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A kind of acetamido azobenzene derivatives and its preparation and application

A technology for acetamidoazobenzene derivatives and derivatives, which is applied in the field of acetamidoazobenzene derivatives and their preparation and application, can solve problems such as not having enough, and achieve the effect of easy separation and purification, and simple preparation methods

Active Publication Date: 2022-01-04
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these inhibitors have selectivity against mutant K-Ras (G12C) protein but not against wild-type K-Ras protein, they do not have the characteristics of controlling the inhibition of K-Ras protein under different conditions

Method used

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  • A kind of acetamido azobenzene derivatives and its preparation and application
  • A kind of acetamido azobenzene derivatives and its preparation and application
  • A kind of acetamido azobenzene derivatives and its preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The preparation process of (E)-2-chloro-N-(4-((4-chlorophenyl) azo) phenyl) acetamide is as follows:

[0038]

[0039] Reagents and conditions: (a) K 2 CO 3 ,H 2O, 10min; (b) AcOH, DCM, r.t. overnight (c) 1) HCl, MeOH, reflux, 9h; 2) NaOH; (d) chloroacetyl chloride, dry DCM, DIPEA, r.t., overnight.

[0040] Specifically, the following steps are included:

[0041] (1), intermediate 1[N-(4-nitrosophenyl)acetamide]

[0042]

[0043] Dissolve potassium hydrogen persulfate compound salt in 50ml of water, add potassium carbonate to adjust the pH to weak acidity, then quickly add 4-aminoacetanilide that has been dissolved in water, the solution quickly produces gray-green foam and gray-green precipitation, and when the gray-green After the foam disappeared and the precipitate settled, the reaction was continued for another 10 minutes to stop. Filtrate to obtain a gray-green precipitate, dissolve it with hot ethanol and filter to remove impurities to obtain a green s...

Embodiment 2

[0054] (E)-2-chloro-N-(4-((2,4-dichlorophenyl) azo) phenyl) acetamide preparation process is as follows:

[0055]

[0056] Reagents and conditions: (a) K 2 CO 3 ,H 2 O, 30min; (b) AcOH, DCM, r.t.overnight (c) 1) HCl, MeOH, reflux, 9h; 2) NaOH; (d) chloroacetyl chloride, dry DCM, DIPEA, r.t., overnight.

[0057] Specifically, the following steps are included:

[0058] (1), intermediate 5[2,4-dichloro-1-nitrosobenzene]

[0059]

[0060] Dissolve 2,4-dichloroaniline in dichloromethane, dissolve potassium hydrogen persulfate complex salt in water, mix under nitrogen protection, and stir overnight at room temperature. After the reaction, the organic phase was washed with 1M hydrochloric acid (10 mL) and saturated brine. Finally, dry the organic phase with anhydrous sodium sulfate, concentrate the product intermediate 5, and directly put it into the next step of reaction.

[0061] (2), intermediate 6[(E)-N-(4-((2,4-dichlorophenyl)azo)phenyl)acetamide]

[0062]

[006...

Embodiment 3

[0071] Preparation of (E)-2-chloro-N-(4-((3,4-dichloro)azo)phenyl)acetamide (9)

[0072] Adopt the synthetic method similar to embodiment 2, difference is:

[0073] (a), the raw material amine described in step 1 adopts 3,4-dichloroaniline

[0074] The final test results are as follows: 1H NMR (400MHz, DMSO-d6): δ10.71(s, 1H), 8.02(s, 1H), 7.92(d, J=7.6Hz, 2H), 7.85(s, 1H), 7.84(s,1H),7.82(d,J=9.2Hz,2H),4.32(s,2H) ppm.HRMS(ESI):[M+H] – C 14 h 11 Cl 3 N 3 O, the target compound Exact mass calculated value: 341.9959, observed value: 341.9967.

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Abstract

The invention relates to an acetamido azobenzene derivative and its preparation and application. The derivative has the general formula and the structure. The acetamidoazobenzene derivatives involved in the present invention have the characteristics of producing structural changes and activity changes under light conditions, exhibiting the structure in structural formula I in a dark environment, and exhibiting the structure in structural formula II after ultraviolet light; the structure II has K‑Ras (G12C) protein inhibitory activity, and structure I has weaker activity. Such compounds can be used for the treatment of K-Ras gene mutation-related tumors, such as rectal cancer, lung cancer and prostate cancer, etc. as selective drugs.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to an acetamidoazobenzene derivative and its preparation and application. Background technique [0002] Ras gene mutations are associated with many cancers, and cancer-related Ras genes are basically single-base mutations, and 99% of the mutations occur at the 12th and 13th glycine and the 61st glutamic acid (Nature reviews cancer, 2011 , 11, 761-774). The distribution of Ras mutations is not uniform among cancers. K-Ras is the gene with the highest mutation frequency, reaching 86%. K-Ras mutations are most common in colorectal cancer, lung cancer (mainly non-small cell lung cancer) and pancreatic cancer. [0003] The K-Ras protein was considered "undruggable" for many years. New technologies in drug discovery have facilitated new therapeutic approaches targeting RAS (McCormick, 2015). At present, research on inhibitors of Ras protein mainly focuses on the following a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C245/08A61P35/00
CPCA61P35/00C07C245/08C07C2601/02
Inventor 朱明彦东多凌葛志华杨卓进梁婧诗
Owner SHANGHAI JIAO TONG UNIV
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