CN108440503A

CN108440503A - The preparation method of the disubstituted quinazoline medicinal compound of the parent nucleus containing triazole

Info

Publication number: CN108440503A
Application number: CN201810314785.8A
Authority: CN
Inventors: 张海英; 周兰兰
Original assignee: Individual
Current assignee: Individual
Priority date: 2018-04-10
Filing date: 2018-04-10
Publication date: 2018-08-24

Abstract

The present invention provides trifluoromethyl shown in a kind of lower formula (I) substitution 2, the 4 disubstituted quinazoline medicinal compounds containing 1,2,3 triazole structure units preparation method,

Description

The preparation method of the disubstituted quinazoline medicinal compound of the parent nucleus containing triazole

Technical field

The present invention provides a kind of disubstituted quinazoline class pharmaceutical intermediate synthetic method, a kind of particularly fluoroform The 2 of the parent nucleus containing triazole of base substitution, 4- disubstituted quinazoline class pharmaceutical synthesis methods belong to organic chemistry filed.

Background technology

Triazole and quinazoline have bioactivity and pharmacological effect as a kind of important nitrogen-containing heterocycle compound, can As the structure fragment of active medicine, in multiple concrete application fields, such as medicine, pesticide and chemical field, which have, widely answers Use foreground.Wherein, quinazoline compounds, which are one kind, has the active nitrogen-containing heterocycle compound of good biological, in antibacterial, resists Scorching, anti-hypertension and anticancer etc. all show excellent activity.Currently, the quinazoline ditosylate salt drug of listing includes：With chest The drug Raltitrexed (Ralitrexed) of thuja acid synzyme (TS) inhibiting effect, antitussive and antiasthmatic medicine, antiallergic tiacrilast (Tiacrilast), the muscle for acting on the wide position of the upper maincenter of spinal cord, and the hyperfunction state of muscle tone being made to alleviate Relaxation medicine afloqualone (Afloqualone)；Hypnotic sedative agent mecloqualone (Mecloqualone) etc..Currently, more and more Compound containing triazole and quinazoline heterocycle is developed and shows with preferable bioactivity and pharmacological effect.Example Such as 4- phenyl -1,2,4- triazoles [4,3-a] quinoline azoles -5 (4 hydrogen) -one be a kind of H1- antihistamines examination (Alagarsamy, V., Arzneimittel Forschung, 2006,56,834-841), pyrazoles [1,5-a] quinazolinone -3- carboxylic acid derivates can be with As anti-inflammatory, antiallergy, anti-parasitic drug (Alexa nder, E.J., US Patent Appl.826163,1978).This two class The synthetic method that compound was reported is, using sulfydryl quinazolinone as key intermediate, and hydration hydrazine reaction, it then proceedes in first Cyclization is heated in acid, obtained 1,2,4- triazole [4,3-a] quinoline azoles -5 (4 hydrogen) -one (Malancona, S. etc., Med.Chem.2010,18,2836-2848).For another example, pass through 2- hydrazino-benzoic acids and N- cyano methylene amides or 2- alkoxies The reaction of methylene malononitrile has respectively obtained -5 (4 hydrogen) -one of 1,2,4- triazoles [4,3-a] quinoline azoles and pyrazoles [1,5-a] quinoline azoles Quinoline ketone -5 (4 hydrogen) -one (Med.Chem.Lett.2009,19,4196-4200).But the above method generally requires multistep reaction, Raw material is not easy to obtain, and substrate application range is restricted.

Find that 4- anilinoquinazolines (PD153035) can be used as the specificity of EGFR tyrosine kinase from Fry in 1994 etc. Since inhibitor, quinazoline compounds become one of the hot spot of tyrosine kinase inhibitor class antineoplastic research and development.There is document Report that 4- anilinoquinazoline class compounds are the active highest found so far, selective best a kind of tyrosine-kinase Enzyme inhibitor.Wherein, 4- substituted anilines quinazoline compounds are that activity is higher in quinazolines tyrosine kinase inhibitor The substitution of a kind of compound, 3 lipophilicity electron-withdrawing groups of 4- anilino-s can increase inhibitory activity, to kinds of tumors such as breast Gland cancer, lung cancer, gastric cancer, prostate cancer all show good antitumor action.There are four small molecules associated therewith at present Drug lists.First generation EGFR inhibitor Gefitinib (Gefitinib) and Erlotinib (Erl otinib) oneself through by the U.S. Food and medicine Surveillance Authority approval treatment non-small cell lung cancer patient.Lapatinib (Lapatinib) is as a kind of two-way Reversible EGFR and HER-2 inhibitor oneself through being approved for the treatment of breast cancer.Vande Thani (Vandetanib) is by me State's independent research was approved in 2011 for treating advanced NSCLC.And all contain in the small-molecule drug of 4 listings identical 4- anilinoquinazoline mother nucleus structures.

