CN108610284A - A kind of preparation method of Rui Gefeini derivatives - Google Patents
A kind of preparation method of Rui Gefeini derivatives Download PDFInfo
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- CN108610284A CN108610284A CN201810305238.3A CN201810305238A CN108610284A CN 108610284 A CN108610284 A CN 108610284A CN 201810305238 A CN201810305238 A CN 201810305238A CN 108610284 A CN108610284 A CN 108610284A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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Abstract
The invention discloses a kind of preparation method of Rui Gefeini derivatives, the present invention filters out best reaction step and reaction condition by many experiments, and entire technological design is reasonable, and operability is strong, and reaction condition is milder, and yield height is, it can be achieved that industrialized production.The present invention is using 3 fluorophenols, 4 chlorine of N methyl, 2 pyridine carboxamide and 4 amino, 3 fluorophenol as raw material, it is reacted by seven steps, synthesis obtains Rui Gefeini derivatives, the Rui Gefeini derivatives purity that the present invention is prepared is high, quality control, safety and efficiency evaluation are carried out to Rui Gefeini, foundation is provided, and Rui Gefeini derivatives pharmacological activity is good, it can develop for blocking tumor cell proliferation, inhibiting the drugs such as Tumor angiogenesis and modulate tumor microenvironment, there is important application value to antitumor drug exploitation.
Description
Technical field
The invention belongs to pharmaceutical synthesis field more particularly to a kind of preparation methods of Rui Gefeini derivatives.
Background technology
Colorectal cancer (colorectal cancer, CRC) is one of clinical most common tumor in digestive tract.It is global annual
About 1,250,000 people are diagnosed as CRC, and more than 600,000 deaths, incidence and case fatality rate occupy the 3rd and the 4th respectively.In
The annual CRC new cases 220,000 of state, death 110,000, incidence and case fatality rate occupy the 5th, are more than 30% CRC patient
The existing DISTANT METASTASES IN when making a definite diagnosis, wherein quite a few patient can not pass through surgical radical treatment.It is that knot is straight based on operation
The primary treatment principle of intestinal cancer.Chinese medicine long-time conditioning is used after early operation excision, chemicotherapy can not had to.It is taken after middle and advanced stage operation
Chinese medicine must be aided with radiotherapy, chemotherapy and molecular targeted therapy simultaneously, recurred, improved the quality of living with improving survival rate and reducing.Mark
The essential drugs of quasi- chemotherapy regimen include fluorouracil and its derivative oxaliplatin and Irinotecan, but cell toxicity medicament often produces
Raw more serious toxicity, and CRC has stronger repellence to chemotherapy, conventional chemotherapy effect is often ineffective, point
The appearance of sub- targeted drug provides new selection for advanced colorectal cancer treatment, combines on the basis of chemotherapy molecular targeted
Drug therapy can further extend the life cycle of patient.These molecular targeted agents include Cetuximab Victibix and shellfish
Monoclonal antibody is cut down, the above two are shown in the mCRC patient of K-Ras wild types for target spot with EGF-R ELISA (EGFR)
Good therapeutic effect, it is a kind of oral multi-kinase inhibitor that the latter, which is target spot Rui Gefeini with vascular endothelial growth factor (VEGF), is led to
Inhibition multiple proteins kinases is crossed, targeting is generated in tumour, tumor vessel occurs and the dimension of tumor microenvironment signal transduction
It holds.
Rui Gefeini (regorafenib, BAY73-4506；Trade name Stivarga) it is a kind of more kinase inhibitions of small molecule
Agent, molecular structure are similar to Sorafenib, differ only in the fluorine atom on intermediate phenyl ring.It is the new of Beyer Co., Ltd's development
Type molecular targeted agents, 2012 Nian9Yue27 U.S. Food and Drug Administrations (FDA) ratify for treating metastatic colon
The carcinoma of the rectum (metastatic colorectal cancer, mCRC), on 2 25th, 2013, FDA approvals were for treating not expert
Art and the invalid advanced GIST patient of other treatment means.Rui Gefeini is a kind of novel oral multiple target point protein kinase inhibition
Agent can block tumor cell proliferation, inhibit Tumor angiogenesis and modulate tumor microenvironment, have good antitumor activity.
