JP2006240999A - Mercaptopyridine-n-oxide compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a mercaptopyridine-N-oxide compound, enabling the regulation of the solubility of a pyrithion compound in water or an organic solvent and further having a high photolytic property suitable as a photo-functional material. <P>SOLUTION: This mercaptopyridine-N-oxide compound is expressed by general formula (I) [wherein, M<SP>1</SP>, M<SP>2</SP>are each a +1 to +3 valent cationic group where the M<SP>1</SP>, M<SP>2</SP>are each the same or different; (m) is an integer of 1-3; R is a substituent; and (n) is an integer of 0-3]. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a photosensitive mercaptopyridine-N-oxide compound.

  Mercaptopyridine-N-oxide is a typical compound used for anti-dandruff agents, fish net antifouling agents, and preservatives, and is generally called pyrithione. For example, pyrithione antibacterial agents are generally known as sodium pyrithione, zinc pyrithione, copper pyrithione and the like. These metal pyrithiones exhibit very high antibacterial activity. For example, sodium pyrithione is unstable and difficult to handle in a dry form, and zinc pyrithione and copper pyrithione have low solubility.

  From the viewpoint of improving handling, a method using insoluble copper pyrithione fine particles according to the application (Patent Document 1), a method of preparing metal pyrithione in situ (Patent Document 2), and a composite with triphenyl (alkylenediamine) boron A body (Patent Document 3) and the like are known. Patent Document 4 describes that the solubility of alcohol-free and polyether-based solvents is improved by forming a complex of metal-free pyrithione with a guanidine derivative. However, none of these pyrithione compounds have a substituent on the pyrithione skeleton.

  On the other hand, pyrithione compounds have photodegradability, and when the compound is irradiated with light having a wavelength from near ultraviolet to visible (300 to 450 nm), the N—O bond is cleaved with a very high quantum yield to generate radicals. This is described in Non-Patent Document 1 or 2. These properties suggest that pyrithione compounds are very promising as photofunctional materials. That is, it is considered that not only photodegradability but also various desired performances can be provided by introducing substituents onto the pyrithione skeleton of the pyrithione compound and deriving various derivatives.

  However, few pyrithione compounds functionalized in the past have been known. For example, although non-patent documents 3 to 5 describe pyrithione compounds having a carboxyl group, they have not been used as optical functional materials exhibiting photodegradability in an aqueous solution. Further, from the viewpoint of solubility of the compound in water, a pyrithione compound having a carboxyl group could not give sufficient solubility.

JP 2001-48884 A JP-T-2001-524964 JP 2002-356475 A Japanese Patent Laid-Open No. 2004-43421 “Journal of the American Chemical Society”, 1996, Vol. 118, p. 10113 “Journal of the American Chemical Society”, 1997, Vol. 119, p. 6457 “Inorganic Chemistry”, 1993, vol. 32, p. 3052 “Biochemistry”, 1983, Vol. 22, p. 5331 “Journal of Coordination Chemistry”, 1992, Vol. 26, p. 1

  An object of the present invention is to provide a mercaptopyridine-N-oxide compound that enables control of the solubility of a pyrithione compound in water or an organic solvent and has high photodegradability suitable as a photofunctional material.

  As a result of intensive studies, the present inventors have obtained a mercaptopyridine-N-oxide compound having a sulfo group as a solubility-imparting site, and provided with this compound a photofunctional material capable of controlling solubility in water or an organic solvent. I found what I could do. The present invention has been made based on such findings.

That is, the present invention
(1) a mercaptopyridine-N-oxide compound represented by the following general formula (I):
Formula (I)

(M ¹ and M ² are each a +1 to +3 valent cationic group, and M ¹ and M ² may be the same or different. M represents an integer of 1 to 2. R represents Represents a substituent, and n represents an integer of 0 to 3.)
(2) In the general formula (I), M ² is a hydrogen atom, a lithium atom, a sodium atom or a potassium atom, and the mercaptopyridine-N-oxide compound according to the item (1), and (3 In the general formula (I), M ² is an alkylammonium group or an alkylphosphonium group, and the mercaptopyridine-N-oxide compound according to the item (1) is provided.
In the present invention, photodegradability (photodegradability) means that a bond between a nitrogen atom contained in a pyrithione nucleus and an oxygen atom bonded thereto is broken by light having a wavelength of 200 to 800 nm (preferably 250 to 500 nm). To be done.

