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Preparation method of 5-(4-chlorphenyl)-1-(2, 4-dichlorophenyl) 4- methylpyrazole-3-formic ether

A technology of dichlorophenyl and methylpyrazole, which is applied in the field of drug synthesis, can solve the problems of low yield and high reaction cost, and achieve the effects of high yield, low synthesis cost and easy industrial scale production

Inactive Publication Date: 2009-11-25
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] The purpose of the present invention is to overcome the high cost of p-chloropropiophenone and oxalic acid diester Claisen condensation reaction caused by the use of organolithium reagents in the prior art and the low yield caused by the use of metal alkoxide compounds, to provide a low-cost, High-efficiency and most simplified preparation method of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylate, which can realize large-scale industrialization production to meet the needs of practical applications

Method used

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  • Preparation method of 5-(4-chlorphenyl)-1-(2, 4-dichlorophenyl) 4- methylpyrazole-3-formic ether
  • Preparation method of 5-(4-chlorphenyl)-1-(2, 4-dichlorophenyl) 4- methylpyrazole-3-formic ether
  • Preparation method of 5-(4-chlorphenyl)-1-(2, 4-dichlorophenyl) 4- methylpyrazole-3-formic ether

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Embodiment 1

[0029] Add 3.2 grams (0.0755mol) of lithium chloride to a solution composed of 6.0 grams (0.0534mol) of potassium tert-butoxide and 60 milliliters of tert-butanol, heat to reflux and stir for 1 hour, then evaporate the tert-butanol solvent under reduced pressure . Add 40 ml of tetrahydrofuran, cool to 0-5°C and stir for 0.5 hours. Add 5.0 g of p-chloropropiophenone (0.030 mol) and stir at room temperature for 0.5 hour, then add 5.7 g of diethyl oxalate (0.0390 mol) and heat up to 35-40° C. for 5 hours. After finishing the reaction, tetrahydrofuran was distilled off to obtain the crude product of 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoic acid ethyl enol lithium salt as a brownish-red thick substance, which was directly used in react in the next step.

[0030] Add 50 milliliters of glacial acetic acid to the crude product of 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoic acid ethyl enol lithium salt, cool and stir, then add 9.6 grams of 2,4-dichlorophenylhydrazine hydrochl...

Embodiment 2

[0034]Add 5.2 g (0.0754 mol) of lithium nitrate to a solution composed of 6.0 g (0.0534 mol) of potassium tert-butoxide and 60 ml of tert-butanol, heat to reflux and stir for 0.5 hour, then evaporate the tert-butanol solvent under reduced pressure. Add 40 ml of tetrahydrofuran, cool to 0-5°C and stir for 0.5 hours. Add 5.0 g of p-chloropropiophenone (0.030 mol) and stir at room temperature for 0.5 hour, then add 5.7 g of diethyl oxalate (0.0390 mol) and heat up to 35-40° C. for 5 hours. After finishing the reaction, tetrahydrofuran was distilled off to obtain the crude product of 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoic acid ethyl enol lithium salt as a brownish-red thick substance, which was directly used in react in the next step.

[0035] Add 50 milliliters of glacial acetic acid to the crude product of 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoic acid ethyl enol lithium salt, cool and stir, then add 9.6 grams of 2,4-dichlorophenylhydrazine hydrochloride (0.0450mol)...

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Abstract

The invention discloses a preparation method of 5-(4-chlorphenyl)-1-(2, 4-dichlorophenyl) 4- methylpyrazole-3-formic ether. In the invention, inorganic lithium salt and cheap organic alkali alkoxy metal compounds are utilized to effectively carry out Claisen condensation reaction on para-chloropropiophenone and CPPO to generate relatively stable enol complex lithium salt of 4-(4- chlorphenyl)-3-methyl-2, 4-dioxo-butyrate. The lithium salt is directly condensed with 2, 4-dichlorobenzene hydrochloride, and then completes cyclization reaction with one pot to make the 5-(4-chlorphenyl)-1-(2, 4-dichlorophenyl) 4- methylpyrazole-3-formic ether with the presence of dehydrating agent thionyl chloride. The invention has the advantages of reasonable design of synthesis process, no costly organolithium reagents, shortened reaction time, high yield of products, simple and convenient operation, low synthesis cost, easy industrial-scale production.

Description

【Technical field】 [0001] The invention relates to the technical field of drug synthesis, in particular, it is a key intermediate 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- Process for the preparation of methylpyrazole-3-carboxylate. 【Background technique】 [0002] 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylate is a key intermediate in the synthesis of the new drug Rimonabant . Rimonabant is a selective cannabinoid receptor-1 antagonist, developed by the French company Sanofi and launched in 2006. It is clinically used for the treatment of weight loss and smoking cessation, and has the effect of improving blood lipid and blood sugar metabolism. Wherein, the structural formulas of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylate and rimonabant are: [0003] [0004] 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylate Rimonabant [0005] The key intermediate 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)...

Claims

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Application Information

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IPC IPC(8): C07D231/14
Inventor 冀亚飞张鹏志万欢段梅莉许煦王毅
Owner EAST CHINA UNIV OF SCI & TECH
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