CN109053597A - A kind of inflammation inhibiting compound and preparation method thereof - Google Patents
A kind of inflammation inhibiting compound and preparation method thereof Download PDFInfo
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- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
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Abstract
The present invention relates to inflammation inhibiting compounds shown in a kind of following formula (7):Wherein, R1‑R3It is each independently selected from H, halogen, C1‑C6Alkyl, halogenated C1‑C6Alkyl, C1‑C6Alkoxy or halogenated C1‑C6Alkoxy, the compound have apparent inflammation inhibitory effect, have good Research Prospects and application potential in drug field.The preparation method of the compound is additionally provided, the preparation method obtains the compound using raw material simple and easy to get as reactant, by three-step reaction, has a good application prospect and researching value.
Description
Technical field
The present invention relates to a kind of nitrogenous fused ring compounds and preparation method thereof, relate more particularly to a kind of inflammation inhibition chemical combination
Object and preparation method thereof belongs to organic chemical synthesis field.
Background technique
Nitrogen-containing heterocycle compound generally all has certain bioactivity and peculiar property, thus in medicine, pesticide, organic
It shines and has a wide range of applications in equal fields and Research Prospects.
As one kind of nitrogen-containing heterocycle compound, quinazoline compounds are widely present in a variety of natural products, and are led to
Often with having good bioactivity, such as weeding, sterilization, desinsection, antiviral, desinsection, antiviral, anti-inflammatory, anti-hypertension, anti-convulsion
Contraction, antitumor, anti-malarial and treating tuberculosis, are furthermore also applied to organic light emission technical field, thus in medicine, agricultural, metallurgy
Good application prospect and potentiality are suffered from Deng all multiple fields.
So far, scientist has found a variety of specific target spot applications of the analog derivative in therapy field, for
A variety of disease causative agents have excellent inhibiting effect.Such as in the prior art it has been found that 2- trichloromethyl -4- arylthio quinoline
Oxazoline derivative has good anti-malarial activity (see Bioorg.Med.Chem.Lett., 21, p 6003-6006,2011
Year), and some 4- heteroarylthio quinazoline derivants have antiproliferative activity (see Bioorg.Med. in certain cancer cells
Chem.Lett., 17, p 2193-2196,2007), certain quinazoline compounds are to EGF-R ELISA (EGFR)
There is very strong inhibiting effect with tyrosine kinase (EGFR-TK), can be used for anticancer.More there are many quinazoline compounds as medicine
Object list marketing, such as hypotensor prazosin, diuretics formic acid quinazolone, anti-intestinal cancer medicine Raltitrexed, Anti-Malarial
Orixine, anticancer drug Gefitinib, germ killing drugs the third oxygen quinoline etc..
Broad application prospect and potential treatment effect just because of quinazoline compounds, the conjunction of respective compound
At the research hotspot and emphasis for seeking to have become already with research organic chemical synthesis with novel quinazoline quinoline class compound.
For example, the preparation method of 2- aryl-quinazoline class compound can be divided into two classes according to the difference of reaction condition: the
One kind is the catalysis annulation that metal participates in, and is mainly used as catalyst using transition metal palladium, copper etc., makes organic amine and phase
The aromatic aldehyde or amide compound cyclization answered form.Second class is then using strong oxidizer such as DDQ, MnO2, the deoxidations such as NaClO
Cyclization.
For another example:
CN103242299A discloses following novel quinazoline quinoline derivant, preparation method and its in organic electroluminescent
Purposes:
Above-mentioned two compound is to pass through Ullman reaction and carbazole and two by 2- (4- bromobenzene) -4- phenylquinazoline respectively
Aniline reaction and obtain.
