CN104529896A - Synthetic method of diaryl substituted isoquinoline compound - Google Patents
Synthetic method of diaryl substituted isoquinoline compound Download PDFInfo
- Publication number
- CN104529896A CN104529896A CN201410757773.4A CN201410757773A CN104529896A CN 104529896 A CN104529896 A CN 104529896A CN 201410757773 A CN201410757773 A CN 201410757773A CN 104529896 A CN104529896 A CN 104529896A
- Authority
- CN
- China
- Prior art keywords
- compound
- synthetic method
- formula
- alkyl
- palladium
- 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
- -1 isoquinoline compound Chemical class 0.000 title claims abstract description 60
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 238000010189 synthetic method Methods 0.000 title claims abstract description 41
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 title claims abstract description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 239000003446 ligand Substances 0.000 claims abstract description 18
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical group [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 101150003085 Pdcl gene Proteins 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000004682 monohydrates Chemical class 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical group 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- OIXUJRCCNNHWFI-UHFFFAOYSA-N 1,2-dioxane Chemical compound C1CCOOC1 OIXUJRCCNNHWFI-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- RBYGDVHOECIAFC-UHFFFAOYSA-L acetonitrile;palladium(2+);dichloride Chemical compound [Cl-].[Cl-].[Pd+2].CC#N.CC#N RBYGDVHOECIAFC-UHFFFAOYSA-L 0.000 claims description 2
- 125000005466 alkylenyl group Chemical group 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 4
- 239000002904 solvent Substances 0.000 abstract description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000012044 organic layer Substances 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 14
- 238000005406 washing Methods 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 0 C*C(c1ccccc1C(C)*)=O Chemical compound C*C(c1ccccc1C(C)*)=O 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 150000002941 palladium compounds Chemical class 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- KABRXLINDSPGDF-UHFFFAOYSA-N 7-bromoisoquinoline Chemical compound C1=CN=CC2=CC(Br)=CC=C21 KABRXLINDSPGDF-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002537 isoquinolines Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 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 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- PTRATZCAGVBFIQ-UHFFFAOYSA-N Abametapir Chemical compound N1=CC(C)=CC=C1C1=CC=C(C)C=N1 PTRATZCAGVBFIQ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BWDJJFIOGWAGNF-UHFFFAOYSA-N C1=NC=CC2=CC=CC=C12.C1(=CC=CC=C1)C1=CC=CC=C1 Chemical compound C1=NC=CC2=CC=CC=C12.C1(=CC=CC=C1)C1=CC=CC=C1 BWDJJFIOGWAGNF-UHFFFAOYSA-N 0.000 description 1
- RSPVMRICCLIGLY-UHFFFAOYSA-N CCC(c1ccccc1CC#N)=O Chemical compound CCC(c1ccccc1CC#N)=O RSPVMRICCLIGLY-UHFFFAOYSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 102000009389 Prostaglandin D receptors Human genes 0.000 description 1
- 108050000258 Prostaglandin D receptors Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Polymers C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003672 ureas Chemical class 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
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
The invention relates to a synthetic method of a diaryl substituted isoquinoline compound. The synthetic method comprises a step of enabling a diaryl carbonyl compound to react with aryl trifluoro-borate in a solvent in the presence of a palladium catalyst, a nitrogen-containing ligand and an accelerant so as to prepare the diaryl substituted isoquinoline compound through one step. The synthetic method is simple in reaction, convenient to operate and high in yield, is a brand-new synthetic method for the diaryl substituted isoquinoline compound, provides a new synthetic route for preparing the compound, and has a good scientific research value and an industrial potential.
Description
Technical field
The present invention relates to a kind of synthetic method of nitrogenous fused heterocyclic compound, particularly a kind of synthetic method of diaryl substituted isoquinoline compound, belongs to organic chemical synthesis field.
Background technology
Relating in vitochemical multiple embody rule field, especially in medicinal chemistry art, nitrogen-containing heterocycle compound is a kind of widely used medicine intermediate, or final active pharmaceutical compounds is also often containing nitrogen heterocyclic ring, exactly because nitrogen-containing heterocycle compound has potential biological activity and pharmaceutical use and is paid close attention to widely.
In miscellaneous nitrogen-containing heterocycle compound, isoquinoline 99.9 skeleton has important function and position, be synthesis multi-medicament important as precursors, fragment and/or intermediate, such as it is the important component part of antibacterials, by introducing isoquinoline 99.9 skeleton, gained medicine has the plurality of advantages such as antibacterial, antiviral, antitumor, antidepressant usually.
