CN109320538A - The bromo- 5- aryl -2-(trimethyl silicon substrate of 3-) -1-(N, N- dimethyl sulfonamide) pyrroles's synthetic method - Google Patents
The bromo- 5- aryl -2-(trimethyl silicon substrate of 3-) -1-(N, N- dimethyl sulfonamide) pyrroles's synthetic method Download PDFInfo
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- CN109320538A CN109320538A CN201811331128.0A CN201811331128A CN109320538A CN 109320538 A CN109320538 A CN 109320538A CN 201811331128 A CN201811331128 A CN 201811331128A CN 109320538 A CN109320538 A CN 109320538A
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- pyrroles
- silicon substrate
- trimethyl silicon
- bromo
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- 239000000758 substrate Substances 0.000 title claims abstract description 66
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- 150000003233 pyrroles Chemical class 0.000 title claims description 73
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 66
- 238000006243 chemical reaction Methods 0.000 claims abstract description 63
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims abstract description 61
- 238000000034 method Methods 0.000 claims abstract description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 124
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 74
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 57
- 125000002252 acyl group Chemical group 0.000 claims description 43
- 239000002904 solvent Substances 0.000 claims description 43
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 41
- 150000001875 compounds Chemical class 0.000 claims description 37
- 239000012074 organic phase Substances 0.000 claims description 36
- 239000007832 Na2SO4 Substances 0.000 claims description 35
- -1 aryl boric acid Chemical compound 0.000 claims description 35
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 35
- 238000005406 washing Methods 0.000 claims description 34
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 30
- 238000000926 separation method Methods 0.000 claims description 29
- 238000004440 column chromatography Methods 0.000 claims description 26
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 25
- 229940125782 compound 2 Drugs 0.000 claims description 25
- 238000001704 evaporation Methods 0.000 claims description 24
- 230000008020 evaporation Effects 0.000 claims description 24
- 229920006395 saturated elastomer Polymers 0.000 claims description 18
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 15
- 239000002994 raw material Substances 0.000 claims description 15
- 239000004327 boric acid Substances 0.000 claims description 14
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 14
- 229940125904 compound 1 Drugs 0.000 claims description 13
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 13
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 claims description 12
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 claims description 11
- 229940125796 compound 3d Drugs 0.000 claims description 11
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 claims description 9
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 claims description 7
- 229940125872 compound 4d Drugs 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 229940125907 SJ995973 Drugs 0.000 claims description 6
- 239000011261 inert gas Substances 0.000 claims description 6
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 claims description 6
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- FZOHYIKLKMOKAJ-UHFFFAOYSA-N methylperoxy(phenoxy)borinic acid Chemical compound COOB(O)OC1=CC=CC=C1 FZOHYIKLKMOKAJ-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000002390 rotary evaporation Methods 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- LBBMOAOCCQOIAQ-UHFFFAOYSA-N methoxy(phenyl)borinic acid Chemical compound COB(O)C1=CC=CC=C1 LBBMOAOCCQOIAQ-UHFFFAOYSA-N 0.000 claims description 3
- KNPNGMXRGITFLE-UHFFFAOYSA-N methylperoxy(phenyl)borinic acid Chemical compound COOB(O)C1=CC=CC=C1 KNPNGMXRGITFLE-UHFFFAOYSA-N 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 3
- 229910052710 silicon Inorganic materials 0.000 claims 3
- 239000010703 silicon Substances 0.000 claims 3
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 claims 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims 2
- GUNGLHWSMWTKSD-UHFFFAOYSA-N [B].CC1=CC=CC=C1 Chemical compound [B].CC1=CC=CC=C1 GUNGLHWSMWTKSD-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 15
- 230000015572 biosynthetic process Effects 0.000 abstract description 13
- 125000001424 substituent group Chemical group 0.000 abstract description 7
- 125000001246 bromo group Chemical group Br* 0.000 abstract description 3
- 238000005859 coupling reaction Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 229930014626 natural product Natural products 0.000 abstract description 3
- MNQAOAHRURIYOI-UHFFFAOYSA-N N,N-dimethyl-1H-pyrrole-2-sulfonamide Chemical class CN(C)S(=O)(=O)C1=CC=CN1 MNQAOAHRURIYOI-UHFFFAOYSA-N 0.000 abstract description 2
- 230000005012 migration Effects 0.000 abstract description 2
- 238000013508 migration Methods 0.000 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 54
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- 239000007788 liquid Substances 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 30
- 239000003480 eluent Substances 0.000 description 27
- 239000007787 solid Substances 0.000 description 24
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- QLVGHFBUSGYCCG-UHFFFAOYSA-N 2-amino-n-(1-cyano-2-phenylethyl)acetamide Chemical compound NCC(=O)NC(C#N)CC1=CC=CC=C1 QLVGHFBUSGYCCG-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 7
- 239000012266 salt solution Substances 0.000 description 7
- 150000003851 azoles Chemical class 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 229910052796 boron Inorganic materials 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 230000006837 decompression Effects 0.000 description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- YVCYOVLYYZRNJC-UHFFFAOYSA-N (2-methoxyphenoxy)boronic acid Chemical compound COC1=CC=CC=C1OB(O)O YVCYOVLYYZRNJC-UHFFFAOYSA-N 0.000 description 1
- KLNUOTURXYOMHQ-UHFFFAOYSA-N C1(=CC=CC=C1)OB(O)O.[O] Chemical compound C1(=CC=CC=C1)OB(O)O.[O] KLNUOTURXYOMHQ-UHFFFAOYSA-N 0.000 description 1
- LVRCEUVOXCJYSV-UHFFFAOYSA-N CN(C)S(=O)=O Chemical class CN(C)S(=O)=O LVRCEUVOXCJYSV-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000006086 Paal-Knorr synthesis reaction Methods 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- FSQBHIPIGPYBCB-UHFFFAOYSA-N anisole;boron Chemical compound [B].COC1=CC=CC=C1 FSQBHIPIGPYBCB-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- OOPSAZSKOMIGFX-UHFFFAOYSA-N boric acid;toluene Chemical compound OB(O)O.CC1=CC=CC=C1 OOPSAZSKOMIGFX-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- MCYYJHPHBOPLMH-UHFFFAOYSA-L disodium;dioxido-oxo-sulfanylidene-$l^{6}-sulfane;hydrate Chemical class O.[Na+].[Na+].[O-]S([O-])(=O)=S MCYYJHPHBOPLMH-UHFFFAOYSA-L 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Polyoxymethylene Polymers And Polymers With Carbon-To-Carbon Bonds (AREA)
Abstract
The invention belongs to the field of chemical synthesis, it is related to 3- bromo- 5- aryl -2- (trimethyl silicon substrate) -1- (N, N- dimethyl sulfonamide) pyrroles's synthetic method, this method from dimethylamino sulphonyl pyrroles, chosen property bromo, coupling reaction, trimethyl silicon substrate migration/bromo-reaction obtain product.The present invention can synthesize 3- bromo- 5- aryl -2- (trimethyl silicon substrate) -1 hydrogen-pyrroles -1-N, N- dimethyl sulfonamide, and reaction process is simple；The present invention can introduce all kinds of substituent groups, have wider application range in drug, natural products synthesis and new material exploitation.The present invention has the characteristics that mild condition, conversion ratio are good, selectivity is high, substituent group introducing is flexible.
