Preparation method and application of naphthylamine compounds and salts thereof

A compound, a technology of naphthylamine, which is applied in the field of preparation of naphthylamine compounds and their salts, can solve the problems of many nitro-reducing impurities, limited species expansion, poor solubility, etc., and achieves low-cost raw materials, inhibition of signal activation, and short steps. Effect

Active Publication Date: 2020-08-21
HENAN RADIOMEDICAL SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The relevant synthetic methods reported at present mainly have the problems of low yield and difficult purification in the synthetic process.
The reason for these two problems is that there are many nitro reduction impurities and poor solubility
This also directly limits the expansion of the types of derivatives of such compounds

Method used

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  • Preparation method and application of naphthylamine compounds and salts thereof
  • Preparation method and application of naphthylamine compounds and salts thereof
  • Preparation method and application of naphthylamine compounds and salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] A kind of preparation method of naphthylamine compound, synthetic route is as follows:

[0035]

[0036] (1) Preparation of compound b

[0037]Compound a (1.0 g, 8.19 mmol, 1.0 eq) and 1,2-dibromoethane (3.85 g, 20.47 mmol, 2.50 eq) were dissolved in 30 ml of anhydrous acetonitrile, and potassium carbonate (1.36 g, 9.83 mmol, 1.2 eq), potassium iodide (13.59 mg, 81.88 μmol, 0.01 eq). Raise the temperature to reflux for 16 hours, TLC monitors the completion of the reaction, filter with diatomaceous earth, spin dry, and purify by column chromatography (volume ratio, ethyl acetate:petroleum ether=15~5:1) to obtain 1.50 g of compound b as a white solid , yield 79.8%.

[0038] (2) Preparation of compound c

[0039] Compound b (1.0 g, 4.37 mmol, 1.0 eq) was dissolved in 40 mL of anhydrous tetrahydrofuran, sodium borohydride (198 mg, 5.24 mmol, 1.2 eq) was added at room temperature, and reacted at room temperature for 1 hour. TLC (petroleum ether: ethyl acetate = 3:1, R...

Embodiment 2

[0046] Embodiment 2: the preparation of compound h

[0047]

[0048] Dissolve compound g (100 mg, 265 μmol, 1.0 eq) in 10 ml of anhydrous methanol, add 37wt% concentrated hydrochloric acid (52.3 mg, 531 umol, 2.0 eq) at room temperature, continue the reaction at room temperature for 2 hours, and spin the solution directly Dry to obtain compound h, brown solid, 119 mg, yield 100%.

Embodiment 3

[0049] Embodiment 3: the preparation of compound i

[0050] Dissolve compound g (100 mg, 265 μmol, 1.0 eq) in 10 ml of anhydrous methanol, add 80% phosphoric acid aqueous solution (52 mg, 531 umol, 2.0 eq) at room temperature, react at 50°C for 12 hours, and spin the solution directly Dry to obtain compound i, a brown-black solid, 152 mg, yield 100%.

[0051] 1. Targeted inhibition of STAT3

[0052] 1. Computer virtual analysis of the interaction between naphthylamino group and SH2 domain of STAT3 protein

[0053] All computer coordination simulation (docking) experiments were completed on the operating platform of sybyl X2.1.1, and the computer coordination simulation (docking) tool used was SUEFLEX DOCK. According to the selected sites (mainly including the phosphorylated tyrosine interaction sites of STAT3SH2 domain lysine (LYS) 591, arginine (ARG) 595 and arginine (ARG) 609 and hydrophobic interaction sites Glutamic acid (GLU) 638 was calculated, and the SH2 domain of S...

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PUM

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Abstract

The invention discloses a preparation method and application of naphthylamine compounds and salts thereof, concretely provides a method for synthesizing the naphthylamine compounds by taking 4-formylphenol as a substrate, and also provides a preparation method of hydrochloride and phosphate of the naphthylamine compounds. The preparation method has the characteristics of short synthesis route, cheap and easily available raw materials, simple post-treatment and purification, relatively high total yield and the like. The method has important significance for expanding the variety of naphthylamine derivatives and researching the naphthylamine derivatives in the aspects of biology and medicine. Meanwhile, the antitumor effect and mechanism of the prepared naphthylamine compounds and hydrochloride and phosphate thereof are further studied, and the result shows that the naphthylamine compounds and hydrochloride and phosphate thereof have the following advantages: (1) cancer cell proliferation, growth or migration is inhibited; and (2) cancer cell apoptosis is promoted or cancer cell migration capability or invasion capability is reduced, and meanwhile, the compounds can also be used as an inhibitor for tyrosine phosphorylation of STAT3.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a preparation method and application of a naphthylamine compound and a salt thereof. Background technique [0002] Signal Transducer and Activator of Transcription 3 (STAT3 for short) is one of the core regulators of cell signal transduction. The activity of STAT3 is strictly controlled in normal cells, but STAT3 is often abnormally expressed and constitutively activated in a variety of tumor cells. The activation of STAT3 signaling can promote the expression of many cancer genes such as cyclin D1 (Cyclin D1), proto-oncogene (Myc), survivin (Survivin) and matrix metalloproteinases (MMPs) (Bournazou E, Bromberg J. Targeting the tumormicroenvironment: JAK-STAT3 signaling. JAKSTAT, 2013, (2):e23828. Yu H, Pardoll D, Jove R, et al. STATs in cancer inflammation and immunity: leading role for STAT3. Nat. Rev. Cancer, 2009, (9) :798–809. Yu H, Jove R. The STATs of cancer-new mol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/088A61K31/4453A61P35/00A61P35/04
CPCC07D295/088A61P35/00A61P35/04
Inventor 徐学军杨争艳徐红运杨玉坡张韶华张尊段超群徐凯刘瑞
Owner HENAN RADIOMEDICAL SCI & TECH CO LTD
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