CN105541715A - 多取代吡啶-1(2h)-酮衍生物及其合成方法与应用 - Google Patents
多取代吡啶-1(2h)-酮衍生物及其合成方法与应用 Download PDFInfo
- Publication number
- CN105541715A CN105541715A CN201610074381.7A CN201610074381A CN105541715A CN 105541715 A CN105541715 A CN 105541715A CN 201610074381 A CN201610074381 A CN 201610074381A CN 105541715 A CN105541715 A CN 105541715A
- Authority
- CN
- China
- Prior art keywords
- formula
- phenyl
- compound
- fluorophenyl
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000010189 synthetic method Methods 0.000 title claims description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 74
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 230000002300 anti-fibrosis Effects 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 30
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 19
- -1 chloro-phenyl- Chemical group 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 14
- 239000003480 eluent Substances 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 14
- 239000011259 mixed solution Substances 0.000 claims description 14
- 238000000926 separation method Methods 0.000 claims description 14
- 238000010898 silica gel chromatography Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000004799 bromophenyl group Chemical group 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003944 tolyl group Chemical group 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 4
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical group NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 abstract description 27
- 229960003073 pirfenidone Drugs 0.000 abstract description 24
- 230000004071 biological effect Effects 0.000 abstract description 15
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 abstract description 2
- 230000035484 reaction time Effects 0.000 abstract description 2
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 15
- 239000007788 liquid Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- 239000000758 substrate Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 7
- 206010016654 Fibrosis Diseases 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 230000009471 action Effects 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 230000003176 fibrotic effect Effects 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 210000001161 mammalian embryo Anatomy 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JDZYVVUJIQYGRX-UHFFFAOYSA-N 1-(3-fluorophenyl)-5-methylpyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC(F)=C1 JDZYVVUJIQYGRX-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BFCJNNBGPNOXMX-UHFFFAOYSA-N C1(=CC=CC=C1)N1C(C=CC=C1)=O.CC=1C=C(C=C(C(=O)O)C1)C(=O)O Chemical compound C1(=CC=CC=C1)N1C(C=CC=C1)=O.CC=1C=C(C=C(C(=O)O)C1)C(=O)O BFCJNNBGPNOXMX-UHFFFAOYSA-N 0.000 description 1
- KZUNQIDMSYQIQI-UHFFFAOYSA-N CC(C(Cc1ccccc1)C1=C2CCCC1)N(Cc(cccc1)c1Cl)C2=O Chemical compound CC(C(Cc1ccccc1)C1=C2CCCC1)N(Cc(cccc1)c1Cl)C2=O KZUNQIDMSYQIQI-UHFFFAOYSA-N 0.000 description 1
- 0 C[C@@]1C(C(NCC(*)=O)=O)=C(C)C*2*1C2 Chemical compound C[C@@]1C(C(NCC(*)=O)=O)=C(C)C*2*1C2 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000004768 organ dysfunction Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种式(II)所示的多取代吡啶-1(2H)-酮衍生物,其合成方法为:氮气保护下,以式(I)所示化合物为原料,在有机溶剂中,碱性物质存在下,于20~80℃反应2~12h,之后反应液经后处理,得到式(II)所示产物;本发明所述化合物的合成操作简单易行,原料廉价易得,反应条件温和,反应时间短,对各种取代基都有很好的兼容性;合成的化合物含有一个新颖的并环吡啶酮结构,具有优于吡非尼酮的抗纤维化生物活性,可用于制备抗纤维化药物。
