CN114409649A - Method for synthesizing indolizidine alkaloid - Google Patents
Method for synthesizing indolizidine alkaloid Download PDFInfo
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- CN114409649A CN114409649A CN202210126984.2A CN202210126984A CN114409649A CN 114409649 A CN114409649 A CN 114409649A CN 202210126984 A CN202210126984 A CN 202210126984A CN 114409649 A CN114409649 A CN 114409649A
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- indolizidine
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- catalyst
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- HAJKHJOABGFIGP-UHFFFAOYSA-N indolizidine Chemical class C1CCCN2CCCC21 HAJKHJOABGFIGP-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 229930005307 indolizidine alkaloid Natural products 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012299 nitrogen atmosphere Substances 0.000 claims abstract description 3
- -1 olefin compound Chemical class 0.000 claims abstract description 3
- 239000003960 organic solvent Substances 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 13
- 150000001336 alkenes Chemical class 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000010949 copper Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000005913 hydroamination reaction Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CKAHWDNDUGDSLE-ARLBYUKCSA-N Pseudolycorine Chemical compound C1N([C@@H]23)CCC3=C[C@H](O)[C@@H](O)[C@H]2C2=C1C=C(OC)C(O)=C2 CKAHWDNDUGDSLE-ARLBYUKCSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 208000008710 Amebic Dysentery Diseases 0.000 description 1
- 206010001986 Amoebic dysentery Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- IFKAWPFVCCFTPS-UHFFFAOYSA-N NP.[Rh] Chemical compound NP.[Rh] IFKAWPFVCCFTPS-UHFFFAOYSA-N 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- SSEUDFYBEOIWGF-AWEZNQCLSA-N Tylophorine Chemical compound C1=C(OC)C(OC)=CC2=C(C=C(C(OC)=C3)OC)C3=C(C[C@H]3N(CCC3)C3)C3=C21 SSEUDFYBEOIWGF-AWEZNQCLSA-N 0.000 description 1
- SSEUDFYBEOIWGF-CQSZACIVSA-N Tylophorine Natural products C1=C(OC)C(OC)=CC2=C(C=C(C(OC)=C3)OC)C3=C(C[C@@H]3N(CCC3)C3)C3=C21 SSEUDFYBEOIWGF-CQSZACIVSA-N 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- VJILFEGOWCJNIK-UHFFFAOYSA-N alpha-dihydro-lycorine Natural products C1CN2CC3=CC=4OCOC=4C=C3C3C2C1CC(O)C3O VJILFEGOWCJNIK-UHFFFAOYSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 230000006538 anaerobic glycolysis Effects 0.000 description 1
- 150000004982 aromatic amines Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 239000012018 catalyst precursor Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- VJILFEGOWCJNIK-MGRBZGILSA-N dihydrolycorine Chemical compound C1CN2CC3=CC=4OCOC=4C=C3[C@H]3[C@H]2[C@H]1C[C@H](O)[C@H]3O VJILFEGOWCJNIK-MGRBZGILSA-N 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
A method for synthesizing indolizidine alkaloids comprises the steps of dissolving an olefin compound and a catalyst in an organic solvent under the nitrogen atmosphere, stirring for reaction, and separating and purifying after the reaction is finished to obtain the indolizidine alkaloids shown in the formula II. In this reaction, Cu (OTf)2As catalyst, the method has the advantages of high catalytic efficiency, simple operation, high product conversion rate which can reach more than 80 percent, wide applicability and quick and high efficiency compared with the prior synthesis method.
Description
Technical Field
The invention relates to a synthesis method of indolizidine alkaloids, in particular to a method for realizing synthesis of indolizidine compounds through intramolecular cyclization amination cascade reaction of olefin under the condition of metal catalysis, and belongs to the technical field of organic pharmaceutical chemistry.
Background
Indolizidine alkaloids are one of important effective components in Chinese herbal medicines, have obvious biological activity, and have important effects on resisting cancer, tumor and other diseases. Along with the research of scientists on diseases such as cancer and the like, natural medicines are also paid attention to, while indolizidine alkaloid has important function in the aspect of resisting diseases, for example tylophorine has good activity of resisting tumor, diminishing inflammation and the like; pseudolycorine has obvious inhibition effect on aerobic oxidation and anaerobic glycolysis of cancer cells; the dihydrolycorine has the effects of resisting amebic dysentery, lowering blood pressure, protecting cerebral ischemia reperfusion injury, and the like. The synthesis of indolizidine compounds can be realized by multiple steps, and the operation is complex, so that the method is especially necessary for meeting the requirement of industrial production and exploring a high-efficiency and convenient synthetic method of indolizidine alkaloids.
Disclosure of Invention
The invention aims to overcome the problems in the existing synthesis of indolizidine compounds and provide a method for synthesizing indolizidine alkaloids.
In order to realize the purpose of the invention, the following technical scheme is adopted: a method for synthesizing indolizidine alkaloids has a structure shown in a formula II, olefin compounds and catalysts shown in the formula I are dissolved in an organic solvent under a nitrogen atmosphere, the mixture is heated, stirred and reacted, and separation and purification are carried out after the reaction is finished, so that the indolizidine alkaloids shown in the formula II are obtained, wherein the reaction formula is as follows:
in the reaction formula, R1Is hydrogen, or an alkyl group having 1 to 6 carbon atoms, or a phenyl group; r2Is hydrogen, or an alkyl group having 1 to 6 carbon atoms, or a phenyl group; r3The copper catalyst is mono-substituted or multi-substituted on a benzene ring, and Cu (OTf)2And the solvent is toluene.
Further, the method comprises the following steps of; cu (OTf)2Is used in an amount of 20% of the molar amount of the olefin.
The invention has the positive and beneficial technical effects that: in this reaction, Cu (OTf)2As catalyst, the method has the advantages of high catalytic efficiency, simple operation, high product conversion rate which can reach more than 80 percent, wide applicability and quick and high efficiency compared with the prior synthesis method.
Detailed Description
In order to more fully explain the implementation of the present invention, the implementation examples of the present invention are provided, which are merely illustrative of the present invention and do not limit the scope of the present invention.
Example 1:
this example is a reaction:
to a round-bottomed flask (20 mL) equipped with a magnetic stirrer, the starting compound (1.0 mmol) in the reaction formula and copper trifluoromethanesulfonate (0.2 mmol) were added, air was replaced three times with nitrogen, toluene (10 mL) as a solvent was added, the reaction mixture was stirred at 90. + -. 10 ℃ for 12 hours, quenched with EDTA, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined. The organic phase was washed with EDTA and saturated brine, respectively, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to give the objective compound (260 mg) in 80% yield.
Example 2:
this example is a reaction:
the starting compound of the reaction formula (0.2 mmol) and copper triflate (0.04 mmol) were added to a heart-shaped flask with a magnetic stirrer, the atmosphere was replaced three times with nitrogen and the solvent toluene (2 mL) was added, the reaction was stirred at 90. + -. 10 ℃ for 12 hours, the reaction was quenched with EDTA, extracted with ethyl acetate (5 mL. times.3), and the organic phases were combined. The organic phase was washed with EDTA and saturated brine, respectively, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to give the objective compound 4 (26 mg) in 64% yield.
Example 2:
this example is a reaction:
to a heart bottle (5 mL) equipped with a magnetic stirrer, the starting compound (0.2 mmol) and copper trifluoromethanesulfonate (0.04 mmol) were added, the air was replaced three times with nitrogen, toluene (2 mL) as a solvent was added, the mixture was stirred at 90. + -. 10 ℃ for 12 hours, the reaction was quenched with EDTA, extracted with ethyl acetate (5 mL. times.3), and the organic phases were combined. The organic phase was washed with EDTA and saturated brine, respectively, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography to give the objective compound 10 (47 mg) in 69% yield.
The starting compounds of formula I in the present application can be obtained by the prior art, for example, by using the following technical schemes disclosed in the following documents:
1.Bender, C. F.; Widenhoefer, R. A., Platinum-Catalyzed Intramolecular Hydroamination of Unactivated Olefins with Secondary Alkylamines. J. Am. Chem. Soc. 2005, 127 (4), 1070-1071.
2.Liu, Z.; Hartwig, J. F., Mild, Rhodium-Catalyzed Intramolecular Hydroamination of Unactivated Terminal and Internal Alkenes with Primary and Secondary Amines. J. Am. Chem. Soc. 2008, 130 (5), 1570-1571.
3.Julian, L. D.; Hartwig, J. F., Intramolecular Hydroamination of Unbiased and Functionalized Primary Aminoalkenes Catalyzed by a Rhodium Aminophosphine Complex. J. Am. Chem. Soc. 2010, 132 (39), 13813-13822.
4.Hesp, K. D.; Tobisch, S.; Stradiotto, M., [Ir(COD)Cl]2 as a Catalyst Precursor for the Intramolecular Hydroamination of Unactivated Alkenes with Primary Amines and Secondary Alkyl- or Arylamines: A Combined Catalytic, Mechanistic, and Computational Investigation. J. Am. Chem. Soc. 2010, 132 (1), 413-426。
after the embodiments of the present invention have been described in detail, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention, and it is intended that all simple modifications, equivalent changes and modifications made to the above embodiments based on the technical spirit of the present invention shall fall within the technical scope of the present invention, and the present invention shall not be limited to the embodiments illustrated in the description.
Claims (2)
1. A method for synthesizing indolizidine alkaloids, wherein the indolizidine alkaloids have a structure shown in a formula II, and is characterized by being synthesized by the following method: dissolving an olefin compound shown in a formula I and a catalyst in an organic solvent under a nitrogen atmosphere, heating, stirring, reacting, separating and purifying after the reaction is finished to obtain indolizidine alkaloid shown in a formula II, wherein the reaction formula is as follows:
in the reaction formula, R1Is hydrogen, or an alkyl group having 1 to 6 carbon atoms, or a phenyl group; r2Is hydrogen, or an alkyl group having 1 to 6 carbon atoms, or a phenyl group; r3The copper catalyst is mono-substituted or multi-substituted on a benzene ring, and Cu (OTf)2And the solvent is toluene.
2. The method for synthesizing indolizidine alkaloids according to claim 1, wherein the method comprises the following steps: cu (OTf)2Is used in an amount of 20% of the molar amount of the olefin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210126984.2A CN114409649A (en) | 2022-02-11 | 2022-02-11 | Method for synthesizing indolizidine alkaloid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210126984.2A CN114409649A (en) | 2022-02-11 | 2022-02-11 | Method for synthesizing indolizidine alkaloid |
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| Publication Number | Publication Date |
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| CN114409649A true CN114409649A (en) | 2022-04-29 |
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|---|---|---|---|
| CN202210126984.2A Pending CN114409649A (en) | 2022-02-11 | 2022-02-11 | Method for synthesizing indolizidine alkaloid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114409649A (en) |
-
2022
- 2022-02-11 CN CN202210126984.2A patent/CN114409649A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 杨春华等: "非活化烯烃的分子内碳胺化反应研究" * |
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Application publication date: 20220429 |
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