CN108586330A - A kind of preparation method and applications of tumor - Google Patents
A kind of preparation method and applications of tumor Download PDFInfo
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- CN108586330A CN108586330A CN201810345498.3A CN201810345498A CN108586330A CN 108586330 A CN108586330 A CN 108586330A CN 201810345498 A CN201810345498 A CN 201810345498A CN 108586330 A CN108586330 A CN 108586330A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a kind of preparation method and applications of tumor, the structural formula of the tumor is shown in following formula,
Description
Technical field
The present invention relates to a kind of preparation method and applications of tumor, belong to pharmaceutical technology field.
Background technology
Compound 4- { 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-N- methyl pyrroles
Pyridine -2- formamides, also referred to as Sorafenib, molecular formula C21H16ClF3N4O3, molecular weight 464.83, structural formula be formula 7.,
Sorafenib is the novel signal transduction inhibitor developed jointly by German Bayer and Onxy companies and more targets
Point antitumor drug, it has dual antitumor action：Both it can be passed by the cell signal that RAF/MEK/ERK is mediated by blocking
Guiding path and the proliferation for directly inhibiting tumour cell can also inhibit the formation of new vessels and cut-out swollen by acting on VEGFR
The nutrition supply of oncocyte and achieve the purpose that contain tumour growth.
In December, 2005, Sorafenib was approved by the FDA in the United States listing in the form of its toluene fulfonate, for previously used
Alpha-interferon or IL-2 do not have response or are unsuitable for advanced renal cell carcinoma (RCC) patient of these therapies, trade name
Nexavar；It goes through within 2006 to enter Chinese market；In July, 2006, Sorafenib obtain the listing approval of European Union；2007
Treatment by European Union's approval for hepatocellular carcinoma.
Patent WO2009111061 discloses a kind of synthetic route of Sorafenib, synthetic route reaction step is long, after
Processing is complicated, and the production cycle is long；A large amount of waste liquid is generated, environment is polluted, energy consumption and production cost will be greatly increased.Patent
CN101671299A discloses a kind of preparation method of Sorafenib, and reaction raw materials have used deadly poisonous compound chloro-carbonic acid benzene
Ester, industrial production danger is huge, and unfriendly to environment.Patent WO2009054004 discloses a kind of synthesis side of Sorafenib
Method, this method not only used with the very strong chloro- 3- benzotrifluorides-phenyl esters of isocyanic acid -4- for causing gene mutation toxicity, and
Since reaction needs the highly basic such as potassium tert-butoxide and it is easy to cause the amido bond fracture of intermediate, to influence the yield of product and pure
Degree.Patent CN101082619 discloses a kind of preparation method of Sorafenib, and the reaction time is up to 5 hours, 4- used
The reaction that chloro- 3- trifluoromethylbenzenes based isocyanate carries out excessively acutely is difficult to control.
Invention content
It is an object of the invention to extend 4- { 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino] benzene
Oxygroup }-N- picoline -2- formamides application, especially use it for the application of tumor.
It is an object of the present invention to provide a kind of tumor, under the structural formula of the tumor is
Shown in formula,
The preparation synthetic route of the tumor is：
The preparation method of the tumor is：
(1), chloro- 3- 5-trifluoromethylanilines of 4- into reaction vessel 1. in phosgene is added 2., and organic solvent is added
It with acid binding agent, is sufficiently stirred and keeps to certain temperature, react, it is chloro- to generate 4- chloro- 3- (trifluoromethyl) phenyl-N-1-
Formamide is 3.；
(2), the chloro- formamides of 4- chloro- 3- (trifluoromethyl) phenyl-N-1- for obtaining step (1) 3. with 4-aminophenol
4. mixing, organic solvent is then added and is stirred with acid binding agent, reacts at a certain temperature, waits for stopping after reaction
Stirring, obtaining 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino], phenol is 5.；
(3), phenol is 5. by the 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino] obtained step (2)
(4- hydroxyl -6- bases) pyridine-N- methyl -2- formamides are added, 6. with catalyst, then to be heated, in the case where controlling temperature condition
Etherification reaction occurs, generates 4- { 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-N- methyl
Pyridine-2-carboxamide is 7..
Further, the step (1) and the organic solvent in step (2) are dimethylbenzene, hexane, cyclohexanone, dichloro
Benzene, ethyl alcohol, ether, propyl acetate, espeleton or ethylene glycol mono-ether.