Description
(一)技术领域
本发明涉及一种新的具有抗纤维化生物活性的化合物——多取代吡啶-1(2H)-酮衍生物及其合成方法与应用。
(二)背景技术
纤维化(fibrosis)是指炎症、损伤等因素引起的组织实质性细胞坏死、组织内细胞的外基质(extracellularmatrix,ECM)异常的增多和过度的沉积引发病理的过程。纤维化有可能发生在人体所有的器官和组织,它可以加剧病情恶化,导致器官功能性障碍,因而导致器官衰竭甚至死亡。随着全球工业化以及人们生活、饮食方式的改变,纤维化疾病的发病率明显增加。因此,纤维化疾病已经严重危害人类的生命健康。
吡非尼酮,英文名为pirfenidone,化学名为5-甲基-1-苯基吡啶-2(1H)-酮,结构式如下所示:
早在1974年,吡非尼酮由美国Marnac公司研究发现,它具有广谱抗纤维化作用,作为第一个上市的小分子抗纤维化药物。2008年12月,吡非尼酮片剂(商品名Pirespa)在日本首先上市。2011年3月,欧盟委员会批准了吡非尼酮片剂(商品名Pirfenex)用于治疗成人轻至中度特发性肺纤维化患者。在美国,吡非尼酮也已经完成了肺纤维化的III期临床试验,以及肾纤维化和多发性硬化症的II期临床试验,并在2014年10月15日作为治疗肺纤维化药物上市。
研究表明,吡非尼酮在临床应用过程中存有一些缺点,比如作用效果较弱、较强的首过效应和体内代谢快等特点。所以,它仍然不能作为理想的抗纤维化药物。
目前对抗纤维化药物的研究主要为两个方向:其一,吡非尼酮骨架的修饰。甲基的取代有利于克服吡非尼酮新陈代谢过快且维持多靶点活性,N取代基修饰有利于提高吡非尼酮生物活性;其二,全新设计合成吡非尼酮类化合物。2011年,胡高云课题组有针对性地设计合成出了6类40个N-取代苯基氢化喹啉酮母核的衍生物,对合成的目标化合物进行了初步活性筛选和构效关系评价。研究结果表明,其中33个具有抑制NIH3T3细胞增殖的活性的目标化合物,其中有23个化合物的抗纤维化生物活性优于氟非尼酮。
而全新设计合成多取代吡啶-1(2H)-酮衍生物以及对其进行抗纤维化生物活性研究至今都未曾报道。
(三)发明内容
本发明的目的是提供一种新的具有抗纤维化生物活性的化合物——多取代吡啶-1(2H)-酮衍生物及其合成方法与应用。本发明全新设计合成了多取代吡啶-1(2H)-酮衍生物,即以含炔基甲酰胺类化合物为原料通过分子内环合最终得到目标产物。本发明化合物具有比同类化合物更好的抗纤维化生物活性。
为实现上述目的,本发明采用如下技术方案:
一种式(II)所示的多取代吡啶-1(2H)-酮衍生物:
式(II)中:
R1为苯基、对甲苯基、间甲苯基、邻甲苯基、对氯苯基、间氯苯基、邻氯苯基、对溴苯基、间溴苯基、邻溴苯基、对甲氧苯基、间甲氧苯基、邻甲氧苯基、对氟苯基、间氟苯基、邻氟苯基或C1~C10烷基,优选苯基、对甲苯基、对氟苯基、间氟苯基或C4~C5烷基;
R2为氢、甲基、甲氧基、氯、溴、氟或碘,优选氢、甲基、氯、溴、氟或碘;
n=1、2或3。
进一步,所述的多取代吡啶-1(2H)-酮衍生物为式(2a)~式(2s)所示化合物之一:
本发明还提供了一种所述多取代吡啶-1(2H)-酮衍生物的合成方法,所述的合成方法为:
氮气保护下,以式(I)所示化合物(含炔基甲酰胺类化合物)为原料,在有机溶剂中,碱性物质存在下,于20~80℃反应2~12h,之后反应液经后处理,得到式(II)所示产物(多取代吡啶-1(2H)-酮衍生物);
式(I)或式(II)中,
R1、R3各自独立为苯基、对甲苯基、间甲苯基、邻甲苯基、对氯苯基、间氯苯基、邻氯苯基、对溴苯基、间溴苯基、邻溴苯基、对甲氧苯基、间甲氧苯基、邻甲氧苯基、对氟苯基、间氟苯基、邻氟苯基或C1~C10烷基;优选R1为苯基、对甲苯基、对氟苯基、间氟苯基或C4~C5烷基;优选R3为苯基、对氟苯基或甲基;
R2为氢、甲基、甲氧基、氯、溴、氟或碘,优选氢、甲基、氯、溴、氟或碘;
n=1、2或3。
本发明所述的合成方法中:
所述的有机溶剂为甲苯、甲醇、二氯甲烷、乙醇、乙腈、四氢呋喃(THF)、乙酸乙酯、二甲基亚砜(DMSO)或N,N-二甲基甲酰胺(DMF);推荐所述有机溶剂的体积用量以式(I)所示化合物的物质的量计为1~5mL/mmol,优选2~4mL/mmol。
所述的碱性物质为氢氧化铯、氢氧化钠、氢氧化钾、甲醇钠、乙醇钠或叔丁醇钾;推荐所述式(I)所示化合物与碱性物质的物质的量之比为1:1~5,优选1:2~4。
通常所述后处理的方法为:反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,以石油醚:乙酸乙酯体积比20~1:1的混合液为洗脱剂,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,即得产物。
本发明通过MTT法测定所述的多取代吡啶-1(2H)-酮衍生物IC50值,吡非尼酮作阳性对照,结果表明本发明化合物具有比吡非尼酮更好的抗纤维化生物活性,在制备抗纤维化药物中具有应用前景。
本发明的优点主要体现在:所述化合物的合成操作简单易行,原料廉价易得,反应条件温和,反应时间短,对各种取代基都有很好的兼容性;合成的化合物含有一个新颖的并环吡啶酮结构,具有优于吡非尼酮的抗纤维化生物活性。
(四)具体实施方式
下面通过具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此。
实施例1~29的反应结果列于表1:
表1实施例1~29的反应结果
实施例1
称取反应底物1a(0.84g,2mmol),N2氛围下,加入乙醇(2mL),然后加入叔丁醇钾(0.90g,8mmol),在室温(25℃)常压下搅拌反应2小时。TLC监测反应,反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,洗脱剂为石油醚:乙酸乙酯体积比20~1:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,得到产物2a0.57g,产率90%。
2-苯基-4-苄基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
棕色液体:1HNMR(500MHz,CDCl3)δ7.48-7.455(m,2H),7.40-7.37(m,3H),7.32(t,J=7.5Hz,2H),7.24(t,J=7.3Hz,1H),7.19(d,J=7.3Hz,2H),6.96(s,1H),3.75(s,2H),2.61(t,J=5.1Hz,2H),2.45(t,J=5.0Hz,2H),1.76-1.69(m,4H);13CNMR(125MHz,CDCl3)δ161.6,147.3,141.4,139.2,132.5,129.0,128.6,128.4,127.9,126.7,126.4,117.7,35.6,26.6,24.2,21.9,21.8;HRMS-ESI[M+H]+CalcdforC22H22NO316.1696,found316.1710.
