JP2008266197A - Method for preparing pure fenofibrate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for preparing pure fenofibrate. <P>SOLUTION: The method for preparing fenofibrate comprises (i) a process for obtaining a fenofibrate reaction mixture, (ii) a process for cooling the reaction mixture to a temperature of 40°C-80°C, (iii) a process for adding a solvent selected from a 1-4C alcohol and a ketone to the reaction mixture, (iv) a process for initially cooling the reaction mixture to a temperature of 10-50°C, stirring the mixture, filtering off a salt and continuing crystallization at 0-5°C all night to crystallize fenofibrate and (v) a process for recovering fenofibrate crystal by filtration, cleaning and drying the crystal at about 60°C and provides fenofibrate having a polymer-impurity content of <0.5%. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention provides a method for preparing pure fenofibrate and a method for purification thereof.

  Formula (I), also known as fenofibrate

2- [4- (4-Chlorobenzoyl) phenoxy] -2-methylpropanoic acid 1-methylethyl ester having the formula: is disclosed in US Pat. No. 4,058,552 as a cholesterol-lowering and antihyperlipidemic agent .

  Several methods for the preparation of fenofibrate are known, for example in US Pat. No. 4,739,101, EP 2151, and US Pat. No. 6,897,333. Fenofibrate provides a compound of formula (II) to give a compound of formula (I)

And a bromine derivative of formula (III)

Are reacted in the presence of a base such as K ₂ CO ₃ or KHCO _{3 in} the presence or absence of a solvent. In general, in the aforementioned patent, the reaction is carried out at a temperature in the range of 80 ° C. to 160 ° C. for a time in the range of 2-3 hours to 2-3 days. The final compound is then obtained by crystallization from aqueous isopropanol.

  However, during the reaction between the compound of formula (II) and the compound of formula (III), a significant amount (up to 1%) of polymeric impurities, ie poly (isopropyl methacrylate) of formula (IV)

(Where n is a number giving an average molecular weight in the range of 50,000 to 200,000). The impurities are difficult to detect and, when performed as described in known methods, are hardly removed from the final compound during the last crystallization.

  Thus, there is a need for improved methods that can minimize the formation of impurities during the reaction or that can be removed during final crystallization and / or purification.

  The present invention relates to an improved process for the preparation of fenofibrate that allows a reduction of the impurity content to less than 0.5%, preferably to less than 0.1%.

The method of the present invention comprises:
i) a compound of formula (II)

And a compound of formula (III)

Reacting with
ii) cooling the reaction mixture at a temperature in the range of 40 ° C to 80 ° C;
iii) adding a solvent selected from C ₁ -C ₄ alcohols and ketones;
iv) initially cooling to a temperature comprised between 10-50 ° C., stirring the mixture, filtering the salt and crystallizing fenofibrate by continuing to crystallize at room temperature at 0-5 ° C. overnight;
v) collecting the fenofibrate crystals by filtration, washing and drying at a temperature of about 60 ° C.

  A further object of the invention is a fenofibrate obtainable by said method, characterized by a content of polymer impurities of formula (IV) of less than 0.5%

(Wherein n has the same meaning as defined above).

  The reaction of compound II with compound III can be carried out by known methods, such as those disclosed in US Pat. No. 6,897,333, in solvents (eg, alcohols such as isopropanol), and alkali metal bicarbonates or other bases. In the presence of

  The reaction mixture is then cooled to a temperature in the range of 40 ° C to 80 ° C, preferably 50 ° C to 70 ° C, most preferably about 60 ° C.

  Isopropanol and acetone are preferred solvents for subsequent steps.

  A decolorizing agent such as charcoal may optionally be added prior to further cooling at a temperature in the range of 10-50 ° C, preferably about 40 ° C. After stirring the mixture for a period of time, preferably 2-3 minutes to 2 hours, most preferably about 30 minutes, the salt and decolorizing agent are filtered, optionally in the presence of a filter aid, and the solid on the filter is removed from the previous step. Wash with the same solvent used in the process. The fenofibrate is then crystallized by cooling the filtrate overnight at room temperature and at 0-5 ° C. for 2-3 hours.

  Finally, to obtain pure fenofibrate with a very low impurity content, the fenofibrate crystals are filtered, washed and then dried at a temperature of about 60 ° C. for 2-3 hours.

Alternatively, the crude fenofibrate containing a high amount of the polymer impurity is
i) fenofibrate, ketone, it preferably suspended in C ₃ -C ₆ ketone,
ii) heating the suspension to reflux until complete dissolution;
iii) C ₁ ~C ₄ adding alcohol,
iv) cooling the solution to a temperature of 0-40 ° C., preferably 10-30 ° C., stirring the suspension overnight at the same temperature, and v) further cooling the mixture to a temperature of 0 ° C.-5 ° C., The resulting crystals may then be filtered, collected and finally further purified by drying the resulting pure fenofibrate at about 60 ° C. overnight.

  The following examples further illustrate the method of the present invention.

Example 1
200 g 4-chloro-4-hydroxybenzophenone, potassium hydrogen carbonate (156 g), 360 g isopropyl α-bromoisobutyrate and isopropanol (400 ml) were placed in a round bottom flask. The mixture was heated to reflux for 48 hours with stirring. After completion of the reaction, the reaction mixture was cooled at about 60 ° C. and isopropanol (560 ml), acetone (240 ml), and a decolorizing agent (4.5 g activated carbon) were added. The suspension was further cooled to about 40 ° C. and stirring was continued for about 30 minutes. The suspension was filtered and the solid was washed on the filter with a mixture of isopropanol and acetone. The filtrate was left at room temperature overnight and then stirred at 0-5 ° C. for a further 3-4 hours. The pure fenofibrate that precipitated was filtered and washed on the filter with isopropanol and water. The compound was collected from the filter and dried at about 60 ° C. for 12 hours to give 220 g of pure fenofibrate.

Example 2
Fenofibrate (100 g) was suspended in acetone (100 ml). The suspension was refluxed to complete solution and then isopropanol (300 ml) was added at about 40-45 ° C. in about 30 minutes. The mixture was cooled to 15-20 ° C. and stirred overnight. The suspension was then stirred at 0-5 ° C. for 4-6 hours, filtered and washed with isopropanol. The product was collected from the filter and dried at about 60 ° C. to give about 80 g of pure fenofibrate.

Claims (5)

Fenofibrate characterized by a content of polymer impurities of formula IV of less than 0.5%

(Where n is a number giving an average molecular weight in the range of 50,000 to 200,000). i) a compound of formula (II)

And a compound of formula (III)

Reacting with
ii) cooling the reaction mixture at a temperature in the range of 40 ° C to 80 ° C;
iii) adding a solvent selected from C ₁ -C ₄ alcohols and ketones;
iv) initially cooling to a temperature comprised between 10-50 ° C., stirring the mixture, filtering the salt and crystallizing fenofibrate by continuing to crystallize at room temperature at 0-5 ° C. overnight;
v) A method for preparing fenofibrate, comprising the steps of collecting fenofibrate crystals by filtration, washing, and drying at a temperature of about 60 ° C.   The process according to claim 2, wherein the reaction mixture is cooled to a temperature of 50C to 70C.   The method of claim 3, wherein the reaction mixture is cooled to 60 ° C.   The process according to claims 2 to 4, wherein the solvent in step iii) is selected from acetone and isopropanol.