Further, the acid binding agent in the step (1) and step (2) be triethylamine, pyridine, N- methylmorpholines,
Diisopropylethylamine, sodium hydroxide, sodium methoxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate, preferential three second of selection
Amine or potassium carbonate.
Further, the catalyst in the step (3) is sulfuric acid, aromatic sulphonic acid, zinc chloride, aluminium chloride or fluorination
Boron.
Further, the step (1) and the reaction temperature in step (2) are 0~5 DEG C.
Further, the heating temperature in the step (3) is 80 DEG C~150 DEG C.
The chloro- formamides of the chloro- 3- of 4- (trifluoromethyl) phenyl-N-1- 3. the rubbing 4. with 4-aminophenol in the step (2)
You are than being 1：1-2.5；
In the step (3) 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino] phenol 5. with (4- hydroxyls
Base -6- bases) 6. the ratio between amount of substance is 1-2.5 to pyridine-N- methyl -2- formamides:1.
Further, the tumor is tablet, capsule or particle.
Further, the tablet, capsule or particle are prepared by tumour medicine and pharmaceutically acceptable auxiliary material.
It is another object of the present invention to provide a kind of tumors in treatment human lung cancer, Humanmachine tumour and people
Application in fibrosarcoma three classes tumour cell has a good application prospect in terms for the treatment of tumour.
Compared with prior art, the present invention having the advantages that：
(1) preparation method of the present invention enormously simplifies operating procedure, and reaction route is short, stablizes in reaction system,
With good controllability, reaction condition is mild, at low cost, and total recovery is higher, and products obtained therefrom has higher purity.
(2) drug of the present invention can inhibit the growth of tumour cell, help to extend patient's service life, improve the life of patient
Quality has good therapeutic effect to human lung cancer, Humanmachine tumour and human fibrosarcoma.
Specific implementation mode
Present invention is further elaborated in following combination specific embodiment, but these embodiments are illustrative of the invention, and
It should not be construed as any restrictions of the scope of the invention.
Embodiment 1
The preparation method of tumor is：
(1), 1. 2. phosgene is added in (10g, 3.2mol) in chloro- 3- 5-trifluoromethylanilines of 4- into reaction vessel, and
Organic solvent and acid binding agent is added, is sufficiently stirred and keeps to certain temperature, react, generates the chloro- 3- of 4- (trifluoromethyl)
The chloro- formamides of phenyl-N-1- are 3. (19.87g, 4.2mol)；
(2), the chloro- formamides of 4- chloro- 3- (trifluoromethyl) phenyl-N-1- for obtaining step (1) 3. (19.87g,
4.2mol) 4. (31.7g, 5.5mol) is mixed with 4-aminophenol, and organic solvent is then added and is stirred with acid binding agent, one
It reacts under constant temperature degree, waits for stopping stirring after reaction, obtain 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyls
Base) amino] phenol is 5. (44.72g, 6.6mol)；
(3), phenol is 5. by the 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino] obtained step (2)
(4- hydroxyl -6- bases) pyridine-N- methyl -2- formamides 6. (40.5g, 5.25mol) and catalysis is added in (44.72g, 6.6mol)
Then agent is heated, etherification reaction occurs in the case where controlling temperature condition, generates 4- { 4- [({ [4- chloro- 3- (trifluoromethyl) benzene
Base] amino } carbonyl) amino] phenoxy group }-N- picoline -2- formamides are 7. (35.9g, 5.6mol).Yield is 88.9%.
Embodiment 2-9
The proportioning of reaction raw materials influences
Change the proportioning of the reaction raw materials in 1 step of embodiment (2), it is other to remain unchanged, probe into raw material proportioning (4-
The chloro- formamides of chloro- 3- (trifluoromethyl) phenyl-N-1- are 3.：4-aminophenol is 4.) to 4- { 4- [({ [the chloro- 3- of 4- (trifluoromethyl)
Phenyl] amino } carbonyl) amino] phenoxy group } influence of-N- picoline -2- formamides 7..
In conjunction with the embodiments 1 with embodiment 2-9, it is apparent that as 4- chloro- 3- (trifluoromethyl) phenyl-N-1- is chloro-
Formamide is 3.：The molar ratio of 4-aminophenol 4. increases, the conversion of the chloro- formamides of 4- chloro- 3- (trifluoromethyl) phenyl-N-1- 3.
Rate is consequently increased, but this does not imply that the chloro- formamides of 4- chloro- 3- (trifluoromethyl) phenyl-N-1- are 3.：4-aminophenol is 4.