实施例2
称取反应底物1a(0.84g,2mmol),N2氛围下,加入甲醇(10mL),然后加入甲醇钠(0.22g,10mmol),在50℃常压下搅拌反应5小时。TLC监测反应,反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,洗脱剂为石油醚:乙酸乙酯体积比20~1:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,得到产物2a0.56g,产率89%。
实施例3
称取反应底物1a(0.84g,2mmol),N2氛围下,加入乙醇(8mL),然后加入乙醇钠(0.27g,8mmol),在60℃常压下搅拌反应6小时。TLC监测反应,反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,洗脱剂为石油醚:乙酸乙酯体积比20~1:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,得到产物2a0.58g,产率92%。
实施例4
称取反应底物1a(0.84g,2mmol),N2氛围下,加入乙醇(5mL),然后加入氢氧化钠(0.16g,4mmol),在80℃下搅拌反应12小时。TLC监测反应,反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,洗脱剂为石油醚:乙酸乙酯体积比20~1:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,得到产物2a0.57g,产率91%。
实施例5
称取反应底物1a(0.84g,2mmol),N2氛围下,加入乙醇(5mL),然后加入氢氧化钾(0.22g,4mmol),在50℃下搅拌反应10小时。TLC监测反应,反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,洗脱剂为石油醚:乙酸乙酯体积比20~1:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,得到产物2a0.53g,产率84%。
实施例6
称取反应底物1a(0.84g,2mmol),N2氛围下,加入CH3CN(5mL),然后加入氢氧化钾(0.22g,4mmol),在50℃下搅拌反应10小时。TLC监测反应,反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,洗脱剂为石油醚:乙酸乙酯体积比20~1:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,得到产物2a0.52g,产率82%。
实施例7
称取反应底物1a(0.84g,2mmol),N2氛围下,加入DMSO(5mL),然后加入氢氧化钾(0.22g,4mmol),在50℃下搅拌反应10小时。TLC监测反应,反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,洗脱剂为石油醚:乙酸乙酯体积比20~1:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,得到产物2a0.53g,产率84%。
实施例8
称取反应底物1a(0.84g,2mmol),N2氛围下,加入DMF(5mL),然后加入氢氧化钾(0.22g,4mmol),在室温(25℃)下搅拌反应10小时。TLC监测反应,反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,洗脱剂为石油醚:乙酸乙酯体积比20~1:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,得到产物2a0.56g,产率89%。
实施例9
称取反应底物1a(0.84g,2mmol),N2氛围下,加入甲苯(5mL),然后加入氢氧化钾(0.22g,4mmol),在50℃下搅拌反应10小时。TLC监测反应,反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,洗脱剂为石油醚:乙酸乙酯体积比20~1:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,得到产物2a0.57g,产率91%。
实施例10
称取反应底物1a(0.84g,2mmol),N2氛围下,加入THF(5mL),然后加入氢氧化钾(0.22g,4mmol),在50℃下搅拌反应10小时。TLC监测反应,反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,洗脱剂为石油醚:乙酸乙酯体积比20~1:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,得到产物2a0.56g,产率88%。
实施例11
称取反应底物1a(0.84g,2mmol),N2氛围下,加入EA(5mL),然后加入氢氧化钾(0.22g,4mmol),在50℃下搅拌反应8小时。TLC监测反应,反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,洗脱剂为石油醚:乙酸乙酯体积比20~1:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,得到产物2a0.59g,产率94%。
实施例12~29
实验操作方法同实施例11。分别称取反应底物1b~1s(2mmol),N2氛围下,加入乙酸乙酯(5mL),然后加入氢氧化钾(0.22g,4mmol),在50℃下搅拌反应6~12小时。TLC监测反应,反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,洗脱剂为石油醚:乙酸乙酯体积比20~1:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,分别得到产物(2b~2s)。
实施例12~29的部分具体反应条件、产量、产率列于表2:
表2实施例12~29的部分具体反应条件、产量、产率
实施例12~29所得产物的物理性质、1H谱、13C谱以及高分辨数据如下所示:
2-对甲苯基-4-苄基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
棕色液体:1HNMR(500MHz,CDCl3)δ7.32(d,J=7.3Hz,2H),7.26(s,4H),7.23(t,J=7.3Hz,1H),7.18(d,J=7.2Hz,2H),6.93(s,1H),3.74(s,2H),2.60(t,J=5.1Hz,2H),2.43(t,J=5.0Hz,2H),2.39(s,3H),1.75-1.68(m,4H);13CNMR(125MHz,CDCl3)δ161.7,147.3,139.3,138.9,137.8,132.7,129.6,128.6,128.5,128.4,126.4,117.7,35.7,26.6,24.2,21.9,21.8,21.1;HRMS-ESI[M+H]+CalcdforC23H24NO330.1852,found330.1860.
