CN116693448A - 吲哚酰胺配体在碳氮偶联反应中的应用 - Google Patents
吲哚酰胺配体在碳氮偶联反应中的应用 Download PDFInfo
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- CN116693448A CN116693448A CN202310656819.2A CN202310656819A CN116693448A CN 116693448 A CN116693448 A CN 116693448A CN 202310656819 A CN202310656819 A CN 202310656819A CN 116693448 A CN116693448 A CN 116693448A
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- Prior art keywords
- phenyl
- reaction
- ligand
- cuprous
- halogen
- Prior art date
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- Pending
Links
- 239000003446 ligand Substances 0.000 title claims abstract description 32
- VFHUJFBEFDVZPJ-UHFFFAOYSA-N 1h-indole-2-carboxamide Chemical compound C1=CC=C2NC(C(=O)N)=CC2=C1 VFHUJFBEFDVZPJ-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000005859 coupling reaction Methods 0.000 title abstract description 13
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical compound [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 title description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 58
- -1 nitrogen heterocyclic compound Chemical class 0.000 claims abstract description 35
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims description 31
- 239000011230 binding agent Substances 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 14
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 150000004030 azacyclic compounds Chemical class 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical group Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 2
- 229940112669 cuprous oxide Drugs 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 229920001225 polyester resin Polymers 0.000 claims 2
- 239000004645 polyester resin Substances 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 150000002390 heteroarenes Chemical class 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000009749 continuous casting Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000006887 Ullmann reaction Methods 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- BHNHHSOHWZKFOX-UHFFFAOYSA-N 2-methyl-1H-indole Chemical compound C1=CC=C2NC(C)=CC2=C1 BHNHHSOHWZKFOX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 150000001502 aryl halides Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001879 copper Chemical class 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 150000007529 inorganic bases Chemical group 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- OQDPVLVUJFGPGQ-UHFFFAOYSA-N 2-[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]pyrimidine Chemical compound C=1C=C2OCOC2=CC=1CN(CC1)CCN1C1=NC=CC=N1 OQDPVLVUJFGPGQ-UHFFFAOYSA-N 0.000 description 1
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 229940035678 anti-parkinson drug Drugs 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- ARQRPTNYUOLOGH-UHFFFAOYSA-N chcl3 chloroform Chemical compound ClC(Cl)Cl.ClC(Cl)Cl ARQRPTNYUOLOGH-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 231100000783 metal toxicity Toxicity 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- QJKBHDRXPAOHSY-UHFFFAOYSA-N morpholine;pyridine Chemical compound C1COCCN1.C1=CC=NC=C1 QJKBHDRXPAOHSY-UHFFFAOYSA-N 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- 230000000361 pesticidal effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229960004310 piribedil Drugs 0.000 description 1
- TUUVEPHKJPCZSB-UHFFFAOYSA-L potassium sodium hydrogen carbonate hydroxide Chemical compound [OH-].[Na+].[K+].OC([O-])=O TUUVEPHKJPCZSB-UHFFFAOYSA-L 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- VZZJRYRQSPEMTK-CALCHBBNSA-N sonidegib Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(N=C1)=CC=C1NC(=O)C1=CC=CC(C=2C=CC(OC(F)(F)F)=CC=2)=C1C VZZJRYRQSPEMTK-CALCHBBNSA-N 0.000 description 1
- 229960005325 sonidegib Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
- B01J2231/4283—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using N nucleophiles, e.g. Buchwald-Hartwig amination
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
- B01J2531/16—Copper
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Indole Compounds (AREA)
Abstract
本发明涉及吲哚酰胺配体在C‑N键偶联反应的应用,用于制备芳杂氮杂环类化合物。由氯代芳杂环化合物和氮杂环类化合物反应制备,在吲哚酰胺配体参与及亚铜催化剂作用下进行,其中,吲哚酰胺配体的结构式为:
Description
技术领域
本发明涉及吲哚酰胺配体在C-N键偶联反应的应用,用于制备芳杂氮杂环类化合物。
背景技术
C-N键构建反应对含氮化合物的合成具有深远的影响,使用芳基卤化物制备的含氮化合物在工业上被广泛应用于医药、农药中间体的合成中,例如抗慢性髓细胞性白血病药物Imatinib、抗帕金森药物Piribedil、抗基底细胞癌药物Sonidegib、抗炎药Mornifiumate等;目前许多C-N偶联反应采用钯配合物作为催化剂。但钯催化剂参与的反应条件常常较为苛刻,对水,氧气要求较高;同时钯催化剂价格昂贵且具有较大的重金属毒性。亚铜催化剂由于其低毒和廉价的特点,在C-N键构建中受到极大的关注,早在20世纪初,Ullmann便报道了使用化学计量铜盐催化芳基卤化物和胺在高温(200℃以上)条件下制备芳胺化合物的Ullmann反应。但因传统的Ullmann反应需要在苛刻的反应条件下才能够进行,比如当量或者过量的铜或者铜盐,高温,强碱,以及较长的反应时间等等,而且往往收率不高。
目前大部分的芳杂环氯代物因其碳卤键较大的惰性,在较低温度下往往难以被金属插入活化,所以芳杂环氯代物参与的C-N键偶联需要在高温下完成反应[(a)Chem.Commun.2011,47,12358.(b)Chem.Sci.2013,4,916.(c)Angew.Chem.2017,129,10705.(d)J.Am.Chem.Soc.2018,140,4721.(e)J.Org.Chem.2018,83,9144],为解决这一难点,近年来,Buchwald,Hartwig和马大为等分别对Ullmann反应的改建做出了开创性的工作,通过使用合适的配体、碱、溶剂等,使该反应可以在较温和的条件下进行,同时还拓展了该反应的适用范围及官能团兼容性,使得该反应成为C-N键构筑的重要方法。其中通过酰胺类双齿配体与亚铜催化剂配位可以高效催化卤代物和胺类化合物C-N偶联制备含氮类化合物,为工业化生产提供高效手段。
发明内容
吲哚酰胺类配体在碳氮偶联反应中的应用研究尚比较少,或缺乏突破性的研究成果。
为实现上述技术目的,本发明采用如下技术方案:
本发明提供了一种吲哚酰胺类配体及其在碳氮偶联反应中的应用。本发明提供的一种吲哚酰胺配体参与的制备芳杂氮杂环类化合物的方法。由氯代芳杂环化合物和氮杂环类化合物反应制备,其反应式如下:
其中:X为碳原子、氧原子、硫原子和氮原子。
R4为烷基、呋喃基、噻吩基、萘基、苯基或者被一个或多个取代基取代的苯基,所述的取代基各自独立为甲基、苯基、甲氧基、三氟甲基、三氟甲氧基或卤素。
R5为烷基、呋喃基、噻吩基、萘基、苯基或者被一个或多个取代基取代的苯基,所述的取代基各自独立为甲基、苯基、甲氧基、三氟甲基、三氟甲氧基或卤素、烷氧基等。
R6为氢、烷基、叔丁氧羰基。
R7为烷基、呋喃基、噻吩基、萘基、苯基或者被一个或多个取代基取代的苯基,所述的取代基各自独立为甲基、苯基、甲氧基、三氟甲基、三氟甲氧基或卤素。
其中,较优选的,上述反应为:
本发明上述碳氮偶联反应在吲哚酰胺类配体的参与下反应。反应中还需要加入亚铜催化剂如亚酮盐类化合物。
所述亚酮盐类化合物可以为卤化亚酮或氧化亚酮等;所述卤化亚酮可以为溴化亚酮、碘化亚酮等。
进一步碳氮偶联反应的具体详细工艺可以为:将亚铜催化剂、配体、缚酸剂和有机溶剂加入到反应瓶中,氮气置换三次后,室温下搅拌1小时后,将氯代芳杂环化合物和氮杂环类化合物加入到反应体系中,将反应升至60~150℃下反应1~48h,TLC监测反应结束,将反应液倒入水中后,乙酸乙酯萃取2~3次得有机相,有机相减压浓缩后,乙酸乙酯:正庚烷=1:2~10柱层析分离、浓缩干燥后得到芳杂氮杂类化合物。
其中,所述氯代芳杂环化合物:氮杂环类化合物:亚铜催化剂:配体:缚酸剂的摩尔比范围为1:1~10:0.01~0.5:0.01~0.5:1~20。
较优选地,氯代芳杂环化合物:氮杂环类化合物:亚铜催化剂:配体:缚酸剂的摩尔比范围为1:1~5:0.01~0.2:0.01~0.2:1~10。
进一步,反应所述有机溶剂选自DMF、DMSO、1,4-二氧六环或甲苯。
进一步,反应所述有机溶剂体积分数为5%~15%。
进一步,亚铜催化剂优选为溴化亚铜,碘化亚铜,氧化亚铜;
进一步,反应所述温度优选为80~120℃。
进一步,反应所述缚酸剂为无机碱。
再进一步,反应所述缚酸剂优选为磷酸钾、磷酸二氢钾、碳酸钾、碳酸钠、氢氧化钾、氢氧化钠。
进一步,所述反应液的后处理方法为:将反应液倒入水中后,乙酸乙酯萃取2~3次得有机相,有机相减压浓缩后,乙酸乙酯:正庚烷=1:2~10柱层析分离、浓缩干燥后制备得到芳杂氮杂环类化合物。
上述吲哚酰胺类配体按照如下合成方法制备:
步骤1:吲哚化合物和羟胺-O-磺酸反应制备得到中间体吲哚伯胺类化合物;
步骤2:中间体吲哚伯胺类化合物与草酰氯经缩合反应制备得到吲哚酰胺类化合物。
反应式如下:
其中:R1为H、甲基或卤素;R2为烷基、呋喃基、噻吩基、萘基、苯基或者被一个或多个取代基取代的苯基,所述的取代基各自独立为甲基、苯基、甲氧基、三氟甲基或卤素等。
反应具体工艺为:步骤1中所述的吲哚化合物溶于有机溶剂后,在0℃下分批加入缚酸剂后,加入羟胺-O-磺酸在0~5℃下反应10~30min后,20~30℃下反应1~48h,反应液倒入冰水后,使用乙酸乙酯萃取得到有机相,以乙酸乙酯/正庚烷=1:1~4,柱层析分离,脱去有机溶剂后干燥得到吲哚伯胺类化合物,所述吲哚化合物、羟胺-O-磺酸和缚酸剂物质的量之比为1.0:1.1~3.5:5~20。
更进一步,步骤1中,吲哚化合物、羟胺-O-磺酸和缚酸剂物质的量之比优选为1.0:1.1~2.5:5~15。
进一步,步骤1中所述的有机溶剂体积分数为10%~50%。
再进一步,步骤1中,所述的有机溶剂选自DMF、DMSO、1,4-二氧六环、甲苯、四氢呋喃或乙酸乙酯。
进一步,步骤1中,所述的缚酸剂为常用的无机碱。
再进一步,步骤1中,所述的缚酸剂优选为氢氧化钾、氢氧化钠碳酸钾或碳酸铯。
进一步,步骤1中,所述反应液的后处理方法为:将反应液倒入冰水后,乙酸乙酯萃取,取有机相减压浓缩后进行硅胶柱层析分离,以石油醚/乙酸乙酯体积比1~4:1的混合液为洗脱剂进行柱层析,收集含目标化合物的洗脱液,蒸除溶剂并干燥,得到中间体吲哚伯胺类化合物。
进一步,步骤2所述中间体吲哚伯胺类化合物溶于四氢呋喃中,在0~5℃下缓慢滴加缚酸剂,滴毕后,在0℃下反应10~30分钟后,滴入草酰氯,继续反应10~30分钟,升至20~30℃反应1~48小时,TLC检测反应结束后,减压蒸馏蒸除溶剂后,水洗涤2~3次后,使用甲基叔丁基醚:正庚烷=1:1~10混合溶剂洗涤2~3次后,干燥得到产物吲哚酰胺类配体,所述吲哚伯胺类化合物、草酰氯和缚酸剂的物质的量之比=1:0.5~5.0:0.5~5.0。
更进一步,步骤2中,比较优选地,吲哚伯胺类化合物、草酰氯和缚酸剂的物质的量之比为1:0.5~3.0:0.5~3.0。
进一步,步骤2中,所述的有机溶剂体积分数为10%~50%。
再进一步,步骤2中,所述的有机溶剂选自二氯甲烷、氯仿、甲苯、四氢呋喃、乙酸乙酯。
进一步,步骤2中,所述的缚酸剂为常用的有机碱等。
再进一步,步骤2中,所述的缚酸剂优选为TEA、DIPEA、DBU。
进一步,步骤2中,所述反应液的后处理方法为:将反应液减压蒸馏蒸除溶剂后,水洗涤2~3次后,使用甲基叔丁基醚:正庚烷=1:1~10混合溶剂洗涤2~3次后,干燥得到产物吲哚酰胺类配体。
具体的,更加优选的,所述的吲哚酰胺类配体选自下列之一:
本发明的有益效果在于:
吲哚酰胺类配体参与的碳氮偶联反应,催化芳杂环氯代物,制备芳杂环化合物,反应条件温和,收率高,适合工业化生产。本发明所述的合成方法中,一方面使用吲哚化合物制备新型吲哚酰胺类配体用于催化C-N偶联反应;另一方面以亚铜催化剂/吲哚酰胺配体为催化剂催化氯代芳杂类化合物和氮杂环类化合物进行反应,后处理分离得到芳杂氮杂环类化合物。所述的芳杂氮杂环类化合物结构是一类重要结构单元,广泛存在于农药和医药领域,在新药物研发方向具有广阔的应用前景。本发明提供的制备方法条件温和、反应原料方便易得,可操作性强。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明,但不以任何形式限制本发明。应当指出的是,对本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进。这些都属于本发明的保护范围。
实施例1:
在250mL圆底烧瓶中依次加入吲哚(11.7g,0.1mol,1.0eq.),100mL DMF混合均匀后置于0℃冰浴中,分批加入KOH(56.1g,1mol,10eq.),保持温度不超过0℃。在反应体系中缓慢加入羟胺-O-磺酸(22.6g,0.2mol,2eq.),控制温度不超过20℃,将反应在0℃下反应10分钟后,将反应体系移到室温下反应16小时。反应结束后,将反应液倒入冰水中,用乙酸乙酯萃取得到有机相,使用200-300目硅胶,展开剂为乙酸乙酯/正庚烷=1/4进行柱层析提纯,得到湿品后,置于真空干燥箱55℃干燥12小时烘干。得到中间体干品8.58g,收率65%。
取中间体干品(1g,7.5mmol,1.0eq.),溶于25mL四氢呋喃中,在0℃冰浴下缓慢滴入三乙胺(0.91g,9mmol,1.2eq.),将反应在0℃下反应10分钟。在0℃下缓慢滴入草酰氯(0.94g,7.5mmol,1.2eq.),出现大量白烟,保持温度不超过5℃,将反应在0℃下反应10分钟后,将反应体系移到室温下反应16小时。反应结束后,蒸干溶剂,并用水洗去三乙胺盐酸盐。过滤,用水洗涤滤饼3次,并用1:10叔丁基醚和正庚烷洗涤3次,得到湿品,真空干燥箱55℃干燥12小时。得到1.5g干品,收率62.5%。1H-NMR(400MHz,DMSO-d6)δ12.35(s,2H),7.59(d,J=8.0Hz,2H),7.34~7.39(m,4H),7.21~7.18(m,2H),7.11~7.08(m,2H),6.53(d,J=3.2Hz,2H).
取相同的反应物,相同的操作步骤下,分别不同当量的羟胺-O-磺酸、不同种类的缚酸剂和不同当量的缚酸剂进行中间体制备的步骤(1)反应,下一步骤反应同上述反应,结果如下表1所示:
表1
编号 | 羟胺-O-磺酸当量 | 缚酸剂种类 | 缚酸剂当量 | 产率(%)a |
1 | 1.1eq. | KOH | 10eq. | 37% |
2 | 2.5eq. | KOH | 10eq. | 32% |
3 | 2.0eq. | NaOH | 5eq. | 33% |
4 | 2.0eq. | Cs2CO3 | 15eq. | 28% |
5 | 2.1eq. | K2CO3 | 10eq. | 26% |
表1中,上标a两步连投的表示分离收率。
取相同的反应物,相同的操作步骤下,分别以不同种类有机溶剂、不同体积的有机溶剂进行中间体制备的步骤(1)反应,步骤反应(2)同上述反应,结果如下表2所示:
表2
编号 | 有机溶剂 | 有机溶剂体积 | 产率(%)a |
1 | DMF | 10V | 31% |
2 | DMSO | 15V | 33% |
3 | 1,4-二氧六环 | 35V | 29% |
4 | 甲苯 | 11V | Trace |
5 | 四氢呋喃 | 50V | 18% |
6 | 乙酸乙酯 | 12V | 12% |
表2中,上标a表示两步连投的分离收率。
取相同的反应物,相同的操作步骤下,进行中间体制备的步骤(1)反应,步骤(2)反应分别不同当量的草酰氯、不同种类的缚酸剂、不同当量的缚酸剂进行中间体制备反应结果如下表3所示:
表3
编号 | 草酰氯当量 | 缚酸剂种类 | 缚酸剂当量 | 产率(%)a |
1 | 0.5eq. | TEA | 0.5eq. | 36% |
2 | 3.0eq. | DIPEA | 3.0eq. | 25% |
3 | 1.1eq. | DBU | 1.5eq. | 18% |
4 | 1.5eq. | TEA | 1.1eq. | 30% |
表3中,上标a表示两步连投的分离收率。
取相同的反应物,相同的操作步骤下进行中间体制备的步骤(1)反应,分别在不同种类有机溶剂和不同体积的有机溶剂下进行步骤(2)反应,结果如下表4所示:
表4
编号 | 有机溶剂 | 有机溶剂体积 | 产率(%)a |
1 | 二氯甲烷 | 10V | 19% |
2 | 氯仿 | 25V | 21% |
3 | 甲苯 | 30V | 15% |
4 | 四氢呋喃 | 26V | 22% |
5 | 乙酸乙酯 | 50V | 23% |
表4中,上标a表示两步连投的分离收率。
实施例2:
与反应实施例1不同之处在于:所用的底物2-甲基吲哚,其它反应条件及操作步骤与反应实施例1相同(两步连投的收率:45%)。1H-NMR(400MHz,DMSO-d6)δ12.22(s,2H),7.49(d,J=7.6,2H),7.39~7.20(m,2H),7.14~7.11(m,2H),7.08~7.04(m,2H),6.27(d,J=40.4,2H),2.31(s,6H).
实施例3:
将CuBr(0.0143g,0.01eq.)、配体(3)-a(0.064g,0.02eq.)、磷酸钾(42.4g,2.0eq.)和113mL DMSO加入到反应瓶中,氮气置换三次后,室温下搅拌1小时后,将2-氯吡啶(11.3g,1.0eq.)和吗啉(10.44g,1.2eq.)加入到反应体系中,将反应升至80℃下反应20h,TLC监测反应结束,将反应液倒入水中后,乙酸乙酯萃取2~3次得有机相,有机相减压浓缩后,乙酸乙酯:正庚烷=1:3柱层析分离、浓缩干燥后得到吡啶吗啉(收率:99%),1H NMR(500MHz,CDCl3)δ8.21~8.19(m,1H),7.52~7.48(m,1H),6.67~6.62(m,2H),3.83~3.81(m,4H),3.50~3.48(m,4H).
取相同的反应物,相同的操作步骤下,分别以当量的吗啉、不同种类的亚铜催化剂、不同当量的亚铜催化剂、不同种类的配体和不同当量的配体进行反应,结果如下表5所示:
表5
表5中,上标a表示分离收率。
取相同的反应物,相同的操作步骤下,分别以不同种类缚酸剂、不同当量缚酸剂、不同种类有机溶剂、不同体积的有机溶剂和不同温度下进行反应,结果如下表2所示:
表6
表6中,上标a表示分离收率。
Claims (10)
1.一种芳杂氮杂环类化合物的制备方法,其特征在于,由氯代芳杂环化合物和氮杂环类化合物反应制备,在吲哚酰胺配体参与及亚铜催化剂作用下进行,
其中,吲哚酰胺配体的结构式为:
亚铜催化剂为亚铜盐类化合物;
R1为H、甲基或卤素;R2为烷基、呋喃基、噻吩基、萘基、苯基或者被一个或多个取代基取代的苯基,所述的取代基各自独立为甲基、苯基、甲氧基、三氟甲基或卤素,
X为碳原子、氧原子、硫原子和氮原子,
R4为烷基、呋喃基、噻吩基、萘基、苯基或者被一个或多个取代基取代的苯基,所述的取代基各自独立为甲基、苯基、甲氧基、三氟甲基、三氟甲氧基或卤素。
R5为烷基、呋喃基、噻吩基、萘基、苯基或者被一个或多个取代基取代的苯基,所述的取代基各自独立为甲基、苯基、甲氧基、三氟甲基、三氟甲氧基或卤素、烷氧基,
R6为氢、烷基、叔丁氧羰基,
R7为烷基、呋喃基、噻吩基、萘基、苯基或者被一个或多个取代基取代的苯基,所述的取代基各自独立为甲基、苯基、甲氧基、三氟甲基、三氟甲氧基或卤素。
2.根据权利要求1所述的制备方法,其特征在于,所述反应为:
其中,吲哚酰胺配体为:
亚铜催化剂为溴化亚铜、碘化亚铜或氧化亚铜。
3.根据权利要求1或2所述的制备方法,其特征在于,所述反应中加入缚酸剂。
4.根据权利要求3所述的制备方法,其特征在于,所述缚酸剂为磷酸钾、磷酸二氢钾、碳酸钾、碳酸钠、氢氧化钾或氢氧化钠。
5.根据权利要求1,2或3所述的制备方法,其特征在于,所述氯代芳杂环化合物:氮杂环类化合物:亚铜催化剂:配体:缚酸剂的摩尔比范围为1:1~10:0.01~0.5:0.01~0.5:1~20。
6.根据权利要求6所述的制备方法,其特征在于,所述氯代芳杂环化合物:氮杂环类化合物:亚铜催化剂:配体:缚酸剂的摩尔比范围为1:1~5:0.01~0.2:0.01~0.2:1~10。
7.根据权利要求1,2或3所述的制备方法,其特征在于,所述反应有机溶剂选自DMF、DMSO、1,4-二氧六环或甲苯。
8.根据权利要求1,2或3所述的制备方法,其特征在于,反应温度为80~120℃。
9.根据权利要求1或2所述的制备方法,其特征在于,所述吲哚酰胺类配体制备包括步骤为,
步骤1:吲哚化合物和羟胺-O-磺酸反应制备得到中间体吲哚伯胺类化合物;
步骤2:中间体吲哚伯胺类化合物与草酰氯经缩合反应制备得到吲哚酰胺类化合物;
其中:R1为H、甲基或卤素;R2为烷基、呋喃基、噻吩基、萘基、苯基或者被一个或多个取代基取代的苯基,所述的取代基各自独立为甲基、苯基、甲氧基、三氟甲基或卤素。
10.一种芳杂氮杂环类化合物的制备方法,其特征在于,在吲哚酰胺配体和溴化亚铜作用下,由氯代芳杂环化合物和氮杂环类化合物反应制备,
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