CN116444491A - Quinolone derivative and preparation method and application thereof - Google Patents
Quinolone derivative and preparation method and application thereof Download PDFInfo
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- CN116444491A CN116444491A CN202310327619.2A CN202310327619A CN116444491A CN 116444491 A CN116444491 A CN 116444491A CN 202310327619 A CN202310327619 A CN 202310327619A CN 116444491 A CN116444491 A CN 116444491A
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- 150000007660 quinolones Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 229920001661 Chitosan Polymers 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000005859 coupling reaction Methods 0.000 claims abstract description 3
- -1 trifluoromethoxy, difluoromethyl Chemical group 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims description 4
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 239000002184 metal Substances 0.000 claims 3
- 150000003839 salts Chemical class 0.000 claims 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 230000000259 anti-tumor effect Effects 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 8
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 6
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical group C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001879 copper Chemical class 0.000 abstract description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical group C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 abstract description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 230000009466 transformation Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 4
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229940124307 fluoroquinolone Drugs 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- YJILUBVUPBRFOH-UHFFFAOYSA-N 7-chloro-1-[4-(4-chlorophenoxy)phenyl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound ClC1=C(C=C2C(C(=CN(C2=C1)C1=CC=C(C=C1)OC1=CC=C(C=C1)Cl)C(=O)O)=O)F YJILUBVUPBRFOH-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a quinolone derivative, a preparation method and application thereof. The invention carries out structural transformation on the N-1 position and the C-7 position of 4-quinolone, respectively introduces a diphenyl ether structure and a pyridine or pyrimidine bipiperazine structure, develops a novel quinolone-diphenyl ether hybrid structure, is used for researching anti-tumor activity, and has better inhibition activity on Umg87 cells. According to the invention, in an organic solvent, chitosan (chitosan) loaded copper salt is used as a catalyst [ CS@Cu (II) ], and the green synthesis of the target compound is realized through a C-N coupling reaction, so that the method has the advantages of high reaction yield, easiness in separation of the catalyst and reusability.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a quinolone derivative, a preparation method and application thereof.
Background
Fluoroquinolones are developed in 1962 and are updated and improved continuously after decades, and the second generation, third generation and fourth generation fluoroquinolones are formed, so that the fluoroquinolones have the advantages of wide antibacterial spectrum, strong bactericidal activity, low toxicity, high curative effect and the like, and are widely used for treating various bacterial infections clinically. Over the last decade, structural modifications have led to the discovery that these compounds also possess many other biological activities, such as anti-tumor, antiviral, anxiolytic, etc., and that certain candidate compounds have entered the clinical stage of research. The quinolone compounds are bacterial topoisomerase II inhibitors, and researches show that the bacterial topoisomerase II has homology with the sequence of the mammalian topoisomerase II around the active site tyrosine, and certain quinolone compounds have stronger inhibition effect on the mammalian topoisomerase II. At present, hundreds of quinolone derivatives with antitumor activity have been reported through structural modification, and the quinolone derivatives are possible to become novel antitumor drugs targeting topoisomerase II. Therefore, designing a novel anti-tumor drug based on a quinolone drug as a structural basis has become a popular field of tumor chemistry.
The invention modifies the structure of 4-quinolone, respectively introduces diphenyl ether structure and pyridine or pyrimidine bipiperazine structure to obtain novel quinolone-diphenyl ether hybrid, and performs primary research on antitumor activity.
Disclosure of Invention
The invention provides a quinolone derivative, a preparation method and application thereof, wherein a diphenyl ether structural unit is introduced into the N-1 position of a 4-quinolone main ring, a pyridine or pyrimidine bipiperazine structure is introduced into the C-7 position, a series of novel quinolone-diphenyl ether hybrids are obtained, and are used for testing the activity of antitumor cells, and a green synthesis method is developed.
