CN106967077B - A kind of chromene simultaneously [2,3-b] quinoline and its preparation method and application - Google Patents
A kind of chromene simultaneously [2,3-b] quinoline and its preparation method and application Download PDFInfo
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- CN106967077B CN106967077B CN201710352936.4A CN201710352936A CN106967077B CN 106967077 B CN106967077 B CN 106967077B CN 201710352936 A CN201710352936 A CN 201710352936A CN 106967077 B CN106967077 B CN 106967077B
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- quinoline
- chromene
- formaldehyde
- hydroresorcinol
- synthetic method
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title claims abstract description 72
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims abstract description 32
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 claims abstract description 25
- SDKQWXCBSNMYBN-UHFFFAOYSA-N 2-chloroquinoline-3-carbaldehyde Chemical compound C1=CC=C2C=C(C=O)C(Cl)=NC2=C1 SDKQWXCBSNMYBN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 6
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- 239000003054 catalyst Substances 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 230000005855 radiation Effects 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 12
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 11
- 238000010189 synthetic method Methods 0.000 claims description 9
- 230000000259 anti-tumor effect Effects 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- WZUNMOMEOMPYKZ-UHFFFAOYSA-N 2,6-dichloroquinoline-3-carbaldehyde Chemical compound N1=C(Cl)C(C=O)=CC2=CC(Cl)=CC=C21 WZUNMOMEOMPYKZ-UHFFFAOYSA-N 0.000 claims description 2
- TZQOMBXDCIPJKW-UHFFFAOYSA-N 2-chloro-6-methoxyquinoline-3-carbaldehyde Chemical compound N1=C(Cl)C(C=O)=CC2=CC(OC)=CC=C21 TZQOMBXDCIPJKW-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- RBSGIVJDQUQHEJ-UHFFFAOYSA-N C(CCC)C1=NC2=CC=CC=C2C=C1C=O Chemical compound C(CCC)C1=NC2=CC=CC=C2C=C1C=O RBSGIVJDQUQHEJ-UHFFFAOYSA-N 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 abstract description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 238000011156 evaluation Methods 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 abstract description 2
- 210000004881 tumor cell Anatomy 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 239000012046 mixed solvent Substances 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000002253 acid Substances 0.000 description 5
- 235000015177 dried meat Nutrition 0.000 description 5
- OFUFXTHGZWIDDB-UHFFFAOYSA-N 2-chloroquinoline Chemical compound C1=CC=CC2=NC(Cl)=CC=C21 OFUFXTHGZWIDDB-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- KIGMPVBHMWSQQG-UHFFFAOYSA-N 6-tert-butyl-2-chloroquinoline-3-carbaldehyde Chemical compound N1=C(Cl)C(C=O)=CC2=CC(C(C)(C)C)=CC=C21 KIGMPVBHMWSQQG-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- -1 nitrogen-containing heterocycle compound Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- LPDFGLZUUCLXGM-UHFFFAOYSA-N 2,6-dichloroquinoline Chemical compound N1=C(Cl)C=CC2=CC(Cl)=CC=C21 LPDFGLZUUCLXGM-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 102000001307 androgen receptors Human genes 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000008371 chromenes Chemical class 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- BADXJIPKFRBFOT-UHFFFAOYSA-N dimedone Chemical compound CC1(C)CC(=O)CC(=O)C1 BADXJIPKFRBFOT-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 1
- 150000002515 isoflavone derivatives Chemical class 0.000 description 1
- 235000008696 isoflavones Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
A kind of chromene simultaneously [2,3-b] quinoline, structure shown in structural formula as I:Wherein, R1For H, CH3O, Cl or (CH3)3Any one in C；R2For H or CH3；R3For H, CH3Or Ph.For the derivative with 2- chloroquinoline -3- formaldehyde or derivatives thereof, malononitrile and 1, hydroresorcinol or derivatives thereof is raw material, one-step synthesis.Synthesis route is simple and direct, mild condition, and total recovery is up to 61% or more.Compound provided by the invention confirms there is preferable external Inhibit proliferaton effect to human body hepatoma cell line HepG2 through pharmacological evaluation, has the function of inhibiting growth of tumour cell, can apply in the preparation of antitumor drugs.
Description
Technical field
The invention belongs to technical field of organic synthesis, it is related to the preparation method of chromene simultaneously [2,3-b] quinoline, and
Application in anti-tumor drug
Background technique
Chromene, also known as chromene, skeleton are widely present in natural products, such as: vitamin E, flavones, isoflavones
Deng all contain chromene skeleton.Chromene derivative has extensive biology and pharmacological activity.Existing antiallergy and anticancer isoreactivity side
The report in face.
