CN109180657A - The preparation method of STAT3 inhibitor - Google Patents
The preparation method of STAT3 inhibitor Download PDFInfo
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- CN109180657A CN109180657A CN201811282947.0A CN201811282947A CN109180657A CN 109180657 A CN109180657 A CN 109180657A CN 201811282947 A CN201811282947 A CN 201811282947A CN 109180657 A CN109180657 A CN 109180657A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention belongs to medicinal chemistry arts, it is related to a kind of STAT3 inhibitor and its application, more particularly to the preparation method of a kind of compound with signal transduction and -3 inhibiting effect of activating transcription factor, the compound has good inhibiting effect to the active MDA-MB-468 cell of STAT3, DU-145 cell with sustained activation.
Description
Technical field
The invention belongs to medicinal chemistry arts, are related to a kind of STAT3 inhibitor and its application, and in particular to one kind has letter
Number conduction and compound, the pharmaceutical composition containing the compound and the chemical combination of -3 inhibiting effect of activating transcription factor
The purposes of object or pharmaceutical composition as cancer treatment drugs.
Technical background
Cancer is the general designation of a major class malignant tumour, its main feature is that without limitation, without end hyperplasia.Cancer cell makes patient's body
Interior nutriment is largely consumed, while releasing a variety of toxin, and human body is made to generate a series of symptoms, cause human body it is thin,
Inability, anaemia, loss of appetite, fever and serious organ function are impaired, cause necrotic hemorrhage concurrent infection, patient finally by
It is dead in organ failure.
Signal transduction and (the Signal Transducer and Activator of of activating transcription factor -3
Transcription-3, STAT3) be a kind of GAP-associated protein GAP that can be activated by different cytokine receptors, cell because
Carrier is served as during son-acceptor interaction, the inherence specificity for keeping signal to transmit in the cell, and pass through induction target
The effect effect of biostimulation is expressed in genetic transcription, other than participating in angiogenesis and immune response, also with the increasing of cell
It grows, survive, breaking up, the close associations such as anti-apoptotic.STAT3 is in kinds of tumor cells (including blood such as leukaemia, Huppert's disease
A variety of entity tumors such as liquid tumour and lung cancer, breast cancer, prostate cancer) in abnormal expression increase, generation with malignant tumour,
Develop closely related.
By inhibiting STAT3 activity to be expected to that cancer cell is made apoptosis occur to achieve the purpose that treating cancer, study recently
It was found that inhibiting STAT3 signal that can overcome the chemical drug resistance including kinds of tumors such as retinoblastoma, lung cancer, leukaemia
Property, successfully research and development are a new antitumor target to STAT3.Therefore, new STAT3 inhibitor is actively found for cancer
Treatment have particularly important meaning.
Summary of the invention
It is an object of the present invention to provide the changes with signal transduction and -3 inhibiting effect of activating transcription factor of general formula I
Object or its pharmaceutically acceptable salt are closed,
It is a further object to provide the compound for preparing logical formula (I) of the invention or its is pharmaceutically acceptable
The method of salt.
It is also another object of the present invention to provide the compound comprising logical formula (I) of the invention or its is pharmaceutically acceptable
The composition of salt and pharmaceutically acceptable carrier, and the compound comprising logical formula (I) of the invention or its is pharmaceutically acceptable
Salt and one or more tumour medicines composition.
Of the invention a further object is that the compound for providing logical formula (I) of the invention or its pharmaceutically acceptable salt exist
Application in treatment and/or prevention tumour medicine.
For above-mentioned purpose, the present invention the following technical schemes are provided:
In a first aspect, the present invention provides logical formula (I) compound represented or its pharmaceutically acceptable salt,
Wherein,
R1Selected from aryl, heteroaryl.
In some preferred embodiments, the compound of the present invention or its pharmaceutically acceptable salt, wherein R1It is selected from
Two ring condensed hetero rings, tricyclic condensed ring and tricyclic condensed hetero ring；In some highly preferred embodiments, the compound of the present invention or
Its pharmaceutically acceptable salt, wherein R1The heteroatomic two rings condensed ring of N, O, S, tricyclic condensed ring are selected from selected from least containing one；
In some highly preferred embodiments, the compound of the present invention or its pharmaceutically acceptable salt, wherein R1Selected from containing
One two ring condensed ring, tricyclic condensed ring containing N, O, S atom.
In some specific embodiments, the compound of the present invention or its pharmaceutically acceptable salt, wherein R1It is selected from
The present invention provides compounds in detail below:
Or its pharmaceutically acceptable salt.
Second aspect, the present invention provide the preparation method of general formula compound of the invention, comprising the following steps:
The compound of formula (1) is made in step a:2- hydroxy acetophenone acetylation；
Step b: the compound of formula (2) is made in the compound cyclization of formula (1)；
Step c: the compound of formula (3) is made in the compound bromo of formula (2)；
Step d: the compound amino of formula (3) replaces the compound that formula (4) are made；
The compound of formula (5) is made in step e:4- nitrobenzene methyl and biuret cyclization；
Step f: the compound of formula (6) is made in the compound chloro of formula (5)；
Step g: the compound of formula (6) reacts the compound that formula (7) are made with the compound of formula (4)；
Step h: the compound and X-R of formula (7)1React the compound that formula (8) are made；
Step i: the compound reduction of formula (8) hydrogenates the compound that formula (9) are made；
Step j: the compound of formula (9) is reacted with acryloyl chloride is made the compounds of this invention, and reaction route is as follows:
In step a, the compound of formula (1) the preparation method comprises the following steps: 2- hydroxy acetophenone, chloroacetic chloride and potassium carbonate are added anti-
It answers in bottle, acetone is added, back flow reaction, after reaction, water, ethyl acetate extraction, anhydrous slufuric acid is added in evaporating solvent under reduced pressure
Sodium is dry, concentration to get.