Value be the bigger the better, 4-aminophenol 4. too high levels in raw material, the chloro- formamides of 4- chloro- 3- (trifluoromethyl) phenyl-N-1- are 3.
Conversion ratio can reduce.1 and embodiment 2-9, the selectivity of reaction determine that optimum feed stock mol ratio 4- is chloro- in conjunction with the embodiments
The chloro- formamides of 3- (trifluoromethyl) phenyl-N-1- are 3.：4. 4-aminophenol is 1：1-2.5.
Embodiment 10-16
The influence of temperature
Change the temperature in 1 step of embodiment (3), it is other to remain unchanged, temperature is probed into 4- { 4- [({ [the chloro- 3- of 4-
(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group } influence of-N- picoline -2- formamides 7..
In conjunction with the embodiments 1 with embodiment 10-16, it is apparent that as the temperature increases, 4- { 4- [({ [the chloro- 3- of 4-
(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group } yield of-N- picoline -2- formamides 7. increases therewith, but
This is not meant to temperature, and the higher the better, and temperature is excessively high, 4- { 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) ammonia
Base] phenoxy group } yield of-N- picoline -2- formamides 7. can reduce, if conversely, temperature is too low, 4- { 4- [({ [the chloro- 3- of 4-
(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group } yield of-N- picoline -2- formamides 7. can also reduce.
Drug of the present invention is measured to human lung cancer cell A549, human melanoma cell A375-S2 and people's fiber meat with mtt assay
The inhibited proliferation of oncocyte HT-1080 three classes tumour cells.
(1) attached cell selects the attached tumor cells of exponential phase, after being digested with pancreatin, with containing 10% calf serum
RPMI l640 culture mediums be made into the cell suspension of 5 × 104/ml, be seeded in 96 well culture plates, per 100 μ l of hole, 37 DEG C,
5%CO2 is cultivated for 24 hours.The culture solution for the sample containing various concentration (10~100 μm of olL-1) that experimental group more renews, control
Group then replaces the culture solution containing isometric solvent, and every group sets 3 parallel holes, and 37 DEG C, 5%CO2 cultivates 48h.Liquid is discarded supernatant, is used
PBS is carefully washed 2 times, and the culture medium of the MTT containing 0.5mg/ml of 100 μ l Fresh is added per hole, and 37 DEG C are continued to cultivate 4h.It is small
The heart discards supernatant, and 150 μ l DMSO are added, and after microoscillator mixing 10min, it is close that light is measured at 492nm with microplate reader
Angle value (OD).
(2) suspension cell selects the cell of exponential phase, is made into the RPMI l640 culture mediums containing 10% calf serum
The cell suspension of 1 × 104/ml is seeded in 96 well culture plates, and per 50 μ l of hole, 37 DEG C, 5%CO2 is cultivated for 24 hours.Experimental group is added
The training containing isometric solvent is then added in the 50 μ l of culture solution of sample containing various concentration (10~100 μm of olL-1), control group
Nutrient solution, every group sets 3 parallel holes, and 37 DEG C, 5%CO2 cultivates 48h, is added the MTT's containing 5mg/ml of 10 μ l Fresh per hole
Culture medium, 37 DEG C are continued to cultivate 4h.With three liquid, (SDS10g, 10M HCl0.1mL, isobutanol 5mL, are diluted to distilled water
100mL) 100 μ l are dissolving crystallized, 37 DEG C of incubation 12h.OD value (OD) is measured at 492nm with microplate reader.
Inhibiting rate (Inhibition Rate, IR%) of the drug to Proliferation of Tumor Cells In Vitro is calculated as follows：
IR%=(1-ODsample/ODcontrol) × 100%
Half-inhibition concentration (the IC of drug is calculated with ICP1.0.0 softwares50)。
As a result it see the table below.
The half-inhibition concentration IC of drug of the present invention50Value is lower.In general, IC50Value can be used for weighing drug-induced
The ability of apoptosis, the numerical value is lower, and inducibility is stronger, and the sensitivity of antibody is higher.The above results show drug of the present invention
There is stronger inhibiting effect to the proliferation of tumour cell, to have very well to human lung cancer, Humanmachine tumour and human fibrosarcoma
Therapeutic effect.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of from which, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended right
It is required that rather than above description limit, it is intended that all changes that will be fallen within the meaning and scope of the equivalent requirements of the claims
Change is included within the present invention.Any label in claim should not be considered as and be limited the claims involved.
