CN106588920A - 1,3-diazabicyclo [1,2-a] quinoline compound as well as preparation method and antitumor application thereof - Google Patents
1,3-diazabicyclo [1,2-a] quinoline compound as well as preparation method and antitumor application thereof Download PDFInfo
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Abstract
The invention relates to a 1,3-diazabicyclo [1,2-a] quinoline compound as well as a preparation method and antitumor application thereof, and belongs to the technical field of pharmaceutical chemistry. The structure of the compound is as shown in a formula (1) (as shown in the description), in the formula (1), Ar is phenyl, halogenated phenyl, alkyl-substituted phenyl, alkoxy group-substituted phenyl, trifluoromethyl-substituted phenyl, nitro-substituted phenyl, cyano-substituted phenyl or thienyl; R1-R4 are halogen atoms, hydrogen atoms, alkyl groups, trifluoromethyl, nitro or piperydyl, wherein n is 1 or 2 or 3. Ex-vivo human-derived tumor cell strain activity screening researches indicate that the compound disclosed by the invention has strong antineoplastic activity for five common tumor cell strains: HCT116, A549, HT29, SGC7901, and HepG2. The antineoplastic activity of most of compounds is higher than that of a positive control medicine namely cisplatin. The 1,3-diazabicyclo [1,2-a] quinoline compound disclosed by the invention has wide application prospects in the respect of preparing antitumor medicines.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of 1,3- diazacyclos with anti-tumor activity are simultaneously
[1,2-a] quinolines and preparation method thereof, and as the purposes of antitumor drug.
Background technology
With the development of society, environmental pollution and food problems are increasingly serious, and cancer has become harm human health
Primary disease.The cancer therapy drug sought a kind of effective, low toxicity and easily prepare has become the emphasis of various countries' medicament research and development.Wherein
The cell toxicant kind anti-cancer drugs of extensive utilization mainly have metal platinum class complex, alkylating agents, antibioticses and adjust immunologic function
Class etc..
Colon-rectum is one of modal malignant tumor of China, occupies Cancer Mortality the 4th at present.In recent years
Come, in obvious ascendant trend, this trend is more apparent in big and medium-sized cities for the sickness rate of colorectal cancer.Equally it is most in western countries
One of common tumor.
And colon-rectum is generally less sensitive to current adoptable chemotherapy or is difficult to treat, for such cancer
The only effective reagent of disease is 5-fluorouracil.When invalid to the polychemotherapy based on 5-fluorouracil, currently without which
Its replacement treatment meanss.Therefore, there are the novel drugs of good therapeutic effect to such cancer for the slight illness for mitigating patient has weight
The realistic meaning wanted.
Quinoline is the parent nucleus of many natural products and biologically active drug structure, such as quinine, chloroquine, camptothecine etc..With
The development of synthesis chemistry, substantial quinoline analog derivative is synthesized, and they have extensive biological activity, for example：
Malaria, antibacterial, anti-inflammatory, antitumor, anti-diabetic, resisting hypertension, AntiHIV1 RT activity etc..Many quinolines chemical combination are had both at home and abroad
The patent report of thing.
WO2013000269 (Zhou Wenqiang) discloses a kind of camptothecin derivative and has anti-lung cancer, inhibitor against colon carcinoma cells activity.
CN201610480497.0 (Huang Shiliang) discloses a kind of 2- and replaces the aromatic ethylene base-N- quinolines that methylate to exist
Prepare the application in antitumor drug.
CN201610399172.X (Tang Dongfeng) disclose a kind of quinoline, quinazoline compounds and its pharmaceutical composition and
Using.
CN201610077368.7 (Zhou Youjun) discloses a kind of suppression of the quinolines Mutiple Targets kinases with anti-tumor activity
Preparation and preparation method thereof.
US9493419 (Johnny Cheuk-on Tang) discloses a kind of quinolines chemical combination with anti-tumor activity
Thing.
US4826850 (Masatoshi Yamato) discloses a class quinoline series antineoplastic medicament.
US5112817 (Nobuyuki Fukazawa) discloses a kind of quinolines with anti-tumor activity.
The content of the invention
It is an object of the invention to provide a class has the 1,3- diazacyclos of anti-tumor activity simultaneously [1,2-a] quinolines chemical combination
Thing and preparation method thereof, and as the purposes of antitumor drug.
For achieving the above object, the technical solution used in the present invention is as follows：
1,3- diazacyclo simultaneously [1,2-a] quinolines, the structure of the compound is as shown in formula I：
Wherein, in formula I, Ar refers to that phenyl, halogenophenyl, alkyl-substituted phenyl, alkoxy substituted phenyl, trifluoromethyl take
For phenyl, nitro substituted-phenyl, cyano group substituted-phenyl or thienyl；
R1～R4For halogen atom, hydrogen atom, alkyl, trifluoromethyl, nitro or piperidyl；
N is 1 or 2 or 3.
The present invention also provides the preparation method of above-mentioned 1,3- diazacyclos simultaneously [1,2-a] quinolines, including as follows
Step：
Existed with the 2- fluorobenzaldehyde class compounds of formula II structure and the heterocycle ketene peptide amine compound of formula III structure
In solvent, heat under alkalescence condition or inorganic salt existence condition, carry out nucleophilic displacement of fluorine and condensation reaction and reacted to TLC detections
Quan Hou, purification obtain 1,3- diazacyclos shown in formula I simultaneously [1,2-a] quinolines；
In formula II, R1～R4For halogen atom, hydrogen atom, alkyl, trifluoromethyl, nitro or piperidyl；
In formula III, Ar refers to that phenyl, halogenophenyl, alkyl-substituted phenyl, alkoxy substituted phenyl, trifluoromethyl replace
Phenyl, nitro substituted-phenyl, cyano group substituted-phenyl or thienyl；N is 1 or 2 or 3.
It is further preferred that described solvent be methanol, ethanol, water, acetone, dichloromethane, chloroform, ethyl acetate,
The mixing of one or more solvents in N,N-dimethylformamide, tetrahydrofuran, toluene, 1,4- dioxane and acetonitrile is molten
Agent.
It is further preferred that described alkali is the mixture of one or more in piperidines, triethylamine and calcium oxide,
Alkali is 1 with the mol ratio of the heterocycle ketene peptide amine compound of formula III structure：0.5～2；Described inorganic salt is calcium chloride,
Inorganic salt is 1 with the mol ratio of the heterocycle ketene peptide amine compound of formula III structure：0.5～2.
It is further preferred that heating-up temperature is 40～110 DEG C.
It is further preferred that the response time is 0.5～24 hour.
It is further preferred that the heterocyclic-ketene-aminal of the 2- fluorobenzaldehyde class compounds of formula II structure and formula III structure
The mol ratio of contracting aminated compoundss is 1：1-3.
The present invention also provide above-mentioned 1,3- diazacyclos simultaneously [1,2-a] quinolines as preparing antitumor drug
Using.
Compared with prior art, its advantage is the present invention：
The present invention is set out with the structure as shown in formula III using the raw material simple and easy to get structure as shown in formula II, by one
Step reaction obtains the target compound with anti-tumor activity (I).The synthesis technique of the invention is simple, and yield is high, and product is stable.
The invention realizes 1,3- of succinct, efficient parallel synthesis diazacyclos simultaneously [1,2-a] quinolines storehouse, and really realizes
Molecular diversity.