Rupam Sarma et al. (" Microwave-promoted efficient synthesisi of
Dihydroquinazolines ", Green Chemistry, 2011,13,718-722) it reports under microwave-assisted, adjacent ammonia
Base arone, aldehyde and urea one react, so that the method for obtaining quinazoline compound, reaction equation are as follows:
2010, Fu et al. was that reaction substrate has synthesized 2- using more economical amide with Liv Ullmann coupling reaction model
Substituted quinazoline compounds, reaction equation are as follows:
Dan Zhao et al. (" Potassium iodide-catalyzed three-component synthesis of
2-arylauinazolines via amination of benzylic of C-H bonds of methylarenes ",
Advanced Synthesis&Catalysis, 2015,357,339-344) in disclose one kind quinoline prepared by adjacent amino aromatic aldehyde
The method of isoxazoline compound, reaction equation are as follows:
CN102321075B, which is disclosed, to be reacted by formula (II) compound with formula (III), then again with imidazoles in solid carbonic acid
The method reacted under potassium catalysis and prepare following logical formula (I) quinazoline derivant:
CN103113311A discloses the preparation method of 2- aryl-quinazoline or 2- heteroaryl quinazoline compounds, the side
Method reacts aryl aldehyde or heteroaryl aldehyde with anthranilamide, obtains 2- arylquinazolinethione or 2- heteroaryl quinoline azoles
Then quinoline ketone obtains 2- aryl-quinazoline by reduction or 2- heteroaryl quinazoline, reaction equation is as follows:
Wu Zhang et al. (" Synthesis of quinazolines via CuO nanoparticles
Catalyzed aerobic oxidative coupling of aromatic alcohols and amidines ",
Organic&Biomolecular Chemistry, 2014,12,5752-5756) report the quinazoline chemical combination of copper oxide catalyzation
The synthetic method of object, reaction equation are as follows:
Wang et al. uses I2/ TBHP is synthesized as oxidation system using 2- aminobenzophenone and benzylamine as raw material
Disubstituted quinazoline compound, reaction equation are as follows:
It as described above, disclosing the quinazoline compound and its synthetic method of various new in the prior art, but is terrible
To the more, quinazoline compound with pharmaceutical activity and its synthetic method is studied, still there are still continue to grind
The necessity studied carefully and explored, this is also one of research hotspot and emphasis in technical field of organic synthesis.
Summary of the invention
In order to seek the novel quinazoline compound and preparation method thereof with pharmaceutical activity, the present inventor is to this progress
Further investigation, after having paid a large amount of creative works, so as to complete the present invention.
Specifically, first aspect, technical solution of the present invention and content are related to a kind of suppression of inflammation shown in following formula (7)
Produced compounds:
Wherein, R1-R3It is each independently selected from H, halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy is halogenated
C1-C6Alkoxy.
In the compound of the invention, the halogen is halogen, may be, for example, F, Cl, Br or I.
In the compound of the invention, the C1-C6The meaning of alkyl refer to straight chain with 1-6 carbon atom or
Branched alkyl may be, for example, methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, tertiary fourth in non-limiting manner
Base, n-pentyl, isopentyl or n-hexyl etc..
In the compound of the invention, the C1-C6The meaning of alkoxy refers to the C with above-mentioned implication1-C6Alkane
The group that base obtains after being connected with oxygen atom.
In the compound of the invention, the halogenated C1-C6The meaning of alkyl refer to halogen with above-mentioned implication with
The C of above-mentioned implication1-C6The group that alkyl obtains after being connected.
In the compound of the invention, the halogenated C1-C6The meaning of alkoxy refers to the halogen with above-mentioned implication
With above-mentioned implication volume C1-C6The group that alkoxy obtains after being connected.
Formula (7) the inflammation inhibiting compound is a kind of completely new compound, because having quinazoline ring and active group
Amino, to subsequent can synthesize more quinazoline compounds as described in above-mentioned " background technique ", be led in multiple technologies
Domain has good application and development potentiality and researching value.And by the present inventor's the study found that the compound and centre
Body compound has apparent inflammation inhibitory effect, has good Research Prospects and application potential in drug field.
The second aspect, technical solution of the present invention and content are related to the preparation side of the formula (7) inflammation inhibiting compound
The route of method, the preparation method is as follows:
Wherein, R1-R3It is as defined above, this is no longer going to repeat them；X is halogen, and the meaning for being somebody's turn to do " halogen " refers to halogen family member
Element non-exclusively may be, for example, F, Cl, Br or I.
The preparation method includes the following steps:
S1: above formula (1) compound and above formula (2) compound in organic solvent, are reacted in the presence of potassium carbonate, instead
It is post-treated after answering, obtain above formula (3) compound；
S2: in organic solvent, in palladium catalyst, organic ligand and acid additives effect under, above formula (3) compound and
Above formula (4) compound is reacted, post-treated after reaction and obtain the formula (5) compound；
S3: above formula (5) and above formula (6) compound in organic solvent, are reacted in the presence of potassium carbonate, and reaction terminates
By post-processing, above formula (7) compound is obtained.
It is further described in the following, detailed to each technical characteristic progress in each step, it is specific as follows.
[step S1]
In step sl, the organic solvent is dimethyl sulfoxide (DMSO).
Wherein, the dosage of the organic solvent there is no stringent restrictions, those skilled in the art can be according to the actual situation
It carries out suitably selection and determines, such as its dosage size is no longer carried out detailed herein with facilitating reaction progress and post-processing
Thin description.
In step sl, the molar ratio of formula (1) compound and the formula (2) compound is 1:0.5-1.5, such as
It can be 1:0.5,1:1 or 1:1.5.
In step sl, the molar ratio of formula (1) compound and potassium carbonate be 1:2-3, may be, for example, 1:2,1:2.5 or
1:3。
In step sl, reaction temperature is 80-120 DEG C, may be, for example, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C or 120 DEG C.
