CN114057650B - Method for preparing 4, 5-dihydropyridazin-3-one compounds by one-pot method - Google Patents
Method for preparing 4, 5-dihydropyridazin-3-one compounds by one-pot method Download PDFInfo
- Publication number
- CN114057650B CN114057650B CN202111316249.XA CN202111316249A CN114057650B CN 114057650 B CN114057650 B CN 114057650B CN 202111316249 A CN202111316249 A CN 202111316249A CN 114057650 B CN114057650 B CN 114057650B
- Authority
- CN
- China
- Prior art keywords
- reaction
- dihydropyridazin
- dihydropyridazine
- compounds
- preparing
- 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.)
- Active
Links
- ORSUMIZRRGPJBR-UHFFFAOYSA-N 4,5-dihydro-1h-pyridazin-6-one Chemical class O=C1CCC=NN1 ORSUMIZRRGPJBR-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- -1 4, 5-dihydropyridazin-3-one compound Chemical class 0.000 claims abstract description 18
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 16
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229940038531 phenylhydrazine hydrochloride Drugs 0.000 claims abstract description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims abstract description 8
- 150000001543 aryl boronic acids Chemical class 0.000 claims abstract description 7
- IAHFWCOBPZCAEA-UHFFFAOYSA-N succinonitrile Chemical compound N#CCCC#N IAHFWCOBPZCAEA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000000654 additive Substances 0.000 claims abstract description 6
- 230000000996 additive effect Effects 0.000 claims abstract description 6
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- 239000007800 oxidant agent Substances 0.000 claims abstract description 4
- 239000011592 zinc chloride Substances 0.000 claims abstract description 4
- 235000005074 zinc chloride Nutrition 0.000 claims abstract description 4
- 230000001590 oxidative effect Effects 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 239000002841 Lewis acid Substances 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 10
- 238000007363 ring formation reaction Methods 0.000 abstract description 7
- 239000000758 substrate Substances 0.000 abstract description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 5
- 230000005494 condensation Effects 0.000 abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 4
- 238000009833 condensation Methods 0.000 abstract description 3
- 229910052759 nickel Inorganic materials 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 229910052723 transition metal Inorganic materials 0.000 abstract description 2
- 150000003624 transition metals Chemical class 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 238000005481 NMR spectroscopy Methods 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 238000004440 column chromatography Methods 0.000 description 20
- 239000003480 eluent Substances 0.000 description 18
- 229940093499 ethyl acetate Drugs 0.000 description 18
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- 229960001866 silicon dioxide Drugs 0.000 description 17
- 239000003208 petroleum Substances 0.000 description 14
- 238000001228 spectrum Methods 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- MFYSUUPKMDJYPF-UHFFFAOYSA-N 2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-n-phenylbutanamide Chemical compound C=1C=CC=CC=1NC(=O)C(C(=O)C)N=NC1=CC=C(C)C=C1[N+]([O-])=O MFYSUUPKMDJYPF-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 1
- NUPJVFNTHQXDSZ-UHFFFAOYSA-N 2,6-diphenyl-4,5-dihydropyridazin-3-one Chemical compound O=C1CCC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 NUPJVFNTHQXDSZ-UHFFFAOYSA-N 0.000 description 1
- NEOMDMOZBNSVAN-UHFFFAOYSA-N 6-(4-chlorophenyl)-2-phenyl-4,5-dihydropyridazin-3-one Chemical compound C1=CC(Cl)=CC=C1C1=NN(C=2C=CC=CC=2)C(=O)CC1 NEOMDMOZBNSVAN-UHFFFAOYSA-N 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- 101001121408 Homo sapiens L-amino-acid oxidase Proteins 0.000 description 1
- 101000827703 Homo sapiens Polyphosphoinositide phosphatase Proteins 0.000 description 1
- 102100026388 L-amino-acid oxidase Human genes 0.000 description 1
- 102100023591 Polyphosphoinositide phosphatase Human genes 0.000 description 1
- 101100012902 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) FIG2 gene Proteins 0.000 description 1
- 101100233916 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) KAR5 gene Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DGOBMKYRQHEFGQ-UHFFFAOYSA-L acid green 5 Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C=CC(=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 DGOBMKYRQHEFGQ-UHFFFAOYSA-L 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001887 anti-feedant effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- UONZSIWVCZNQCF-UHFFFAOYSA-N hydrazinecarbonyl acetate Chemical compound CC(=O)OC(=O)NN UONZSIWVCZNQCF-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 150000004715 keto acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000004031 phenylhydrazines Chemical class 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Chemical group 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
技术领域Technical Field
本发明属于有机合成领域，具体涉及一种4,5-二氢哒嗪-3-酮类化合物的合成方法。The invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing 4,5-dihydropyridazine-3-one compounds.
背景技术Background Art
4,5-二氢哒嗪-3-酮是一类非常重要的五元含氮杂环结构骨架，具有广泛的生物活性，可用作抗菌、强效镇痛、抗炎、拒食、除草、抗高血压和抗血小板活性、抗癌作用和其他预期的生物学和药理学特性等。现有的4,5-二氢哒嗪-3-酮的合成可通过Wittig试剂与芳基腙的反应或α-酮酯与肼基羰基乙酸酯的缩合，亦或是炔烃与芳基肼的催化反应；通过酮酸及其衍生物与烷基肼或苯肼的反应也可生成相应的哒嗪酮。然而，现有的合成方法需要遭受苛刻的反应条件，且反应底物结构复杂需要额外的合成及分离提纯步骤得到，从而导致反应的原子经济性和步骤经济性差。因此，寻求发展新的简便高效的4,5-二氢哒嗪-3-酮类化合物的合成方法显得尤为重要。4,5-Dihydropyridazin-3-one is a very important five-membered nitrogen-containing heterocyclic structure skeleton with a wide range of biological activities. It can be used as an antibacterial, potent analgesic, anti-inflammatory, antifeedant, herbicide, antihypertensive and antiplatelet activity, anticancer effect and other expected biological and pharmacological properties. The existing synthesis of 4,5-dihydropyridazin-3-one can be achieved through the reaction of Wittig reagent with aryl hydrazone or the condensation of α-ketoester with hydrazine carbonyl acetate, or the catalytic reaction of alkyne with aryl hydrazine; the corresponding pyridazinones can also be generated by the reaction of ketoacids and their derivatives with alkyl hydrazines or phenylhydrazines. However, the existing synthesis methods need to be subjected to harsh reaction conditions, and the reaction substrates are complex in structure and require additional synthesis and separation and purification steps, resulting in poor atom economy and step economy of the reaction. Therefore, it is particularly important to seek to develop new, simple and efficient synthesis methods for 4,5-dihydropyridazin-3-one compounds.