Institute's invention compound with tying to people-rectal cancer (HCT116), human lung cancer (A549), human colon carcinoma (HT29), people
Gastric cancer (SGC7901), human liver cancer (HepG2) preferably anti-tumor activity.Experimentation shows, compound 2,17～28 pairs
The IC of HCT116 cell strains50(μ g/mL) is respectively 4.75,4.06,6.35,5.00,4.48,5.06,5.32,6.38,7.70,
8.44,5.65,8.53,8.72, the respectively less than IC of cisplatin50(μ g/mL)=8.74, and both less than 10 μ g/mL, it is aobvious relative to cisplatin
Superior active anticancer is shown.Compound 17 and compound 21 are to HCT116 (people's knot-rectal cancer), A549 (pulmonary carcinoma), HT29 (knot
Intestinal cancer), SGC7901 (gastric cancer), HepG2 (hepatocarcinoma) cell strain show superior active anticancer, IC50Value is right much smaller than positive
According to the IC of drugs Cisplatin50Value, and both less than 10 μ g/mL.
Description of the drawings
Mono-crystalline structures figures of the Fig. 1 for compound 49.
Specific embodiment
With reference to embodiment, the present invention is described in further detail.
It will be understood to those of skill in the art that the following example is merely to illustrate the present invention, and should not be regarded as limiting this
Bright scope.Unreceipted particular technique or condition person in embodiment, according to technology or condition described by document in the art
Or carry out according to product description.The unreceipted production firm person such as agents useful for same, instrument, is and can pass through to buy what is obtained
Conventional products.
Raw material of the present invention can be prepared by the known method of this area or be obtained by commercially available prod.
The 1,3- diazacyclos general side that simultaneously [1,2-a] quinolines synthesize of the present invention explained further below
Method, but the preparation method of 1,3- of present invention diazacyclos simultaneously [1,2-a] quinolines is not limited to this.
Simultaneously [1,2-a] quinolines method is as follows for the 1,3- diazacyclos of the synthesis present invention：
Existed with the 2- fluorobenzaldehyde class compounds of formula II structure and the heterocycle ketene peptide amine compound of formula III structure
In solvent, heat under alkalescence condition or inorganic salt existence condition.After TLC detection reactions completely, after purification, pure formula I is obtained
Target product, concrete reaction equation are as follows：
In formula II, R1～R4 is halogen atom, hydrogen atom, alkyl, trifluoromethyl, nitro or piperidyl.
In formula III, Ar refers to that phenyl, halogenophenyl, alkyl-substituted phenyl, alkoxy substituted phenyl, trifluoromethyl replace
Phenyl, nitro substituted-phenyl, cyano group substituted-phenyl or thienyl；N is 1 or 2 or 3.
After reaction, way of purification is usually filtered, and is washed with a small amount of solvent, is taken solid and is added organic solvent and aqueous alkali extraction, so
After take organic faciess concentration after be recrystallized to give product, but purification process not limited to this of the present invention.
In reaction, solvent does not make concrete regulation, is often acetone, dichloromethane, chloroform, ethyl acetate, N, N- dimethyl methyls
The mixed solvent of one or more solvents in amide, tetrahydrofuran, toluene, 1,4- dioxane and acetonitrile；Alkali is not made specifically
Regulation is often piperidines, one or more in triethylamine and calcium oxide；Inorganic salt is calcium chloride；Reaction temperature does not make concrete rule
It is fixed, it is often 40～110 DEG C；Response time does not make concrete regulation, is often 0.5～24 hour.Course of reaction using TLC detect with
Track, stops heating after reaction completely, product recrystallization or washing or extraction solvent do not make concrete regulation, and extractant is often chlorine
One kind and sodium bicarbonate or aqueous sodium carbonate, recrystallization or cleaning solvent Chang Weiyi in imitative, ethyl acetate and dichloromethane
The mixed solvent of the mixed solvent, chloroform and petroleum ether of acetoacetic ester and petroleum ether.
In reaction, the formula III compound for 1 mM, formula II compound amount are 1～3 mM.Reaction
Yield is typically 90～98%.
The compound of formula II is known, or can be prepared according to known methods, and great majority are commercially available.
The compound of formula III is known, or can be prepared according to known methods.
The present invention is from 2- fluorobenzaldehydes class compound shown in raw material formula II and the heterocyclic ketene semiamine shown in formula III of being easy to get
Class compound sets out, by a series of new 1,3- diazacyclos of one pot process simultaneously [1,2-a] quinolines (I).
Human tumor cell line experiment is carried out to the compound of the present invention：HCT116 (Human colorectal carcinoma), A549 (pulmonary carcinoma),
HT29 (colon cancer), SGC7901 (gastric cancer), HepG2 (hepatocarcinoma).By cell tests compound incubation 144 hours, then adopt
MTT algoscopys measure cytotoxicity (1983,65,55 " the quick ratio of cell viability of Mossman, T.J.Immunol.Methods
Color method of testing；The quantitative application of cytotoxicity and growth inhibited lymphokine ".Green, L.M.J.Immunol.Methods
1984,70,257 " the quick colorimetric tests of cell viability；The quantitative application of cytotoxicity and growth inhibited lymphokine ").
The data obtained confirms that the compound of the present invention has obvious work to entity tumor, particularly pulmonary carcinoma and colorectal cancer
Property.
The day dosage of the compounds of this invention is 0.01mg-10mg/kg.Preferred day dosage for about 0.2mg is extremely
2mg/kg body weight, for the patient of body weight about 70kg, using the single dose administration about 14mg to about 140mg in 24 hours
Active substance.The dosage range can be adjusted to obtain more preferable therapeutic effect.The reactive compound of the present invention can pass through
Orally, the mode such as intravenous administration, intramuscular administration, subcutaneous administration is administered.
The compound of the present invention can be used to cause the agent combination of tumour regression to be administered with other, increase describedization to cooperate with
The antitumous effect of compound.The present invention compound can respectively from different cancer therapy drugs, such as：Cisplatin, husky profit platinum, 5- fluorine urine are phonetic
Pyridine, amycin, gemcitabine, taxol, vincristine, hydroxy camptothecin, topotecan, irinotecan combination administration (combination
Administration ratio 1：10～10：1).
The compound of at least one invention of the pharmaceutical composition of the present invention comprising therapeutically effective amount is mixed with pharmaceutically useful
Thing.
Orally administered composition includes the capsule suitable for oral administration, tablet, pill, suspension or syrup.
To prepare the pharmaceutical composition for parenteral, active component can be mixed in solution or suspension.
The present invention is described in detail with reference to part specific embodiment.These embodiments are merely to illustrate the present invention,
Rather than limit the scope of the present invention.Preparation scheme in embodiment is only preferred version, but be the invention is not limited in excellent
Select preparation scheme.
Part I synthetic example
Embodiment 1：Synthesize 4- (4- fluoro benzoyls) -7- nitro -1,2- glyoxalidine simultaneously [1,2-a] quinoline (compound
1)
1- (4- fluorophenyls) -2- (imidazolidine -2- subunits) second -1- ketone (1 mM) is added in 25 milliliters of round-bottomed flasks
After 5- nitrobenzaldehydes (3 mMs) fluoro- with 2-, Isosorbide-5-Nitrae-dioxane (15 milliliters) and piperidines (1 mM) magnetic force is added to stir
Mix down and be heated at 65 DEG C, react 2 hours.Petroleum ether/dichloromethane=10 are used after filtration:1 mixed solvent washing precipitation, obtains
Yellow fluffy solid.Extracting yellow solid, adds chloroform and saturated sodium bicarbonate aqueous solution, takes organic faciess with saturation after extraction
Sodium-chloride water solution is washed, and collects chloroform with anhydrous sodium sulfate drying, adds petroleum ether recrystallization after partial solvent is evaporated off,
After filtration, dry yellow solid product 4- (4- fluoro benzoyls) -7- nitro -1,2- glyoxalidine simultaneously (change by [1,2-a] quinoline
Compound 1), yield 94%.Fusing point：229～230 DEG C.
