Chiral 1,2-dihydropyridine compound as well as preparation method and application thereof

A technology for dihydropyridine and aldehyde compounds, applied in the direction of organic chemistry, etc., can solve the problems of reduced applicability of synthetic methods, difficult synthesis, and poor reaction universality.

Active Publication Date: 2019-12-20
EAST CHINA NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] In summary, the problems in the currently developed chiral 1,2-dihydropyridine synthesis methods include: (1) The ring closure reaction starting from chiral substrates has poor universality due to limited chiral substrates; ( 2) The addition reaction to pyridinium salt usually requires the participation of metal reagents, which leads to the reduction of the application of the synthetic method in the field of medicine; (3) The synthesis of different substituted pyridinium salts requires the preparation of different substituted pyridines in advance, and the synthesis is relatively difficult. resulting in poor generalizability of responses

Method used

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  • Chiral 1,2-dihydropyridine compound as well as preparation method and application thereof
  • Chiral 1,2-dihydropyridine compound as well as preparation method and application thereof
  • Chiral 1,2-dihydropyridine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0162]

[0163]Under nitrogen protection, add imine 1a (410mg, 2.0mmol), propionaldehyde 2a (348mg, 6mmol) and dry redistilled acetonitrile (15mL) into a 25mL Schlenk tube, then stir at 0°C for 12h, a white solid Precipitation, acetonitrile and excess propionaldehyde 2a were removed by rotary evaporation. The white solid crude intermediate was transferred to a 10 mL Schlenk sealed tube, added dry redistilled ethyl acetate (6 mL), ylide 4a (636 mg, 2 mmol), and stirred at 80° C. for 12 h. Return to room temperature, add SiCl under nitrogen protection 4 (72μL, 0.6mmol), react at 40°C for 5h. The system was returned to room temperature, and the reaction solution was slowly added dropwise to 0°C saturated sodium bicarbonate solution (20 mL) to quench the reaction, extracted with ethyl acetate (3×15 mL), the organic phases were combined, and dried over anhydrous sodium sulfate. Column chromatography, eluent (petroleum ether / diethyl ether=20:1). Compound 6a was obtained as a c...

Embodiment 2

[0165]

[0166] Under nitrogen protection, add imine 1a (410mg, 2.0mmol), propionaldehyde 2a (348mg, 6mmol) and dry redistilled acetonitrile (15mL) into a 25mL Schlenk tube, then stir at 0°C for 12h, a white solid Precipitation, acetonitrile and excess propionaldehyde 2a were removed by rotary evaporation. The white solid crude intermediate was transferred to a 10 mL Schlenk sealed tube, dry redistilled dichloromethane (6 mL) and ylide 4b (664 mg, 2 mmol) were added, and stirred at 80° C. for 12 h. Return to room temperature, add SiCl under nitrogen protection 4 (48μL, 0.4mmol), react at 40°C for 8h. The system was returned to room temperature, and the reaction solution was slowly added dropwise to 0°C saturated sodium bicarbonate solution (20 mL) to quench the reaction, extracted with ethyl acetate (3×15 mL), the organic phases were combined, and dried over anhydrous sodium sulfate. Column chromatography, eluent (petroleum ether / diethyl ether=20:1). The colorless oily c...

Embodiment 3

[0168]

[0169] Under nitrogen protection, add imine 1a (422mg, 2.0mmol), propionaldehyde 2a (348mg, 6mmol) and dry redistilled acetonitrile (15mL) into a 25mL Schlenk tube, then stir at 0°C for 12h, a white solid Precipitation, acetonitrile and excess propionaldehyde 2a were removed by rotary evaporation. The white solid crude intermediate was transferred to a 10 mL Schlenk-sealed tube, added dry redistilled ethyl acetate (6 mL), ylide 4a (636 mg, 2 mmol), and stirred at 90° C. for 12 h. Return to room temperature, add SiCl under nitrogen protection 4 (72μL, 0.6mmol), react at 30°C for 5h. The system was returned to room temperature, and the reaction solution was slowly added dropwise to 0°C saturated sodium bicarbonate solution (20 mL) to quench the reaction, extracted with ethyl acetate (3×15 mL), the organic phases were combined, and dried over anhydrous sodium sulfate. Column chromatography, eluent (petroleum ether / diethyl ether=20:1). The colorless oily compound 6c...

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Abstract

The invention discloses a synthesis method for preparing chiral polysubstituted 1,2-dihydropyridine as well as polysubstituted pyridine and chiral piperidine derived from chiral polysubstituted 1,2-dihydropyridine by using a "one-pot serial connection method". The method comprises the following step: by taking an imine compound and an aldehyde compound as raw materials, performing an asymmetric Mannich reaction, a Wittig reaction and an intramolecular ring-closing reaction in sequence, so as to synthesize a chiral 1,2-dihydropyridine compound with high three-dimensional selectivity. The product does not need to be purified, and a polysubstituted pyridine compound can be prepared through oxidation aromatization through further "one-pot serial connection", and a polysubstituted chiral piperidine compound can be also prepared through catalytic hydrogenation after separation and purification. The method starts from simple and easily obtained raw materials, separation and purification of anintermediate are avoided, and compounds of 1,2-dihydropyridine, polysubstituted pyridine and chiral piperidine are efficiently synthesized through simples steps of operation. Nitrogenous six-memberedring frameworks which are synthesized by using the method and disclosed by the invention are all common in many natural products and medicine molecules, and have great significances for acceleratingmedicine research and development.

Description

technical field [0001] The invention belongs to the technical field of organic compound technology application, and relates to a class of chiral 1,2-dihydropyridine compounds and their preparation methods and applications, in particular to a class of chiral 1,2-dihydropyridine compounds and a " "One-pot cascading method" to construct chiral 1,2-dihydropyridine, multi-substituted pyridine and chiral piperidine compounds. Background technique [0002] Nitrogen-containing heterocyclic compounds are an important class of molecular skeletons, which widely exist in natural products and drug molecules. As of the 1990s, among the 1086 small-molecule drugs approved by the US Food and Drug Administration (FDA), as many as 59% of the drugs contained nitrogen heterocyclic skeletons (J.T.Njardarson, et al.J.Med.Chem.2014 , 57, 10257.). Therefore, research and development of efficient methods for constructing nitrogen-heterocyclic skeletons has become particularly important in the field...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/18C07D213/04C07D213/08C07D213/16C07D213/65C07D409/04C07D471/10C07D211/16
CPCC07D213/04C07D409/04C07D471/10C07D213/16C07D213/65C07D213/08C07D211/16C07D211/18Y02P20/55
Inventor 周剑穆博帅崔效源余金生曾兴平
Owner EAST CHINA NORMAL UNIV
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