Quinoline is also benzo pyridine or azanaphthalene, is a kind of very important nitrogen-containing heterocycle compound, especially in pharmacy work
It is had a wide range of applications in industry.Moreover, they are also the parent nucleus of many natural products and biologically active drug structure, and such as: chlorine
The peaceful alkali of quinoline, camel, camptothecine.By the continuous research of drug scholar, a large amount of quinoline derivatives are synthesized, and it
Have extensive bioactivity, such as: anti-malarial, antibacterial, anti-inflammatory, antitumor, anti-diabetic, anti-asthma, anti-hypertension,
Anti- Alzheimer that disease, platelet aggregation-against, AntiHIV1 RT activity isoreactivity.
Chromene and quinoline are a kind of important fused heterocyclic compounds, have extensive bioactivity, in medicine
Object chemical field has important application value.Such as: simultaneously to can be used as beta-selective female for [4,3-b] quinoline for 6H- chromene
Androgen receptor ligand.In addition, since it is with very strong photoluminescent property, chromene and quinoline can also be applied to biology at
Picture.There are the derivatives such as chromene of the document report with spirane structure and quinoline that there is good anti-tumor activity recently, as a result table
Such bright compound has cytotoxic activity to breast cancer, cervical carcinoma.So design and synthesize some structure novels have color
Simultaneously quinoline has certain meaning to alkene.
Summary of the invention
The object of the present invention is to provide a kind of synthesis of new chromene simultaneously [2,3-b] quinoline, through extracorporeal anti-tumor
Active testing, such compound have preferable anti-tumor activity.
A kind of chromene simultaneously [2,3-b] quinoline, structure shown in structural formula as I:
Wherein, R1For H, CH3O, Cl or (CH3)3Any one in C；R2For H or CH3；R3For H, CH3Or Ph.
A kind of synthetic method such as chromene simultaneously [2,3-b] quinoline, with 2- chloroquinoline -3- formaldehyde or derivatives thereof,
Malononitrile and 1, hydroresorcinol or derivatives thereof are raw material, and one-step synthesis Formulas I compound represented, reaction equation is such as
Under:
2- chloroquinoline -3- the formaldehyde derivatives are the chloro- 6- methoxy quinoline -3- formaldehyde of 2-, 2,6- dichloroquinoline -3-
Any one in formaldehyde and the chloro- 6- tert-butyl quinoline-3-formaldehyde of 2-；The hydroresorcinol derivative is 5,5- diformazan
Any one of base-hydroresorcinol, 5- phenyl-hydroresorcinol.
The solvent of reaction is acetonitrile, tetrahydrofuran, toluene, ethylene glycol, N,N-dimethylformamide (DMF), water and ethyl alcohol
Any one of, wherein preferred alcohol.The catalyst of reaction can be alkali, such as sodium hydroxide, sodium carbonate, cesium carbonate, hexahydro
Pyridine is also possible to acid, such as p-methyl benzenesulfonic acid, acetic acid either organic micromolecule catalyst such as L-PROLINE.Preferably L-
Proline.
Mole of 2- chloroquinoline -3- formaldehyde or derivatives thereof, malononitrile, hydroresorcinol or derivatives thereof and catalyst
Than for 1:1:1:0.1~0.6.It is preferred that 1:1:1:0.5.Reaction carries out in microwave reactor, and the temperature of reaction is 80~110
DEG C, preferably 100 DEG C, the effect of microwave can accelerate to react.
Preferably, 2- chloroquinoline -3- formaldehyde, malononitrile and 1, hydroresorcinol are catalyst in microwave using L-PROLINE
Under radiation, 100 DEG C are reacted 20 minutes, and the molar ratio of raw material is 2- chloroquinoline -3- formaldehyde: malononitrile: 1, hydroresorcinol: L- dried meat
Propylhomoserin=1:1:1:0.5.
The chromene that the present invention synthesizes simultaneously [2,3-b] quinoline is a kind of quite stable compound, these compounds
There is preferable external Inhibit proliferaton effect to human body hepatoma cell line HepG2, show by anti tumor activity in vitro test
Most compounds have apparent anti-tumor activity, and wherein compound Ic, Id, Ig, Ii has good anti-tumor activity, it
IC50It is worth as follows:
The utility model has the advantages that synthesis route of the invention is simple and direct, mild condition, up to 61% or more, the present invention mentions total recovery
For chromene simultaneously [2,3-b] quinoline through pharmacological evaluation confirm that there is human body hepatoma cell line HepG2 it is preferable external
Inhibit proliferaton effect has the function of inhibiting growth of tumour cell, can apply in the preparation of antitumor drugs.