Proton nmr spectra (deuterated dimethyl sulfoxide, 300 instrument of Bruker AM):δ=3.88-3.95 (m, 2H, CH2N),
4.01-4.08 (m, 2H, NCH2), 6.98 (d, J=9.3Hz, 1H, ArH), 7.35 (t, J=8.9Hz, 2H, ArH), 7.80 (s,
1H, CH), 7.97-8.02 (m, 2H, ArH), 8.24-8.28 (m, 1H, ArH), 8.45 (d, J=2.4Hz, 1H, ArH).
Carbon-13 nmr spectra (deuterated dimethyl sulfoxide, 300 instrument of Bruker AM):δ=45.5,53.5,112.4,115.8
(d, J=21.8Hz), 119.1,124.9,127.2 129.4,132.4,132.6 (d, J=9.8Hz), 136.2,139.5,
143.9,152.8,165.4 (d, J=251.3Hz), 190.9.
High resolution mass spectrum C18H13FN3O3[M+H]+, theoretical value 338.0935；Measured value, 338.0935.
Embodiment 2：Synthesis three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinolines of 5- (4- chlorobenzene formacyls) -7,8,10-
Quinoline (compound 2)
1- (4- chlorphenyls) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone (1 milli is added in 25 milliliters of round-bottomed flasks
Mole, 0.44 gram) and 2, after 3,5,6- tetrafluorobenzene carbaldehydes (3 mMs, 0.44 gram), add (15 milliliters) works of Isosorbide-5-Nitrae-dioxane
For solvent, catalyst piperidines (0.5 mM) and anhydrous calcium chloride (0.5 mM) is added to be heated to 110 under magnetic stirring
DEG C, react 12 hours.Petrol ether/ethyl acetate=10 are used after filtration:1 mixed solvent washing precipitation, takes precipitation afterwards, adds
Washed with saturated sodium bicarbonate aqueous solution after ethyl acetate dissolving, take organic faciess and washed with saturated sodium-chloride water solution.Collect second
Anhydrous sodium sulfate drying is used after acetoacetic ester, is added appropriate petroleum ether to there is precipitation to generate after partial solvent is evaporated off, is filtered to take solid
Three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinoline of yellow product 5- (4- chlorobenzene formacyls) -7,8,10- is obtained after soma is dry
(compound 2), yield 95%.Fusing point：199～199.5 DEG C.
Proton nmr spectra (deuterated dimethyl sulfoxide+perchloric acid, 600 instrument of Bruker AM):δ=2.16 (m, 2H, CH2),
3.54 (m, 2H, CH2N), 4.67 (m, 2H, NCH2), 7.71 (d, J=8.2Hz, 2H, ArH), 7.99 (d, J=8.3Hz, 2H,
ArH), 8.26-8.31 (m, 1H, A rH), 8.48 (s, 1H, CH).
Carbon-13 nmr spectra (deuterated dimethyl sulfoxide+perchloric acid, 600 instrument of Bruker AM):δ=18.3,39.1,50.8
(d, J=19.5Hz), 112.7 (m), 113.6 (d, J=16.5Hz), 124.8,125.1,129.6,132.7,134.9,
135.1,140.3,143.5 (d, J=6.3Hz), 145.6,146.8,150.7,190.9.
Enantiomeric excess (deuterated dimethyl sulfoxide+perchloric acid, 600 instrument of Bruker AM):δ=- 145.3 (m), -138.3
(m), -115.8.
High resolution mass spectrum C19H13ClF3N2O[M+H]+, theoretical value 377.0663；Measured value, 377.0665.
Embodiment 3：Synthesis 5- (4- chlorobenzene formacyls) -8- (trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a] quinolines
Quinoline (compound 3)
1- (4- chlorphenyls) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone (1 milli is added in 25 milliliters of round-bottomed flasks
Mole) and 2- fluoro- 5- (trifluoromethyl) benzaldehydes (2 mMs) after, add Isosorbide-5-Nitrae-dioxane (15 milliliters) as solvent, plus
Enter catalyst piperidines (0.5 mM), and anhydrous calcium chloride (0.5 mM) is heated to 75 DEG C under magnetic stirring, reaction 6 is little
When.With a small amount of petroleum ether/chloroform=10 after filtration:2 mixed solvent washing precipitation, is taken precipitation afterwards and is dissolved with dichloromethane,
Organic layer is washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution.Chloroform is collected afterwards with anhydrous sulfur
Sour sodium is dried, and adds appropriate hexamethylene to there is precipitation to generate, obtain yellow and produce after filtering to take solid drying after partial solvent is evaporated off
Product 5- (4- chlorobenzene formacyls) -8- (trifluoromethyl) -2,3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 3), yield
96%.Fusing point：181～182 DEG C.
Proton nmr spectra (deuterated dimethyl sulfoxide, 300 instrument of Bruker AM):δ=1.85-1.88 (m, 2H, CH2),
3.22-3.26 (m, 2H, CH2N), 3.89-3.92 (m, 2H, NCH2), 7.37 (d, J=8.7Hz, 1H, ArH), 7.51 (s, 1H,
CH), 7.55 (d, J=8.4Hz, 2H, ArH), 7.75 (d, J=9.0Hz, 1H, ArH), 7.87-7.90 (m, 3H, ArH).
Carbon-13 nmr spectra (deuterated dimethyl sulfoxide, 300 instrument of Bruker AM):δ=19.5,43.0,43.9,112.1,
119.5,121.0 (d, J=33.0Hz), 124.3 (d, J=270.0Hz), 125.8,127.0,128.8,130.4,130.8,
134.9,136.2,138.2,143.4,146.8,193.2.
High resolution mass spectrum C20H15ClF3N2O[M+H]+, theoretical value 391.0820；Measured value, 391.0816.
Embodiment 4：Synthesize 4- (4- chlorobenzene formacyls) 7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound
4)
Replace 1- (4- the fluorophenyls) -2- in embodiment 1 with 1- (4- chlorphenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(imidazolidine -2- subunits) second -1- ketone, with the Isosorbide-5-Nitrae-dioxane in ethanol alternate embodiment 1 as reaction dissolvent, at 40 DEG C
Reaction 12 hours, is obtained yellow solid 4- (4- chlorobenzene formacyls) 7- nitro -1, and 2- dihydro-imidazols simultaneously (change by [1,2-a] quinoline
Compound 4), yield 98%.Fusing point：273～278 DEG C.
High resolution mass spectrum C18H13ClN3O3[M+H]+, theoretical value 354.0640；Measured value, 354.0638.
Embodiment 5：Synthesis 4- (4- benzoyl bromides) (7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound
5)
Replace 1- (4- the fluorophenyls) -2- in embodiment 1 with 1- (4- bromophenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(imidazolidine -2- subunits) second -1- ketone, with the piperidines in triethylamine (0.75 mM) alternate embodiment 1, carries out reaction available
Yellow solid 4- (4- benzoyl bromides) (7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 5), yield 97%.
Fusing point：282～283 DEG C.
High resolution mass spectrum C18H13BrN3O3[M+H]+, theoretical value 398.0135；Measured value, 398.0137.
Embodiment 6：Synthesize 4- benzoyl -7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 6)
Replace 1- (the 4- fluorophenyls) -2- (miaows in embodiment 1 with 2- (imidazolidine -2- subunits) -1- diphenylphosphino ethane -1- ketone
Oxazolidine -2- subunits) second -1- ketone, and anhydrous calcium chloride (0.5 mM) is added, react 30 minutes, yellow solid 4- benzene is obtained
Formoxyl -7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 6), yield 97%.Fusing point：285～286 DEG C.