在Larock以及Lu课题组工作的开创下，有关过渡金属催化官能团化氰基底物的亲核加成/串联环合反应已经成为构筑含氮杂环化合物的有效途径。近年来，通过有机合成化学的发展，通过控制反应条件选择性实现在一锅中多组分参与的多米诺环合反应，为重要的有机结构骨架的构筑提供了具有优异步骤经济性的合成途径。Under the pioneering work of Larock and Lu's research group, transition metal-catalyzed nucleophilic addition/tandem cyclization reactions of functionalized cyano substrates have become an effective way to construct nitrogen-containing heterocyclic compounds. In recent years, through the development of organic synthetic chemistry, the domino cyclization reaction with multiple components participating in one pot can be selectively achieved by controlling the reaction conditions, providing a synthetic route with excellent step economy for the construction of important organic structural frameworks.
发明内容Summary of the invention
本发明提供了一种一锅法高效制备4,5-二氢哒嗪-3-酮类化合物的新方法。该合成方法底物简单易得，操作简便，化学选择性好，官能团兼容性好。The invention provides a new method for efficiently preparing 4,5-dihydropyridazine-3-one compounds in one pot. The synthetic method has simple and easy-to-obtain substrates, simple operation, good chemical selectivity and good functional group compatibility.
一种新颖且高效的4,5-二氢哒嗪-3-酮类化合物的合成方法，包括如下步骤：将丁二腈、芳基硼酸、苯肼盐酸盐，镍催化剂，路易斯酸添加剂加入到有机溶剂中，氮气条件下加热到80～100℃进行反应，反应12～24h，反应完全后，后处理(萃取以及柱层色谱分离)得到所述的4,5-二氢哒嗪-3-酮类化合物；A novel and efficient method for synthesizing 4,5-dihydropyridazine-3-one compounds comprises the following steps: adding succinonitrile, arylboronic acid, phenylhydrazine hydrochloride, a nickel catalyst, and a Lewis acid additive into an organic solvent, heating to 80-100° C. under nitrogen conditions for reaction, reacting for 12-24 hours, and after the reaction is complete, post-processing (extraction and column chromatography separation) to obtain the 4,5-dihydropyridazine-3-one compounds;
所述的芳基硼酸化合物结构如式(II)所示：The structure of the aryl boronic acid compound is shown in formula (II):
所述的苯肼盐酸盐的结构如式(III)所示：The structure of the phenylhydrazine hydrochloride is shown in formula (III):
所述的4,5-二氢哒嗪-3-酮类化合物的结构如式(I)所示：The structure of the 4,5-dihydropyridazine-3-one compound is shown in formula (I):
式(I)～(III)中，Ar为取代或者未取代的芳基或者杂环芳基，所述芳基或者杂环芳基上的取代基选自烷基、烷氧基、苯基、卤素、酯基、硝基或三氟甲基。R2选自烷基、卤素、三氟甲基、叔丁基、甲氧基或者硝基。In formula (I) to (III), Ar is a substituted or unsubstituted aryl or heterocyclic aryl, and the substituent on the aryl or heterocyclic aryl is selected from alkyl, alkoxy, phenyl, halogen, ester, nitro or trifluoromethyl. R2 is selected from alkyl, halogen, trifluoromethyl, tert-butyl, methoxy or nitro.
在本专利中，我们利用市售的结构简单、廉价易得的丁二腈直接作为反应底物，通过在第一过渡金属镍催化剂的作用下，通过与芳基硼酸和苯肼盐酸盐作用，通过经历氰基的加成、分子内缩合以及环合历程实现在一锅中高效制备4,5-二氢哒嗪-3-酮类化合物。该合成方法显示出了优越的步骤经济性、以及良好的官能团兼容性。我们以Ni(dppp)Cl2为催化剂，氯化锌作为添加剂，以四氢呋喃作为有机反应溶剂，在氮气的反应氛围100℃下反应24小时能够顺利合成一系列不同官能团取代的4,5-二氢哒嗪-3-酮类化合物。该方法条件温和、简单，操作简便，在无需额外的金属氧化剂条件下，为制备4,5-二氢哒嗪-3-酮类化合物提供了一种绿色、高效的合成新方法。In this patent, we use commercially available simple, cheap and easily available succinonitrile directly as a reaction substrate, and through the first transition metal nickel catalyst, through the reaction with arylboronic acid and phenylhydrazine hydrochloride, through the addition of cyano group, intramolecular condensation and cyclization process, we can achieve efficient preparation of 4,5-dihydropyridazine-3-one compounds in one pot. This synthesis method shows excellent step economy and good functional group compatibility. We use Ni(dppp)Cl 2 as a catalyst, zinc chloride as an additive, and tetrahydrofuran as an organic reaction solvent. We can successfully synthesize a series of 4,5-dihydropyridazine-3-one compounds with different functional group substitutions by reacting at 100°C in a nitrogen reaction atmosphere for 24 hours. This method has mild conditions, simple operation, and easy operation. It provides a new green and efficient synthesis method for the preparation of 4,5-dihydropyridazine-3-one compounds without the need for additional metal oxidants.
作为优选，所述的R1选自氢、甲基、甲氧基、苯基、氟、氯、溴、碘、酯基、三氟甲基、萘基或者噻吩等杂芳基硼酸；R2选自甲基、叔丁基、甲氧基、硝基取代苯肼盐酸盐。Preferably, R1 is selected from hydrogen, methyl, methoxy, phenyl, fluorine, chlorine, bromine, iodine, ester, trifluoromethyl, naphthyl or thiophene and other heteroaryl boronic acids; R2 is selected from methyl, tert-butyl, methoxy, nitro-substituted phenylhydrazine hydrochloride.
本发明中，直接利用简单、廉价易得的丁二腈作为反应底物，与芳基硼酸、苯肼盐酸盐在镍的催化体系中，通过经历氰基加成/分子内缩合/环合反应历程实现一锅高效制备4,5-二氢哒嗪-3-酮类化合物。In the present invention, simple, cheap and easily available succinonitrile is directly used as a reaction substrate, and arylboronic acid and phenylhydrazine hydrochloride are reacted in a nickel catalytic system to achieve a one-pot efficient preparation of 4,5-dihydropyridazine-3-one compounds through a cyano addition/intramolecular condensation/cyclization reaction process.
作为优选，所述的镍催化剂为Ni(dppp)Cl2。Preferably, the nickel catalyst is Ni(dppp)Cl 2 .
作为优选，所述的路易斯酸添加剂为氯化锌。Preferably, the Lewis acid additive is zinc chloride.
作为优选，所述的有机溶剂为四氢呋喃(THF)。Preferably, the organic solvent is tetrahydrofuran (THF).
作为优选，反应温度为100℃，反应时间为24小时。Preferably, the reaction temperature is 100° C. and the reaction time is 24 hours.