Specific embodiment
Embodiment 1
By 2- chloroquinoline -3- formaldehyde (0.2mmol), malononitrile (0.2mmol) and 5,5- dimethyl-hydroresorcinol
(0.2mmol) is added in 5mL microwave reaction pipe, is added L-PROLINE (0.1mmol) and ethyl alcohol 2mL, will be reacted the seal of tube,
Stirring 10 seconds in advance, mixture react 30 minutes in 100 DEG C under microwave radiation, after reaction, reaction system are cooled to
Room temperature is filtered after solid is precipitated, then is carried out being recrystallized to give 2- (3,3- dimethyl -1- with the mixed solvent of DMF and water
Oxo -2,3,4,12- tetrahydro -1H- chromene simultaneously [2,3-b] quinoline -12- base) malononitrile (Ia): yield 71%；m.p.:248-
250℃；IR(KBr,ν,cm-1):3047,2920,2254,1622,1598,1448,1399,1215,1091,1055,1027,
999,752,689；1H NMR(400MHz,DMSO-d6) (δ, ppm): 8.71 (s, 1H, ArH), 8.07 (d, J=7.6Hz, 1H,
), ArH 7.94 (d, J=8.4Hz, 1H, ArH), 7.88-7.84 (m, 1H, ArH), 7.67-7.63 (m, 1H, ArH), 5.23 (d, J
=4.0Hz, 1H, CH), 5.00 (d, J=4.0Hz, 1H, CH), 2.81 (d, J=18.0Hz, 1H, CH), 2.68 (d, J=
18.0Hz, 1H, CH), 2.48 (d, J=16.0Hz, 1H, CH), 2.35 (d, J=16.0Hz, 1H, CH), 1.16 (s, 3H, CH3),
1.14(s,3H,CH3)。
Embodiment 2
According to the method for embodiment 1,2- chloroquinoline -3- formaldehyde is changed into 6- methoxyl group -2- chloroquinoline -3- formaldehyde, with L-
Proline is catalyst, reacts 30 minutes under microwave radiation, is recrystallized to give target product 2- with the mixed solvent of DMF and water
(9- methoxyl group -3,3- dimethyl -1- oxo -2,3,4,12- tetrahydro -1H- chromene simultaneously [2,3-b] quinoline -12- base) malononitrile
(Ib): yield 74%；m.p.:268-270℃；IR(KBr,ν,cm-1):2896,2254,1635,1613,1466,1356,
1238,1216,1142,1112,1029,834；1H NMR(400MHz,DMSO-d6)(δ,ppm):8.57(s,1H,ArH),7.84
(d, J=9.2Hz, 1H, ArH), 7.51-7.48 (m, 1H, ArH), 7.45 (d, J=2.4Hz, 1H, ArH), 5.20 (d, J=
4.0Hz, 1H, CH), 4.97 (d, J=3.6Hz, 1H, CH), 3.93 (s, 3H, CH3), O 2.79 (d, J=17.6Hz, 1H, CH),
2.65 (d, J=17.2Hz, 1H, CH), 2.45 (d, J=16.4Hz, 1H, CH), 2.33 (d, J=16.4Hz, 1H, CH), 1.15
(s,3H,CH3),1.13(s,3H,CH3)。
Embodiment 3
According to the method for embodiment 1,2- chloroquinoline -3- formaldehyde is changed into 6- tert-butyl -2- chloroquinoline -3- formaldehyde, with L-
Proline is catalyst, reacts 30 minutes under microwave radiation, is recrystallized to give target product 2- with the mixed solvent of DMF and water
(9- tert-butyl -3,3- dimethyl -1- oxo -2,3,4,12- tetrahydro -1H- chromene simultaneously [2,3-b] quinoline -12- base) malononitrile
(Ic): yield 75%；m.p.:228-230℃；IR(KBr,ν,cm-1):2960,2937,2254,1642,1611,1439,
1394,1346,1265,1236,1212,1174,1145,1118,1024,997,831；1HNMR(400MHz,DMSO-d6)(δ,
Ppm): 8.68 (s, 1H, ArH), 8.01-7.89 (m, 3H, ArH), 5.25 (d, J=3.6Hz, 1H, CH), 4.99 (d, J=
3.6Hz, 1H, CH), 2.81 (d, J=18.0Hz, 1H, CH), 2.52 (d, J=18.8Hz, 2H, CH2), 2.36 (d, J=
16.0Hz,1H,CH),1.41(s,9H,(CH3)3C)。
Embodiment 4
According to the method for embodiment 1,2- chloroquinoline -3- formaldehyde is changed into 2,6- dichloroquinoline -3- formaldehyde, with L-PROLINE