2-间甲苯基-4-苄基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
棕色液体:1HNMR(500MHz,CDCl3)δ7.36-7.30(m,3H),7.25-7.15(m,6H),6.96(s,1H),3.75(s,2H),2.61(t,J=5.0Hz,2H),2.44(t,J=5.2Hz,2H),2.40(s,3H),1.75-1.69(m,4H);13CNMR(125MHz,CDCl3)δ161.7,147.3,141.4,139.4,139.1,132.7,129.0,128.8,128.7,128.4,127.4,126.5,123.7,117.7,35.7,26.7,24.3,22.0,21.9,21.3;HRMS-ESI[M+H]+CalcdforC23H24NO330.1852,found330.1863.
2-邻甲苯基-4-苄基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
棕色液体:1HNMR(500MHz,CDCl3)δ7.28-7.22(m,5H),7.18(t,J=7.4Hz,1H),7.14(t,J=8.2Hz,3H),6.76(s,1H),3.69(s,2H),2.57(t,J=5.2Hz,2H),2.40(t,J=5.0Hz,2H),2.13(s,3H),1.72-1.67(m,4H);13CNMR(125MHz,CDCl3)δ161.3,147.3,140.6,139.3,135.1,132.5,130.9,128.6,128.5,128.3,127.4,126.8,126.4,117.6,35.6,26.6,24.1,21.9,21.7,17.7;HRMS-ESI[M+H]+CalcdforC23H24NO330.1852,found330.1840.
2-对氯苯基-4-苄基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
黄色固体:m.p.126-127℃;1HNMR(500MHz,CDCl3)δ7.41(d,J=8.6Hz,2H),7.35-7.30(m,4H),7.24(t,J=7.4Hz,1H),7.18(d,J=7.3Hz,2H),6.89(s,1H),3.75(s,2H),2.60(t,J=4.8Hz,2H),2.44(t,J=4.8Hz,2H),1.75-1.69(m,4H);13CNMR(125MHz,CDCl3)δ161.4,147.5,139.8,139.0,133.64,132.0,129.1,128.6,128.4,127.9,126.4,118.1,35.6,26.6,24.2,21.8,21.7;HRMS-ESI[M+H]+CalcdforC22H21ClNO350.1306,found350.1314.
2-间氯苯基-4-苄基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
黄色液体:1HNMR(500MHz,CDCl3)δ7.43(t,J=1.9Hz,1H),7.40-7.28(m,5H),7.24(t,J=7.4Hz,1H),7.18(d,J=7.3Hz,2H),6.91(s,1H),3.75(s,2H),2.60(t,J=5.1Hz,2H),2.44(t,J=5.0Hz,2H),1.75-1.68(m,4H);13CNMR(125MHz,CDCl3)δ161.3,147.6,142.3,139.0,134.5,131.9,130.0,128.7,128.6,128.3,128.1,127.1,126.4,124.9,118.1,35.6,26.6,24.2,21.8,21.7;HRMS-ESI[M+H]+CalcdforC22H21ClNO350.1306,found350.1321.
2-邻氯苯基-4-苄基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
黄色液体:1HNMR(500MHz,CDCl3)δ7.56-7.52(m,1H),7.381-7.36(m,3H),7.32(t,J=7.3Hz,2H),7.24(t,J=7.3Hz,1H),7.20d,J=7.3Hz,2H),6.79(s,1H),3.77(d,J=16.2Hz,1H),3.73(d,J=16.2Hz,1H),2.64-2.60(m,2H),2.47-2.43(m,2H),1.76-1.71(m,4H);13CNMR(125MHz,CDCl3)δ161.2,139.2,138.8,132.2,131.8,130.4,129.8,129.5,128.7,128.6,128.4,127.6,126.4,117.7,35.6,26.6,24.0,21.8,21.7;HRMS-ESI[M+H]+CalcdforC22H21ClNO350.1306,found350.1311.