同现有技术相比，本发明的有益效果体现在：Compared with the prior art, the beneficial effects of the present invention are as follows:
(1)本发明通过利用市售简单、廉价易得的丁二腈作为反应底物，通过在镍催化体系下与芳基硼酸和苯肼盐酸盐的串联环合反应，实现在一锅中高效制备4,5-二氢哒嗪-3-酮类化合物。该反应的催化体系绿色环保、步骤经济性且反应条件简单温和，可有效避免金属氧化剂的使用。(1) The present invention uses commercially available simple, cheap and easily available succinonitrile as a reaction substrate, and realizes efficient preparation of 4,5-dihydropyridazine-3-one compounds in one pot through a series cyclization reaction with arylboronic acid and phenylhydrazine hydrochloride under a nickel catalytic system. The catalytic system of the reaction is green and environmentally friendly, the steps are economical, and the reaction conditions are simple and mild, which can effectively avoid the use of metal oxidants.
(2)本发明的合成方法操作简单，官能团兼容性好，可顺利地扩大到克级规模。(2) The synthetic method of the present invention is simple to operate, has good functional group compatibility, and can be smoothly expanded to a gram scale.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1为实施例1得到的化合物的氢谱和碳谱谱图；FIG1 is a hydrogen spectrum and a carbon spectrum of the compound obtained in Example 1;
图2为实施例5得到的化合物的氢谱和碳谱谱图；FIG2 is a hydrogen spectrum and a carbon spectrum of the compound obtained in Example 5;
图3为实施例9得到的化合物的氢谱和碳谱谱图；FIG3 is a hydrogen spectrum and a carbon spectrum of the compound obtained in Example 9;
图4为实施例10得到的化合物的氢谱和碳谱谱图；FIG4 is a hydrogen spectrum and a carbon spectrum of the compound obtained in Example 10;
图5为实施例17得到的化合物的氢谱和碳谱谱图；FIG5 is a hydrogen spectrum and a carbon spectrum of the compound obtained in Example 17;
图6为实施例18得到的化合物的氢谱和碳谱谱图；FIG6 is a hydrogen spectrum and a carbon spectrum of the compound obtained in Example 18;
其中，氢谱在500MHz核磁仪器上进行测试。碳谱在125MHz核磁仪器上进行测试。测试条件均为室温下使用四甲基硅烷作内标，样品用氘代氯仿溶解。The hydrogen spectrum was tested on a 500MHz nuclear magnetic resonance instrument. The carbon spectrum was tested on a 125MHz nuclear magnetic resonance instrument. The test conditions were all room temperature with tetramethylsilane as the internal standard and the samples were dissolved in deuterated chloroform.
具体实施方式DETAILED DESCRIPTION
下面结合具体实施例对本发明做进一步的描述，以下具体实施例是本发明的最优实施方式。The present invention is further described below in conjunction with specific embodiments. The following specific embodiments are the best implementation methods of the present invention.
实施例1～18Examples 1 to 18
按照表1的原料配比在25mL封管中加入丁二腈(0.6mmol)，芳基硼酸(II，0.8mmol)、苯肼盐酸盐(III，0.3mmol)、Ni(dppp)Cl2(0.03mmol)、ZnCl2(0.6mmol)和有机溶剂THF(2mL)，混合搅拌均匀，在氮气氛围下，在油浴(100℃)下反应24h。按照表1的反应条件反应完成后，冷却，用饱和食盐水洗，收集有机相用硫酸钠干燥，硅胶拌样，经过柱层析纯化得到相应的4,5-二氢哒嗪-3-酮类化合物(I)，反应过程如下式所示：According to the raw material ratio in Table 1, succinonitrile (0.6mmol), arylboronic acid (II, 0.8mmol), phenylhydrazine hydrochloride (III, 0.3mmol), Ni(dppp)Cl 2 (0.03mmol), ZnCl 2 (0.6mmol) and organic solvent THF (2mL) were added to a 25mL sealed tube, mixed and stirred evenly, and reacted in an oil bath (100°C) under a nitrogen atmosphere for 24h. After the reaction was completed according to the reaction conditions in Table 1, the mixture was cooled, washed with saturated brine, the organic phase was collected, dried with sodium sulfate, mixed with silica gel, and purified by column chromatography to obtain the corresponding 4,5-dihydropyridazine-3-one compound (I). The reaction process is shown in the following formula:
表1实施例1～18的原料配比Table 1 Raw material ratios of Examples 1 to 18
表2实施例1～14的反应条件和反应结果Table 2 Reaction conditions and reaction results of Examples 1 to 14
表1和表2中，T为反应温度，t为反应时间In Table 1 and Table 2, T is the reaction temperature and t is the reaction time
实施例1～18制备得到部分化合物的结构确认数据：The structural confirmation data of some compounds prepared in Examples 1 to 18 are as follows:
2,6-diphenyl-4,5-dihydropyridazin-3(2H)-one(I-1):off white solid(41.3mg,55％).mp:96-98℃.Column chromatography on silica gel(Eluent:petroleumether/ethyl acetate,4/1).1H NMR(400MHz,CDCl3)δ7.81-7.78(m,2H),7.60(d,J＝8.0Hz,2H),7.43-7.39(m,5H),7.27(t,J＝7.6Hz,1H),3.07(t,J＝8.0Hz,2H),2.77(t,J＝8.0Hz,2H).13C NMR(101MHz,CDCl3)δ165.4,151.6,141.3,135.5,130.1,128.7,128.6,125.7,125.1,125.0,28.1,22.9.HRMS(ESI)m/z:[M+H]+Calcd for C16H15N2O 251.1179；Found251.1170.2,6-diphenyl-4,5-dihydropyridazin-3(2H)-one(I-1):off white solid(41.3mg,55%).mp:96-98℃.Column chromatography on silica gel(Eluent: petroleumether/ethyl acetate,4/1). 1 H NMR (400MHz, CDCl 3 ) δ7.81-7.78(m,2H),7.60(d,J＝8.0Hz,2H),7.43-7.39(m,5H) ,7.27(t,J＝7.6Hz,1H),3.07(t,J＝8.0Hz,2H),2.77(t,J＝8.0Hz,2H). 13 C NMR (101MHz, CDCl 3 )δ165.4,151.6,141.3,135.5,130.1,128.7,128.6,125.7,125.1,125.0,28.1,22.9.HRMS(ESI)m/z:[M+H] + Calcd for C 16 H 15 N 2 O 251.1179; Found251.1170.
