Acetamino azobenzene derivative and preparation and application thereof

A technology for acetamidoazobenzenes and derivatives is applied in the fields of acetamidoazobenzene derivatives and their preparation and application, can solve problems such as lack of availability, and achieve the effects of easy separation and purification, and a simple and convenient preparation method

Active Publication Date: 2019-04-05
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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  • Acetamino azobenzene derivative and preparation and application thereof
  • Acetamino azobenzene derivative and preparation and application thereof
  • Acetamino azobenzene derivative and preparation and application thereof

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 acetamino azobenzene derivative and preparation and application thereof. The derivative has a structure in a general formula as shown in the specification. The acetamino azobenzene derivative has characteristics of structural changes and activity changes under illumination conditions, is in a structure of a structural formula I in a dark environment and is in a structure of a structural formula II after ultraviolet irradiation, wherein the structure II has K-Ras(G12C) protein inhibiting activity, and the structure I is weak in activity. The compound can be used forpreparation of selective medicines for treatment of K-Ras gene mutation related tumors such as colorectal cancer, lung cancer and prostatic cancer.

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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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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