CN110845423A - 一种1,2-取代苯并咪唑类化合物的制备方法 - Google Patents
一种1,2-取代苯并咪唑类化合物的制备方法 Download PDFInfo
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- -1 2-substituted benzimidazole compound Chemical class 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims abstract description 25
- IQQRAVYLUAZUGX-UHFFFAOYSA-N 1-butyl-3-methylimidazolium Chemical compound CCCCN1C=C[N+](C)=C1 IQQRAVYLUAZUGX-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 10
- 229910052751 metal Inorganic materials 0.000 claims abstract description 10
- 239000002184 metal Substances 0.000 claims abstract description 10
- 230000008569 process Effects 0.000 claims abstract description 9
- 150000003934 aromatic aldehydes Chemical class 0.000 claims abstract description 7
- 239000012429 reaction media Substances 0.000 claims abstract description 6
- 239000007809 chemical reaction catalyst Substances 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 238000009833 condensation Methods 0.000 abstract description 28
- 230000005494 condensation Effects 0.000 abstract description 28
- 238000005859 coupling reaction Methods 0.000 abstract description 28
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 230000003197 catalytic effect Effects 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 7
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 2
- 230000004913 activation Effects 0.000 abstract 1
- 238000003912 environmental pollution Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 42
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 230000008878 coupling Effects 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- LCFXRSKBJWQHON-UHFFFAOYSA-N 1-benzyl-2-phenylbenzimidazole Chemical compound C=1C=CC=CC=1C1=NC2=CC=CC=C2N1CC1=CC=CC=C1 LCFXRSKBJWQHON-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 6
- 150000001556 benzimidazoles Chemical class 0.000 description 5
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- UVMQRFWHAZDRCC-UHFFFAOYSA-N 2-(4-methylphenyl)-1-[(4-methylphenyl)methyl]benzimidazole Chemical compound C1=CC(C)=CC=C1CN1C2=CC=CC=C2N=C1C1=CC=C(C)C=C1 UVMQRFWHAZDRCC-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- QIIBJPKLEORIRR-UHFFFAOYSA-M 1-ethyl-3-methylimidazol-3-ium;1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate Chemical compound CC[N+]=1C=CN(C)C=1.[O-]S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F QIIBJPKLEORIRR-UHFFFAOYSA-M 0.000 description 2
- BOEYUPXPCHEKSH-UHFFFAOYSA-N 2-(2-methoxyphenyl)-1-[(2-methoxyphenyl)methyl]benzimidazole Chemical compound COC1=CC=CC=C1CN1C2=CC=CC=C2N=C1C1=CC=CC=C1OC BOEYUPXPCHEKSH-UHFFFAOYSA-N 0.000 description 2
- GUAGBLGYTHNENO-UHFFFAOYSA-N 2-(2-nitrophenyl)-1-[(2-nitrophenyl)methyl]benzimidazole Chemical compound [O-][N+](=O)C1=CC=CC=C1CN1C2=CC=CC=C2N=C1C1=CC=CC=C1[N+]([O-])=O GUAGBLGYTHNENO-UHFFFAOYSA-N 0.000 description 2
- VNPLFUKISOPQID-UHFFFAOYSA-N 2-(4-fluorophenyl)-1-[(4-fluorophenyl)methyl]benzimidazole Chemical compound C1=CC(F)=CC=C1CN1C2=CC=CC=C2N=C1C1=CC=C(F)C=C1 VNPLFUKISOPQID-UHFFFAOYSA-N 0.000 description 2
- YDUZZETWBAQFAY-UHFFFAOYSA-N 2-(4-methoxyphenyl)-1-[(4-methoxyphenyl)methyl]benzimidazole Chemical compound C1=CC(OC)=CC=C1CN1C2=CC=CC=C2N=C1C1=CC=C(OC)C=C1 YDUZZETWBAQFAY-UHFFFAOYSA-N 0.000 description 2
- QMOHHWDLZNVTJO-UHFFFAOYSA-N 2-(4-propan-2-ylphenyl)-1-[(4-propan-2-ylphenyl)methyl]benzimidazole Chemical compound C1=CC(C(C)C)=CC=C1CN1C2=CC=CC=C2N=C1C1=CC=C(C(C)C)C=C1 QMOHHWDLZNVTJO-UHFFFAOYSA-N 0.000 description 2
- LVNWRCUZCYLLND-UHFFFAOYSA-N 2-bromo-1-ethyl-3-methyl-2h-imidazole Chemical compound CCN1C=CN(C)C1Br LVNWRCUZCYLLND-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000002608 ionic liquid Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- NJMWOUFKYKNWDW-UHFFFAOYSA-N 1-ethyl-3-methylimidazolium Chemical compound CCN1C=C[N+](C)=C1 NJMWOUFKYKNWDW-UHFFFAOYSA-N 0.000 description 1
- DTPNNAHLVMHKGI-UHFFFAOYSA-N 2-(2-chlorophenyl)-1-[(2-chlorophenyl)methyl]benzimidazole Chemical compound ClC1=CC=CC=C1CN1C2=CC=CC=C2N=C1C1=CC=CC=C1Cl DTPNNAHLVMHKGI-UHFFFAOYSA-N 0.000 description 1
- RQJPMQCTRFMZIH-UHFFFAOYSA-N 2-(4-nitrophenyl)-1-[(4-nitrophenyl)methyl]benzimidazole Chemical compound C1=CC([N+](=O)[O-])=CC=C1CN1C2=CC=CC=C2N=C1C1=CC=C([N+]([O-])=O)C=C1 RQJPMQCTRFMZIH-UHFFFAOYSA-N 0.000 description 1
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 description 1
- HGGLDADJQQPKKC-UHFFFAOYSA-N 2-butyl-1-methylimidazole Chemical compound CCCCC1=NC=CN1C HGGLDADJQQPKKC-UHFFFAOYSA-N 0.000 description 1
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 1
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 1
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical class [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical class [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- WTWBUQJHJGUZCY-UHFFFAOYSA-N cuminaldehyde Chemical compound CC(C)C1=CC=C(C=O)C=C1 WTWBUQJHJGUZCY-UHFFFAOYSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002506 iron compounds Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0278—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre
- B01J31/0281—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member
- B01J31/0284—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member of an aromatic ring, e.g. pyridinium
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
- B01J2231/4283—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using N nucleophiles, e.g. Buchwald-Hartwig amination
-
- 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)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种以1‑丁基‑3‑甲基咪唑六氟磷酸盐([BMIm][PF6])为反应介质,无金属和酸条件下邻苯二胺和芳香醛通过缩合偶联反应合成一系列1,2‑取代苯并咪唑类化合物的方法。本发明的合成工艺简单,使用[BMIm][PF6]作为反应催化剂,具有较高的催化产率;不需要使用任何酸或金属催化剂,降低了合成工艺的成本,避免了药物合成中的重金属残留的问题,与传统有机溶剂相比,减少了对环境的污染,同时[BMIm][PF6]反应体系无需活化就可以重复使用6次,仍然具有较好的反应活性实现了1,2‑取代苯并咪唑化合物的绿色合成。
Description
技术领域
本发明属于有机合成领域,具体涉及一种1,2-取代苯并咪唑类 化合物的制备方法。
背景技术
苯并咪唑衍生物是一类含有两个氮原子的苯并杂环化合物,是多 种药物的结构单元。由于苯并咪唑衍生物具有多样的生物活性,而被 广泛应用于临床医学:例如抗溃疡,抗高血压,抗病毒,抗真菌,抗癌 等药物。同时,苯并咪唑衍生物在光学性能也有较好表现。基于苯并 咪唑衍生物有着良好的实际应用价值,它的合成方法已经成为有机合 成研究的焦点之一。1,2-取代苯并咪唑类衍生物的传统合成方法主要 是通过1,2-苯二胺和醛缩偶联合来实现。该缩合偶联反应一般是在 酸、金属或其他助剂的条件下才能实现合成目标(反应式I)。
例如,Salehi研究小组报道了在酸性条件下邻苯二胺与芳香醛的 缩合偶联反应表现出高选择性。2016年,Manesh研究小组在无溶剂 条件下,以铁化合物为催化剂,实现了1,2-苯二胺与芳醛的缩合偶联。 虽然这些方法为合成1,2-取代苯并咪唑化合物提供了有效的途径,并 取得了好的催化效率,但也存在一些不足,例如酸、金属催化剂的使 用、反应体系不能循环,这些都会影响该缩合偶联反应在工业过程中 的实际应用价值。因此,发现一些简单、绿色、可循环的合成方法, 仍然是这一研究领域的良好策略。
发明内容
本发明的目的是提供一种在1-丁基-3-甲基咪唑六氟磷酸盐 ([BMIm][PF6])中,无需任何酸或金属催化剂的条件下,由1,2-苯二 胺衍生物与芳醛合成1,2-取代苯并咪唑的衍生物,并能够得到较高收 率(反应式I)。
其中,R1表示给电子基团或者吸电子基团,优选为氢、C1-C6烷基、 C1-C6烷氧基、卤代C1-C6烷基、C3-C6环烷基、羟基、氰基、C1-C6烷基 氨基、二(C1-C6烷基)NH、三(C1-C6烷基)N、卤素、磺酸基、硝基、(C 1-C6烷基)C(O)-、(C1-C6烷基)C(O)O-;
其中,m表示为0、1、2、3的正数;
其中,Ar表示被选自0、1、2、3个R2取代的苯基、吡啶基或者呋 喃基;其中R2表示给电子基团或者吸电子基团,优选为氢、C1-C6烷基、 C1-C6烷氧基、卤代C1-C6烷基、羟基、氰基、C1-C6烷基氨基、二(C1- C6烷基)NH、三(C1-C6烷基)N、卤素、磺酸基、硝基、(C1-C6烷基)C(O)-、(C1-C6烷基)C(O)O-。
在本发明的优选技术方案中,其中R1优选为氢;
在本发明的优选技术方案中,其中Ar优选为苯基;
在本发明的优选技术方案中,其中反应温度优选为100-130℃, 更优选为120℃;
在本发明的优选技术方案中,其中反应物1,2-苯二胺衍生物与芳 香醛类化合物的用量摩尔比约为1:2;
在本发明的优选技术方案中,其中反应物1,2-苯二胺衍生物与[B MIm][PF6]催化剂的用量摩尔比为1:3;
除此之外,本发明的催化剂[BMIm][PF6]还可以重复循环使用, 并且经循环时候后,依然保持较高的催化活性。
在本发明的定义中C1-C6烷基是表示具有1、2、3、4、5、6个碳原 子的直链或支链烷基,包括但不限于甲基、乙基、正丙基、异丙基、 正丁基、异丁基、叔丁基、正戊基、异戊基等。
本发明具有如下优点:
1、合成工艺简单,使用[BMIm][PF6]作为反应催化剂,具有较高的 催化产率;
2、不需要使用任何酸或金属催化剂,降低了合成工艺的成本,避 免了药物合成中的重金属残留的问题;
3、[BMIm][PF6]的难挥发性与传统有机溶剂相比,减少了对环境的 污染,实现了1,2-取代苯并咪唑化合物的绿色合成。
4、实现催化剂重复利用的一般做法是将催化剂固定在惰性载体上, 从而提高催化剂的利用效率。固载催化剂制备是一个多步骤、 繁琐的工艺过程,且制备过程中容易引入新的杂质,这就限制 了它们的实际应用价值。本文在无负载的条件下,以对甲基苯 甲醛和1,2-苯二胺为研究对象,探索了[BMIm][PF6]循环使用的 情况,实验结果表明,当[BMIm][PF6]循环使用了6次后,[BMI m][PF6]仍然具有良好的反应活性。
具体实施方式
1实验部分
1.1仪器与试剂
熔点仪:WRS-1B;核磁共振仪:Bruker AVANCEⅢHD 400。
所用的药品和试剂均为市售的分析纯或化学纯,未进一步处理。 柱层析使用300~400目硅胶。
1.2 1,2-取代苯并咪唑类化合物的合成
(1)1-苄基-2-苯基苯并咪唑的合成(3a)
在反应管中加入1,2-苯二胺(1mmol)、苯甲醛(2.05mmol)和[B MIm][PF6](1.0克),在120℃油浴下反应,TLC跟踪反应,反应完 成后,冷却降至室温,加入饱和食盐水15mL,用乙酸乙酯萃取(10 mL×3),分液,有机相用无水MgSO4干燥,过滤后,减压蒸去乙酸乙 酯得粗产物,经柱色谱分离得到目标产物3a。
(2)1-(4-甲基苄基)-2-(4-甲基苯基)苯并咪唑(3b)的合成
在反应管中加入1,2-苯二胺(1mmol)、对甲基苯甲醛(2.05mm ol)和[BMIm][PF6](1.0克),在120℃油浴下反应,TLC跟踪反应。 反应完成后,冷却降至室温,加入饱和食盐水15mL,用乙酸乙酯萃 取(10mL×3),分液,有机相用无水MgSO4干燥,过滤后,减压蒸去 有机溶剂得粗产物,经柱色谱分离得到目标产物3b。
2、结果与讨论
2.1不同催化剂的类型对缩合偶联反应的影响
以1,2-苯二胺(1a)(1mmol)与苯甲醛(2a)(2.05mmol)为缩 合偶联反应模板,在无金属或酸的条件下,在120℃反应条件下研究 了离子液体(3mmol)的类型对缩合偶联反应的影响(如表1所示)。 其中,1-丁基-3-甲基咪唑六氟磷酸盐[BMIm][PF6]表现出最好的反应 活性(比较7)。当溴化四丁基铵、1-丁基-3-甲基咪唑四氟硼酸盐、溴 化-1-乙基-3-甲基咪唑、1-乙基-3-甲基咪唑九氟丁磺酸盐、1-乙基-3- 甲基咪唑双三氟甲磷酰亚胺盐作为反应介质时,缩合偶联反应能够得 到中等左右的收率(比较例2-5,8),当使用1-磺酸丁基-3-甲基咪唑内 盐和1-丁基-3-甲基咪唑四氟化铁盐为反应介质时,缩合偶联反应几 乎得不到目标产物(比较例1,6)。
表1不同催化剂的类型对缩合偶联反应的影响
比较例 | 离子液 | 产率 |
1 | 1-磺酸丁基-3-甲基咪唑内盐 | 无产物 |
2 | 四丁基溴化铵 | 51% |
3 | 1-丁基-3-甲基咪唑四氟硼酸盐 | 65% |
4 | 溴化-1-乙基-3-甲基咪唑 | 48% |
5 | 1-乙基-3-甲基咪唑九氟丁磺酸盐 | 58% |
6 | 1-丁基-3-甲基咪唑四氟化铁盐 | 无产物 |
7 | 1-丁基-3-甲基咪唑六氟磷酸盐 | 80% |
8 | 1-乙基-3-甲基咪唑双三氟甲磷酰亚胺盐 | 48% |
2.2不同反应温度对缩合偶联反应的影响
以1,2-苯二胺(1a)(1mmol)与苯甲醛(2a)(2.05mmol)为缩合 偶联反应模板,在无金属或酸的条件下,研究了反应温度对1-丁基- 3-甲基咪唑六氟磷酸盐[BMIm][PF6](3mmol)对催化缩合偶联反应的 影响(反应结果如表2所示),当反应温度为100℃和130℃时,缩合 偶联产率分别下到62%和49%。
表2反应对缩合偶联反应的影响
比较例 | 反应温度 | 产率 |
7 | 120℃ | 80% |
8 | 100℃ | 62% |
9 | 130℃ | 49% |
结论:通过对比试验可以看出,以1,2-苯二胺(1a)(1mmol) 与苯甲醛(2a)(2.05mmol)为缩合偶联反应模板,在无金属或酸的条 件下,在120℃反应条件下以1-丁基-3-甲基咪唑六氟磷酸盐作为催化 剂时对缩合偶联的产率最佳。
2.3 1-丁基-3-甲基咪唑六氟磷酸盐作为催化剂催化不同反应底物的 缩合偶联
以1,2-苯二胺(1mmol)与不同芳香醛(2.05mmol)为反应 底物,在无金属或酸的条件下,以1-丁基-3-甲基咪唑六氟磷酸盐 [BMIm][PF6](3mmol)作为催化剂,在反应温度为120℃下对催化 缩合偶联反应的影响(反应结果如表3所示)
表3不同反应底物的缩合偶联
比较例 | 芳香醛类型 | 产率 |
10 | 对甲基苯甲醛 | 65% |
11 | 4-异丙基苯甲醛<sup>3c</sup> | 73% |
12 | 4-甲氧基苯甲醛<sup>3d</sup> | 78% |
13 | 2-甲氧基苯甲醛<sup>3e</sup> | 58% |
14 | 4-氯苯甲醛<sup>3f</sup> | 60% |
15 | 2-氯苯甲醛<sup>3g</sup> | 52% |
16 | 4-氟苯甲醛<sup>3h</sup> | 62% |
17 | 4-硝基苯甲醛<sup>3i</sup> | 50% |
18 | 2-硝基苯甲醛<sup>3j</sup> | 36% |
19 | 呋喃醛<sup>3k</sup> | 58% |
20 | 吡啶-2-甲醛<sup>3l</sup> | 55% |
在最佳的反应介质[BMIm][PF6]中,选择了一系列醛与1,2-苯二 胺进行缩合偶联反应,实验结果见表3。在[BMIm][PF6]的条件下,含 有吸电子基团醛的反应活性比含有给电子基团醛要差(比较例10-比 较例18)。例如,当含有异丙基时,缩合偶联产率可达78%(比较例 11),可是当含有硝基时,产率下降到50%(比较例17-比较例18)。 当取代基位于邻位时,由于位阻效应,不管是吸电子还是给电子的醛 进行缩合偶联反应时,产率都有所下降。另外,芳香环上含有杂原子 的醛也能和1,2-苯二胺发生缩合偶联,产率也能够达到中等以上(比 较例19-20)。
2.4[BMIm][PF6]在缩合偶联反应中循环使用
在反应管中加入1,2-苯二胺(1mmol)、苯甲醛(2.05mmol)和 [BMIm][PF6](2.0克),在120℃油浴下反应,TLC跟踪反应.反应完 成后,冷却降至室温,用石油醚/乙酸乙酯萃取(石油醚∶乙酸乙酯 =5∶1,10mL×6),将石油醚/乙酸乙酯有机相用无水MgSO4干燥,过滤后,减压蒸去溶剂得粗产物,经柱色谱分离得到目标产物1-苄基-2- 苯基苯并咪唑。将被萃取后的反应体系加热去掉残留石油醚/乙酸乙 酯,冷却至室温,往反应管中继续加入1,2-苯二胺(1mmol)和苯甲醛 (2.05mmol)进行下一次缩合偶联反应。结果如表4所示,从表4可以 看出,经6次循环使用后,[BMIm][PF6]在催化1,2-苯二胺与对甲基 苯甲醛制备1-苄基-2-苯基苯并咪唑的反应中能够保持较高的催化活 性。
表4探索[BMIm][PF6]在缩合偶联反应中循环使用的情况
比较例 | 1a | 2b | 3b | 4b | 5b | 6b |
产率 | 78% | 77% | 75% | 75% | 74% | 72% |
3、产物结构标征
1-苄基-2-苯基苯并咪唑(3a):白色固体,收率80%,m.p.130~13 1℃;1H NMR(400MHz,CDCl3)δ:7.89(d,J=8.0Hz,1H),7.7 0~7.67(m,2H),7.47~7.42(m,3H),7.34~7.28(m,4H),7.25~7. 19(m,2H),7.11~7.08(m,2H),5.44(s,2H);13C NMR(100MH z,CDCl3)δ:154.1,143.0,136.3,136.0,130.0,129.9,129.2,129.0, 128.7,127.7,125.9,123.0,122.7,119.9,110.5,48.3。
1-(4-甲基苄基)-2-(4-甲基苯基)苯并咪唑(3b):白色固体,收率6 5%,m.p.124~125℃;1H NMR(400MHz,CDCl3)δ:7.77(d,J= 8.0Hz,1H),7.50(d,J=8.0Hz,2H),7.22~7.09(m,5H),7.03(d, J=8.0Hz,2H),6.90(d,J=8.0Hz,2H),5.30(s,2H),2.31(s,3H),2.23(s,3H);13C NMR(100MHz,CDCl3)δ:154.2,143.1,134.0, 137.4,136.0,133.4,129.6,129.4,129.1,127.1,125.8,122.8,122.5, 119.7,110.4,48.1,21.4,21.0。
1-(4-异丙基苄基)-2-(4-异丙基苯基)苯并咪唑(3c):白色固体,收 率73%,m.p.175~176℃;1H NMR(400MHz,DMSO)δ:7.72~7. 66(m,3H),7.42~7.38(m,3H),7.25~7.18(m,2H),7.15(d,J=8. 0Hz,2H),6.92(d,J=8.0Hz,2H),5.53(s,2H),2.99~2.92(m,1H),2.84~2.78(m,1H),1.23(d,J=6.8Hz,6H),1.13(d,J=6.8H z,6H);13C NMR(100MHz,DMSO)δ:153.3,150.2,147.6,142.7, 135.9,134.3,129.0,127.7,126.8,126.7,126.0,122.5,122.1,119. 1,111.1,47.2,33.3,33.0,23.7,23.6。
1-(4-甲氧基苄基)-2-(4-甲氧基苯基)-苯并咪唑(3d):白色固体,收 率78%,m.p.128~130℃;1H NMR(400MHz,DMSO)δ:7.69~7. 67(m,3H),7.45~7.42(m,1H),7.24~7.18(m,2H),7.09(d,J=8.6 Hz,2H),6.94(d,J=8.6Hz,2H),6.84(d,J=8.6Hz,2H),5.49(s,2H),3.82(s,3H),3.68(s,3H);13C NMR(100MHz,DMSO) δ:160.4,158.5,153.2,142.7,135.8,130.5,128.8,127.4,122.4,12 2.3,122.0,119.0,114.2,114.2,111.0,55.3,55.0,46.9。
1-(2-甲氧基苄基)-2-(2-甲氧基苯基)苯并咪唑(3e):白色固体,收 率58%,m.p.152~153℃;1H NMR(400MHz,DMSO)δ:7.69~7. 67(m,1H),7.53~7.49(m,1H),7.44~7.42(m,1H),7.37~7.35 (m,1H),7.22~7.15(m,4H),7.07(t,J=7.4Hz,1H),6.91(d,J=8. 2Hz,1H),6.75(t,J=7.4Hz,1H),6.59(d,J=6.8Hz,1H),5.22(s, 2H),3.67(s,3H),3.66(s,3H);13C NMR(100MHz,DMSO)δ: 157.1,156.4,151.9,142.9,135.2,131.9,131.6,128.7,127.5,124.2, 122.2,121.6,120.5,120.1,119.5,119.1,111.5,110.9,110.7,55.3, 55.3,42.8。
1-(4-氯苄基)-2-(4-氯苯基)苯并咪唑(3f):白色固体,收率60%,m. p.136~138℃;1H NMR(400MHz,DMSO)δ:7.75~7.72(m,3 H),7.59(d,J=8.4Hz,2H),7.49~7.47(m,1H),7.35(d,J=8.4 Hz,2H),7.29~7.23(m,2H),7.02(d,J=8.4Hz,2H),5.59(s,2H); 13CNMR(100MHz,DMSO)δ:152.0,142.6,135.9,135.8,134.8, 132.1,130.7,128.9,128.8,128.7,128.0,123.0,122.4,119.4,111. 0,46.8。
1-(2-氯苄基)-2-(2-氯苯基)苯并咪唑(3g):白色固体,收率52%, m.p.155~156℃;1H NMR(400MHz,DMSO)δ:7.79~7.70(m, 1H),7.61(dd,J=8.0,0.8Hz,1H),7.56~7.52(m,1H),7.51~7.47 (m,2H),7.44~7.36(m,2H),7.31~7.22(m,3H),7.17~7.13(m, 1H),6.65(dd,J=7.8,1.2Hz,1H),5.42(s,2H);13C NMR(100M Hz,DMSO)δ:150.9,142.5,135.0,133.4,133.2,132.3,131.9,131. 7,129.8,129.5,129.4,128.3,127.5,127.4,123.2,122.4,119.7,11 1.0,45.2。
1-(4-氟苄基)-2-(4-氟苯基)苯并咪唑(3h):白色固体,收率62%, m.p.110~111℃;1H NMR(400MHz,DMSO)δ:7.78~7.20(m, 3H),7.50~7.47(m,1H),7.36(t,J=8.8Hz,2H),7.28~7.22(m,2 H),7.13~7.08(m,2H),7.05~7.01(m,2H),5.56(s,2H);13C N MR(100MHz,DMSO)δ:163.4(d,J=156.2Hz),161.0(d,J=152. 2Hz),152.3,142.6,135.8,133.0(d,J=3.0Hz),131.4(d,J=8.4 Hz),128.2(d,J=8.4Hz),126.6(d,J=3.0Hz),122.8,122.3,119.3, 115.9(d,J=21.6Hz),115.6(d,J=21.6Hz),111.1,46.8。
1-(4-硝基苄基)-2-(4-硝基苯基)苯并咪唑(3i):黄色固体,收率5 0%,m.p.185~187℃;1H NMR(400MHz,CDCl3)δ:8.31(d,J= 8.8Hz,2H),8.23(d,J=8.8Hz,2H),7.93(d,J=8.0Hz,1H),7.84 (d,J=8.8Hz,2H),7.42~7.36(m,2H),7.34~7.20(m,3H),5.58 (s,2H);13C NMR(100MHz,CDCl3)δ:151.3,148.7,147.9,143.0, 142.8,135.8,135.6,130.0,126.7,124.6,124.1,123.9,120.7,110. 2,48.0。
1-(2-硝基苄基)-2-(2-硝基苯基)苯并咪唑(3j):黄色固体,收率3 6%,m.p.169~171℃;1H NMR(400MHz,CDCl3)δ:8.15~8.11 (m,2H),7.84(d,J=8.0Hz,1H),7.68~7.65(m,2H),7.50~7.45 (m,3H),7.37~7.27(m,2H),7.14(d,J=8.0Hz,1H),6.94(d,J=7.6Hz,1H),5.69(s,2H);13C NMR(100MHz,CDCl3)δ:149.8,1 49.0,147.0,143.1,134.8,134.2,133.2,132.0,131.4,131.3,128.9, 128.3,125.4,125.3,125.1,123.9,123.1,120.5,110.2,45.7。
1-(呋喃-2-甲基)-2-(呋喃-2-基)苯并咪唑(3k):淡黄色固体,收率5 8%,m.p.88~89℃;1H NMR(400MHz,DMSO)δ:8.01(d,J=0.8 Hz,1H),7.73(d,J=8.0Hz,1H),7.66(d,J=7.2Hz,1H),7.54(d, J=0.8Hz,1H),7.31~7.23(m,3H),6.76~6.75(m,1H),6.48(d, J=2.9Hz,1H),6.38~6.37(m,1H),5.77(s,2H);13C NMR(100 MHz,DMSO)δ:149.8,145.0,144.8,143.4,143.2,142.5,135.3,1 22.9,122.5,119.0,112.9,112.1,110.8,110.6,108.7,40.9。
1-(吡啶-2-甲基)-2-(吡啶-2-基)苯并咪唑(3l):淡黄色固体,收率5 5%,m.p.130~131℃;1H NMR(400MHz,CDCl3)δ:8.49~6.46 (m,2H),8.38(d,J=8.0Hz,1H),7.78~7.71(m,2H),7.38~7.35 (m,1H),7.27(d,J=8.0Hz,1H),7.22~7.16(m,3H),7.05~7.02 (m,1H),6.80(d,J=8.0Hz,1H),6.20(s,2H);13C NMR(100MH z,CDCl3)δ:157.4,150.3,149.8,149.1,148.6,142.6,136.8,136.7 8,136.7,124.5,123.8,123.7,122.9,122.2,120.9,120.0,110.7,51. 0。
上述实施例仅为充分说明本发明而列举的具体实施例,本发明的 保护范围以权利要求书的内容为准,而不限于上述具体实施方式。说 明书中公开的所有内容,以及公开的所有方法和步骤,都可以任意组 合,除非这些特征和/或步骤是相互排斥的组合。说明书中公开每一个 技术特征,除非另有说明,都可以被实现相同、等同或类似目的的技 术特征所替换。因此,除非另有说明,本发明公开的每个技术特征仅 是通常系列中的等同或类似的技术特征的一个实例。本领域的技术人 员在本发明基础上所作的不脱离本发明实质内容的等同替代或变换, 亦均在本发明的保护范围之内。而这样的修改亦均在本发明的保护范 围之内。本申请引用的每个参考文献在此均引用其全文。
Claims (7)
1.一种无需任何酸或金属催化剂的条件下由1,2-苯二胺衍生物与芳醛制备1,2-取代苯并咪唑的衍生物的方法,其特征在于:所述方法是在1-丁基-3-甲基咪唑六氟磷酸盐([BMIm][PF6])作为反应介质和催化剂下进行的,
其中,R1表示给电子基团或者吸电子基团,优选为氢、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C3-C6环烷基、羟基、氰基、C1-C6烷基氨基、二(C1-C6烷基)NH、三(C1-C6烷基)N、卤素、磺酸基、硝基、(C 1-C6烷基)C(O)-、(C1-C6烷基)C(O)O-;
其中,m表示为0、1、2、3的正数;
其中,Ar表示被选自0、1、2、3个R2取代的苯基、吡啶基或者呋喃基;其中R2表示给电子基团或者吸电子基团,优选为氢、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、羟基、氰基、C1-C6烷基氨基、二(C1-C6烷基)NH、三(C1-C6烷基)N、卤素、磺酸基、硝基、(C1-C6烷基)C(O)-、(C1-C6烷基)C(O)O-。
2.如权利要求1所述的方法,其中R1优选为氢。
3.如权利要求1所述的方法,其中Ar表示苯基。
4.如权利要求1所述的方法,其中反应温度优选为100-130℃,更优选为120℃。
5.如权利要求1-4任一项所述的方法,其中反应物1,2-苯二胺衍生物与芳香醛类化合物的用量摩尔比约为1:2。
6.如权利要求1-4任一项所述的方法,其中反应物1,2-苯二胺衍生物与[BMIm][PF6]催化剂的用量摩尔比为1:3。
7.如权利要求1-6任一项所述的方法,其中,所述的反应介质和催化剂[BMIm][PF6]可以循环利用。
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