2-phenyl-6-(p-tolyl)-4,5-dihydropyridazin-3(2H)-one(I-2):red oil(33.3mg,42％).Column chromatography on silica gel(Eluent:petroleum ether/ethylacetate,4/1).1H NMR(500MHz,CDCl3)δ7.69(d,J＝8.5Hz,2H),7.60(d,J＝8.0Hz,2H),7.41(t,J＝8.0Hz,2H),7.28-7.21(m,3H),3.05(t,J＝8.0Hz,2H),2.75(t,J＝8.0Hz,2H),2.38(s,3H).13C NMR(125MHz,CDCl3)δ165.4,151.7,141.4,140.3,132.7,129.4,128.5,125.5,125.1,124.9,28.1,22.9,21.4.HRMS(ESI)m/z:[M+Na]+Calcd for C17H16N2NaO 287.1155；Found287.1169.2-phenyl-6-(p-tolyl)-4,5-dihydropyridazin-3(2H)-one(I-2):red oil(33.3mg,42%).Column chromatography on silica gel(Eluent:petroleum ether /ethylacetate, 4/1). 1 H NMR (500MHz, CDCl 3 ) δ7.69 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.41 (t, J = 8.0 Hz,2H),7.28-7.21(m,3H),3.05(t,J＝8.0Hz,2H),2.75(t,J＝8.0Hz,2H),2.38(s,3H). 13 C NMR(125MHz ,CDCl 3 )δ165.4,151.7,141.4,140.3,132.7,129.4,128.5,125.5,125.1,124.9,28.1,22.9,21.4.HRMS(ESI)m/z:[M+Na] + Calcd for C 17 H 16 N 2 NaO 287.1155; Found287.1169.
2-phenyl-6-(m-tolyl)-4,5-dihydropyridazin-3(2H)-one(I-3):red oil(38.0mg,48％).Column chromatography on silica gel(Eluent:petroleum ether/ethylacetate,4/1).1H NMR(500MHz,CDCl3)δ7.62-7.57(m,4H),7.42(t,J＝8.0Hz,2H),7.31-7.21(m,3H),3.06(t,J＝8.0Hz,2H),2.76(t,J＝8.0Hz,2H),2.39(s,3H).13C NMR(125MHz,CDCl3)δ165.4,151.9,141.3,138.4,135.5,130.8,128.5,125.7,125.6,125.0,123.3,28.1,23.0,21.5.HRMS(ESI)m/z:[M+Na]+Calcd for C17H16N2NaO 287.1155；Found287.1160.2-phenyl-6-(m-tolyl)-4,5-dihydropyridazin-3(2H)-one(I-3):red oil(38.0mg,48%).Column chromatography on silica gel(Eluent:petroleum ether /ethylacetate, 4/1). 1 H NMR (500MHz, CDCl 3 ) δ7.62-7.57 (m, 4H), 7.42 (t, J = 8.0Hz, 2H), 7.31-7.21 (m, 3H), 3.06 (t,J＝8.0Hz,2H),2.76(t,J＝8.0Hz,2H),2.39(s,3H). 13 C NMR (125MHz, CDCl 3 )δ165.4,151.9,141.3,138.4,135.5,130.8,128.5,125.7,125.6,125.0,123.3,28.1,23.0,21.5.HRMS(ESI)m/z:[M+Na] + Calcd for C 17 H 16 N 2 NaO 287.1155; Found 287.1160.
2-phenyl-6-(o-tolyl)-4,5-dihydropyridazin-3(2H)-one(I-4):red oil(19.8mg,25％).Column chromatography on silica gel(Eluent:petroleum ether/ethylacetate,4/1).1H NMR(500MHz,CDCl3)δ7.56(d,J＝8.0Hz,2H),7.41-7.36(m,3H),7.30-7.25(m,4H),3.00(t,J＝8.0Hz,2H),2.78(t,J＝8.0Hz,2H),2.48(s,3H).13C NMR(125MHz,CDCl3)δ165.3,155.2,141.1,136.5,135.8,131.3,129.2,128.5,128.0,125.6,125.0,124.9,28.3,26.6,21.1.HRMS(ESI)m/z:[M+Na]+Calcd for C17H16N2NaO 287.1155；Found287.1157.2-phenyl-6-(o-tolyl)-4,5-dihydropyridazin-3(2H)-one(I-4):red oil(19.8mg,25%).Column chromatography on silica gel(Eluent:petroleum ether /ethylacetate,4/1). 1 H NMR (500MHz, CDCl 3 ) δ7.56 (d, J = 8.0Hz, 2H), 7.41-7.36 (m, 3H), 7.30-7.25 (m, 4H), 3.00 (t,J＝8.0Hz,2H),2.78(t,J＝8.0Hz,2H),2.48(s,3H). 13 C NMR (125MHz, CDCl 3 )δ165.3,155.2,141.1,136.5,135.8,131.3,129.2,128.5,128.0,125.6,125.0,124.9,28.3,26.6,21.1.HRMS(ESI)m/z:[M+Na] + Calcd for C 17 H 16 N 2 NaO 287.1155; Found 287.1157.
6-(4-methoxyphenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-5):redoil(26.1 mg,31％).Column chromatography on silica gel(Eluent:petroleum ether/ethyl acetate,4/1).1H NMR(500MHz,CDCl3)δ7.75(d,J＝9.0Hz,2H),7.60(d,J＝8.0Hz,2H),7.41(t,J＝8.0Hz,2H),7.26(t,J＝7.0Hz,1H),6.92(d,J＝9.0Hz,2H),3.83(s,3H),3.04(t,J＝8.0Hz,2H),2.75(t,J＝8.0Hz,2H).13C NMR(125MHz,CDCl3)δ165.4,161.2,151.4,141.4,128.5,128.0,127.7,125.5,124.9,114.0,55.4,28.1,22.8.HRMS(ESI)m/z:[M+H]+Calcd for C17H17N2O2 281.1285；Found 281.1279.6-(4-methoxyphenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-5):redoil(26.1 mg,31%).Column chromatography on silica gel(Eluent:petroleum ether/ ethyl acetate, 4/1). 1 H NMR (500MHz, CDCl 3 ) δ7.75 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.41 (t, J = 8.0 Hz,2H),7.26(t,J＝7.0Hz,1H),6.92(d,J＝9.0Hz,2H),3.83(s,3H),3.04(t,J＝8.0Hz,2H),2.75( t, J=8.0Hz, 2H). 13 C NMR (125MHz, CDCl 3 )δ165.4,161.2,151.4,141.4,128.5,128.0,127.7,125.5,124.9,114.0,55.4,28.1,22.8.HRMS(ESI)m/z:[M+H] + Calcd for C 17 H 17 N 2 O 2 281.1285; Found 281.1279.