In step b, the compound of formula (2) the preparation method comprises the following steps: take 2- acetoxy acetophenone in reaction flask, be added
DMSO dissolves, and sodium hydrogen is added portionwise at 0-5 DEG C, finishes, is warmed to room temperature stirring, after reaction, water is added into reaction solution, dilute
Hydrochloric acid tune pH value is to faintly acid, and ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to give grease, adds into gained grease
Enter acetic acid and concentrated hydrochloric acid, about, reaction terminates back flow reaction, and reaction solution is spin-dried for, and water, ethyl acetate extraction, anhydrous slufuric acid is added
Sodium it is dry to get.
In step c, the compound of formula (3) the preparation method comprises the following steps: by the compound of formula (2), N-bromosuccinimide and
Benzoyl peroxide is added in reaction flask, adds carbon tetrachloride to dissolve, back flow reaction, after reaction, reaction solution add water, acetic acid second
Ester extraction, anhydrous sodium sulfate is dry, column chromatographic purifying to get.
In step d, the compound of formula (4) the preparation method comprises the following steps: the compound of formula (3) is added in reaction flask, DMF is added
Dissolution is added ammonium hydroxide, is stirred at room temperature, and after reaction, water is added in reaction solution, and ethyl acetate extraction, anhydrous sodium sulfate is dry, mistake
Filter, is spin-dried for, and ethyl acetate is added, and the ethyl acetate hydrogen chloride solution that saturation is added after stirring and dissolving is given birth to supernatant layer without precipitating
At, filtering, it is dry to get.
In step e, the compound of formula (5) the preparation method comprises the following steps: weigh 4- nitrobenzoic acid in reaction flask, methanol is added
Thionyl chloride is added dropwise in dissolution, drips and finishes back flow reaction, and after reaction, decompression is spin-dried for, and saturated sodium bicarbonate solution is added and adjusts pH
To 7-8, ethyl acetate extraction, anhydrous sodium sulfate is dry, concentration to get.
In step f, the compound of formula (6) the preparation method comprises the following steps: weigh biuret in reaction flask, glycol dinitrate is added
Ether dissolves, and sodium hydride is added portionwise at 0-5 DEG C, finishes, is stirred to react at 50 DEG C, add 4- nitrobenzene methyl, finish,
It is warming up to 85 DEG C of reaction 20h to be after reaction poured into water reaction solution, adjusts pH to acidity, filtering, filter cake with concentrated hydrochloric acid
Drying to get.
In step g, the compound of formula (7) the preparation method comprises the following steps: by 6- (4- nitrobenzophenone) -1,3,5-triazines -2,4-
(1H, 3H)-diketone is added in reaction flask, and phosphorus oxychloride, phosphorus pentachloride, 105 DEG C of reactions, after reaction, by reaction solution are added
Be poured into water, methylene chloride extraction, anhydrous sodium sulfate it is dry to get.
In step h, the compound of formula (8) the preparation method comprises the following steps: the compound of modus ponens (6) in reaction flask, be added tetrahydro
Furans dissolution, be added formula (4) compound, sodium carbonate, back flow reaction, filtering to get.
In step i, the compound of formula (9) the preparation method comprises the following steps: in microwave reaction bottle, sequentially add the chemical combination of formula (8)
Object, 1- methyl indol -4- borate, [bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex, x-
Phos, cesium carbonate and 1,4- dioxane/H2O, dissolution, argon gas displacement, 105 DEG C of microwave reactions, concentration, column chromatographic purifying, i.e.,
?.
The third aspect, the present invention provide pharmaceutical composition, and it includes the compound of the present invention or its is pharmaceutically acceptable
Salt.
In some embodiments, the present invention provide pharmaceutical composition, it includes the compound of the present invention or its pharmaceutically
Acceptable salt, also comprising one or more selected from following composition: tyrosine protein enzyme inhibitor, EGFR inhibitor, VEGFR
Inhibitor, Bcr-Abl inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, mek inhibitor, histone deacetylase
Enzyme inhibitor, VEGF antibody, EGF antibody, HIV kinases inhibitor, HMG-CoA reductase inhibitor etc..
In some embodiments, the present invention provides the compound of the present invention or its pharmaceutically acceptable salt and comprising this
The pharmaceutical composition of the compound of invention or its pharmaceutically acceptable salt, the compound or pharmaceutical composition are for treating
And/or pre- anti-cancer.
Can by the compound of the present invention or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, diluent or
Excipient is prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.Medication include, but are not limited to it is intradermal,
In intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, such as be passed through
It is transfused or injects, applied by the approach that transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) absorb.Administration can be with
It is whole body or local.The example of oral administration preparation includes solid or liquid dosage form, specifically, include tablet, pill,
Granula, pulvis, capsule, syrup, emulsion, suspension etc..The preparation can be prepared by methods known in the art, and include
The conventional use of carrier of field of pharmaceutical preparations, diluent or excipient.
Fourth aspect, present invention offer general formula I compound represented of the present invention or its pharmaceutically acceptable salt, or comprising
Purposes of its pharmaceutical composition in the drug of preparation treatment and/or pre- anti-cancer, wherein the cancer be selected from prostate,
Breast cancer, melanoma, Papillary thyroid carcinoma, cholangiocarcinoma, colon cancer, oophoroma, lung cancer, malignant lymphatic tumor, Yi Jipi
Skin, colon, thyroid gland, lung and ovary primary and recurrent solid tumor or leukaemia.
Specific embodiment
Representative embodiment is protection model and is not intended to limit the present invention in order to better illustrate the present invention below
It encloses.