Description
Technical field
The invention belongs to the field of chemical synthesis, are related to a kind of bromo- 5- aryl -2- (trimethyl silicane of regio-selective synthesis 3-
Base) -1- (N, N- dimethyl sulfonamide) pyrroles method.
Background technique
Substituted azole is the important composition unit of many natural products, in pesticide, high molecular material, enzyme, protein, biology
The biomedicine fields such as alkali, which have, to be widely applied.Wherein synthesize the bromo- 5- aryl -2- of 3- (trimethyl silicon substrate) -1- (N, N- dimethyl
Sulfonamide) pyrroles is the important step for preparing substituted azole, substituted azole, which is widely present in antibacterial, antiviral etc., has biology living
In the diagnosis and treatment drug of property.Therefore the synthetic method receives great attention.
The synthetic method of polysubstituted pyrrole is more at present, including classical Paal-Knorr synthesis and some novel synthesis sides
Method, such as utilize transition-metal catalysis, multicomponent Hantzch reaction, " one kettle way " synthesis etc..But some of them method
Need the conditions such as high temperature and pressure, catalyst preparation process complexity, reaction substrate narrow scope, substituent group not flexible there are reaction etc.
Disadvantage, it is therefore desirable to which a variety of substituted azoles, reaction condition can be synthesized mildly and can flexibly introduce the conjunction of substituent group by designing one
At route.The present invention designs 3- bromo- 5- aryl -2- (trimethyl silicon substrate) -1- (N, the N- dimethyl sulfonamide) pyrroles of synthesis, is
The important intermediate for synthesizing polysubstituted pyrrole, provides new method for the synthesis of other azole compounds.
Summary of the invention
In view of the problems of the existing technology, the present invention provides a kind of more by selective bromo and Suzuki coupling synthesis
The route of three substituted azoles of kind.Using nitrogen, protection pyrroles is initial feed, anti-by the bromo-reaction and coupling of regioselectivity
Substituent group should be flexibly introduced on pyrrole ring.The method can synthesize 3- bromo- 5- aryl -2- (trimethyl silicon substrate) -1- (N, N- bis-
Methylsulfonamides) pyrroles, reaction process is simple.In addition this route can introduce all kinds of substituent groups, in drug, natural products
Synthesis and new material exploitation have wider application range.
In order to achieve the above object, the technical solution adopted by the present invention are as follows:
A kind of bromo- 5- aryl -2- of regio-selective synthesis 3- (trimethyl silicon substrate) -1- (N, N- dimethyl sulfonamide) pyrroles
Method, from dimethylamino sulphonyl pyrroles, migration/bromo-reaction of chosen property bromo, coupling reaction, trimethyl silicon substrate
Product is obtained, the reaction equation for synthesizing 2,3,5-, tri- substituted azole is as follows:
Specifically includes the following steps:
The first step synthesizes compound 1 (2,4- bis- (trimethyl silicon substrate) -1- (N, N- dimethylsulphonylamino) pyrroles)
Under inert gas shielding, with 2,5- bis- (trimethyl silicon substrate) -1- (N, N- dimethylsulphonylamino) pyrroles for raw material,
In the presence of chloroform and hydrochloric acid, 0.5h is reacted at room temperature.Suitable saturated sodium bicarbonate solution is added into round-bottomed flask, uses ether
Organic phase is collected in extraction, successively with water and saturated common salt water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains
Colourless liquid is purified through column chromatography for separation, obtains compound 1.
Second step synthesizes compound 2
Under inert gas protection, compound 1 and N- bromo-succinimide (NBS) are added in reaction dissolvent, ice
After being reacted 1 hour under water bath condition, saturated aqueous sodium thiosulfate is added, collects organic phase after being extracted with ether,
Water and saturated common salt water washing organic phase are used respectively, then use anhydrous Na2SO4Dry, rotary evaporation removes solvent rear pillar chromatography point
From obtaining compound 2.
The reaction dissolvent is DMF, THF, ether etc.；The molar ratio of the compound 1, NBS is 1:(1.2-1.5)
Third step synthesizes compound 3a-3d
Under inert gas protection, using compound 2, aryl boric acid as raw material, be dissolved in reaction dissolvent, add alkali and
(four triphenylphosphines) palladium carries out Suzuki coupling reaction in alkaline environment under the catalysis of tetra-triphenylphosphine palladium, obtains mixing and produces
Object, reaction temperature are 110 DEG C, and the reaction time is 0.5-1 hours；Water is added into mix products, is extracted with ether, collects
Organic phase uses water and saturated common salt water washing organic phase respectively, then uses anhydrous Na2SO4Dry, rotary evaporation removes solvent rear pillar
Chromatography respectively obtains compound 3a-3d.The molar ratio of the compound 2, aryl boric acid, alkali, four (triphenylphosphine palladiums)
For 1:(1-2): (5-8): (0.1-0.2).
The aryl boric acid be O-methoxy phenyl boric acid, meta-methoxy phenyl boric acid, to methoxyphenylboronic acid, to methylbenzene
Boric acid respectively corresponds compound 3a-3d: final to synthesize compound 3a when starting aryl boric acid is O-methoxy phenyl boric acid；When
It is final to synthesize compound 3b when starting aryl boric acid is meta-methoxy phenyl boric acid；When starting aryl boric acid is to methoxybenzene boron
It is final to synthesize compound 3c when sour；It is final to synthesize compound 3d when starting aryl boric acid is to methylphenylboronic acid.
The compound 3a is 2- (o-methoxyphenyl) -4- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group)
Pyrroles；3b is 2- (m-methoxyphenyl) -4- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；3c is 2- (to first
Oxygen phenyl) -4- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；3d is 2- (p-methylphenyl) -4- (trimethyl
Silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles.