It for catalyst, is reacted 30 minutes under microwave radiation, being recrystallized to give target product 2- with the mixed solvent of DMF and water, (9- is chloro-
3,3- dimethyl -1- oxo -2,3,4,12- tetrahydro -1H- chromene simultaneously [2,3-b] quinoline -12- base) malononitrile (Id): yield
70%；m.p.:264-266℃；IR(KBr,ν,cm-1):2901,2257,1637,1345,1232,1212,1024,993,827,
763；1H NMR(400MHz,DMSO-d6) (δ, ppm): 8.69 (s, 1H, ArH), 8.25 (d, J=2.4Hz, 1H, ArH), 7.96
(d, J=9.2Hz, 1H, ArH), 7.89-7.86 (m, 1H, ArH), 5.23 (d, J=4.4Hz, 1H, CH), 5.00 (d, J=
4.0Hz, 1H, CH), 2.80 (d, J=18.0Hz, 1H, CH), 2.67 (d, J=18.0Hz, 1H, CH), 2.47 (d, J=
16.4Hz, 1H, CH), 2.34 (d, J=16.4Hz, 1H, CH), 1.15 (s, 3H, CH3),1.13(s,3H,CH3)。
Embodiment 5
According to the method for embodiment 1, by dimethyl -1 5,5-, hydroresorcinol changes 1 into, hydroresorcinol, with L- dried meat ammonia
Acid is catalyst, reacts 30 minutes under microwave radiation, is recrystallized to give target product 2- (1- with the mixed solvent of DMF and water
Oxo -2,3,4,12- tetrahydro -1H- chromene simultaneously [2,3-b] quinoline -12- base) malononitrile (Ie): yield 75%；m.p.:272-
274℃；IR(KBr,ν,cm-1):2930,2253,1656,1634,1498,1240,1214,1184,1048,1024,789,
764；1H NMR(400MHz,DMSO-d6) (δ, ppm): 8.71 (s, 1H, ArH), 8.07 (d, J=8.0Hz, 1H, ArH), 7.94
(d, J=8.4Hz, 1H, ArH), 7.88-7.84 (m, 1H, ArH), 7.67-7.63 (m, 1H, ArH), 5.14 (d, J=4.0Hz,
1H, CH), 5.00 (d, J=3.6Hz, 1H, CH), 2.85-2.82 (m, 2H, CH2),2.49-2.43(m,2H,CH2),2.15-
1.97(m,2H,CH2)。
Embodiment 6
According to the method for embodiment 2, by dimethyl -1 5,5-, hydroresorcinol changes 1 into, hydroresorcinol, with L- dried meat ammonia
Acid is catalyst, reacts 30 minutes under microwave radiation, is recrystallized to give target product 2- (9- with the mixed solvent of DMF and water
Methoxyl group -1- oxo -2,3,4,12- tetrahydro -1H- chromene simultaneously [2,3-b] quinoline -12- base) malononitrile (If): yield 73%；
m.p.:278-280℃；IR(KBr,ν,cm-1):2912,2254,1629,1614,1504,1457,1398,1358,1218,
1142,1025,1002,829,785；1H NMR(400MHz,DMSO-d6) (δ, ppm): 8.57 (s, 1H, ArH), 7.84 (d, J=
9.2Hz, 1H, ArH), 7.51-7.48 (m, 1H, ArH), 7.45 (d, J=2.8Hz, 1H, ArH), 5.11 (d, J=4.0Hz, 1H,
), CH 4.97 (d, J=3.6Hz, 1H, CH), 3.92 (s, 3H, CH3O),2.84-2.82(m,2H,CH2),2.49-2.47(m,2H,
CH2),2.15-1.96(m,2H,CH2)。
Embodiment 7
According to the method for embodiment 3, by dimethyl -1 5,5-, hydroresorcinol changes 1 into, hydroresorcinol, with L- dried meat ammonia
Acid is catalyst, reacts 30 minutes under microwave radiation, is recrystallized to give target product 2- (9- with the mixed solvent of DMF and water
Tert-butyl -1- oxo -2,3,4,12- tetrahydro -1H- chromene simultaneously [2,3-b] quinoline -12- base) malononitrile (Ig): yield 73%；
m.p.:246-248℃；IR(KBr,ν,cm-1):2956,2931,2257,1639,1504,1393,1236,1211,1185,
1047,1023,995,831,763；1H NMR(400MHz,DMSO-d6)(δ,ppm):8.66(s,1H,ArH),8.00-7.97
(m, 1H, ArH), 7.93 (d, J=2.0Hz, 1H, ArH), 7.87 (d, J=8.8Hz, 1H, ArH), 5.12 (d, J=3.6Hz,