The preparation of 1 2- aminomethyl -4H- chromene -4- keto hydrochloride of embodiment
The preparation of step 1 2- acetoxy acetophenone
2- hydroxy acetophenone (100mmol), chloroacetic chloride (250mmol) and potassium carbonate (500mmol) are added in reaction flask,
300ml acetone is added, back flow reaction 12h, after reaction, water, ethyl acetate extraction, anhydrous sulphur is added in evaporating solvent under reduced pressure
Sour sodium is dry, is concentrated to give grease, directly throws in next step.
The preparation of step 2 2- methyl -4H- chromene -4- ketone
2- acetoxy acetophenone (50mmol) is weighed in reaction flask, 100ml DMSO is added and dissolves, at 0-5 DEG C in batches
It is added sodium hydrogen (150mmol), finishes, be warmed to room temperature stirring 3h and water, dilute hydrochloric acid tune pH are added into reaction solution after reaction
It is worth faintly acid, ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to give grease, and 100ml second is added into gained grease
Acid and 5 drop concentrated hydrochloric acids, back flow reaction about 3h, reaction terminate, reaction solution are spin-dried for, and water, ethyl acetate extraction, anhydrous slufuric acid is added
Sodium is dry, and column chromatographic purifying obtains title compound.
ES:M/Z 161 [M+H]+。
The preparation of step 3 2- bromomethyl -4H- chromene -4- ketone
By step 2 gained 2- methyl -4H- chromene -4- ketone (10mmol), N-bromosuccinimide (NBS, 10mmol) and
Benzoyl peroxide (BPO, 0.95mmol) is added in reaction flask, and 20ml carbon tetrachloride is added to dissolve, back flow reaction 12h, reaction knot
Shu Hou, reaction solution add water, and ethyl acetate extraction, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains title compound.
ES:M/Z 239 [M+H]+。
The preparation of step 4 2- aminomethyl -4H- chromene -4- keto hydrochloride
Step 3 gained 2- bromomethyl -4H- chromene -4- ketone (0.5mmol) is added in reaction flask, it is molten that 5ml DMF is added
Solution is added 2ml ammonium hydroxide, 12h is stirred at room temperature, and after reaction, water, ethyl acetate extraction is added in reaction solution, and anhydrous sodium sulfate is done
Dry, filtering is spin-dried for, and ethyl acetate 5ml is added, and the ethyl acetate hydrogen chloride solution of saturation is added after stirring and dissolving to supernatant layer nothing
Precipitating generates, and filters, dry, obtains title compound.
ES:M/Z 239 [M+H]+。
The preparation of chloro- 6- (4- the nitrobenzophenone) -1,3,5- triazine of 2 2,4- of embodiment bis-
The preparation of step 1 4- nitrobenzene methyl
4- nitrobenzoic acid (250mmol) is weighed in reaction flask, the dissolution of 300mL methanol is added, thionyl chloride is added dropwise
(375mmol) drips and finishes back flow reaction 12h, and after reaction, decompression is spin-dried for, and saturated sodium bicarbonate solution is added and adjusts pH to 7-
8, ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to give title compound, directly throws in next step.
The preparation of step 2 6- (4- nitrobenzophenone) -1,3,5- triazine -2,4- (1H, 3H)-diketone
Biuret (100mmol) is weighed in reaction flask, the dissolution of 150mL glycol dimethyl ether is added, adds in batches at 0-5 DEG C
Enter sodium hydride (83.4mmol), finish, be stirred to react 1h at 50 DEG C, adds 4- nitrobenzene methyl (83.4mmol), add
Finish, be warming up to 85 DEG C of reaction 20h and be after reaction poured into water reaction solution, adjusts pH to acidity with concentrated hydrochloric acid, filter, filter
Cake drying, obtains title compound.
ES:M/Z 235 [M+H]+。
The preparation of step 3 2,4- bis- chloro- 6- (4- nitrobenzophenone) -1,3,5- triazine
6- (4- nitrobenzophenone) -1,3,5-triazines -2,4- (1H, 3H)-diketone (200mmol) is added in reaction flask, is added
Entering 200mL phosphorus oxychloride, phosphorus pentachloride (800mmol), reaction solution is poured into water by 105 DEG C of reaction 12h after reaction, and two
Chloromethanes extraction, anhydrous sodium sulfate is dry, is concentrated to give title compound.
ES:M/Z 275 [M+H]+。
The chloro- 6- of 3 4- of embodiment (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine
Preparation
Chloro- 6- (4- the nitrobenzophenone) -1,3,5- triazine (50mmol) of 2 gains 2,4- of embodiment bis- is weighed in reaction flask
In, the dissolution of 100mL tetrahydrofuran is added, 1 gains 2- aminomethyl -4H- chromene -4- keto hydrochloride 2- (trifluoro of embodiment is added
Methyl)-pyridine -4- amine (55mmol), sodium carbonate (100mmol), back flow reaction 72h, filtering, column chromatographic purifying obtains title compound
Object.
ES:M/Z 416 [M+H]+。
Embodiment 44- (1- methyl indol -4- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone group) -
The preparation of 1,3,5- triazine -2- amine
In 30ml microwave reaction bottle, the chloro- 6- of 4- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone is sequentially added
Base) -1,3,5- triazine -2- amine (10mmol), 1- methyl indol -4- borate (10mmol), [bis- (diphenylphosphines) two of 1,1'-
Luxuriant iron] palladium chloride dichloromethane complex (0.1mmol), x-phos (0.4mmol), cesium carbonate (100mmol) and 1,4- bis-
Six rings of oxygen/H2O (60ml/10ml), dissolution, argon gas displacement, 105 DEG C of microwave reaction 90min, concentration, column chromatographic purifying obtain title
Compound.