The technical scheme adopted by the invention is as follows:
a quinolone derivative having a chemical structural formula represented by general formula (I):
wherein X is N or CH;
R 1 、R 2 、R 3 respectively one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, mercapto, cyano, nitro, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, monofluoromethyl and fluoromethoxy;
R 4 、R 5 is one of hydrogen, halogen, cyano and nitro;
the structural formula corresponds to the formula (I-a):
wherein X is N or CH;
R 1 、R 2 respectively one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, mercapto, cyano, nitro, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, monofluoromethyl and fluoromethoxy;
the invention also provides a preparation method of the 4-quinolone-hybrid compound, which comprises the following steps:
in an organic solvent, a copper salt loaded by chitosan (chitosan) is used as a catalyst [ CS@Cu (II) ], and organic amine is used as alkali, and under a certain temperature, the raw material (II) and the raw material III are subjected to a coupling reaction to obtain the target compound I.
The chitosan-supported catalyst is selected from CS@CuCl 2 、CS@CuBr 2 、CS@Cu(OAc) 2 、CS@Ni(NO 3 ) 2 、CS@Ni(SO 4 ) 2 One of them.
The organic solvent is selected from one of sulfolane, dimethyl sulfoxide, N-dimethyl formyl (DMF) and N, N-dimethyl acetamide (DMAc).
The organic amine is selected from one of triethylamine, ethylenediamine, diisopropylamine, tetramethyl ethylenediamine and tert-butylamine.
The mass ratio of the raw material II to the copper salt as the active ingredient in the supported catalyst is 1: (0.01-1).
The invention further provides application of the quinolone derivative in antibacterial drugs and antitumor drugs.
The novel quinolone derivative (I) prepared by the invention has the application of antitumor cell activity. The anti-tumor cells comprise human breast cancer cells (MCF-7), human liver cancer cells (HepG 2), glioma cancer cells (U87 mg) and human lung cancer cells (A549).
Compared with the prior art, the invention has the beneficial effects that:
(1) The quinolone derivative has anti-tumor cell proliferation activity, and particularly has excellent inhibition effect on U78mg cells;
(2) The invention adopts chitosan loaded copper salt as the catalyst to prepare the novel quinolone compound, and has the advantages of easy separation, recycling, mild process conditions and the like.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The quinolone derivative (I) prepared by the invention is shown in table 1:
table 1 library table of compounds
| Compounds of formula (I) | X | R 1 | R 2 | R 3 | R 4 | R 5 |
| Ⅰ-1 | N | H | H | H | H | F |
| Ⅰ-2 | N | 4-Me | H | H | H | F |
| Ⅰ-3 | N | 3-Me | H | H | H | F |
| Ⅰ-4 | N | 2-Me | H | H | H | F |
| Ⅰ-5 | N | 4-Cl | H | H | H | F |
| Ⅰ-6 | N | 3-Cl | H | H | H | F |
| Ⅰ-7 | N | 2-Cl | H | H | H | F |
| Ⅰ-8 | N | 4-OMe | H | H | H | F |
| Ⅰ-9 | N | 3-OMe | H | H | H | F |
| Ⅰ-10 | N | 2-OMe | H | H | H | F |
| Ⅰ-11 | N | 4-F | H | H | H | F |
