Naphthoyl amine derivative, and preparation method and application thereof

A technology for naphthylcarboxamide and derivatives, applied in the field of naphthylcarboxamide derivatives, can solve the problems of low yield, unsuitable industrial production, high price, etc., achieve high yield, simple and easy control of the reaction process, and reduce reaction cost Effect

Inactive Publication Date: 2013-09-11
HUAQIAO UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] International patent WO2010139180A1 discloses the structure and synthesis method of a naphthylamide derivative of a protein kinase inhibitor and a histone deacetylase inhibitor. In the patent synthesis method: 1) the first step is 6-hydroxynaphthoic acid and 4, The cesium carbonate that the ether-forming reaction catalyst of 7-dichloroquinoline uses is expensive, and toxicity is bigger, and the pollution of environment is big; 2) reaction conditions are harsh, and productive rate is lower
Therefore, this preparation method is not suitable for industrialized production

Method used

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  • Naphthoyl amine derivative, and preparation method and application thereof
  • Naphthoyl amine derivative, and preparation method and application thereof
  • Naphthoyl amine derivative, and preparation method and application thereof

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preparation example Construction

[0043] The present invention also relates to a kind of preparation method of naphthylcarboxamide derivative, described preparation method is as follows:

[0044] Step 10. Dissolve compound II in ethanol, then add concentrated sulfuric acid dropwise, heat and reflux at 78-85°C for 4-5 hours, distill off the solvent under reduced pressure, add ethyl acetate, then use saturated sodium bicarbonate and saturated chlorine NaCl was washed 2-3 times respectively, the organic phases were combined, and the solvent was distilled off under reduced pressure to obtain compound III. The reaction equation is as follows:

[0045]

[0046] Wherein, compound II is 6-hydroxyl-2-naphthoic acid, and compound III is 6-hydroxyl-2-naphthoic acid;

[0047] Step 20. Dissolve the obtained compound III in DMF, stir in the ice bath, slowly add the DMF solution containing NaH dropwise, stir in the ice bath for half an hour, remove the ice bath, wait until the temperature returns to room temperature, slowly...

Embodiment 1

[0056] Compound 6-hydroxyl-2-naphthoic acid 1.88g (10mmol) was dissolved in 40 milliliters of ethanol, added 4 drops of concentrated sulfuric acid, heated to reflux at 80°C for 5 hours, and then the solvent was removed under reduced pressure to obtain compound 6-hydroxyl-2- Ethyl naphthoate 1.98g (9.2mmol), yield 91.7%;

[0057] The obtained compound 6-hydroxyl-2-naphthoic acid ethyl ester 1.98g (9.2mmol) was dissolved in 5 milliliters of DMF, stirred under ice bath, slowly added dropwise the DMF solution 10 milliliters containing 0.52g (21.7mmol) of NaH, ice The bath was stirred for half an hour, the ice bath was removed, and when the temperature returned to room temperature, 10 ml of DMF solution containing 2.19g (11.1mmol) 4,7-dichloroquinoline and 0.38g (1.8mmol) KI was slowly added dropwise, and stirred for half an hour , reacted at 110° C. for 8-10 hours, then removed the solvent under reduced pressure to obtain the reaction mixture, separated by silica gel column chroma...

Embodiment 2

[0064] Compound 6-hydroxyl-2-naphthoic acid 3.53g (20mmol) was dissolved in 40 milliliters of ethanol, added 8 drops of concentrated sulfuric acid, heated to reflux at 80°C for 5 hours, and then the solvent was removed under reduced pressure to obtain compound 6-hydroxyl-2- Ethyl naphthoate 4.01g (18.5mmol), yield 92.5%;

[0065] Dissolve 2.01 g (18.5 mmol) of the compound 6-hydroxyl-2-ethyl naphthoate in 5 mL of DMF, stir in an ice bath, slowly add 15 mL of a DMF solution containing 1.02 g (41.7 mmol) of NaH, and place in an ice bath Stir for half an hour, remove the ice bath, wait for the temperature to return to room temperature, slowly drop into 15 ml of DMF solution containing 3.68g (18.6mmol) 4,7-dichloroquinoline, and 0.69g (4.16mmol) KI, stir for half an hour, React at 110°C for 8-10 hours, then remove the solvent under reduced pressure to obtain the reaction mixture, which is separated by silica gel column chromatography, the gradient of the mobile phase is: V (n-hexa...

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Abstract

The invention provides a naphthoyl amine derivative, and a preparation method and an application of the same. The naphthoyl amine derivative is N-(3- trifluoromethyl phenyl)-6-[(7- chloroquinoline-4-oxo) phenolic ether]-2- naphthoyl amine; the N-(3- trifluoromethyl phenyl)-6-[(7- chloroquinoline-4-oxo) phenolic ether]-2- naphthoyl amine can be used as protein kinase inhibitor and histone deacetylase inhibitor, and can be used for treating diseases caused by protein kinase dysregulation. The naphthoyl amine derivative can effectively treat the diseases caused by protein kinase dysregulation, and has the advantages of high bioavailability, obvious antitumor activity and low toxicity; moreover, the naphthoyl amine derivative is low in preparation reaction cost and higher in yield, the reaction process is simple and easy to control, so that the naphthoyl amine derivative is suitable for industrial production.

Description

【Technical field】 [0001] The present invention relates to a kind of naphthyl carboxamide derivative, its preparation method and application. 【Background technique】 [0002] Protein kinases are a class of enzymes that catalyze the phosphorylation of proteins, particularly on specific tyrosine, serine, and threonine residues in proteins. Protein kinases play key roles in regulating many cellular physiological processes, including metabolism, cell proliferation, cell differentiation, cell survival, immune response, and angiogenesis. Many diseases are associated with abnormal cellular responses regulated by protein kinases. These diseases include inflammation, autoimmune diseases, cancer, neurological and neurodegenerative diseases, cardiovascular diseases, metabolic diseases, allergies, asthma and hormone-related diseases (Tan, S-L, 2006, J. Immunol, 176: 2872- 2879; A.eaal.2006, J.Immunol.177:1886-1893; Salek-Ardakani, S.etal.2005, J.Immunol.175:7635-7641; Kim, J.et al.2004,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/233A61K31/47A61P35/00A61P3/00A61P5/00A61P37/08
Inventor 王立强韩静吴振
Owner HUAQIAO UNIVERSITY
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