In step sl, the reaction time is 8-16 hours, be may be, for example, 8 hours, 10 hours, 12 hours, 14 hours or 16
Hour.
In step sl, after reaction the post-processing is specific as follows: after reaction, reaction mixture being poured into
It in water, and is extracted with ethyl acetate twice, merges organic phase, be washed with water and use anhydrous Na2SO4It is dry, vacuum distillation, by institute
Residue is obtained by silica gel flash column chromatography (using the mixture of the methylene chloride of volume ratio 50:1 and ethyl acetate as elution
Agent) it is eluted, it collects eluent and evaporates removing eluant, eluent, to obtain above formula (3) compound.
Wherein, in the silica gel flash column chromatography purification process, suitable elution can be determined by TLC tracing and monitoring
Terminal.
[step S2]
In step s 2, the palladium catalyst is acid chloride (Pd (OAc)2), palladium acetylacetonate (Pd (acac)2), chlorination
Palladium, tris(dibenzylideneacetone) dipalladium (Pd2(dba)3) or palladium trifluoroacetate (Pd (TFA)2) in any one, most preferably
Acid chloride (Pd (OAc)2)。
In step s 2, the organic ligand is any one in following formula L1-L6,
The organic ligand is most preferably L1.
In step s 2, the acid additives are p-methyl benzenesulfonic acid monohydrate, acetic acid, trifluoroacetic acid, benzoic acid, first
Any one in alkyl sulfonic acid, trifluoromethayl sulfonic acid or camphorsulfonic acid, preferably p-methyl benzenesulfonic acid monohydrate or camphorsulfonic acid,
Most preferably p-methyl benzenesulfonic acid monohydrate.
In step s 2, the organic solvent be tetrahydrofuran (THF), n,N-Dimethylformamide (DMF), dimethyl it is sub-
Any one in sulfone (DMSO), ethyl alcohol, Isosorbide-5-Nitrae-dioxane, methylene chloride, hexamethylene or toluene, preferably toluene, dichloro
Methane or hexamethylene, most preferably toluene.
Wherein, the dosage of the organic solvent there is no stringent restrictions, those skilled in the art can be according to the actual situation
It carries out suitably selection and determines, such as its dosage size is no longer carried out detailed herein with facilitating reaction progress and post-processing
Thin description.
In step s 2, the molar ratio of formula (3) compound and the formula (4) compound is 1:1.5-2.5, such as
It can be 1:1.5,1:2 or 1:2.5.
In step s 2, the molar ratio of formula (3) compound and the palladium catalyst is 1:0.02-0.1, such as can
For 1:0.02,1:0.04,1:0.06,1:0.08 or 1:0.1.
In step s 2, the molar ratio of formula (3) compound and the organic ligand is 1:0.05-0.15, such as can
For 1:0.05,1:0.1 or 1:0.15.
In step s 2, the molar ratio of formula (3) compound and the acid additives is 1:8-12, be may be, for example,
1:8,1:10 or 1:12.
In step s 2, reaction temperature is 70-90 DEG C, may be, for example, 70 DEG C, 80 DEG C or 90 DEG C in non-limiting manner.
In step s 2, the reaction time, there is no particular limitation, such as can detect the residual of raw material by liquid chromatogram or TLC
Allowance is how many and determines the suitable reaction time, may be, for example, 16-28 hours, and for example, 16 hours in non-limiting manner, 20 small
When, 24 hours or 28 hours.
In step s 2, the post-processing after reaction can be specific as follows: after reaction, by reaction system nature
It is cooled to room temperature, is washed with unsaturated carbonate aqueous solutions of potassium, add ethyl acetate extraction three times, merge organic phase, use is anhydrous
Na2SO4Dry, vacuum distillation, residue is by silica gel flash column chromatography (with the petroleum ether of volume ratio 16:1 and ethyl acetate
Mixture is as eluant, eluent) it is eluted, it collects eluent and evaporates removing eluant, eluent, to obtain above formula (5) compound.
Wherein, in the silica gel flash column chromatography purification process, suitable elution can be determined by TLC tracing and monitoring
Terminal.
[step S3]
In step s3, the organic solvent is methylene chloride.
Wherein, the dosage of the organic solvent there is no stringent restrictions, those skilled in the art can be according to the actual situation
It carries out suitably selection and determines, such as its dosage size is no longer carried out detailed herein with facilitating reaction progress and post-processing
Thin description.
In step s3, the molar ratio of formula (5) compound and the formula (6) compound is 1:0.8-1.2, such as
It can be 1:0.8,1:1 or 1:1.2.
In step s3, the molar ratio of formula (5) compound and potassium carbonate be 1:0.8-1.2, may be, for example, 1:0.8,
1:1 or 1:1.2.