| Ⅰ-12 | N | 4-C 2 H 5 | H | H | H | F |
| Ⅰ-13 | N | 4-(t-Bu) | H | H | H | F |
| Ⅰ-14 | N | 4-OCF 3 | H | H | H | F |
| Ⅰ-15 | N | 4-Cl | 3-Cl | H | H | F |
| Ⅰ-16 | N | 4-Me | 3-Me | H | H | F |
| Ⅰ-17 | N | 4-Cl | 3-Cl | 2-Cl | H | F |
| Ⅰ-18 | CH | H | H | H | H | F |
| Ⅰ-19 | CH | 4-Me | H | H | H | F |
| Ⅰ-20 | CH | 4-Cl | H | H | H | F |
| Ⅰ-21 | CH | 4-OMe | H | H | H | F |
| Ⅰ-22 | CH | 4-F | H | H | H | F |
| Ⅰ-23 | CH | 4-C 2 H 5 | H | H | H | F |
| Ⅰ-24 | CH | 4-(t-Bu) | H | H | H | F |
| Ⅰ-25 | CH | 4-OCF 3 | H | H | H | F |
Example 1
Preparation of 6-fluoro-7- (2-pyridylpiperazin-1-yl) -4-oxo-1- (4- (4-chlorophenoxy) phenyl) -1, 4-dihydroquinoline-3-carboxylic acid Compound I-20
Into a 10mL reaction tube was charged the starting material 6-fluoro-7-chloro-4-oxo-1- (4- (4-chlorophenoxy) phenyl) -1, 4-dihydroquinoline-3-carboxylic acid (0.44 g,1.0 mmol), 1- (pyridin-2-yl) piperazine (0.326 g,2.0 mmol), CS@Cu (OAc) 2 (5% loading, 0.363 g), tetramethyl ethylenediamine (0.232 g,2.0 mmol) and dimethyl sulfoxide (3.0 g), at 50℃for 6 hours, and TLC monitored the end of the reaction. After the completion, cooling the reaction liquid to room temperature, adding 20mL of purified water into the reaction system, extracting for 2-3 times by using ethyl acetate, and combining organic layers; the organic layer was washed twice with water, washed with saturated sodium chloride, and the organic layer was collected, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and the target compound was isolated by column chromatography in 62.5% yield.
1 H NMR(600MHz,CDCl 3 )δ14.92(s,1H),8.66(s,1H),8.20(dd,J＝4.8,1.6Hz,1H),8.07(d,J＝12.9Hz,1H),7.55-7.50(m,1H),7.43-7.41(m,2H),7.40-7.36(m,2H),7.22-7.18(m,2H),7.14-7.06(m,2H),6.70-6.43(m,2H),6.44(d,J＝7.0Hz,1H),3.81-3.57(m,4H),3.41-3.11(m,4H)； 13 C NMR(150MHz,CDCl 3 )δ176.87,166.46,158.76,158.52,154.01,153.64,152.35,147.57(d,J＝23.7Hz),145.39(d,J＝10.4Hz),138.89,137.35,134.30,129.95,129.81,128.18,121.02,119.39(d,J＝7.9Hz),118.99,113.52,111.97(d,J＝23.6Hz),108.10,106.74,105.43,105.40,48.96,48.92,44.51.
Example 2
Compound I-5:6-fluoro-7- (2-pyrimidinylpiperazin-1-yl) -4-oxo-1- (4- (4-chlorophenoxy) phenyl) -1, 4-dihydroquinoline-3-carboxylic acid
Into a 10mL reaction tube was charged the starting material 6-fluoro-7-chloro-4-oxo-1- (4- (4-chlorophenoxy) phenyl) -1, 4-dihydroquinoline-3-carboxylic acid (0.44 g,1.0 mmol), 1- (pyridin-2-yl) piperazine (0.328 g,2.0 mmol), CS@Cu (OAc) 2 (5% loading, 0.363 g), tetramethyl ethylenediamine (0.232 g,2.0 mmol) and dimethyl sulfoxide (3.0 g), at 50℃for 6 hours, and TLC monitored the end of the reaction. After the completion, cooling the reaction liquid to room temperature, adding 20mL of purified water into the reaction system, extracting for 2-3 times by using ethyl acetate, and combining organic layers; the organic layer was washed twice with water, washed with saturated sodium chloride, and the organic layer was collected, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and the target compound was isolated by column chromatography in 61.1% yield.