  Since the compound of the present invention has photodegradability (photodegradability) and a sulfo group, a photoresponsive material and an antibacterial material that are soluble in water or an organic solvent can be provided. Moreover, the solubility can be freely controlled by selecting a counter cation of the sulfo group.

Hereinafter, the compound represented by formula (I) of the present invention will be described in detail.
The compound represented by the general formula (I) of the present invention is characterized by having a sulfo group on the pyrithione skeleton.
In general, derivatives of sulfonic acids have improved hydrophilicity when protons or alkali metal ions are counter-salts. Hydrophobic long-chain aryl or alkylammonium salts have improved hydrophobicity and dissolved in organic solvents. Sexually improves. In addition, when an insoluble salt is formed using an alkaline earth metal or the like, the solubility of the salt can be remarkably lowered, and a hardly soluble state can be obtained. Further, when a salt is formed with perfluoroalkylamine, the solubility in a fluorine-based medium can be significantly increased.
Since the compound of the present invention has a sulfo group on the pyrithione skeleton, the solubility of the pyrithione compound can be freely controlled by selecting the counter cation group as described above.

  In the general formula (I), m represents an integer of 1 or 2, and is preferably 1. The sulfo group may be substituted at any position of the pyrithione ring, but when m is 1, the ortho position or para position of the mercapto group is preferable, and the para position is particularly preferable. When m is 2, it is preferably substituted at the ortho position and the para position.

M ¹ and M ² are each a +1 to +3 valent cationic group, and M ¹ and M ² may be the same or different. In the present invention, the cationic group refers to a group that ionizes to form a cation.
As the +1 to +3 valent cationic group, a hydrogen atom, an ammonium group, an alkylammonium group (for example, triethylammonium group, tetrabutylammonium group, cetyltrimethylammonium group, perfluorotributylammonium group), an alkylphosphonium group (for example, , Tetrabutylphosphonium group, butyltrimethylphosphonium group), arylphosphonium group (for example, benzyltriphenylphosphonium group, tetraphenylphosphonium group), alkylsulfonium group (for example, trimethylsulfonium group, benzyldimethylsulfonium group), arylsulfonium group ( For example, triphenylsulfonium group, benzylmethylphenylsulfonium group), alkylsilyl group (for example, trimethylsilyl group, triisopropylpropyl group). Silyl group) and metal atoms are preferred, hydrogen atom, ammonium group, alkylammonium group, alkylsilyl group, alkali metal, alkaline earth metal, tin (Sn), iron (Fe), zinc (Zn), nickel (Ni) , Copper (Cu), cobalt (Co), silver (Ag), aluminum (Al), chromium (Cr), manganese (Mn), mercury (Hg), gallium (Ga), gadolinium (Gd), rhodium (Rh) Platinum (Pt) and iridium (Ir) are more preferable.

When M ¹ is a polyvalent cationic group (preferably a metal atom), a complex may be formed between molecules of the pyrithione compound represented by the general formula (I). Complexes containing may be formed. When a complex is formed between molecules, M ¹ can be coordinated to an oxygen atom that is bonded to a nitrogen atom contained in the pyrithione nucleus.
M ¹ includes hydrogen atom, sodium (Na), potassium (K), calcium (Ca), zinc (Zn), nickel (Ni), iron (Fe), copper (Cu), silver (Ag), platinum ( Pt) and iridium (Ir) are most preferable.