6-([1,1'-biphenyl]-4-yl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-6):light brown solid(58.7 mg,60％),mp:123-125℃.Column chromatography onsilica gel(Eluent:petroleum ether/ethyl acetate,4/1).1H NMR(500MHz,CDCl3)δ7.86(d,J＝8.5Hz,2H),7.64-7.60(m,6H),7.46-7.35(m,4H),7.36(t,J＝7.5Hz,1H),7.27(t,J＝7.5Hz,1H),3.07(t,J＝8.0Hz,2H),2.77(t,J＝8.0Hz,2H).13C NMR(125MHz,CDCl3)δ165.3,151.2,142.7,141.3,140.2,134.4,129.0,128.6,127.9,127.3,127.1,125.6,125.6,124.9,28.1,22.9.HRMS(ESI)m/z:[M+H]+Calcd for C22H19N2O 327.1492；Found327.1501.6-([1,1'-biphenyl]-4-yl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-6): light brown solid (58.7 mg, 60%), mp:123-125℃.Column chromatography onsilica gel(Eluent:petroleum ether/ethyl acetate,4/1). 1 H NMR(500MHz, CDCl 3 )δ7.86(d,J＝8.5Hz,2H),7.64- 7.60(m,6H),7.46-7.35(m,4H),7.36(t,J＝7.5Hz,1H),7.27(t,J＝7.5Hz,1H),3.07(t,J＝8.0Hz,2H ), 2.77 (t, J=8.0Hz, 2H). 13 C NMR (125MHz, CDCl 3 )δ165.3,151.2,142.7,141.3,140.2,134.4,129.0,128.6,127.9,127.3,127.1,125.6,125.6,124.9,28.1,22.9.HRMS(ESI)m/z:[M+H] + Calcd for C 22 H 19 N 2 O 327.1492; Found 327.1501.
6-(4-fluorophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-7):lightgreen oil(41.8 mg,52％).Column chromatography on silica gel(Eluent:petroleumether/ethyl acetate,4/1).1H NMR(500MHz,CDCl3)δ7.80-7.77(m,2H),7.59-7.57(m,2H),7.43-7.40(m,2H),7.29-7.25(m,1H),7.11-7.08(m,2H),3.05(t,J＝8.0Hz,2H),2.77(t,J＝8.0Hz,2H).13C NMR(125MHz,CDCl3)δ165.1,163.9(C-F,1JC-F＝248.8Hz),150.5,141.2,131.7(C-F,4JC-F＝2.5Hz),128.6,128.1(C-F,3JC-F＝8.8Hz),125.7,124.9,115.7(C-F,2JC-F＝21.2Hz),28.0,22.9.HRMS(ESI)m/z:[M+H]+Calcd for C16H14FN2O269.1085；Found269.1092.6-(4-fluorophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-7):lightgreen oil(41.8 mg,52%).Column chromatography on silica gel(Eluent:petroleumether/ ethyl acetate,4/1). 1 H NMR (500MHz, CDCl 3 ) δ7.80-7.77(m,2H),7.59-7.57(m,2H),7.43-7.40(m,2H),7.29-7.25( m, 1H), 7.11-7.08 (m, 2H), 3.05 (t, J = 8.0Hz, 2H), 2.77 (t, J = 8.0Hz, 2H). 13 C NMR (125MHz, CDCl 3 ) δ 165.1, 163.9 (CF, 1 J CF =248.8Hz),150.5,141.2,131.7(CF, 4 J CF =2.5Hz),128.6,128.1(CF, 3 J CF =8.8Hz),125.7,124.9,115.7(CF, 2 J CF =21.2Hz) ,28.0,22.9.HRMS(ESI)m/z:[M+H] + Calcd for C 16 H 14 FN 2 O269.1085; Found269.1092.
6-(4-chlorophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-8):lightyellow oil(56.2 mg,66％).Column chromatography on silica gel(Eluent:petroleumether/ethyl acetate,4/1).1H NMR(500MHz,CDCl3)δ7.74(d,J＝8.5Hz,2H),7.57(d,J＝8.0Hz,2H),7.44-7.38(m,4H),7.28(t,J＝7.5Hz,1H),3.07(t,J＝8.0Hz,2H),2.79(t,J＝8.0Hz,2H).13C NMR(125MHz,CDCl3)δ165.1,150.2,141.1,136.1,133.9,128.9,128.6,127.4,125.7,124.9,27.9,22.8.HRMS(ESI)m/z:[M+H]+Calcd for C16H14ClN2O 285.0789；Found 285.0791.6-(4-chlorophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-8):lightyellow oil(56.2 mg,66%).Column chromatography on silica gel(Eluent:petroleumether/ ethyl acetate, 4/1). 1 H NMR (500MHz, CDCl 3 ) δ7.74 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.44-7.38 (m, 4H ), 7.28 (t, J = 7.5Hz, 1H), 3.07 (t, J = 8.0Hz, 2H), 2.79 (t, J = 8.0Hz, 2H). 13 C NMR (125MHz, CDCl 3 )δ165.1,150.2,141.1,136.1,133.9,128.9,128.6,127.4,125.7,124.9,27.9,22.8.HRMS(ESI)m/z:[M+H] + Calcd for C 16 H 14 ClN 2 O 285.0789; Found 285.0791.
6-(4-bromophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-9):lightyellow oil(68.9 mg,70％).Column chromatography on silica gel(Eluent:petroleumether/ethyl acetate,4/1).1H NMR(500MHz,CDCl3)δ7.65(d,J＝9.0Hz,2H),7.57-7.52(m,4H),7.41(t,J＝8.0Hz,2H),7.27(t,J＝7.5Hz,1H),3.03(t,J＝8.0Hz,2H),2.76(t,J＝8.0Hz,2H).13C NMR(125MHz,CDCl3)δ165.1,150.3,141.2,134.4,131.8,128.6,127.6,125.7,124.9,124.4,27.9,22.7.HRMS(ESI)m/z:[M+H]+Calcd for C16H14BrN2O 329.0284；Found 329.0296.6-(4-bromophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-9):lightyellow oil(68.9 mg,70%).Column chromatography on silica gel(Eluent:petroleumether/ ethyl acetate,4/1). 1 H NMR (500MHz, CDCl 3 ) δ7.65 (d, J＝9.0Hz, 2H), 7.57-7.52 (m, 4H), 7.41 (t, J＝8.0Hz, 2H ), 7.27 (t, J = 7.5Hz, 1H), 3.03 (t, J = 8.0Hz, 2H), 2.76 (t, J = 8.0Hz, 2H). 13 C NMR (125MHz, CDCl 3 )δ165.1,150.3,141.2,134.4,131.8,128.6,127.6,125.7,124.9,124.4,27.9,22.7.HRMS(ESI)m/z:[M+H] + Calcd for C 16 H 14 BrN 2 O 329.0284; Found 329.0296.
