JP2015182981A - Pyrazine-2,5-dipropionic acid monoester and production method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide stable pyrazine-2,5-dipropionic acid derivatives.SOLUTION: Pyrazine-2,5-dipropionic acid monoalkyl esters and their production method are provided.

Description

  The present invention relates to a pyrazine-2,5-dipropionic acid monoester and a method for producing the same.

  The production method of 5-aminolevulinic acid is roughly divided into a chemical synthesis method and a microbial fermentation method. In the microbial fermentation method, methods using anaerobic bacteria, algae, photosynthetic bacteria, various genetically modified bacteria and the like as microbial catalysts have been reported. In particular, a fermentation method in which a microorganism belonging to the genus Rhodobacter is not typical (Patent Document 1).

  In the production of 5-aminolevulinic acid by microbial fermentation, pyrazine-2,5-dipropionic acid (hereinafter also referred to as “PDPA”), which is a dimer of 5-aminolevulinic acid, is generated as a by-product. I know. Moreover, 5-aminolevulinic acid hydrochloride is used as a diagnostic agent for discriminating between tumor tissue and normal tissue of malignant glioma, and PDPA is also shown as a contaminant in the diagnostic agent.

  On the other hand, dicarboxylic acid is a material that is widely used as a polymer raw material. In particular, terephthalic acid is industrially used, and polyethylene terephthalate is produced on a large scale by reaction with ethylene glycol. Thus, PDPA can also be applied as a polymer raw material.

Japanese Patent Laid-Open No. 11-42083

However, since PDPA is a dicarboxylic acid, the intramolecular dehydration reaction may proceed, so there is a problem in long-term stability, and there has been a problem in its use.
Therefore, a more stable PDPA derivative that can be easily converted to PDPA is desired.

  Therefore, as a result of examining and seeking a more stable derivative of PDPA, the present inventors have found that a PDPA monoester obtained by reacting PDPA with an alcohol is stable for a long period of time and can be easily converted to PDPA. Was completed.

  That is, the present invention provides the following [1] to [3].

[1] (Formula 1)

(Wherein R ¹ represents an alkyl group having ^{1 to} 16 carbon atoms)
A pyrazine-2,5-dipropionic acid monoester represented by:
[2] The pyrazine-2,5-dipropionic acid monoester according to [1], wherein R ¹ is an isopropyl group.
[3] Pyrazine-2,5-dipropionic acid or a reactive derivative thereof and formula (2)
R ² OH (2)
(Wherein R ² represents an alkyl group having 1 to 16 carbon atoms)
The method for producing a pyrazine-2,5-dipropionic acid monoester according to [1], wherein the alcohol represented by the formula (1) is reacted.

  Since pyrazine-2,5-dipropionic acid monoester (1) is stable under normal storage conditions and can be easily converted to PDPA, it can be used for the production of PDPA at the time of use.

It is a 1H-NMR measurement result of Example 1 of this invention. It is a 13C-NMR measurement result of Inventive Example 1.

  The PDPA monoester of the present invention is a compound represented by the following formula (1).

(Wherein R ¹ represents an alkyl group having 1 to 18 carbon atoms)

Examples of the alkyl group having 1 to 18 carbon atoms represented by R ¹ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, and isopentyl group. Group, neopentyl group, tert-pentyl group, 2-methylbutyl group, n-hexyl group, isohexyl group, 3-methylpentyl group, ethylbutyl group, n-heptyl group, 2-methylhexyl group, n-octyl group, isooctyl group Tert-octyl group, 2-ethylhexyl group, 3-methylheptyl group, n-nonyl group, isononyl group, 1-methyloctyl group, ethylheptyl group, n-decyl group, 1-methylnonyl group, n-undecyl group, 1,1-dimethylnonyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl Group, n- hexadecyl group, n- heptadecyl group, n- octadecyl group.

Among these alkyl groups, an alkyl group having 1 to 7 carbon atoms is preferable. More preferable examples of the alkyl group having 1 to 7 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and neopentyl. Group, tert-pentyl group, 2-methylbutyl group, n-hexyl group, isohexyl group, 3-methylpentyl group, ethylbutyl group, n-heptyl group and 2-methylhexyl group.
Among these alkyl groups, an alkyl group having 1 to 4 carbon atoms is more preferable, and an isopropyl group is more preferable.

The PDPA monoester (1) of the present invention can be produced, for example, by reacting PDPA or a reactive derivative thereof with an alcohol represented by R ¹ OH (R ¹ is the same as described above).