As described above, the solubility of the pyrithione compound in the solvent can be controlled by selecting the counter cation group bonded to the sulfo group, that is, M ² .
In order to impart water solubility to the pyrithione compound, M ² is preferably a hydrogen atom or an alkali metal, and particularly preferably a hydrogen atom, lithium, sodium or potassium.
In order to give the pyrithione compound solubility in an organic solvent, M ² is preferably an alkylammonium group, an alkylphosphonium group, an arylphosphonium group, an alkylsulfonium group or an arylsulfonium group, more preferably an alkylammonium group or an alkylphosphonium group. Alkyl ammonium groups are particularly preferred. Further, when M ² is ammonium using a fluorine-containing alkylamine, the affinity for the fluorocarbon can be improved.
Further, when sustained release is required for applications such as antibacterial agents, M ² is preferably an alkaline earth metal, more preferably magnesium, calcium or strontium, and particularly preferably calcium.

  Examples of the substituent R of the compound represented by the general formula (I) include a hydrogen atom, a halogen atom (for example, fluorine, chlorine, bromine), an alkyl group (including a cycloalkyl group and a bicycloalkyl group); for example, methyl, ethyl , Propyl, isopropyl, sec-butyl, t-butyl, 2-ethylhexyl, 2-methylsulfonylethyl, 3-phenoxypropyl, trifluoromethyl, cyclopentyl), an aryl group (eg, phenyl, 4-t-butylphenyl, 2 , 4-di-t-amylphenyl), heterocyclic groups (for example, imidazolyl, pyrazolyl, triazolyl, 2-furyl, 2-thienyl, 2-pyrimidinyl, 2-benzothiazolyl), cyano group, nitro group, amino group, alkyl An oxy group (for example, methoxy, ethoxy, 2-methoxyethoxy, 2-methoxy Sulfonylethoxy), aryloxy group (for example, phenoxy, 2-methylphenoxy, 4-t-butylphenoxy, 3-nitrophenoxy), acylamino group (for example, acetamide, benzamide), alkylamino group (for example, methylamino, Butylamino, diethylamino, methylbutylamino), anilino group (eg, phenylamino, 2-chloroanilino), ureido group (eg, phenylureido, methylureido, N, N-dibutylureido), sulfamoylamino group (eg, N, N-dipropylsulfamoylamino), mercapto group, alkylthio group (for example, methylthio, octylthio, 2-phenoxyethylthio), arylthio group (for example, phenylthio, 2-butoxy-5-t-octylphenylthio) 2-carboxyphenylthio), alkyloxycarbonylamino group (for example, methoxycarbonylamino), sulfonamide group (for example, methanesulfonamide, benzenesulfonamide, p-toluenesulfonamide), carbamoyl group (for example, N-ethyl) Carbamoyl, N, N-dibutylcarbamoyl), sulfamoyl group (eg, N-ethylsulfamoyl, N, N-dipropylsulfamoyl, N-phenylsulfamoyl), sulfonyl group (eg, methanesulfonyl, octanesulfonyl, Benzenesulfonyl, toluenesulfonyl), alkyloxycarbonyl group (for example, methoxycarbonyl, butyloxycarbonyl), heterocyclic oxy group (for example, 1-phenyltetrazol-5-oxy, 2-tetrahydropyra) Nyloxy), azo groups (eg, phenylazo, 4-methoxyphenylazo, 4-pivaloylaminophenylazo, 2-hydroxy-4-propanoylphenylazo), acyloxy groups (eg, acetoxy), carbamoyloxy groups (eg, N-methylcarbamoyloxy, N-phenylcarbamoyloxy), aryloxycarbonylamino group (for example, phenoxycarbonylamino), imide group (for example, N-succinimide, N-phthalimide), heterocyclic thio group (for example, 2- Benzothiazolylthio, 2,4-di-phenoxy-1,3,5-triazole-6-thio, 2-pyridylthio), sulfinyl group (eg 3-phenoxypropylsulfinyl), phosphonyl group (eg phenoxyphosphonyl) , Octyloxyphos Nyl, phenylphosphonyl), aryloxycarbonyl group (eg phenoxycarbonyl), acyl group (eg acetyl, 3-phenylpropanoyl, benzoyl), phosphino group, phosphinyl group, phosphinyloxy group, phosphinylamino Groups and the like. Among these, R is particularly preferably a hydrogen atom.