6-(4-iodophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-10):brownsolid(67.7 mg,60％)mp:98-100℃.Column chromatography on silica gel(Eluent:petroleum ether/ethyl acetate,4/1).1H NMR(400MHz,CDCl3)δ7.73(d,J＝8.0Hz,2H),7.57-7.50(m,4H),7.41(t,J＝7.6Hz,2H),7.27(t,J＝7.6Hz,1H),3.02(t,J＝8.0Hz,2H),2.76(t,J＝8.0Hz,2H).13C NMR(101MHz,CDCl3)δ165.1,150.4,141.2,137.8,135.0,128.6,127.7,125.7,124.9,96.4,27.9,22.6.HRMS(ESI)m/z:[M+H]+Calcd for C16H14IN2O377.0145；Found 377.0133.6-(4-iodophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-10):brownsolid(67.7 mg,60%)mp:98-100℃.Column chromatography on silica gel (Eluent: petroleum ether/ethyl acetate, 4/1). 1 H NMR (400MHz, CDCl 3 ) δ7.73 (d, J = 8.0Hz, 2H), 7.57-7.50 (m, 4H), 7.41 (t, J＝7.6Hz, 2H), 7.27 (t, J＝7.6Hz, 1H), 3.02 (t, J＝8.0Hz, 2H), 2.76 (t, J＝8.0Hz, 2H). 13 C NMR (101MHz, CDCl 3 )δ165.1,150.4,141.2,137.8,135.0,128.6,127.7,125.7,124.9,96.4,27.9,22.6.HRMS(ESI)m/z:[M+H] + Calcd for C 16 H 14 IN 2 O377.0145 ;Found 377.0133.
ethyl 4-(6-oxo-1-phenyl-1,4,5,6-tetrahydropyridazin-3-yl)benzoate(I-11):light brown solid(73.4 mg,76％),mp:59-60℃.Column chromatography onsilica gel(Eluent:petroleum ether/ethyl acetate,4/1).1H NMR(500MHz,CDCl3)δ8.08(d,J＝8.5Hz,2H),7.86(d,J＝8.5Hz,2H),7.58(d,J＝7.5Hz,2H),7.44(t,J＝7.5Hz,2H),7.30(t,J＝7.5Hz,1H),4.40(q,J＝7.0Hz,2H),3.13(t,J＝8.0Hz,2H),2.82(t,J＝8.0Hz,2H),1.41(t,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3)δ166.1,165.1,150.2,141.1,139.4,131.5,129.8,128.6,125.8,125.9,124.9,61.2,27.9,22.9,14.3.HRMS(ESI)m/z:[M+H]+Calcd for C19H19N2O3 323.1390；Found 323.1388.ethyl 4-(6-oxo-1-phenyl-1,4,5,6-tetrahydropyridazin-3-yl)benzoate(I-11): light brown solid(73.4 mg,76%),mp:59-60℃ .Column chromatography onsilica gel(Eluent:petroleum ether/ethyl acetate,4/1). 1 H NMR(500MHz,CDCl 3 )δ8.08(d,J＝8.5Hz,2H),7.86(d,J＝8.5Hz,2H),7.58(d,J＝7.5Hz,2H),7.44(t,J＝7.5Hz,2H) ,7.30(t,J＝7.5Hz,1H),4.40(q,J＝7.0Hz,2H),3.13(t,J＝8.0Hz,2H),2.82(t,J＝8.0Hz,2H),1.41 (t, J=7.0Hz, 3H). 13 C NMR (125MHz, CDCl 3 )δ166.1,165.1,150.2,141.1,139.4,131.5,129.8,128.6,125.8,125.9,124.9,61.2,27.9,22.9,14.3.HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 19 N 2 O 3 323.1390; Found 323.1388.
2-phenyl-6-(4-(trifluoromethyl)phenyl)-4,5-dihydropyridazin-3(2H)-one(I-12):brown solid(72.5 mg,76％),mp:79-81℃.Column chromatography on silicagel(Eluent:petroleum ether/ethyl acetate,4/1).1H NMR(500MHz,CDCl3)δ7.91(d,J＝8.0Hz,2H),7.67(d,J＝8.0Hz,2H),7.57(d,J＝8.0Hz,2H),7.43(t,J＝7.5Hz,2H),7.30(t,J＝7.5Hz,1H),3.12(t,J＝8.0Hz,2H),2.82(t,J＝8.0Hz,2H).13C NMR(125MHz,CDCl3)δ165.0,149.7,141.1,138.8,131.6(C-F,2JC-F＝32.8Hz),128.6,125.9,125.4,125.6(C-F,3JC-F＝3.8Hz),124.9,123.9(C-F,1JC-F＝272.2Hz),27.8,22.9.HRMS(ESI)m/z:[M+H]+Calcdfor C17H14F3N2O 319.1053；Found 319.1053.2-phenyl-6-(4-(trifluoromethyl)phenyl)-4,5-dihydropyridazin-3(2H)-one(I-12): brown solid (72.5 mg, 76%), mp: 79-81℃. Column chromatography on silicagel(Eluent:petroleum ether/ethyl acetate,4/1). 1 H NMR(500MHz, CDCl 3 )δ7.91(d,J＝8.0Hz,2H),7.67(d,J＝8.0Hz, 2H),7.57(d,J＝8.0Hz,2H),7.43(t,J＝7.5Hz,2H),7.30(t,J＝7.5Hz,1H),3.12(t,J＝8.0Hz,2H) ,2.82(t,J=8.0Hz,2H). 13 C NMR (125MHz, CDCl 3 )δ165.0,149.7,141.1,138.8,131.6(CF, 2 J CF =32.8Hz),128.6,125.9,125.4,125.6(CF, 3 J CF =3.8Hz),124.9,123.9(CF, 1 J CF =272.2 Hz),27.8,22.9.HRMS(ESI)m/z:[M+H] + Calcdfor C 17 H 14 F 3 N 2 O 319.1053; Found 319.1053.
6-(naphthalen-2-yl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-13):solid(28.8 mg,32％),mp:135-137℃.Column chromatography on silica gel(Eluent:petroleum ether/ethyl acetate,4/1).1H NMR(500MHz,CDCl3)δ8.12-8.07(m,2H),7.89-7.84(m,3H),7.64(d,J＝7.5Hz,2H),7.53-7.43(m,4H),7.29(t,J＝7.5Hz,1H),3.21(t,J＝8.0Hz,2H),2.83(t,J＝8.0Hz,2H).13C NMR(125MHz,CDCl3)δ165.4,151.3,141.3,134.0,133.0,132.9,128.6,128.6,128.4,127.8,127.2,125.7,125.2,125.0,123.2,28.1,22.8.HRMS(ESI)m/z:[M+H]+Calcd for C20H17N2O 301.1335；Found 301.1344.6-(naphthalen-2-yl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one(I-13): solid (28.8 mg, 32%), mp: 135-137℃.Column chromatography on silica gel(Eluent:petroleum ether/ethyl acetate,4/1). 1 H NMR(500MHz, CDCl 3 )δ8.12-8.07(m,2H),7.89-7.84(m,3H),7.64(d, J＝7.5Hz,2H),7.53-7.43(m,4H),7.29(t,J＝7.5Hz,1H),3.21(t,J＝8.0Hz,2H),2.83(t,J＝8.0Hz, 2H). 13 C NMR (125MHz, CDCl 3 )δ165.4,151.3,141.3,134.0,133.0,132.9,128.6,128.6,128.4,127.8,127.2,125.7,125.2,125.0,123.2,28.1,22.8.HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 17 N 2 O 301.1335; Found 301.1344.