1H, CH), 4.97 (d, J=3.6Hz, 1H, CH), 2.84-2.81 (m, 2H, CH2),2.48-2.46(m,2H,CH2),2.14-
1.99(m,2H,CH2),1.40(s,9H,(CH3)3C)。
Embodiment 8
According to the method for embodiment 4, by dimethyl -1 5,5-, hydroresorcinol changes 1 into, hydroresorcinol, with L- dried meat ammonia
Acid is catalyst, reacts 30 minutes under microwave radiation, is recrystallized to give target product 2- (9- with the mixed solvent of DMF and water
Chloro- 1- oxo -2,3,4,12- tetrahydro -1H- chromene simultaneously [2,3-b] quinoline -12- base) malononitrile (Ih): yield 68%；
m.p.:292-294℃；IR(KBr,ν,cm-1):2895,2256,1630,1486,1391,1341,1234,1185,1024,
995,921,827；1H NMR(400MHz,DMSO-d6)(δ,ppm):8.68(s,1H,ArH),8.24(s,1H,ArH),7.96-
7.93(m,1H,ArH),7.88-7.84(m,1H,ArH),5.14-5.12(m,1H,CH),5.01-4.96(m,1H,CH),
2.89-2.92(m,4H,2×CH2),2.15-1.96(m,2H,CH2)。
Embodiment 9
According to the method for embodiment 1, by dimethyl -1 5,5-, hydroresorcinol changes phenyl -1 5- into, hydroresorcinol, with
L-PROLINE is catalyst, reacts 30 minutes under microwave radiation, is recrystallized to give target product with the mixed solvent of DMF and water
2- (1- oxo -3- phenyl -2,3,4,12- tetrahydro -1H- chromene simultaneously [2,3-b] quinoline -12- base) malononitrile (Ii): yield
64%；m.p.:226-228℃；IR(KBr,ν,cm-1):2936,2257,1636,1497,1397,1240,1203,1024,
993,761；1H NMR(400MHz,CDCl3) (δ, ppm): 8.75-8.73 (m, 1H, ArH), 8.09 (d, J=8.4Hz, 1H,
), ArH 7.95 (d, J=8.0Hz, 1H, ArH), 7.89-7.85 (m, 1H, ArH), 7.68-7.64 (m, 1H, ArH), 7.47-
7.34(m,4H,ArH),7.31-7.25(m,1H,ArH),5.18-5.13(m,1H,CH),5.08-5.05(m,1H,CH),
3.67-3.50(m,1H,CH),3.26-3.13(m,1H,CH),3.06-2.99(m,1H,CH),2.88-2.74(m,1H,CH),
2.68-2.63(m,1H,CH)。
Embodiment 10
According to the method for embodiment 3, by dimethyl -1 5,5-, hydroresorcinol changes phenyl -1 5- into, hydroresorcinol, with
Hexahydropyridine is catalyst, reacts 30 minutes under microwave radiation, is recrystallized to give target product with the mixed solvent of DMF and water
2- (9- tert-butyl -1- oxo -3- phenyl -2,3,4,12- tetrahydro -1H- chromene simultaneously [2,3-b] quinoline -12- base) malononitrile
(Ij): yield 67%；m.p.:248-250℃；IR(KBr,ν,cm-1):2963,2933,2255,1638,1502,1418,
1366,1239,1205,1123,1098,1025,999,947,833；1H NMR(400MHz,DMSO-d6)(δ,ppm):8.73-
8.72(m,1H,ArH),8.04-7.91(m,3H,ArH),7.50-7.30(m,5H,ArH),5.20-5.15(m,1H,CH),
5.09-5.05(m,1H,CH),3.70-3.53(m,1H,CH),3.26-3.16(m,1H,CH),3.08-3.02(m,1H,CH),
2.95-2.88(m,1H,CH),2.71-2.66(m,1H,CH),1.44(s,9H,(CH3)3C)。
Embodiment 11
According to the method for embodiment 4, by dimethyl -1 5,5-, hydroresorcinol changes phenyl -1 5- into, hydroresorcinol, with
P-methyl benzenesulfonic acid is catalyst, is reacted 30 minutes under microwave radiation, is recrystallized to give target with the mixed solvent of DMF and water and produces
Object 2- (the chloro- 1- oxo -3- phenyl -2,3,4,12- tetrahydro -1H- chromene of 9- simultaneously [2,3-b] quinoline -12- base) malononitrile
(Ik): yield 69%；m.p.:270-272℃；IR(KBr,ν,cm-1):2902,2256,1639,1492,1454,1444,