High resolution mass spectrum C18H14N3O3[M+H]+, theoretical value 320.1030；Measured value, 320.1029.
Embodiment 7：Synthesis 4- is to toluyl groups -7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 7)
Replace 1- (4- the fluorophenyls) -2- in embodiment 1 with 2- (imidazolidine -2- subunits) -1- (p-methylphenyl) second -1- ketone
(imidazolidine -2- subunits) second -1- ketone, and calcium oxide (0.5 mM) is added, carry out reaction and yellow solid 4- is obtained to toluene
Formoxyl -7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 7), yield 95%.Fusing point：283～284 DEG C.
High resolution mass spectrum C19H16N3O3[M+H]+, theoretical value 334.1186；Measured value, 334.1186.
Embodiment 8：Synthesis 4- (4- anisoyl) -7- nitro -1,2- dihydro-imidazols simultaneously (change by [1,2-a] quinoline
Compound is 8)
Replace 1- (the 4- fluorobenzene in embodiment 1 with 2- (imidazolidine -2- subunits) -1- (4- methoxyphenyls) second -1- ketone
Base) -2- (imidazolidine -2- subunits) second -1- ketone, and with the Isosorbide-5-Nitrae-dioxy six in the mixed solvent alternate embodiment 1 of second alcohol and water
Ring is reacted 24 hours, yellow solid 4- (4- anisoyl) -7- nitro -1,2- dihydro-imidazols is obtained as solvent
And [1,2-a] quinoline (compound 8), yield 93%.Fusing point：260～261 DEG C.
High resolution mass spectrum C19H16N3O4[M+H]+, theoretical value 350.1135；Measured value, 350.1132.
Embodiment 9：Synthesize 4- (2- Thenoyls) -7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound
9)
Replaced with 2- (imidazolidine-2- subunits)-1- (thiophene-2- bases) second-1- ketone 1- (4- fluorophenyls) in embodiment 1-
2- (imidazolidine -2- subunits) second -1- ketone, and the Isosorbide-5-Nitrae-dioxane in water consumption substitution embodiment 1, used as solvent, reaction 24 is little
When, it is obtained orange solids 4- (2- Thenoyls) -7- nitro -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 9),
Yield 90%.Fusing point：274～275 DEG C.
High resolution mass spectrum C16H12N3O3S[M+H]+, theoretical value 326.0594；Measured value, 326.0595.
Embodiment 10：Synthesis 5- (4- fluoro benzoyls) -8- nitro -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (is changed
Compound is 10)
Replace 1- (the 4- fluorobenzene in embodiment 1 with 1- (4- fluorophenyls) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone
Base) -2- (imidazolidine -2- subunits) second -1- ketone, with the mixed solvent alternate embodiment 1 of ethanol, Isosorbide-5-Nitrae-dioxane and toluene
Isosorbide-5-Nitrae-dioxane as solvent, carry out reaction and yellow solid 5- (4- fluoro benzoyls) -8- nitro -2,3- bis- be obtained
Hydrogen -1H- pyrimidos [1,2-a] quinoline (compound 10), yield 94%.Fusing point：225–226℃.
High resolution mass spectrum C19H15FN3O3[M+H]+, theoretical value 352.1092；Measured value, 352.1088.
Embodiment 11：Synthesis 5- (4- chlorobenzene formacyls) -8- nitro -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (is changed
Compound is 11)
Replace 1- (the 4- fluorobenzene in embodiment 1 with 1- (4- chlorphenyls) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone
Base) -2- (imidazolidine -2- subunits) second -1- ketone carries out reaction and yellow solid 5- (4- chlorobenzene formacyls) -8- nitro -2 is obtained,
3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 11), yield 96%.Fusing point：272～273 DEG C.
High resolution mass spectrum C19H15ClN3O3[M+H]+, theoretical value 368.0796；Measured value 368.0795.
Embodiment 12：Synthesis 5- (4- benzoyl bromides) -8- nitro -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (is changed
Compound is 12)
Replace 1- (the 4- fluorobenzene in embodiment 1 with 1- (4- bromophenyls) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone
Base) -2- (imidazolidine -2- subunits) second -1- ketone carries out reaction and yellow solid 5- (4- benzoyl bromides) -8- nitro -2 is obtained,
3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 12), yield 95%.Fusing point：264～265 DEG C.
High resolution mass spectrum C19H15BrN3O3[M+H]+, theoretical value 412.0291；Measured value, 412.0291.
Embodiment 13：Synthesis 5- benzoyl -8- nitro -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (compounds
13)
Replace 1- (4- the fluorophenyls) -2- in embodiment 1 with 1- phenyl -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone
(imidazolidine -2- subunits) second -1- ketone carries out reaction, and that yellow solid 5- benzoyl -8- nitro -2,3- dihydro -1H- are obtained is phonetic
Pyridine simultaneously [1,2-a] quinoline (compound 13), yield 96%.Fusing point：285～286 DEG C.
High resolution mass spectrum C19H16N3O3[M+H]+, theoretical value 334.1186；Measured value, 334.1186.
Embodiment 14：5- is to toluyl groups -8- nitro -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (chemical combination for synthesis
Thing is 14)
Replace 1- (the 4- fluorobenzene in embodiment 1 with 2- (- 2 (1H)-subunit of tetrahydropyrimidine) -1- (p-methylphenyl) second -1- ketone
Base) -2- (imidazolidine -2- subunits) second -1- ketone carries out reaction and yellow solid 5- is obtained to toluyl groups -8- nitro -2,3-
Dihydro -1H- pyrimidos [1,2-a] quinoline (compound 14), yield 92%.Fusing point：281～282 DEG C.
High resolution mass spectrum C20H18N3O3[M+H]+, theoretical value 348.1343；Measured value, 348.1341.
Embodiment 15：Synthesis 5- (4- anisoyl) -8- nitro -2,3- dihydro -1H- pyrimidos [1,2-a] quinolines
Quinoline (compound 15)
Replace the 1- (4- in embodiment 1 with 1- (4- methoxyphenyls) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone
Fluorophenyl) -2- (imidazolidine -2- subunits) second -1- ketone carries out reaction and yellow solid 5- (4- anisoyl) -8- is obtained
Nitro -2,3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 15), yield 91%.Fusing point：221～222 DEG C.
High resolution mass spectrum C20H18N3O4[M+H]+, theoretical value 364.1292；Measured value, 364.1293.
Embodiment 16：Synthesis 5- (2- Thenoyls) -8- nitro -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (is changed
Compound is 16)
Replace 1- (the 4- fluorine in embodiment 1 with 2- (- 2 (1H)-subunit of tetrahydropyrimidine) -1- (thiophene -2- bases) second -1- ketone
Phenyl) -2- (imidazolidine -2- subunits) second -1- ketone carries out reaction and orange/yellow solid 5- (2- Thenoyls) -8- nitre is obtained
Base -2,3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 16), yield 91%.Fusing point：274～275 DEG C.
High resolution mass spectrum C17H14N3O3S[M+H]+, theoretical value 340.0750；Measured value, 340.0752.
Embodiment 17：Synthesis 6- (4- chlorobenzene formacyls) -9- nitro -1,2,3,4- tetrahydrochysenes-[1,3] diazepine simultaneously [1,
2-a] quinoline (compound 17)
Replace the 1- (4- in embodiment 1 with 1- (4- chlorphenyls) -2- (1,3- Diazesuberane -2- subunits) second -1- ketone
Fluorophenyl) -2- (imidazolidine -2- subunits) second -1- ketone carries out reaction and yellow solid 6- (4- chlorobenzene formacyls) -9- nitre is obtained
Base -1,2,3,4- tetrahydrochysenes-[1,3] diazepine simultaneously [1,2-a] quinoline (compound 17), yield 93%.Fusing point：232～233
℃。
High resolution mass spectrum C20H17ClN3O3[M+H]+, theoretical value 382.0953；Measured value, 382.0952.