2-对溴苯基-4-苄基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
白色固体:m.p.132-133℃;1HNMR(500MHz,CDCl3)δ7.57(d,J=8.7Hz,2H),7.32(t,J=7.5Hz,2H),7.27(d,J=8.7Hz,2H),7.24(d,J=7.4Hz,1H),7.18(d,J=7.2Hz,2H),6.88(s,1H),3.74(s,2H),2.59(t,J=4.9Hz,2H),2.44(t,J=4.7Hz,2H),1.74-1.69(m,4H);13CNMR(125MHz,CDCl3)δ161.2,147.6,140.1,138.9,132.1,131.8,128.5,128.3,128.2,126.4,121.6,118.1,35.5,26.5,24.1,21.7,21.6;HRMS-ESI[M+H]+CalcdforC22H21BrNO394.0801,found394.0807.
2-邻溴苯基-4-苄基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
黄色液体:1HNMR(500MHz,CDCl3)δ7.72(dd,J=8.1,1.2Hz,1H),7.45-7.28(m,5H),7.25-7.20(m,3H),6.78(s,1H),3.78(d,J=16.1Hz,1H),3.73(d,J=16.1Hz,1H),2.63-2.60(m,2H),2.49-2.44(m,2H),1.76-1.62(m,4H);13CNMR(125MHz,CDCl3)δ161.2,147.8,140.5,139.2,133.6,132.2,130.0,129.6,128.9,128.6,128.5,128.4,126.4,121.8,117.6,35.7,26.6,24.1,21.9,21.7;HRMS-ESI[M+H]+CalcdforC22H21BrNO394.0801,found394.0796.
2-邻碘苯基-4-苄基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
黄色液体:1HNMR(500MHz,CDCl3)δ7.96(dd,J=8.0,1.2Hz,1H),7.35-7.31(m,3H),7.46(td,J=7.7,1.3Hz,1H),7.25-7.22(m,3H),7.14(td,J=7.8,1.6Hz,1H),6.74(s,1H),3.79(d,J=16.2Hz,1H),3.73(d,J=16.2Hz,1H),2.66-2.58(m,2H),2.50-2.40(m,2H),1.77-1.69(m,4H);13CNMR(125MHz,CDCl3)δ161.1,147.9,144.2,139.9,139.3,132.2,130.1,129.4,129.1,128.9,128.6,128.5,126.4,117.8,97.4,35.8,26.7,24.1,21.9,21.8;HRMS-ESI[M+H]+CalcdforC22H21INO442.0668,found442.0679.
2-苯基-4-对甲苄基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
黄色固体:m.p.124-125℃;1HNMR(500MHz,CDCl3)δ7.49-7.45(m,2H),7.41-7.36(m,3H),7.13(d,J=8.0Hz,2H),7.08(d,J=8.0Hz,2H),6.96(s,1H),3.71(s,2H),2.63(t,J=5.0Hz,2H),2.46(t,J=5.0Hz,2H),2.34(s,3H),1.76-1.70(m,4H);13CNMR(125MHz,CDCl3)δ161.4,147.2,141.2,135.9,135.7,132.2,129.1,128.8,128.3,128.1,127.7,126.5,117.9,35.1,26.4,24.1,21.7,21.6,20.8;HRMS-ESI[M+H]+CalcdforC23H24NO330.1852,found330.1865.
2-苯基-4-对氟苄基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
黄色液体:1HNMR(500MHz,CDCl3)δ7.47-7.44(m,2H),7.39-7.36(m,3H),7.15-7.12(m,2H),6.99(t,J=8.7Hz,2H),6.93(s,1H),3.71(s,2H),2.59(t,J=4.9Hz,2H),2.41(t,J=4.8Hz,2H),1.74-1.69(m,4H);13CNMR(125MHz,CDCl3)δ161.50(d,J=244.8Hz),161.4,147.1,141.3,134.8(d,J=3.2Hz),132.4,129.8(d,J=7.9Hz),129.0,128.7,127.9,126.6,117.6,115.4(d,J=21.7Hz),34.8,26.5,24.2,21.8,21.7;HRMS-ESI[M+H]+CalcdforC22H21FNO334.1602,found334.1618.
2-苯基-4-间氟苄基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
白色固体:m.p.118-119℃;1HNMR(500MHz,CDCl3)δ7.43-7.40(m,2H),7.37-7.31(m,3H),7.25-7.22(m,1H),6.97(s,1H),6.94(d,J=7.8Hz,1H),6.89-6.84(m,2H),3.70(s,2H),2.58(t,J=4.9Hz,2H),2.38-2.36(m,2H),1.70-1.64(m,4H);13CNMR(125MHz,CDCl3)δ162.7(d,J=245.9Hz),161.2,146.8,141.9(d,J=6.8Hz),141.0,132.4,129.7(d,J=8.2Hz),128.7,128.4,127.6,126.3,123.7(d,J=2.2Hz),116.7,114.9(d,J=21.5Hz),113.0(d,J=20.9Hz),35.0,26.3,23.9,21.5,21.4;HRMS-ESI[M+H]+CalcdforC22H21FNO334.1602,found334.1612.