2-phenyl-6-(thiophen-3-yl)-4,5-dihydropyridazin-3(2H)-one(I-14):redoil(23.1 mg,30％).Column chromatography on silica gel(Eluent:petroleum ether/ethyl acetate,4/1).1H NMR(500MHz,CDCl3)δ7.59-7.57(m,4H),7.42(t,J＝8.0Hz,2H),7.35-7.34(m,1H),7.28(d,J＝7.5Hz,1H),3.06(t,J＝8.0Hz,2H),2.78(t,J＝8.0Hz,2H).13C NMR(125MHz,CDCl3)δ165.2,148.2,141.2,138.6,128.5,125.6,125.6,125.7,125.0,124.9,28.1,23.7.HRMS(ESI)m/z:[M+H]+Calcd for C14H13N2OS 257.0743；Found257.0755.2-phenyl-6-(thiophen-3-yl)-4,5-dihydropyridazin-3(2H)-one(I-14):redoil(23.1 mg,30%).Column chromatography on silica gel(Eluent:petroleum ether/ethyl acetate,4/1). 1 H NMR (500MHz, CDCl 3 ) δ7.59-7.57(m,4H),7.42(t,J＝8.0Hz,2H),7.35-7.34(m,1H) ,7.28(d,J＝7.5Hz,1H),3.06(t,J＝8.0Hz,2H),2.78(t,J＝8.0Hz,2H). 13 C NMR (125MHz, CDCl 3 )δ165.2,148.2,141.2,138.6,128.5,125.6,125.6,125.7,125.0,124.9,28.1,23.7.HRMS(ESI)m/z:[M+H] + Calcd for C 14 H 13 N 2 OS 257.0743; Found257.0755.
6-phenyl-2-(p-tolyl)-4,5-dihydropyridazin-3(2H)-one(I-15):off whitesolid(22.2 mg,28％)mp:116-118℃..Column chromatography on silica gel(Eluent:petroleum ether/ethyl acetate,4/1).1H NMR(500MHz,CDCl3)δ7.80-7.79(m,2H),7.45(d,J＝8.5Hz,2H),7.42-7.40(m,3H),7.22(d,J＝8.5Hz,2H),3.08(t,J＝8.0Hz,2H),2.77(t,J＝8.0Hz,2H),2.37(s,3H).13C NMR(125MHz,CDCl3)δ165.3,151.3,138.8,136.5,135.5,129.9,129.2,128.6,125.1,124.9,28.0,22.9,21.1.HRMS(ESI)m/z:[M+Na]+Calcdfor C17H16N2NaO 287.1155；Found 287.1159.6-phenyl-2-(p-tolyl)-4,5-dihydropyridazin-3(2H)-one(I-15):off whitesolid(22.2 mg,28%)mp:116-118℃..Column chromatography on silica gel (Eluent: petroleum ether/ethyl acetate, 4/1). 1 H NMR (500MHz, CDCl 3 ) δ7.80-7.79 (m, 2H), 7.45 (d, J＝8.5Hz, 2H), 7.42- 7.40(m,3H),7.22(d,J＝8.5Hz,2H),3.08(t,J＝8.0Hz,2H),2.77(t,J＝8.0Hz,2H),2.37(s,3H). 13 C NMR (125MHz, CDCl 3 )δ165.3,151.3,138.8,136.5,135.5,129.9,129.2,128.6,125.1,124.9,28.0,22.9,21.1.HRMS(ESI)m/z:[M+Na] + Calcdfor C 17 H 16 N 2 NaO 287.1155 ;Found 287.1159.
2-(4-(tert-butyl)phenyl)-6-phenyl-4,5-dihydropyridazin-3(2H)-one(I-16):brown solid(20.2 mg,22％),mp:133-135℃.Column chromatography on silicagel(Eluent:petroleum ether/ethyl acetate,4/1).1H NMR(500MHz,CDCl3)δ7.81-7.79(m,2H),7.50(d,J＝9.0Hz,2H),7.45-7.40(m,5H),3.09(t,J＝8.0Hz,2H),2.78(t,J＝8.0Hz,2H),1.34(s,9H).13C NMR(125MHz,CDCl3)δ165.3,151.4,149.5,138.7,135.5,129.9,128.6,125.1,125.5,124.5,34.6,31.4,28.0,22.9.HRMS(ESI)m/z:[M+H]+Calcdfor C20H23N2O307.1805；Found 307.1801.2-(4-(tert-butyl)phenyl)-6-phenyl-4,5-dihydropyridazin-3(2H)-one(I-16): brown solid (20.2 mg, 22%), mp: 133-135 ℃.Column chromatography on silicagel(Eluent:petroleum ether/ethyl acetate,4/1). 1 H NMR(500MHz, CDCl 3 )δ7.81-7.79(m,2H),7.50(d,J＝9.0Hz,2H ),7.45-7.40(m,5H),3.09(t,J＝8.0Hz,2H),2.78(t,J＝8.0Hz,2H),1.34(s,9H). 13 C NMR (125MHz, CDCl 3 )δ165.3,151.4,149.5,138.7,135.5,129.9,128.6,125.1,125.5,124.5,34.6,31.4,28.0,22.9.HRMS(ESI)m/z:[M+H] + Calcdfor C 20 H 23 N 2 O307.1805; Found 307.1801.
2-(4-methoxyphenyl)-6-phenyl-4,5-dihydropyridazin-3(2H)-one(I-17):light brown solid(34.5 mg,41％),mp:125-128℃.Column chromatography on silicagel(Eluent:petroleum ether/ethyl acetate,4/1).1H NMR(500MHz,CDCl3)δ7.80-7.78(m,2H),7.53-7.40(m,5H),6.95-6.93(m,2H),3.82(s,3H),3.08(t,J＝8.0Hz,2H),2.77(t,J＝8.0Hz,2H).13C NMR(125MHz,CDCl3)δ165.4,158.2,151.4,135.5,134.4,130.0,128.6,125.4,125.1,113.9,55.5,27.9,22.9.HRMS(ESI)m/z:[M+H]+Calcd for C17H17N2O2281.1285；Found 281.1275.2-(4-methoxyphenyl)-6-phenyl-4,5-dihydropyridazin-3(2H)-one(I-17): light brown solid (34.5 mg, 41%), mp: 125-128℃.Column chromatography on silicagel(Eluent:petroleum ether/ethyl acetate,4/1). 1 H NMR(500MHz, CDCl 3 )δ7.80-7.78(m,2H),7.53-7.40(m,5H),6.95-6.93(m ,2H),3.82(s,3H),3.08(t,J＝8.0Hz,2H),2.77(t,J＝8.0Hz,2H). 13 C NMR (125MHz, CDCl 3 )δ165.4,158.2,151.4,135.5,134.4,130.0,128.6,125.4,125.1,113.9,55.5,27.9,22.9.HRMS(ESI)m/z:[M+H] + Calcd for C 17 H 17 N 2 O 2 281.1285; Found 281.1275.
