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Method for synthesizing 3,5-disubstituted pyrazole

A synthesis method and a two-substitution technology, which are applied in 3 fields, can solve the problems of high difficulty in separation and purification, poor economy, and high synthesis cost, and achieve the effects of concise synthesis method, reduced dosage and improved yield.

Active Publication Date: 2011-08-17
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The purpose of the present invention is: to develop a simple, convenient and economical practical synthesis method of 3,5-disubstituted pyrazoles, which mainly solves the technical problems of separation and purification difficulty, high synthesis cost and poor economy in existing synthesis methods. Using reasonable solvent screening, through the investigation of the amount of reactants, reaction time and reaction temperature to improve synthesis efficiency and reduce costs, so that a large number of 3,5-disubstituted pyrazole compounds can be synthesized

Method used

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  • Method for synthesizing 3,5-disubstituted pyrazole
  • Method for synthesizing 3,5-disubstituted pyrazole
  • Method for synthesizing 3,5-disubstituted pyrazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]

[0030] In the first step, p-methoxybenzaldehyde (136mg, 1mmol) was dissolved in 6mL of toluene, then p-toluenesulfonyl hydrazide (186mg, 1mmol) was added, and stirred at room temperature for 3 hours; in the second step, 5mol / L of Sodium hydroxide aqueous solution (0.2mL, 1mmol) was stirred at room temperature for 20 minutes; in the third step, phenylacetylene (153mg, 1.5mmol) was added, and the temperature was raised to 45°C, and the reaction was completed after 12 hours. After cooling to room temperature, the solvent and a little water were evaporated by rotary evaporation, and the organic phase was eluted with ethyl acetate. LCMS showed that the purity of the crude product was 85%.

[0031] The above crude product is separated by preparative plate, obtains 220 mg product, proton nuclear magnetic resonance spectrum [ 1 H NMR (400MHz, CDCl 3 ): δ=7.72(d, 2H), 7.63(d, 2H), 7.38(t, 2H), 7.32(t, 1H), 6.90(d, 2H), 6.75(s, 1H), 3.82(s, 3H)] shows the correct structure...

Embodiment 2

[0033]

[0034] In the first step, 5-bromopyridine-3-carbaldehyde (186mg, 1mmol) was dissolved in 6 mL of toluene, then p-toluenesulfonyl hydrazide (186mg, 1mmol) was added, and stirred at room temperature for 3 hours; in the second step, 5mol / L sodium hydroxide aqueous solution (0.2mL, 1mmol), stirred at room temperature for 20 minutes; the third step, added phenylacetylene (153mg, 1.5mmol), heated to 45°C, and reacted for 12 hours to complete the reaction. After cooling to room temperature, the solvent and a little water were evaporated by rotary evaporation, and the organic phase was eluted with ethyl acetate. LCMS showed that the purity of the crude product was 96%.

[0035] The crude product above is separated by preparative plate, obtains 260mg product, proton nuclear magnetic resonance spectrum [ 1 H NMR (400MHz, CDCl 3 ): δ=9.15(s, 1H), 8.21(s, 1H), 8.19(s, 1H), 7.72(d, 2H), 7.38(t, 2H), 7.32(t, 1H), = 6.75(s , 1H)] shows the correct structure; m / z=301 (M+H + )....

Embodiment 3

[0037]

[0038] In the first step, dissolve p-benzaldehyde (106 mg, 1 mmol) in 6 mL of toluene, then add p-toluenesulfonyl hydrazide (186 mg, 1 mmol), and stir at room temperature for 3 hours; in the second step, add 5 mol / L of sodium hydroxide Aqueous solution (0.2mL, 1mmol) was stirred at room temperature for 20 minutes; in the third step, p-methylphenylacetylene (174mg, 1.5mmol) was added, the temperature was raised to 45°C, and the reaction was completed after 12 hours. After cooling to room temperature, the solvent and a little water were evaporated by rotary evaporation, and the organic phase was eluted with ethyl acetate. LCMS showed that the purity of the crude product was 91%.

[0039] The crude product above is separated by preparative plate, obtains 210mg product, proton nuclear magnetic resonance spectrum [ 1 H NMR (400MHz, CDCl 3): δ=7.72(d, 2H), 7.63(d, 2H), 7.32(t, 1H), 7.18(d, 2H), 6.90(d, 2H), 6.75(s, 1H), 2.18(s, 3H)] shows the correct structure; m / z=235...

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Abstract

The invention relates to a practical synthetic method for 3, 5-disubstituted pyrazole, and the method solves the defects of long reaction time, large consumption of alkyne, low yield and being difficult to synthesize great amount of compounds of the existing method. The technical proposal is as follows: aldehyde compounds which are dissolved into a solvent react with sulfonyl hydrazine compounds,thus obtaining diazo compounds, then the diazo compounds react with alkyne under alkali and the 3, 5-disubstituted pyrazole is obtained. The method is characterized in that the solvent is toluene, the mol ratio of the aldehyde compounds and the sulfonyl hydrazine compounds in the first step of the reaction is 1; the alkali added in the second step is NaOH aqueous solution, the content of NaOH hasthe same valent weight with the hydrazine; 1.5 valent weight of diazo compounds are added in the third step, and pure target product is obtained by conventional processing after the reaction.

Description

Technical field: [0001] The invention relates to a practical method for synthesizing 3,5-disubstituted pyrazoles. The optimized reaction conditions for synthesizing 3,5-disubstituted pyrazoles are obtained through reasonable experimental means. technical background: [0002] Pyrazole compounds have a wide range of biological activities [Chinese Journal of Pesticides; 2005; 44; 491-495.]. In terms of medicine and pesticides, its application range is extremely wide, and it has been involved in many fields such as weeding, insecticide, acaricide, fungicide and plant growth regulation [Modern Agrochemicals; 2006; 5; 6-12.]. In recent years, the research on 3,5-disubstituted pyrazoles has made great progress, and their applications are becoming more and more extensive. The synthetic methods of 3,5-disubstituted pyrazoles are: 1) α, β-unsaturated ketone and hydrazine [Bull.Chem.Soc.Jpn.; 1991,68,719-720.] or 1,3-diketone Ring-closing synthesis with hydrazine [J.Organomet.Chem.; ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/12C07D401/04
Inventor 李建源潘雪华季丽柏祝贺海鹰陈曙辉李革
Owner 上海药明康德新药开发有限公司
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