For isoquinoline compound and synthesis thereof, researcher has synthesized and various new isoquinoline compound and preparation method thereof, thus provide basic raw material for the synthesis of final medical compounds, such as, there are following isoquinoline compound and/or its synthetic method in prior art:
Disclose a kind of synthetic method of 7-bromo-isoquinoline in CN102875465A, become bromine method by diazotization, in non-aqueous solvent, obtain 7-bromo-isoquinoline through polystep reaction, concrete reaction process is as follows:
CN102627604A discloses two class isoquinilone derivatives and the application as cancer therapy drug thereof, and find that it has human cancer cell through research and suppress significantly and kill activity, described two class isoquinoline compound structural formulas are as follows:
WO2012086727A discloses a kind of isoquinoline 99.9-6-sulfone amide derivative, and this derivative can be used to treat glaucoma, Bulbi hypertonia and circulation system disease, and this derivant structure is as follows:
This derivative, by many synthetic routes, obtains through reacting up at least 4 steps.
WO2012026529A discloses a kind of novel synthesis of isoquinilone derivatives, and be included under at least one in nitrile solvents, amide solvent, sulfoxide type solvents and ureas solvent and alkali exists, formula III compound and formula II compound are obtained by reacting formula I:
WO2011162274A discloses a kind of isoquinilone derivatives, and it can be used as CRTH2 inhibitor, and structural formula is as follows:
This compound is obtained, the loaded down with trivial details and expensive reagents of reaction process by least 5 steps reactions.
WO2010027889A discloses a kind of method of substituted isoquinoline formula I, and described method comprises:
Under methyl alcohol and high price iodine oxygenant exist, with anhydrous acid process formula A compound, then products therefrom is used chlorizating agent process, thus obtains formula I, its Chinese style I and A structural formula of compound as follows:
CN101544636A discloses a kind of polyhalogenated isoquinoline formula I derivative and the synthetic method thereof with pharmaceutical activity, and described derivative grinds reacting by heating by II and III under condition of no solvent, then adds catalyzer and continues reaction and obtain:
As mentioned above, although disclose the multiple method preparing isoquinoline compound in prior art, these methods or reactions steps various, or product yield is lower, or employ expensive reagent, still cannot meet at present for the extensive and easy requirement of isoquinoline compound preparation method.Therefore for the exploration of the preparation method of isoquinoline compound, an important development direction in this field current and focus is still.
Summary of the invention
In view of this, in order to solve as too low in yield, the many defects such as process is loaded down with trivial details, expensive reagents is rare that exist in above-mentioned prior art, the present inventor conducts in-depth research for the chemical synthesis process of isoquinoline compound, after paying a large amount of creative work, thus completes the present invention.
At this, applicant is intended to illustrate, technical scheme of the present invention is in state natural sciences fund (numbering: be accomplished under subsidy 21472140), express thanks at this.
The present invention relates to a kind of synthetic method of diaryl substituted isoquinoline compound, described method comprises in a solvent, under palladium catalyst, containing n-donor ligand and promotor exist, make that diaryl carbonyl compound and aryl trifluoroborate react and a step has obtained isoquinoline compound.
Specifically, the invention provides the synthetic method of diaryl substituted isoquinoline compound shown in a kind of formula (I),
Described method comprises:
Under palladium catalyst, containing n-donor ligand and promotor exist, formula (II) compound and formula (III) compound react in reaction solvent, the diaryl substituted isoquinoline compound of production (I),
Wherein: R
1be selected from H, halogen, nitro, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group or phenyl;
R
2be selected from H, halogen or C
1-C
6alkyl;
M is alkali metal;
Ar
1, Ar
2be phenyl independently of one another, with 1-5 substituent phenyl, naphthyl or with 1-5 substituent naphthyl;
Described substituting group is halogen, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group or phenyl.
In described synthetic method of the present invention, described palladium catalyst is organic palladium or inorganic palladium compound.Such as can be palladium acetylacetonate (Pd (acac)
2), acid chloride, palladium trifluoroacetate, Palladous chloride, Na
2pdCl
4, Pd (NH
3)
4cl
2, Pd (PPh
3)
4, PdCl
2(dppf), dppePdCl
2, Na
2pdCl
2, PdCl
2(CH
3cN)
2, PdCl
2(PPh
3)
2, Pd (NH
3)
4cl
2, PdCl
2(cod) any one in or any multiple mixture.
Preferably, described palladium catalyst is selected from palladium acetylacetonate (Pd (acac)
2), any one in acid chloride, palladium trifluoroacetate, Palladous chloride or multiple mixture, most preferably be palladium acetylacetonate (Pd (acac)
2).
In described synthetic method of the present invention, described containing n-donor ligand is L1 or L2:
Wherein, X
1-X
8be selected from H or C independently of one another
1-C
6alkyl, Y
1-Y
4be selected from H, C independently of one another
1-C
6alkyl or phenyl.