1234,1200,1024,997,839,762；1H NMR(400MHz,CDCl3)(δ,ppm):8.73-8.71(m,1H,ArH),
8.27-7.86(m,1H,ArH),7.98-7.96(m,1H,ArH),7.89-7.86(m,1H,ArH),7.47-7.34(m,4H,
ArH),7.31-7.25(m,1H,ArH),5.19-5.14(m,1H,CH),5.08-5.05(m,1H,CH),3.67-3.50(m,
1H,CH),3.26-3.11(m,1H,CH),3.06-2.98(m,1H,CH),2.87-2.77(m,1H,CH),2.68-2.63(m,
1H,CH)。
Claims (8)
1. a kind of synthetic method of chromene simultaneously [2,3-b] quinoline, structure shown in structural formula as I:
Wherein, R1For H, CH3O, Cl or (CH3)3Any one in C；R2For H or CH3；R3For H, CH3Or Ph；It is characterized in that,
With 2- chloroquinoline -3- formaldehyde or derivatives thereof, malononitrile and 1, hydroresorcinol or derivatives thereof is raw material, one-step synthesis Formulas I
Compound represented, reaction equation are as follows:
2. the synthetic method of chromene as described in claim 1 simultaneously [2,3-b] quinoline, which is characterized in that the 2-
Chloroquinoline -3- formaldehyde derivatives are the chloro- 6- methoxy quinoline -3- formaldehyde of 2-, 2,6- dichloroquinoline -3- formaldehyde and chloro- uncle 6- of 2-
Any one in butyl quinoline-3-formaldehyde；The hydroresorcinol derivative is 5,5- dimethyl -1,3- hexamethylene two
Any one of ketone, 5- phenyl-hydroresorcinol.
3. the synthetic method of chromene as described in claim 1 simultaneously [2,3-b] quinoline, which is characterized in that reaction it is molten
Agent is any one of acetonitrile, tetrahydrofuran, toluene, ethylene glycol, N,N-dimethylformamide, water and ethyl alcohol.
4. the synthetic method of chromene as described in claim 1 simultaneously [2,3-b] quinoline, which is characterized in that reaction is urged
Agent is any one in sodium hydroxide, sodium carbonate, cesium carbonate, hexahydropyridine, p-methyl benzenesulfonic acid, acetic acid and L-PROLINE or several
Kind.
5. the synthetic method of chromene as claimed in claim 4 simultaneously [2,3-b] quinoline, which is characterized in that 2- chloroquinoline-
The molar ratio of 3- formaldehyde or derivatives thereof, malononitrile, hydroresorcinol or derivatives thereof and catalyst be 1:1:1:0.1~
0.6。
6. the synthetic method of chromene as described in claim 1 simultaneously [2,3-b] quinoline, which is characterized in that reaction is micro-
It is carried out in wave reactor, the temperature of reaction is 80~110 DEG C.
7. the synthetic method of chromene as described in claim 1 simultaneously [2,3-b] quinoline, which is characterized in that 2- chloroquinoline-
3- formaldehyde, malononitrile and 1, hydroresorcinol are catalyst under microwave radiation using L-PROLINE, and 100 DEG C are reacted 20 minutes, former
The molar ratio of material is 2- chloroquinoline -3- formaldehyde: malononitrile: hydroresorcinol: L-PROLINE=1:1:1:0.5.
8. a kind of chromene of synthetic method as described in claim 1 preparation simultaneously [2,3-b] quinoline prepare it is antitumor
Application in drug.
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