The compound represented by the general formula (I) is the same compound as the thione compound represented by the following general formula (II) which is a tautomer.
Formula (II)

In the formula, M ¹ , M ² , m, R and n have the same meanings as those in the general formula (I), and preferred ranges thereof are also the same.

  Although the preferable specific example of a compound represented with general formula (I) or (II) below is shown, this invention is not limited to these.

Next, a method for synthesizing the compound of the present invention will be described.
The compound of the present invention is obtained by sulfonating a substituted or unsubstituted 2-aminopyridine compound, substituting an amino group with a hydroxyl group and then a halogen atom, oxidizing a nitrogen atom and then substituting the halogen atom with a sulfur atom. Can be synthesized. Thereafter, if necessary, the counter ion of the sulfo group and the counter ion of the mercapto group are further substituted to synthesize a compound imparted with water-soluble, oil-soluble, and hardly soluble properties.

  The sulfonation of the 2-aminopyridine compound can be performed using a general sulfonating agent such as concentrated sulfuric acid, fuming sulfuric acid, sulfur trioxide, chlorosulfuric acid, amidosulfuric acid, and fluorosulfuric acid. Concentrated sulfuric acid is preferably used from the viewpoint of cost and safety. At this time, since water is generated with the progress of the reaction and the reaction rate is remarkably reduced, it is preferable to carry out the reaction while removing the water generated by vacuum distillation or azeotropic distillation. The reaction can be carried out in the range of 0 ° C to 200 ° C, preferably in the range of 30 ° C to 180 ° C, more preferably in the range of 80 ° C to 140 ° C. As the solvent, a sulfonating agent such as sulfuric acid may be used alone as a solvent, but the reaction may be carried out using a high boiling point solvent in order to perform azeotropic dehydration.

  In the general formula (I), m representing the number of sulfo groups is 1 or 2, but this can be controlled by changing the sulfonation conditions. Under the above-mentioned preferable sulfonation conditions, a compound having m = 1 is likely to be obtained. However, for example, by using concentrated sulfuric acid to react at a reaction temperature of 180 ° C. and a reaction time of 10 hours, a compound having m = 2 can be obtained.

  Next, in the step of substituting the amino group of the 2-aminopyridinesulfonic acid compound with a halogen atom, the amino group is diazotized and then converted into a hydroxyl group, and the resulting 2-hydroxypyridinesulfonic acid compound is halogenated. preferable. The diazotization of the amino group can be performed by adding an aqueous solution or powder of sodium nitrite in the presence of an acid, and can also be performed using other general diazotizing agents. The produced 2-diazonium pyridine sulfonic acid compound is an unstable compound, and immediately releases nitrogen to be converted into a 2-hydroxypyridine sulfonic acid compound. The amount of sodium nitrite used is preferably 1 to 10 equivalents, more preferably 1.1 to 5 equivalents. The reaction can be carried out at a temperature of -10 ° C to 50 ° C. However, since the diazotization reaction is exothermic, the reaction is preferably carried out between 0 ° C and 20 ° C.

  Halogenation of the obtained 2-hydroxypyridine sulfonic acid compound is performed using a reactive agent of a chlorine compound such as phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus trichloride, carbon tetrachloride-triphenylphosphine. The 2-chloropyridine sulfonic acid compound can be obtained by It is also preferable to use an amide compound (for example, dimethylformamide, dimethylacetamide) as a catalyst according to the reactant. In this case, the sulfonic acid moiety may be converted to sulfonyl chloride. In this case, the target 2-chloropyridine sulfonic acid compound is obtained by hydrolyzing the sulfonyl chloride after extraction with an organic solvent. Can do. In the synthesis of the compound of the present invention, a bromine compound can be used in addition to the exemplified chlorine compound, and a brominating agent such as thionyl bromide, hydrobromic acid, bromine-triphenylphosphine, or the like is used. Preferably thionyl bromide.