Embodiment 18：Synthesis 6- is to toluyl groups -9- nitro -1,2,3,4- tetrahydrochysenes-[1,3] diazepine simultaneously [1,2-
A] quinoline (compound 18)
Replace the 1- (4- in embodiment 1 with 2- (1,3- Diazesuberane -2- subunits) -1- (p-methylphenyl) second -1- ketone
Fluorophenyl) -2- (imidazolidine -2- subunits) second -1- ketone carry out reaction be obtained yellow solid 6- to toluyl groups -9- nitros -
1,2,3,4- tetrahydrochysene-[1,3] diazepine simultaneously [1,2-a] quinoline (compound 18), yield 92%.Fusing point：238～239 DEG C.
High resolution mass spectrum C21H20N3O3[M+H]+, theoretical value 362.1499；Measured value, 362.1500.
Embodiment 19：Synthesis three fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols of 4- (4- fluoro benzoyls) -6,7,9-
And [1,2-a] quinoline (compound 19)
1- (4- fluorophenyls) -2- (imidazolidine -2- subunits) second -1- ketone (1 mM) is added in 25 milliliters of round-bottomed flasks
With 2, after 3,4,5,6- pentafluorobenzaldehydes (2 mMs), Isosorbide-5-Nitrae-dioxane (15 milliliters) and piperidines (1.5 mMs) are added,
And anhydrous CaCl2(1.2 mMs), are heated to 101 DEG C of backflows, react 8 hours under magnetic agitation.Negate lower floor after answering dark red
Color grease, adds chloroform and saturated aqueous sodium carbonate, takes organic faciess and washed with saturated sodium-chloride water solution after extraction,
Chloroform is collected with anhydrous sodium sulfate drying, petroleum ether recrystallization after partial solvent is evaporated off, is added, it is redly dry after filtration
Three fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols of solid product 4- (4- fluoro benzoyls) -6,7,9- simultaneously [1,2-a] quinoline
(compound 19), yield 92%.Fusing point：170～171 DEG C.
High resolution mass spectrum C23H20F4N3O[M+H]+, theoretical value 430.1537；Measured value, 430.1533.
Embodiment 20：Synthesis three fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols of 4- (4- chlorobenzene formacyls) -6,7,9-
And [1,2-a] quinoline (compound 20)
Replaced with 1- (4- chlorphenyls)-2- (imidazolidine-2- subunits) second-1- ketone 1- (4- fluorophenyls) in embodiment 19-
2- (imidazolidine -2- subunits) second -1- ketone, it is with the Isosorbide-5-Nitrae-dioxane in toluene alternate embodiment 19 as solvent, anti-at 110 DEG C
Answer 6 hours, red solid 4- (4- chlorobenzene formacyls) -6,7,9- tri- fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols are obtained
And [1,2-a] quinoline (compound 20), yield 93%.Fusing point：160～161 DEG C.
High resolution mass spectrum C23H20ClF3N3O[M+H]+, theoretical value 446.1242；Measured value, 446.1239.
Embodiment 21：Synthesis three fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols of 4- (4- benzoyl bromides) -6,7,9-
And [1,2-a] quinoline (compound 21)
Replaced with 1- (4- bromophenyls)-2- (imidazolidine-2- subunits) second-1- ketone 1- (4- fluorophenyls) in embodiment 19-
2- (imidazolidine -2- subunits) second -1- ketone, with the CaCl in CaO alternate embodiments 192, carry out reaction and orange solids 4- be obtained
(4- benzoyl bromides) -6,7,9- tri- fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 21),
Yield 92%.Fusing point：181～182 DEG C.
High resolution mass spectrum C23H20BrF3N3O[M+H]+, theoretical value 490.0735；Measured value, 490.0737.
Embodiment 22：Synthesize three fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols of 4- benzoyls -6,7,9- simultaneously [1,2-
A] quinoline (compound 22)
Replace 1- (the 4- fluorophenyls) -2- (miaows in embodiment 19 with 2- (imidazolidine -2- subunits) -1- diphenylphosphino ethane -1- ketone
Oxazolidine -2- subunits) second -1- ketone carries out reaction and three fluoro- 8- (piperidines -1- of Orange red solid 4- benzoyls -6,7,9- is obtained
Base) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 22), yield 93%.Fusing point：186～187 DEG C.
High resolution mass spectrum C23H21F3N3O[M+H]+, 412.1631 measured value of theoretical value, 412.1633.
Embodiment 23：Synthesis 4- to three fluoro- 8- (piperidin-1-yl) -1,2- dihydro-imidazols of toluyl groups -6,7,9- simultaneously
[1,2-a] quinoline (compound 23)
Replaced with 2- (imidazolidine-2- subunits)-1- (p-methylphenyl) second-1- ketone 1- (4- fluorophenyls) in embodiment 19-
2- (imidazolidine -2- subunits) second -1- ketone carries out reaction and yellow solid 4- is obtained to three fluoro- 8- (piperazines of toluyl groups -6,7,9-
Pyridine -1- bases) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 23), yield 92%.Fusing point：136～137 DEG C.
High resolution mass spectrum C24H23F3N3O[M+H]+, theoretical value 426.1788；Measured value, 326.1789.
Embodiment 24：Synthesis three fluoro- 8- (piperidin-1-yl) -1,2- dihydros of 4- (4- anisoyl) -6,7,9- -
Imidazo [1,2-a] quinoline (compound 24)
Replace 1- (the 4- fluorobenzene in embodiment 19 with 2- (imidazolidine -2- subunits) -1- (4- methoxyphenyls) second -1- ketone
Base) -2- (imidazolidine -2- subunits) second -1- ketone carries out reaction and Orange red solid 4- (4- anisoyl) -6,7 is obtained,
Tri- fluoro- 8- (piperidin-1-yl) of 9- -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 24), yield 91%.Fusing point：167～
168℃。
High resolution mass spectrum C24H23F3N3O2[M+H]+, theoretical value 442.1737；Measured value, 442.1737.
Embodiment 25：Synthesis three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinolines of 5- (4- fluoro benzoyls) -7,8,10-
Quinoline (compound 25)
Replace 1- (the 4- chlorobenzenes in embodiment 2 with 1- (4- fluorophenyls) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone
Base) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone, and with the Isosorbide-5-Nitrae-dioxane in methanol alternate embodiment 2 as molten
Agent, reacts 8 hours at 50 DEG C, -7,8,10- tri- fluoro- 2,3- dihydros -1H- of yellow solid 5- (4- fluoro benzoyls) is obtained
Pyrimido [1,2-a] quinoline (compound 25), yield 92%.Fusing point：179℃.
High resolution mass spectrum C19H13F4N2O[M+H]+, theoretical value 361.0959；Measured value, 361.0959.
Embodiment 26：Synthesis three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinolines of 5- (4- benzoyl bromides) -7,8,10-
Quinoline (compound 26)
Replace 1- (the 4- chlorobenzenes in embodiment 2 with 1- (4- bromophenyls) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone
Base) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone, and with the Isosorbide-5-Nitrae-dioxane in acetone alternate embodiment 2 as molten
Agent, reacts 24 hours at 40 DEG C, and reaction is obtained -7,8,10- tri- fluoro- 2,3- bis- of yellow solid 5- (4- benzoyl bromides)
Hydrogen -1H- pyrimidos [1,2-a] quinoline (compound 26), yield 95%.Fusing point：193～194 DEG C.