Described containing n-donor ligand is preferably any one in following formula L-1 to L-4:
Described containing n-donor ligand most preferably is L-1, and namely 2,2 '-dipyridyl (being sometimes abbreviated as below " bpy ").
In described method of the present invention, C
1-C
6the implication of alkyl refers to the straight or branched alkyl with 1-6 carbon atom, such as can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl or n-hexyl etc. in non-limiting manner.
In described method of the present invention, C
1-C
6alkoxyl group refers to " C defined above
1-C
6alkyl " be connected with O atom after group.
In described method of the present invention, unless otherwise prescribed, the halogen in halogen or halo such as can be F, Cl, Br or I.
In described synthetic method of the present invention, M is alkali metal, such as, can be Li, Na or K.
In described method of the present invention, Ar
1or Ar
2be phenyl independently of one another, with 1-5 substituent phenyl, naphthyl or with 1-5 substituent naphthyl, phenyl or naphthyl wherein can replace by 1-5 above-mentioned substituting group, such as can be 1,2,3,4 or 5 substituting groups replace.
In described synthetic method of the present invention, described promotor is the monohydrate of trifluoroacetic acid (TFA), following formula (IV) compound or formula (IV) compound:
Wherein R is H, nitro or C
1-C
6alkyl.
Described promotor is preferably the monohydrate of formula (IV) compound or formula (IV) compound, the more preferably monohydrate of formula (IV) compound, further be preferably tosic acid or tosic acid monohydrate, most preferably be tosic acid monohydrate.
In described synthetic method of the present invention, described reaction solvent is water, benzene,toluene,xylene, chlorobenzene, 1,4-dioxane, 1,6-dioxane, tetrahydrofuran (THF) (THF), 2-methyltetrahydrofuran, N, one or more in dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), methylene dichloride, trichloromethane, tetracol phenixin, ethylene dichloride, normal hexane, ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol, butanols, amylalcohol, hexanol etc., most preferably are water.The consumption of reaction solvent is not particularly limited, and can select according to the common practise in organic synthesis field, such as, select to make to react the amount steadily can carrying out, be easy to control, or is convenient to the amount etc. of aftertreatment.
In described synthetic method of the present invention, described formula (II) compound is 1:1-3 with the mol ratio of (III) compound, this scope includes any sub-range scope wherein, also include any concrete point value wherein, exemplarily such as can be 1:1,1:1.2,1:1.4,1:1.6,1:1.8,1:2,1:2.2,1:2.4,1:2.6,1:2.8 or 1:3.
In described synthetic method of the present invention, the mole dosage of described palladium catalyst is the 2-10% of formula (II) compound mole dosage, such as, can be 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.
In described synthetic method of the present invention, the mol ratio of described palladium catalyst and described containing n-donor ligand is 1:2-3, such as, can be 1:1.2,1:1.5,1:1.7,1:1.9,1:2,1:2.2,1:2.4,1:2.6,1:2.8 or 1:3.
In described synthetic method of the present invention, described formula (II) is 1:5-15 with the mol ratio of described promotor, such as, can be 1:5,1:7,1:9,1:10,1:12,1:14 or 1:15.
In described synthetic method of the present invention, temperature of reaction is 60-140 DEG C, such as can be 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C, 120 DEG C, 130 DEG C or 140 DEG C in non-limiting manner.
In described synthetic method of the present invention, reaction times, there is no particular limitation, such as by liquid chromatographic detection object product or raw material residual percentage and determine the suitable reaction times, it typically is 15-30 hour, is such as 15 hours, 17 hours, 19 hours, 21 hours, 23 hours, 25 hours, 27 hours, 29 hours or 30 hours in non-limiting manner.
In described synthetic method of the present invention, the aftertreatment after reaction terminates can be following method: after reaction terminates, by mixture impouring ethyl acetate, use saturated NaHCO in turn
3the aqueous solution and salt water washing, after aqueous layer with ethyl acetate extraction, merge organic layer (namely merge the organic layer after washing and extract the organic layer obtained), use anhydrous Na
2sO
4drying, negative pressure evaporation is except desolventizing, and residue is purified by flash column chromatography (n-hexane/ethyl acetate, both volume ratios are 1:1-3), obtains target product.
In described synthetic method of the present invention, exemplify as one, Ar
1for phenyl, 3-aminomethyl phenyl or 4-chloro-phenyl-.
In described synthetic method of the present invention, exemplify as one, Ar
2for phenyl, 3-aminomethyl phenyl, 4-chloro-phenyl-or naphthalene-2-base.
In described synthetic method of the present invention, exemplify as one, R
1for H or Br.
In described synthetic method of the present invention, exemplify as one, R
2for H.