1 H NMR(400MHz,CDCl 3 )δ8.64(s,1H),8.31(d,J＝4.8Hz,2H),8.06(d,J＝12.9Hz,1H),7.41(d,J＝8.8Hz,2H),7.36(d,J＝8.8Hz,2H),7.17(d,J＝8.8Hz,2H),7.08(d,J＝8.8Hz,2H),6.53(t,J＝4.8Hz,1H),6.42(d,J＝7.0Hz,1H),4.00-3.90(m,4H),3.22-3.05(m,4H).
Examples 3 to 25
Method referring to example 1, the preparation of each target product is shown in table 2 below:
TABLE 2
| Compounds of formula (I) | Yield% |
| Ⅰ-1 | 76.7 |
| Ⅰ-2 | 72.8 |
| Ⅰ-3 | 85.2 |
| Ⅰ-4 | 79.3 |
| Ⅰ-5 | 80.3 |
| Ⅰ-6 | 54.7 |
| Ⅰ-7 | 65.9 |
| Ⅰ-8 | 56.9 |
| Ⅰ-9 | 55.9 |
| Ⅰ-10 | 79.0 |
| Ⅰ-11 | 80.0 |
| Ⅰ-12 | 67.0 |
| Ⅰ-13 | 84.9 |
| Ⅰ-14 | 59.0 |
| Ⅰ-15 | 70.0 |
| Ⅰ-16 | 78.7 |
| Ⅰ-17 | 69.4 |
| Ⅰ-18 | 69.0 |
| Ⅰ-19 | 76.4 |
| Ⅰ-20 | 77.3 |
| Ⅰ-21 | 75.1 |
| Ⅰ-22 | 75.0 |
| Ⅰ-23 | 80.3 |
| Ⅰ-24 | 80.4 |
| Ⅰ-25 | 82.5 |
The antitumor activity test is shown in table 3:
table 3 compound antitumor cell Activity study
As can be seen from the test data in the table above, compounds I-15, I-20 and I-21 have better inhibitory activity against Umg87 cells at the same level as cisplatin.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. It is therefore intended that the following claims be interpreted as including the preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
Claims (8)
1. The quinolone derivative is characterized by having a chemical structural formula shown in a general formula (I):
wherein X is N or CH;
R 1 、R 2 、R 3 respectively one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, mercapto, cyano, nitro, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, monofluoromethyl and fluoromethoxy;
R 4 、R 5 is one of hydrogen, halogen, cyano and nitro.
2. The quinolone derivative according to claim 1, wherein the structural formula corresponds to formula (I-a):
wherein X is N or CH;
R 1 、R 2 is one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, mercapto, cyano, nitro, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, monofluoromethyl and fluoromethoxy.
3. A process for the preparation of a carbostyril derivative according to claim 1 or 2, comprising the steps of:
in an organic solvent, taking chitosan-loaded metal salt as a catalyst and organic amine as alkali, and carrying out coupling reaction on a raw material (II) and a raw material (III) at a certain temperature to obtain a quinolone derivative with a structure shown in a formula (I);
4. a process for the preparation of a quinolone derivative as claimed in claim 3, wherein the chitosan-supported metal salt is selected from cs@cucl 2 、CS@CuBr 2 、CS@Cu(OAc) 2 、CS@Ni(NO 3 ) 2 、CS@Ni(SO 4 ) 2 One of them.
5. The method for producing a quinolone derivative as defined in claim 3, wherein the organic solvent is one selected from the group consisting of sulfolane, dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide.
6. The method for producing a quinolone derivative as defined in claim 3, wherein the organic amine is one selected from the group consisting of triethylamine, ethylenediamine, diisopropylamine, tetramethylethylenediamine, and t-butylamine.
7. The method for producing a quinolone derivative as claimed in claim 3, wherein the ratio of the amount of the material II to the amount of the metal salt as the active ingredient in the supported catalyst is 1: (0.01-1).
8. Use of a quinolone derivative according to claim 1 or 2 for the preparation of an antitumor drug.
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