2-苯基-4-正己基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
黄色液体:1HNMR(500MHz,CDCl3)δ7.46(t,J=7.8Hz,2H),7.38-7.36(m,3H),6.96(s,2H),2.62-2.56(m,4H),2.37-2.34(m,2H),1.79-1.76(m,4H),1.53-1.47(m,2H),1.39-1.29(m,6H),0.89(t,J=6.8Hz,3H);13CNMR(125MHz,CDCl3)δ161.4,147.1,141.6,130.9,128.9,128.1,127.7,126.7,119.3,31.6,29.7,29.2,29.1,26.3,24.2,22.5,22.0,21.9,13.9;HRMS-ESI[M+H]+CalcdforC21H28NO310.2165,found310.2175.
2-苯基-4-正戊基-5,6,7,8-四氢环己烷并[c]吡啶-1(2H)-酮
黄色液体:1HNMR(500MHz,CDCl3)δ7.48-7.45(m,2H),7.40-7.37(m,3H),6.96(s,1H),2.62-2.56(m,4H),2.37-2.34(m,2H),1.81-1.75(m,4H),1.54-1.48(m,2H),1.36-1.34(m,4H),0.91(tJ=6.9Hz,3H);13CNMR(125MHz,CDCl3)δ161.5,147.2,141.6,130.9,129.0,128.2,127.8,126.7,119.4,31.7,29.5,29.2,26.4,24.3,22.5,22.0,21.9,14.0;HRMS-ESI[M+H]+CalcdforC20H26NO296.2009,found296.2020.
2-苯基-4-苄基-5,6,7-三氢环戊烷并[c]吡啶-1(2H)-酮
黄色液体:1HNMR(500MHz,CDCl3)δ7.44(t,J=7.5Hz,2H),7.40-7.35(m,3H),7.31(t,J=7.6Hz,2H),7.23(d,J=7.4Hz,1H),7.19(d,J=7.4Hz,2H),7.03(s,1H),3.73(s,2H),2.89(t,J=7.5Hz,2H),2.71(t,J=7.6Hz,2H),2.07-2.00(m,2H);13CNMR(125MHz,CDCl3)δ159.7,155.1,140.9,138.8,134.4,132.7,128.7,128.3,128.2,127.6,126.5,126.2,116.3,35.9,32.7,30.2,22.8;HRMS-ESI[M+H]+CalcdforC21H20NO302.1539,found302.1552.
2-苯基-4-苄基-5,6,7,8,9-五氢环庚烷并[c]吡啶-1(2H)-酮
黄色液体:1HNMR(500MHz,CDCl3)δ7.47(t,J=7.5Hz,2H),7.43-7.37(m,3H),7.32(t,J=7.5Hz,2H),7.22(t,J=7.3Hz,1H),7.18(d,J=7.3Hz,2H),7.03(s,1H),3.79(s,2H),2.97-2.95(m,2H),2.63-2.61(m,2H),1.81-1.72(m,2H),1.61-1.56(m,2H),1.36-1.31(m,2H);13CNMR(125MHz,CDCl3)δ161.6,153.8,141.6,139.7,134.2,133.2,128.9,128.4,128.2,127.8,126.6,126.3,117.0,36.7,32.2,30.3,26.2,26.0,25.4;HRMS-ESI[M+H]+CalcdforC23H24NO330.1852,found330.1854.
实施例30
多取代吡啶-1(2H)-酮衍生物抗纤维化生物活性测定
选取小鼠的胚胎成纤维细胞NIH3T3为研究对象,以吡非尼酮做为阳性对照,采用MTT法来考察合成的多取代吡啶-1(2H)-酮衍生物对NIH3T3细胞增殖的抑制作用强度,通过IC50值可以比较吡非尼酮以及这一系列化合物之间的生物活性差异。
抗纤维化生物活性测定实施例如下:
采用MTT比色法,小鼠胚胎成纤维细胞用含10%小牛血清的DMEM培养基,37℃下,在含5%的CO2加湿细胞培养箱培养。将NIH3T3细胞接种于96孔板中,每孔10000细胞,继续培养4h。待细胞贴壁后,换成含不同浓度多取代吡啶-1(2H)-酮衍生物和吡非尼酮的含5%的小牛血清的培养基,每个浓度设置3个复孔。培养72小时后,在每孔中加入5%的MTT溶液(20uL),4小时后,将MTT吸出,每孔再加入MTT溶解液DMSO(100uL),待MTT完全溶解。15min后,在490nm下,使用酶标仪测定OD值,用OriginPro8.0处理数据得到吡非尼酮和多取代吡啶-1(2H)-酮衍生物的IC50值,结果见表3。
表3本发明多取代吡啶-1(2H)-酮衍生物和吡非尼酮抗纤维化生物活性测定结果
由表3可知:
(1)多取代吡啶-1(2H)-酮衍生物的生物活性都较吡非尼酮好,只有对位的Cl取代由于溶解性的关系,得不到相对生物活性;
(2)N-苯环上有取代基对生物活性有很大促进作用,2j(R2=o-I)活性最高,为吡非尼酮的214倍。其次,2b(R2=p-CH3),2c(R2=m-CH3),2d(R2=o-CH3),2f(R2=m-Cl)的活性也优于吡非尼酮超过100倍;
(3)R1取代基对生物活性均有促进作用,其中2p(R1=-(CH2)3CH3)活性最高,为吡非尼酮的201倍;
(4)环并吡啶酮的生物活性优于吡非尼酮,说明并入环有助于吡非尼酮活性提高。
Claims (9)
1.一种式(II)所示的多取代吡啶-1(2H)-酮衍生物:
式(II)中:
R1为苯基、对甲苯基、间甲苯基、邻甲苯基、对氯苯基、间氯苯基、邻氯苯基、对溴苯基、间溴苯基、邻溴苯基、对甲氧苯基、间甲氧苯基、邻甲氧苯基、对氟苯基、间氟苯基、邻氟苯基或C1~C10烷基;
R2为氢、甲基、甲氧基、氯、溴、氟或碘;
n=1、2或3。
2.如权利要求1所述的多取代吡啶-1(2H)-酮衍生物,其特征在于,所述R1为苯基、对甲苯基、对氟苯基、间氟苯基或C4~C5烷基;所述R2为氢、甲基、氯、溴、氟或碘。
