JP2008201740A - Method for purifying edaravone and highly pure edaravone - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for profitably obtaining highly pure edaravone capable of being supplied as a stock medicine for injections, and to provide the highly pure edaravone of its resulting product. <P>SOLUTION: This method for purifying the edaravone is characterized by recrystallizing crude edaravone from an organic solvent in the presence of a reducing agent. The highly pure edaravone, wherein the purity of the edaravone is ≥99.9%, and the highly pure edaravone, wherein the edaravone substantially does not contain the oxidative polymer of the edaravone as an impurity or has its content of ≤0.1% are disclosed. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention relates to a purification method and a high-purity edaravone of the brain protective agent edaravone (general name) represented by the following chemical structural formula.

Since edaravone is administered directly into the blood as an infusion solution in physiological saline, it is desirable that the drug substance used in the formulation be as pure as possible in order to avoid the occurrence of side effects due to impurities. Ideally, it is 100%.
Although there are many reports on preparations and production methods of edaravone as conventional techniques (Non-Patent Documents 1 to 3 and the like), there is no specific description on the purity.
Therefore, HPLC analysis of the purity of commercially available edaravone (chemical name: 3-methyl-1-phenyl-2-pyrazolin-5-one) revealed that it was 99.3% to 99.8%.

“Pharmaceutical Journal”, Vol. 124, No. 3, 2004, p. 99-111 “Journal of Heterocyclic Chemistry”, 1984, Vol. 21, p. 1747-1752 “Trends in Heterocyclic Chemistry”, 1990, No. 1, p. 55-62

  An object of the present invention is to provide a method for industrially advantageously obtaining high-purity edaravone that can be used as a drug substance for an infusion solution dissolved in physiological saline, and to provide a high-purity edaravone as a result.

The present inventor considers that the above problem can be solved by searching for the best conditions for the simplest recrystallization method as a purification method because it is preferable as an industrial production method for an active pharmaceutical ingredient. , Earnestly studied.
However, depending on the choice of solvent, addition of acidic or alkaline compounds, silica chromatography, temperature conditions, etc., the oxidative polymer contained in the crude product cannot be removed successfully or is caused during the recrystallization operation. It was concluded that side reactions such as the oxidative polymerization reaction of edaravone were inevitable and edaravone with a purity higher than 99.8% could not be obtained.
However, when a small amount of reducing agent was added to the organic solvent and recrystallization of crude edaravone was attempted by a normal operation, 99.9% high-purity edaravone could be obtained.
Therefore, further investigations were conducted on preferable reaction conditions and the like, and the present invention that achieves the intended purpose could be completed.

That is, according to the present invention, the following method and high-purity edaravone can be provided.
(1) A method for purifying edaravone, comprising recrystallizing crude edaravone from an organic solvent in the presence of a reducing agent.
(2) The method according to (1) above, wherein the reducing agent is sodium borohydride, sodium cyanoborohydride, or lithium borohydride.
(3) The method according to (1) or (2) above, wherein the organic solvent is ethanol or hydrous ethanol.
(4) High purity edaravone having a purity of 99.9% or more.
(5) The high-purity edaravone according to (4), wherein the high-purity edaravone is substantially free of an oxidative polymer as an impurity or has a content of 0.1% or less.

  According to the present invention, the reducing agent present in the organic solvent causes the oxidative polymer contained in the crude edaravone to be solubilized in the organic solvent, or during the dissolution operation of the crude edaravone and until crystal precipitation. Side reactions such as oxidative polymerization that can occur during the period are suppressed, and high purity edaravone of 99.9% or more can be obtained.

In the present invention, “crude edaravone” means edaravone that can be easily obtained by a conventional method and has a purity of up to about 99.8%. Moreover, as a reducing agent used in this invention, a mild reducing agent is preferable, for example, sodium borohydride, sodium cyanoborohydride, lithium borohydride etc. can be mentioned. The amount used may be in a very small amount. For example, the reducing agent is preferably about 0.01 to 0.05 mol per mol of edaravone.
Examples of the organic solvent used include alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, diisopropyl ether and tetrahydrofuran, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide. These water-containing solvents can be mentioned. Among these organic solvents, ethanol is preferable, and ethanol containing 50% or less of water is particularly preferable. The amount of the organic solvent to be used can be appropriately increased or decreased depending on the type of the organic solvent, and a preferable amount can be selected. Usually, about 1 to 10 parts by weight is preferable with respect to 1 part by weight of crude edaravone, and ethanol or water content is contained. In the case of ethanol, it is about 3 parts by weight.
The recrystallization method is not particularly difficult. According to a conventional method, crude edaravone is heated and dissolved in an organic solvent and allowed to stand at room temperature or cooled to precipitate crystals.
In the present invention, the purity of edaravone and the content of its oxidative polymer displayed in the present invention represent numerical values derived from measurement results obtained by ordinary high performance liquid chromatography.

  Hereinafter, although an example explains, the present invention is not limited to these.