In step s3, reaction temperature is room temperature.
In step s3, the reaction time is 3-7 hours, be may be, for example, 3 hours, 4 hours, 5 hours, 6 hours or 7 hours.
In step s3, after reaction the post-processing is specific as follows: after reaction, by reaction mixture water
Washing, and be extracted twice with enough ethyl acetate, merge organic phase, is washed with water and uses anhydrous Na2SO4It is dry, vacuum distillation,
By gained residue by silica gel flash column chromatography (using the mixture of the petroleum ether of volume ratio 8:1 and ethyl acetate as elution
Agent) it is eluted, it collects eluent and evaporates removing eluant, eluent, to obtain above formula (7) compound.
Wherein, in the silica gel flash column chromatography purification process, suitable elution can be determined by TLC tracing and monitoring
Terminal.
As described above, the present invention provides a kind of described formula (7) inflammation inhibiting compound and preparation method thereof, the chemical combination
Object is a kind of completely new compound, can the subsequent more quinoline azoles of synthesis with quinazoline ring and active group amino etc.
Quinoline class compound, and the compound and its intermediate have apparent inflammation inhibitory effect, so that multiple technical fields have
Good application and development potentiality and researching value.
Detailed description of the invention
Attached drawing 1 is inhibitory effect figure of the compounds of this invention K1-K2 to IL-6.
Specific embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes and mesh of these exemplary embodiments
Be only used to enumerate the present invention, any type of any restriction not is constituted to real protection scope of the invention, it is more non-to incite somebody to action this
The protection scope of invention is confined to this.
Embodiment 1
Reaction route are as follows:
Specifically comprise the following steps:
S1: in the appropriate organic solvent dimethyl sulfoxide (DMSO) into reaction vessel, 100mmol above formula (1) is added and changes
Object, 50mmol above formula (2) compound and 300mmol potassium carbonate are closed, is stirred to react at 80 DEG C 16 hours；
After reaction, reaction mixture is poured into water, and be extracted with ethyl acetate twice, merged organic phase, use water
It washs and uses anhydrous Na2SO4It is dry, vacuum distillation, by gained residue by silica gel flash column chromatography (with volume ratio 50:1's
The mixture of methylene chloride and ethyl acetate is as eluant, eluent) it is eluted, it collects eluent and evaporates removing eluant, eluent, thus
Obtain above formula (3) compound for white solid, yield 96.1%.
1H NMR(500MHz,DMSO-d6) δ 8.46 (s, 1H), 8.24 (d, J=8Hz, 1H), 8.12 (d, J=7.5Hz,
1H), 7.93-7.98 (m, 2H), 7.86 (d, J=8Hz, 1H), 7.75-7.82 (m, 2H), 7.66 (t, J=7.5Hz, 1H).
S2: at room temperature, 100mmol above formula (3) compound, 150mmol above formula (4) are added into appropriate organic solvent toluene
Compound, 10mmol acid chloride, 5mmol organic ligand L1 and 1200mmol p-methyl benzenesulfonic acid monohydrate, then stirring heating
It is stirred to react 28 hours to 70 DEG C and at such a temperature；
After reaction, it by reaction system cooled to room temperature, is washed with unsaturated carbonate aqueous solutions of potassium, adds acetic acid
Ethyl ester extracts three times, merges organic phase, uses anhydrous Na2SO4It is dry, vacuum distillation, residue by silica gel flash column chromatography (with
The petroleum ether of volume ratio 16:1 and the mixture of ethyl acetate are as eluant, eluent) it is eluted, it collects eluent and evaporates removing
Eluant, eluent is named as K1, yield 89.5% to obtain above formula (5) compound for yellow solid.
Fusing point: 147-148 DEG C.
1H NMR(500MHz,DMSO-d6) δ 8.56 (d, J=8.5Hz, 1H), 8.11 (d, J=8.5Hz, 1H), 8.02
(d, J=8.5Hz, 1H), 7.97 (t, J=7.5Hz, 1H), 7.84-7.86 (m, 2H), 7.61-7.65 (m, 4H), 7.49 (s,
2H), 7.20 (t, J=8.5Hz, 1H), 6.87 (d, J=8.5Hz, 1H), 6.64 (t, J=7.5Hz, 1H).
S3: in the appropriate organic solvent dichloromethane into reaction vessel, addition 100mmol above formula (5) compound,
Reaction 3 hours is stirred at room temperature in 80mmol above formula (6) compound and 120mmol potassium carbonate；
After reaction, reaction mixture is washed with water, and is extracted twice with enough ethyl acetate, merge organic phase,
It is washed with water and uses anhydrous Na2SO4It is dry, vacuum distillation, by gained residue by silica gel flash column chromatography (with volume ratio 8:1
Petroleum ether and ethyl acetate mixture as eluant, eluent) eluted, collect eluent simultaneously evaporate removing eluant, eluent, thus
Above formula (7) compound for faint yellow solid is obtained, K2, yield 98.6% are named as.
