Naphthalene ring-amido pyrimidine type compound and preparation method and application thereof

An aminopyrimidine and compound technology, applied in the field of compound preparation, can solve problems such as high toxicity, difficult source, drug resistance, etc., and achieve the effects of short synthesis route, simple preparation method and low requirement for experimental equipment

Active Publication Date: 2020-05-12
GUIZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although paclitaxel, vinblastine and other tubulin inhibitor anti-tumor drugs have been successfully used in cli

Method used

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  • Naphthalene ring-amido pyrimidine type compound and preparation method and application thereof
  • Naphthalene ring-amido pyrimidine type compound and preparation method and application thereof
  • Naphthalene ring-amido pyrimidine type compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of a kind of 4-(4-methoxynaphthalen-1-yl)-5-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine (1)

[0038] The structural formula of compound 1 is as follows:

[0039]

[0040] Concrete preparation steps are as follows:

[0041] Step 1: Add 5ml of trifluoroacetic acid to 1-methoxynaphthalene (1.5mmol), 3,4,5-trimethoxyphenylacetic acid (1.0mmol), and trifluoroacetic anhydride (2.0mmol), and stir at room temperature for 12 hours, spin-dried, separated and purified by silica gel column chromatography to obtain 1-(4-methoxynaphthalen-1-yl)-2-(3,4,5-trimethoxyphenyl)ethan-1-one.

[0042] Step 2: Mix 1-(4-methoxynaphthalen-1-yl)-2-(3,4,5-trimethoxyphenyl)ethan-1-one (1.0 mmol), DMF-DMA (10.0 mmol) was placed in a reaction flask, refluxed for 24 hours, and was spin-dried to obtain (E)-3-(dimethylamino)-1-(4-methoxynaphthalene-1-yl)-2-(3 ,4,5-trimethoxyphenyl)prop-2-en-1-one.

[0043] Step 3: Add (E)-3-(dimethylamino)-1-(4-methoxynaphthalen-1-yl)-2-(3,4,5-trimethoxy...

Embodiment 2

[0049] Preparation of a kind of 4-(4-methoxynaphthalen-1-yl)-5-(4-methoxyphenyl)pyrimidin-2-amine (2)

[0050] The structural formula of compound 2 is as follows:

[0051]

[0052] Concrete preparation steps are as follows:

[0053] Step 1: Add 5ml of trifluoroacetic acid to 1-methoxynaphthalene (1.5mmol), 4-methoxyphenylacetic acid (1.0mmol), and trifluoroacetic anhydride (2.0mmol), stir at room temperature for 12 hours, spin dry , separated and purified by silica gel column chromatography to obtain 1-(4-methoxynaphthalen-1-yl)-2-(4-methoxyphenyl)ethan-1-one.

[0054] Step 2: Place 1-(4-methoxynaphthalen-1-yl)-2-(4-methoxyphenyl)ethan-1-one (1.0mmol), DMF-DMA (10.0mmol) in In the reaction bottle, reflux reaction for 24 hours, and spin dry to obtain (E)-3-(dimethylamino)-1-(4-methoxynaphthalene-1-yl)-2-(4-methoxy phenyl)prop-2-en-1-one.

[0055] Step 3: Add (E)-3-(dimethylamino)-1-(4-methoxynaphthalen-1-yl)-2-(4-methoxyphenyl)prop-2-ene-1 - Ketone (0.5mmol), guanidine ...

Embodiment 3

[0060] Preparation of a kind of 4-(4-methoxynaphthalene-1-yl)-5-(4-methylphenyl)pyrimidin-2-amine (3)

[0061] The structural formula of compound 3 is as follows:

[0062]

[0063] Concrete preparation steps are as follows:

[0064] Step 1: Add 5ml of trifluoroacetic acid to 1-methoxynaphthalene (1.5mmol), 4-methylphenylacetic acid (1.0mmol), and trifluoroacetic anhydride (2.0mmol), stir at room temperature for 12 hours, spin dry, Separation and purification by silica gel column chromatography gave 1-(4-methoxynaphthalen-1-yl)-2-(4-methylphenyl)ethan-1-one.

[0065] Step 2: 1-(4-methoxynaphthalen-1-yl)-2-(4-methylphenyl)ethan-1-one (1.0 mmol), DMF-DMA (10.0 mmol) were placed in the reaction In the bottle, reflux for 24 hours, and spin dry to obtain (E)-3-(dimethylamino)-1-(4-methoxynaphthalene-1-yl)-2-(4-methylphenyl ) prop-2-en-1-one.

[0066] Step 3: Add (E)-3-(dimethylamino)-1-(4-methoxynaphthalen-1-yl)-2-(4-methylphenyl)prop-2-ene-1- Ketone (0.5mmol), guanidine hyd...

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Abstract

The invention discloses a naphthalene ring-aminopyrimidine type compound as well as a preparation method and application thereof, and belongs to the technical field of preparation of new drug compounds. The preparation method disclosed by the invention comprises the following steps: carrying out an acylation reaction between 1-methoxynaphthalene and substituted phenylacetic acid to prepare 1-(4-methoxynaphthalene-1-yl)-2-substituted phenylethane-1-one; carrying out a reaction between 1-(4-methoxynaphthalene-1-yl)-2-substituted phenylethane-1-one and DMF-DMA to prepare (E)-3-(dimethylamino)-1-(4-methoxynaphthalene-1-yl)-2-substituted phenylpropyl-2-ene-1-one, and finally performing a ring closing reaction with guanidine hydrochloride and potassium carbonate to obtain the naphthalene ring-aminopyrimidine compound as shown in the general formular (I) in the specification. The naphthalene ring-amidopyrimidine compound disclosed by the invention has good activity of inhibiting tubulin polymerization, can effectively inhibit the proliferation activity of human breast cancer MCF-7 cells, can be used as a novel lead compound for antitumor drug research, and is suitable for market popularization and application.

Description

technical field [0001] The invention belongs to the technical field of compound preparation, and in particular relates to a naphthalene ring-aminopyrimidine type compound, a preparation method thereof and an application in preparation of tubulin inhibitor antitumor drugs. Background technique [0002] Microtubules are composed of α and β tubulin dimers and are key components of the eukaryotic cytoskeleton. Microtubules are involved in a variety of cellular functions such as maintenance of cell shape, cell signaling, secretion, intracellular transport, and cell division. During mitosis in eukaryotic cells, microtubules form a spindle that guides chromosome division into two daughter cells. Disruption of microtubule function can cause dividing cells to arrest in the G2 / M phase, leading to apoptosis. Tubulin has become one of the important targets in the current research and development of anticancer drugs. Although paclitaxel, vinblastine and other tubulin inhibitor antineo...

Claims

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Application Information

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IPC IPC(8): C07D239/42A61P35/00
CPCA61P35/00C07D239/42
Inventor 王广成彭知云王亚静巩仔鹏李勇军马雪
Owner GUIZHOU MEDICAL UNIV
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