ES:M/Z 511 [M+H]+。
5 4- of embodiment (1- methyl indol -4- base) -6- (4- aminophenyl)-N- (2- methyl -4H- chromene -4- ketone group) -
The preparation of 1,3,5- triazine -2- amine
Weigh 4 gains 4- of embodiment (1- methyl indol -4- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine (1mmol), 10%Pd-C (10mg) in reaction flask, be added 15ml methanol, at 1
Normal atmosphere pressure, H21h is restored, reaction is stopped, title compound is concentrated in filtering, is directly used in next step.
ES:M/Z 481 [M+H]+。
6 4- of embodiment (1- methyl indol -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4-
Ketone group) -1,3,5- triazine -2- amine preparation
4- (1- methyl indol -4- base) -6- (4- aminophenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3 is weighed,
It is molten that 15ml anhydrous methylene chloride is added in reaction flask in 5- triazine -2- amine (0.1mmol), diisopropylethylamine (0.3mmol)
Solution is slowly dropped into methylene chloride (1ml) solution dissolved with allyl acyl chlorides (0.12mmol), and 10min fully reacting is concentrated,
Column chromatographic purifying obtains title compound.
1H-NMR(500MHz,DMSO-d6)δ:1.91-1.92(1H,m),2.00-2.02(2H,m),2.65-2.67(2H,
m),3.69(3H,s),4.42-4.45(1H,m),4.89(1H,s),5.50-5.51(1H,m),5.55(1H,s),6.02-6.03
(1H,m),6.40-6.42(1H,m),6.45-6.47(1H,m),6.95-6.97(1H,m),7.07-7.09(2H,m),7.35-
7.40(2H,m),7.52-7.55(2H,m),7.68-7.70(2H,m),7.81-7.83(2H,m),8.34(1H,s),10.09
(1H,brs)。
ES:M/Z 535 [M+H]+。
7 4- of embodiment (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5- triazine -2- amine preparation
The preparation of the chloro- 9- ethyl -9H- carbazole of step 1 4-
4- chlorine carbazole (5.46mmol) is weighed in reaction flask, 20mL THF dissolution is added, is cooled to -10 DEG C, NaH is added
(14mmol), finishes, and after stirring 30 minutes, adds bromoethane (6mmol), finishes, reacts at room temperature 3h, and reaction terminates, and water quenching is added to go out,
Ethyl acetate extraction, dry, concentration is prepared chromatogram purification and obtains the chloro- 9- ethyl -9H- carbazole of 4-.
ES:M/Z 230 [M+H]+。
The preparation of step 2 4- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- ethyl -9H- carbazole
Weigh the chloro- 9- ethyl -9H- carbazole (1mmol) of step 1 gains 4-, connection pinacol borate (1.1mmol), vinegar
Sour potassium (2mmol) and 1,1'- bis(diphenylphosphino) ferrocene dichloropalladium (Pd (dppf) Cl2, 2mmol) and in reaction flask, add
Entering 5mL Isosorbide-5-Nitrae-dioxane, for 24 hours, after reaction, water is added in 100 DEG C of reactions under the conditions of nitrogen protection, and ethyl acetate extracts,
Merge organic phase, saturated common salt water washing merges organic phase, dries, filters, and is concentrated, and column chromatographic purifying obtains title compound.
Step 3 4- (9- ethyl -9H- carbazole -4- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone
Base) -1,3,5- triazine -2- amine preparation
With step 2 gains 4- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- ethyl -9H- carbazole,
Embodiment 3 the chloro- 6- of gains 4- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine,
[1,1'- bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, x-phos and cesium carbonate are raw material, same to embodiment
Title compound is made in 4 method.
ES:M/Z 575 [M+H]+。
Step 4 4- (9- ethyl -9H- carbazole -4- base) -6- (4- aminophenyl)-N- (2- methyl -4H- chromene -4- ketone
Base) -1,3,5- triazine -2- amine preparation
With step 3 gains 4- (9- ethyl -9H- carbazole -4- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine be raw material, with embodiment 5 method be made title compound.
ES:M/Z 545 [M+H]+。
Step 5 4- (9- ethyl -9H- carbazole -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -
4- ketone group) -1,3,5- triazine -2- amine preparation
With step 4 gains 4- (9- ethyl -9H- carbazole -4- base) -6- (4- aminophenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine and allyl acyl chlorides be raw material, title compound is made in the method with embodiment 6.
1H NMR(600MHz,CDCl3) (δ, ppm): 10.12 (s, 1H), 8.12 (m, 1H), 7.80~7.82 (m, 2H),
7.78~7.79 (m, 1H), 7.67~7.69 (m, 2H), 7.50~7.52 (m, 2H), 7.43~7.45 (m, 2H), 7.31~
7.32 (m, 2H), 7.07~7.09 (m, 2H), 6.97~6.99 (m, 1H), 6.68~6.70 (m, 1H), 6.02~6.04 (m,
1H), 5.56 (s, 1H), 5.50~5.52 (m, 1H), 4.88 (s, 1H), 4.46~4.51 (m, 3H), 3.06~3.08 (m, 2H),
2.81~2.84 (m, 2H), 2.01~2.03 (brs, 2H), 1.91~1.93 (brs, 1H), 1.30~1.31 (t, 3H)
ES:M/Z 599 [M+H]+。
8 4- of embodiment (9-Fluorenone -2- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone
Base) -1,3,5- triazine -2- amine preparation
The preparation of step 1 2- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9-Fluorenone
With the bromo- 9-Fluorenone of 2-, connection pinacol borate, potassium acetate and 1,1'- bis(diphenylphosphino) ferrocene dichloropalladium
For raw material, title compound is made in the method with 7 step 2 of embodiment.
ES:M/Z 307 [M+H]+。
Step 2 4- (9-Fluorenone -2- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5-
The preparation of triazine -2- amine
With step 1 gains 2- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9-Fluorenone, 3 institute of embodiment
Obtain the chloro- 6- of object 4- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine, [1,1'- bis- (two
Phenylphosphine) ferrocene] palladium chloride dichloromethane complex, x-phos and cesium carbonate be raw material, with embodiment 4 method be made
Title compound.