Fusing point: 188-189 DEG C.
1H NMR(500MHz,DMSO-d6)δ13.52(s,1H),8.77-8.81(m,2H), 8.09-8.15(m,3H),
7.97 (d, J=7.5Hz, 2H), 7.89 (d, J=7Hz, 2H), 7.79 (t, J=7.5Hz, 1H), 7.60-7.71 (m, 5H),
7.49 (t, J=8Hz, 2H), 7.33 (t, J=7.5 Hz, 1H).
Embodiment 2
Reaction route is the same as embodiment 1.
Specifically comprise the following steps:
S1: in the appropriate organic solvent dimethyl sulfoxide (DMSO) into reaction vessel, formula (1) described in 100mmol is added
(2) compound of formula described in compound, 150mmol and 200mmol potassium carbonate are stirred to react 8 hours at 120 DEG C；
After reaction, reaction mixture is poured into water, and be extracted with ethyl acetate twice, merged organic phase, use water
It washs and uses anhydrous Na2SO4It is dry, vacuum distillation, by gained residue by silica gel flash column chromatography (with volume ratio 50:1's
The mixture of methylene chloride and ethyl acetate is as eluant, eluent) it is eluted, it collects eluent and evaporates removing eluant, eluent, thus
Obtain the formula (3) compound for white solid, yield 95.8%.
Formula (3) compound of nuclear-magnetism characterize data with 1 step S1 of embodiment.
S2: at room temperature, formula (3) compound described in 100mmol is added into appropriate organic solvent toluene, described in 250mmol
Formula (4) compound, 2mmol acid chloride, 15mmol organic ligand L1 and 800mmol p-methyl benzenesulfonic acid monohydrate, are then stirred
It is warming up to 90 DEG C and is stirred to react at such a temperature 16 hours；
After reaction, it by reaction system cooled to room temperature, is washed with unsaturated carbonate aqueous solutions of potassium, adds acetic acid
Ethyl ester extracts three times, merges organic phase, uses anhydrous Na2SO4It is dry, vacuum distillation, residue by silica gel flash column chromatography (with
The petroleum ether of volume ratio 16:1 and the mixture of ethyl acetate are as eluant, eluent) it is eluted, it collects eluent and evaporates removing
Eluant, eluent, to obtain the formula (5) compound for yellow solid, yield 88.9%.
Fusing point is with nuclear-magnetism characterize data with formula (5) compound of 1 step S2 of embodiment.
S3: in the appropriate organic solvent dichloromethane into reaction vessel, formula (5) compound described in addition 100mmol,
Reaction 7 hours is stirred at room temperature in (6) compound of formula described in 120mmol and 80mmol potassium carbonate；
After reaction, reaction mixture is washed with water, and is extracted twice with enough ethyl acetate, merge organic phase,
It is washed with water and uses anhydrous Na2SO4It is dry, vacuum distillation, by gained residue by silica gel flash column chromatography (with volume ratio 8:1
Petroleum ether and ethyl acetate mixture as eluant, eluent) eluted, collect eluent simultaneously evaporate removing eluant, eluent, thus
Obtain the formula (7) compound for faint yellow solid, yield 98.8%.
Fusing point is with nuclear-magnetism characterize data with formula (7) compound of 1 step S3 of embodiment.
Embodiment 3
Reaction route is the same as embodiment 1.
Specifically comprise the following steps:
S1: in the appropriate organic solvent dimethyl sulfoxide (DMSO) into reaction vessel, formula (1) described in 100mmol is added
(2) compound of formula described in compound, 100mmol and 250mmol potassium carbonate are stirred to react 12 hours at 100 DEG C；
After reaction, reaction mixture is poured into water, and be extracted with ethyl acetate twice, merged organic phase, use water
It washs and uses anhydrous Na2SO4It is dry, vacuum distillation, by gained residue by silica gel flash column chromatography (with volume ratio 50:1's
The mixture of methylene chloride and ethyl acetate is as eluant, eluent) it is eluted, it collects eluent and evaporates removing eluant, eluent, thus
Obtain the formula (3) compound for white solid, yield 96.4%.
Formula (3) compound of nuclear-magnetism characterize data with 1 step S1 of embodiment.
