Preparation method and application of chiral 3, 6-diazabicyclo [3.2.1] octane derivative

A technology for diazabicyclo and derivatives, applied in the field of preparation of chiral 3,6-diazabicyclo[3.2.1]octane derivatives, which can solve the problem of high corrosiveness and toxicity of raw materials and long steps , harsh reaction conditions, etc., to achieve the effect of cheap raw materials, simple steps, and easy-to-obtain raw materials

Active Publication Date: 2021-10-22
HUNAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above method not only has long steps, but also has high corrosive and toxic raw materials, and the reaction conditions are harsh, such as low temperature minus 78°C, etc.
Moreover, the 3,6-diazabicyclo[3.2.1]octane derivatives synthesized by the above method are mainly obtained as racemic compounds, and the synthesis of their chirality has not been reported.

Method used

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  • Preparation method and application of chiral 3, 6-diazabicyclo [3.2.1] octane derivative
  • Preparation method and application of chiral 3, 6-diazabicyclo [3.2.1] octane derivative
  • Preparation method and application of chiral 3, 6-diazabicyclo [3.2.1] octane derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] This example provides the synthesis of 3,6-diazabicyclo[3.2.1]octane derivatives, the steps are as follows:

[0032]

[0033]S1. the molar weight is the silver catalyst of 2~4mol% of the terminal alkene amides of α-substitution and the chiral phosphine-amide ligand that the molar weight is 2~4% of the terminal alkene amides of α-substituted room temperature is 1 ~2h, then add azomethine ylide and α-substituted terminal olefin amide, stir at a certain temperature for a reaction time t 1 2 to 24;

[0034] S2. Add alkali in step S1, stir reaction time t at room temperature 2 1h ~ 12h, until the reaction is complete;

[0035] S3. Add saturated saline solution to the solution system that has reacted completely in step S2, and use CH 2 Cl 2 Extract 3 times, combine organic phase;

[0036] S4. adding anhydrous Na in the organic phase gained in step S3 2 SO 4 Dry, filter and concentrate under reduced pressure, elute through the column with ethyl acetate and petroleum ...

Embodiment 2

[0038] In this example, according to the method provided in Example 1, 3,6-diazabicyclo[3.2.1]octane was prepared according to the material parameters listed in the table below, as shown in Table 1 below:

[0039] Table 1

[0040]

[0041]

Embodiment 3

[0043] According to the preparation method described in Example 1, the following substances were synthesized:

[0044]

[0045] Wherein, Et is ethyl.

[0046] Calculate the product yield of each material as in Table 2:

[0047] Table 2

[0048] serial number Product yield (%) Ee(%) serial number Product yield (%) Ee(%) 3a 93 95 3i 87 94 3b 87 93 3j 92 96 3c 78 91 3k 95 94 3d 96 95 3l 97 96 3e 86 94 3m 93 95 3f 90 95 3n 81 91 3g 86 96 3o 67 96 3h 97 94 3q 71 95

[0049] The examples were used to prepare chiral 3,6-diazabicyclo[3.2.1]octane derivatives, and the prepared products were characterized by hydrogen spectrum and carbon spectrum.

[0050] Described product structural formula and characterization data are as follows:

[0051] Characterization data of compound 3a

[0052]

[0053] 1 H NMR (400MHz, CDCl 3 )δ7.45(d, J=8.4Hz, 2H), 7.33-7.23(m, 4H), 7.17-7.14(m, 2H), 7....

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Abstract

The invention discloses a preparation method of a chiral 3, 6-diazabicyclo [3.2.1] octane derivative. According to the chiral 3, 6-diazabicyclo [3.2.1] octane derivative, monovalent silver salt is combined with different chiral phosphine-amide ligands to synergistically catalyze 1, 3-dipolar cycloaddition reaction between different series of azomethine ylide and alpha-substituted terminal olefin amide, and the chiral 3, 6-diazabicyclo [3.2.1] octane derivative is directly obtained through intramolecular cyclization under the treatment of strong base. The preparation method disclosed by the invention is simple in steps, relatively cheap and easily available in raw materials, low in corrosion degree and relatively low in toxicity, and simple and easily-realized in reaction conditions. The 3, 6-diazabicyclo [3.2.1] octane derivative obtained according to the preparation method of the chiral 3, 6-diazabicyclo [3.2.1] octane derivative can be applied to a drug inhibitor or a drug intermediate.

Description

technical field [0001] The present invention relates to the technical field of octane derivative synthesis, more specifically, to a preparation method and application of chiral 3,6-diazabicyclo[3.2.1]octane derivatives. Background technique [0002] 3,6-diazabicyclo[3.2.1]octane derivatives not only have important medical research value (such as in the inhibition of thrombin activity and as fragment inhibitors of serine protease structure), but also its derivatives are Key intermediates for the synthesis of quinolone antibacterial drugs, antihypertensive drugs, hypoglycemic drugs and antitumor drugs. [0003] According to literature reports, in 1988, the Kleinman group used cyclopentadiene and imine as raw materials to synthesize 3,6-diazabis through Diels-Alder reaction, ozone ring opening, Mannich reaction and sodium cyanoborohydride reduction. Cyclo[3.2.1]octane derivatives (reference: J. Org. Chem., 1988, 53(4), 896-899). In 2010 and 2014, the Kudryavtsev group reporte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08C07F7/18C07F9/6558B01J31/24
CPCC07D471/08C07F7/1804C07F7/1892C07F9/65583B01J31/2404C07B2200/07B01J2531/17B01J2531/0213B01J2531/0261
Inventor 王海飞邓启福张凯强陈知刚
Owner HUNAN UNIV OF TECH
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