Based on the embodiments of the present invention, those of ordinary skill in the art are obtained without making creative work
The every other embodiment obtained, shall fall within the protection scope of the present invention.
Claims (10)
1. a kind of tumor, it is characterised in that：The structural formula of the tumor be following formula shown in,
。
2. a kind of preparation method of tumor, it is characterised in that：The preparation synthetic route of the tumor is：
。
3. a kind of preparation method of tumor according to claim 2, it is characterised in that：The treatment tumour medicine
The preparation method of object is：
（1）, chloro- 3- 5-trifluoromethylanilines of 4- into reaction vessel 1. in phosgene is added 2., and organic solvent is added and ties up
Sour agent is sufficiently stirred and keeps to certain temperature, reacts, and generates the chloro- 3- of 4-（Trifluoromethyl）The chloro- formyls of phenyl-N-1-
Amine is 3.；
（2）, by step（1）The obtained chloro- 3- (trifluoromethyls of 4-）3. 4. the chloro- formamides of phenyl-N-1- are mixed with 4-aminophenol
It closes, organic solvent is then added and is stirred with acid binding agent, reacts at a certain temperature, waits for stopping stirring after reaction
It mixes, obtains 4- [({ [the chloro- 3- of 4-（Trifluoromethyl）Phenyl] amino } carbonyl) amino] phenol is 5.；
（3）, by step（2）Obtained 4- [({ [the chloro- 3- of 4-（Trifluoromethyl）Phenyl] amino } carbonyl) amino] 5. phenol is added
（4- hydroxyl -6- bases）Then pyridine-N- methyl -2- formamides are heated, are occurred in the case where controlling temperature condition 6. with catalyst
Etherification reaction generates 4- { 4- [({ [the chloro- 3- of 4-（Trifluoromethyl）Phenyl] amino } carbonyl) amino] phenoxy group }-N- methyl pyrroles
Pyridine -2- formamides 7., i.e. tumor.
4. a kind of preparation method of tumor according to claim 3, it is characterised in that：The step（1）With
Step（2）In organic solvent be dimethylbenzene, hexane, cyclohexanone, dichloro-benzenes, ethyl alcohol, ether, propyl acetate, espeleton
Or ethylene glycol mono-ether；The step（1）With step（2）In acid binding agent be triethylamine, it is pyridine, N- methylmorpholines, two different
Propylethylamine, sodium hydroxide, sodium methoxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate, preferential selection triethylamine or
Potassium carbonate.
5. a kind of preparation method of tumor according to claim 3, it is characterised in that：The step（3）In
Catalyst be sulfuric acid, aromatic sulphonic acid, zinc chloride, aluminium chloride or boron fluoride.
6. a kind of preparation method of tumor according to claim 3, it is characterised in that：The step（1）With
Step（2）In reaction temperature be 0~5 DEG C.
7. a kind of preparation method of tumor according to claim 3, it is characterised in that：The step（3）In
Heating temperature be 80 DEG C~150 DEG C.
8. a kind of preparation method of tumor according to claim 3, it is characterised in that：The step（2）In
Chloro- 3- (the trifluoromethyls of 4-）3. the chloro- formamides of phenyl-N-1- are 1 with the molar ratio of 4-aminophenol 4.：1-2.5；
The step（3）Middle 4- [({ [the chloro- 3- of 4-（Trifluoromethyl）Phenyl] amino carbonyl) amino] and phenol 5. with（4- hydroxyls-
6- bases）6. the ratio between amount of substance is 1-2.5 to pyridine-N- methyl -2- formamides:1.
9. a kind of tumor, it is characterised in that：The tumor is tablet, capsule or particle.
10. a kind of tumor according to claim 1, it is characterised in that：The tumor is being treated
Application in human lung cancer, Humanmachine tumour and human fibrosarcoma's three classes tumour.
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| WO2015051149A1 (en) * | 2013-10-04 | 2015-04-09 | The Trustees Of Columbia University In The City Of New York | Sorafenib analogs and uses thereof |
| CN104945333A (en) * | 2014-03-27 | 2015-09-30 | 沈阳药科大学 | Perilla alcohol analogs, and preparation and application thereof |
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2018
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009034308A2 (en) * | 2007-09-10 | 2009-03-19 | Cipla Limited | Process for the preparation of a raf kinase inhibitor and intermediates for use in the process |
| CN102190616A (en) * | 2010-03-18 | 2011-09-21 | 苏州泽璟生物制药有限公司 | Method and process for synthesizing and producing deuterated omega-diphenyl urea |
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