S2: at room temperature, formula (3) compound described in 100mmol is added into appropriate organic solvent toluene, described in 200mmol
Formula (4) compound, 6mmol acid chloride, 10mmol organic ligand L1 and 1000mmol p-methyl benzenesulfonic acid monohydrate, are then stirred
It is warming up to 80 DEG C and is stirred to react at such a temperature 22 hours；
After reaction, it by reaction system cooled to room temperature, is washed with unsaturated carbonate aqueous solutions of potassium, adds acetic acid
Ethyl ester extracts three times, merges organic phase, uses anhydrous Na2SO4It is dry, vacuum distillation, residue by silica gel flash column chromatography (with
The petroleum ether of volume ratio 16:1 and the mixture of ethyl acetate are as eluant, eluent) it is eluted, it collects eluent and evaporates removing
Eluant, eluent, to obtain the formula (5) compound for yellow solid, yield 89.4%.
Fusing point is with nuclear-magnetism characterize data with formula (5) compound of 1 step S2 of embodiment.
S3: in the appropriate organic solvent dichloromethane into reaction vessel, formula (5) compound described in addition 100mmol,
Reaction 5 hours is stirred at room temperature in (6) compound of formula described in 100mmol and 100mmol potassium carbonate；
After reaction, reaction mixture is washed with water, and is extracted twice with enough ethyl acetate, merge organic phase,
It is washed with water and uses anhydrous Na2SO4It is dry, vacuum distillation, by gained residue by silica gel flash column chromatography (with volume ratio 8:1
Petroleum ether and ethyl acetate mixture as eluant, eluent) eluted, collect eluent simultaneously evaporate removing eluant, eluent, thus
Obtain the formula (7) compound for faint yellow solid, yield 98.9%.
Fusing point is with nuclear-magnetism characterize data with formula (7) compound of 1 step S3 of embodiment.
Some technical characteristics in step S2 are investigated below, to carry out creative choosing to most preferably condition
It selects, it is specific as follows.
The investigation of technical characteristic in step S2
The investigation of catalyst
Comparative example S201-S203: except the catalyst acetic acid palladium in step S2 is replaced with palladium acetylacetonate (Pd respectively
(acac)2) outside, other operations are constant, to repeat to implement embodiment 1-3, sequentially obtain comparative example S201-S203.
Comparative example S204-S206: in addition to the catalyst acetic acid palladium in step S2 is replaced with palladium chloride respectively, other operations
It is constant, to repeat to implement embodiment 1-3, sequentially obtain comparative example S204-S206.
Comparative example S207-S209: except the catalyst acetic acid palladium in step S2 is replaced with three (dibenzalacetones) respectively
Two palladium (Pd2(dba)3) outside, other operations are constant, to repeat to implement embodiment 1-3, sequentially obtain comparative example S207-
S209。
Comparative example S210-S212: except the catalyst acetic acid palladium in step S2 is replaced with palladium trifluoroacetate (Pd respectively
(TFA)2) outside, other operations are constant, to repeat to implement embodiment 1-3, sequentially obtain comparative example S210-S212.
As a result it see the table below 1 (the wherein yield that products collection efficiency refers to compound (5) in step S2).
Table 1
Wherein, each comparative example and products collection efficiency have corresponding corresponding relationship, for example, with regard to comparative example S201-S203 and
Speech, the products collection efficiency of S201 is 52.4%, the products collection efficiency of S202 is 52.9% and the products collection efficiency of S203 is 52.3%, remaining
And such statement in following table also has similar corresponding relationship, this is no longer going to repeat them.
It can be seen that change slightly all can lead to significantly changing in effect for the catalyst in step S2,
Such as when for palladium trifluoroacetate, although similar with acid chloride height, its yield still has significant decrease.This proves that catalyst exists
Selection in type has the unobviousness in unpredictability and effect.
The investigation of organic ligand
In addition to the other organic ligands for respectively replacing with organic ligand L1 in the following table 2, other operations are constant, thus weight
Embodiment 1-3 is implemented again, and used organic ligand, embodiment corresponding relationship and products collection efficiency see the table below 2 (wherein product productions
Rate refers to the yield of compound (5) in step S2).
Table 2
It can be seen that for organic ligand, most preferably L1, and other organic ligands have significant drop in effect
It is low；It can also be seen that even using very similar L2-L3, effect is also significantly reduced, and L5 is even unable to get
Product, it is obvious that this, which proves that the selection of organic ligand is not,.
The investigation of acid additives
Comparative example S219-S221: other in addition to the p-methyl benzenesulfonic acid monohydrate in step S2 is replaced with acetic acid respectively
Operation is constant, to repeat to implement embodiment 1-3, sequentially obtains comparative example S219-S221.
Comparative example S222-S224: in addition to the p-methyl benzenesulfonic acid monohydrate in step S2 is replaced with trifluoroacetic acid respectively,
Other operations are constant, to repeat to implement embodiment 1-3, sequentially obtain comparative example S222-S224.
Comparative example S225-S227: in addition to the p-methyl benzenesulfonic acid monohydrate in step S2 is replaced with benzoic acid respectively,
Its operation is constant, to repeat to implement embodiment 1-3, sequentially obtains comparative example S225-S227.
Comparative example S228-S230: in addition to the p-methyl benzenesulfonic acid monohydrate in step S2 is replaced with Loprazolam respectively,
Other operations are constant, to repeat to implement embodiment 1-3, sequentially obtain comparative example S228-S230.
Comparative example S231-S233: except the p-methyl benzenesulfonic acid monohydrate in step S2 is replaced with fluoroform sulphur respectively
Sour outer, other operations are constant, to repeat to implement embodiment 1-3, sequentially obtain comparative example S231-S233.
Comparative example S234-S236: in addition to the p-methyl benzenesulfonic acid monohydrate in step S2 is replaced with camphorsulfonic acid respectively,
Other operations are constant, to repeat to implement embodiment 1-3, sequentially obtain comparative example S234-S236.
As a result 3 (the wherein yields that products collection efficiency refers to compound (5) in step S2) be see the table below.
Table 3
Product is not detected in NR expression.
It can be seen that change slightly all can lead to significant in effect for the acid additives in step S2
Change, such as when for benzoic acid, although similar with p-methyl benzenesulfonic acid monohydrate height, but still is unable to get product.This card
Selection of the bright acid additives in type has the unobviousness in unpredictability and effect.
The investigation of organic solvent
In addition to the other organic solvents replaced with organic solvent toluene in the following table 4 respectively, other operations are constant, thus
Repetition implements embodiment 1-3, and used organic solvent, embodiment corresponding relationship and products collection efficiency see the table below 4 (wherein products
Yield refers to the yield of compound (5) in step S2).
Table 4
It can be seen that for organic solvent, most preferably toluene, and other organic solvents have significantly in effect
It reduces, or even is unable to get product, it is obvious that this, which proves that the selection of organic solvent is not,.
Pharmaceutical activity test
Experimentation is as follows:
1, meat soup is configured, specially uses peptone 0.5g, NaCl 0.25g, soluble starch 3g and beef extract 0.15g
Aqua sterilisa is settled to 50ml；
2, by 0.22 μm of membrane filtration of gained meat soup, filtered broth is obtained；
3, to the mouse intraperitoneal injection of the ICR hero mouse of weight 18-22g (being purchased from Wenzhou Medical University's Experimental Animal Center)
5ml meat soup puts to death ICR hero mouse after 72h, isolated primary macrophage；
4, (every hole 5 × 10 is inoculated into six orifice plates after isolated primary cell centrifugation being resuspended5A cell), then every hole
Middle 1640 complete medium (Gibco) of addition 2ml, by cell culture volumetric concentration be 5%CO2, 37 DEG C of cell incubator
In；
5,4-6 hours after cell is adherent, 1640 fresh culture mediums are replaced；
6, after cell adherent 24 hours, 1640 fresh culture mediums are replaced again, the compounds of this invention, which is added, in every hole makes it
Concentration is 10nM, and then adding lipopolysaccharides LPS (purchased from Sigma-Aldrich) makes its concentration 0.5mg/ml, continues to cultivate
24 hours；
7, cell culture medium is collected, according to the mouse IL-6 enzyme linked immunosorbent assay (ELISA) for being purchased from eBioscience Inc
(ELISA) the operation instruction operation of kit, the IL-6 measured in culture medium is horizontal, and passes through measurement total protein concentration normalizing
Change, (i.e. ordinate is %) is as a result indicated with the percentage to LPS.
The results are shown in attached figure 1, there it can be seen that the compound of the present invention K2 and midbody compound K1 are for IL-6
With apparent inhibitory effect, wherein the inhibitory effect of K2 will further be better than K1, so that there is superior anti-inflammatory activity,
Drug field has good Research Prospects and application potential.
In conclusion the compound has aobvious the present invention provides a kind of inflammation inhibiting compound and preparation method thereof
The anti-inflammatory activity of work has good Research Prospects and application potential in drug field, and the synthetic method is with simple and easy to get
Raw material is reactant, and the inflammation inhibiting compound is obtained by three-step reaction, is had a good application prospect and researching value.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit protection model of the invention
It encloses.In addition, it should also be understood that, after reading the technical contents of the present invention, those skilled in the art can make the present invention each
Kind change, modification and/or variation, all these equivalent forms equally fall within guarantor defined by the application the appended claims
Within the scope of shield.
Claims (10)
1. inflammation inhibiting compound shown in a kind of following formula (7):
Wherein, R1-R3It is each independently selected from H, halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy or halogenated C1-C6
Alkoxy.