The reaction for obtaining an N-oxide compound by oxidizing a 2-halopyridinesulfonic acid compound is preferably carried out in a reaction system containing water. A reaction solvent containing 15% by weight or more of water is preferable, and a salt of persulfuric acid is preferable as the oxidizing agent in this case. From the viewpoints of reactivity, cost and safety, 2K ₂ SO ₅ · KHSO ₄ · K ₂ SO ₄ (OXONE, trade name, manufactured by DuPont) is particularly preferable.
Moreover, it is also possible to oxidize using 30% hydrogen peroxide water using an organic acid as a solvent. As the organic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid are preferable, and trifluoroacetic acid is particularly preferable.

  The reaction of substituting a halogen atom in a 2-halopyridinesulfonic acid-N-oxide compound with a sulfur atom is a known method in unsubstituted pyrithione (for example, “Journal of the American Chemical Society”, 1950, 72, p. 4362). As a solvent for the reaction, water or an alcohol solvent is preferable.

M ¹ in the compound represented by the general formula (I) can be derived from the thus synthesized pyrithione compound by a known method. For example, “Journal of Inorganic and Nuclear Chemistry”, 1964, Vol. 26, p. 1277 can be easily synthesized by reacting an aqueous solution of a target metal compound with an aqueous solution of a pyrithione compound.

Furthermore, M ² in the compound represented by the general formula (I) can be easily substituted by sulfonic acid ion exchange. For example, M ² can be easily replaced with an alkali metal by treatment with an alkali metal acetate in an alcohol solvent. Further, M ² can be easily substituted with an alkyl ammonium group by using water or an alcohol-based solution of an alkyl amine or an alkyl ammonium salt compound. It is possible to synthesize in the same manner using fluorine-containing amines.
Further, ion exchange may be performed using a strongly acidic ion exchange resin.

  The compound of the present invention can be used as a photofunctional material, and in particular, can be used for anti-dandruff agents, antiseptics, pharmaceuticals, agricultural chemicals, and the like.

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to these.

<Synthesis of Exemplary Compound (1) (2-mercaptopyridine-5-sulfonic acid-N-oxide)>
A mixture of 150 g of 2-aminopyridine and 420 g of concentrated sulfuric acid was reacted at 130 ° C. for 5 hours under reduced pressure. After cooling to 70 ° C., 375 mL of methanol was added. The obtained white crystals were filtered and washed with methanol to obtain 198 g of 2-aminopyridine-5-sulfonic acid (yield 71%).

  100 g of 2-aminopyridine-5-sulfonic acid was suspended in 900 mL of water, and 340 mL of an aqueous solution of 147 g of sodium nitrite was added dropwise at 5 ° C. or lower over 2 hours. After dropping, the mixture was further stirred for 2 hours while raising the temperature to room temperature. The reaction solution was concentrated under reduced pressure and recrystallized from water to obtain 78 g of 2-hydroxypyridine-5-sulfonic acid (yield 78%).

  A mixture of 105 g of 2-hydroxypyridine-5-sulfonic acid and 30 mL of N, N-dimethylformamide was heated to 100 ° C., and 470 g of thionyl chloride was added dropwise over 2 hours. After the addition, the mixture was further reacted for 1 hour, and then the reaction solution was poured into ice water, and the product was extracted with 1 L of ethyl acetate. After distilling off the solvent, 300 mL of methanol and 60 mL of concentrated hydrochloric acid were added and heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure and recrystallized from water to obtain 44 g of 2-chloropyridine-5-sulfonic acid (yield 38%).

_{2K 2 SO 5 -KHSO 4 -K 2} SO 4 (OXONE, trade name, manufactured by DuPont) and 2-chloro-5-sulfonic acid 20g of an aqueous solution of 63 g 200 mL was added, followed by stirring at room temperature for 12 hours. Methanol (500 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hour. The operation of adding methanol again, filtering, and concentration under reduced pressure was repeated twice to obtain an orange oil. This was purified with a Sephadex column (Sephadex LH-20, trade name, manufactured by Pharmacia, eluent: methanol) to obtain 20 g of 2-chloropyridine-5-sulfonic acid-N-oxide (yield 94). %).