3.如权利要求1所述的多取代吡啶-1(2H)-酮衍生物,其特征在于,所述的多取代吡啶-1(2H)-酮衍生物为式(2a)~式(2s)所示化合物之一:
4.一种如权利要求1所述的多取代吡啶-1(2H)-酮衍生物的合成方法,其特征在于,所述的合成方法为:
氮气保护下,以式(I)所示化合物为原料,在有机溶剂中,碱性物质存在下,于20~80℃反应2~12h,之后反应液经后处理,得到式(II)所示产物;
所述的有机溶剂为甲苯、甲醇、二氯甲烷、乙醇、乙腈、四氢呋喃、乙酸乙酯、二甲基亚砜或N,N-二甲基甲酰胺;
所述的碱性物质为氢氧化铯、氢氧化钠、氢氧化钾、甲醇钠、乙醇钠或叔丁醇钾;
所述式(I)所示化合物与碱性物质的物质的量之比为1:1~5;
式(I)或式(II)中,
R1、R3各自独立为苯基、对甲苯基、间甲苯基、邻甲苯基、对氯苯基、间氯苯基、邻氯苯基、对溴苯基、间溴苯基、邻溴苯基、对甲氧苯基、间甲氧苯基、邻甲氧苯基、对氟苯基、间氟苯基、邻氟苯基或C1~C10烷基;
R2为氢、甲基、甲氧基、氯、溴、氟或碘;
n=1、2或3。
5.如权利要求4所述的合成方法,其特征在于,所述有机溶剂的体积用量以式(I)所示化合物的物质的量计为1~5mL/mmol。
6.如权利要求5所述的合成方法,其特征在于,所述有机溶剂的体积用量以式(I)所示化合物的物质的量计为2~4mL/mmol。
7.如权利要求4所述的合成方法,其特征在于,所述式(I)所示化合物与碱性物质的物质的量之比为1:2~4。
8.如权利要求4所述的合成方法,其特征在于,所述后处理的方法为:反应结束后,反应液经减压浓缩,所得浓缩物进行硅胶柱层析分离,以石油醚:乙酸乙酯体积比20~1:1的混合液为洗脱剂,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,即得产物。
9.如权利要求1所述的多取代吡啶-1(2H)-酮衍生物在制备抗纤维化药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610074381.7A CN105541715B (zh) | 2016-02-02 | 2016-02-02 | 多取代吡啶-1(2h)-酮衍生物及其合成方法与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610074381.7A CN105541715B (zh) | 2016-02-02 | 2016-02-02 | 多取代吡啶-1(2h)-酮衍生物及其合成方法与应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105541715A true CN105541715A (zh) | 2016-05-04 |
CN105541715B CN105541715B (zh) | 2019-04-09 |
Family
ID=55821330
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610074381.7A Active CN105541715B (zh) | 2016-02-02 | 2016-02-02 | 多取代吡啶-1(2h)-酮衍生物及其合成方法与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105541715B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113861111A (zh) * | 2021-11-23 | 2021-12-31 | 浙江工业大学 | N-芳基-4-硫(硒)乙基多元环并[c]-1-吡啶酮衍生物及其合成方法和应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104395319A (zh) * | 2012-06-29 | 2015-03-04 | 普克塞尔公司 | 用作ampk的活化剂的噻吩并吡啶酮衍生物 |
CN104822687A (zh) * | 2012-10-02 | 2015-08-05 | 英特穆恩公司 | 抗纤维化吡啶酮类 |
WO2015153683A1 (en) * | 2014-04-02 | 2015-10-08 | Intermune, Inc. | Anti-fibrotic pyridinones |
-
2016
- 2016-02-02 CN CN201610074381.7A patent/CN105541715B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104395319A (zh) * | 2012-06-29 | 2015-03-04 | 普克塞尔公司 | 用作ampk的活化剂的噻吩并吡啶酮衍生物 |
CN104822687A (zh) * | 2012-10-02 | 2015-08-05 | 英特穆恩公司 | 抗纤维化吡啶酮类 |
WO2015153683A1 (en) * | 2014-04-02 | 2015-10-08 | Intermune, Inc. | Anti-fibrotic pyridinones |
Non-Patent Citations (2)
Title |
---|
WANLI CHEN,ET AL: "DBU-PromotedCyclization of ortho-(3-Hydroxy-1-alkynyl)benzamide: Synthesis of trans-3,4-Dihydroisoquinolin-1(2H)-ones and (E)-4-(1-Alkenyl)isoquinolin-1(2H)-ones and (E)-4-(1-Alkenyl)isoquinolin-1(2H)-ones", 《J.ORG.CHEM.》 * |
郭成: "吡非尼酮的合成及结构确证", 《安徽医药》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113861111A (zh) * | 2021-11-23 | 2021-12-31 | 浙江工业大学 | N-芳基-4-硫(硒)乙基多元环并[c]-1-吡啶酮衍生物及其合成方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