" CORRECT " research confirms, is the TKI for having therapeutic activity to metastatic colorectal cancer patient, is based on the data,
The U.S. FDA of in September, 2012 has approved the mCRC patient for treating multi-thread standard regimens treatment failure.It is domestic then just
Carrying out multicenter III clinical trial phases of the Rui Gefeini for treating Chinese mCRC patient.
With the progress in epoch, the raising of scientific and technological level, people to drug before marketing drugs to that must carry out quality, safety
Property and the importance etc. of efficiency scientific evaluation, which have, more fully to be recognized, wherein with drug quality it is closely related be drug institute
Control containing derivative.Derivative is often related with drug safety, and also related with efficiency in a few cases.Therefore, it controls
Derivative level processed is increasingly paid attention to by medical personal during drug development.
Rui Gefeini derivatives are a kind of derivatives generated in Rui Gefeini building-up processes, to Rui Gefeini derivatives
Relevant pharmacology, pharmacokinetic study are carried out, control sample can be provided for the quality control of bulk pharmaceutical chemicals Rui Gefeini, to
Promote the research of Rui Gefeini.But about the research of Rui Gefeini derivatives, there is not been reported.
Invention content
Goal of the invention：The goal of the invention of the present invention is to provide a kind of preparation method of Rui Gefeini derivatives, this method work
Skill reasonable design, yield is high, and operating process facilitates controllable, to be prepared Rui Gefeini derivatives yield height, at low cost.
In order to achieve the above object, the present invention uses following scheme：
A kind of preparation method of Rui Gefeini derivatives, which is characterized in that include the following steps：
(1) it takes 3- fluorophenols to be dissolved in organic solvent, potassium tert-butoxide is added under ice bath, stirs at room temperature, N- first is added
Base -4- Chloro-2-Pyridyle formamides, are stirred to react at 60 DEG C -130 DEG C, obtain compound III, structural formula is as follows：
(2) it takes the compound III to be dissolved in the concentrated sulfuric acid, nitric acid and sulfuric acid mixture is added, compounds Ⅳ is obtained by the reaction,
Structural formula is as follows：
(3) it takes 4- amino -3- fluorophenols (compound V) to be dissolved in di-tert-butyl dicarbonate, three is added under condition of ice bath
Compound VI is obtained by the reaction in inidum chloride, and structural formula is as follows：
(4) it takes the compounds Ⅳ and the compound VI to be dissolved in n,N-Dimethylformamide, inorganic base, reaction is added
Compound VII is obtained, structural formula is as follows：
(5) it takes the compound VII to be dissolved in organic solvent, trifluoroacetic acid is added, compound VIII is obtained by the reaction；
(6) it takes compound VIII to be suspended in the in the mixed solvent of second alcohol and water, is added ammonium chloride, iron powder and concentrated hydrochloric acid, 20~
100 DEG C are reacted 1~3 hour, obtain compound Ⅸ, structure is as follows：
(7) it takes the compound Ⅸ to be dissolved in ethyl acetate, the chloro- 3- trifluoromethyl phenyl isocyanates ester (compounds of 4- is added
Ⅹ) it, is reacted 0.5~2 hour at 0~80 DEG C, obtains compound Ⅺ, is i.e. Rui Gefeini derivatives, structural formula is as follows：
Preferably, the preparation method of above-described Rui Gefeini derivatives, the organic solvent described in step (1)
For dimethyl sulfoxide (DMSO) or n,N-Dimethylformamide, the N- methyl -4- Chloro-2-Pyridyles formamide, 3- fluorophenols and the tert-butyl alcohol
The ratio between amount of substance of potassium is 1:1:1~1:2:3.
Preferably, the preparation method of above-described Rui Gefeini derivatives, the organic solvent described in step (1)
For n,N-Dimethylformamide, the amount of the substance of the N- methyl -4- Chloro-2-Pyridyles formamide, 3- fluorophenols and potassium tert-butoxide
The ratio between be 1:2:2.5, the reaction temperature is 100 DEG C.
Preferably, the preparation method of above-described Rui Gefeini derivatives, the reaction temperature described in step (2)
It it is 0 DEG C, the reaction time is 2 hours.The volume ratio of nitric acid and sulfuric acid is 1 in nitric acid and sulfuric acid mixture:1~1:3.