The alkali is potassium carbonate.The reaction dissolvent is n,N-Dimethylformamide, and every 0.1mmol compound 2 is corresponding
5-8mL reaction dissolvent.
4th step synthesizes compound 4a-4d
Under air conditions, the compound 3a-3d obtained using third step column separation is sub- with N- bromo succinyl as raw material
Bromo-reaction occurs for amine (NBS), obtains mix products, and reaction temperature is 0 DEG C, and the reaction time is 0.5-1 hours；To mix products
Middle addition saturated aqueous sodium thiosulfate, is extracted with ether, collects organic phase, uses water and saturated common salt water washing respectively
Organic phase, anhydrous Na2SO4Dry, column separation after solvent removed by evaporation at reduced pressure respectively obtains compound 4a-4d.The chemical combination
The molar ratio of object 3a-3d:N- bromo-succinimide is 1:(1.2-1.5).
When raw material is compound 3a 2- (o-methoxyphenyl) -4- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group)
It is final to synthesize compound 4a when pyrroles；When raw material is compound 3b 2- (m-methoxyphenyl) -4- (trimethyl silicon substrate) -1-
It is final to synthesize compound 4b when (N, N- dimethyl methyl acyl group) pyrroles；When raw material is compound 3c 2- (p-methoxyphenyl) -4-
It is final to synthesize compound 4c when (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；When raw material is compound 3d 2-
It is final to synthesize compound 4d when (p-methylphenyl) -4- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles.
The compound 4a is 2- (trimethyl silicon substrate) -3- bromo- 5- (o-methoxyphenyl) -1- (N, N- dimethyl sulphonyl
Base) pyrroles；4b is 2- (trimethyl silicon substrate) -3- bromo- 5- (m-methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles；4c
For 2- (trimethyl silicon substrate) -3- bromo- 5- (p-methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles；4d is 2- (trimethyl
Silicon substrate) -3- bromo- 5- (p-methylphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles.
The reaction dissolvent is N,N-dimethylformamide；The corresponding 5-8mL reaction dissolvent of every 0.1mmol compound 3.
The invention has the benefit that the present invention above occurs using donor residues is connected on 2 phenyl ring, at pyrrole ring 3
Bromo-reaction in situ, and migrated with trimethyl silicon substrate β → α；Substituent group is flexibly introduced by Suzuki coupling reaction；It is not required to
Pyrrole ring is constructed, is raw material using pyrroles cheap and easy to get, at low cost, synthetic method is simple.
Detailed description of the invention
Fig. 1 is nuclear magnetic resonance spectroscopy (ppm, the CDCl of 1 compound 3a of embodiment3)；
Fig. 2 is carbon-13 nmr spectra (ppm, the CDCl of 2 compound 3a of embodiment3)；
Fig. 3 is nuclear magnetic resonance spectroscopy (ppm, the CDCl of 1 compound 3b of embodiment3)；
Fig. 4 is carbon-13 nmr spectra (ppm, the CDCl of 2 compound 3b of embodiment3)；
Fig. 5 is nuclear magnetic resonance spectroscopy (ppm, the CDCl of 1 compound 3c of embodiment3)；
Fig. 6 is carbon-13 nmr spectra (ppm, the CDCl of 2 compound 3c of embodiment3)；
Fig. 7 is nuclear magnetic resonance spectroscopy (ppm, the CDCl of 1 compound 3d of embodiment3)；
Fig. 8 is carbon-13 nmr spectra (ppm, the CDCl of 2 compound 3d of embodiment3)；
Fig. 9 is nuclear magnetic resonance spectroscopy (ppm, the CDCl of 1 compound 4a of embodiment3)；
Figure 10 is carbon-13 nmr spectra (ppm, the CDCl of 2 compound 4a of embodiment3)；
Figure 11 is nuclear magnetic resonance spectroscopy (ppm, the CDCl of 1 compound 4b of embodiment3)；
Figure 12 is carbon-13 nmr spectra (ppm, the CDCl of 2 compound 4b of embodiment3)；
Figure 13 is nuclear magnetic resonance spectroscopy (ppm, the CDCl of 1 compound 4c of embodiment3)；
Figure 14 is carbon-13 nmr spectra (ppm, the CDCl of 2 compound 4c of embodiment3)；
Figure 15 is nuclear magnetic resonance spectroscopy (ppm, the CDCl of 1 compound 4d of embodiment3)；
Figure 16 is carbon-13 nmr spectra (ppm, the CDCl of 2 compound 4d of embodiment3)。
Specific embodiment
Below in conjunction with attached drawing and technical solution, a specific embodiment of the invention is further illustrated.
Embodiment 1
The first step synthesizes compound 1
2,5- bis- (trimethyl silicon substrate) -1- (N, N- dimethylsulphonylamino) pyrroles is separately added into 100mL round-bottomed flask
(2.06g, 6.5mmol), chloroform (20mL) and hydrochloric acid (30 μ L), react 0.5h at room temperature.It is added into round-bottomed flask suitable
Saturated sodium bicarbonate solution is extracted with ether (10mL × 3), collects organic phase, anhydrous successively with water and saturated common salt water washing
Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, purifies through column chromatography for separation, with n-hexane/ether (60:1,
V/v it is) eluant, eluent, obtains white solid 1.61g, yield 78%；mp:54-58℃；1H NMR(500MHz,CDCl3)δ7.19
(d, J=1.5Hz, 1H, pyrrole-H), 6.50 (d, J=1.5Hz, 1H, pyrrole-H), 2.79 (s, 6H, Me-H), 0.32
(s,9H,TMS-H),0.21(s,9H,TMS-H)；13C NMR(125MHz,CDCl3)δ137.3,130.41,128.15,
122.57,38.47,0.46,0.4；HRMS(ESI-TOF)for C6H10N2O2S[M+H]+:calcd 319.1341.found
319.1341.
Second step synthesizes compound 2
Compound 1 (574mg, 1.8mmol) is added into bis- mouthfuls of flasks of 50mL under nitrogen protection, NBS (385.4mg,
2.165mmol) and THF (25mL), 1h is stirred at 0 DEG C.Suitable saturated sodium thiosulfate solution is added into mixture, uses second
Ether extracts (15mL × 3), merges organic phase, successively uses water and saturated common salt water washing, anhydrous Na2SO4Dry, reduction vaporization removes
Solvent is removed, colourless liquid is obtained, is purified through column chromatography for separation, using n-hexane/ether as eluant, eluent, obtains colourless liquid 481mg,
Yield 82%；1H NMR (500MHz, CDCl3) δ 7.22 (d, J=2.0Hz, 1H), 6.30 (d, J=2.0Hz, 1H), 2.93 (s,
6H),0.19(s,9H)；13C NMR(125MHz,CDCl3)δ129.9,121.2,120.8,100.0,38.1,1.0.HRMS
(ESI-TOF)for C9H17BrN2O2SSi[M+H]+:calcd,325.0042.found 325.0038.
Third step synthesizes compound 3a-3d
Compound 2 (194.4mg, 0.60mmol), adjacent first are separately added into two mouthfuls of flasks of 50mL under nitrogen protection
Oxygroup phenyl boric acid (1.2mmol), 2M K2CO3(3mL),Pd(PPh3)4(20mg, 0.02mmol) and DMF (10mL) are used as solvent,
Reaction is terminated after reacting 1h under the conditions of 110 DEG C.Suitable water is added in mixture, is extracted, is associated with ether (8mL × 3)
Machine phase, saturated salt solution and water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, chromatographs through column
Separating-purifying obtains compound 2- (o-methoxyphenyl) -4- (trimethyl silicon substrate) -1- using n-hexane/ether as eluant, eluent
(N, N- dimethyl methyl acyl group) pyrroles (3a) is white solid 170mg, yield 84%；mp:62-67℃；1H NMR(500MHz,
CDCl3) δ 7.38-7.35 (m, 1H, Ar-H), 7.33-7.31 (m, 1H, Ar-H), 7.26 (d, J=1.8Hz, 1H, pyrrole-
), H 7.01-6.91 (m, 2H, Ar-H), 6.24 (d, J=1.8Hz, 1H, pyrrole-H), 3.82 (s, 3H, Me-H), 2.54 (s,
6H,Me-H),0.26(s,9H,TMS-H)；13C NMR(125MHz,CDCl3)δ158.5,132.9,131.4,130.00,
128.8,121.5,119.8,119.6,118.7,110.5,55.5,37.4,0.6.HRMS(ESI-TOF)for
C16H24N2O3SSi[M+H]+:calcd 353.1355.found 353.1357.
Compound 2 (194.4mg, 0.60mmol), first are separately added into two mouthfuls of flasks of 50mL under nitrogen protection
Oxygroup phenyl boric acid (1.2mmol), 2M K2CO3(3mL),Pd(PPh3)4(20mg, 0.02mmol) and DMF (10mL) are used as solvent,
Reaction is terminated after reacting 1h under the conditions of 110 DEG C.Suitable water is added in mixture, is extracted, is associated with ether (8mL × 3)
Machine phase, saturated salt solution and water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, chromatographs through column
Separating-purifying, using n-hexane/ether as eluant, eluent, obtain compound (m-methoxyphenyl) -4- (trimethyl silicon substrate) -1- (N,
N- dimethyl methyl acyl group) pyrroles (3b) is white solid 170mg, yield 84%；mp:62-67℃；1H NMR(500MHz,
CDCl3) δ 7.38-7.35 (m, 1H, Ar-H), 7.33-7.31 (m, 1H, Ar-H), 7.26 (d, J=1.8Hz, 1H, pyrrole-
), H 7.01-6.91 (m, 2H, Ar-H), 6.24 (d, J=1.8Hz, 1H, pyrrole-H), 3.82 (s, 3H, Me-H), 2.54 (s,
6H,Me-H),0.26(s,9H,TMS-H)；13C NMR(125MHz,CDCl3)δ158.5,132.9,131.5,130.0,128.8,
121.5,119.8,119.6,118.7,110.5,55.5,37.4,0.6.HRMS(ESI-TOF)for C16H24N2O3SSi[M+H
]+:calcd 353.1355.found 353.1357.
It is separately added into compound 2 (194.4mg, 0.60mmol) into two mouthfuls of flasks of 50mL under nitrogen protection, to first
Oxygroup phenyl boric acid (1.2mmol), 2M K2CO3(3mL),Pd(PPh3)4(20mg, 0.02mmol) and DMF (10mL) are used as solvent,
Reaction is terminated after reacting 1h under the conditions of 110 DEG C.Suitable water is added in mixture, is extracted, is associated with ether (8mL × 3)
Machine phase, saturated salt solution and water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, chromatographs through column
Separating-purifying, using n-hexane/ether as eluant, eluent, obtain compound 2- (p-methoxyphenyl) -4- (trimethyl silicon substrate) -1- (N,
N- dimethyl methyl acyl group) pyrroles (3c) is white solid 163mg, yield 77%；mp:76-79℃；1H NMR(500MHz,
CDCl3) δ 7.43 (d, J=8.8Hz, 2H, Ar-H), 7.24 (d, J=1.8Hz, 1H, pyrrole-H), 6.90 (d, J=
8.8Hz, 2H, Ar-H), 6.20 (d, J=1.8Hz, 1H, pyrrole-H), 3.83 (s, 3H, Me-H), 2.44 (s, 6H, Me-H),
0.23(s,9H,TMS-H)；13C NMR(125MHz,CDCl3)δ159.5,135.3,131.9,129.7,124.5,119.5,
118.7,113.0,55.2,37.3,0.7.HRMS(ESI-TOF)for C16H24N2O3SSi[M+Na]+:calcd
375.1175.found 375.1174.
It is separately added into compound 2 (194.4mg, 0.60mmol) into two mouthfuls of flasks of 50mL under nitrogen protection, to first
Base phenyl boric acid (1.2mmol), 2M K2CO3(3mL),Pd(PPh3)4(20mg, 0.02mmol) and DMF (10mL) are used as solvent,
Reaction is terminated after reacting 1h under the conditions of 110 DEG C.Suitable water is added in mixture, is extracted with ether (8mL × 3), merges organic
Phase, saturated salt solution and water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, through column chromatography point
From purification, using n-hexane/ether as eluant, eluent, compound 2- (p-methylphenyl) -4- (trimethyl silicon substrate) -1- (N, N- is obtained
Dimethyl methyl acyl group) pyrroles (3d) is white solid 135mg, yield 67%；mp:83-86℃；1H NMR(500MHz,CDCl3)
δ 7.27 (d, J=7.3Hz, 2H, Ar-H), 7.12 (s, 1H, pyrrole-H), 7.05 (d, J=7.7Hz, 2H, Ar-H), 6.09
(s,1H,pyrrole-H),2.31(s,6H,Me-H),2.25(s,3H,Me-H),0.1(s,9H,TMS-H)；13C NMR
(125MHz,CDCl3)δ138.0,135.7,130.5,129.9,129.2,128.4,119.7,118.9,37.4,21.3,
0.6.HRMS(ESI-TOF)for C16H24N2O2SSi[M+Na]+:calcd 359.1225.found 359.1225.
4th step synthesizes compound 4a-4d
Under air conditions, compound 3a (176mg, 0.5mmol) is added in bis- mouthfuls of flasks of 50mL, NBS (0.6mmol)
With DMF (10mL), 1h is stirred at 0 DEG C, terminates reaction.Appropriate saturated aqueous sodium thiosulfate is added in mixture, uses ether
(8mL × 3) extraction, merges organic phase, successively uses water and saturated common salt water washing, anhydrous Na2SO4It is dry, it is molten that removing is evaporated under reduced pressure
Agent obtains colourless liquid, purifies through column chromatography for separation, using n-hexane/ether as eluant, eluent, obtains compound 4a.2- (adjacent methoxy
Base phenyl) the bromo- 5- of -3- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (4a), it is colourless oil liquid 144mg,
Yield 67%；1H NMR(500MHz,CDCl3) δ 7.34 (dd, J=1.8, J=0.8Hz, 1H, Ar-H), 7.22 (dd, J=7.4,
J=1.8Hz, 1H, Ar-H), 6.96-6.93 (m, 1H, Ar-H), 6.89 (d, J=8.0Hz, 1H, Ar-H), 6.10 (s, 1H,
pyrrole-H),3.81(s,3H,Me-H),2.82(s,6H,Me-H),0.32(s,9H,TMS-H)；13C NMR(125MHz,
CDCl3)δ158.2,136.1,130.9,129.8,123.9,123.6,119.7,118.5,110.2,107.1,55.3,37.8,
1.2.HRMS(ESI-TOF)for C16H23BrN2O3SSi[M+H]+:calcd 431.0460.found 431.0453.
Under air conditions, compound 3b (0.5mmol) is added in bis- mouthfuls of flasks of 50mL, NBS (106mg, 0.6mmol)
With DMF (10mL), 1h is stirred at 0 DEG C, terminates reaction.Appropriate saturated aqueous sodium thiosulfate is added in mixture, uses ether
(8mL × 3) extraction, merges organic phase, successively uses water and saturated common salt water washing, anhydrous Na2SO4It is dry, it is molten that removing is evaporated under reduced pressure
Agent obtains colourless liquid, purifies through column chromatography for separation, using n-hexane/ether as eluant, eluent, obtains compound 2- (meta-methoxy
Phenyl) the bromo- 5- of -3- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (4b) is white solid 168mg, yield
78%；mp:108-110℃；1H NMR(500MHz,CDCl3) δ 7.26 (t, J=7.9Hz, 1H, Ar-H), 7.00-6.98 (m,
1H,Ar-H),6.97-6.95(m,1H,Ar-H),6.90-6.87(m,1H,Ar-H),6.10(s,1H,pyrrole-H),3.82
(s,3H,Me-H),2.73(s,6H,Me-H),0.32(s,9H,TMS-H)；13C NMR(125MHz,CDCl3)δ158.7,
139.6,135.0,128.4,124.7,122.3,119.6,115.5,113.6,108.7,55.2,38.0,1.3.HRMS(ESI-
TOF)for C16H23BrN2O3SSi[M+H]+:calcd 431.0460.found 431.0465.
Under air conditions, compound 3c (0.5mmol) is added in bis- mouthfuls of flasks of 50mL, NBS (106mg, 0.6mmol)
With DMF (10mL), 1h is stirred at 0 DEG C, terminates reaction.Appropriate saturated aqueous sodium thiosulfate is added in mixture, uses ether
(8mL × 3) extraction, merges organic phase, successively uses water and saturated common salt water washing, anhydrous Na2SO4It is dry, it is molten that removing is evaporated under reduced pressure
Agent obtains colourless liquid, purifies through column chromatography for separation, using n-hexane/ether as eluant, eluent, obtains compound 2- (to methoxyl group
Phenyl) the bromo- 5- of -3- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (4c) is white solid 189mg, yield
88%；mp:88-92℃；1H NMR(500MHz,CDCl3) δ 7.32 (d, J=8.7Hz, 2H, Ar-H), 6.89 (d, J=8.7Hz,
2H,Ar-H),6.10(s,1H,pyrrole-H),3.83(s,3H,Me-H),2.72(s,6H,Me-H),0.32(s,9H,TMS-
H)；13C NMR(125MHz,CDCl3)δ159.3,139.5,131.2,126.1,124.6,119.2,112.8,108.0,55.2,
37.9,1.3.HRMS(ESI-TOF)for C16H23BrN2O3SSi[M+Na]+:calcd 453.0280.found 453.0263.
Under air conditions, compound 3d (0.5mmol) is added in bis- mouthfuls of flasks of 50mL, NBS (106mg, 0.6mmol)
With DMF (10mL), 1h is stirred at 0 DEG C, terminates reaction.Appropriate saturated aqueous sodium thiosulfate is added in mixture, uses ether
(8mL × 3) extraction, merges organic phase, successively uses water and saturated common salt water washing, anhydrous Na2SO4It is dry, it is molten that removing is evaporated under reduced pressure
Agent obtains colourless liquid, purifies through column chromatography for separation, using n-hexane/ether as eluant, eluent, obtains compound 2- (to methylbenzene
Base) the bromo- 5- of -3- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (4d) is white solid 157mg, yield
76%；mp:115-118℃；1H NMR(500MHz,CDCl3) δ 7.29 (d, J=8.0Hz, 2H, Ar-H), 7.16 (d, J=
8.0Hz,2H,Ar-H),6.11(s,1H,pyrrole-H),2.72(s,6H,Me-H),2.38(s,3H,Me-H),0.31(s,
9H,TMS-H)；13C NMR(125MHz,CDCl3)δ139.89,137.79,130.89,129.82,128.18,124.73,
119.38,108.25,37.99,21.30,1.22.HRMS(ESI-TOF)for C16H24BrN2O2SSi[M+Na]+:calcd,
437.0331.found 437.0316。
Embodiment 2
The first step synthesizes compound 1
With embodiment 1.
Second step synthesizes compound 2
Compound 1 (574mg, 1.8mmol) is added into bis- mouthfuls of flasks of 50mL under nitrogen protection, NBS (480.6mg,
2.7mmol) and THF (25mL), 1h is stirred under the conditions of ice-water bath.It is molten that suitable saturated sodium thiosulfate is added into mixture
Liquid extracts (15mL × 3) with ether, merges organic phase, successively uses water and saturated common salt water washing, anhydrous Na2SO4It is dry, decompression
Evaporation of solvent obtains colourless liquid, purifies through column chromatography for separation, with n-hexane/ether (60:1, v/v) for eluant, eluent, obtains
To colourless liquid 465mg, yield 80%.
Third step synthesizes compound 3a-3d
It is separately added into compound 2 (0.60mmol) into two mouthfuls of flasks of 50mL under nitrogen protection, O-methoxy benzene boron
Sour (1.0mmol), 2M K2CO3(2mL),Pd(PPh3)4(10mg, 0.01mmol) and DMF (6mL) are used as solvent, in 110 DEG C of items
Reaction is terminated after reacting 0.5h under part.Suitable water is added in mixture, is extracted with ether (8mL × 3), merges organic phase, satisfies
With saline solution and water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, mentions through column chromatography for separation
It is pure, using n-hexane/ether as eluant, eluent, obtain compound 3a:2- (o-methoxyphenyl) -4- (trimethyl silicon substrate) -1- (N, N-
Dimethyl methyl acyl group) pyrroles (3a), white solid 165mg, yield 78%.
It is separately added into compound 2 (0.60mmol) into two mouthfuls of flasks of 50mL under nitrogen protection, meta-methoxy benzene boron
Sour (1.1mmol), 2M K2CO3(3mL),Pd(PPh3)4(20mg, 0.02mmol) and DMF (10mL) are used as solvent, at 110 DEG C
Under the conditions of react 0.5h after terminate reaction.Suitable water is added in mixture, is extracted with ether (8mL × 3), merges organic phase,
Saturated salt solution and water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, mentions through column chromatography for separation
It is pure, using n-hexane/ether as eluant, eluent, obtain compound 3b:2- (m-methoxyphenyl) -4- (trimethyl silicon substrate) -1- (N, N-
Dimethyl methyl acyl group) pyrroles (3b), white solid 150mg, yield 71%.
It is separately added into compound 2 (194.4mg, 0.60mmol) into two mouthfuls of flasks of 50mL under nitrogen protection, to first
Oxygen phenyl boric acid (1.3mmol), 2M K2CO3(3mL),Pd(PPh3)4(20mg, 0.02mmol) and DMF (10mL) are used as solvent,
Reaction is terminated after reacting 0.5h under the conditions of 110 DEG C.Suitable water is added in mixture, is extracted, is associated with ether (8mL × 3)
Machine phase, saturated salt solution and water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, chromatographs through column
Separating-purifying obtains compound 3c:2- (p-methoxyphenyl) -4- (trimethyl silicon substrate) -1- using n-hexane/ether as eluant, eluent
(N, N- dimethyl methyl acyl group) pyrroles (3c), white solid 158mg, yield 75%.
It is separately added into compound 2 (194.4mg, 0.60mmol) into two mouthfuls of flasks of 50mL under nitrogen protection, to first
Base phenyl boric acid (1.5mmol), 2M K2CO3(3mL),Pd(PPh3)4(20mg, 0.02mmol) and DMF (10mL) are used as solvent,
Reaction is terminated after reacting 0.5h under the conditions of 110 DEG C.Suitable water is added in mixture, is extracted, is associated with ether (8mL × 3)
Machine phase, saturated salt solution and water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, chromatographs through column
Separating-purifying obtains compound 3d:2- (p-methylphenyl) -4- (trimethyl silicon substrate) -1- using n-hexane/ether as eluant, eluent
(N, N- dimethyl methyl acyl group) pyrroles (3d), white solid 141mg, yield 70%.
4th step synthesizes compound 4a-4d
Under air conditions, compound 3a (0.5mmol) is added in bis- mouthfuls of flasks of 50mL, NBS (106mg, 0.6mmol)
With DMF (10mL), 0.5h is stirred at 0 DEG C, terminates reaction.Appropriate saturated aqueous sodium thiosulfate is added in mixture, uses second
Ether (8mL × 3) extraction, merges organic phase, successively uses water and saturated common salt water washing, anhydrous Na2SO4It is dry, it is evaporated under reduced pressure and removes
Solvent obtains colourless liquid, purifies through column chromatography for separation, using n-hexane/ether as eluant, eluent, obtains compound 4a:2- (adjacent first
Phenyl) the bromo- 5- of -3- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (4a) synthesis, white solid
141mg, yield 86%.
Under air conditions, compound 3b (0.5mmol) is added in bis- mouthfuls of flasks of 50mL, NBS (115.7mg,
0.65mmol) and DMF (10mL), 0.5h is stirred at 0 DEG C, terminate reaction.Appropriate saturated sodium thiosulfate water is added in mixture
Solution is extracted with ether (8mL × 3), merges organic phase, successively uses water and saturated common salt water washing, and anhydrous Na 2SO4 is dry, subtracts
Evaporation of solvent is pressed, colourless liquid is obtained, is purified through column chromatography for separation, using n-hexane/ether as eluant, eluent, obtain compound
4b:(m-methoxyphenyl) the bromo- 5- of -3- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (4b) synthesis, white
Solid 170mg, yield 80%.
Under air conditions, compound 3c (0.5mmol) is added in bis- mouthfuls of flasks of 50mL, NBS (88.9mg,
0.5mmol) and DMF (10mL), 0.5h is stirred at 0 DEG C, terminate reaction.It is water-soluble that appropriate saturated sodium thiosulfate is added in mixture
Liquid is extracted with ether (8mL × 3), merges organic phase, successively uses water and saturated common salt water washing, anhydrous Na2SO4It is dry, decompression
Evaporation of solvent obtains colourless liquid, purifies through column chromatography for separation, using n-hexane/ether as eluant, eluent, obtains compound
4c:2- (p-methoxyphenyl) -3- bromo- 5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (4c), white solid
168mg, yield 78%.
Under air conditions, compound 3d (0.5mmol) is added in bis- mouthfuls of flasks of 50mL, NBS (115.7mg,
0.65mmol) and DMF (10mL), 1h is stirred at 0 DEG C, terminate reaction.It is water-soluble that appropriate saturated sodium thiosulfate is added in mixture
Liquid is extracted with ether (8mL × 3), merges organic phase, successively uses water and saturated common salt water washing, anhydrous Na2SO4It is dry, decompression
Evaporation of solvent obtains colourless liquid, purifies through column chromatography for separation, using n-hexane/ether as eluant, eluent, obtains compound
4d:2- (p-methylphenyl) -3- bromo- 5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (4d), white solid
165mg, yield 80%.
Embodiment 3
The first step synthesizes compound 1
With embodiment 1.
Second step synthesizes compound 2
Compound 1 (636.3mg, 2.0mmol) is added into bis- mouthfuls of flasks of 50mL under nitrogen protection, NBS (445.0mg,
2.5mmol) and THF (30mL), 1h is stirred at 0 DEG C.Suitable saturated sodium thiosulfate solution is added into mixture, uses ether
It extracts (20mL × 3), merges organic phase, successively use water and saturated common salt water washing, anhydrous Na2SO4It is dry, it is evaporated under reduced pressure and removes
Solvent obtains colourless liquid, purifies through column chromatography for separation, with n-hexane/ether (60:1, v/v) for eluant, eluent, obtains colourless liquid
Body 557mg, yield 86%.
Third step synthesizes compound 3a-3d
It is separately added into compound 2 (0.40mmol) into two mouthfuls of flasks of 50mL under nitrogen protection, O-methoxy benzene boron
Sour (0.48mmol), 2M K2CO3(2mL),Pd(PPh3)4(8mg, 0.008mmol) and DMF (5mL) are used as solvent, at 110 DEG C
Under the conditions of react 1h after terminate reaction.Suitable water is added in mixture, is extracted with ether (5mL × 3), merges organic phase, satisfies
With saline solution and water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, mentions through column chromatography for separation
It is pure, using n-hexane/ether as eluant, eluent, obtain compound 3a.2- (o-methoxyphenyl) -4- (trimethyl silicon substrate) -1- (N, N-
Dimethyl methyl acyl group) pyrroles (3a), white solid 112mg, yield 80%.
It is separately added into compound 2 (0.40mmol) into two mouthfuls of flasks of 50mL under nitrogen protection, meta-methoxy benzene boron
Sour (0.8mmol), 2M K2CO3(3mL),Pd(PPh3)4(10mg, 0.01mmol) and DMF (8mL) are used as solvent, in 110 DEG C of items
Reaction is terminated after reacting 1h under part.Suitable water is added in mixture, is extracted with ether (8mL × 3), merges organic phase, saturation
Saline solution and water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, purifies through column chromatography for separation,
Using n-hexane/ether as eluant, eluent, compound 3b is obtained.2- (m-methoxyphenyl) -4- (trimethyl silicon substrate) -1- (N, N- bis-
Methyl sulphonyl) pyrroles (3b), white solid 98mg, yield 70%.
It is separately added into compound 2 (0.50mmol) into two mouthfuls of flasks of 50mL under nitrogen protection, to methoxy phenyl boric acid
(1.0mmol), 2M K2CO3(5mL),Pd(PPh3)4(10mg, 0.01mmol) and DMF (8mL) are used as solvent, in 110 DEG C of conditions
Reaction is terminated after lower reaction 1h.Suitable water is added in mixture, is extracted with ether (8mL × 3), merges organic phase, saturation food
Salt water and water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, purifies through column chromatography for separation, with
N-hexane/ether is eluant, eluent, obtains compound 3c.2- (p-methoxyphenyl) -4- (trimethyl silicon substrate) -1- (N, N- dimethyl
Sulfonyl) pyrroles (3c), white solid 137mg, yield 78%.
It is separately added into compound 2 (0.50mmol) into two mouthfuls of flasks of 50mL under nitrogen protection, to methylphenylboronic acid
(0.6mmol), 2M K2CO3(3mL),Pd(PPh3)4(10mg, 0.01mmol) and DMF (8mL) are used as solvent, in 110 DEG C of conditions
Reaction is terminated after lower reaction 1h.Suitable water is added in mixture, is extracted with ether (8mL × 3), merges organic phase, saturation food
Salt water and water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, purifies through column chromatography for separation, with
N-hexane/ether is eluant, eluent, obtains compound 3d.2- (p-methylphenyl) -4- (trimethyl silicon substrate) -1- (N, N- dimethyl
Sulfonyl) pyrroles (3d), white solid 115mg, yield 69%.
4th step synthesizes compound 4a-4d
Under air conditions, compound 3a (0.3mmol) is added in bis- mouthfuls of flasks of 50mL, NBS (80mg, 0.45mmol)
With DMF (5mL), 1h is stirred at 0 DEG C, terminates reaction.Appropriate saturated aqueous sodium thiosulfate is added in mixture, uses ether
(5mL × 3) extraction, merges organic phase, successively uses water and saturated common salt water washing, anhydrous Na2SO4It is dry, it is molten that removing is evaporated under reduced pressure
Agent obtains colourless liquid, purifies through column chromatography for separation, using n-hexane/ether as eluant, eluent, obtains compound 4a.2- (adjacent methoxy
Base phenyl) the bromo- 5- of -3- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (4a) synthesis, white solid 90mg,
Yield 70%.
Under air conditions, compound 3b (0.45mmol) is added in bis- mouthfuls of flasks of 50mL,
NBS (96mg, 0.54mmol) and DMF (5mL) stirs 1h at 0 DEG C, terminates reaction.It is added in mixture appropriate full
And sodium thiosulfate solution, it is extracted with ether (5mL × 3), merges organic phase, successively use water and saturated common salt water washing, nothing
Water Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains colourless liquid, purifies through column chromatography for separation, is to wash with n-hexane/ether
De- agent, obtains compound 4d.2- (m-methoxyphenyl) -3- bromo- 5- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrrole
Cough up the synthesis of (4b), white solid 147mg, yield 76%.
Under air conditions, compound 3c (0.5mmol) is added in bis- mouthfuls of flasks of 50mL, NBS (0.6mmol) and DMF
(10mL) stirs 1h at 0 DEG C, terminates reaction.Appropriate saturated aqueous sodium thiosulfate is added in mixture, with ether (8mL ×
3) it extracts, merges organic phase, successively use water and saturated common salt water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains
It to colourless liquid, is purified through column chromatography for separation, using n-hexane/ether as eluant, eluent, obtains compound 4c.2- is (to methoxybenzene
Base) the bromo- 5- of -3- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (4c), white solid 182mg, yield 85%.
Under air conditions, compound 3d (0.6mmol) is added in bis- mouthfuls of flasks of 50mL, NBS (0.6mmol) and DMF
(10mL) stirs 1h at 0 DEG C, terminates reaction.Appropriate saturated aqueous sodium thiosulfate is added in mixture, with ether (8mL ×
3) it extracts, merges organic phase, successively use water and saturated common salt water washing, anhydrous Na2SO4Dry, solvent removed by evaporation at reduced pressure obtains
It to colourless liquid, is purified through column chromatography for separation, using n-hexane/ether as eluant, eluent, obtains compound 4d.2- is (to methylbenzene
Base) the bromo- 5- of -3- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles (4d), white solid 181mg, yield 73%.
Embodiments of the present invention above described embodiment only expresses, but it cannot be understood as special to the present invention
The limitation of the range of benefit, it is noted that for those skilled in the art, without departing from the inventive concept of the premise,
Various modifications and improvements can be made, these are all belonged to the scope of protection of the present invention.
Claims (8)
1.3- bromo- 5- aryl -2- (trimethyl silicon substrate) -1- (N, N- dimethyl sulfonamide) pyrroles's synthetic method, which is characterized in that
Reaction equation is as follows:
The following steps are included:
The first step synthesizes compound 1 (2,4- bis- (trimethyl silicon substrate) -1- (N, N- dimethylsulphonylamino) pyrroles)
Under inert gas shielding, with 2,5- bis- (trimethyl silicon substrate) -1- (N, N- dimethylsulphonylamino) pyrroles for raw material, in chloroform
In the presence of hydrochloric acid, after room temperature reaction, saturated sodium bicarbonate solution is added, organic phase is washed after extraction, then use anhydrous Na2SO4It is dry
Column chromatography for separation after dry, solvent removed by evaporation at reduced pressure obtains compound 1；
Second step synthesizes compound 2
Under inert gas protection, compound 1 and N- bromo-succinimide (NBS) are added in reaction dissolvent, ice-water bath
Under the conditions of react 1 hour, add saturated aqueous sodium thiosulfate, organic phase washed after extraction, then use anhydrous Na2SO4It is dry
Dry, rotary evaporation removes column chromatography for separation after solvent, obtains compound 2；
Third step synthesizes compound 3a-3d
Under inert gas protection, it using compound 2, aryl boric acid as raw material, is dissolved in reaction dissolvent, adds alkali and (4 3
Phenylphosphine) palladium occurs Suzuki coupling reaction, obtains mix products in alkaline environment under the catalysis of tetrakis triphenylphosphine palladium,
Reaction temperature is 110 DEG C, and the reaction time is 0.5-1 hours；Water is added into mix products, is collected after being extracted with ether organic
Phase uses water and saturated common salt water washing organic phase respectively, then uses anhydrous Na2SO4Dry, rotary evaporation removes solvent rear pillar chromatography
Separation, respectively obtains compound 3a-3d；The compound 2, aryl boric acid, alkali, tetrakis triphenylphosphine palladium molar ratio be 1:
1-2:5-8:0.1-0.2；
The aryl boric acid be O-methoxy phenyl boric acid, meta-methoxy phenyl boric acid, to methoxyphenylboronic acid, to methylbenzene boron
Acid respectively corresponds compound 3a-3d: final to synthesize compound 3a when starting aryl boric acid is O-methoxy phenyl boric acid；Work as original
It is final to synthesize compound 3b when expecting that aryl boric acid is meta-methoxy phenyl boric acid；When starting aryl boric acid is to methoxyphenylboronic acid
When, it is final to synthesize compound 3c；It is final to synthesize compound 3d when starting aryl boric acid is to methylphenylboronic acid；The change
Conjunction object 3a is 2- (o-methoxyphenyl) -4- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；3b is 2- (first
Phenyl) -4- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；3c is 2- (p-methoxyphenyl) -4- (front three
Base silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles；3d is 2- (p-methylphenyl) -4- (trimethyl silicon substrate) -1- (N, N- bis-
Methyl sulphonyl) pyrroles；
4th step synthesizes compound 4a-4d
Under air conditions, the compound 3a-3d obtained using third step occurs as raw material with N- bromo-succinimide (NBS)
Bromo-reaction obtains mix products, and reaction temperature is 0 DEG C, and the reaction time is 0.5-1 hours；Saturation is added into mix products
Sodium thiosulfate solution collects organic phase after being extracted with ether, use water and saturated common salt water washing organic phase respectively, anhydrous
Na2SO4Dry, column separation after solvent removed by evaporation at reduced pressure respectively obtains compound 4a-4d；The compound 3a-3d:N- bromine
Molar ratio for succimide is 1:1.2-1.5；
When raw material is compound 3a 2- (o-methoxyphenyl) -4- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles
When, it is final to synthesize compound 4a；When raw material is compound 3b 2- (m-methoxyphenyl) -4- (trimethyl silicon substrate) -1- (N, N-
Dimethyl methyl acyl group) pyrroles when, it is final to synthesize compound 4b；When raw material is compound 3c 2- (p-methoxyphenyl) -4- (front three
Base silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles when, it is final to synthesize compound 4c；When raw material is compound 3d 2- (to first
Base phenyl) -4- (trimethyl silicon substrate) -1- (N, N- dimethyl methyl acyl group) pyrroles when, it is final to synthesize compound 4d；The compound
4a is 2- (trimethyl silicon substrate) -3- bromo- 5- (o-methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles；4b is 2- (front three
Base silicon substrate) -3- bromo- 5- (m-methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles；4c is 2- (trimethyl silicon substrate) -3-
Bromo- 5- (p-methoxyphenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles；4d is the bromo- 5- of 2- (trimethyl silicon substrate) -3- (to first
Base phenyl) -1- (N, N- dimethyl methyl acyl group) pyrroles.
2. the method according to claim 1, wherein the molar ratio of compound 1 described in second step, NBS are
1:1.2-1.5。
3. method according to claim 1 or 2, which is characterized in that reaction dissolvent described in third step is N, N- diformazan
Base formamide, the corresponding 5-8mL reaction dissolvent of every 0.1mmol compound 2.
4. method according to claim 1 or 2, which is characterized in that alkali described in third step is potassium carbonate.
5. according to the method described in claim 3, it is characterized in that, alkali described in third step is potassium carbonate.
6. method described according to claim 1 or 2 or 5, which is characterized in that reaction dissolvent described in the 4th step is N, N- bis-
Methylformamide；The corresponding 5-8mL reaction dissolvent of every 0.1mmol compound 3.
7. according to the method described in claim 3, it is characterized in that, reaction dissolvent described in the 4th step is N, N- dimethyl methyl
Amide；The corresponding 5-8mL reaction dissolvent of every 0.1mmol compound 3.
8. according to the method described in claim 4, it is characterized in that, reaction dissolvent described in the 4th step is N, N- dimethyl methyl
Amide；The corresponding 5-8mL reaction dissolvent of every 0.1mmol compound 3.
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| JIAN-HUI LIU等: "Highly Regioselective Synthesis of 2,3,4-Trisubstituted 1H-Pyrroles: A Formal Total Synthesis of Lukianol A", 《J. ORG. CHEM.》 * |
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| CN109134342B (en) * | 2018-09-11 | 2021-08-20 | 大连理工大学 | Preparation method of 3, 4-disubstituted pyrrole |
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