Example 1
169.52 g of crude edaravone (purity 99.83%) was dissolved in 510 ml of ethanol by heating, and 1.11 g of sodium borohydride was added to this solution with stirring under heat and stirred overnight. When the precipitated crystals were recrystallized from ethanol, high-purity edaravone (recovery 56%) having a purity of edaravone of 99.9633% and an edaravone oxidative polymer content of 0.006% was obtained.

Example 2
In place of sodium borohydride used in Example 1, 66.2 mg of sodium cyanoborohydride was used, and 1.74 g of crude edaravone (purity 99.84%) was treated in the same manner, and the purity of edaravone was increased. 99.956% and edaravone oxidative polymer was 0.009% high purity edaravone (recovery rate 63%).

Reference example 1
Methyl acetoacetate 122.23 g (purity 95%: Nacalai Tesque) (1.00 mol) and phenylhydrazine 114.70 g (purity 99%: Nacalai Tesque), or 82-84 ° C./0.8 mmHg (Distilled under reduced pressure) (1.05 mol) was gradually added at 30 ° C. or lower with stirring, and the mixture was stirred for 0.5 hours after completion of the dropwise addition. Then, the hot water bath temperature was raised to 100 ° C. and heated for 2 hours under a nitrogen atmosphere. After confirming the disappearance of 3- (2-phenylhydrazono) butanoic acid methyl ester as a reaction intermediate by TLC analysis, the reaction solution was diluted with 320 ml of 50% aqueous ethanol while hot and stirred overnight at room temperature. The precipitated crystals were collected by suction filtration, washed with 50% aqueous ethanol and dried under reduced pressure at room temperature to obtain the target edaravone 169.53 g (purity 99.83%) (yield: 97.4%). It was.

Melting point: 129.5 ° C
IR (cm < ^-1 >; KBr): 3130,1600,1520,1500,1160,804,692
Elemental analysis: measured value (%) C: 69.01, H: 5.83, N: 16.02
Calculated value (%) C: 68.95, H: 5.79, N: 16.08
FAB-MS (m / z): Measured value 175.08783 ([MH] ⁺ )
Calculated value 175.08715 ([MH] ⁺ )
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.17 (3H, s), 3.40 (2H, s), 7.17 (1H, brt, J = 8 Hz), 7.39 (2H , Br t, J = 8 Hz), 7.85 (2H, br t, J = 8 Hz)
¹³ C-NMR (CDCl ₃ ) δ (ppm): 17, 43, 119, 125, 129, 138, 157, 171

Reference example 2
In Reference Example 1, the target edaravone was isolated in a yield of 97.4% by dissolving the reaction solution in 50% aqueous ethanol. The filtrate was concentrated, and the residue was concentrated on a silica gel column (chloroform). The following oxidative polymer was able to be isolated by separating over (methanol system).

Melting point: 323-326 ° C. (decomposition)
IR (cm < ^-1 >; KBr): 3069,1593,1560,1491,1402,1365,1308,1294,1220,831,746
FAB-MS (m / z): Measured value 347.15149 ([MH] ⁺ )
Calculated 347.15080 ([MH] ⁺ )
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.16 (6H, brs), 7.23 (2H, brt, J = 8 Hz), 7.46 (4H, brt, J = 8 Hz) ), 7.77 (4H, br d, J = 8 Hz), 11.53 (2H, br)

Comparative Example 1
When recrystallization of 5.23 g (purity 99.73%) of crude edaravone from 15 ml of ethanol, a product with a purity of 99.83% (edaravone oxidative polymer content of 0.025%) was recovered. Obtained at 72.3%.

Comparative Example 2
Although the operation of Comparative Example 1 was repeated, a product having an edaravone purity higher than 99.84% (edaravone oxidative polymer content of 0.1% or less) could not be obtained.

The purity of the edaravone and the content ratio of the oxidative polymer are calculated from the area ratio of the high performance liquid chromatograph measured under the following conditions.
Measuring instrument: Shimadzu LC-10AT system Measuring conditions: Column: Cosmosil 5C18 AR-11
Column temperature: 40 ° C
Mobile phase: 0.05 molar ammonium hydrogen phosphate-phosphate buffer
pH 3.00: methanol (70: 30 → 50: 50 →
(70:30 gradient system)
Measurement wavelength: 243 nm
Flow rate: 1.0 ml / min

According to the present invention, highly purified edaravone that cannot be obtained simply by repeating the method of recrystallization from an organic solvent can be easily obtained, which is advantageous for industrial production.
Moreover, the high purity edaravone of 99.9% or more obtained by this invention is suitable for manufacture of the infusion solution melt | dissolved in the safer physiological saline.

Claims (5)

  A method for purifying edaravone comprising recrystallizing crude edaravone from an organic solvent in the presence of a reducing agent.   The process according to claim 1, wherein the reducing agent is sodium borohydride, sodium cyanoborohydride or lithium borohydride.   The method according to claim 1 or 2, wherein the organic solvent is ethanol or hydrous ethanol.   High-purity edaravone with a purity of 99.9% or more.   The high-purity edaravone according to claim 4, which contains substantially no oxidative polymer as an impurity or has a content of 0.1% or less.