High resolution mass spectrum C19H13BrF3N2O[M+H]+, theoretical value 421.0158；Measured value, 421.1059.
Embodiment 27：Three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinoline of synthesis 5- benzoyls -7,8,10- (is changed
Compound is 27)
Replace 1- (4- the chlorphenyls) -2- in embodiment 2 with 1- phenyl -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone
(- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone, and with the Isosorbide-5-Nitrae-dioxane in acetone alternate embodiment 2 as solvent, 40
React 24 hours at DEG C, carry out reaction and yellow solid 5- benzoyl -7,8,10- tri- fluoro- 2,3- dihydros -1H- pyrimidines are obtained
And [1,2-a] quinoline (compound 27), yield 94%.Fusing point：191～192 DEG C.
High resolution mass spectrum C19H14F3N2O[M+H]+, theoretical value 343.1053；Measured value, 343.1054.
Embodiment 28：5- is to three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinoline of toluyl groups -7,8,10- for synthesis
(compound 28)
Replace 1- (the 4- chlorobenzenes in embodiment 2 with 2- (- 2 (1H)-subunit of tetrahydropyrimidine) -1- (p-methylphenyl) second -1- ketone
Base) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone, and with the Isosorbide-5-Nitrae-two in DMF alternate embodiment 2
Six ring of oxygen carries out reaction and yellow solid 5- is obtained to toluyl groups -7 as solvent, 8,10- tri- fluoro- 2,3- dihydros -1H-
Pyrimido [1,2-a] quinoline (compound 28), yield 92%.Fusing point：196～197 DEG C.
High resolution mass spectrum C20H16F3N2O[M+H]+, theoretical value 357.1209；Measured value, 357.1208.
Embodiment 29：Synthesis three fluoro- 2,3- dihydros -1H- pyrimido [1,2- of 5- (4- anisoyl) -7,8,10-
A] quinoline (compound 29)
Replace the 1- (4- in embodiment 2 with 1- (4- methoxyphenyls) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone
Chlorphenyl) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and yellow solid 5- (4- methoxybenzoyls is obtained
Base) -7,8,10- tri- fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 29), yield 90%.Fusing point：174～
175℃。
High resolution mass spectrum C20H16F3N2O2[M+H]+, theoretical value 373.1158；Measured value, 373.1158.
Embodiment 30：Synthesis three fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinolines of 5- (2- Thenoyls) -7,8,10-
Quinoline (compound 30)
Replace 1- (the 4- chlorine in embodiment 2 with 2- (- 2 (1H)-subunit of tetrahydropyrimidine) -1- (thiophene -2- bases) second -1- ketone
Phenyl) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and yellow solid 5- (2- Thenoyls) -7 is obtained,
8,10- tri- fluoro- 2,3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 30), yield 91%.Fusing point：178～179 DEG C.
High resolution mass spectrum C17H12F3N2OS[M+H]+, theoretical value 349.0617；Measured value, 349.0618.
Embodiment 31：Synthesize three fluoro- 1,2- dihydro-imidazols of 4- (4- fluoro benzoyls) -6,7,9- simultaneously [1,2-a] quinoline
(compound 31)
Replace 1- (4- the chlorphenyls) -2- in embodiment 2 with 1- (4- fluorophenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and red solid 4- (4- fluoro benzoyls) -6,7,9- three is obtained
Fluoro- 1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 31), yield 93%.Fusing point：178～179 DEG C.
High resolution mass spectrum C18H11F4N2O[M+H]+, theoretical value 347.0802；Measured value, 347.0801.
Embodiment 32：Synthesize three fluoro- 1,2- dihydro-imidazols of 4- (4- chlorobenzene formacyls) -6,7,9- simultaneously [1,2-a] quinoline
(compound 32)
Replace 1- (4- the chlorphenyls) -2- in embodiment 2 with 1- (4- chlorphenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and red solid 4- (4- chlorobenzene formacyls) -6,7,9- three is obtained
Fluoro- 1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 32), yield 95%.Fusing point：176～177 DEG C.
High resolution mass spectrum C18H11ClF3N2O[M+H]+, theoretical value 363.0507；Measured value, 363.0503.
Embodiment 33：Synthesize three fluoro- 1,2- dihydro-imidazols of 4- (4- benzoyl bromides) -6,7,9- simultaneously [1,2-a] quinoline
(compound 33)
Replace 1- (4- the chlorphenyls) -2- in embodiment 2 with 1- (4- bromophenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and orange solids 4- (4- benzoyl bromides) -6,7,9- three is obtained
Fluoro- 1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 33), yield 94%.Fusing point：203～204 DEG C.
High resolution mass spectrum C18H12BrF3N2O[M+H]+, theoretical value 407.0001；Measured value, 407.0000.
Embodiment 34：Synthesize three fluoro- 1,2- dihydro-imidazols of 4- benzoyls -6,7,9- simultaneously [1,2-a] quinoline (compound
34)
Replace 1- (4- the chlorphenyls) -2- (four in embodiment 2 with 2- (imidazolidine -2- subunits) -1- diphenylphosphino ethane -1- ketone
- 2 (1H)-subunit of hydrogen pyrimidine) second -1- ketone carries out reaction and three fluoro- 1,2- bis- of orange solids 4- benzoyl -6,7,9- is obtained
Hydrogen-imidazo [1,2-a] quinoline (compound 34), yield 94%.Fusing point：195～196 DEG C.
High resolution mass spectrum C18H12F3N2O[M+H]+, theoretical value 329.0896；Measured value, 329.0894.
Embodiment 35：Synthesis 4- to three fluoro- 1,2- dihydro-imidazols of toluyl groups -6,7,9-, simultaneously (change by [1,2-a] quinoline
Compound is 35)
Replace 1- (4- the chlorphenyls) -2- in embodiment 2 with 2- (imidazolidine -2- subunits) -1- (p-methylphenyl) second -1- ketone
(- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and Orange red solid 4- is obtained to toluyl groups -6,7,9- three
Fluoro- 1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 35), yield 92%.Fusing point：185～186 DEG C.
High resolution mass spectrum C19H14F3N2O[M+H]+, theoretical value 343.1053；Measured value, 343.1050.
Embodiment 36：Synthesize three fluoro- 1,2- dihydro-imidazols of 4- (4- anisoyl) -6,7,9- simultaneously [1,2-a] quinoline
Quinoline (compound 36)
Replace 1- (the 4- chlorobenzenes in embodiment 2 with 2- (imidazolidine -2- subunits) -1- (4- methoxyphenyls) second -1- ketone
Base) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carry out reaction be obtained orange solids 4- (4- anisoyl) -
6,7,9- tri- fluoro- 1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 36), yield 93%.Fusing point：192～193 DEG C.
High resolution mass spectrum C19H14F3N2O2[M+H]+, theoretical value 359.1002；Measured value 359.0999.
Embodiment 37：Synthesize three fluoro- 1,2- dihydro-imidazols of 4- (2- Thenoyls) -6,7,9- simultaneously [1,2-a] quinoline
(compound 37)
Replaced with 2- (imidazolidine-2- subunits)-1- (thiophene-2- bases) second-1- ketone 1- (4- chlorphenyls) in embodiment 2-
2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and orange solids 4- (2- Thenoyls) -6,7,9- three is obtained
Fluoro- 1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 37), yield 92%.Fusing point：170～171 DEG C.
High resolution mass spectrum C16H10F3N2OS[M+H]+, theoretical value 335.0460；Measured value 335.0464.
