JP2997035B2 - Method for producing porphyrin alkali salt - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing porphyrin alkali salt with high purity.

2. Description of the Related Art Methods for producing porphyrin alkali salts include, for example, protoporphyrin disodium (hereinafter, referred to as PPN).
Are known. In this method, crude protoporphyrin dimethyl ester is recrystallized using a hydrophobic solvent to obtain protoporphyrin dimethyl ester (hereinafter, referred to as PPME), and further, an alcohol solution of sodium hydroxide is added using a similar solvent. It is added (Japanese Patent Publication No. 52-37042).

However, this method is industrially superior as a method for producing high-purity PPN, and although residual solvents and the like can be removed by performing a vacuum drying step, it is necessary to prevent other impurities from being mixed into the bulk drug substance. It was not enough to be satisfied because he could not escape.

Problems to be Solved by the Invention The present invention overcomes the drawbacks of the conventional method for producing a porphyrin alkali salt such as PPN and provides a method for industrially easily and efficiently producing a high-purity porphyrin alkali salt. It was done for the purpose of doing.

Means for Solving the Problems The present inventors have conducted various studies to develop an industrial production method of a high-purity porphyrin alkali salt. One possible source, esters such as PPME, can be removed because they dissolve in hydrophobic reaction solvents, but excess alkali hydroxides, such as sodium hydroxide, do not dissolve in hydrophobic reaction solvents and can be removed. Is difficult, and the alkyl acetate is dissolved in the reaction solvent by adding alkyl acetate to the reaction system in which excess alkali hydroxide is present and converting the excess alkali hydroxide to alkali acetate. Alkali acetate produced by the reaction is also more easily dissolved and removed in the reaction solvent than alkali hydroxide. Is removed, it found that can achieve the purpose, and completed the present invention based on this finding.

That is, in the present invention, an porphyrin alkyl ester is mixed with a reaction solvent, an alcohol solution of an alkali hydroxide is added thereto, and the mixture is allowed to react.Then, by adding an alkyl acetate to the reaction mixture, excess alkali hydroxide is added. To convert porphyrin into alkali acetate.

 Hereinafter, the present invention will be described in detail.

In the method of the present invention, the porphyrin alkyl ester is first mixed well with the reaction solvent.

As the reaction solvent, an inert hydrophobic solvent is generally used, and among them, toluene, benzene, xylene, dichloroethane, trichloroethane, tetrahydrofuran,
Dimethyl sulfoxide, pyridine and the like are preferably used.

In the method of the present invention, an alcohol solution of an alkali hydroxide is then added to the mixed system and reacted. As the alcohol, alkanol is usually used, and among them, lower alkanol such as methanol and ethanol is preferable. The usage ratio of the alcohol is selected in the range of usually 3 to 20 times, preferably 5 to 15 times the weight of the alkali hydroxide used. The amount of the alkali hydroxide used is slightly larger than the stoichiometric amount with respect to the porphyrin alkyl ester charged, and is usually 2 to 2 in molar ratio.
The amount is selected in the range of 2.5 times, preferably 2 to 2.2 times. The reaction is usually performed at 60 to 120 ° C. for 10 minutes to 2 hours.

In the method of the present invention, an alkyl acetate is further added to the reaction mixture thus obtained in the form of a 5 to 50-fold alcohol solution, followed by purification treatment. The proportion of the alkyl acetate used is selected in a molar ratio of 1 to 3 (alkyl acetate / alkali hydroxide), preferably 1 to 1.2 times, relative to the excess alkali hydroxide in the reaction mixture. This purification reaction usually takes 30 to 100
C., preferably at 50-80.degree. C. for 20 minutes to 1 hour.

In the method of the present invention, the purity of the porphyrin alkali salt can be further increased by washing the product with a lower alkanol if necessary.

Effect of the Invention According to the method of the present invention, by adding an alkyl acetate to the reaction mixture, excess alkali hydroxide can be converted to alkali acetate and removed, and a high-purity porphyrin alkali salt can be obtained. It has a remarkable effect.

EXAMPLES Next, the method of the present invention will be described in more detail with reference to examples.

The water content, the sodium content, the potassium content, and the purity were determined by converting the values to the corresponding anhydrides.

Example 1 15.0 g of PPME was put into 300 ml of toluene, and the mixture was heated at 80 ° C on a water bath.
After heating and stirring for 30 minutes, a solution of 2.53 g of sodium hydroxide dissolved in 30 ml of methanol was added, and the mixture was heated and stirred at 80 ° C. for 40 minutes.

Next, the reaction solution thus obtained was subjected to A, B, C
The reaction product was collected from the reaction solution of A by suction filtration and dried under reduced pressure to obtain 4.53 g of PPN crystals (hereinafter referred to as 1A). To the reaction solution of B, add 12.5 ml of methanol,
After heating and stirring for 30 minutes at, the reaction product was collected by suction filtration and dried under reduced pressure to obtain 5.20 g of PPN crystals (hereinafter, referred to as 1B). To the reaction solution of C, 13.5 ml of a methanol solution containing 1.25 ml of ethyl acetate was added, and the mixture was heated and stirred at 60 ° C. for 30 minutes. The reaction product was collected by suction filtration, dried under reduced pressure,
5.70 g of N crystal (hereinafter referred to as 1C) was obtained.

The PPN crystals (1A, 1B, 1C) thus obtained were measured for water content, sodium content, and purity relative to a PPN standard. Table 1 shows the results.

From this, 1A and 1B have a theoretical sodium content (7.58
%), While 1C was approximately stoichiometric while containing about 1% more sodium.

Example 2 12.0 g of PPME was put into 300 ml of xylene, and the mixture was heated at 80 ° C on a water bath.
After heating and stirring for 30 minutes, a solution of 2.84 g of potassium hydroxide dissolved in 30 ml of ethanol was added, and the mixture was heated and stirred at 80 ° C. for 40 minutes.

Next, the reaction liquid thus obtained was added to A and B for 2 hours.
The reaction solution was separated, and the reaction product was collected by suction filtration from the reaction solution of A, and dried under reduced pressure to obtain 6.88 g of crystals of dipotassium protoporphyrin (hereinafter, referred to as PPK) (hereinafter, referred to as 2A).
To the reaction solution of B, 15 ml of an ethanol solution containing 1.35 ml of methyl acetate was added, and the mixture was stirred while heating at 60 ° C. for 30 minutes. 6.72 g).

The thus obtained PPK crystals (2A, 2B) were measured for water content, potassium content and purity relative to a PPK standard product. Table 2 shows the results.

Thus, the potassium content of 2A was about 1.9% higher than the theoretical amount (12.24%), while that of 2B was almost the same as the theoretical amount.

As is clear from the above results, when comparing the 1B production process and the 1C production process of Example 1, it is not possible to sufficiently remove excess sodium hydroxide simply by adding methanol and washing, but it is difficult to remove a small amount of sodium hydroxide. It has been found that by adding ethyl acetate, excess sodium hydroxide can be sufficiently removed and the purity of PPN can be greatly improved.

Also, as is clear from the results of Example 2, similar results were obtained when methyl acetate was used instead of ethyl acetate.
Furthermore, it was found that the purity of PPK could be improved as in PPN.

Claims (1)

(57) [Claims] 1. An alkyl porphyrin ester is mixed with a reaction solvent, an alcohol solution of an alkali hydroxide is added thereto, and the mixture is allowed to react. Then, an alkyl acetate is added to the reaction mixture to remove excess alkali hydroxide. A method for producing an alkaline porphyrin salt, which comprises converting into an alkaline acetate.