Compared with prior art, the present invention by selecting type (II) and (III) compound as reaction substrate, using palladium compound as catalyzer, by the synergy of specific containing n-donor ligand promotor, one-step synthesis obtains diaryl substituted isoquinoline compound.Described method reaction is simple, easy and simple to handle, yield is high, is a kind of brand-new synthetic method of diaryl substituted isoquinoline compound, for the preparation of diaryl substituted isoquinoline compound provides new synthetic route.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not any type of any restriction is formed to real protection scope of the present invention, more non-protection scope of the present invention is confined to this.
Wherein following group refers to following implication:
Me: methyl
Ph: phenyl.
3-MePh:3-tolyl.
4-ClPh:4-chloro-phenyl-.
The synthesis of embodiment 1:1,3-bis-tolyl isoquinoline 99.9
In reaction vessel, add 100ml water, 20mmol formula (II) compound, 20mmol formula (III) compound, 0.4mmol palladium acetylacetonate, 0.8mmol containing n-donor ligand L-1 and 100mmol tosic acid monohydrate, stir lower reaction 30 hours in 60 DEG C.After reaction terminates, by mixture impouring ethyl acetate, use saturated NaHCO in turn
3the aqueous solution and salt water washing, after aqueous layer with ethyl acetate extraction, merge organic layer (namely merge the organic layer after washing and extract the organic layer obtained), use anhydrous Na
2sO
4drying, negative pressure evaporation is except desolventizing, and residue is purified by flash column chromatography (n-hexane/ethyl acetate, both volume ratios are 1:1), obtains the target product into liquid.Productive rate is 83.6%, and purity is 99.2% (HPLC).
Nucleus magnetic resonance:
1hNMR (500MHz, CDCl
3) δ 8.11 (d, J=10Hz, 1H), 8.05 (d, J=10Hz, 2H), 7.98 (d, J=10Hz, 1H), 7.93 (d, J=5Hz, 1H), 7.68 (dd, J=10Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=10Hz, 1H), 7.43-7.52 (m, 2H) 7.39 (dd, J=5Hz, 1H), 7.33 (d, J=10Hz, 1H), 7.22 (d, J=10Hz, 1H), 2.49 (s, 3H), 2.46 (s, 3H).
Embodiment 2:1,3-bis-synthesis of rubigan isoquinoline 99.9
In reaction vessel, add 100ml water, 20mmol formula (II) compound, 40mmol formula (III) compound, 1mmol palladium acetylacetonate, 3mmol containing n-donor ligand L-1 and 200mmol tosic acid monohydrate, stir lower reaction 20 hours in 80 DEG C.After reaction terminates, by mixture impouring ethyl acetate, use saturated NaHCO in turn
3the aqueous solution and salt water washing, after aqueous layer with ethyl acetate extraction, merge organic layer (namely merge the organic layer after washing and extract the organic layer obtained), use anhydrous Na
2sO
4drying, negative pressure evaporation is except desolventizing, and residue is purified by flash column chromatography (n-hexane/ethyl acetate, both volume ratios are 1:2), obtains the target product into solid.Productive rate is 93.8%, and purity is 98.5% (HPLC).
Fusing point: 150-151 DEG C;
Nucleus magnetic resonance:
1hNMR (500MHz, CDCl
3) δ 8.06-8.15 (m, 4H), 7.94 (d, J=10Hz, 1H), 7.69-7.75 (m, 3H), 7.53-7.56 (m, 3H), 7.46 (d, J=10Hz, 2H).
The synthesis of embodiment 3:1,3-dibiphenylyl-4-base isoquinoline 99.9
In reaction vessel, add 100ml water, 20mmol formula (II) compound, 60mmol formula (III) compound, 2mmol palladium acetylacetonate, 5mmol containing n-donor ligand L-1 and 300mmol tosic acid monohydrate, stir lower reaction 15 hours in 140 DEG C.After reaction terminates, by mixture impouring ethyl acetate, use saturated NaHCO in turn
3the aqueous solution and salt water washing, after aqueous layer with ethyl acetate extraction, merge organic layer (namely merge the organic layer after washing and extract the organic layer obtained), use anhydrous Na
2sO
4drying, negative pressure evaporation is except desolventizing, and residue is purified by flash column chromatography (n-hexane/ethyl acetate, both volume ratios are 1:3), obtains target product.Productive rate is 68.8%, and purity is 98.9% (HPLC).
Fusing point: 114.7-116.5 DEG C;
Nucleus magnetic resonance:
1h NMR (500MHz, CDCl
3) δ 8.21-8.20 (m, 2H), 8.08-8.07 (m, 2H), 7.94-7.93 (m, 1H), 7.77-7.76 (m, 2H), 7.70-7.67 (m, 1H), 7.55-7.49 (m, 5H), 7.43-7.40 (m, 1H).
