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Method for asymmetric catalytic synthesis of spirocyclic tetrahydrocarbazoline compound

A technology of carbazoline and compound, which is applied in the field of synthesizing spiro tetrahydrocarbazoline compounds, can solve the problems of narrow types of spiro tetrahydrocarbazoline compounds, cannot be constructed at the same time, and high cost, and achieve a simple and clean reaction system Effect

Active Publication Date: 2015-09-23
SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the types of spiro tetrahydrocarbazoline compounds synthesized are relatively narrow, and at the same time, only 1-position chirality can be constructed, but 1 and 3-position chirality cannot be simultaneously constructed.
[0015] In summary, although there are already some catalytic systems that can synthesize spirocyclic tetrahydrocarbazoline compounds with high yield and high enantioselectivity through asymmetric catalysis, the universality of substrates is relatively narrow, and there are no It is possible to synthesize 1,3-position chiral spirocyclic tetrahydrocarbazoline compounds with high antimalarial activity by catalytic methods, while the optical isomers with high antimalarial activity (1R, 3S) need to be resolved by chiral method can only be obtained, the cost is high, and the benefit is low

Method used

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  • Method for asymmetric catalytic synthesis of spirocyclic tetrahydrocarbazoline compound
  • Method for asymmetric catalytic synthesis of spirocyclic tetrahydrocarbazoline compound
  • Method for asymmetric catalytic synthesis of spirocyclic tetrahydrocarbazoline compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Different chiral amine oxides and nickel trifluoromethanesulfonate [Ni(OTf) 2 ] Catalyzed reaction of unsymmetrical 3-alkenylindole with isatin-derived ketimine aza-Diels-Alder.

[0048]

[0049] Add nickel trifluoromethanesulfonate [Ni(OTf) 2 ] (0.01mmol), chiral amine oxide L (0.01mmol), isatin-derived ketimine 2a (0.1mmol), stirrer, add dichloromethane (15.5mmol), activate at 30°C for 30min. Take 1mL round bottom flask B, weigh compound 1a (0.15mmol) into it, add 3.1mmol dichloromethane to dissolve. Add the B reaction solution dropwise to A, stir for 48 hours, add 0.2 mL HCl (6.0 mol / L solution) to the reaction solution, stir for 6 hours at 30°C, add saturated NaHCO 3 The solution was neutralized to neutral, dichloromethane extracted, anhydrous Na 2 SO 4 Dry, filter with suction, concentrate, and pass through a column with petroleum ether / ethyl acetate (or heptane, or hexane / ethyl acetate, or heptane / ethyl acetate, etc.) to obtain compound I-a with ...

Embodiment 2

[0052] Example 2: Chiral amine oxide L-RaPr at -10°C 3 With nickel trifluoromethanesulfonate [Ni(OTf) 2 ] Catalyzed reaction of asymmetric 3‐alkenylindole with isatin-derived ketimine aza-Diels-Alder

[0053]

[0054] Add nickel trifluoromethanesulfonate [Ni(OTf) 2 ] (0.01mmol), chiral amine oxide L-RaPr 3 (0.01mmol), isatin-derived ketimine 2a (0.1mmol), stirrer, add dichloromethane (15.5mmol), activate at 30°C for 30min, and cool the reaction solution in test tube A to -10°C. Take 1mL round bottom flask B, weigh compound 1a (0.15mmol) into it, add 3.1mmol dichloromethane to dissolve, and cool to -10°C. Add the reaction liquid from bottle B to A dropwise, stir and react at -10°C for 192h, add 0.2mL HCl (6.0mol / L solution) to the reaction liquid, stir at 30°C for 6h, add saturated NaHCO 3 The solution was neutralized to neutral, dichloromethane extracted, anhydrous Na 2 SO 4 Dry, filter with suction, concentrate, and use petroleum ether / ethyl acetate (or heptane, or h...

Embodiment 3

[0055] Example 3: Chiral amine oxide L-RaPr 3 With nickel trifluoromethanesulfonate [Ni(OTf) 2 ] Catalytic aza-Diels-Alder reactions of unsymmetrical 3-alkenylindoles with different isatin-derived ketimines

[0056]

[0057] Add nickel trifluoromethanesulfonate [Ni(OTf) 2 ] (0.01mmol), chiral amine oxide L-RaPr 3 (0.01mmol) (chiral amine oxide L-RaPr 3 With nickel trifluoromethanesulfonate Ni(OTf) 2 molar ratio of 1.0:1.0), isatin-derived ketimine (0.1mmol), stirrer, add dichloromethane (15.5mmol), activate at 30°C for 30min, cool the reaction solution in test tube A to -10°C . Take 1mL round bottom flask B, weigh compound 1a (0.15mmol) into it, add 3.1mmol dichloromethane to dissolve, and cool to -10°C. Add the reaction liquid in B dropwise to A, stir and react at -10°C for 96-192h, add 0.2mL HCl (6.0mol / L solution) to the reaction liquid, stir at 30°C for 6h, add saturated NaHCO 3 The solution was neutralized to neutral, dichloromethane extracted, anhydrous Na 2 S...

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Abstract

The invention discloses a method for asymmetric catalytic synthesis of a spirocyclic tetrahydrocarbazoline compound, comprising the steps: by taking 3-alkenyl indole and isatin derived ketimine as raw materials, a complex formed by chiral amine oxide and nickel trifluoromethane sulfonate as a catalyst and dichloromethane as a solvent, performing reaction on the raw materials at (-30) DEG C to (-10) DEG C at the normal pressure for 96-192h; then adding 6.0M HCl(solution) and performing reaction at 30 DEG C for 4-48h to obtain the chiral spirocyclic tetrahydro carbazoline compound, wherein the yield of the chiral spirocyclic tetrahydro carbazoline compound can reach up to 95%, and the enantioselectivity can reach up to 99%. According to the method provided by the invention, the catalytic reaction conforms with the green chemistry atom economy and has a good prospect in industrial application, thereby providing a new path for asymmetric synthesis of compounds with high anti-malarial activity (NITD609).

Description

Technical field [0001] The present invention uses hand-based oxide-nickel nickelsulfonate [ni (OTF) 2 ] As a catalyst, an asymmetric catalytic synthetic pilot tetrazolerine compound. Background technique [0002] The threaded tetrahydrodidoline compound has the structure of the following compound I. It is a new type of molecule with antimalarial biological activity.Represented by NITD609, the molecule contains two hand -centered centers, of which (1R, 3S) optical heterogeneous has high antimalarial biological activity. [0003] [0004] In 2010, Keller and others reported on J.Med.chem. (2010,53,5155). [0005] [0006] This method is based on the compound II as the raw material to prepare the compound III through a one -step formaldehyde reaction, and then reacts with the nitro ethane reaction to obtain the corresponding compound IV.The PicTet -Spengler reacts to obtain the disappearing target pilot tetrahydropidazolein compound VII, and finally obtains (1R, 3S) optical isom...

Claims

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Application Information

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IPC IPC(8): C07D471/20
CPCC07D471/20
Inventor 冯小明郑海丰刘小华林丽丽
Owner SICHUAN UNIV
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