15 mL of an aqueous solution containing 2.7 g of sodium sulfide nonahydrate and 2.0 g of sodium hydrosulfide hydrate was heated to 90 ° C., and 10 mL of an aqueous solution of 2.6 g of 2-chloropyridine-5-sulfonic acid-N-oxide was added dropwise. did. The mixture was further stirred for 30 minutes while being heated, then cooled, and 10 mL of concentrated hydrochloric acid was carefully added. After concentration under reduced pressure, 5 mL of methanol was added, solids insoluble in methanol were removed, and then purified with a Sephadex column (Sephadex LH-20, trade name, eluent: methanol) to give 3.0 g of exemplary compound (1). Obtained (yield 100%).
¹ H-NMR (D ₂ O): δ 7.68-7.79 (m, 2H), 8.68 (s, 1H)

<Measurement of photodegradability>
The synthesized exemplary compound (1) was dissolved in ion-exchanged water at a concentration of 3.86 × 10 ⁻⁴ mol / L, and this was placed in a 1 cm quartz cell, and an absorptiometer (multichannel detector PMA11, trade name, Hamamatsu). The absorbance was measured using Photonics Co., Ltd. The absorbance of this solution at 339 nm was 1.72. When this solution was irradiated with light from a fluorescent lamp with an emission center wavelength of 365 nm and 23 W for 30 seconds from a distance of 45 mm and the absorbance was measured in the same manner, the absorbance at 339 nm decreased to 0.28.
From this, it was found that the pyrithione compound of the exemplary compound (1) exhibits photodegradability in an aqueous solution.

<Solubilization in organic solvents, photodegradability>
Exemplified compound (1) (104 mg, 0.50 mmol) was dissolved in 1 mL of water, 1 mL of chloroform and tri-n-octylamine (220 μL, 0.50 mmol) were added, and the mixture was vigorously stirred. The organic layer was separated, 10 μL of it was diluted with 10 mL of chloroform and placed in a 1 cm quartz cell, and the absorbance was measured using an absorptiometer (multichannel detector PMA11, trade name, manufactured by Hamamatsu Photonics). This solution had a near-ultraviolet region having a λmax of 352 nm and an absorbance of 1.42. When this solution was irradiated with light from a fluorescent lamp with an emission center wavelength of 365 nm and 23 W for 30 seconds from a distance of 45 mm and the absorbance was measured in the same manner, the absorbance at 352 nm decreased to 0.08. From this, it was found that the pyrithione compound of the exemplary compound (1) can be given solubility in an organic solvent, and further, it itself exhibits photodegradability in an organic solvent.

When Exemplified Compound (1) (50 mg, 0.25 mmol) was taken in a test tube and 1 mL of DMF was added and stirred, a suspension was obtained. When triethylamine (40 μL) was added to this and stirred, it dissolved and became a uniform solution. 10 μL of this solution was diluted with 10 mL of DMF and placed in a 1 cm quartz cell, and the absorbance was measured using an absorptiometer (multichannel detector PMA11, trade name, manufactured by Hamamatsu Photonics Co., Ltd.). Λmax was 355 nm, and its absorbance was 1.12. When this solution was irradiated with light from a fluorescent lamp with an emission center wavelength of 365 nm and 23 W for 30 seconds from a distance of 45 mm and the absorbance was measured in the same manner, the absorbance at 355 nm decreased to 0.10. From this, it was found that by changing the counter cation of the pyrithione compound of the exemplary compound (1), it becomes soluble in an organic solvent and further exhibits photodegradability in an organic solvent.

Claims (3)

Mercaptopyridine-N-oxide compounds represented by the following general formula (I).
Formula (I)

(In the formula, M ¹ and M ² are each a +1 to +3 valent cationic group, and M ¹ and M ² may be the same or different. M represents an integer of 1 to 2) R represents a substituent, and n represents an integer of 0 to 3.) The mercaptopyridine-N-oxide compound according to claim 1, wherein M ² in the general formula (I) is a hydrogen atom, a lithium atom, a sodium atom or a potassium atom. The mercaptopyridine-N-oxide compound according to claim 1, wherein M ² in the general formula (I) is an alkylammonium group or an alkylphosphonium group.