Triazole has the stability of aromatic rings and good bio-compatibility, and the pharmacophore of different substrates is passed through three Nitrogen azoles loop chain is connected into as a molecule, and product can improve the binding ability with biological targets by hydrogen bond and dipole effect, Have numerous triazole derivatives and is widely used in clinic as the drugs such as antibacterial, antitumor, anti-inflammatory, anti-hypertension.Separately Outside, 1,2,3- triazoles are can to play a variety of non-covalent interactions due to easily forming hydrogen bond, coordinate bond etc., thus extensively For constructing a plurality of types of functional moleculars such as high molecular material, new catalyst, drug and its supermolecule drug.In recent years, Especially in field of medicaments, 1,2,3-triazoles female ring is widely used in designing novel drugs molecule, and there are many contain 1,2,3- so far The compound of triazole female ring enters clinical trial or has been used for clinic, is related to antibacterium, antimycotic, treating tuberculosis, antiviral, anti- Multiple therapy fields such as tumour, anticoagulation and other angiocardiopathies.Ticagrelor (Ticagrelor) is by AstraZeneca public affairs A kind of novel, selective small molecule anticoagulant of department's research and development and first reversible mating type take orally P2Y12 Adenosine diphosphate receptor antagonists.There is apparent inhibiting effect to platelet aggregation caused by ADP, can effectively improve acute coronary disease The symptom of patient.The molecular structure of Ticagrelor, one of nuclear structure are exactly 1 with pyrimido ring, and 2,3- triazoles are female Ring.The Ticagrelor having disclosed prepares document, although process route and preparation method are varied, core methed is equal It is to grind the various improvement done in technical foundation in the original of Astrazeneca AB.These synthetic routes and method are summarized, finds it It is most of be formerly to build pyrimidine ring on the basis of, then by the amino nitrosation on pyrimidine ring, with another ortho position amino one It rises and forms 1,2,3- triazole female ring structures, Ticagrelor is then prepared.However, the preparation method is excessively cumbersome, cost It is higher, for simplifying the preparation of such compound, especially simplifies 1,2,3- triazole female ring structures of structure, be advantageous to improve Product quality and yield.

In addition, at present studies have reported that, for develop high-efficiency low-toxicity antitumor drug, by triazole and schiff bases biology Active component segment is introduced into respectively in 4- anilinoquinazoline structural units, has synthesized the novel 4- anilino- quinoline azoles containing triazole Quinoline Schiff bases compound, has a wide range of applications in terms of medicine.In China, Wei Jinjian etc. is reported in target molecule It is middle introduce 1,2,3- triazole rings can often improve original drug molecule dissolubility, pharmacodynamics and pharmacokinetic property (《China Pharmaceutical journal》,2011,46,481-485).Ding S. report the work that triazole ring is introduced in target molecule, have obtained very The good compound of more structure novels, active anticancer (《J.Med.Chem.》, 2012,55,10198-10203).

For the compounds process for production thereof containing triazole and quinazoline heterocycle, prepares one of key point and be triazole parent nucleus Structure.There are many seminars to report the synthetic method of 1,2,3- triazoles in recent years, it is most common to prepare 1,2,3 three Nitrogen azoles method is：Terminal Acetylenes hydrocarbon and two component of organic nitrine synthesize 1,2,3- triazoles under the conditions of catalyst (common copper catalysis). For example, by the bromo- 4- triazobenzenes methyl ethers of 2- for antitumor drug combretastatin analog synthesis in (Kristin, Med.Chem.2008,16,4829).