Embodiment 38：Synthesis 5- (4- fluoro benzoyls) -8- (trifluoromethyl) -2,3- dihydros -1H- pyrimidos [1,2-a]
Quinoline (compound 38)
Replace 1- (the 4- chlorobenzenes in embodiment 3 with 1- (4- fluorophenyls) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone
Base) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and light yellow solid 5- (4- fluoro benzoyls) -8- is obtained
(trifluoromethyl) -2,3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 38), yield 94%.Fusing point：172～173 DEG C.
High resolution mass spectrum C20H15F4N2O[M+H]+, theoretical value 3375.1115；Measured value, 375.1113.
Embodiment 39：Synthesis 5- (4- benzoyl bromides) -8- (trifluoromethyl) -2,3- dihydros -1H- pyrimidos [1,2-a]
Quinoline (compound 39)
Replace 1- (the 4- chlorobenzenes in embodiment 3 with 1- (4- bromophenyls) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone
Base) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and light yellow solid 5- (4- benzoyl bromides) -8- is obtained
(trifluoromethyl) -2,3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 39), yield 96%.Fusing point：195～196 DEG C.
High resolution mass spectrum C20H15BrF3N2O[M+H]+, theoretical value 435.0314；Measured value, 435.0317.
Embodiment 40：Synthesis 5- benzoyl -8- (trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a] quinoline (is changed
Compound is 40)
Replace 1- (4- the chlorphenyls) -2- in embodiment 2 with 1- phenyl -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone
(- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carry out reaction be obtained light yellow solid 5- benzoyl -8- (trifluoromethyl) -
2,3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 40), yield 95%.Fusing point：187～188 DEG C.
High resolution mass spectrum C20H16F3N2O[M+H]+, theoretical value 357.1209；Measured value, 357.1205.
Embodiment 41：5- is to toluyl groups -8- (trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,2-a] quinolines for synthesis
Quinoline (compound 41)
Replace 1- (the 4- chlorobenzenes in embodiment 3 with 2- (- 2 (1H)-subunit of tetrahydropyrimidine) -1- (p-methylphenyl) second -1- ketone
Base) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and light yellow solid 5- is obtained to toluyl groups -8-
(trifluoromethyl) -2,3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 41), yield 94%.Fusing point：226～227 DEG C.
High resolution mass spectrum C21H18F3N2O[M+H]+, theoretical value 371.1366；Measured value, 371.1363.
Embodiment 42：Synthesis 5- (4- anisoyl) -8- (trifluoromethyl) -2,3- dihydro -1H- pyrimidos [1,
2-a] quinoline (compound 42)
Replace the 1- (4- in embodiment 3 with 1- (4- methoxyphenyls) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone
Chlorphenyl) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and white solid 5- (4- methoxybenzoyls is obtained
Base) -8- (trifluoromethyl) -2,3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 42), yield 93%.Fusing point：191～
192℃。
High resolution mass spectrum C21H18F3N2O2[M+H]+, theoretical value 387.1315；Measured value 387.1317.
Embodiment 43：Synthesis 5- (2- Thenoyls) -8- (trifluoromethyl) -2,3- dihydros -1H- pyrimidos [1,2-a]
Quinoline (compound 43)
Replace 1- (the 4- chlorine in embodiment 2 with 2- (- 2 (1H)-subunit of tetrahydropyrimidine) -1- (thiophene -2- bases) second -1- ketone
Phenyl) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and white solid 5- (2- Thenoyls) -8- is obtained
(trifluoromethyl) -2,3- dihydros -1H- pyrimidos [1,2-a] quinoline (compound 43), yield 92%.Fusing point：209～210 DEG C.
High resolution mass spectrum C18H14F3N2OS[M+H]+, theoretical value 363.0773；Measured value, 363.0777.
Embodiment 44：Synthesize 4- (4- fluoro benzoyls) -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline
(compound 44)
Replace 1- (4- the chlorphenyls) -2- in embodiment 3 with 1- (4- fluorophenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and yellow solid 4- (4- fluoro benzoyls) -7- (fluoroforms is obtained
Base) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 44), yield 95%.Fusing point：194～195 DEG C.
High resolution mass spectrum C19H13F4N2O[M+H]+, theoretical value 361.0959；Measured value, 361.0958.
Embodiment 45：Synthesize 4- (4- chlorobenzene formacyls) -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline
(compound 45)
Replace 1- (4- the chlorphenyls) -2- in embodiment 3 with 1- (4- chlorphenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and yellow solid 4- (4- chlorobenzene formacyls) -7- (fluoroforms is obtained
Base) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 45), yield 97%.Fusing point：232～233 DEG C.
High resolution mass spectrum C19H13ClF3N2O[M+H]+, theoretical value 377.0663；Measured value 377.0664.
Embodiment 46：Synthesize 4- (4- benzoyl bromides) -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline
(compound 46)
Replace 1- (4- the chlorphenyls) -2- in embodiment 3 with 1- (4- bromophenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and yellow solid 4- (4- benzoyl bromides) -7- (fluoroforms is obtained
Base) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 46), yield 97%.Fusing point：237～238 DEG C.
High resolution mass spectrum C19H13BrF3N2O[M+H]+, theoretical value 421.0158；Measured value 421.0158.
Embodiment 47：Synthesize 4- benzoyl -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (chemical combination
Thing is 47)
Replace 1- (4- the chlorphenyls) -2- (four in embodiment 3 with 2- (imidazolidine -2- subunits) -1- diphenylphosphino ethane -1- ketone
- 2 (1H)-subunit of hydrogen pyrimidine) second -1- ketone carries out reaction and yellow solid 4- benzoyl -7- (trifluoromethyl) -1,2- two is obtained
Hydrogen-imidazo [1,2-a] quinoline (compound 47), yield 95%.Fusing point：212～213 DEG C.
High resolution mass spectrum C19H14F3N2O[M+H]+, theoretical value 343.1053；Measured value, 343.1050.
Embodiment 48：Synthesis 4- is to toluyl groups -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline
(compound 48)
Replace 1- (4- the chlorphenyls) -2- in embodiment 3 with 2- (imidazolidine -2- subunits) -1- (p-methylphenyl) second -1- ketone
(- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and yellow solid 4- is obtained to toluyl groups -7- (fluoroforms
Base) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 48), yield 92%.Fusing point：249～250 DEG C.
High resolution mass spectrum C20H16F3N2O[M+H]+, theoretical value 357.1209；Measured value, 357.1210.
Embodiment 49：Synthesis 4- (4- anisoyl) -7- (trifluoromethyl) -1,2- dihydro-imidazols are simultaneously [1,2-a]
Quinoline (compound 49)
Replace 1- (the 4- chlorobenzenes in embodiment 3 with 2- (imidazolidine -2- subunits) -1- (4- methoxyphenyls) second -1- ketone
Base) -2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carry out reaction be obtained yellow solid 4- (4- anisoyl) -
7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 49), yield 92%.Fusing point：228～229 DEG C.Its
Mono-crystalline structures are as shown in Figure 1.
High resolution mass spectrum C20H16F3N2O2[M+H]+, theoretical value 373.1158；Measured value, 373.1160.
Embodiment 50：Synthesize 4- (2- Thenoyls) -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline
(compound 50)
Replaced with 2- (imidazolidine-2- subunits)-1- (thiophene-2- bases) second-1- ketone 1- (4- chlorphenyls) in embodiment 3-
2- (- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and orange solids 4- (2- Thenoyls) -7- (trifluoros is obtained
Methyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 50), yield 93%.Fusing point：208～209 DEG C.