The synthesis of embodiment 4:1,3-dinaphthyl-2-base isoquinoline 99.9
In reaction vessel, add 100ml water, 20mmol formula (II) compound, 50mmol formula (III) compound, 0.8mmol palladium acetylacetonate, 2mmol containing n-donor ligand L-1 and 150mmol tosic acid monohydrate, stir lower reaction 20 hours in 100 DEG C.After reaction terminates, by mixture impouring ethyl acetate, use saturated NaHCO in turn
3the aqueous solution and salt water washing, after aqueous layer with ethyl acetate extraction, merge organic layer (namely merge the organic layer after washing and extract the organic layer obtained), use anhydrous Na
2sO
4drying, negative pressure evaporation is except desolventizing, and residue is purified by flash column chromatography (n-hexane/ethyl acetate, both volume ratios are 1:1), obtains the target product into solid.Productive rate is 87.5%, and purity is 98.7% (HPLC).
Fusing point: 116.5-118.4 DEG C;
Nucleus magnetic resonance:
1h NMR (500MHz, CDCl
3) δ 8.29-8.27 (m, 3H), 8.21-8.19 (m, 1H), 8,12 (s, 1H), 8.06-8.04 (m, 1H), 7,99-7.96 (m, 4H), 7.71-7.68 (m, 1H), 7.60-7.51 (m, 5H), 7.45-7.42 (m, 1H).
The synthesis of bromo-1, the 3-phenylbenzene isoquinoline 99.9 of embodiment 5:7-
In reaction vessel, add 100ml water, 20mmol formula (II) compound, 30mmol formula (III) compound, 1.5mmol palladium acetylacetonate, 3.5mmol containing n-donor ligand L-1 and 250mmol tosic acid monohydrate, stir lower reaction 16 hours in 80 DEG C.After reaction terminates, by mixture impouring ethyl acetate, use saturated NaHCO in turn
3the aqueous solution and salt water washing, after aqueous layer with ethyl acetate extraction, merge organic layer (namely merge the organic layer after washing and extract the organic layer obtained), use anhydrous Na
2sO
4drying, negative pressure evaporation is except desolventizing, and residue is purified by flash column chromatography (n-hexane/ethyl acetate, both volume ratios are 1:2), obtains the target product into solid.Productive rate is 63.1%, and purity is 98.8% (HPLC).
Fusing point: 136-137 DEG C;
Nucleus magnetic resonance:
1hNMR (500MHz, CDCl
3) δ 8.18-8.26 (m, 3H), 8.01 (s, 1H), 7.71-7.79 (m, 4H), 7.47-7.58 (m, 5H), 7.39-7.42 (m, 1H).
Can be found out by above-described embodiment 1-5, when adopting the compound system constructed by reaction substrate of the present invention, catalyzer, part and promotor, corresponding diaryl substituted isoquinoline compound can be obtained with higher yields and high purity by various types of diaryl carbonyl compound and phenylboronate.
Embodiment 6-11
All replace with except following palladium compound except by catalyst acetyl acetone palladium wherein, implement embodiment 6-11 respectively in the mode identical with embodiment 1-5, the productive rate of embodiment corresponding relation and corresponding diaryl substituted isoquinoline compound is as shown in the table.
As seen from the above table, when adopting acid chloride, palladium trifluoroacetate and Palladous chloride, the productive rate of corresponding product all has significant reduction, this demonstrate that palladium acetylacetonate has best catalytic performance and unique catalysis specificity.
Embodiment 12-21
All replace with except following palladium compound except by catalyst acetyl acetone palladium wherein, implement embodiment 12-21 respectively in the mode identical with embodiment 1-5, the productive rate of embodiment corresponding relation and corresponding diaryl isoquinoline compound is as shown in the table.
Note: "--" represents unreacted.
As seen from the above table, when adopting other palladium compound, react hardly.
Embodiment 22-33
Except when aqueous solvent wherein all to be replaced with as solvent in following table, implement embodiment 22-33 respectively in the mode identical with embodiment 1-5, the productive rate of embodiment corresponding relation and corresponding diaryl isoquinoline compound is as shown in the table.
As seen from the above table, when adopting other organic solvent, reaction also can be carried out, but productive rate has significant reduction, thus demonstrates in this organic reaction, and for organic solvent, the water for non-organic solvent has best solvent effect on the contrary.
Embodiment 34-44
Replace with except following part except by ligand L-1 wherein, implement embodiment 34-45 respectively in the mode identical with embodiment 1-5, the productive rate of embodiment corresponding relation and corresponding diaryl isoquinoline compound is as shown in the table.
