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Novel ciprofibrate synthesis method

A new method and condensation technology, applied in the field of synthesizing ciprofibrate, can solve the problems of difficult large-scale industrialization, expensive raw materials, difficult operation, etc., and achieve the effect of simple and convenient industrial operation, stable process and convenient post-processing

Active Publication Date: 2015-12-23
ZHEJIANG NEXCHEM PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method raw material is more expensive, and BBr 3 Volatile, poor stability, difficult to operate in industry, difficult to large-scale industrialization

Method used

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  • Novel ciprofibrate synthesis method
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  • Novel ciprofibrate synthesis method

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Embodiment 1

[0050] A new method for synthesizing ciprofibrate, using p-hydroxybenzaldehyde as a starting material to obtain ciprofibrate through condensation decarboxylation, etherification, ring formation and alcoholysis, the specific steps include:

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

[0052] Add 130g of p-hydroxybenzaldehyde, 165g of malonic acid, 600mL of DMF, and 7.8g of diethylamine into a 1L reaction flask, and heat to 150°C for 6h (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 500 mL of ethyl acetate and 100 mL of water to the residue for dilution, and adjust to 3-4 with 2 mol / L dilute hydrochloric acid in an ice bath. Separation, the organic phase was washed once with 200mL2mol / L sodium carbonate aqueous solution solvent, washed once with 200mL water, and finally washed once with 200mL saturated brine, dried over anhydrous sodium sulfate, filtered...

Embodiment 2

[0061] A new method for synthesizing ciprofibrate, using p-hydroxybenzaldehyde as a starting material to obtain ciprofibrate through condensation decarboxylation, etherification, ring formation and alcoholysis, the specific steps include:

[0062] (1) Preparation of p-hydroxystyrene (Ⅱ)

[0063] Add 150g of p-hydroxybenzaldehyde, 154g of malonic acid, 550mL of toluene, and 9g of pyrrolidine into a 1L reaction flask, and heat to 150°C for 6h (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 550 mL of ethyl acetate and 150 mL of water to the residue for dilution, and adjust to 3-4 with 2 mol / L dilute hydrochloric acid in an ice bath. Separation, the organic phase was washed once with 250mL2mol / L sodium carbonate aqueous solution solvent, washed once with 250mL water, and finally washed once with 250mL saturated brine, dried over anhydrous sodium sulfate, filtere...

Embodiment 3

[0072] A new method for synthesizing ciprofibrate, using p-hydroxybenzaldehyde as a starting material to obtain ciprofibrate through condensation decarboxylation, etherification, ring formation and alcoholysis, the specific steps include:

[0073] (1) Preparation of p-hydroxystyrene (Ⅱ)

[0074] Dissolve 130Kg of p-hydroxybenzaldehyde and 165Kg of malonic acid in 600Kg of DMF, pump the mixed solution into a 1000L stainless steel reaction axe, turn on the mechanical stirring, and then pump in 7.8Kg of ethylenediamine. Steam was heated to 150°C for 6h (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 500L ethyl acetate and 100L water to the concentrated ax for dilution, and slowly add 2mol / L dilute hydrochloric acid dropwise to adjust the pH to 3-4. Separation, the organic phase was washed once with 200L2mol / L sodium carbonate aqueous solution solvent, washed onc...

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Abstract

The invention discloses a novel ciprofibrate synthesis method. The novel ciprofibrate synthesis method comprises the specific steps that p-hydroxy benzaldehyde (I) and malonic acid perform condensation decarboxylation reaction in the presence of an alkaline catalyst to obtain p-hydroxystyrene (II), the p-hydroxystyrene (II) reacts with 2-halogenated isobutyrate under the action of alkali to obtain an etherification product (III), the etherification product (III) and chloroform perform cyclization reaction under the alkaline condition and under the action of a phase transfer catalyst to obtain a cyclization product (IV), and the cyclization product (IV) is subjected to alcoholysis, acidification and recrystallization in an alkaline solution to obtain ciprofibrate (V). The novel ciprofibrate synthesis method comprises few synthesis steps, industrial operation is simple and convenient, the conditions are moderate and are easy to control, almost no possibility of explosion and other accidents exists, operation is safe, aftertreatment is convenient, a process is stable, large-scale industrial production is easy to achieve, only conventional acid, alkali and solvents are used in the whole reaction process, the novel ciprofibrate synthesis method is low in cost and is environmentally friendly, and the yield is improved by above 15%.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a new method for synthesizing 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). This method involves t...

Claims

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Application Information

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IPC IPC(8): C07C59/72C07C51/09
CPCC07C37/20C07C51/09C07C67/307C07C67/31C07C67/343C07C59/72C07C69/712C07C39/20
Inventor 袁伟成余斌赵建强陈明丰徐小英周鸣强祝云明刘斌
Owner ZHEJIANG NEXCHEM PHARMA
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