2-(4-nitrophenyl)-6-phenyl-4,5-dihydropyridazin-3(2H)-one(I-18):yellow solid(23.1 mg,26％),mp:110-112℃.Column chromatography on silica gel(Eluent:petroleum ether/ethyl acetate,4/1).1H NMR(500MHz,CDCl3)δ8.27(d,J＝9.5Hz,2H),7.95(d,J＝9.5Hz,2H),7.84-7.82(m,2H),7.48-7.47(m,3H),3.14(t,J＝8.0Hz,2H),2.84(t,J＝8.0Hz,2H).13C NMR(125MHz,CDCl3)δ165.7,153.3,146.3,144.9,135.0,130.6,128.8,125.2,124.0,123.8,28.3,22.9.HRMS(ESI)m/z:[M+H]+Calcd forC16H14N3O3 296.1030；Found 296.1034.2-(4-nitrophenyl)-6-phenyl-4,5-dihydropyridazin-3(2H)-one(I-18):yellow solid(23.1 mg,26%),mp:110-112℃.Column chromatography on silica gel(Eluent:petroleum ether/ethyl acetate,4/1). 1 H NMR(500MHz, CDCl 3 )δ8.27(d,J＝9.5Hz,2H),7.95(d,J＝9.5Hz,2H) ,7.84-7.82(m,2H),7.48-7.47(m,3H),3.14(t,J＝8.0Hz,2H),2.84(t,J＝8.0Hz,2H). 13 C NMR (125MHz, CDCl 3 )δ165.7,153.3,146.3,144.9,135.0,130.6,128.8,125.2,124.0,123.8,28.3,22.9.HRMS(ESI)m/z:[M+H] + Calcd forC 16 H 14 N 3 O 3 296.1030; Found 296.1034.
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111316249.XA CN114057650B (en) | 2021-11-08 | 2021-11-08 | Method for preparing 4, 5-dihydropyridazin-3-one compounds by one-pot method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111316249.XA CN114057650B (en) | 2021-11-08 | 2021-11-08 | Method for preparing 4, 5-dihydropyridazin-3-one compounds by one-pot method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114057650A CN114057650A (en) | 2022-02-18 |
| CN114057650B true CN114057650B (en) | 2023-03-28 |
Family
ID=80274800
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111316249.XA Active CN114057650B (en) | 2021-11-08 | 2021-11-08 | Method for preparing 4, 5-dihydropyridazin-3-one compounds by one-pot method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114057650B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006138656A2 (en) * | 2005-06-17 | 2006-12-28 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid-1 receptor modulators |
| WO2012020780A1 (en) * | 2010-08-10 | 2012-02-16 | 武田薬品工業株式会社 | Heterocyclic compound and use thereof |
| CN106573898A (en) * | 2014-08-14 | 2017-04-19 | 豪夫迈·罗氏有限公司 | Novel pyridazones and triazinones for the treatment and prophylaxis of hepatitis b virus infection |
| WO2020242245A1 (en) * | 2019-05-29 | 2020-12-03 | 에스티팜 주식회사 | Phthalazinone compounds and use thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7632837B2 (en) * | 2005-06-17 | 2009-12-15 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid-1 receptor modulators |
-
2021
- 2021-11-08 CN CN202111316249.XA patent/CN114057650B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006138656A2 (en) * | 2005-06-17 | 2006-12-28 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid-1 receptor modulators |
| WO2012020780A1 (en) * | 2010-08-10 | 2012-02-16 | 武田薬品工業株式会社 | Heterocyclic compound and use thereof |
| CN106573898A (en) * | 2014-08-14 | 2017-04-19 | 豪夫迈·罗氏有限公司 | Novel pyridazones and triazinones for the treatment and prophylaxis of hepatitis b virus infection |
| WO2020242245A1 (en) * | 2019-05-29 | 2020-12-03 | 에스티팜 주식회사 | Phthalazinone compounds and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114057650A (en) | 2022-02-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2023548666A (en) | 3-Fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]indene-7 Method of preparing -yl)oxy)-benzonitrile | |
| CN110981877A (en) | Novel method for synthesizing indolo [1,2-a ] quinoxaline derivative | |
| CN112239424B (en) | A kind of aristolochia alkaloid and preparation method of intermediate thereof | |
| CN111303028A (en) | A kind of 4-cyano-2-difluoromethyl substituted quinoline compound and synthetic method | |
| CN114057650B (en) | Method for preparing 4, 5-dihydropyridazin-3-one compounds by one-pot method | |
| CN114031556B (en) | Synthetic method for preparing 5-amino-N-aryl-3-arylpyrazole compound by green one-pot method | |
| CN113185536A (en) | Synthesis method of pyrazolidone benzo 1, 3-oxygen-nitrogen hetero-compound | |
| CN113004215B (en) | A kind of synthetic method of 2,4,5-tri-substituted oxazole compounds | |
| CN114149379B (en) | Synthesis method for synthesizing multi-substituted oxazole product from simple aromatic carboxylic acid and cyano-substituted ester compound | |
| CN115160211B (en) | Green synthesis method of isoindolinone compound | |
| CN115124460B (en) | Binaphthyl axis chiral ligand containing coordination unit, preparation method and application thereof | |
| CN113582929B (en) | A kind of synthetic method of 2,5-disubstituted imidazole compounds | |
| CN112125843B (en) | A kind of preparation method of 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone compound | |
| CN102766095B (en) | Preparation method of electron-deficient group-containing multi-substituted pyrazole derivative | |
| CN113105460A (en) | Synthesis method of 6-hydroisoindolo [2, 1-alpha ] indole compound | |
| CN115160270B (en) | Synthesis method of 2,3, 5-trisubstituted furan derivative | |
| CN118908898A (en) | Efficient synthesis method of 3,4, 6-triaryl substituted pyridazine compound | |
| CN119661448A (en) | Simple and convenient synthesis method of 3, 5-disubstituted pyridazine compound | |
| CN114605273B (en) | Method for synthesizing arylaminophenol compound by palladium-catalyzed CO-participated 1, 4-eneyne aromatization reaction | |
| CN114195726B (en) | A kind of preparation method of arylamine compound substituted by 1,2,4-triazolyl | |
| CN114349684B (en) | Synthetic method of benzo [ c, d ] indole imine derivative | |
| CN115215810B (en) | Preparation method of heating-promoted 5-trifluoromethyl-substituted 1,2, 4-triazole compound | |
| CN115232063B (en) | A kind of synthetic method of benzo[c,d]indole compound containing bromine or chlorine | |
| CN118702624A (en) | A 2,4-diaryl-3-thioquinoline compound, its sulfone oxide and preparation method thereof | |
| CN112225685B (en) | 3-cyanoindole compound, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |