Synthesis method and application of axially chiral 9-aryl tetrahydroacridine

A technology for the synthesis of aryl tetrahydroacridines, which is applied in the fields of organic chemistry and organic chemistry, can solve the problems of small C-C bond rotation energy barrier, loss of drug development field, and inability to form anti-rotational chirality, etc., to achieve technological process The effect of short, simple preparation process

Inactive Publication Date: 2020-09-25
HEZE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the racemic tetrahydroacridine is synthesized by this method. Since there is no group in the ortho position of the aryl group, the rotation energy barrier of the C-C bond between the 9-position aryl group and acridine is relatively small, and it cannot form atropic chirality.
[0005] Thus, the prior art has not utilized atropselective catalytic asymmetry A protocol for the preparation of axially chiral quinoline-aryl backbones, partly resulting in many lost opportunities in the field of drug development

Method used

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  • Synthesis method and application of axially chiral 9-aryl tetrahydroacridine
  • Synthesis method and application of axially chiral 9-aryl tetrahydroacridine
  • Synthesis method and application of axially chiral 9-aryl tetrahydroacridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1 Preparation of axial chiral 9-aryl tetrahydroacridine compounds

[0031] Sequentially add activated Molecular sieve powder (100mg), chiral phosphoric acid catalyst (10.0mg, 0.015mmol), 2-naphthylamine (5.7mg, 0.040mmol), (2-amino-4-chlorophenyl) (1-naphthyl) ketone ( 2-amino-4-chlorophenyl)(naphthalen-1-yl)methanone (0.10mmol), carbon tetrachloride (0.2mL), chloroform (0.8mL) and cyclohexanone (0.30mmol), with tetrafluoro thread seal cap. The reaction mixture was placed in a preheated 80°C oil bath for 4 days, and thin layer chromatography showed that the starting material had disappeared. The reaction process is shown in Reaction Formula II, and the catalyst structure is shown in Formula 1.

[0032] The reaction mixture was directly separated by silica gel column chromatography, using ethyl acetate:petroleum ether (30:1 to 10:1) as the mobile phase, followed by thin layer chromatography, and the product was collected. 26.4 mg of a white solid were obt...

Embodiment 2

[0035] Optimization and selection of embodiment 2 reaction conditions

[0036] Under the same reaction conditions as in Example 1, the different additives added have a significant impact on product and reaction rate, as shown in table 1, it is the impact on reaction and product when using different reaction solvents and additives,

[0037] The selection and output effect of additives in the reaction of table 1

[0038]

[0039] As shown in Table 1: The addition of molecular sieves can improve the enantioselectivity and reaction rate, and 2-naphthylamine can accelerate the reaction and slightly increase the enantioselectivity. The solvent is CCl 4 The reaction rate is faster, but the enantioselectivity becomes worse, while using CHCl 3 and CCl 4 A mixed solvent can reduce the reaction temperature, accelerate the reaction rate, and also improve the enantioselectivity of the compound reaction.

Embodiment 3

[0040] The selection of embodiment 3 substrate and corresponding product

[0041] 1, as figure 1 The alicyclic ketones shown as reaction substrates are reacted according to Reaction Formula III, (2-amino-4-chlorophenyl)(1-naphthyl)methanone 1a (28.1mg, 0.10mmol), alicyclic Ketone 2a-l (0.30mmol), chiral phosphoric acid (15mol%), 2-naphthylamine (40mol%), Molecular sieves (100mg) were added to CHCl 3 (0.8mL) and CCl 4 (0.2mL) in a mixed solvent at 80°C in an oil bath to seal the reaction. The 3aa-3ah reaction time is 4 days, and the 3ai-3al reaction time is 5 days. The above yields are isolated yields. The enantiomeric excess (ee value) and diastereomeric ratio (dr) of the product were separated and analyzed by HPLC chiral stationary phase method.

[0042]

[0043] 2, as figure 2 The shown 2-aminoaryl ketone compound is used as the reaction substrate, and the reaction is carried out according to the reaction formula IV

[0044]

[0045] Reaction conditions: 2-am...

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Abstract

The invention discloses a synthesis method of an axially chiral 9-aryl tetrahydroacridine compound. The synthesis method comprises the following steps: reacting a 2-amino diaryl ketone compound with cyclohexanone or a derivative thereof in an organic solvent at 70-90 DEG C by using chiral spiro phosphoric acid as a catalyst according to a reaction formula I to obtain the 9-aryl tetrahydroacridinecompound, wherein R1 is selected from any one of hydrogen, halogen or alkyl, R2 is selected from any one of alkyl or halogen, and R3 is selected from one of hydrogen, alkyl or aryl. The invention further provides the axially chiral 9-aryl tetrahydroacridine compound synthesized by the method and application of the axially chiral 9-aryl tetrahydroacridine compound. By adopting the synthesis method,the reaction enantiomer excess value reaches 95%, the separation yield is 60% or above, and an effective way is provided for synthesis of chiral drug molecules with similar frameworks.

Description

Technical field: [0001] The invention relates to the technical field of organic compound synthesis, in particular to a synthesis method of axial chiral 9-aryl tetrahydroacridine. Background technique: [0002] Acridine compounds are considered to be important skeletons in the field of drug synthesis because of their wide range of pharmacological and biological activities. Tacrine, a new drug based on tetrahydroacridine to treat Alzheimer's disease, is currently the only drug approved to treat this devastating disease. In recent years, many biologically active compounds with such advantageous structures have been designed and synthesized in the process of drug molecular screening. In addition, many studies have shown that the non-racemate has better drug activity than the corresponding racemate. [0003] The methodological examples based on quinoline skeleton synthesis are very rich, and many famous reactions have been developed, as early as more than 130 years ago The cy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D219/04C07D221/18C07D221/16C07D491/052C07D495/04C07D219/02
CPCC07B2200/09C07D219/02C07D219/04C07D221/16C07D221/18C07D491/052C07D495/04
Inventor 邵友东程道娟汪涛
Owner HEZE UNIV
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