It has been proposed earliest from Huisgen using this method come since synthesizing 1,2,3- triazole compounds, the method is gradual It is used widely, however in most cases, what this method obtained is the mix products of regional isomerism, and is confined to strong Electrophilic alkynes participates in reaction.Later, Fokin and Sharpless reported the azide and terminal alkynes of Cu (I) catalysis Conversion zone selectively synthesize bis- substitution -1,2,3- triazole compounds of 1,4- method (Angew.Chem., Int.Ed.2002,41,2596-259

9.).Wang in 2008 etc. reports the Terminal Acetylenes of bromination copper catalysis and organic nitrine synthesizes 1,4- under the conditions of water phase The nitrogen azoles [Green Chem., 2008,10,452-456] of two substitution -1,2,3- triazoles.A lonso in 2010 etc. are reported The Terminal Acetylenes of Nanometer Copper CuNPs catalysis synthesizes bis- substitution -1,2,3- triazoles of 1,4- under alkaline conditions with organic nitrine (Eur.J.Org.Chem.2010,1875-1884)。

As it can be seen that aryl azide chemical combination object can be synthesized for the new drug of the ring containing triazole and substrate screening provides more choosings It selects.Meanwhile azide increasingly becomes structure triazole especially 1, the important source material of 2,3- triazole compounds.At present The method of 1,2,3- triazoles is synthesized other than the click cycloaddition reactions of copper catalysis, other transition metal such as rhodium, ruthenium, iridium etc. It can also be used for being catalyzed this kind of cycloaddition reaction synthesis 1,2,3- triazole compounds.With currently to sustainable development increasingly Pay attention to, becomes the new issue being widely noticed using 1,2,3- triazole compounds are synthesized without transition metal-catalyzed method. For example, document once reported ketones with Enamino-esters and sulfonyl azide under the conditions of alkali promotes by the fracture of N-N keys in sulfonyl azide and enamine Carbon-to-carbon rupture reaction between carbonyl and α-carbon in ketone generates the method that 1,5- bis- replaces 1,2,3- triazoles (Angew.Chem.Int.Ed.2013,52,13265-13268)。

But at present in the prior art, there is reaction, reaction time mistake in above-mentioned 1,2,3- triazole parent nucleus synthetic methods Long, the shortcomings of cost is higher, and raw material Terminal Acetylenes needs multistep to synthesize, and therefore find a kind of raw material and be easy to get, easy to operate, Environmentally protective method synthesizes 1,2, the 3- triazole compounds especially 4- anilinoquinazoline class compounds containing triazole, Still it is important goal in research.

In addition, since trifluoromethyl can increase the lipophilicity of compound, metabolic stability and bioavilability, therefore Trifluoromethyl is widely used in antiviral, cancer drug development.For the 4- anilinoquinazoline class compounds containing triazole, In conjunction with the structure of triazole, it is necessary to introduce alkyl trifluoromethyl using easy method, avoid Grignard Reagent in the prior art The methods of the organometallic reagent hydrocarbyl lithium that uses.

As described above, although having been disclosed for quinazoline derivant, 1 in the prior art, 2,3- triazole derivatives it is more Kind synthetic method, but for containing quinazoline and 1, the compound synthesis method of 2,3- triazole recombiner units, which especially synchronizes, draws The high-efficiency synthesis method report for entering alkyl trifluoromethyl substituent is few, and there are still the necessity for continuing research, this is also exactly this hair Where the bright purpose being accomplished and power.

Invention content

To overcome prior art defect, contain 1,2,3- triazole knots the present invention provides the substitution of a kind of alkyl trifluoromethyl 2, the 4- disubstituted quinazolines medicinal compound of structure unit and its preparation method of intermediate, to be to find newly antitumor Or antiviral activity compound opens up an efficient synthetic method.

Specifically, the present invention relates to the preparation methods of compounds of Formula I：

Wherein, in the compound of formula I, each substituent group is defined as：

X is H, C1-C6 alkane or the ester group that carbon atom number is 2-6；

R₁It does not take for H, halogen, C1-C6 alkyl, C1-C6 alkoxies, nitro, amino, amide groups, the substitution of C1-C6 alkyl or The C6-C10 aryl in generation, the substituted or unsubstituted C5-C10 heteroaryls containing at least one nitrogen-atoms of C1-C6 alkyl；

R₂For C1-C6 alkyl, C2-C6 ester groups, substitution or unsubstituted C6-C10 aryl or C5-C10 heteroaryls；

N is the positive integer of 1-5；

Ar is phenyl, substituted-phenyl or the substituted or unsubstituted C6-C10 aryl in addition to phenyl or C5-C10 heteroaryls.

Wherein, in the present invention, the C1-C6 alkyl refers to the alkyl for having 1-6 carbon atom, may be, for example, methyl, second Base, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, tertiary butyl, n-pentyl, isopentyl, n-hexyl etc..

The C1-C6 alkoxies refer to then the group after " C1-C6 alkyl " defined above is connected with O atom.

The halogen is F, Cl, Br or I.Wherein, the halogen is preferably fluorine, chlorine or bromine.

In the present invention, the aryl or substituted aryl replaced by aryl known in the art or conventional substituent group that A bit, such as phenyl, tolyl, ethylbenzene, 1- naphthalenes, 2- naphthalenes etc..

In the present invention, the heteroaryl be this field it is common containing N, O, S etc. it is heteroatomic those, it may for example comprise but not It is limited to：Furyl, thienyl, pyrrole radicals, oxazolyls, thiazolyl, imidazole radicals, isoxazolyls, isothiazolyl, pyrazolyl, benzo Furyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazoles base, benzoxazine, benzene And isothiazolyl, indyl, isoindolyl, pyranose, pyridyl group, pyrazinyl, pyrimidine radicals, pyridazinyl, quinolyl, isoquinolin Base, quinoxalinyl, quinazolyl, card oxazolyl, acridinyl, phenazinyl, triazolyl, tetrazole radical, thiadiazoles, pyrrolidinyl, tetrahydrochysene Imidazole radicals, tetrahydro-pyrazole base, piperidyl, morpholinyl, piperazinyl etc..Substituted heteroaryl is the upper of the common group substitution in this field State heteroaryl.

The reaction equation of preparation of compounds of formula I of the present invention is as follows：

Wherein each substituent group is as defined above.

Specifically, the preparation method of compound of formula I of the present invention, includes the following steps：

S1：In organic solvent and in the presence of peroxide radical initiator, organometallic salt catalysts, formula (II) compound replaces with trifluoromethyl iodate alkane, azidotrimethylsilane are reacted, and formula (III) intermediate compound is obtained Object,

S2：Under nitrogen protection in organic solvent, in alkali and in the presence of bis- (2- diphenylphosphines phenyl) ether ligands, formula (III) compound carries out cycloaddition reaction with cycloaddition reagent, to obtain the formula (I) compound；The cycloaddition reagent Selected from β-oxo carboxylic acid's ester or acetylene compound.

Wherein, in the synthetic method of the present invention, formula (II) raw material compound can be commercially available or according to ability Domain conventional synthesis process is made, including but not limited to, can be by the quinoline that alkenyl replaces and aromatic amine compounds Ar-NH2 Heating reaction is made.For example, specifically, 2- alkenyl -4- halogen substituted quinazolines and aniline being added in isopropanol solvent, are warming up to 90-100 DEG C of back flow reaction, TLC detection reactions, waits stopping reaction after the completion of reacting, filter while hot, filter cake is washed with ethyl alcohol, then It is dried in vacuo to obtain solid 2- substituted alkenyl-N- phenyl-quinazoline -4- amine.

In the synthetic method of the present invention, in the step S1, the organic solvent is dichloromethane, toluene, four One or more of hydrogen furans, dioxane, ethyl acetate, acetonitrile or ethers, the preferred ether of ethers, methyl tertiary butyl ether, second Glycol dimethyl ether, Propylene Glycol Dimethyl Ether etc..

In the synthetic method of the present invention, the amount of the organic solvent is not particularly limited, art technology Personnel can select suitable amount according to this field conventional technical means and the control and progress of reaction.

In step sl, the peroxide radical initiator be benzoyl peroxide, peroxidized t-butyl perbenzoate, Benzoyl peroxide tert-butyl acetate, di-t-butyl peroxide, cumyl peroxide, perbenzoic acid, tert-butyl hydroperoxide, Peroxidating propionyl or peroxidating butyryl etc., preferably acyl class or esters peroxide.

In step sl, the organometallic salt catalysts are metal salts of trifluoromethane sulphonic acid or hexafluorophosphoric acid metal salt, gold Belong to and is selected from copper, iron or rare earth metal, preferably trifluoromethanesulfonic acid ferrous iron, copper trifluoromethanesulfcomposite, four acetonitrile copper of hexafluorophosphoric acid.

In the synthetic method of the present invention, as a kind of specific embodiment, step S1 detailed processes are：

Under inert gas protection, by formula (II) compound, iodate hydride compounds, azidotrimethylsilane, peroxide It is 1 in molar ratio with catalyst:1.5-2:2-3:1.5-2.5:The ratio of 0.01-0.05 is dissolved in organic solvent, at 0~60 DEG C At a temperature of be stirred to react 1~6 hour, after reaction, filtering, vacuum distillation, pillar layer separation purify to obtain formula III compound.

Wherein, in above-mentioned steps S1, it is preferable that the reaction temperature is 25-50 DEG C, and the reaction time is 2-4 hours.

The present invention the synthetic method in, in the step S2, the organic solvent be selected from tetrahydrofuran, toluene, It is one or more in DMF, ethyl acetate, chloroform, isopropanol.

In step s 2, the alkali is sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butyl alcohol lithium, sodium tert-butoxide, tertiary fourth It is one or more in potassium alcoholate, n-BuLi, diisopropyl ethyl amine or triethylamine, preferably diisopropyl ethyl amine or three second Amine.

Wherein, in step s 2, when using terminal alkyne compound as cycloaddition reagent, to accelerate the progress of reaction, it is preferable that The cuprous salts such as cuprous iodide, stannous chloride can be added as catalysts.

In the synthetic method of the present invention, in the step S2, reflux time is 2-5 hours, may be, for example, 2 Hour, 2.5 hours, 3 hours.

In the synthetic method of the present invention, as a kind of specific embodiment, step S2 detailed processes are：

Under nitrogen protection, by formula (III) compound, cycloaddition reagent β-oxo carboxylic acid's ester, alkali and bis- (2- diphenylphosphines Phenyl) ether in molar ratio be 1:1-1.5:0.2-0.5:The ratio of 0.01-0.05 is dissolved in organic solvent, heating reflux reaction 2- 5 hours, and handled through refluxing toluene, to obtain the formula (I) compound, the wherein R on triazole unit₂Replace for 5- Base.

In the synthetic method of the present invention, alternatively specific embodiment, step S2 detailed processes are：

Under nitrogen protection, by formula (III) compound, cycloaddition reagent acetylene compound, alkali, cuprous catalysis agent and double (2- diphenylphosphines phenyl) ether is 1 in molar ratio:1-1.5:0.2-0.5:0.5-1:Organic solvent is added in the ratio of 0.01-0.05 In, it is heated to reflux carry out cycloaddition reaction, to obtain the formula (I) compound；Wherein R on triazole unit₂It is taken for 4- Dai Ji.

Preferably, in the synthetic method of the formula (I) compound, product after reaction can be filtered, washed, do After dry, it is further purified using organic solvent recrystallization or silica gel column chromatography refined.

In addition, as another aspect of the present invention, the present invention also provides the Formulas I chemical combination obtained in above-mentioned preparation method Object can be used as antitumor drug precursor or pharmaceutical intermediate compound.

Beneficial effects of the present invention include but not limited to following aspect：

1. provided by the invention, containing quinazoline and 1, the compound synthesis method of 2,3- triazole units, step is short, production Rate is high, and easy to operate, post-processing step is easy routine operation；

2. it is (usual more than ten or even tens small to overcome prior art reaction time length for cycloaddition step in the method for the present invention When) defect, the General reactions time is in 5 hours；

3. the present invention provides the effective ways of 1,2,3- triazoles of 4-, 5- substitutions of high selectivity, simultaneously Also disubstituted product can be synthesized, those skilled in the art can need the substituent group position of 1,2,3- triazole of selection according to actual product It sets, substrate applicability is wide；

4. the method for the present invention, which in the step of synthesizing azido quinazoline intermediate, synchronizes, introduces trifluoromethyl substitution Base, the use for the grignard organometallic reagent for avoiding prior art Poisoning high, raw material is simple, derives from a wealth of sources, and simplifies preparation Flow improves products collection efficiency.

As described above, the present invention provides formula (I) compound synthesis method, the synthetic method is easy to operate, reacts road Line is short, and total recovery is high, achieves good selective product, new synthetic route is provided for the preparation of such compound, There are good application value and potentiality in industry and scientific research.

Meanwhile 2 containing 1,2,3- triazole structure units and trifluoromethyl substituent shown in Formulas I provided by the invention, 4- disubstituted quinazoline analog derivatives open effective way for exploitation new type antineoplastic medicine and other drugs, have good Market application prospect.

Specific implementation mode

Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and Purpose is only used for enumerating the present invention, not constitutes any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action Protection scope of the present invention is confined to this.

Embodiment 1：

It is prepared by azide intermediate product

In tubular reactor, vacuumizes and replaced twice with nitrogen, under nitrogen protection atmosphere, 10ml methyl- terts are added Butyl ether solvent, by formula (II) compound on 1mmol, 2mmol above formula iodate hydride compounds, 2.5mmol azidotrimethylsilanes, 2mmol benzoyl peroxides tert-butyl acetate and four acetonitrile copper catalyst of 0.02mmol hexafluorophosphoric acids are dissolved in above-mentioned solvent, at 30 DEG C At a temperature of be stirred to react 2 hours, after reaction, reaction solution is cooled to room temperature, filtering, vacuum distillation remove solvent, column chromatography Separating-purifying obtains formula III compound, yield 92.7%.IR(KBr)：ν 3329,3050,2961,2904,2870,2811,2732, 2101,1634,1523,1441,1141,875cm^-1。

Embodiment 2:

It is prepared by azide intermediate product

In tubular reactor, vacuumizes and replaced twice with nitrogen, under nitrogen protection atmosphere, bis- chloroethenes of 10ml are added Alkane solvents, iodate hydride compounds, 2.5mmol shown in the compound of formula (II) shown in 1mmol embodiments 1,2mmol embodiments 1 are folded Nitrogen trimethyl silane, 2mmol benzoyl peroxides and 0.02mmol trifluoromethanesulfonic acid ferrous iron catalyst are dissolved in above-mentioned dichloroethanes In solvent, it is stirred to react under ambient temperature 3 hours, after reaction, reaction solution room temperature filtering, vacuum distillation removes solvent, Column chromatography for separation purifies to obtain formula III compound 0.87mmol, yield 87.5%.

Embodiment 3-5：Prepare following formula I triazole product

Embodiment 3

Under nitrogen protection, formula (III) compound, the 1.2mmol benzene first 1mmol above-described embodiments 1 or 2 being prepared Ethyl acetoacetic acid ethyl ester, 0.5mmol sodium tert-butoxides and bis- (the 2- diphenylphosphines phenyl) ethers of 0.05mmol are dissolved in 8ml isopropanol solvents, It is heated to reflux 2.5h, reaction solution is poured into 20ml deionized waters and with concentrated hydrochloric acid tune pH to acidity, unit containing triazole is precipitated Solid intermediate product, triazole unit 4-, 5- replaces by carboxyl, phenyl respectively；Further, by obtained solid mistake Filter washing handles 10-15min after vacuum drying in 10ml reflux in toluene decarboxylations, and vacuum distillation removes toluene, recrystallizes, from And the above-mentioned formula of white solid (I) compound for obtaining 5- substituted 1,2,4-triazole units, wherein R₂The phenyl replaced for 5-, production Produce rate 85.4%,¹³CNMR(100MHz,DMSO,δ,ppm)：δ164.74,157.84,143.89,136.48,136.14, 135.21,133.27,130.46,131.27,129.32,128.81,127.11,126.52,124.98,123.99,121.14, 112.65,52.51,25.51。

Embodiment 4

Under nitrogen protection, formula (III) compound for 1mmol embodiments 1 or 2 being prepared, 1mmol end alkynyl radical chemical combination Object is to Methoxy-phenylacetylene, 0.2mmol diisopropyl ethyl amines, 1mmol cuprous iodides and bis- (the 2- diphenylphosphine benzene of 0.05mmol Base) ether is dissolved in 10ml toluene, is heated to reflux 4.5h, it filters, washing, ethyl alcohol recrystallization after vacuum drying, to obtain 4- Formula (I) compound, wherein R described in the white powder of substituted 1,2,4-triazole unit₂For 4- replace to methoxybenzene, yield 91.2%, m.p.153-155.

Embodiment 5

Under nitrogen protection, 1mmol formulas (III) compound for embodiment 1 or 2 being prepared, 1.5mmol acetylenedicarboxylic acids Diethylester, 0.2mmol triethylamines and bis- (the 2- diphenylphosphines phenyl) ethers of 0.05mmol are dissolved in 10ml toluene, and 90 DEG C are heated to reflux 4h is filtered, and washing recrystallizes after vacuum drying, to obtain the formula (I) compound solid, wherein triazole unit 4,5- Position is replaced by-COOEt, yield 86%, m.p.157-158 DEG C.

Embodiment 6

Except the Formula II compound in embodiment 1 is replaced withExcept, remaining reaction condition is the same as real Example 1, embodiment 4 are applied, R is made₂For the triazole quinazoline compound of 5- phenyl, yield 81.3%, m.p.166-167 ℃；¹³C-NMR(100MHz,DMSO,δ,ppm)：163.42,156.55,142.76,137.94,137.45,135.68, 132.88,129.73,129.40,129.32,128.98,127.92,127.72,125.80,124.20,123.87,122.37, 121.59,121.27,1119.77,111.15,51.50,23.98,20.18。

Embodiment 7

Except the Formula II raw materials of compound in embodiment 6 is replaced withExcept, remaining reaction condition is same R is made in embodiment 6₂For the triazole quinazoline compound of 5- phenyl, product is white solid, yield 87.8%, m.p.162-164℃。

Wherein, the raw materials used preparation of the embodiment is as follows：By 10mmol 2- vinyl -8- Trifluoromethylquinocarboxylics with 10mmol m-anisidines are added in 100ml isopropanol solvents, are warming up to 95 DEG C of back flow reactions, and TLC detection reactions wait reacting Stop reaction after the completion, filters while hot, filter cake is washed with ethyl alcohol, is then dried in vacuo to obtain Formula II raw materials of compound 2- vinyl- N- anisyls -8- trifluoromethyls-quinazoline -4- amine.

Comparative example 1

In addition to bis- (2- diphenylphosphines phenyl) ether ligands in embodiment 3 are removed, reaction time and remaining reaction item Part is constant, implements comparative example 1, products collection efficiency 75.1%.

After the reaction was continued 8 hours, yield is up to 83.4%.

Comparative example 2

In addition to bis- (2- diphenylphosphines phenyl) ether ligands in embodiment 4 are removed, reaction time and remaining reaction item Part is constant, implements comparative example 2, triazole 4- substitution product yields are only 68.2%.

After the reaction was continued 6 hours, yield only up to 75.8%.

It can be seen that bis- (the 2- diphenylphosphines phenyl) ethers of ligand to cycloaddition reaction as co-catalyst in addition to having reaction Except facilitation, also replacing the selection of based products to generate the triazole 4- that end alkynyl radical cycloaddition reagent participates in has significantly Anchoring is helped to act on, to have certain influence to final product selectively substitution, this may be since it coordinates catalyst association With the similar effect for reducing triazole ring 4- substitution reactions position free radical activation energy is played, so as to promote 4- substitution productions Object reacts.

Effect example

Anti tumor activity in vitro is tested:With mtt assay, it is thin that logarithmic phase is collected using human breast cancer cell (MCF-7) cell line Born of the same parents adjust concentration of cell suspension, and 200pl is added per hole, and bed board makes cell to be measured adjust density to 5000/hole.Carbon dioxide 5% lower 37 DEG C of percent by volume is incubated 24 hours, until cell monolayer is paved with bottom hole, the embodiment 3,4 of 10 concentration gradients is added to change Object is closed, per hole 200pl；37 DEG C of incubation 72h, set low-speed oscillation 15min on shaking table.It is measured at enzyme-linked immunosorbent assay instrument 490nm The light absorption value in each hole calculates IC₅₀It is worth (μM), measures 3 compound IC of embodiment₅₀Value is 23.56 ± 1.43,4 compound of embodiment IC₅₀Value is 26.86 ± 1.78.

It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limitation 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 and are protected defined by the application the appended claims Within the scope of shield.

