CN116284009A - Method for continuously preparing 4, 5-imidazolinyl spiro pyrazolone compound by utilizing photocatalysis microchannel - Google Patents
Method for continuously preparing 4, 5-imidazolinyl spiro pyrazolone compound by utilizing photocatalysis microchannel Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 21
- -1 5-imidazolinyl spiro pyrazolone compound Chemical class 0.000 title claims abstract description 20
- 230000001699 photocatalysis Effects 0.000 title claims abstract description 8
- 238000007146 photocatalysis Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- 230000035484 reaction time Effects 0.000 claims abstract description 18
- 239000012456 homogeneous solution Substances 0.000 claims abstract description 13
- MPYOKHFSBKUKPQ-UHFFFAOYSA-N n'-phenylbenzenecarboximidamide Chemical compound C=1C=CC=CC=1C(N)=NC1=CC=CC=C1 MPYOKHFSBKUKPQ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000011941 photocatalyst Substances 0.000 claims abstract description 9
- 238000002347 injection Methods 0.000 claims abstract description 7
- 239000007924 injection Substances 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 239000000654 additive Substances 0.000 claims abstract description 5
- 230000000996 additive effect Effects 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 51
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 19
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical group ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 claims description 4
- UEEXRMUCXBPYOV-UHFFFAOYSA-N iridium;2-phenylpyridine Chemical compound [Ir].C1=CC=CC=C1C1=CC=CC=N1.C1=CC=CC=C1C1=CC=CC=N1.C1=CC=CC=C1C1=CC=CC=N1 UEEXRMUCXBPYOV-UHFFFAOYSA-N 0.000 claims description 4
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 4
- 229910020366 ClO 4 Inorganic materials 0.000 claims description 3
- 239000004813 Perfluoroalkoxy alkane Substances 0.000 claims description 3
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 3
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical group BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 3
- 229920011301 perfluoro alkoxyl alkane Polymers 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
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- JFJNVIPVOCESGZ-UHFFFAOYSA-N 2,3-dipyridin-2-ylpyridine Chemical compound N1=CC=CC=C1C1=CC=CN=C1C1=CC=CC=N1 JFJNVIPVOCESGZ-UHFFFAOYSA-N 0.000 claims description 2
- PRWATGACIORDEL-UHFFFAOYSA-N 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile Chemical compound C12=CC=CC=C2C2=CC=CC=C2N1C1=C(C#N)C(N2C3=CC=CC=C3C3=CC=CC=C32)=C(N2C3=CC=CC=C3C3=CC=CC=C32)C(N2C3=CC=CC=C3C3=CC=CC=C32)=C1C#N PRWATGACIORDEL-UHFFFAOYSA-N 0.000 claims description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- GCGRXVMGBHYMDA-UHFFFAOYSA-N 5-fluoro-2,4,6-tris(N-phenylanilino)benzene-1,3-dicarbonitrile Chemical compound C1(=CC=CC=C1)N(C1=C(C#N)C(=C(C(=C1C#N)N(C1=CC=CC=C1)C1=CC=CC=C1)F)N(C1=CC=CC=C1)C1=CC=CC=C1)C1=CC=CC=C1 GCGRXVMGBHYMDA-UHFFFAOYSA-N 0.000 claims description 2
- FNPNRZLYTIVLNO-UHFFFAOYSA-N Cl(=O)(=O)(=O)O.C1(=C(C(=CC(=C1)C)C)C1C2=CC=CC=C2N(C=2C=CC=CC12)C)C Chemical compound Cl(=O)(=O)(=O)O.C1(=C(C(=CC(=C1)C)C)C1C2=CC=CC=C2N(C=2C=CC=CC12)C)C FNPNRZLYTIVLNO-UHFFFAOYSA-N 0.000 claims description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 2
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- VWNQJLIVSOOFBX-UHFFFAOYSA-L ruthenium(2+);dichloride;hexahydrate Chemical compound O.O.O.O.O.O.Cl[Ru]Cl VWNQJLIVSOOFBX-UHFFFAOYSA-L 0.000 claims description 2
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims description 2
- 229930192474 thiophene Chemical group 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 18
- 239000006227 byproduct Substances 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 238000004904 shortening Methods 0.000 abstract 1
- 238000000926 separation method Methods 0.000 description 29
- 238000005086 pumping Methods 0.000 description 28
- 239000012295 chemical reaction liquid Substances 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 229940125782 compound 2 Drugs 0.000 description 15
- 238000004821 distillation Methods 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- 238000000605 extraction Methods 0.000 description 15
- 238000005406 washing Methods 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 238000001228 spectrum Methods 0.000 description 10
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 5
- 125000003003 spiro group Chemical group 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 150000003413 spiro compounds Chemical class 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- 101150033538 Rala gene Proteins 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical group COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229940083761 high-ceiling diuretics pyrazolone derivative Drugs 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- 239000011259 mixed solution Substances 0.000 description 1
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- 229930014626 natural product Natural products 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
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000006362 organocatalysis Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for continuously preparing 4, 5-imidazolinyl spiro pyrazolone compounds by utilizing photocatalysis microchannels, which is characterized in that 4-alkyl pyrazolone compounds shown in a formula 1, N-phenyl benzamidine shown in a formula 2, a photocatalyst, an additive and a solvent are mixed together to prepare a homogeneous solution, then a syringe pump is used for single-strand sample injection, the homogeneous solution is introduced into a sample injection port of a microchannel reaction device provided with a light source, and the reaction is carried out in the device, so that a reaction solution containing the 4, 5-imidazolinyl spiro pyrazolone compounds can be obtained. The invention adopts the photocatalysis microchannel reaction device to continuously prepare the 4, 5-imidazolinyl spiro pyrazolone compound, thereby greatly shortening the reaction time, having fewer byproducts and high product yield. Meanwhile, the method does not need to add an expensive metal catalyst and operate at high temperature, and is low in cost, high in safety and environment-friendly.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for continuously preparing 4, 5-imidazolinyl spiro pyrazolone compounds by utilizing photocatalysis microchannels.
Background
A helical heterocycle is a special backbone and key building block found in many natural products and bioactive molecules. At present, spiro compounds play an important role in the field of new drugs, because the spiro framework can reduce conformational entropy pairs when binding with protein targets. As an important class of spiro compounds, spiro pyrazolone motifs are also ubiquitous in compounds having significant biological activity, such as antibacterial, anti-inflammatory, antitumor, analgesic, ralA, and 4-phosphodiesterase inhibitors, and the like. In the last decade, organic chemists have put a great deal of effort into the efficient synthesis of structurally diverse spiropyrazolones and developed several synthetic methods. Among them, the organocatalytic cycloaddition reaction is the most commonly used method, and although these methods have constructed a large number of spiro pyrazolone derivatives, the synthesis of spiro pyrazolone containing a five-membered nitrogen-containing ring is still immature. Therefore, the development of a simple and efficient method for synthesizing the spiro pyrazolone with different nitrogen heterocycles has important significance.
Meanwhile, the imidazoline compound has wide and obvious biological activity, and is a very important nitrogenous heterocyclic compound. In view of the pharmacological and biological activities of the spiropyrazolone and the imidazoline, the part combining the spiropyrazolone and the imidazoline can greatly help the discovery of new drugs, and the imidazolinyl spiropyrazolone compound has extremely high application value in the field of organic synthesis.
Disclosure of Invention
This section is intended to outline some aspects of embodiments of the invention and to briefly introduce some preferred embodiments.
As one of the aspects of the present invention, the present invention provides a method for continuously preparing 4, 5-imidazolinyl spiro pyrazolone compounds using a photocatalytic microchannel reaction apparatus. Solves the problems of long reaction time, complicated steps, more byproducts, low yield and the like in the prior art, and realizes the synthesis of 4, 5-imidazolinyl-containing spiro pyrazolone compounds in a green, simple and efficient way.
In order to solve the technical problems, the invention discloses a method for continuously preparing 4, 5-imidazolinyl spiro pyrazolone compounds by utilizing a photocatalysis microchannel, which is characterized in that 4-alkyl pyrazolone compounds shown in a formula 1, N-phenyl benzamidine shown in a formula 2, a photocatalyst, an oxidant, a solvent and the like are mixed together to prepare a homogeneous solution, then the homogeneous solution is injected into an injection port of a microchannel reaction device provided with a light source by using an injection pump in a single-strand injection manner, and the reaction is carried out in the device to obtain a reaction solution containing the 4, 5-imidazolinyl spiro pyrazolone compounds shown in a formula 3.
Wherein,,
r is selected from benzene, 4-methylbenzene, 4-methoxybenzene, 4-bromobenzene, 4-chlorobenzene, 3-methylbenzene, 3-chlorobenzene, 2-methylbenzene, 2-chlorobenzene, thiophene or pyridyl; further preferably, R is selected from benzene, 4-methylbenzene, 4-bromobenzene, 3-chlorobenzene, 3-methylbenzene.
Wherein the photocatalyst is (4, 4 '-di-tert-butyl-2, 2' -bipyridine) bis [ (2-pyridyl) phenyl]Iridium (III) hexafluorophosphate ({ lr (ppy) 2 (dtbbpy)}PF 6 ) 10-methyl-9-mesityl acridine perchlorate (Mes-Acr) + ClO 4 - ) Terpyridine ruthenium dichloride hexahydrate (Ru (bpy) 2 Cl 2 ·6H 2 O), tris (2-phenylpyridine) iridium (Ir (ppy) 3 ) Any one or a combination of more than one of Eosin Y (Eosin Y), 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (4 CzlPN) and 2,4, 6-tri (diphenylamino) -5-fluoro isophthalonitrile (3 DPAFIPN); preferably, the photocatalyst is (4, 4 '-di-tert-butyl-2, 2' -bipyridine) bis [ (2-pyridyl) phenyl]Iridium (III) hexafluorophosphate ({ Ir (ppy) 2 (dtbbpy)}PF 6 )。
Wherein the additive is any one or more than two of potassium persulfate, sodium persulfate, ammonium persulfate, tert-butyl hydroperoxide, tert-butyl peroxide, hydrogen peroxide, m-chloroperoxybenzoic acid, trifluoroacetic acid, acetic acid and p-toluenesulfonic acid. Preferably, the additives are potassium persulfate and trifluoroacetic acid; preferably, the molar ratio of potassium persulfate to N-phenylbenzamidine is 1:1 to 3:1, the molar ratio of trifluoroacetic acid to N-phenylbenzamidine is 0.5:1 to 2:1, more preferably, the molar ratio of potassium persulfate to N-phenylbenzamidine is 2:1, and the molar ratio of trifluoroacetic acid to N-phenylbenzamidine is 1:1.
Wherein the concentration of the 4-alkyl pyrazolone compound shown in the formula 1 in the mixed homogeneous solution is 0.01-0.30mmol/mL. Preferably, the concentration of the 4-alkylppyrazolone compound of formula 1 in the mixed homogeneous solution is 0.03mmol/mL.
Wherein the concentration of the N-phenylbenzamidine shown in the formula 2 in the mixed homogeneous solution is 0.01-0.30mmol/mL. Preferably, the concentration of N-phenylbenzamidine of formula 2 in the mixed homogeneous solution is 0.02mmol/mL.
Wherein the dosage of the photocatalyst is 1-20mol% of N-phenyl benzamidine shown in a formula 2; preferably, the photocatalyst is used in an amount of 2mol% of N-phenylbenzamidine represented by formula 2.
Wherein the solvent is any one or a combination of a plurality of acetonitrile, 1, 2-dichloroethane, ethanol, dichloromethane, trifluoroethanol, hexafluoroisopropanol, dimethyl sulfoxide and water; preferably, the solvent is a mixed solvent of acetonitrile and water in a volume ratio of 1:1.
Wherein, the micro-channel reaction device provided with the light source comprises a feed pump (Baoding Leifu Fluid Technology Co.Ltd, (TYD 01-01-CE type)), a micro-channel reactor, a light source and a receiver; wherein, the feed pump is connected in series with the micro-channel reactor and the receiver through the pipeline in turn, and the micro-channel reactor is arranged under the irradiation of the light source.
Wherein the micro-channel reactor is of a pore canal structure, the pore canal material is perfluoroalkoxyalkane, the size and the inner diameter of the micro-channel reactor are 0.5-1.0mm, and the volume of the micro-channel reactor is 2-20mL; preferably, the microchannel reactor has a dimensional inner diameter of 0.5mm and a volume of 2mL.
Wherein the temperature of the reaction is 0-30 ℃; preferably, the reaction temperature is 25 DEG C
Wherein the residence time of the reaction is 30s-2h; preferably, the residence time is 10min.
Wherein the light source is a lamp band or a bulb, the intensity is 5-60W, and the wavelength is 435-577nm; preferably, the light source is an LED blue light source, the intensity is 50W, and the wavelength is 460-470nm.
The invention has the beneficial effects that: the invention provides a brand-new preparation method of the visible light catalytic 4, 5-imidazolinyl spiro pyrazolone, which can be realized only under the irradiation of light, has the advantages of high safety, little environmental pollution, green, high efficiency, low cost, greatly reduced reaction time, improved reaction rate, simple and convenient operation and high reaction continuity, and is beneficial to continuous uninterrupted amplified production.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for the description of the embodiments will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art. Wherein:
FIG. 1 is a schematic illustration of the reaction scheme of the present invention.
FIG. 2 is a hydrogen and carbon spectrum of FIG. 3 a.
FIG. 3 is a hydrogen and carbon spectrum of FIG. 3 b.
FIG. 4 is a hydrogen and carbon spectrum of 3 c.
FIG. 5 is a hydrogen and carbon spectrum of 3 d.
FIG. 6 is a hydrogen and carbon spectrum of FIG. 3 e.
FIG. 7 is a hydrogen and carbon spectrum of FIG. 3 f.
FIG. 8 is a hydrogen spectrum and a carbon spectrum of 3 g.
FIG. 9 is a hydrogen spectrum and a carbon spectrum for 3 h.
Detailed Description
In order that the above-recited objects, features and advantages of the present invention will become more apparent, a more particular description of the invention will be rendered by reference to specific embodiments thereof.
The microchannel reaction device provided with a light source described in the following examples includes a feed pump (Baoding Leifu Fluid Technology co.ltd, (TYD 0101 CE type)), a microchannel reactor, a light source, and a receiver; wherein, the feeding pump, the micro-channel reactor and the receiver are connected in series sequentially through pipelines, and the micro-channel reactor is arranged under the irradiation of the light source; wherein the microchannel reactor is of a pipeline structure, the pipeline is made of perfluoroalkoxyalkane, the size and the inner diameter of the microchannel reactor are 0.5mm, and the volume of the microchannel reactor is 2mL; the light source is an LED blue light source, the intensity is 50W, and the wavelength is 460-470nm.
The following procedure is followed in the examples below: (1) Adding the mixed homogeneous solution prepared in proportion into a syringe pump; (2) Injecting the mixture into a micro-channel reaction device provided with a light source by using a syringe pump to perform reaction; (3) The reaction liquid flowing out is collected, and the product yield is calculated by column chromatography separation weighing mode.
Example 1:
synthesis of compound 3 a:
compound 1a (0.3 mmol,0.079 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), trifluoroacetic acid (0.2 mmol,0.023 g) and Ir (ppy) 2 (dtbbpy)PF 6 (0.004 mmol,0.0037 g) in a volume ratio of acetonitrile to water of 10 mL. Then pumping the mixture into a microchannel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), the pumping flow rate is 0.2mL/min, the reaction time in the microchannel reactor is 10min, collecting the reaction liquid, and obtaining a product 3a after extraction and water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the average product yield is 91% +/-1%.
As shown in the figure 2 of the drawings, 1 H NMR(400MHz，Chloroform-d)δ7.84(d，J＝7.9Hz，2H)，7.61(d，J＝7.2Hz，2H)，7.42-7.29(m，10H)，7.24-7.19(m，1H)，7.12-7.08(m，2H)，7.05-7.02(m，1H)，6.82(d，J＝7.6Hz，2H)，6.00(s，1H)，1.59(s，3H)ppm； 23 C NMR(100MHz，Chloroform-d)δ172.7，162.5，159.6，139.1，137.8，137.0，130.7，129.6，129.3，129.3，129.0，128.7，128.4，128.3，126.7，126.3，125.6，125.0，119.1，81.8，78.9，15.3ppm；HRMS(ESI-TOF)：m/z calcd for C 30 H 25 N 4 O[M+H] + 457.2023，found 457.2020.
comparative example 1:
compound 1a (0.3 mmol,0.079 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), trifluoroacetic acid (0.2 mmol,0.023 g) and Mes-Acr + ClO 4 - (0.04 mmol,0.0016 g) in a volume ratio of acetonitrile to water of 10 mL. Then pumping the mixture into a microchannel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), pumping the mixture into the reaction pipeline at the inflow rate of 0.2mL/min, reacting for 10min in the microchannel reactor, collecting a reaction liquid, and obtaining a product 3a after extraction and water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the average separation yield is 69% +/-2%.
Comparative example 2:
compound 1a (0.3 mmol,0.079 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), trifluoroacetic acid (0.2 mmol,0.023 g) and Ru (bpy) were combined 2 Cl 2 ·6H 2 O (0.04 mmol,0.0030 g) was dissolved in 10mL acetonitrile to water at a ratio of 1: 1. Then pumping into a microchannel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), pumping into the flow rate is 0.2mL/min, the reaction time in the microchannel reactor is 10min, collecting reaction liquid, and obtaining a product 3a after extraction and water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the separation yield is 51%.
Comparative example 3:
compound 1a (0.3 mmol,0.079 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), trifluoroacetic acid (0.2 mmol,0.023 g) and Ir (ppy) 2 (dtbbpy)PF 6 (0.04 mmol,0.0037 g) in 10mL of a mixed solution of dimethyl sulfoxide and water in a volume ratio of 1:1. Then pumped into a micro-channel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), the pumping flow rate is 0.2mL/min, and the reaction time in the micro-channel reactor is 10min, collecting a reaction liquid, and obtaining a product 3a after extraction and water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the separation yield is 55%.
Comparative example 4:
compound 1a (0.3 mmol,0.079 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), trifluoroacetic acid (0.2 mmol,0.023 g) and Ir (ppy) 2 (dtbbpy)PF 6 (0.004 mmol,0.0037 g) in a volume ratio of acetonitrile to water of 10 mL. Then pumping the mixture into a microchannel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), the pumping flow rate is 0.2mL/min, the reaction time in the microchannel reactor is 10min, collecting the reaction liquid, and obtaining a product 3a after extraction and water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the average separation yield is 74% +/-4%.
Comparative example 5:
compound 1a (0.3 mmol,0.079 g), compound 2 (0.2 mmol,0.039 g), ammonium persulfate (0.4 mmol,0.0913 g), trifluoroacetic acid (0.2 mmol,0.023 g) and Ir (ppy) 2 (dtbbpy)PF 6 (0.004 mmol,0.0037 g) in a volume ratio of acetonitrile to water of 10 mL. Then pumping the mixture into a microchannel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), the pumping flow rate is 0.2mL/min, the reaction time is 10min, collecting a reaction liquid, and obtaining a product 3a after extraction water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the average separation yield is 65% +/-2%.
Comparative example 6:
compound 1a (0.3 mmol,0.079 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), p-toluenesulfonic acid (0.2 mmol,0.034 g) and lr (ppy) 2 (dtbbpy)PF 6 (0.004 mmol,0.0037 g) in a volume ratio of acetonitrile to water of 10 mL. Then pumping the mixture into a microchannel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), the pumping flow rate is 0.2mL/min, the reaction time in the microchannel reactor is 10min, collecting the reaction liquid, and obtaining a product 3a after extraction and water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the average separation yield is 76% +/-2%.
Comparative example 7:
compound 1a (0.3 mmol,0.079 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), trifluoroacetic acid (0.2 mmol,0.023 g) and Ir (ppy) 2 (dtbbpy)PF 6 (0.004 mmol,0.0037 g) in a volume ratio of acetonitrile to water of 10 mL. Then pumping the mixture into a microchannel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), the pumping flow rate is 0.5mL/min, the reaction time in the microchannel reactor is 4min, collecting the reaction liquid, and obtaining a product 3a after extraction and water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the average separation yield is 71% +/-3%.
Example 2:
synthesis of compound 3 b:
compound 1b (0.3 mmol,0.083 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), trifluoroacetic acid (0.2 mmol,0.023 g) and Ir (ppy) 2 (dtbbpy)PF 6 (0.004 mmol,0.0037 g) in a volume ratio of acetonitrile to water of 10 mL. Then pumping into a microchannel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), pumping into the flow rate is 0.2mL/min, the reaction time in the microchannel reactor is 10min, collecting reaction liquid, and obtaining a product 3b after extraction and water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the separation yield is 85%.
As shown in the figure 3 of the drawings, 1 H NMR(400MHz，Chloroform-a)δ7.84(d，J＝7.7Hz，2H)，7.61(d，J＝8.5Hz，2H)，7.39(t，J＝16.0Hz，3H)，7.30(t，J＝15.0Hz，2H)，7.25-7.18(m，3H)，7.10(m，J＝20.6Hz，4H)，7.04-7.01(m，1H)，6.81(d，J＝7.5Hz，2H)，5.97(s，1H)，2.31(s，3H)，1.61(s，3H)ppm； 13 C NMR(100MHz，Chloroform-d)δ172.8，162.3，137.9，137.9，134.0，130.7，129.7，129.4，129.3，129.0，128.4，126.6，126.2，125.6，125.0，119.1，81.9，79.0，21.3，15.3ppm；HRMS(ESI-TOF)：m/z calcd for C 31 H 27 N 4 O[M+H] + 471.2179，found 471.2180.
example 3:
synthesis of Compound 3 c:
compound 1c (0.3 mmol,0.102 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), trifluoroacetic acid (0.2 mmol,0.023 g) and lr (ppy) 2 (dtbbpy)PF 6 (0.04 mmol,0.0037 g) in 10mL acetonitrile to water volume ratio of 1: 1. Then pumping the mixture into a microchannel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), the pumping flow rate is 0.2mL/min, the reaction time is 10min, collecting the reaction liquid, and obtaining a product 3c after extraction water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the separation yield is 89%. As shown in figure 4 of the drawings, 1 H NMR(400MHz，Chloroform-d)δ7.83(d，J＝7.9Hz，2H)，7.59(d，J＝7.3Hz，2H)，7.45(d，J＝8.4Hz，2H)，7.39(t，J＝7.8Hz，3H)，7.32-7.28(m，2H)，7.25-7.18(m，3H)，7.12-7.08(m，2H)，7.05-7.02(m，1H)，6.82(d，J＝7.7Hz，2H)，5.93(s，1H)，1.65(s，3H)ppm； 13 C NMR(100MHz，Chloroform-d)δ172.4，162.7，159.4，139.01，137.7，136.2，131.8，130.9，129.4，129.4，129.2，129.1，128.4，128.4，126.4，125.8，125.0，122.3，119.0，81.7，78.4，15.3ppm；HRMS(ESI-TOF)：m/z calcd for C 30 H 24 N 4 OBr[M+H] + 535.1128，found 535.1121.
example 4:
synthesis of Compound 3 d:
compound 1d (0.3 mmol,0.089 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), trifluoroacetic acid (0.2 mm)ol,0.023 g) and lr (ppy) 2 (dtbbpy)PF 6 (0.004 mmol,0.0037 g) in a volume ratio of acetonitrile to water of 10 mL. Then pumping the mixture into a microchannel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), the pumping flow rate is 0.2mL/min, the reaction time is 10min, collecting the reaction liquid, and obtaining a product after extraction water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the separation yield is 90%. As shown in figure 5 of the drawings, 1 H NMR(400MHz，Chloroform-d)δ7.81(d，√＝7.7Hz，2H)，7.60(d，J＝8.4Hz，2H)，7.49(s，1H)，7.43-7.38(m，3H)，7.34-7.28(m，3H)，7.24-7.20(m，2H)，7.12(t，J＝8.1Hz，3H)，7.07-7.04(m，1H)，6.83(d，J＝7.5Hz，2H)，5.95(s，1H)，1.66(s，3H)ppm； 13 C NMR(100MHz，Chloroform-d)δ172.4，162.8，159.3，139.2，139.0，137.7，134.8，130.9，130.1，129.4，129.4，129.3，129.1，128.5，128.4，127.1，126.5，125.8，125.0，124.8，119.2，78.3，15.3ppm；HRMS(ESI-TOF)∶m/z calcd for C 30 H 24 N 4 OCl[M+H] + 491.1633，found 491.1631.
example 5:
synthesis of compound 3 e:
compound 1e (0.3 mmol,0.083 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), trifluoroacetic acid (0.2 mmol,0.023 g) and lr (ppy) 2 (dtbbpy)PF 6 (0.004 mmol,0.0037 g) in a volume ratio of acetonitrile to water of 10 mL. Then pumping the mixture into a microchannel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), the pumping flow rate is 0.2mL/min, the reaction time is 10min, collecting the reaction liquid, and obtaining a product 3e after extraction water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the separation yield is 88%. As shown in figure 6 of the drawings, 1 H NMR(400MHz，Chloroform-a)δ7.83(d，J＝7.9Hz，2H)，7.62(d，J＝7.3Hz，2H)，7.38(t，J＝7.9Hz，3H)，7.29(t，J＝7.5Hz，2H)，7.27-7.17(m，3H)，7.14-7.07(m，4H)，7.03-6.99(m，1H)，6.82(d，J＝7.7Hz，2H)，5.98(s，1H)，2.27(s，3H)，1.63(s，3H)ppm； 13 C NMR(100MHz，Chloroform-d)δ172.6，162.3，159.7，139.17，138.2，137.8，136.8，130.7，129.6，129.2，129.0，128.9，128.5，128.3，127.3，126.2，125.6，124.9，123.7，119.1，81.9，79.1，21.4，15.2ppm；HRMS(ESI-TOF)：m/z calcd for C 31 H 27 N 4 O[M+H] + 471.2179，found 471.2179.
example 6:
synthesis of compound 3 f:
compound 1f (0.3 mmol,0.092 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), trifluoroacetic acid (0.2 mmol,0.023 g) and lr (ppy) 2 (dtbbpy)PF 6 (0.04 mmol,0.0037 g) in 10mL acetonitrile to water volume ratio of 1: 1. Then pumping the mixture into a microchannel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), the pumping flow rate is 0.2mL/min, the reaction time is 10min, collecting a reaction liquid, and obtaining a product 3f after extraction water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the average yield is 84% +/-2%. As shown in figure 7 of the drawings, 1 H NMR(400MHz，Chloroform-d)δ8.24(d，J＝8.5Hz，2H)，7.86(d，J＝7.9Hz，2H)，7.62(dd，J＝14.1，8.0Hz，4H)，7.47-7.44(m，3H)，7.39-7.35(m，2H)，7.30-7.28(m，1H)，7.20-7.16(m，2H)，7.14-7.10(m，1H)，6.87(d，J＝7.5Hz，2H)，6.07(s，1H)，1.71(s，3H)ppm； 13 C NMR(100MHz，Chloroform-d)δ172.0，163.3，158.8，147.9，144.5，138.8，137.6，131.1，129.5，129.3，129.2，129.1，128.5，127.8，126.8，126.0，125.1，124.0，119.0，81.7，78.2，15.3ppm；HRMS(ESI-TOF)：m/z calcd for C 30 H 24 N 5 O 3 [M+H] + 502.1873，found 502.1873.
example 7:
synthesis of Compound 3 g:
compound 1g (0.3 mmol,0.083 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), trifluoroacetic acid (0.2 mmol,0.023 g) and lr (ppy) 2 (dtbbpy)PF 6 (0.004 mmol,0.0037 g) in a volume ratio of acetonitrile to water of 10 mL. Then pumping the mixture into a microchannel reactor for reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), the pumping flow rate is 0.2mL/min, the reaction time is 10min, collecting a reaction liquid, and obtaining 3g of a product after extraction water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation, wherein the average separation yield is 81% +/-1%. As shown in figure 8 of the drawings, 1 H NMR(400MHz，Chloroform-a)δ7.80-7.78(m，2H)，7.65-7.61(m，3H)，7.41-7.36(m，3H)，7.32-7.28(m，2H)，7.25-7.17(m，3H)，7.14-7.09(m，3H)，7.07-7.03(m，1H)，6.85-6.82(m，2H)，6.14(s，1H)，2.10(s，3H)，1.43(s，3H)ppm； 13 C NMR(100MHz，Chloroform-d)δ172.9，162.4，159.6，139.0，137.7，135.9，135.6，130.8，130.6，129.7，129.4，129.3，129.1，128.5，128.3，128.2，126.6，126.0，125.8，125.6，118.9，80.5，76.2，19.1，15.5ppm；HRMS(ESI-TOF)：m/z calcd for C 31 H 27 N 4 O[M+H] + 471.2179，found 471.2179.
example 8:
synthesis of Compound 3 h:
compound 1h (0.3 mmol,0.089 g), compound 2 (0.2 mmol,0.039 g), potassium persulfate (0.4 mmol,0.108 g), trifluoroacetic acid (0.2 mmol,0.023 g) and Ir (ppy) 2 (dtbbpy)PF 6 (0.004 mmol,0.0037 g) in a volume ratio of acetonitrile to water of 10 mL. Then pumped into the microchannel reactorCarrying out reaction (the inner diameter of a reaction pipeline is 0.5mm, the volume is 2 mL), the pumping flow rate is 0.2mL/min, the reaction time is 10min, collecting reaction liquid, and obtaining a product after extraction water washing, anhydrous sodium sulfate drying, reduced pressure distillation and column chromatography separation for 3h, wherein the average separation yield is 83% +/-3%. As shown in the figure 9 of the drawings, 1 H NMR(400MHz，Chloroform-d)δ7.71-7.69(m，1H)，7.61-7.59(m，2H)，7.40-7.38(m，3H)，7.32-7.28(m，3H)，7.25-7.18(m，4H)，7.11-7.05(m，4H)，6.85-6.83(m，2H)，6.18(s，1H)，2.42(s，3H)ppm； 23 C NMR(100MHz，Chloroform-d)δ168.3，164.2，159.5，138.9，137.5，134.6，132.6，131.5，130.8，129.6，129.5，129.4，129.3，128.8，128.4，126.8，126.7，126.0，125.4，119.2，80.5，72.2，14.2ppm；HRMS(ESI-TOF)：m/z calcd for C 30 H 24 N 4 OCI[M+H] + 491.1633，found 491.1631.
it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered in the scope of the claims of the present invention.
Claims (10)
1. A method for continuously preparing 4, 5-imidazolinyl spiro pyrazolone compounds by utilizing photocatalysis microchannels is characterized in that 4-alkyl pyrazolone compounds shown in a formula 1, N-phenyl benzamidine shown in a formula 2, a photocatalyst, an additive and a solvent are mixed together to prepare a homogeneous solution, and then the homogeneous solution is injected into a sample injection port of a microchannel reaction device provided with a light source by using a syringe pump for single-strand sample injection to react to obtain a reaction solution containing the 4, 5-imidazolinyl spiro pyrazolone compounds shown in a formula 3;
wherein,,
r is selected from benzene, 4-methylbenzene, 4-bromobenzene, 3-methylbenzene, 3-chlorobenzene, 2-methylbenzene, 2-chlorobenzene, thiophene or pyridyl;
wherein the photocatalyst is (4, 4 '-di-tert-butyl-2, 2' -bipyridine) bis [ (2-pyridyl) phenyl]Iridium (III) hexafluorophosphate ({ Ir (ppy) 2 (dtbbpy)}PF 6 ) 10-methyl-9-mesityl acridine perchlorate (Mes-Acr) + ClO 4 - ) Terpyridine ruthenium dichloride hexahydrate (Ru (bpy) 2 Cl 2 ·6H 2 O), tris (2-phenylpyridine) iridium (Ir (ppy) 3 ) Any one or a combination of more than one of Eosin Y (Eosin Y), 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (4 CzIPN) and 2,4, 6-tri (diphenylamino) -5-fluoro isophthalonitrile (3 DPAFIPN).
2. The method according to claim 1, wherein the additive is any one or a combination of several of potassium persulfate, sodium persulfate, ammonium persulfate, tert-butyl hydroperoxide, tert-butyl peroxide, hydrogen peroxide, m-chloroperoxybenzoic acid, trifluoroacetic acid, acetic acid and p-toluenesulfonic acid.
3. The method according to claim 1, wherein the concentration of the 4-alkylppyrazolone compound of formula 1 in the homogeneous solution is from 0.01 to 0.30mmol/mL.
4. The process according to claim 1 or 2, wherein the concentration of N-phenylbenzamidine of formula 2 in the homogeneous solution is 0.01-0.30mmol/mL.
5. The method according to claim 1 or 2, wherein the photocatalyst is used in an amount of 1 to 20mol% of the N-phenylbenzamidine represented by formula 2.
6. The method according to claim 1 or 2, wherein the solvent is any one or a combination of acetonitrile, 1, 2-dichloroethane, ethanol, dichloromethane, trifluoroethanol, hexafluoroisopropanol, dimethyl sulfoxide and water.
7. The method according to claim 1 or 2, wherein the microchannel reaction device provided with a light source comprises a feed pump, a microchannel reactor, a light source and a receiver; wherein, the feed pump is connected in series with the micro-channel reactor and the receiver through the pipeline in turn, and the micro-channel reactor is arranged under the irradiation of the light source.
8. The method according to claim 7, wherein the microchannel reactor has a pipeline structure, the pipeline is made of perfluoroalkoxyalkane, the size and the inner diameter of the microchannel reactor are 0.5-1.0mm, and the volume of the microchannel reactor is 2-20mL.
9. The method according to claim 1 or 2, wherein the temperature of the reaction is 0-30 ℃; the reaction time is 30s-2h.
10. The method according to claim 1 or 2, wherein the light source is an LED blue light source with an intensity of 5-60W and a wavelength of 435-577nm.
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Citations (2)
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| CN111484452A (en) * | 2020-05-11 | 2020-08-04 | 南京工业大学 | Method for continuously preparing dihydro benzo [ j ] phenanthridine compound containing trifluoromethyl functional group by using microchannel reaction device |
| CN114262296A (en) * | 2021-12-21 | 2022-04-01 | 南京工业大学 | Method for synthesizing imidazole compounds by using microchannel reaction device |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111484452A (en) * | 2020-05-11 | 2020-08-04 | 南京工业大学 | Method for continuously preparing dihydro benzo [ j ] phenanthridine compound containing trifluoromethyl functional group by using microchannel reaction device |
| CN114262296A (en) * | 2021-12-21 | 2022-04-01 | 南京工业大学 | Method for synthesizing imidazole compounds by using microchannel reaction device |
Non-Patent Citations (2)
| Title |
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| XU, HUI;: "Regiodivergent Synthesis of 4, 5\'- and 4, 4\'-Imidazolinyl Spiropyrazolones from 4-Alkylidene Pyrazolones and Amidines", ORGANIC LETTERS, vol. 23, no. 14, pages 5305 - 5310 * |
| ZHANG, SAI;: "Electrooxidative [3 + 2] annulation of amidines with alkenes for the synthesis of spiroimidazolines", CHINESE CHEMICAL LETTERS, vol. 33, no. 12, pages 5128 - 5131, XP087133863, DOI: 10.1016/j.cclet.2022.04.006 * |
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