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A kind of preparation method of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylate

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

Inactive Publication Date: 2011-12-14
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • A kind of preparation method of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylate
  • A kind of preparation method of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylate
  • A kind of preparation method of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylate

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Experimental program
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Effect test

Embodiment 1

[0030] Add 3.2 g (0.0755 mol) of lithium chloride to a solution composed of 6.0 g (0.0534mol) of potassium tert-butoxide and 60 ml of tert-butanol, heat and reflux for 1 hour, then distill off the tert-butanol solvent under reduced pressure . Add 40 ml of tetrahydrofuran, cool to 0-5°C and stir for 0.5 hour. Then add 5.0 g of p-chloropropiophenone (0.030 mol), stir at room temperature for 0.5 hours, then add 5.7 g of diethyl oxalate (0.0390 mol), and raise the temperature to 35-40°C for 5 hours. After the reaction, the tetrahydrofuran was distilled off to obtain the crude 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester lithium salt as a brown-red thick substance, which was used directly In the next step reaction.

[0031] Add 50 ml of glacial acetic acid to the obtained crude 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyrate ethylenol lithium salt, cool and stir, and then add 9.6 g of 2,4-Dichlorophenylhydrazine hydrochloride (0.0450mol), and the reaction was stirred...

Embodiment 2

[0035] 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 and reflux for 0.5 hours, and then distill off the tert-butanol solvent under reduced pressure. Add 40 ml of tetrahydrofuran, cool to 0-5°C and stir for 0.5 hour. Then add 5.0 g of p-chloropropiophenone (0.030 mol), stir at room temperature for 0.5 hours, then add 5.7 g of diethyl oxalate (0.0390 mol), and increase the temperature to 35-40°C for 5 hours. After the reaction, the tetrahydrofuran was distilled off to obtain the crude 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyrate ethylenol lithium salt as a brownish-red thick substance, which was used directly In the next step reaction.

[0036] Add 50 ml of glacial acetic acid to the obtained crude 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyrate ethylenol lithium salt, cool and stir, and then add 9.6 g of 2,4-Dichlorophenylhydrazine hydrochloride (0.0450mol), and the reaction was st...

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Abstract

The invention discloses a preparation method of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylate. The Claisen condensation reaction of p-chloropropiophenone and oxalic acid diester is effectively carried out by using inorganic lithium salt and cheap organic alkali alkoxy metal compound to generate the corresponding stable 4-(4-chlorophenyl)-3-methyl- Enol complex lithium salt of 2,4-dioxobutyrate; direct condensation of the lithium salt with 2,4-dichlorophenylhydrazine hydrochloride in acetic acid followed by the presence of the dehydrating agent thionyl chloride One-pot cooking completes the ring closure reaction to obtain 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylate. The invention has the advantages of reasonable synthetic process design; no expensive organolithium reagent; shortened reaction time; high product yield, simple and convenient operation, low synthetic cost and easy industrial scale production.

Description

【Technical Field】 [0001] The present invention relates to the technical field of drug synthesis. Specifically, it is a key intermediate 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-of a new type of drug Rimonabant Preparation method 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 a new drug Rimonabant . Rimonaban is a selective cannabinoid receptor-1 antagonist, developed by Sanofe of France and listed in 2006. It is clinically used in the treatment of weight loss and smoking cessation, and has the effect of improving blood lipid and blood glucose metabolism. Among them, 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-dichlor...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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