2. the preparation method of formula (7) inflammation inhibiting compound as described in claim 1, the route of the preparation method are as follows:
Wherein, R1-R3Definition with the definition in claim 1, X is halogen；
The preparation method includes the following steps:
S1: above formula (1) compound and above formula (2) compound in organic solvent, are reacted in the presence of potassium carbonate, reaction knot
Shu Houjing post-processing, obtains above formula (3) compound；
S2: in organic solvent, under the effect of palladium catalyst, organic ligand and acid additives, above formula (3) compound and above formula
(4) compound is reacted, post-treated after reaction and obtain the formula (5) compound；
S3: above formula (5) and above formula (6) compound in organic solvent, are reacted in the presence of potassium carbonate, are passed through after reaction
Post-processing, obtains above formula (7) compound.
3. preparation method as claimed in claim 2, it is characterised in that: in step sl, the organic solvent is dimethyl
Sulfoxide (DMSO).
4. such as the described in any item preparation methods of claim 2-3, it is characterised in that: in step sl, formula (1) compound
Molar ratio with the formula (2) compound is 1:0.5-1.5.
5. such as the described in any item preparation methods of claim 2-4, it is characterised in that: in step sl, formula (1) compound
Molar ratio with potassium carbonate is 1:2-3.
6. such as the described in any item preparation methods of claim 2-5, it is characterised in that: in step sl, reaction temperature 80-
120 DEG C, the reaction time is 8-16 hours.
7. such as the described in any item preparation methods of claim 2-6, it is characterised in that: in step s 2, the palladium catalyst is
Acid chloride (Pd (OAc)2), palladium acetylacetonate (Pd (acac)2), palladium chloride, tris(dibenzylideneacetone) dipalladium (Pd2(dba)3)
Or palladium trifluoroacetate (Pd (TFA)2) in any one, most preferably acid chloride (Pd (OAc)2)。
8. such as the described in any item synthetic methods of claim 2-7, it is characterised in that: in step s 2, the organic ligand is
Any one in following formula L1-L6,
The organic ligand is most preferably L1.
9. such as the described in any item preparation methods of claim 2-8, it is characterised in that: in step s 2, the acid additives
For in p-methyl benzenesulfonic acid monohydrate, acetic acid, trifluoroacetic acid, benzoic acid, Loprazolam, trifluoromethayl sulfonic acid or camphorsulfonic acid
Any one, preferably p-methyl benzenesulfonic acid monohydrate or camphorsulfonic acid, most preferably p-methyl benzenesulfonic acid monohydrate.
10. such as the described in any item preparation methods of claim 2-9, it is characterised in that: in step s 2, the organic solvent is
Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl alcohol, 1,4- dioxane, dichloromethane
Any one in alkane, hexamethylene or toluene, preferably toluene, methylene chloride or hexamethylene, most preferably toluene.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1333757A (en) * | 1998-08-28 | 2002-01-30 | 西奥斯股份有限公司 | Quinazoline derivatives as medicaments |
| WO2003097615A1 (en) * | 2002-05-17 | 2003-11-27 | Scios, Inc. | TREATMENT OF FIBROPROLIFERATIVE DISORDERS USING TGF-β INHIBITORS |
| WO2004010929A2 (en) * | 2002-07-25 | 2004-02-05 | Scios, Inc. | METHODS FOR IMPROVEMENT OF LUNG FUNCTION USING TGF-β INHIBITORS |
| WO2006058201A2 (en) * | 2004-11-23 | 2006-06-01 | Reddy Us Therapeutics, Inc. | Heterocyclic and bicyclic compounds, compositions and methods |
| CN1921864A (en) * | 2003-12-24 | 2007-02-28 | 西奥斯公司 | Treatment of malignant gliomas with TGF-beta inhibitors |
-
2018
- 2018-06-14 CN CN201810612770.XA patent/CN109053597B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1333757A (en) * | 1998-08-28 | 2002-01-30 | 西奥斯股份有限公司 | Quinazoline derivatives as medicaments |
| US20030069248A1 (en) * | 1998-08-28 | 2003-04-10 | Sarvajit Chakravarty | Quinazoline derivatives as medicaments |
| WO2003097615A1 (en) * | 2002-05-17 | 2003-11-27 | Scios, Inc. | TREATMENT OF FIBROPROLIFERATIVE DISORDERS USING TGF-β INHIBITORS |
| WO2004010929A2 (en) * | 2002-07-25 | 2004-02-05 | Scios, Inc. | METHODS FOR IMPROVEMENT OF LUNG FUNCTION USING TGF-β INHIBITORS |
| CN1921864A (en) * | 2003-12-24 | 2007-02-28 | 西奥斯公司 | Treatment of malignant gliomas with TGF-beta inhibitors |
| WO2006058201A2 (en) * | 2004-11-23 | 2006-06-01 | Reddy Us Therapeutics, Inc. | Heterocyclic and bicyclic compounds, compositions and methods |
Non-Patent Citations (8)
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