CN105541715B (zh) | 2019-04-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Zhang et al. | Cooperative N-heterocyclic carbene (NHC)–Lewis acid-mediated regioselective umpolung formal [3+ 2] annulations of alkynyl aldehydes with isatins | |
CN111978236B (zh) | 一种n-取代-3-吗啉基-4-苯硒基马来酰亚胺化合物的制备方法 | |
EP3567043A1 (en) | Thienopyrimidine derivative, preparation method therefor, and application thereof in manufacturing of antitumor drugs | |
Hingane et al. | An efficient new route towards biologically active isocryptolepine and γ-carboline derivatives using an intramolecular thermal electrocyclization strategy | |
CN106565742B (zh) | 吲哚酮螺四氢硫代吡喃类衍生物及其制备方法和应用 | |
CN108314658B (zh) | 一种多取代噁唑衍生物的制备方法 | |
Tang et al. | Synthesis of novel β-amino ketones containing ap-aminobenzoic acid moiety and evaluation of their antidiabetic activities | |
CN114539252A (zh) | 一种2,3-二氢喹啉-4-酮生物活性骨架及其合成方法和应用 | |
CN111269228B (zh) | 一类具有荧光活性的吲哚嗪环-1,2-二酮及其衍生物的制备方法 | |
CN106146334A (zh) | 2,3-二芳基-2-炔丙酰胺基-3-芳基氨基丙酸甲酯衍生物及其制备方法和应用 | |
CN105541715A (zh) | 多取代吡啶-1(2h)-酮衍生物及其合成方法与应用 | |
CN102070503B (zh) | 一种制备吡咯衍生物的方法 | |
CN113105459B (zh) | 一种三唑并嘧啶衍生物及其制备方法和应用 | |
CN105820174A (zh) | 一种多取代噻吩并吲哚衍生物的制备方法 | |
CN113024572B (zh) | 螺旋-γ-内酰胺化合物及其合成方法与应用 | |
CN114605421A (zh) | 螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架及其合成方法和应用 | |
CN111233745B (zh) | (e)1-(9-烷基-咔唑-3-)-丙烯酸及其制备方法 | |
CN109305970B (zh) | 1,7-二取代氨甲基-2,8-二羟基-Tr*ger’s Base催化剂制备及应用 | |
CN109384753B (zh) | 一种2-苯基-3-甲基苯并呋喃类化合物的合成方法 | |
Mousavi et al. | Metal-free syntheses of new azocines via addition reactions of enaminones with acenaphthoquinone followed by oxidative cleavages of the corresponding vicinal diols | |
CN103755715B (zh) | 苯并呋喃并[2,3-c]吡啶化合物及其合成方法 | |
CN108530368B (zh) | 有机碱催化巴比妥酸与二烯二腈加成反应的方法 | |
Kapoor et al. | Organocatalytic Asymmetric Synthesis of 1, 2, 4-Trisubstituted Azetidines by Reductive Cyclization of Aza-Michael Adducts of Enones | |
Szemes et al. | Diastereoselective access to hexahydro-and octahydrofuro [f] indolizines analogues of phenanthro [f] indolizidines alkaloids | |
CN102295582A (zh) | 一种α-位季碳的α,β-二胺酸衍生物的制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
EE01 | Entry into force of recordation of patent licensing contract | ||
EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20160504 Assignee: QINGYUAN ZUISANGONG WINE INDUSTRY Co.,Ltd. Assignor: JIANG University OF TECHNOLOGY Contract record no.: X2023980037301 Denomination of invention: Multi substituted pyridine-1 (2H) - ketone derivatives and their synthesis methods and applications Granted publication date: 20190409 License type: Common License Record date: 20230703 |