Method for preparing hypolipidemic medicine ciprofibrate with p-coumaric acid

A technology for p-coumaric acid and ciprofibrate, which is applied in the synthesis field of the hypolipidemic drug ciprofibrate, can solve problems such as serious environmental pollution, and achieves the effects of safe operation, environmental friendliness, and ease of large-scale industrial production.

Active Publication Date: 2016-01-13
CHENGDU LIKAI CHIRAL TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has the problem of ortho-para selectivity in the nitrification step, and a large amount of nitric acid is used in the nitrification and diazotization reactions, causing serious environmental pollution.

Method used

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  • Method for preparing hypolipidemic medicine ciprofibrate with p-coumaric acid
  • Method for preparing hypolipidemic medicine ciprofibrate with p-coumaric acid
  • Method for preparing hypolipidemic medicine ciprofibrate with p-coumaric acid

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Effect test

Embodiment 1

[0050] A method for preparing the blood lipid-lowering drug ciprofibrate by using p-coumaric acid, using p-coumaric acid as a starting material to obtain ciprofibrate through the processes of decarboxylation, etherification, cyclization, and alcoholysis, the specific steps include:

[0051] (1) Preparation of p-hydroxystyrene (Ⅱ)

[0052] Add 150 g of p-coumaric acid, 750 mL of DMF, and 9 g of potassium acetate into a 1 L reaction flask, and heat to 150° C. for 2-3 h (monitored by TLC). After the reaction was complete, the reaction solution was cooled down to room temperature, and concentrated to dry DMF under reduced pressure. Add 200mL ethyl acetate and 100mL water to the residue, stir for 15min, separate the liquids, extract the water phase once more with 100mL ethyl acetate, combine the organic phases, wash the organic phase once with 100mL2mol / L sodium carbonate aqueous solution solvent, wash once with 100mL water Wash once, and finally wash once with 100mL saturated br...

Embodiment 2

[0060] A method for preparing the blood lipid-lowering drug ciprofibrate by using p-coumaric acid, using p-coumaric acid as a starting material to obtain ciprofibrate through the processes of decarboxylation, etherification, cyclization, and alcoholysis, the specific steps include:

[0061] (1) Preparation of p-hydroxystyrene (Ⅱ)

[0062] Add 150g of p-coumaric acid, 550mL of DMA, and 9g of sodium acetate into a 1L reaction flask, and heat to 150°C for 2-3h (monitored by TLC). After the reaction was complete, the reaction liquid was lowered to room temperature, and concentrated under reduced pressure to dry DMA. Add 200mL ethyl acetate and 100mL water to the residue, stir for 15min, separate the liquids, extract the water phase once more with 100mL ethyl acetate, combine the organic phases, wash the organic phase once with 100mL2mol / L sodium carbonate aqueous solution solvent, wash once with 100mL water Wash once, and finally wash once with 100mL saturated brine, dry over an...

Embodiment 3

[0070] A method for preparing the blood lipid-lowering drug ciprofibrate by using p-coumaric acid, using p-coumaric acid as a starting material to obtain ciprofibrate through the processes of decarboxylation, etherification, cyclization, and alcoholysis, the specific steps include:

[0071] (1) Preparation of p-hydroxystyrene (Ⅱ)

[0072] Dissolve 150Kg of p-coumaric acid in 710Kg of DMF, pump the mixture into a 1000L stainless steel reaction axe, start mechanical stirring, and then add 9Kg of potassium acetate. Steam was heated to 150°C for 2-3h (monitored by HPLC). After the reaction is complete, turn off the steam, pass circulating water down to room temperature, and recover DMF under reduced pressure. Add 180Kg ethyl acetate and 100Kg water to the concentrated ash under stirring, stir for 30min, separate the liquids, extract the water phase with 90Kg ethyl acetate once, combine the organic phases, and wash the organic phase once with 100Kg2mol / L sodium carbonate aqueous ...

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Abstract

The invention discloses a method for preparing a hypolipidemic medicine ciprofibrate with p-coumaric acid. The method comprises the following specific steps: p-coumaric acid (I) is subjected to a decarboxylation reaction under the effect of an alkaline catalyst, such that p-hydroxystyrene (II) is obtained; p-hydroxystyrene (II) is subjected to a reaction with 2-haloisobutyrate under the effect of alkali, such that an etherified product (III) is obtained; under an alkaline condition, the etherified product (III) and chloroform are subjected to a cyclization reaction under the effect of a phase transfer catalyst, such that a cyclized product (IV) is obtained; the cyclized product (IV) is subjected to alcoholysis and acidification in an alkali solution; and recrystallization is carried out, such that ciprofibrate (V) is obtained. The method provided by the invention has the advantages of short synthesis process, safe operation and easy post-treatment. The method is suitable for large-scale industrialized productions, and almost has no possibility of causing accidents such as explosion. During the entire reaction process, only conventional acid, alkali and solvent are used, such that the cost is low. The solvent can be recovered and reused, such that the method is environment-friendly. With the method, the yield is improved by more than 20%.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing the blood lipid-lowering drug ciprofibrate. Background technique [0002] Ciprofibrate (ciprofibrate), also known as chlorocycloproteramine, chemically named 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropionic acid, is a French race A kind of hypolipidemic drug developed by Nuofi (Synthelabo) company in 1985, its structural formula is as follows: [0003] [0004] The method for synthesizing ciprofibrate mainly contains the following reports at present: [0005] Disclosed in CN1238324C is a raw material with styrene or (2,2-dichlorocyclopropyl) benzene, through Friedel-Crafts reaction, Baeyer-Villiger oxidation, hydrolysis to obtain p-hydroxyl-2,2-dichlorocyclopropyl phenyl, then condensed with methyl bromoisobutyrate, and finally hydrolyzed under alkaline conditions to obtain ciprofibrate with a total yield of 56% (calculated as styrene...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/72C07C51/02
CPCC07C37/50C07C51/02C07C67/343C07C59/72C07C69/712C07C39/20
Inventor 袁伟成赵建强周鸣强徐小英余斌刘斌陈明丰陈浩
Owner CHENGDU LIKAI CHIRAL TECH
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