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1-substitution phenyl-4-polysubstitution phenyl-5-methylmercapto-1H pyrazole compound with anti-hepatoma activity

A compound, -1H technology, applied in organic chemistry, drug combination, antineoplastic drugs, etc., can solve problems such as high price and drug resistance

Inactive Publication Date: 2014-09-03
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the current commercialized drugs have problems such as high price and drug resistance, so there is an urgent need for new drugs with anti-liver cancer activity

Method used

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  • 1-substitution phenyl-4-polysubstitution phenyl-5-methylmercapto-1H pyrazole compound with anti-hepatoma activity
  • 1-substitution phenyl-4-polysubstitution phenyl-5-methylmercapto-1H pyrazole compound with anti-hepatoma activity
  • 1-substitution phenyl-4-polysubstitution phenyl-5-methylmercapto-1H pyrazole compound with anti-hepatoma activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The synthesis of embodiment 12-chloro-4-fluoro-5-aminophenyl ethyl carbonate 2

[0030] Add 5.26g (20mmol) of ethyl 2-chloro-4-fluoro-5-nitrophenylcarbonate, 10mL of glacial acetic acid and 24mL of water into a 250mL four-neck flask, heat to 40-50°C to dissolve, then add 5.04 g (90mmol) reduced iron powder, stirring vigorously. After the addition, react at 70-80°C for 0.5h, TLC detects that the reaction is complete, stop the reaction, add an appropriate amount of ethyl acetate to the system, keep stirring for 5-10min, filter to remove iron sludge, and wash the filter cake three times with ethyl acetate. Combine the filtrates, wash the filtrate with saturated sodium bicarbonate solution to weak alkalinity, separate with saturated saline, and dry the organic phase with anhydrous sodium sulfate. After filtration and precipitation, the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate=20:1 (V:V)) to obtain 3.96 g of an orange-red so...

Embodiment 2

[0033] Synthesis of Example 22-fluoro-4-chloro-5-ethoxyacyloxyphenylfluoroborate diazonium salt 3

[0034] Add 4.66g (20mmol) 2 into a 100mL four-necked flask, slowly add 13.4mL of 18% dilute hydrochloric acid, stir and heat to 40-45°C, after complete dissolution, cool the reaction system to -5°C in an ice-salt bath. Add dropwise a cold solution made of 1.52g (22mmol) sodium nitrite and 2.2mL water, control the temperature below -5°C, after the dropwise addition, continue to stir for 30min, and suction filter under cooling, the filtrate is light yellow. Slowly add 7.6mL of 40% cold fluoboric acid solution dropwise to the filtrate under stirring, and control the temperature below -15°C, a yellow solid is produced. After 15 minutes, the dropwise addition was completed, and the stirring was continued for 45 minutes. Stop stirring, cool at low temperature for 3 hours, filter with suction, wash the filter cake successively with 4 mL of cold dilute fluoroboric acid, 4 mL of 50% eth...

Embodiment 3

[0037] Synthesis of Example 32-chloro-4-fluoro-5-(2-oxopropyl) ethyl phenyl carbonate 4

[0038] In a 250mL two-necked bottle, add 0.27g (1.9mmol) cuprous oxide and 33mL (300mmol) isopropenyl acetate, under the protection of argon, add 5.00g (15mmol) 3 in batches, and control the reaction temperature between 25 and 30°C . After stirring for 0.5 hours, 1.23g (15mmol) of anhydrous sodium acetate was added. After the addition was complete, the temperature was controlled and the reaction was continued for 6h. Suction filtration was performed, and the filter cake was washed with a small amount of dichloromethane. The filtrate was collected and precipitated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate=20:1 (V:V)) to obtain 3.04 g of a yellow solid with a yield of 74.0%. m.p.: 54~56℃.

[0039] 1 H NMR (400MHz, δ: ppm, CDCl 3 ): 7.20 (d, 3 J H-F =8.8Hz, 1H, Ar-H), 7.09(d, 4 J H-F =6.7Hz, 1H, Ar-H), 4...

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Abstract

The invention relates to the synthesis and anti-hepatoma activity study of a 1-substitution phenyl-3-methyl-4-(2-fluorine-4-chlorine-5-propargyloxyphenyl)-5-methylmercapto-1H pyrazole compound (A). The compound (A) is prepared through the following steps of reducing 2-chlorine-4-fluorine-5-nitro phenyl ethyl carbonate with iron powder, carrying out diazotization and Meerwein arylation reaction and reacting with carbon disulfide and dimethyl sulfate to obtain 2-chlorine-4-fluorine-5-(1,1-dimethylthio-3-oxo-1-alkene-2-group) phenyl ethyl carbonate (5), hydrolyzing the (5), then reacting with propargyl bromide to obtain 4,4-dimethylthio-3-(2-fluorine-4-chlorine-5-propargyloxyphenyl) butane-3-alkene-2-ketone (6), and finally with ethyl alcohol as a solvent, reacting (6) with different substituted phenylhydrazine hydrochlorides under reflux condition to generate the compound (A). Test results indicate that both the degrees of the compound A for inhibiting HepG2 cancer cells and promoting cell apoptosis are greater than or equal to control drug cyclophosphamide.

Description

【Technical field】 [0001] The invention relates to the technical field of anti-liver cancer drugs and their preparation, and synthesizes 1-substituted phenyl-3-methyl-4-(2-fluoro-4-chloro-5-propargyloxyphenyl)-5-methyl Sulfur-1H pyrazole compounds, and their anti-hepatoma activity was determined. 【Background technique】 [0002] Primary liver cancer is a common malignant tumor. In my country, the morbidity and mortality of liver cancer are second only to lung cancer. How to improve the objective curative effect and survival benefits of patients with liver cancer is a challenge for pharmacologists and medical scientists. In recent years, some new drugs have made some progress in the research and clinical application of liver cancer, which are mainly divided into two categories: one is monoclonal antibodies, and the other is small molecule compounds (Imai, K.; Takaoka, A . Nature Reviews Cancer 2006, 6(9), 714). Monoclonal antibodies for the treatment of liver cancer include...

Claims

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Application Information

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IPC IPC(8): C07D231/18A61P35/00
CPCC07D231/18
Inventor 胡方中程心心杨晓兵李丹阚晓丽顾瀚魏乃翔邹小毛
Owner NANKAI UNIV
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