Except when part being changed to following part, implement embodiment 40-44 respectively in the mode identical with embodiment 1-5 respectively:
Find that the productive rate of corresponding diaryl isoquinoline compound is 16.9-33.4%.
As can be seen here, part of the present invention for reaction carry out smoothly obtaining with the high yield of product there is significant influence, wherein 2,2 '-dipyridyl has best synergy, even if there is 4 of identical precursor structure with it, 4 '-dimethylbipyridine or 5,5 '-dimethylbipyridine all can not obtain so identical reaction effect.
Embodiment 45-49
Replace with except following promotor except by tosic acid monohydrate wherein, implement embodiment 45-49 respectively in the mode identical with embodiment 1-6, the productive rate of embodiment corresponding relation and corresponding diaryl substituted isoquinoline compound is as shown in the table.
Embodiment 50-54
Except not using promotor, implement embodiment 53-58 respectively in the mode identical with embodiment 1-5, the productive rate of embodiment corresponding relation and corresponding diaryl substituted isoquinoline compound is as shown in the table.
Note: "--" represents and do not contain.
From embodiment 45-54, promotor has remarkably influenced for the productive rate of product, and wherein tosic acid monohydrate has best accelerating system effect, even if adopt tosic acid, its productive rate is also remarkable in tosic acid monohydrate.And when not using promotor, then products collection efficiency significantly reduces, even without research necessity and lose industrialized potentiality
In sum, can clearly be found out by above-mentioned all embodiments, when namely employing method of the present invention uses the palladium catalyst (especially palladium acetylacetonate) being selected from palladium, be selected from the containing n-donor ligand (especially L-1) of L-1 to L-4, and suitable solvent (especially water) and Suitable accelerators (especially tosic acid monohydrate) form complex reaction system time, diaryl substituted isoquinoline compound can be obtained with high yield and high purity, it is a kind of brand-new synthetic method having very much prospects for commercial application, for the efficient quick synthesis of diaryl substituted isoquinoline compound provides brand-new synthetic route.
Should be appreciated that the purposes of these embodiments is only not intended to for illustration of the present invention limit the scope of the invention.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (10)
1. a synthetic method for diaryl substituted isoquinoline compound shown in formula (I),
Described method comprises:
Under palladium catalyst, containing n-donor ligand and promotor exist, formula (II) compound and formula (III) compound react in reaction solvent, the diaryl substituted isoquinoline compound of production (I),
Wherein: R
1be selected from H, halogen, nitro, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group or phenyl;
R
2be selected from H, halogen or C
1-C
6alkyl;
M is alkali metal;
Ar
1, Ar
2be phenyl independently of one another, with 1-5 substituent phenyl, naphthyl or with 1-5 substituent naphthyl;
Described substituting group is halogen, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group or phenyl.
2. synthetic method as claimed in claim 1, is characterized in that: described palladium catalyst is palladium acetylacetonate (Pd (acac)
2), acid chloride, palladium trifluoroacetate, Palladous chloride, Na
2pdCl
4, Pd (NH
3)
4cl
2, Pd (PPh
3)
4, PdCl
2(dppf), dppePdCl
2, Na
2pdCl
2, PdCl
2(CH
3cN)
2, PdCl
2(PPh
3)
2, Pd (NH
3)
4cl
2, PdCl
2(cod) any one in or any multiple mixture; Preferably, described palladium catalyst is selected from palladium acetylacetonate (Pd (acac)
2), any one in acid chloride, palladium trifluoroacetate, Palladous chloride or multiple mixture, most preferably be palladium acetylacetonate (Pd (acac)
2).
3. synthetic method as claimed in claim 1 or 2, is characterized in that: described containing n-donor ligand is L1 or L2:
Wherein, X
1-X
8be selected from H or C independently of one another
1-C
6alkyl, Y
1-Y
4be selected from H, C independently of one another
1-C
6alkyl or phenyl;
Be preferably any one in following formula L-1 to L-4:
Most preferably be L-1.
4. the synthetic method as described in any one of claim 1-3, is characterized in that: described promotor is the monohydrate of trifluoroacetic acid (TFA), following formula (IV) compound or formula (IV) compound:
Wherein R is H, nitro or C
1-C
6alkyl.
Be preferably the monohydrate of formula (IV) compound or formula (IV) compound, the more preferably monohydrate of formula (IV) compound, further be preferably tosic acid or tosic acid monohydrate, most preferably be tosic acid monohydrate.
5. the synthetic method as described in any one of claim 1-4, it is characterized in that: described reaction solvent is water, benzene,toluene,xylene, chlorobenzene, 1,4-dioxane, 1,6-dioxane, tetrahydrofuran (THF) (THF), 2-methyltetrahydrofuran, N, one or more in dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), methylene dichloride, trichloromethane, tetracol phenixin, ethylene dichloride, normal hexane, ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol, butanols, amylalcohol, hexanol etc., most preferably are water.
6. the synthetic method as described in any one of claim 1-5, is characterized in that: described formula (II) compound is 1:1-3 with the mol ratio of (III) compound.
7. the synthetic method as described in any one of claim 1-6, is characterized in that: the mole dosage of described palladium catalyst is the 2-10% of formula (II) compound mole dosage.
8. the synthetic method as described in any one of claim 1-7, is characterized in that: the mol ratio of described palladium catalyst and described containing n-donor ligand is 1:2-3.
9. the synthetic method as described in any one of claim 1-8, is characterized in that: described formula (II) is 1:5-15 with the mol ratio of described promotor.
10. synthetic method as claimed in claim 9, is characterized in that: temperature of reaction is 60-140 DEG C; Reaction times is 15-30 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410757773.4A CN104529896B (en) | 2014-12-11 | 2014-12-11 | Synthetic method of diaryl substituted isoquinoline compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410757773.4A CN104529896B (en) | 2014-12-11 | 2014-12-11 | Synthetic method of diaryl substituted isoquinoline compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104529896A true CN104529896A (en) | 2015-04-22 |
| CN104529896B CN104529896B (en) | 2017-05-03 |
Family
ID=52845576
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410757773.4A Expired - Fee Related CN104529896B (en) | 2014-12-11 | 2014-12-11 | Synthetic method of diaryl substituted isoquinoline compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104529896B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632039A (en) * | 2016-12-15 | 2017-05-10 | 温州医科大学附属第二医院 | Synthetic method of antitumor nitrogen-containing heterocyclic drug intermediates |
| CN106674050A (en) * | 2016-12-15 | 2017-05-17 | 温州大学 | Synthetic method of benzophenone substituted isoquinoline compound |
| CN106674109A (en) * | 2016-12-15 | 2017-05-17 | 温州医科大学附属第二医院 | Method for synthesizing anti-cancer inhibitor intermediate |
| CN106674106A (en) * | 2016-12-15 | 2017-05-17 | 温州医科大学附属第二医院 | Synthetic method of topoisomerase I inhibitor |
| CN106674107A (en) * | 2016-12-15 | 2017-05-17 | 温州医科大学附属第二医院 | Synthesis method of anti-tumor medicine compound |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4786443A (en) * | 1987-03-11 | 1988-11-22 | Shell Oil Company | Process for the carbonylation of olefinically unsaturated compounds with a palladium catalyst |
| CN101429165A (en) * | 2007-11-09 | 2009-05-13 | 温州大学 | Synthesis of quinazoline ketone compounds |
| CN102503883A (en) * | 2011-10-18 | 2012-06-20 | 上海交通大学 | Method for selectively preparing isoindoline-1-ketone derivative or isoquinoline-1-ketone derivative |
| WO2012093271A1 (en) * | 2010-12-16 | 2012-07-12 | H4Sep Kft | A new palladium catalyst, method for its preparation and its use |
| CN103288730A (en) * | 2012-02-27 | 2013-09-11 | 海洋王照明科技股份有限公司 | Organic semiconductor material containing quinoline, preparation method of organic semiconductor material and organic electroluminescent device |
| CN103435558A (en) * | 2013-09-02 | 2013-12-11 | 温州大学 | Synthetic method of quinazoline derivative |
-
2014
- 2014-12-11 CN CN201410757773.4A patent/CN104529896B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4786443A (en) * | 1987-03-11 | 1988-11-22 | Shell Oil Company | Process for the carbonylation of olefinically unsaturated compounds with a palladium catalyst |
| CN101429165A (en) * | 2007-11-09 | 2009-05-13 | 温州大学 | Synthesis of quinazoline ketone compounds |
| WO2012093271A1 (en) * | 2010-12-16 | 2012-07-12 | H4Sep Kft | A new palladium catalyst, method for its preparation and its use |
| CN102503883A (en) * | 2011-10-18 | 2012-06-20 | 上海交通大学 | Method for selectively preparing isoindoline-1-ketone derivative or isoquinoline-1-ketone derivative |
| CN103288730A (en) * | 2012-02-27 | 2013-09-11 | 海洋王照明科技股份有限公司 | Organic semiconductor material containing quinoline, preparation method of organic semiconductor material and organic electroluminescent device |
| CN103435558A (en) * | 2013-09-02 | 2013-12-11 | 温州大学 | Synthetic method of quinazoline derivative |
Non-Patent Citations (4)
| Title |
|---|
| ALICIA S. CÁNEPA,等: "A Novel Synthesis of 1-Substituted 2H-Isoquinolin-3-ones", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 * |
| ALICIA S. CÁNEPA,等: "Convenient Synthesis of N-Substituted 1-Alkyl and 1-Aryl-3-Aminoisoquinolines", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 * |
| SUNG HWAN KIM,等: "An expedient synthesis of poly-substituted 1-arylisoquinolines from δ-ketonitriles via indium-mediated Barbier reaction protocol", 《TETRAHEDRON LETTERS》 * |
| 郭锦棠,等: "钯-稀土催化一氧化碳和苯乙烯交替共聚反应", 《催化学报》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632039A (en) * | 2016-12-15 | 2017-05-10 | 温州医科大学附属第二医院 | Synthetic method of antitumor nitrogen-containing heterocyclic drug intermediates |
| CN106674050A (en) * | 2016-12-15 | 2017-05-17 | 温州大学 | Synthetic method of benzophenone substituted isoquinoline compound |
| CN106674109A (en) * | 2016-12-15 | 2017-05-17 | 温州医科大学附属第二医院 | Method for synthesizing anti-cancer inhibitor intermediate |
| CN106674106A (en) * | 2016-12-15 | 2017-05-17 | 温州医科大学附属第二医院 | Synthetic method of topoisomerase I inhibitor |
| CN106674107A (en) * | 2016-12-15 | 2017-05-17 | 温州医科大学附属第二医院 | Synthesis method of anti-tumor medicine compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104529896B (en) | 2017-05-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104529896A (en) | Synthetic method of diaryl substituted isoquinoline compound | |
| CN104610250B (en) | 1,2,3-thiadiazole-5-formamidine compound containing three N-heterocycles and synthesis | |
| CN104529895A (en) | Synthetic method of nitrogen-containing heterocyclic compound | |
| CN103224436B (en) | The preparation method of the amino diaryl ketone compound of a kind of neighbour | |
| CN103058942A (en) | One-pot synthetic method for 1,2,3-triazole compounds | |
| CN112679420B (en) | Preparation method of 2,5-dibromopyridine | |
| CN105218621B (en) | Dehydroabietic acid benzimidazole Schiff base heterocyclic derivatives with anti-tumor activity and preparation method therefor and application thereof | |
| CN106588788B (en) | The method of one pot of two-step method synthesis 1,2,3- triazole compound | |
| CN101417972A (en) | 3-methylene-indol-2-one derivates and preparation method thereof | |
| CN104557701A (en) | Preparation method of isoquinoline derivative | |
| CN105198718A (en) | Preparation method for buparvaquone | |
| CN103880822A (en) | 2,4,6-trisubstituted pyrimidine compounds containing 1,2,3-triazole, preparation method and application thereof | |
| CN104592144A (en) | New method for preparing oxazole derivative | |
| CN103059010B (en) | Isosorbide-5-Nitrae-benzoxazinone-1,2,3-triazole compound with anti-mycotic activity and preparation method thereof | |
| CN104844590B (en) | A kind of N methyl Ciprofloxacin (rhodanine beta-unsaturated ketone) amide derivatives and its preparation method and application | |
| CN102659708A (en) | Structure and preparation method for heterocyclic aryl acetylene compounds containing benzoxazole and benzothiazole groups | |
| TWI829641B (en) | A method for preparing pyrimidone compound | |
| Mallikarjun | Synthesis, characterization and biological activity of schiff base metal complexes | |
| CN104016898A (en) | 3,4-disubstituted pyrrole compound as well as preparation method and application thereof | |
| CN108358903B (en) | Synthesis method of 2-substituted heterocyclic quinazolinone compound | |
| CN104098524B (en) | 1-meta-methoxy benzoyl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine and Synthesis and applications | |
| CN114195792A (en) | Synthesis method of 1,2, 3-triazole quinoxalinone derivative | |
| CN102432636A (en) | Triphenylphosphine oxide connecting bisoxazoline ligand, preparation method and application thereof | |
| CN104974217B (en) | One class dehydroabietic acid quinoxaline derivant and its preparation method and application | |
| Sheng et al. | Generation of 4-substituted coumarins via C–H bond activation under palladium bromide–copper (I) bromide cooperative catalysis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Chen Jiuxi Inventor after: Wu Huayue Inventor after: Liu Miaochang Inventor after: Ding Jinchang Inventor after: Gao Wenxia Inventor after: Huang Xiaobo Inventor before: Wu Huayue Inventor before: Chen Jiuxi Inventor before: Liu Miaochang Inventor before: Ding Jinchang Inventor before: Gao Wenxia Inventor before: Huang Xiaobo |
|
| CB03 | Change of inventor or designer information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170503 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |