CN115785092A - Method for preparing beta-carboline compound by iodine catalytic oxidation method - Google Patents
Method for preparing beta-carboline compound by iodine catalytic oxidation method Download PDFInfo
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- CN115785092A CN115785092A CN202211448653.7A CN202211448653A CN115785092A CN 115785092 A CN115785092 A CN 115785092A CN 202211448653 A CN202211448653 A CN 202211448653A CN 115785092 A CN115785092 A CN 115785092A
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- carboline
- catalytic oxidation
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- AIFRHYZBTHREPW-UHFFFAOYSA-N cis-beta-Carboline Acid Natural products N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 238000000034 method Methods 0.000 title claims abstract description 43
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229910052740 iodine Inorganic materials 0.000 title claims abstract description 32
- 239000011630 iodine Substances 0.000 title claims abstract description 32
- -1 beta-carboline compound Chemical class 0.000 title claims abstract description 22
- 230000003197 catalytic effect Effects 0.000 title claims abstract description 16
- 230000003647 oxidation Effects 0.000 title claims abstract description 16
- 238000007254 oxidation reaction Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 139
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract description 16
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical class C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 102
- 239000002904 solvent Substances 0.000 claims description 41
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- 238000001816 cooling Methods 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 21
- 239000003208 petroleum Substances 0.000 claims description 17
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 15
- 238000004440 column chromatography Methods 0.000 claims description 15
- 239000003480 eluent Substances 0.000 claims description 15
- 238000000605 extraction Methods 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 238000013375 chromatographic separation Methods 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 14
- 230000008569 process Effects 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000002994 raw material Substances 0.000 description 28
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- 238000004809 thin layer chromatography Methods 0.000 description 26
- 238000012544 monitoring process Methods 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical class C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 13
- 229940125782 compound 2 Drugs 0.000 description 13
- 239000012043 crude product Substances 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 13
- 239000005457 ice water Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 12
- 238000004821 distillation Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 2
- IZGDXVLRMHXOJV-SFHVURJKSA-N (3s)-4-[2-[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]ethyl-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1CCP(O)(=O)C[C@@H](O)CC(O)=O IZGDXVLRMHXOJV-SFHVURJKSA-N 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 description 2
- 229940125796 compound 3d Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229930005303 indole alkaloid Natural products 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 2
- 229960000835 tadalafil Drugs 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 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 description 1
- WHQUHTXULUACFD-KRWDZBQOSA-N (3s)-4-[[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]methoxy-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1COP(O)(=O)C[C@@H](O)CC(O)=O WHQUHTXULUACFD-KRWDZBQOSA-N 0.000 description 1
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
- NSBVOLBUJPCPFH-UHFFFAOYSA-N 5h-pyrido[3,2-b]indole Chemical compound C1=CN=C2C3=CC=CC=C3NC2=C1 NSBVOLBUJPCPFH-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000234435 Lilium Species 0.000 description 1
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- BWPHZMZTAXRILJ-UHFFFAOYSA-N [Se].C(=O)=O Chemical compound [Se].C(=O)=O BWPHZMZTAXRILJ-UHFFFAOYSA-N 0.000 description 1
- RLFKILXOLJVUNF-UHFFFAOYSA-N abecarnil Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OCC1=CC=CC=C1 RLFKILXOLJVUNF-UHFFFAOYSA-N 0.000 description 1
- 229950000552 abecarnil Drugs 0.000 description 1
- DORMTBIPKNPJPY-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.IC1=CC=CC=C1 DORMTBIPKNPJPY-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 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 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 1
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a method for preparing beta-carboline compounds by an iodine catalytic oxidation method, which relates to the technical field of carboline compound synthesis and comprises the following steps: the tryptamine derivative and aldehyde are subjected to a Pictet-Schpengler (Pictet-Spengler) reaction to obtain a beta-tetrahydrocarboline compound, and the intermediate is not required to be separated; and then, reacting at 85-120 ℃ for 12-20h by using iodine as a catalyst and dimethyl sulfoxide (DMSO) as a reaction solvent in the air atmosphere to obtain the beta-carboline compound, wherein the reaction conditions adopted by the synthetic route are mild, the operation steps and the post-treatment process are simple, the product yield is high, and the total yield of the reaction is 38% -78%.
Description
Technical Field
The invention relates to the technical field of synthesis of carboline compounds, in particular to a method for preparing beta-carboline compounds by an iodine catalytic oxidation method.
Background
The beta-carboline (carboline) alkaloid is a compound with a tricyclic framework structure of indolopyridine, and belongs to tryptamine indole alkaloids. Beta-carbolines are a large group of naturally occurring or synthetic indole alkaloids with varying degrees of aromaticity, which are widely distributed in the natural world, including various plants, marine organisms, and human tissues and fluids, and have a variety of biological activities, including sedation, anxiolysis, anti-tumor, anti-viral, anti-hypnotic, anti-parasitic, anti-bacterial, and therapeutic sexual dysfunction. For example, tadalafil (Tadalafil), also known as siei or schiz, is a selective and reversible cyclic guanosine monophosphate specific phosphodiesterase 5 inhibitor, which was developed by foley corporation as a primary drug, and is used to solve the problem of male erectile dysfunction, has the characteristics of rapid onset of action and long duration of drug effect, and is not affected by high-fat diet and alcohol intake. After that, the lilies filed for two indications for the treatment of pulmonary hypertension and for the treatment of benign prostatic hyperplasia. Ebencaril (Abecarnil) is also a beta-carboline drug for the treatment of anxiety disorders, and has significant anxiolytic and anticonvulsant activity.
Previously, the most common synthetic strategies for β -carbolines were: the beta-tetrahydrocarboline compound is prepared in advance and then is prepared through oxidative dehydrogenation. The series of reactions are mostly carried out in the presence of transition metals (palladium, iron, copper, etc.) or under the condition of a large amount of oxidants (selenium carbon dioxide, manganese dioxide, sulfur, common oxidants, 2-iodoxybenzoic acid, N-bromosuccinimide, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, iodobenzene acetate, etc.). The reaction conditions are harsh, and therefore, a new method for preparing the beta-carboline compound is needed.
Disclosure of Invention
The invention aims to provide a method for preparing beta-carboline compounds by an iodine catalytic oxidation method, which has the advantages of mild reaction conditions, short reaction steps, higher reaction yield and simple operation steps and post-treatment process.
In order to achieve the purpose, the invention provides the following scheme:
the invention provides a method for preparing beta-carboline compounds by an iodine catalytic oxidation method, which comprises the following steps: the tryptamine derivatives and the aldehyde compounds are subjected to a Pictet-Spengler reaction (Pictet-Spengler) to obtain an intermediate beta-tetrahydrocarboline compound, and the intermediate is not required to be separated; and then, reacting for 12-20h at 85-120 ℃ by taking iodine as a catalyst and dimethyl sulfoxide (DMSO) as a reaction solvent to prepare the beta-carboline compound.
In the synthetic method, the catalyst is iodine, the dosage is 5.0mol percent, the dosage is less, and the oxidant is air, so the synthetic method is green and environment-friendly.
Further, the reaction route of the method for preparing the beta-carboline compound by the iodine catalytic oxidation method is as follows: .
R 2 = H, phenyl, C,
Or meta-or para-substituted phenyl, wherein the substituents are independently selected from Me, et, F, br, cl, CF 3 Or OMe.
Further, the reaction was carried out under an air atmosphere.
Further, the formula of the tryptamine derivative is as follows:
(ii) a Wherein R is 1 ＝CO 2 Me，CO 2 Et，H。
Further, the aldehyde compound has a structural formula of R 2 CHO; wherein R is 2 = H, phenyl, C,
Or meta-or para-substituted phenyl, wherein the substituents are independently selected from Me, et, F, br, cl, CF 3 Or OMe.
Further, the mass ratio of the tryptamine derivative to the aldehyde compound is 1: 1.1.
Furthermore, after the reaction is finished, the method also comprises the processes of extraction, drying and column chromatography separation.
Further, the extraction specifically comprises the following steps: after the reaction is finished, cooling to room temperature, adding a saturated sodium thiosulfate solution, extracting with ethyl acetate, repeatedly extracting for 3 times, and combining organic layer solutions to obtain an extract liquid;
the volume ratio of the saturated sodium thiosulfate solution to the ethyl acetate is 1.
Further, the drying is performed by drying the extract with anhydrous sodium sulfate and then evaporating the solvent.
Further, the eluent in the column chromatographic separation is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2:1.
the invention discloses the following technical effects:
1. the reaction condition is mild, a transition metal catalyst is not needed, the reaction is carried out at the temperature of 85-120 ℃, the energy consumption is low, the environment protection is facilitated, and the large-scale preparation of the beta-carboline compound is facilitated.
2. The reaction has better atom economy, high product yield and total reaction yield of 38-78%.
3. The synthetic route is short, and the reaction operation process is simple.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but rather as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every intervening value, to the extent any stated value or intervening value in a stated range, and any other stated or intervening value in a stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The description and examples are intended to be illustrative only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.
In the examples of the invention, the raw materials are all commercially available.
The reaction route of the method for preparing the beta-carboline compound by the iodine catalytic oxidation method is as follows:
R 2 = H, phenyl, C,
Or meta-or para-substituted phenyl, wherein the substituents are independently selected from Me, et, F, br, cl, CF 3 Or OMe.
Adding a magnetic stirrer, tryptophan derivative 1 (0.2 mmol) and an aldehyde compound 2 (1.1 equiv.,0.22 mmol) into a 25mL reaction tube under the condition of air, adding anhydrous dichloromethane (3.0 mL), cooling the reaction to 0 ℃ in an ice water bath, slowly adding trifluoroacetic acid (2.5 equiv.,0.5mmol,38 μ L) at the speed of 20 μ L/min, continuing the reaction for 0.5h, then returning the reaction to room temperature, reacting for 12-20h (monitoring by thin layer chromatography), and after the raw materials are completely reacted, distilling under reduced pressure to remove the solvent to obtain a solid compound which is directly used for the next reaction. Under the condition of air, adding iodine (5.0 mol%,2.5 mg), dimethyl sulfoxide (DMSO) solvent (2.0 mL) and a magnetic stirrer into a 25mL reaction tube, then placing the reaction in an oil bath kettle at 85-120 ℃ for heating reaction for 12-20h (monitoring by thin layer chromatography), cooling the reaction tube to room temperature after the raw materials are completely reacted, then adding 4mL of saturated sodium thiosulfate solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent by reduced pressure distillation, and then separating the crude product by column chromatography (eluent, petroleum ether: ethyl acetate =1, volume ratio), thus obtaining the beta-carboline compound.
Example 1 Synthesis of beta-carbolines 3a (R) 1 ＝CO 2 Me；R 2 ＝ph)
Adding a magnetic stirrer, tryptophan derivative 1 (0.2 mmol) and an aldehyde compound 2 (1.1 equiv.,0.22 mmol) into a 25mL reaction tube under the condition of air, adding anhydrous dichloromethane (3.0 mL), cooling the reaction to 0 ℃ in an ice water bath, slowly adding trifluoroacetic acid (2.5 equiv.,0.5mmol,38 μ L) at the speed of 20 μ L/min, continuing the reaction for 0.5 hour, then returning the reaction to room temperature, reacting for 12 hours (monitoring by thin layer chromatography), and after the raw materials are completely reacted, distilling under reduced pressure to remove the solvent to obtain a solid compound which is directly used for the next reaction. In a 25mL reaction tube under the condition of air, adding iodine (5.0 mol%,2.5 mg), a DMSO solvent (2.0 mL) and a magnetic stirrer, then placing the reaction in an oil bath kettle at 120 ℃ for heating reaction for 12 hours (monitoring by thin layer chromatography), cooling the reaction tube to room temperature after the raw materials are completely reacted, then adding 4mL of a saturated sodium thiosulfate solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove the solvent, and then separating the crude product by column chromatography (eluent, petroleum ether: ethyl acetate =3, volume ratio), so as to obtain the beta-carboline compound 3a (43.5 mg, yield 72%). 1 H NMR(400MHz,CDCl 3 ):δ8.90(br,s,1H),8.88(s,1H),8.23-8.21(m,1H),7.93-7.90(m,2H),7.62-7.51(m,4H),7.48-7.43(m,1H),7.40-7.36(m,1H),4.05(s,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ):166.9,142.9,140.5,138.0,137.6,135.1,129.7,129.2,129.0,128.3,122.1,122.0,121.1,117.0,111.9,52.7.
Example 2 Synthesis of beta-carbolines 3bTo (R) 1 ＝CO 2 Me；R 2 = p-phenylmethyl group)
Adding a magnetic stirrer, a tryptophan derivative 1 (0.2 mmol) and an aldehyde compound 2 (1.1 equiv.,0.22 mmol) into a 25mL reaction tube under the condition of air, adding anhydrous dichloromethane (3.0 mL), cooling the reaction to 0 ℃ in an ice water bath, slowly adding trifluoroacetic acid (2.5 equiv.,0.5mmol,38 μ L) at the speed of 20 μ L/min, continuing the reaction for 0.5 hour, then returning the reaction to room temperature, reacting for 12 hours (monitoring by thin layer chromatography), and after the raw materials are completely reacted, distilling under reduced pressure to remove the solvent to obtain a solid compound which is directly used for the next reaction. In a 25mL reaction tube under the condition of air, adding iodine (5.0 mol%,2.5 mg), DMSO solvent (2.0 mL) and a magnetic stirrer, then placing the reaction in an oil bath kettle at 120 ℃ for heating reaction for 15 hours (monitoring by thin layer chromatography), cooling the reaction tube to room temperature after the raw materials are completely reacted, then adding 4mL of saturated sodium thiosulfate solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove the solvent, and then separating the crude product by column chromatography (eluent, petroleum ether: ethyl acetate =1, volume ratio) to obtain the beta-carboline compound 3b (44.1 mg, yield 70%). 1 H NMR(400MHz,DMSO-d 6 ):δ11.88(br,s,1H),8.90(s,1H),8.43-8.41(m,1H),7.94-7.92(m,2H),7.71-7.68(m,1H),7.62-7.58(m,1H),7.46-7.44(m,2H),7.35-7.31(m,1H),3.93(s,3H),2.45(s,3H)； 13 C{ 1 H}NMR(100MHz,DMSO-d 6 ):166.1,142.2,141.4,138.5,136.6,134.7,134.5,129.3,129.0,128.6,128.5,122.0,121.1,120.4,116.5,112.8,52.0,21.0.
Example 3 Synthesis of beta-carbolines 3c (R) 1 ＝CO 2 Me；R 2 = o-benzyl group)
Adding a magnetic stirrer, a tryptophan derivative 1 (0.2 mmol) and an aldehyde compound 2 (1.1 equiv.,0.22 mmol) into a 25mL reaction tube under the condition of air, adding anhydrous dichloromethane (3.0 mL), cooling the reaction to 0 ℃ in an ice water bath, slowly adding trifluoroacetic acid (2.5 equiv.,0.5mmol,38 μ L) at the speed of 20 μ L/min, continuing the reaction for 0.5 hour, then returning the reaction to room temperature, reacting for 12 hours (monitoring by thin layer chromatography), and after the raw materials are completely reacted, distilling under reduced pressure to remove the solvent to obtain a solid compound which is directly used for the next reaction. In a 25mL reaction tube under the condition of air, adding iodine (5.0 mol%,2.5 mg), DMSO solvent (2.0 mL) and a magnetic stirrer, then placing the reaction in an oil bath kettle at 120 ℃ for heating reaction for 16 hours (monitoring by thin layer chromatography), cooling the reaction tube to room temperature after the raw materials are completely reacted, then adding 4mL of saturated sodium thiosulfate solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove the solvent, and then separating the crude product by column chromatography (eluent, petroleum ether: ethyl acetate =1, volume ratio), so as to obtain the beta-carboline compound 3c (45.7 mg, yield 72%). 1 H NMR(400MHz,DMSO-d 6 ):δ11.90(br,s,1H),8.92(s,1H),8.44-8.42(m,1H),7.81-7.79(m,2H),7.71-7.69(m,1H),7.63-7.59(m,1H),7.55-7.51(m,1H),7.39-7.37(m,1H),7.35-7.31(m,1H),3.94(s,3H),2.48(s,3H)； 13 C{ 1 H}NMR(100MHz,DMSO-d 6 ):166.1,142.3,141.4,138.0,137.4,136.6,134.6,129.6,129.1,129.0,128.7,128.6,125.7,122.0,121.1,120.4,116.6,112.7,52.0,21.2.
Example 4 Synthesis of beta-carboline Compound 3d
Adding a magnetic stirrer, tryptophan derivative 1 (0.2 mmol) and aldehyde compound 2 (1.1 equiv.,0.22 mmol) into a 25mL reaction tube under the condition of air, adding anhydrous dichloromethane (3.0 mL), cooling the reaction to 0 ℃ in an ice-water bath, slowly adding trifluoroacetic acid (2.5 equiv.,0.5mmol,38 μ L) at the speed of 20 μ L/min, and continuing the reaction for 0.5hThen, the reaction is returned to room temperature for 12 hours (monitored by thin layer chromatography), and after the raw materials completely react, the solvent is removed by reduced pressure distillation to obtain a solid compound which is directly used for the next reaction. In a 25mL reaction tube, iodine (5.0 mol%,2.5 mg), DMSO solvent (2.0 mL) and a magnetic stirrer were added under air conditions, then the reaction was placed in an oil bath kettle at 100 ℃ for heating reaction for 18 hours (monitored by thin layer chromatography), after the reaction of the raw materials was completed, the reaction tube was cooled to room temperature, then 4mL of saturated sodium thiosulfate solution was added, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate, distillation under reduced pressure to remove the solvent, and then the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate =1, volume ratio), yielding β -carboline compound 3d (49.4 mg, yield 77%). 1 H NMR(400MHz,DMSO-d 6 ):δ11.98(br,s,1H),8.93(s,1H),8.44-8.42(m,1H),8.08-8.05(m,2H),7.70-7.68(m,1H),7.63-7.59(m,1H),7.50-7.45(m,2H),7.35-7.31(m,1H),3.93(s,3H)； 13 C{ 1 H}NMR(100MHz,DMSO-d 6 ):166.1,162.6(d,J＝244.4Hz),141.5,141.1,136.6,134.5,134.0(d,J＝2.9Hz),130.9(d,J＝8.3Hz),129.3,128.8,122.1,121.2,120.5,116.8,115.8(d,J＝21.4Hz),112.8,52.1； 19 F NMR(376MHz,DMSO-d 6 ):-112.56to-112.64(m,1F).
Example 5 Synthesis of beta-carbolines 3e
Adding a magnetic stirrer, a tryptophan derivative 1 (0.2 mmol) and an aldehyde compound 2 (1.1 equiv.,0.22 mmol) into a 25mL reaction tube under the condition of air, adding anhydrous dichloromethane (3.0 mL), cooling the reaction to 0 ℃ in an ice water bath, slowly adding trifluoroacetic acid (2.5 equiv.,0.5mmol,38 μ L) at the speed of 20 μ L/min, continuing the reaction for 0.5 hour, then returning the reaction to room temperature, reacting for 12 hours (monitoring by thin layer chromatography), and after the raw materials are completely reacted, distilling under reduced pressure to remove the solvent to obtain a solid compound which is directly used for the next reaction. In a 25mL reaction tube, iodine was added under air conditions(5.0 mol%,2.5 mg), DMSO solvent (2.0 mL) and a magnetic stirrer, then the reaction was placed in an oil bath at 100 ℃ for heating reaction for 18 hours (monitored by thin layer chromatography), after the raw materials were completely reacted, the reaction tube was cooled to room temperature, then 4mL of saturated sodium thiosulfate solution was added, extraction was performed with ethyl acetate, anhydrous sodium sulfate was dried, the solvent was removed by distillation under reduced pressure, and then the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate =1, volume ratio), to obtain β -carboline compound 3e (45.4 mg, yield 67%). 1 H NMR(400MHz,DMSO-d 6 ):δ12.00(br,s,1H),8.95(s,1H),8.45-8.43(m,1H),8.05-8.03(m,2H),7.71-7.68(m,3H),7.64-7.60(m,1H),7.36-7.32(m,1H),3.93(s,3H)； 13 C{ 1 H}NMR(100MHz,DMSO-d 6 ):166.0,141.5,140.8,136.7,136.3,134.6,133.8,130.5,129.4,128.9,122.2,121.1,120.6,117.0,112.8,52.2.
Example 6 Synthesis of beta-carbolines 3f
Adding a magnetic stirrer, tryptophan derivative 1 (0.2 mmol) and an aldehyde compound 2 (1.1 equiv.,0.22 mmol) into a 25mL reaction tube under the condition of air, adding anhydrous dichloromethane (3.0 mL), cooling the reaction to 0 ℃ in an ice water bath, slowly adding trifluoroacetic acid (2.5 equiv.,0.5mmol,38 μ L) at the speed of 20 μ L/min, continuing the reaction for 0.5 hour, then returning the reaction to room temperature, reacting for 12 hours (monitoring by thin layer chromatography), and after the raw materials are completely reacted, distilling under reduced pressure to remove the solvent to obtain a solid compound which is directly used for the next reaction. Adding iodine (5.0 mol%,2.5 mg), DMSO solvent (2.0 mL) and magnetic stirrer into a 25mL reaction tube under the condition of air, then placing the reaction in an oil bath kettle at 100 ℃ for heating reaction for 20 hours (monitoring by thin layer chromatography), cooling the reaction tube to room temperature after the raw materials are completely reacted, then adding 4mL of saturated sodium thiosulfate solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove the solvent, and then separating the crude product by column chromatography (eluent, petroleum oil, etc.)Ether ethyl acetate =1, volume ratio), to obtain β -carboline compound 3f (46.7 mg, yield 61%). 1 H NMR(400MHz,DMSO-d 6 ):δ12.00(br,s,1H),8.95(s,1H),8.45-8.43(m,1H),7.99-7.95(m,2H),7.85-7.82(m,2H),7.69-7.67(m,1H),7.63-7.59(m,1H),7.36-7.32(m,1H),3.93(s,3H)； 13 C{ 1 H}NMR(100MHz,DMSO-d 6 ):166.0,141.5,140.9,136.7,136.6,134.6,131.8,130.8,129.4,128.9,122.5,122.2,121.1,120.6,117.1,112.8,52.2.
Example 7 Synthesis of beta-carbolines 3g
Adding a magnetic stirrer, a tryptophan derivative 1 (0.2 mmol) and an aldehyde compound 2 (1.1 equiv.,0.22 mmol) into a 25mL reaction tube under the condition of air, adding anhydrous dichloromethane (3.0 mL), cooling the reaction to 0 ℃ in an ice water bath, slowly adding trifluoroacetic acid (2.5 equiv.,0.5mmol,38 μ L) at the speed of 20 μ L/min, continuing the reaction for 0.5 hour, then returning the reaction to room temperature, reacting for 12 hours (monitoring by thin layer chromatography), and after the raw materials are completely reacted, distilling under reduced pressure to remove the solvent to obtain a solid compound which is directly used for the next reaction. In a 25mL reaction tube, iodine (5.0 mol%,2.5 mg), DMSO solvent (2.0 mL) and a magnetic stirrer were added under air conditions, then the reaction was placed in an oil bath kettle at 120 ℃ for heating reaction for 15 hours (monitored by thin layer chromatography), after the raw materials were completely reacted, the reaction tube was cooled to room temperature, 4mL of saturated sodium thiosulfate solution was added, followed by extraction with ethyl acetate, drying with anhydrous sodium sulfate, distillation under reduced pressure to remove the solvent, and then the crude product was subjected to column chromatography (eluent, petroleum ether: ethyl acetate =1, volume ratio) to obtain 3g (28.8 mg, yield 39%) of β -carboline compound. 1 H NMR(400MHz,DMSO-d 6 ):δ12.07(br,s,1H),8.98(s,1H),8.46-8.44(m,1H),8.23-8.20(m,2H),8.00-7.98(m,2H),7.69-7.67(m,1H),7.64-7.60(m,1H),7.37-7.33(m,1H),3.93(s,3H)； 13 C{ 1 H}NMR(100MHz,DMSO-d 6 ):165.9,141.6,141.4,140.4,136.8,134.8,129.6,129.5,129.2(q,J＝28.0Hz),129.0,125.7(q,J＝4.0Hz),124.3(q,J＝270.0Hz),122.2,121.1,120.7,117.4,112.8,52.2； 19 F NMR(376MHz,DMSO-d 6 ):-61.02(s,3F).
Example 8 Synthesis of beta-carbolines Compound 3h
Adding a magnetic stirrer, a tryptophan derivative 1 (0.2 mmol) and an aldehyde compound 2 (1.1 equiv.,0.22 mmol) into a 25mL reaction tube under the condition of air, adding anhydrous dichloromethane (3.0 mL), cooling the reaction to 0 ℃ in an ice water bath, slowly adding trifluoroacetic acid (2.5 equiv.,0.5mmol,38 μ L) at the speed of 20 μ L/min, continuing the reaction for 0.5 hour, then returning the reaction to room temperature, reacting for 12 hours (monitoring by thin layer chromatography), and after the raw materials are completely reacted, distilling under reduced pressure to remove the solvent to obtain a solid compound which is directly used for the next reaction. Under the condition of air, iodine (5.0 mol%,2.5 mg), a DMSO solvent (2.0 mL) and a magnetic stirrer are added into a 25mL reaction tube, then the reaction is placed in an oil bath kettle at 120 ℃ for heating reaction for 15 hours (monitoring by thin layer chromatography), after the raw materials are completely reacted, the reaction tube is cooled to room temperature, then a saturated sodium thiosulfate solution is added for 4mL, extraction is carried out by ethyl acetate, anhydrous sodium sulfate is dried, the solvent is removed by reduced pressure distillation, and then the crude product is subjected to column chromatography separation (eluent, petroleum ether: ethyl acetate =1, volume ratio), so that the beta-carboline compound is obtained for 3 hours (45.1 mg, yield 68%). 1 H NMR(400MHz,CDCl 3 ):δ9.06(br,s,1H),8.81(s,1H),8.20-8.19(m,1H),7.82-7.78(m,2H),7.60-7.55(m,2H),7.38-7.34(m,1H),6.94-6.90(m,2H),4.04(s,3H),3.79(s,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ):167.0,160.2,142.8,140.6,137.9,135.0,130.1,129.5,129.4,128.9,122.1,121.9,121.0,116.5,114.3,111.9,55.3,52.6.
Example 9 Synthesis of beta-carboline Compound 3i
Adding a magnetic stirrer, a tryptophan derivative 1 (0.2 mmol) and an aldehyde compound 2 (1.1 equiv.,0.22 mmol) into a 25mL reaction tube under the condition of air, adding anhydrous dichloromethane (3.0 mL), cooling the reaction to 0 ℃ in an ice water bath, slowly adding trifluoroacetic acid (2.5 equiv.,0.5mmol,38 μ L) at the speed of 20 μ L/min, continuing the reaction for 0.5 hour, then returning the reaction to room temperature, reacting for 12 hours (monitoring by thin layer chromatography), and after the raw materials are completely reacted, distilling under reduced pressure to remove the solvent to obtain a solid compound which is directly used for the next reaction. In a 25mL reaction tube under the condition of air, iodine (5.0 mol%,2.5 mg), DMSO solvent (2.0 mL) and a magnetic stirrer are added, then the reaction is placed in an oil bath kettle at 100 ℃ for heating reaction for 16 hours (monitored by thin layer chromatography), after the raw materials are completely reacted, the reaction tube is cooled to room temperature, then 4mL of saturated sodium thiosulfate solution is added, then ethyl acetate is used for extraction, anhydrous sodium sulfate is dried, the solvent is removed by distillation under reduced pressure, and then the crude product is subjected to column chromatography separation (eluent, petroleum ether: ethyl acetate =1, volume ratio), so that the beta-carboline compound 3i (48.3 mg, yield 78%) is obtained. 1 H NMR(400MHz,DMSO-d 6 ):δ11.90(br,s,1H),8.87(s,1H),8.43-8.41(m,1H),8.15-8.14(m,1H),7.80-7.77(m,2H),7.66-7.61(m,1H),7.37-7.33(m,2H),3.94(s,3H)； 13 C{ 1 H}NMR(100MHz,DMSO-d 6 ):165.6,142.3,141.5,136.3,132.4,129.8,128.9,128.8,128.4,126.7,122.0,121.1,120.7,116.5,112.9,52.1.
Example 9 Synthesis of beta-carbolines 3j
Under the condition of air, a magnetic stirrer, tryptophan derivative 1 (0.2 mmol) and aldehyde compound 2 (1.1 equiv.,0.22 mmol) were added to a 25mL reaction tube, then anhydrous dichloromethane (3.0 mL) was added, the reaction was cooled to 0 ℃ in an ice-water bath, and trifluoroacetic acid (2.5 equi) was slowly added at a rate of 20. Mu.L/minv.,0.5mmol,38 μ L) for 0.5 hour, then returning the reaction to room temperature for 12 hours (monitoring by thin layer chromatography), and after the reaction of the raw materials is completed, distilling under reduced pressure to remove the solvent to obtain a solid compound which is directly used for the next reaction. In a 25mL reaction tube, iodine (5.0 mol%,2.5 mg), DMSO solvent (2.0 mL) and a magnetic stirrer were added under air conditions, then the reaction was placed in an oil bath kettle at 100 ℃ for heating reaction for 20 hours (monitored by thin layer chromatography), after the reaction of the raw materials was completed, the reaction tube was cooled to room temperature, then 4mL of saturated sodium thiosulfate solution was added, followed by extraction with ethyl acetate, drying with anhydrous sodium sulfate, removal of the solvent by distillation under reduced pressure, and then the crude product was separated by column chromatography (eluent, petroleum ether: ethyl acetate =1, volume ratio), yielding β -carboline compound 3j (36.8 mg, yield 52%). 1 H NMR(400MHz,DMSO-d 6 ):δ12.38(br,s,1H),9.10(s,1H),8.87-8.85(m,1H),8.80-8.77(m,1H),8.64-8.62(m,1H),8.52-8.50(m,1H),8.10-8.06(m,2H),7.95-7.91(m,1H),7.74-7.68(m,2H),7.41-7.37(m,1H),4.00(s,3H)； 13 C{ 1 H}NMR(100MHz,DMSO-d 6 ):165.9,156.5,147.2,141.6,137.3,137.2,136.1,135.3,130.4,129.9,129.1,127.9,127.6,127.4,122.2,120.9,120.8,118.9,118.6,113.6,52.3.
Example 10 Synthesis of beta-carboline Compound 3k
Adding a magnetic stirrer, a tryptophan derivative 1 (0.2 mmol) and an aldehyde compound 2 (1.1 equiv.,0.22 mmol) into a 25mL reaction tube under the condition of air, adding anhydrous dichloromethane (3.0 mL), cooling the reaction to 0 ℃ in an ice water bath, slowly adding trifluoroacetic acid (2.5 equiv.,0.5mmol,38 μ L) at the speed of 20 μ L/min, continuing the reaction for 0.5 hour, then returning the reaction to room temperature, reacting for 12 hours (monitoring by thin layer chromatography), and after the raw materials are completely reacted, distilling under reduced pressure to remove the solvent to obtain a solid compound which is directly used for the next reaction. Iodine (5.0 mol%,2.5 mg) and DMSO solvent (2) were added to a 25mL reaction tube under air conditions0 mL) and a magnetic stirrer, then placing the reaction in an oil bath kettle at 120 ℃ for heating reaction for 15 hours (monitoring by thin layer chromatography), cooling the reaction tube to room temperature after the raw materials are completely reacted, then adding 4mL of saturated sodium thiosulfate solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent by reduced pressure distillation, and then separating the crude product by column chromatography (eluent, petroleum ether: ethyl acetate =3, volume ratio) to obtain beta-carboline compound 3k (49.5 mg, yield 78%). 1 H NMR(400MHz,DMSO-d 6 ):δ11.96(br,s,1H),8.92(s,1H),8.45-8.43(m,1H),8.03-8.00(m,2H),7.71-7.56(m,5H),7.35-7.31(m,1H),4.41(q,J＝7.2Hz,2H),1.38(t,J＝7.2Hz,3H)； 13 C{ 1 H}NMR(100MHz,DMSO-d 6 ):165.6,142.2,141.5,137.6,137.0,134.6,129.2,129.1,128.9,128.8,128.7,122.1,121.2,120.5,116.7,112.8,60.7,14.5.
Example 11 Synthesis of beta-carbolines 3l
Adding a magnetic stirrer, tryptophan derivative 1 (2.0 mmol) and aldehyde compound 2 (1.1 equiv.,2.2 mmol) into a 25mL reaction tube under the condition of air, adding anhydrous dichloromethane (8.0 mL), cooling the reaction to 0 ℃ in an ice water bath, slowly adding trifluoroacetic acid (2.5 equiv.,5.0mmol, 380. Mu.L) at the speed of 20 mu.L/min, continuing the reaction for 0.5 hour, then returning the reaction to room temperature, reacting for 12 hours (monitored by thin layer chromatography), and after the raw materials are completely reacted, distilling under reduced pressure to remove the solvent to obtain a solid compound which is directly used for the next reaction. Adding iodine (5.0 mol%,25 mg), DMSO solvent (2.0 mL) and magnetic stirrer into 25mL reaction tube under air condition, heating the reaction in 85 deg.C oil bath for 20 hr (monitoring by thin layer chromatography), cooling to room temperature after the raw materials react completely, adding saturated sodium thiosulfate solution 4mL, extracting with ethyl acetate, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove solvent, and separating the crude product by column chromatography (eluent, petroleum ether: ethyl acetate)Ethyl acetate =2, volume ratio) to obtain 3l (183.2 mg, yield 38%) of β -carboline compound, in this example, part of the raw materials were decomposed, so the yield was low. 1 H NMR(400MHz,CDCl 3 ):δ9.93(br,s,1H),8.61-8.59(m,1H),8.16-8.13(m,2H),7.63-7.56(m,2H),7.35-7.31(m,1H),4.60(q,J＝7.2Hz,2H),1.54(t,J＝7.2Hz,3H)； 13 C{ 1 H}NMR(100MHz,CDCl 3 ):166.9,140.7,138.9,137.2,131.5,129.8,129.4,121.9,120.9,120.7,118.6,111.8,62.0,14.5.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.
Claims (9)
1. A method for preparing beta-carboline compounds by an iodine catalytic oxidation method is characterized by comprising the following steps: carrying out a Pictet-Schpengler reaction on the tryptamine derivative and an aldehyde compound to obtain an intermediate beta-tetrahydrocarboline compound without separating the intermediate; and then, reacting for 12-20h at 85-120 ℃ by taking iodine as a catalyst and dimethyl sulfoxide as a reaction solvent to prepare the beta-carboline compound.
2. The method for preparing beta-carboline compounds by the iodine catalytic oxidation method according to claim 1, wherein the reaction is carried out in an air atmosphere.
3. The method for preparing beta-carboline compounds by using the iodine catalytic oxidation method according to claim 1, wherein the structure formula of the tryptamine derivative is as follows:
4. The method for preparing beta-carboline compounds by using iodine catalytic oxidation method according to claim 1, wherein the aldehyde compound has a structural formula R 2 CHO; wherein R is 2 = H, phenyl, C,
Or meta-or para-substituted phenyl, wherein the substituents are independently selected from Me, et, F, br, cl, CF 3 Or OMe.
5. The method for preparing beta-carboline compounds by using the iodine catalytic oxidation method as claimed in claim 1, wherein the ratio of the tryptamine derivatives to the aldehyde compounds is 1: 1.1.
6. The method for preparing beta-carboline compounds by using the iodine catalytic oxidation method according to claim 1, wherein the method further comprises the steps of extraction, drying and column chromatography separation after the reaction is finished.
7. The method for preparing beta-carboline compounds by the iodine catalytic oxidation method according to claim 6, wherein the extraction specifically comprises the following steps: after the reaction is finished, cooling to room temperature, adding a saturated sodium thiosulfate solution, extracting with ethyl acetate, repeatedly extracting for 3 times, and combining organic layer solutions to obtain an extract liquid;
the volume ratio of the saturated sodium thiosulfate solution to the ethyl acetate is 1.
8. The method for preparing beta-carboline compounds according to claim 6, wherein the drying is performed by drying the extract with anhydrous sodium sulfate and then evaporating the solvent.
9. The method for preparing beta-carboline compounds by using the iodine catalytic oxidation method according to claim 6, wherein the eluent in the column chromatographic separation is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2:1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114456117A (en) * | 2022-03-03 | 2022-05-10 | 曲靖师范学院 | Iodine-promoted method for preparing N-arylpyrazole compound |
| CN114539157A (en) * | 2022-03-03 | 2022-05-27 | 曲靖师范学院 | Method for preparing 4-iodo-N-arylpyrazole compound by iodine-promoted oxidation method |
| CN115073377A (en) * | 2022-06-23 | 2022-09-20 | 曲靖师范学院 | Method for preparing N-arylpyrazole compound by iodine catalytic oxidation method and product thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114456117A (en) * | 2022-03-03 | 2022-05-10 | 曲靖师范学院 | Iodine-promoted method for preparing N-arylpyrazole compound |
| CN114539157A (en) * | 2022-03-03 | 2022-05-27 | 曲靖师范学院 | Method for preparing 4-iodo-N-arylpyrazole compound by iodine-promoted oxidation method |
| CN115073377A (en) * | 2022-06-23 | 2022-09-20 | 曲靖师范学院 | Method for preparing N-arylpyrazole compound by iodine catalytic oxidation method and product thereof |
Non-Patent Citations (2)
| Title |
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| LI LIU 等: "Fitness of driving force and catalytic space in chiral catalyst design. Application of axial biscarboline NeO chiral catalyst for enantioselective allylation of allyltrichlorosilane to bulky substituted aldehydes", 《TETRAHEDRON》, vol. 71, 2 April 2015 (2015-04-02), pages 3296 * |
| ZI-XUAN WANG 等: "Direct Biomimetic Synthesis of β‑Carboline Alkaloids from Two Amino Acids", 《THE JOURNAL OF ORGANIC CHEMISTRY》, vol. 83, 22 August 2018 (2018-08-22), pages 12247 * |
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