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1-hydropyrrolizine derivatives and their synthetic methods and applications

A synthetic method and compound technology, which is applied in the field of medicine, can solve the problems of complex experimental operation conditions, long steps, and low compatibility between substrates and functional groups, and achieve good anti-tumor activity, short cycle time, and simple and easy-to-control synthetic methods.

Active Publication Date: 2021-03-23
GUANGXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing synthetic methods of 1-hydropyrrolazine analogs have disadvantages such as long steps, low compatibility of substrates and functional groups, or complicated experimental operating conditions.

Method used

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  • 1-hydropyrrolizine derivatives and their synthetic methods and applications
  • 1-hydropyrrolizine derivatives and their synthetic methods and applications
  • 1-hydropyrrolizine derivatives and their synthetic methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] The 1-hydropyrrolazine derivatives of the present invention are synthesized according to the following synthetic route.

[0051]

[0052] 3aa:R 1 = Ph, R 2 = Ph, R 3 = Me,R 4 = Me,R 5 =CO 2 Et, R 6 =CO 2 Et;

[0053] 3ba:R 1 = 4-MeOC 6 h 4 , R 2 = 4-MeOC 6 h 4 , R 3 = Me,R 4 = Me,R 5 =CO 2 Et, R 6 =CO 2 Et;

[0054] 3ca:R 1 = 4-CF 3 C 6 h 4 , R 2 = 4-CF 3 C 6 h 4 , R 3 = Me,R 4 = Me,R 5 =CO 2 Et, R 6 =CO 2 Et;

[0055] 3da:R 1 =3-BrC 6 h 4 , R 2 = 4-BrC 6 h 4 , R 3 = Me,R 4 = Me,R 5 =CO 2 Et, R 6 =CO 2 Et;

[0056] 3ea:R 1 = Ph, R 2 = Ph, R 3 = H, R 4 = Ph, R 5 =CO 2 Et, R 6 =CO 2 Et;

[0057] 3fa:R 1 = Ph, R 2 = Ph, R 3 =Et,R 4 =Et,R 5 =CO 2 Et, R 6 =CO 2 Et;

[0058] 3ga:R 1 = Ph, R 2 = Ph, R 3 , R 4 =(CH 2 ) 4 , R 5 =CO 2 Et, R 6 =CO 2 Et;

[0059] 3ab:R 1 = Ph, R 2 = Ph, R 3 = Me,R 4 = Me,R 5 =CO 2 n Bu, R 6 =CO 2 n Bu;

[0060] 3ac:R 1 = Ph, R 2 = Ph, R 3 = Me,R 4 = Me,R ...

Embodiment 2

[0090] The 1-hydropyrrolazine derivatives of the present invention are synthesized according to the following synthetic route.

[0091]

[0092] 3ag:R 1 = Ph, R 2 = Ph, R 3 = Me,R 4 = Me,R 5 = H, R 6 =COCH 3 ;

[0093] 3ah:R 1 = Ph, R 2 = Ph, R 3 = Me,R 4 = Me,R 5 = Ph, R 6 = CN;

[0094] 3ai:R 1 = Ph, R 2 = Ph, R 3 = Me,R 4 = Me,R 5 = H, R 6 =CONMe(OMe);

[0095] 3aj:R 1 = Ph, R 2 = Ph, R 3 = Me,R 4 = Me,R 5 = Ph, R 6 = 4-MeC 6 h 4 SO 2 .

[0096] N-alkenyl α, β-unsaturated nitrone substrate 1 (0.3mmol), alkyne reagent 2 (0.6mmol), catalyst (target 3ag-3aj catalysts were ferric acetate, copper chloride, trifluoro Copper methanesulfonate and cuprous bromide) (0.03mmol) are placed in reaction tube, add 3mL organic solvent (the organic solvent that target object 3ag-3aj adopts is respectively benzene, cyclohexane, ether, composed of dioxane and Hexane mixed at a volume ratio of 1:2), stirred and reacted at 40°C for 3 to 15 hours, the obtained re...

experiment example 1

[0105] Experimental Example 1: The 1-hydropyrrolazine derivatives of the present invention were tested for their inhibitory activity against various human tumor strains in vitro:

[0106] (1) Cell culture: MGC-803, HepG-2, NCI-H460, SKOV3, T24, 7702 cells were cultured in a medium containing 10% (volume ratio) fetal bovine serum and 1% (volume ratio) double antibody (containing penicillin and Streptomycin) in DMEM medium at 37°C, 5% CO 2 and 95% air incubator, and change the medium every other day. After the cells were confluent, they were passaged and frozen.

[0107](2) Seed plate: Take the cells in the logarithmic growth phase, remove the old medium, wash twice with PBS, digest the cells with trypsin, add new medium after the cells become round, stop the digestion of the cells and pipette the suspended cells to prepare into a single cell suspension. Take an appropriate amount of cell suspension, add a certain amount of medium to dilute, inoculate into a 96-well plate, 18...

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Abstract

The invention discloses a series of 1-hydropyrrolizine derivatives as well as a synthesis method and application thereof. The 1-hydropyrrolizine derivatives provided by the invention have a structureas shown in the following formula (I); and the synthesis method comprises the following steps: taking a compound as shown in the following formula (II), a compound shown in a formula (III) and a catalyst to be placed in an organic solvent; and reacting in the presence of oxygen to obtain a crude target product. The method provided by the invention is simple and easy to control, short in cycle andfree of anhydrous and anaerobic conditions; part of the obtained 1-hydropyrrolizine derivatives have good antitumor activity; and the compounds having structures as shown in the formulas (I), (II) and(III) are as follows: (Refer to Specification).

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to 1-hydropyrrolizine derivatives and their synthesis methods and applications. Background technique [0002] 1-hydropyrrolizine derivatives widely exist in many natural products and drug molecules. At present, there are two main methods for synthesizing 1-hydropyrrolizine derivatives: one is four-step reactions such as addition and cyclization of halogenated nitrile compounds by Grignard reagents (J.Med.Chem.2009, 52, 4968; J. Org. Chem. 2016, 81, 4112). Another method is through the intramolecular hydroformylation of allylpyrrole aldehyde (ACSCatal. 2016, 6, 2673). However, the existing synthetic methods of 1-hydropyrrolizine analogues have disadvantages such as long steps, low compatibility of substrates and functional groups, or complicated experimental operating conditions. Contents of the invention [0003] The technical problem to be solved by the present invention is t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61P35/00
CPCA61P35/00C07D487/04
Inventor 莫冬亮邹宁焦继文冯钰潘成学苏桂发
Owner GUANGXI NORMAL UNIV