol Sodium（324 mg, 6.0 mmol）.Under nitrogen protection, 100 °C are heated to, stir 8 h, TLC detection reactions are complete.It is cooled to room Temperature, reaction solution is poured into 50 mL water, watery hydrochloric acid acidifying, ethyl acetate（3×60 mL）Extraction, organic phase is washed with water two It is secondary.Merge organic phase, anhydrous sodium sulfate drying, column chromatography purifying（Ethyl acetate/alcohol/water：1000：13:10）, obtain yellow powder 120 mg of end, the gross production rate of two steps is 70 %.
Hydrogen is composed and carbon spectrum result is：
1H-NMR (400 MHz, DMSO-d6): δ 13.73 (br s, 1H, ArCOOH), 12.25 (s, 1H, ArOH), 12.23 (s, 1H, ArOH), 8.10 (br s, 1H, ArH), 7.83 (t, J = 8.0 Hz, 1H, ArH), 7.72 (d, J = 8.0 Hz, 1H, ArH), 7.71 (s, 1H, ArH), 7.40 (d, J = 8.0 Hz, 1H, ArH).
13C-NMR (400 MHz, DMSO-d6): δ = 116.3, 118.8, 119.0, 119.7, 124.8, 125.4, 133.4, 133.9, 137.9, 138.5, 161.8, 162.1, 165.7, 187.1, 187.4 ppm.
Test example 1
A kind of antitumor activity detection of anthraquinone analog compound of the compounds of this invention
The anti tumor activity in vitro for carrying out compound using MTT methods is studied.Each tumour cell is inoculated with respectively in 96 orifice plates, carefully Born of the same parents' density is 5 × 104Individual/ml；Next day adds compound, and concentration is respectively 100 μ g/ml, 10 μ g/ml, 1 μ g/ml medicines and uses DMSO is diluted, while setting DMSO control groups, every group sets 3 multiple holes, and administration volume is 100 μ l/ holes；Cell is containing 5% CO2's After 37 DEG C of incubators continue to cultivate 44h, 20 μ l MTT are added per hole（5mg/ml）, continue to cultivate 4h；Supernatant is abandoned in suction, is added per hole 100 μ l DMSO, on ELIASA, vibrate 600s, the OD values at detection 570nm；Independent experiment in triplicate more than.Result shows Show, the compound that the present invention is previously mentioned is to various tumor cell strains, including human liver cancer cell HepG2, human colon cancer cell HCT-8 Cell, human lung cancer cell A549 have different degrees of inhibited proliferation, and to the shadow of normal cell L02 under respective concentration Sound is smaller, shows that compound in certain safe range, has inhibited proliferation to the tumour cell of in vitro culture, the results are shown in Table 1。
Inhibiting rate of the compounds of this invention of table 1 to experiment tumour cell
Summarize：The compound that the present invention is provided has obvious antitumor activity.

Claims (6)

1. a kind of anthraquinone analog compound（It is named as：1,5- dihydroxy -3- carboxyl -9,10- anthraquinones）, it is characterised in that general structure It is as follows；
Molecular formula is：C15H8O6, molecular weight is 284.
2. the synthetic method of a kind of anthraquinone analog compound described in claim 1, it is characterised in that comprise the following steps：
a）With M-phthalic acid（II）It is initiation material in the case where sulfuric acid makees solvent condition, with N-bromosuccinimide reaction, obtains To midbody compound（III）；
b）By step a）The compound for obtaining（III）In sodium hydrate aqueous solution, using cuprous oxide as catalyst, reflux condition Under part, reaction generation midbody compound（IV）；
c）The compound obtained by step b)（IV）With sulphur acid as catalyst, with ethanol synthesis, chemical combination is generated under reflux conditions Thing（V）；
d）The compound obtained by step c)（V）Solvent is made with dichloromethane, DMAP (DMAP) makees catalyst, With dimethyl dicarbonate butyl ester（Boc2O）Reaction generation intermediate（VI）；
e）With m-methoxybenzoic acid（VII）It is raw material, glacial acetic acid makees solvent, with bromine reacting generating compound（VIII）；
f）The compound obtained by step e)（VIII）With thionyl chloride reaction, compound is generated（IX）, add wherein in reaction solution Enter a drop DMF as catalyst；
g）The compound obtained by step d)（VI）First with organic base TMPMgBr.Then and acyl chlorides LiCl is acted on,（IX）Reaction life Into important intermediate（X）, wherein double salt CuCl2LiCl makees catalyst；
h）The compound obtained by step g)（X）Make solvent in methanol/water, lithium hydroxide is used as alkali, hydrolysis generation compound （XI）；
I) compound obtained by step h)（XI）160oUnder the melting salt action of C alchlors/sodium chloride, cyclization, dehydration Generation compound（XII）；
J) compound obtained by step i)（XII）, solvent is done with HMPA (HMPA), reacted with sodium methoxide, plus Heat is to 100oC, stirs 8 hours, obtains final product 1,5- dihydroxy -3- carboxyl -9,10- anthraquinones.
3. purposes of a kind of anthraquinone analog compound in antineoplastic is prepared as claimed in claim 1.
4. the tumour that anthraquinone analog compound is related in the purposes in preparing antineoplastic as claimed in claim 3 includes liver Cancer, lung cancer, colon cancer.
5. it is active component with a kind of anthraquinone analog compound described in claim 1, individually or with reference to one or more pharmaceutically may be used The excipient or vehicle group of receiving are into pharmaceutical composition.
6. containing a kind of pharmaceutical composition of anthraquinone analog compound described in claim 1 can be injection, oral agents, creme, Spray.
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CN112250562A (en) * 2020-10-22 2021-01-22 怀化宝华生物科技有限公司 Synthetic method of 2-bromo-5-methoxybenzoic acid
CN114516817A (en) * 2022-02-14 2022-05-20 九江善水科技股份有限公司 Chemical intermediate and preparation method thereof

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CN109970605A (en) * 2019-04-28 2019-07-05 麦科勒（滁州）新材料科技有限公司 A kind of isocyanates and its preparation method and application with flame-retarding characteristic
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