Preferably, the preparation method of above-described Rui Gefeini derivatives, the compound V described in step (3)
It is 1 with the ratio between the amount of substance of indium trichloride:0.01~1:0.5.
Preferably, the preparation method of above-described Rui Gefeini derivatives, the compound V described in step (3)
Amount ratio with the substance of indium trichloride is 1:0.05,35 DEG C is reacted 2 hours.
Preferably, the preparation method of above-described Rui Gefeini derivatives, the inorganic base described in step (4) are
Sodium carbonate, potassium carbonate or cesium carbonate react 8~16 hours at 60~120 DEG C.
Preferably, the preparation method of above-described Rui Gefeini derivatives, the inorganic base described in step (4) are
Potassium carbonate, the ratio between amount of the compounds Ⅳ, compound VI and inorganic alkaloid substance are 1:1:2, reaction temperature is 120 DEG C, reaction
Time is 16 hours.
Preferably, the preparation method of above-described Rui Gefeini derivatives, the organic solvent described in step (5)
For dichloromethane, reaction temperature is 25 DEG C, 1 hour reaction time.
Preferably, the preparation method of above-described Rui Gefeini derivatives, the reaction time described in step (6)
It it is 3 hours, reaction temperature is 80 DEG C；
Preferably, the preparation method of above-described Rui Gefeini derivatives, step (7) reaction time are 0.5
Hour, reaction temperature is 25 DEG C.The ratio between compound Ⅸ, amount of substance of compound Ⅹ 1:2.5.
The beneficial effects of the invention are as follows：
The present invention provides a kind of preparation method of Rui Gefeini derivatives, the present invention screens to obtain most by many experiments
Good reaction step and reaction condition；The preparation method technological design is reasonable, and operating method is simple, raw material is easy to get, technique can be put
Big production, purity is high, reaction process is controllable and environmental protection effect is good, it can be achieved that industrialized production.
The Rui Gefeini derivatives that the present invention is prepared can be commented for quality, safety and the efficiency science of Rui Gefeini
Valence provides important evidence, and Rui Gefeini derivatives pharmacological activity is good, can develop for blocking tumor cell proliferation, inhibiting swollen
The drugs such as tumor vascularization and modulate tumor microenvironment have important application value to antitumor drug exploitation.
Description of the drawings
Fig. 1 is the preparation technology flow chart of Rui Gefeini derivatives provided by the invention.
Specific implementation mode
With reference to specific embodiment, the present invention is furture elucidated, it should be understood that these embodiments are merely to illustrate the present invention
Rather than limit the scope of the invention, after having read the present invention, various equivalences of the those skilled in the art to the present invention
The modification of form falls within the application range as defined in the appended claims.
Embodiment 1
1, the screening experiment of the step of preparation method of Rui Gefeini derivatives (1)
(1) it takes 3- fluorophenols to be dissolved in the organic solvent of 10~30 volumes, potassium tert-butoxide is added under ice bath, stirs at room temperature
It mixes 30 minutes, N- methyl -4- Chloro-2-Pyridyle formamides is added, are stirred 5 hours at 60 DEG C -130 DEG C, point board monitoring has been reacted
Entirely；Reaction solution is poured into ice water, is extracted with ethyl acetate, purifies to obtain compound III, 3- fluorophenols, N- first through column chromatography
The ratio between the amount of substance of base -4- Chloro-2-Pyridyles formamide and potassium tert-butoxide, the screening experiment data such as following table of reaction dissolvent：
It is as follows that reaction temperature changes experimental data：
Show that the best reaction organic solvent of step (1) is n,N-Dimethylformamide, the N- by the above the selection result
The ratio between amount of substance of methyl -4- Chloro-2-Pyridyles formamide, 3- fluorophenols and potassium tert-butoxide is 1:2:2.5, the reaction temperature
It is 100 DEG C.
2, the screening experiment of the step of preparation method of Rui Gefeini derivatives (2)
(2) it takes 0.11mol compound IIIs to be dissolved in the 130mL concentrated sulfuric acids, 26mL nitric acid and sulfuric acid mixture (volume 1 is added:
1) it, stirs 0.5~2 hour and reacts.Reaction solution is poured into ice-water bath, is more than 8 with onium hydroxide solution tune pH value, then uses acetic acid
Ethyl ester extracts, and purifies to obtain compounds Ⅳ through column chromatography；
Reaction temperature, the experimental data are shown in the following table for reaction time screening：
By the above screening experiment the result shows that：The best reaction temperature of step (2) is 0 DEG C, and optimum reacting time is 2 small
When.
3, the screening experiment of the step of preparation method of Rui Gefeini derivatives (3)
(3) 0.15mol 4- amino -3- fluorophenols (compound V) are taken to be dissolved in 36mL di-tert-butyl dicarbonates, in ice bath
Under the conditions of be added indium trichloride, 35 DEG C are reacted 2 hours, and reaction solution is diluted with ethyl acetate, pure through washing, drying, column chromatography
Change obtains yellow solid compound VI；
Compound V and the experimental data of the ratio between the amount of substance of indium trichloride are as follows：
By the above screening experiment the result shows that：The amount ratio of step (3) compound V and the optimisation substance of indium trichloride is 1:
0.05,35 DEG C is reacted 2 hours.
4, the screening experiment of the step of preparation method of Rui Gefeini derivatives (4)
(4) it takes compounds Ⅳ and compound VI to be dissolved in 230mLN, in dinethylformamide, is added under the conditions of nitrogen protection
Inorganic base reacts 8~16 hours at 60~120 DEG C, and reaction solution is yellow suspension, is diluted with water and then is extracted with ethyl acetate
It takes, purifies to obtain dark oil compound VII through drying, concentration, column chromatography；
Inorganic base, compounds Ⅳ, compound VI and the screening experiment data of the ratio between the amount of inorganic alkaloid substance are as follows：
Reaction temperature and reaction time experimental data are as follows：
By the above screening experiment, the result shows that, step (4) optimum reaction condition is：Inorganic base is potassium carbonate, compounds Ⅳ,
The ratio between compound VI and the amount of inorganic alkaloid substance are 1:1:2, best reaction temperature is 120 DEG C, and the best reaction time is 16
Hour.
5, the screening experiment of the step of preparation method of Rui Gefeini derivatives (6)
(6) it takes 0.015mol compounds VIII to be suspended in the in the mixed solvent of the second alcohol and water of 33mL, ammonium chloride, iron powder is added
And concentrated hydrochloric acid, 20~80 DEG C are reacted 1~3 hour, and the reaction was complete forms dark solution, reaction solution is cooled to room temperature, under ice bath
400mL water is added, is extracted with ethyl acetate, organic phase merges, and is 20 with volume ratio after drying:1 dichloromethane：Methanol
Make eluant, eluent, pillar layer separation obtains Ⅸ, of compound as white solid
Reaction temperature and the screening experiment data in reaction time are as follows：
By the above screening experiment, the result shows that, step (6) optimum reaction condition is：Reaction temperature is 80 DEG C, the reaction time
It is 3 hours.
6, the screening experiment of the step of preparation method of Rui Gefeini derivatives (7)
(7) it takes 0.010mol compounds Ⅸ to be dissolved in 83mL ethyl acetate, the chloro- 3- trifluoromethyls of 0.026mol 4- is added
Phenyl isocyanate (compound Ⅹ) reacts 30min at 25 DEG C, forms bright yellow solution, and reaction solution concentration is evaporated removing second
Acetoacetic ester is 20 with volume ratio:1 dichloromethane：Methanol makees eluant, eluent, and pillar layer separation obtains compound as white solid Ⅺ.
The experimental data of the magnitude relation of the substance of compound Ⅸ, compound Ⅹ is as follows：
By the above screening experiment, the result shows that, step (7) optimum reaction condition is：The substance of compound Ⅸ, compound Ⅹ
The ratio between amount be 1:2.5.
Embodiment 2
A kind of preparation method of Rui Gefeini impurity, includes the following steps：
(1) it takes 3- fluorophenols to be dissolved in the n,N-Dimethylformamide of 30 volumes, potassium tert-butoxide, room temperature is added under ice bath
Lower stirring 30 minutes, is added N- methyl -4- Chloro-2-Pyridyle formamides, is stirred 5 hours at 100 DEG C, and point board monitoring has been reacted
Entirely；Reaction solution is poured into ice water, is extracted with ethyl acetate, purifies to obtain compound III through column chromatography；Reaction yield
89.56%.The ratio between amount of substance of the N- methyl -4- Chloro-2-Pyridyles formamide, 3- fluorophenols and potassium tert-butoxide is 1:2:
2.5。
Compound III1H NMR (400MHz, DMSO~d6):δ8.80(d,1H),δ8.55(d,1H),δ7.56(dd,
1H),δ7.44(d,1H),δ7.23(m,3H),δ7.11(m,1H),δ2.79(d,3H).MS:247.2[M-H]+。
(2) 0.11mol compound IIIs is taken to be dissolved in the 130mL concentrated sulfuric acids, be added 26mL nitric acid and sulfuric acid mixture (volume it
Than being 1:1) it, is stirred to react 2 hours for 0 DEG C.Reaction solution is poured into ice-water bath, is more than 8 with onium hydroxide solution tune pH value, then uses
Ethyl acetate extracts, and purifies to obtain compounds Ⅳ through column chromatography；Yield 64.3%；Compounds Ⅳ1H NMR(400MHz,DMSO
~d6):δ8.54(d,1H),δ8.20(t,1H),δ8.02(m,1H),δ7.85(d,1H),δ7.11(m,1H),δ6.98(m,
2H),δ3.02(m,3H).MS:292.1[M-H]+。
(3) 0.15mol 4- amino -3- fluorophenols (compound V) are taken to be dissolved in 36mL di-tert-butyl dicarbonates, in ice bath
Under the conditions of be added indium trichloride, the amount ratio of compound V and the optimisation substance of indium trichloride is 1:0.05,35 DEG C is reacted 2 hours,
Reaction solution is diluted with ethyl acetate, purifies to obtain yellow solid compound VI through washing, drying, column chromatography；Yield is
73.6%；
The MS of compound VI:228.3[M-H]+。1HNMR (400MHz, DMSO~d6):8.24 (- OH hydrogen), δ 7.85 (d,
1H), δ 7.11 (d, 1H), δ 6.98 (s, 1H), δ 1.3~2.1 (m, 9H), 4.87 (- NH).
(4) it takes compounds Ⅳ and compound VI to be dissolved in 230mLN, in dinethylformamide, is added under the conditions of nitrogen protection
Potassium carbonate reacts 16 hours at 120 DEG C, and the ratio between amount of compounds Ⅳ, compound VI and inorganic alkaloid substance is 1:1:2；Reaction
Liquid is yellow suspension, is diluted with water and then is extracted with ethyl acetate, and purifies to obtain dark oil through drying, concentration, column chromatography
Compound VII；
The mass spectrum for closing object VII is MS:521.2[M-H]+。1HNMR (400MHz, DMSO~d6):δ9.15(m,1H),δ8.67
~8.01 (m, 4H), δ 5.61 (m, 1H), δ 7.77~6.86 (d, 5H), δ 2.85 (m, 3H), δ 1.38 (s, 9H)
(5) it takes compound VII to be dissolved in 380mL dichloromethane, 114mL trifluoroacetic acids is added, 25 DEG C are reacted 1 hour, reaction
Liquid becomes black suspension, and ice water dilution is added after concentration, with sodium hydroxide solution alkali tune, is extracted through ethyl acetate, is dry, dense
Contracting, again with methanol crystallization purifying obtain yellow solid compound VIII, yield 81.93%；Compound VIII1H NMR
(400MHz, DMSO~d6):δ8.80(d,1H),δ8.57(d,1H),δ8.16(d,1H),δ7.54(d,1H),δ7.27(m,
1H),δ7.04(m,2H),δ6.80(m,3H),δ5.15(s,2H),δ2.79(d,3H).MS:399.3[M-H]+。
(6) it takes 0.015mol compounds VIII to be suspended in the in the mixed solvent of the second alcohol and water of 33mL, ammonium chloride, iron powder is added
And concentrated hydrochloric acid, 80 DEG C are reacted 3 hours, and the reaction was complete forms dark solution, and reaction solution is cooled to room temperature, is added under ice bath
400mL water, is extracted with ethyl acetate, and organic phase merges, and is 20 with volume ratio after drying:1 dichloromethane：Methanol is washed
De- agent, pillar layer separation obtain compound as white solid Ⅸ；Yield 84.5%.The mass spectrum of compound Ⅸ is MS:369.2[M-H]+,1H
NMR (400MHz, DMSO~d6):δ 8.80~8.01 (m, 3H), δ 7.61 (m, 1H), δ 7.04 (d, 1H), δ 6.60~6.20 (m,
5H), δ 5.10~5.20 (s, 4H), δ 2.85 (d, 3H)
(7) it takes 0.010mol compounds Ⅸ to be dissolved in 83mL ethyl acetate, the chloro- 3- trifluoromethyls of 0.026mol 4- is added
Phenyl isocyanate (compound Ⅹ), the ratio between compound Ⅸ, amount of substance of compound Ⅹ are 1:2.5, it is reacted at 25 DEG C
30min forms bright yellow solution, and reaction solution concentration is evaporated removing ethyl acetate, is 20 with volume ratio:1 dichloromethane：First
Alcohol makees eluant, eluent, and pillar layer separation obtains compound as white solid Ⅺ, yield 78.2%.
Compound Ⅺ1H NMR (400MHz, DMSO~d6):δ9.71(s,1H),δ9.44(s,1H),δ8.75(d,
1H),δ8.62(s,1H),δ8.65(s,1H),δ8.50(d,1H),δ8.32(d,1H),δ8.11(s,2H),δ8.04(t,1H),δ
7.62 (m, 4H), δ 7.41 (d, 1H), δ 7.22~6.95 (m, 4H), δ 6.77 (d, 1H), δ 2.79 (d, 3H) .MS:833.2[M-
H]+。
The external anti-human colorectal cancer experiment of embodiment 3
Cell strain：Human colorectal cancer cells strain SW480；96 orifice plates are purchased from Costar companies；RMPI1640 culture mediums are purchased from
Gibco companies；DMEM culture mediums are purchased from Gibco companies；Newborn bovine serum is purchased from Hangzhou Chinese holly company；Tetrazolium bromide (MTT) and
DMSO is purchased from Amresco companies.
Laboratory apparatus used in following embodiment is as follows：
Laboratory apparatus：Superclean bench (Suzhou purifies model SW-CJ-IFD), CO2Incubator (SANYO models：XD-
101), microplate reader BIO-RAD (Model NO.550Serial NO.16971).
Experimental method used in following embodiment is as follows：
Experimental method：Rui Gefeini derivative (the compounds that the embodiment of the present invention 2 is prepared using improvement mtt assay
Ⅺ) Tuberculosis in vitro rectum cancer cell experiment is carried out：Human colorectal cancer cells SW480 is digested with pancreatin, is counted, be made it is dense
Degree is 5 × 104The cell suspension of a/ml.100 μ l cell suspensions will be added in 96 orifice plates per hole (per hole 5 × 103A cell), so
37 DEG C are placed on, 5%CO2It is cultivated 24 hours in incubator；It is dense to required different gradients with non-fully culture medium dilution drug
The 100 corresponding pastille culture mediums of μ L are added per hole, while setting up negative control group for degree, vehicle control group and positive controls, then
96 orifice plates are placed in 37 DEG C, 5%CO2It is cultivated 72 hours in incubator.Then 20 μ LMTT (5mg/ml) are added per hole, continue to train
It supports 4 hours, terminates culture, discard culture medium, be added 150 μ LDMSO dissolvings per hole, the gently mixing of shaking table 10 minutes.λ=
Absorbance, that is, OD values per hole are detected with microplate reader under two wavelength of 4570nm, 620nm, it is thin using the average value of each multiple holes as the group
The OD values of born of the same parents, calculate the inhibiting rate of each drug.
Experimental result shows the Rui Gefeini derivatives (compound Ⅺ) that the embodiment of the present invention 1 is prepared, and is tied to people straight
Colon-cancer cell all has stronger inhibiting effect.It is as shown in the table for experimental result.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Rui Gefeini derivatives, which is characterized in that include the following steps：
(1) it takes 3- fluorophenols to be dissolved in organic solvent, potassium tert-butoxide is added under ice bath, stirs at room temperature, N- methyl -4- is added
Chloro-2-Pyridyle formamide is stirred to react at 60 DEG C -130 DEG C, obtains compound III, and structural formula is as follows：
(2) it takes the compound III to be dissolved in the concentrated sulfuric acid, nitric acid and sulfuric acid mixture is added, compounds Ⅳ, structure is obtained by the reaction
Formula is as follows：
(3) it takes 4- amino -3- fluorophenols (compound V) to be dissolved in di-tert-butyl dicarbonate, tri-chlorination is added under condition of ice bath
Compound VI is obtained by the reaction in indium, and structural formula is as follows：
(4) it takes the compounds Ⅳ and the compound VI to be dissolved in n,N-Dimethylformamide, inorganic base is added, is obtained by the reaction
Compound VII, structural formula is as follows：
(5) it takes the compound VII to be dissolved in organic solvent, trifluoroacetic acid is added, compound VIII is obtained by the reaction；
(6) it takes compound VIII to be suspended in the in the mixed solvent of second alcohol and water, is added ammonium chloride, iron powder and concentrated hydrochloric acid, 20~100 DEG C
Reaction 1~3 hour, obtains compound Ⅸ, structure is as follows：
(7) it takes the compound Ⅸ to be dissolved in ethyl acetate, the chloro- 3- trifluoromethyl phenyl isocyanates esters (compound Ⅹ) of 4- is added,
It is reacted 0.5~2 hour at 0~80 DEG C, obtains compound Ⅺ, is i.e. Rui Gefeini derivatives, structural formula is as follows：
2. the preparation method of Rui Gefeini derivatives according to claim 1, which is characterized in that having described in step (1)
Solvent is dimethyl sulfoxide (DMSO) or N,N-dimethylformamide.N- methyl -4- Chloro-2-Pyridyles the formamide, 3- fluorophenols with
The ratio between amount of substance of potassium tert-butoxide is 1:1:1~1:2:3.
3. the preparation method of Rui Gefeini derivatives according to claim 1 or 2, which is characterized in that described in step (1)
Organic solvent is n,N-Dimethylformamide, the N- methyl -4- Chloro-2-Pyridyles formamide, 3- fluorophenols and potassium tert-butoxide
The ratio between amount of substance is 1:2:2.5, the reaction temperature is 100 DEG C.
4. the preparation method of Rui Gefeini derivatives according to claim 1, which is characterized in that anti-described in step (2)
It is 0 DEG C to answer temperature, and the reaction time is 2 hours.
5. the preparation method of Rui Gefeini derivatives according to claim 1, which is characterized in that the change described in step (2)
It is 1 to close the ratio between object V and the amount of substance of indium trichloride:0.01~1:0.5.
6. the preparation method of Rui Gefeini derivatives according to claim 1, which is characterized in that the change described in step (3)
The amount ratio for closing object V and the substance of indium trichloride is 1:0.05,35 DEG C is reacted 2 hours.
7. the preparation method of Rui Gefeini derivatives according to claim 1, which is characterized in that the nothing described in step (4)
Machine alkali is sodium carbonate, potassium carbonate or cesium carbonate, is reacted 8~16 hours at 60~120 DEG C.
8. the preparation method of the Rui Gefeini derivatives according to claim 1 and 7, which is characterized in that described in step (4)
Inorganic base is potassium carbonate, and the ratio between amount of the compounds Ⅳ, compound VI and inorganic alkaloid substance is 1:1:2, reaction temperature 120
DEG C, the reaction time is 16 hours.
9. the preparation method of Rui Gefeini derivatives according to claim 1, which is characterized in that having described in step (5)
Solvent is dichloromethane, 25 DEG C of reaction temperature, 1 hour reaction time.
10. the preparation method of Rui Gefeini derivatives according to claim 1, which is characterized in that anti-described in step (6)
It is 3 hours between seasonable, the reaction temperature is 80 DEG C；Step (7) reaction time is 0.5 hour, and reaction temperature is 25 DEG C；Chemical combination
The ratio between the amount of substance 1 of object Ⅸ, compound Ⅹ:2.5.
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