Claims

1. a kind of disubstituted quinazoline compounds of the unit of triazole structure containing 1,2,3- of the substitution of trifluoromethyl shown in following formula I Preparation method,

It is characterised in that it includes following steps：

S1：In organic solvent, in the presence of peroxide radical initiator, organometallic salt catalysts, make formula (II) chemical combination Formula III midbody compound is obtained by the reaction with the iodate alkane of trifluoromethyl substitution, azidotrimethylsilane in object,

S2：Under nitrogen protection in organic solvent, in alkali and in the presence of bis- (2- diphenylphosphines phenyl) ether ligands, formula (III) compound carries out cycloaddition reaction with cycloaddition reagent, to obtain the formula (I) compound；The cycloaddition reagent Selected from β-oxo carboxylic acid's ester or acetylene compound；

Wherein, above-mentioned various substituent group is defined as：

X is H, C1-C6 alkane or the ester group that carbon atom number is 2-6；

R₁It is substituted or unsubstituted for H, halogen, C1-C6 alkyl, C1-C6 alkoxies, nitro, amino, amide groups, C1-C6 alkyl C6-C10 aryl, the substituted or unsubstituted C5-C10 heteroaryls containing at least one nitrogen-atoms of C1-C6 alkyl；

N is the positive integer of 1-5；

2. synthetic method according to claim 1, it is characterised in that：In the step S1, the organic solvent is dichloro One or more of methane, toluene, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile or ethers.

3. synthetic method according to claim 1, it is characterised in that：The peroxide radical initiator is selected from peroxide Change benzoyl, peroxidized t-butyl perbenzoate, benzoyl peroxide tert-butyl acetate, di-t-butyl peroxide, cumyl peroxide, Perbenzoic acid, tert-butyl hydroperoxide, peroxidating propionyl or peroxidating butyryl.

4. synthetic method according to claim 1, it is characterised in that：The organometallic salt catalysts are trifluoromethanesulfonic acid Metal salt or hexafluorophosphoric acid metal salt, metal are selected from copper, iron or rare earth metal；It is preferred that trifluoromethanesulfonic acid is ferrous, trifluoromethanesulfonic acid Copper, four acetonitrile copper of hexafluorophosphoric acid.

5. according to the synthetic method described in claim 1-4, which is characterized in that step S1 detailed processes are：It is protected in inert gas It is 1 in molar ratio by Formula II compound, iodate hydride compounds, azidotrimethylsilane, peroxide and catalyst under shield: 1.5-2:2-3:1.5-2.5:The ratio of 0.01-0.05 is dissolved in organic solvent, and it is small to be stirred to react 1~6 at a temperature of 0~60 DEG C When, after reaction, filtering, vacuum distillation, column chromatography for separation purify to obtain formula III compound.

6. synthetic method according to claim 1, which is characterized in that in step S2, the organic solvent is selected from tetrahydrochysene furan It mutters, is in toluene, DMF, ethyl acetate, chloroform, isopropanol one or more；The alkali be sodium methoxide, potassium methoxide, sodium ethoxide, Potassium ethoxide, tert-butyl alcohol lithium, sodium tert-butoxide, potassium tert-butoxide, n-BuLi, diisopropyl ethyl amine or one kind or more in triethylamine Kind.

7. synthetic method according to claim 1, which is characterized in that in step S2, use terminal alkyne compound for cycloaddition When reagent, to accelerate the progress of reaction, cuprous iodide or stannous chloride is added as catalysts.

8. synthetic method according to claim 1, which is characterized in that step S2 detailed processes are：Under nitrogen protection, will Formula (III) compound, cycloaddition reagent β-oxo carboxylic acid's ester, alkali and bis- (2- diphenylphosphines phenyl) ethers are 1 in molar ratio:1- 1.5:0.2-0.5:The ratio of 0.01-0.05 is dissolved in organic solvent, heating reflux reaction 2-5 hours, and through refluxing toluene at Reason, to obtain the R on triazole unit₂The formula (I) compound replaced for 5-.

9. synthetic method according to claim 1, which is characterized in that step S2 detailed processes are：Under nitrogen protection, will Formula (III) compound, cycloaddition reagent acetylene compound, alkali, cuprous catalysis agent and bis- (2- diphenylphosphines phenyl) ethers by mole Than being 1:1-1.5:0.2-0.5:0.5-1:The ratio of 0.01-0.05 is added in organic solvent, and it is anti-to be heated to reflux progress cycloaddition It answers, to obtain R on triazole unit₂The formula (I) compound replaced for 4-.

10. the compound of formula I being prepared by any of the above-described preparation method.