Examples of reactive derivatives of PDPA include acid halides and acid anhydrides. Such a reactive derivative may be isolated as a raw material, but can also be used as a reaction mixture without isolation.
In addition, when PDPA is used directly, the reaction can be performed in the presence of a condensing agent such as dicyclohexylcarbodiimide.

  Specific examples of alcohols that can be used include alcohols having 1 to 18 carbon atoms, specifically methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, 1-hexanol, These isomers including linear alkyl alcohols such as heptanol, 1-octanol, 1-nonanol, 1-decanol, 1-undecanol, 1-dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, etc. It is possible to use branched alkyl alcohols such as 2-propanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, and 2,2-dimethyl-1-propanol.

  The reaction is carried out by adding dropwise a condensing agent such as thionyl chloride to PDPA and alcohol at about 0 to 100 ° C. under normal pressure. Here, thionyl chloride is used to convert PDPA to acid chloride. For this purpose, phosphorus trichloride, phosphorus pentachloride, phosphoryl chloride, oxalyl chloride and the like can be used instead of thionyl chloride. Alternatively, PDPA and thionyl chloride may be reacted to synthesize acid chloride and then reacted with alcohol.

  Since PDPA is used as a raw material, there is concern about the progress of the diesterification reaction, but it can be suppressed using a general method. Specifically, the concentration of thionyl chloride is lowered and the reaction temperature is lowered.

  Next, the reaction may be stopped by stopping the heating when heating, stopping the cooling when cooling, and recovering the product by liquid-liquid extraction (solvent extraction). Moreover, you may refine | purify by general methods, such as a chromatography and recrystallization, as needed.

  The PDPA monoester of the present invention can be converted to PDPA by removing the protecting group by general acid hydrolysis or base hydrolysis reaction.

(Production Example 1) Production of PDPA 350 g of 5-aminolevulinic acid hydrochloride was dissolved in 3.5 L of ion-exchanged water. While stirring this, 750 mL of 5 mol / L aqueous sodium hydroxide solution was added to adjust the pH of the solution to 7.0. The solution was stirred overnight with strong bubbling.
On the next day, 760 mL of 5 mol / L hydrochloric acid was added to the solution to adjust the pH to 1.0, and the generated precipitate was collected by filtration and washed with 875 mL of 1 mol / L hydrochloric acid. After this solid was air-dried, 101 g of a solid was obtained. This solid was placed in 800 mL of pure water and suspended and stirred for 1 hour. The solid was collected by suction filtration, washed with pure water, and then washed with 8 L of acetone. This was dried under reduced pressure at room temperature to obtain 58.7 g of PDPA.

Production Example 2 Production of PDPA-mono-iPr Crystal Using 10 g of PDPA obtained in Production Example 1, it was dissolved in 200 mL of isopropyl alcohol. To this was added a mixed solution of 10 mL of chloroform and 5.3 g of thionyl chloride, and the mixture was stirred at 60 ° C. for about 40 minutes to confirm dissolution. Thereafter, heating was stopped, 400 mL of pure water and 200 mL of diisopropyl ether were added and stirred, and the aqueous layer was removed with a separatory funnel. Thereafter, 200 mL of pure water was added again and stirred, and the aqueous layer was removed with a separatory funnel. Thereafter, 200 mL of a saturated aqueous sodium chloride solution was added and stirred, and the aqueous layer was removed with a separating funnel. Thereafter, 2 g of sodium chloride was added, and the mixture was stirred at room temperature for 16 hours, filtered to remove sodium chloride, and then concentrated to dryness. This was rectified by centrifugal chromatography using a developing solvent of hexane: ethyl acetate = 4: 1 and concentrated to dryness to recover 1.99 g. ¹ H-NMR and ¹³ C-NMR of PDPA monoisopropyl ester are shown in FIG. The obtained PDPA monoisopropyl ester was stable even when stored at ordinary room temperature.

Claims (3)

(Formula 1)

(Wherein R ¹ represents an alkyl group having ^{1 to} 16 carbon atoms)
A pyrazine-2,5-dipropionic acid monoester represented by: The pyrazine-2,5-dipropionic acid monoester according to claim 1, wherein R ¹ is an isopropyl group. Pyrazine-2,5-dipropionic acid or its reactive derivative and formula (2)
R ² OH (2)
(Wherein R ² represents an alkyl group having 1 to 16 carbon atoms)
The method for producing a pyrazine-2,5-dipropionic acid monoester according to claim 1, wherein the alcohol is reacted with an alcohol represented by the formula:

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