ES:M/Z 560 [M+H]+。
Step 3 4- (9-Fluorenone -2- base) -6- (4- aminophenyl)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5-
The preparation of triazine -2- amine
With step 2 gains 4- (9-Fluorenone -2- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone
Base) -1,3,5-triazines -2- amine be raw material, with embodiment 5 method be made title compound.
ES:M/Z 630 [M+H]+。
Step 4 4- (9-Fluorenone -2- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- chromene -4- ketone group) -
The preparation of 1,3,5- triazine -2- amine
With step 3 gains 4- (9-Fluorenone -2- base) -6- (4- aminophenyl)-N- (2- methyl -4H- chromene -4- ketone
Base) -1,3,5-triazines -2- amine and allyl acyl chlorides be raw material, title compound is made in the method with embodiment 6.
1H NMR(600MHz,CDCl3) (δ, ppm): 10.12 (s, 1H), 8.44~8.45 (m, 2H), 8.34~8.36 (m,
1H), 7.80~7.82 (m, 2H), 7.66~7.69 (m, 3H), 7.56~7.56 (m, 1H), 7.50~7.52 (m, 2H), 7.46
~7.48 (m, 1H), 7.40~7.42 (m, 1H), 7.07~7.09 (m, 2H), 6.48~6.50 (m, 1H), 6.02~6.04 (m,
1H), 5.56 (s, 1H), 5.50~5.52 (m, 1H), 4.89 (s, 1H), 4.46~4.51 (m, 1H), 3.06~3.08 (m, 2H),
2.81~2.84 (m, 2H), 2.01~2.03 (brs, 2H), 1.91~1.93 (brs, 1H)
ES:M/Z 584 [M+H]+。
9 4- of embodiment (dibenzo [b, d] thiophene -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5- triazine -2- amine preparation
The preparation of step 1 4- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- oxo -9H- thioxanthene
With the bromo- dibenzo of 2- [b, d] thiophene, connection boric acid pinacol ester, potassium acetate and [1,1'- bis- (diphenylphosphines) two cyclopentadienyl
Iron] palladium chloride be raw material, with 7 step 2 of embodiment method be made title compound.
ES:M/Z 311 [M+H]+。
Step 2 4- (dibenzo [b, d] thiophene -4- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone
Base) -1,3,5- triazine -2- amine preparation
With step 1 gains 4- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine)-dibenzo [b, d] thiophene,
Embodiment 3 the chloro- 6- of gains 4- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2- amine,
[1,1'- bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, x-phos and cesium carbonate are raw material, same to embodiment
Title compound is made in 4 method.
ES:M/Z 564 [M+H]+。
Step 3 4- (dibenzo [b, d] thiophene -4- base) -6- (4- aminophenyl)-N- (2- methyl -4H- chromene -4- ketone
Base) -1,3,5- triazine -2- amine preparation
With step 2 gains 4- (dibenzo [b, d] thiophene -4- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine be raw material, with embodiment 5 method be made title compound.
ES:M/Z 534 [M+H]+。
Step 4 4- (dibenzo [b, d] thiophene -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5- triazine -2- amine preparation
With step 3 gains 4- (dibenzo [b, d] thiophene -4- base) -6- (4- aminophenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine and allyl acyl chlorides be raw material, title compound is made in the method with embodiment 6.
1H NMR(600MHz,CDCl3) (δ, ppm): 10.12 (s, 1H), 8.47~8.48 (m, 1H), 7.97~7.98 (m,
1H), 7.79~7.81 (m, 3H), 7.67~7.69 (m, 2H), 7.50~7.52 (m, 3H), 7.38~7.40 (m, 2H), 7.28
~7.30 (m, 1H), 7.07~7.09 (m, 2H), 6.48~6.50 (m, 1H), 6.01~6.03 (m, 1H), 5.55 (s, 1H),
5.50~5.52 (m, 1H), 4.89 (s, 1H), 4.47~4.50 (m, 1H), 3.06~3.08 (m, 2H), 2.81~2.83 (m,
2H), 2.01~2.03 (brs, 2H), 1.91~1.93 (brs, 1H)
ES:M/Z 588 [M+H]+。
10 4- of embodiment (dibenzo [b, d] thiophene -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H-
Chromene -4- ketone group) -1,3,5- triazine -2- amine DE ZHIBEI
The preparation of the chloro- 9- oxo -9H- thioxanthene of step 1 2-
4.5g thiosalicylic acid, 12.5g chlorobenzene are weighed in reaction flask, the 40mL concentrated sulfuric acid is slowly added into, is reacted at 75 DEG C
Reaction solution is poured slowly into 60 DEG C of water by 2h under stiring after reaction, and ethyl acetate extraction, anhydrous sodium sulfate is dry, mistake
Filter, is spin-dried for obtaining title compound.
ES:M/Z 247 [M+H]+。
The preparation of step 2 2- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- oxo -9H- thioxanthene
With the chloro- 9- oxo -9H- thioxanthene of 2-, connection boric acid pinacol ester, potassium acetate and [two cyclopentadienyl of 1,1'- bis- (diphenylphosphines)
Iron] palladium chloride be raw material, with 7 step 2 of embodiment method be made title compound.
ES:M/Z 339 [M+H]+。
Step 3 4- (9- oxo -9H- thioxanthene -2- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone
Base) -1,3,5- triazine -2- amine preparation
With step 2 gains 2- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) -9- oxo -9H- thia
Anthracene, embodiment 3 the chloro- 6- of gains 4- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2-
Amine, [1,1'- bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, x-phos and cesium carbonate are raw material, with real
Title compound is made in the method for applying example 4.
ES:M/Z 592 [M+H]+。
Step 4 4- (9- oxo -9H- thioxanthene -2- base) -6- (4- aminophenyl)-N- (2- methyl -4H- chromene -4- ketone
Base) -1,3,5- triazine -2- amine preparation
With step 3 gains 4- (9- oxo -9H- thioxanthene -2- base) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine be raw material, with embodiment 5 method be made title compound.
ES:M/Z 562 [M+H]+。
Step 5 4- (dibenzo [b, d] thiophene -4- base) -6- (4- allyl amido phenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5- triazine -2- amine preparation
With step 4 gains 4- (9- oxo -9H- thioxanthene -2- base) -6- (4- aminophenyl)-N- (2- methyl -4H- color
Alkene -4- ketone group) -1,3,5-triazines -2- amine and allyl acyl chlorides be raw material, title compound is made in the method with embodiment 6.
1H NMR(600MHz,CDCl3) (δ, ppm): 10.12 (s, 1H), 7.81~7.83 (m, 2H), 7.68~7.70 (m,
2H), 7.57~7.59 (m, 1H), 7.51~7.52 (m, 2H), 7.44~7.46 (m, 1H), 7.39~7.40 (m, 1H), 7.28
~7.30 (m, 2H), 7.19~7.20 (m, 1H), 7.07~7.09 (m, 2H), 6.64~6.65 (m, 1H), 6.48~6.50 (m,
1H), 6.01~6.03 (m, 1H), 5.56 (s, 1H), 5.50~5.52 (m, 1H), 4.89 (s, 1H), 4.46~4.48 (m, 1H),
3.06~3.08 (m, 2H), 2.81~2.83 (m, 2H), 2.00~2.03 (brs, 2H), 1.91~1.92 (brs, 1H)
ES:M/Z 616 [M+H]+。
11 4- of embodiment (spiral shell [cyclopropane -1,9 '-fluorenes] -2 '-yls) -6- (4- allyl amido phenyl)-N- (2- methyl -
4H- chromene -4- ketone group) -1,3,5- triazine -2- amine preparation
The preparation of the bromo- 9- of step 12- (2- bromoethyl) -9H- fluorenes
2g 2- bromine fluorenes is weighed in reaction flask, 10mL TH dissolution is added, 9.8ml hexamethyl two is slowly added in -78 DEG C
Silicon substrate finishes, and continues after stirring 1h at this temperature, is warming up to 0 DEG C, gained mixture is slowly added into 10ml and is dissolved with
In 10.5g 1,2- Bromofume THF solution, the reaction was continued at 0 DEG C, and 1h is added 1ml methanol and is quenched, remove after reaction
Solvent, column chromatographic purifying obtain title compound.
1H NMR(400MHz,DMSO-d6)δppm:7.83-7.91(m,3H),7.57-7.65(m,2H),7.37-7.41
(m,2H),4.16(m,1H),3.40-3.44(m,2H),2.43-2.50(m,2H)。
The preparation of step 22 '-bromine spiral shell [cyclopropane -1,9 '-fluorenes]
1.1g step 1 gained 2- bromo- 9- (2- bromoethyl) -9H- fluorenes is weighed in reaction flask, 5mL DMF dissolution is added, in
It is slowly added to 248mg NaH at 0 DEG C, finishes, is warmed to room temperature reaction 12h, after reaction, 1mL saturated ammonium chloride solution is added
It is quenched, the dilution of 20ml ethyl acetate is added, successively with 10% LiCl solution, saturated common salt water washing, merge organic phase, it is anhydrous
Sodium sulphate dries, filters, and ethyl acetate is removed under reduced pressure, and column chromatographic purifying obtains title compound.
1H NMR(400MHz,DMSO-d6)δppm:7.87-7.95(m,2H),7.51-7.53(m,1H),7.46(s,1H),
7.31-7.38(m,2H),7.19-7.21(m,1H),1.80-1.86(m,2H),1.74-1.79(m,2H)。
The preparation of step 32- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) spiral shell [cyclopropane -1,9 '-fluorenes]
With 2 '-bromine spiral shells [cyclopropane -1,9 '-fluorenes], connection pinacol borate, potassium acetate and 1,1'- bis- (diphenyl phosphine) two
Luxuriant iron palladium chloride is raw material, and title compound is made in the method with 7 step 2 of embodiment.
ES:M/Z 319 [M+H]+。
Step 4 4- (spiral shell [cyclopropane -1,9 '-fluorenes] -2 '-yls) -6- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -
4- ketone group) -1,3,5- triazine -2- amine preparation
With step 3 gains 2- (4,4,5,5- tetramethyl -1,3,2- dioxolane borine) spiral shell [cyclopropane -1,9 ' -
Fluorenes], embodiment 3 the chloro- 6- of gains 4- (4- nitrobenzophenone)-N- (2- methyl -4H- chromene -4- ketone group) -1,3,5- triazine -2-
Amine, [1,1'- bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, x-phos and cesium carbonate are raw material, with real
Title compound is made in the method for applying example 4.
ES:M/Z 572 [M+H]+。
Step 5 4- (spiral shell [cyclopropane -1,9 '-fluorenes] -2 '-yls) -6- (4- aminophenyl)-N- (2- methyl -4H- chromene -
4- ketone group) -1,3,5- triazine -2- amine preparation
With step 4 gains 4- (spiral shell [cyclopropane -1,9 '-fluorenes] -2 '-yls) -6- (4- nitrobenzophenone)-N- (2- methyl -
4H- chromene -4- ketone group) -1,3,5-triazines -2- amine be raw material, with embodiment 5 method be made title compound.
ES:M/Z542 [M+H]+。
Step 6 4- (spiral shell [cyclopropane -1,9 '-fluorenes] -2 '-yls) -6- (4- allyl amido phenyl)-N- (2- methyl -4H-
Chromene -4- ketone group) -1,3,5- triazine -2- amine preparation
With step 5 gains 4- (spiral shell [cyclopropane -1,9 '-fluorenes] -2 '-yls) -6- (4- aminophenyl)-N- (2- methyl -
4H- chromene -4- ketone group) -1,3,5-triazines -2- amine and allyl acyl chlorides be raw material, title compound is made in the method with embodiment 6
Object.
1H NMR(600MHz,CDCl3) (δ, ppm): 10.12 (s, 1H), 7.87~7.89 (m, 1H), 7.81~7.83 (m,
2H), 7.75~7.77 (m, 1H), 7.68~7.70 (m, 2H), 7.53~7.55 (m, 2H), 7.39~7.40 (m, 1H), 7.35
~7.38 (m, 2H), 7.28~7.30 (m, 1H), 7.18~7.20 (m, 1H), 6.48~6.50 (m, 1H), 6.01~6.02 (m,
1H), 5.56 (s, 1H), 5.50~5.52 (m, 1H), 4.89 (s, 1H), 4.46~4.48 (m, 1H), 3.06~3.09 (m, 2H),
2.80~2.82 (m, 2H), 2.00~2.03 (brs, 2H), 1.91~1.92 (brs, 1H), 0.92~0.94 (m, 2H), 0.65
~0.67 (m, 2H)
ES:M/Z 596 [M+H]+。
Experimental example 1: biological activity determination
Compound prepares: the full-automatic microwell plate pretreatment system of POD810 is added compound prepared by the embodiment of the present invention
Enter in orifice plate, compound initial concentration is 100uM, and each compound does duplicate hole, 2 times of dilutions, 10 points.
The culture of cell: prostate gland cancer cell DU-145, human breast cancer cell MDA-MB-468 are used contain 15% tire respectively
The RPMI-1640 culture medium of cow's serum (FBS) is cultivated in 37 degree of incubators, and logarithmic growth phase cell is for testing.
The experiment of MTT cells viability: prostate gland cancer cell DU-145, human breast cancer cell MDA-MB-468 are inoculated with respectively
(5-10 × 10 in 96 orifice plates4Cells/well), 48h is handled with the compound of embodiment 6 to 11 respectively, is added 20 in every hole
μ l3- (4,5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromide (MTT) hatches 4h, and 100 μ in every hole are then added
LDMSO sets low-speed oscillation 10min on shaking table, dissolves crystal sufficiently.It is measured at enzyme-linked immunosorbent assay instrument OD490nm each
The light absorption value in hole handles to obtain homologous thread and IC using GraphPad Prism50Value, the results are shown in Table 1.
Table 1
The experimental results showed that the present invention is thin to the active MDA-MB-468 cell of STAT3, DU-145 with sustained activation
Born of the same parents have good inhibiting effect.
Claims (10)
1. the preparation method of STAT3 inhibitor shown in formula (I), it is characterised in that: the following steps are included:
The compound of formula (1) is made in step a:2- hydroxy acetophenone acetylation；
Step b: the compound of formula (2) is made in the compound cyclization of formula (1)；
Step c: the compound of formula (3) is made in the compound bromo of formula (2)；
Step d: the compound amino of formula (3) replaces the compound that formula (4) are made；
The compound of formula (5) is made in step e:4- nitrobenzene methyl and biuret cyclization；
Step f: the compound of formula (6) is made in the compound chloro of formula (5)；
Step g: the compound of formula (6) reacts the compound that formula (7) are made with the compound of formula (4)；
Step h: the compound and X-R of formula (7)1React the compound that formula (8) are made；
Step i: the compound reduction of formula (8) hydrogenates the compound that formula (9) are made；
Step j: the compound of formula (9) is reacted with acryloyl chloride is made STAT3 inhibitor shown in formula (I), and reaction route is as follows:
Wherein, the structural formula of STAT3 inhibitor shown in formula (I) are as follows:
Wherein,
R1Selected from aryl, heteroaryl.
2. the preparation method of STAT3 inhibitor shown in formula (I) as described in claim 1, it is characterised in that: in step a, formula
(1) compound the preparation method comprises the following steps: by 2- hydroxy acetophenone, chloroacetic chloride and potassium carbonate be added reaction flask in, be added acetone, return
Water is added in stream reaction, after reaction, evaporating solvent under reduced pressure, and ethyl acetate extraction, anhydrous sodium sulfate is dry, concentration to get.
3. the preparation method of STAT3 inhibitor shown in formula (I) as described in claim 1, it is characterised in that: in step b, formula
(2) compound the preparation method comprises the following steps: take 2- acetoxy acetophenone in reaction flask, be added DMSO dissolution, at 0-5 DEG C in batches
Sodium hydrogen is added, finishes, is warmed to room temperature stirring, after reaction, is added water into reaction solution, dilute hydrochloric acid tune pH value to faintly acid,
Ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to give grease, and acetic acid and concentrated hydrochloric acid, reflux are added into gained grease
About, reaction terminates for reaction, and reaction solution is spin-dried for, and is added water, ethyl acetate extraction, anhydrous sodium sulfate it is dry to get.
4. the preparation method of STAT3 inhibitor shown in formula (I) as described in claim 1, it is characterised in that: in step c, formula
(3) compound the preparation method comprises the following steps: the compound, N-bromosuccinimide and benzoyl peroxide of formula (2) are added anti-
It answers in bottle, carbon tetrachloride is added to dissolve, back flow reaction, after reaction, reaction solution add water, ethyl acetate extraction, anhydrous sodium sulfate
It is dry, column chromatographic purifying to get.