High resolution mass spectrum C17H12F3N2OS[M+H]+, theoretical value 349.0617；Measured value 349.0614.
Embodiment 51：Synthesize 4- (2- chlorobenzene formacyls) -7- (trifluoromethyl) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline
(compound 51)
Replace 1- (4- the chlorphenyls) -2- in embodiment 3 with 1- (2- chlorphenyls) -2- (imidazolidine -2- subunits) second -1- ketone
(- 2 (1H)-subunit of tetrahydropyrimidine) second -1- ketone carries out reaction and red solid 4- (2- chlorobenzene formacyls) -7- (fluoroforms is obtained
Base) -1,2- dihydro-imidazols simultaneously [1,2-a] quinoline (compound 51), yield 95%.Fusing point：223～224 DEG C.
High resolution mass spectrum C19H13ClF3N2O[M+H]+, theoretical value 377.0665；Measured value 377.0665.
More than synthesized by 1,3- diazacyclos simultaneously [1,2-a] quinolines, structure is as shown in table 1.
The structural formula of 1. 1,3- diazacyclos of table simultaneously [1,2-a] quinolines
The antitumous effect of Part II the compounds of this invention
Application examples
51 compounds of the present invention are carried out testing for three-type-person's class tumor cell line：HCT116 (people's Colon and rectums
Cancer), A549 (pulmonary carcinoma), HT29 (colon cancer), SGC7901 (gastric cancer), HepG2 (hepatocarcinoma).By cell tests compound incubation
144 hours, cytotoxicity (Mossman, T.J.Immunol.Methods 1983,65,55 is measured using MTT algoscopys then
" the quick colorimetric test of cell viability；The quantitative application of cytotoxicity and growth inhibited lymphokine ".Green,
1984,70,257 " the quick colorimetric tests of cell viability of L.M.J.Immunol.Methods；Cytotoxicity and growth inhibited
The quantitative application of lymphokine "), as a result as shown in table 2.
The data obtained confirms that the compound of the present invention is to entity tumor such as people's knot-rectal cancer (HCT116), human lung cancer
(A549), human colon carcinoma (HT29), human gastric cancer (SGC7901), human liver cancer (HepG2) preferably anti-tumor activity.Wherein, chemical combination
The IC of 2,17～28 pairs of people's knot-rectal cancer (HCT116) cell strains of thing50(μ g/mL) is respectively 4.75,4.06,6.35,5.00,
4.48,5.06,5.32,6.38,7.70,8.44,5.65,8.53,8.72, the respectively less than IC of positive control medicine cisplatin50(μg/
ML)=8.74, and both less than 10 μ g/mL, superior active anticancer is shown relative to cisplatin.Compound 17 and compound 21 pairs
HCT116 (people's knot-rectal cancer), A549 (pulmonary carcinoma), HT29 (colon cancer), SGC7901 (gastric cancer), HepG2 (hepatocarcinoma) cell strain are equal
Superior active anticancer, IC are shown all50Value is much smaller than the IC of positive control medicine cisplatin50(μ g/mL) value, and both less than
10μg/mL。
Can be seen that according to data in table 2, for formula I structural compounds according to the present invention, when the n in formula I is 2 Hes
When 3, IC50Value be significantly less than n for 1 when, illustrate the increase with n, active anticancer strengthens therewith.In addition, when in formula I
When Ar refers to the phenyl for electron withdraw group replacement, IC50The Ar that value is significantly less than in formula I refers to the benzene replaced for electron donating group
Base.The replacement of electron withdraw group is illustrated, is conducive to the enhancing of activity.Compound 17 in embodiment 17, n=2 and Ar refer to inhale
The phenyl that electron group replaces, to HCT116 (people's knot-rectal cancer), A549 (pulmonary carcinoma), HT29 (colon cancer), SGC7901 (stomaches
Cancer), HepG2 (hepatocarcinoma) cell strain all shows superior active anticancer.IC50Value is much smaller than matched group cisplatin.
Cytotoxic activity of 2 the compounds of this invention of table to human tumor cell line
Note：IC in table50Value unit is μ g/mL；"-" is represented not to be surveyed.
Ultimate principle, principal character and the advantages of the present invention of the present invention has been shown and described above.The technology of the industry
Personnel it should be appreciated that the present invention is not restricted to the described embodiments, the simply explanation described in above-described embodiment and description this
The principle of invention, without departing from the spirit and scope of the present invention, the present invention also has various changes and modifications, these changes
Change and improvement is both fallen within scope of the claimed invention.The claimed scope of the invention by appending claims and its
Equivalent thereof.
Claims (8)
1.1,3- diazacyclos simultaneously [1,2-a] quinolines, it is characterised in that the structure of the compound is as shown in formula I：
Wherein, in formula I, Ar refers to phenyl, halogenophenyl, alkyl-substituted phenyl, alkoxy substituted phenyl, trifluoromethyl substituted benzene
Base, nitro substituted-phenyl, cyano group substituted-phenyl or thienyl；
R1～R4For halogen atom, hydrogen atom, alkyl, trifluoromethyl, nitro or piperidyl；
N is 1 or 2 or 3.
2. the preparation method of simultaneously [1, the 2-a] quinolines of 1, the 3- diazacyclos described in claim 1, it is characterised in that
Comprise the steps：
With the 2- fluorobenzaldehyde class compounds of formula II structure and the heterocycle ketene peptide amine compound of formula III structure in solvent
In, heat under alkalescence condition or inorganic salt existence condition, carry out nucleophilic displacement of fluorine and condensation reaction complete to TLC detection reactions
Afterwards, purification, that is, obtain 1,3- diazacyclos shown in formula I simultaneously [1,2-a] quinolines；
In formula II, R1～R4For halogen atom, hydrogen atom, alkyl, trifluoromethyl, nitro or piperidyl；
In formula III, Ar refers to phenyl, halogenophenyl, alkyl-substituted phenyl, alkoxy substituted phenyl, trifluoromethyl substituted benzene
Base, nitro substituted-phenyl, cyano group substituted-phenyl or thienyl；N is 1 or 2 or 3.
3. the preparation method of 1,3- diazacyclos according to claim 2 simultaneously [1,2-a] quinolines, its feature exist
In described solvent is methanol, ethanol, water, acetone, dichloromethane, chloroform, ethyl acetate, DMF, tetrahydrochysene
The mixed solvent of one or more solvents in furan, toluene, 1,4- dioxane and acetonitrile.
4. the preparation method of 1,3- diazacyclos according to claim 2 simultaneously [1,2-a] quinolines, its feature exist
In described alkali is the heterocycle alkene of the mixture of one or more in piperidines, triethylamine and calcium oxide, alkali and formula III structure
The mol ratio of ketone contracting aminated compoundss is 1：0.5～2；Described inorganic salt is calcium chloride, and inorganic salt is miscellaneous with formula III structure
The mol ratio of annulenones contracting aminated compoundss is 1：0.5～2.
5. the preparation method of 1,3- diazacyclos according to claim 2 simultaneously [1,2-a] quinolines, its feature exist
In heating-up temperature is 40～110 DEG C.
6. the preparation method of 1,3- diazacyclos according to claim 2 simultaneously [1,2-a] quinolines, its feature exist
In the response time is 0.5～24 hour.
7. the preparation method of 1,3- diazacyclos according to claim 2 simultaneously [1,2-a] quinolines, its feature exist
In the 2- fluorobenzaldehyde class compounds of formula II structure with the mol ratio of the heterocycle ketene peptide amine compound of formula III structure are
1：1～3.
8. the 1,3- diazacyclos described in claim 1 simultaneously [1,2-a] quinolines as prepare antitumor drug should
With.
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