5. the preparation method of STAT3 inhibitor shown in formula (I) as described in claim 1, it is characterised in that: in step d, formula
(4) compound the preparation method comprises the following steps: the compound of formula (3) is added in reaction flask, DMF dissolution is added, ammonium hydroxide, room temperature is added
Water, ethyl acetate extraction is added in stirring, after reaction, reaction solution, and anhydrous sodium sulfate is dried, filtered, is spin-dried for, and acetic acid second is added
Ester, the ethyl acetate hydrogen chloride solution that saturation is added after stirring and dissolving are generated to supernatant layer without precipitating, filtering, it is dry to get.
6. the preparation method of STAT3 inhibitor shown in formula (I) as described in claim 1, it is characterised in that: in step e, formula
(5) compound the preparation method comprises the following steps: weigh 4- nitrobenzoic acid in reaction flask, methanol dissolution is added, thionyl chloride is added dropwise,
It drips and finishes back flow reaction, after reaction, decompression is spin-dried for, and saturated sodium bicarbonate solution is added and adjusts pH to 7-8, ethyl acetate extraction
It takes, anhydrous sodium sulfate is dry, is concentrated to get 4- nitrobenzene methyl；It takes biuret in reaction flask, glycol dinitrate is added
Ether dissolves, and sodium hydride is added portionwise at 0-5 DEG C, finishes, is stirred to react 1h at 50 DEG C, add 4- nitrobenzene methyl, add
Finish, be warming up to 85 DEG C of reactions, after reaction, reaction solution is poured into water, adjusts pH to acidity, filtering, filter cake with concentrated hydrochloric acid
Drying to get.
7. the preparation method of STAT3 inhibitor shown in formula (I) as described in claim 1, it is characterised in that: in step f, formula
(6) compound reacts the preparation method comprises the following steps: 6- (4- nitrobenzophenone) -1,3,5- triazine -2,4- (1H, 3H)-diketone is added
In bottle, phosphorus oxychloride, phosphorus pentachloride is added, after reaction, reaction solution is poured into water for 105 DEG C of reactions, methylene chloride extraction
Take, anhydrous sodium sulfate it is dry to get.
8. the preparation method of STAT3 inhibitor shown in formula (I) as described in claim 1, it is characterised in that: in step g, formula
(7) compound the preparation method comprises the following steps: the compound of modus ponens (6) in reaction flask, be added tetrahydrofuran dissolution, be added formula (4)
Compound, sodium carbonate, back flow reaction, filtering to get.
9. the preparation method of STAT3 inhibitor shown in formula (I) as described in claim 1, it is characterised in that: in step h, formula
(8) compound the preparation method comprises the following steps: in microwave reaction bottle, sequentially add compound, the X-R1, [1,1'- bis- (two of formula (7)
Phenylphosphine) ferrocene] palladium chloride dichloromethane complex, x-phos, cesium carbonate and Isosorbide-5-Nitrae-dioxane/H2O, dissolution, argon
Gas displacement, 105 DEG C of microwave reactions, concentration, column chromatographic purifying to get.
10. the preparation method of STAT3 inhibitor shown in formula (I) as described in claim 1, it is characterised in that: in step i,
The compound of formula (9) the preparation method comprises the following steps: methanol in reaction flask, is added in the compound of modus ponens (8), Pd-C, it is big in 1 standard
Under air pressure, H2Reduction reaction stops reaction, filters, concentration；In step j, the compound of formula (10) the preparation method comprises the following steps: modus ponens
(9) compound, diisopropylethylamine are added anhydrous methylene chloride dissolution, are slowly dropped into dissolved with allyl in reaction flask
The dichloromethane solution of acyl chlorides, fully reacting, concentration, column chromatographic purifying to get.
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| CN112300088A (en) * | 2020-11-26 | 2021-02-02 | 郑州海阔光电材料有限公司 | Synthetic method of 2, 4-dihalogen-6-aryl substituted triazine derivative |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102417479A (en) * | 2011-08-29 | 2012-04-18 | 南京大学 | STAT3 small molecular selective inhibitor and preparation method and application thereof |
| CN102858770A (en) * | 2010-02-17 | 2013-01-02 | 德比欧法姆有限公司 | Bicyclic Compounds And Their Uses As Dual C-src / Jak Inhibitors |
| CN102884062A (en) * | 2009-12-23 | 2013-01-16 | 嘉世高制药公司 | Aminopyrimidine kinase inhibitors |
| US20140045908A1 (en) * | 2011-02-25 | 2014-02-13 | Synta Pharmaceuticals Corp. | Hsp90 inhibitory compounds in treating jak/stat signaling-mediated cancers |
| US20180002290A1 (en) * | 2012-06-14 | 2018-01-04 | Mayo Foundation For Medical Education And Research | Pyrazole derivatives as inhibitors of stat3 |
-
2018
- 2018-10-31 CN CN201811282947.0A patent/CN109180657A/en not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102884062A (en) * | 2009-12-23 | 2013-01-16 | 嘉世高制药公司 | Aminopyrimidine kinase inhibitors |
| CN102858770A (en) * | 2010-02-17 | 2013-01-02 | 德比欧法姆有限公司 | Bicyclic Compounds And Their Uses As Dual C-src / Jak Inhibitors |
| US20140045908A1 (en) * | 2011-02-25 | 2014-02-13 | Synta Pharmaceuticals Corp. | Hsp90 inhibitory compounds in treating jak/stat signaling-mediated cancers |
| CN102417479A (en) * | 2011-08-29 | 2012-04-18 | 南京大学 | STAT3 small molecular selective inhibitor and preparation method and application thereof |
| US20180002290A1 (en) * | 2012-06-14 | 2018-01-04 | Mayo Foundation For Medical Education And Research | Pyrazole derivatives as inhibitors of stat3 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112300088A (en) * | 2020-11-26 | 2021-02-02 | 郑州海阔光电材料有限公司 | Synthetic method of 2, 4-dihalogen-6-aryl substituted triazine derivative |
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