JPH05112593A - New tetraphenylporphyrin glycoside - Google Patents

Abstract

PURPOSE:To provide the title new glycoside containing glycosyl residue such as of lactose, highly soluble in water, good in bioavailability, useful as a recording material, therapeutic agent or a precursor for metal complexes with catalytic function. CONSTITUTION:Acetic anhydride is added to a mixture of a lactose monohydrate an sodium acetate followed by reaction at 100 deg.C for 4hr to produce octa-0-acetyl lactose, which is then dissolved in chloroform followed by adding phosphorus tribromide to the solution to make a reaction at room temperature for 4 hr to form hepta-O-acetyl lactosyl bromide. Thence, p-hydroxybenzaldehyde is added to thus bromide followed by reaction at 50 deg.C for 2hr to produce p- formylphenylhepta-O-acetyl lactoside. A Lewis acid and pyrrole are then added to this lactoside to carry out reaction at room temperature followed by addition of chloranil to make a reaction under heating, and the product is purified using a column chromatography, thus obtaining the objective compound of formula I [R is phenylglycoside residue of formula II (R1 to R3 are each H or glycoside residue such as of lactose)].

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a tetraphenylporphine glycoside having a novel disaccharide bonded thereto, which exhibits excellent solubility in water.

[0002]

2. Description of the Related Art Tetraphenylporphine has been conventionally used as a model compound for a substance having a porphyrin skeleton such as hemoglobin or chlorophyll.
However, tetraphenylporphine itself is sparingly soluble in organic solvents and insoluble in water. Therefore, in order to improve the solubility, various measures such as introducing an alkyl group, a sulfonic acid group, a carboxyl group or an amino group into the phenyl group have been made.

On the other hand, as a tetraphenylporphine glycoside, up to now, there is only an example in J. Am. Chem. Soc., 111, 9125 (1989), in which helicine was synthesized as a raw material. It is described that glucose is bound to the ortho position of the phenyl group of tetraphenylporphine, and it is soluble in water, but in practice it is difficult to dissolve it to arbitrarily high concentrations. In addition, there is xylose-bound tetraphenylporphine, which is a monosaccharide that the present inventors applied for earlier, but it is also poorly soluble in water and cannot be said to be water-soluble (Japanese Patent Application No. 3). -219152).

By the way, recently, tetraphenylporphine or its derivative has been attracting attention as a recording material for photochemical hole burning which enables ultra-high density optical recording. However, at this stage, this photochemical hole burning recording is possible only at an extremely low temperature, so that raising the operating temperature is one of the practical problems. Up to now, there have been few successful cases of high temperature operation, Jpn.J.Appl.Phys., 27, L1304 (1988) and Appl.P.
There is only hys.Lett., 53,935 (1988). The success of these high temperature operations is believed to be due to hydrogen bonding between the dye molecules and the surrounding matrix, and the development of superior recording materials that enable higher temperature operations is awaited. ..

In recent years, porphine derivatives have been used as a therapeutic material for photodynamic therapy.
Some clinical cases have been reported. In this case, it is very slow in terms of solubility until it is taken up by the body,
There is a drawback in that it takes a long time for treatment and burdens the patient. When the porphine derivative is water-soluble, an extremely excellent therapeutic effect can be expected. Furthermore, although various metal complexes of porphyrin derivatives have been investigated as organic synthesis reaction catalysts, their application range may be dramatically expanded by improving their solubility.

[0006]

Since various excellent effects can be expected when the porphine derivative is water-soluble as described above, the present invention provides a tetraphenylporphine compound having excellent solubility in water. The purpose is to provide a glycoside.

[0007]

The present inventors have provided a novel recording material for photochemical hole burning, a therapeutic agent as a photodynamic therapy, or a precursor of a tetraphenylporphine metal complex having a function as a catalyst. Therefore, as a result of earnestly researching the above compound, its synthesis was successful. That is, the tetraphenylporphine glycoside compound of the present invention has the general formula (I)

[Wherein R is the following formula (II)

Embedded image (wherein _one of R ₁ , R ₂ and R ₃ is a lactose or maltose glycoside residue, and the rest are hydrogen atoms. Also, the substitution configuration on the anomeric carbon of the glycoside residue is Is either α- or β-). ]
It is represented by.

The tetraphenylporphine glycoside compound represented by the general formula (I) is a novel compound not described in the literature. The compound of the general formula (I) of the present invention can be synthesized by combining the methods known per se, but the following method is the most efficient. That is, lactose or maltose is acetylated with acetic anhydride using anhydrous sodium acetate as a catalyst to obtain octaacetate. The obtained octaacetate was dissolved in chloroform,
The anomeric carbon is brominated with a hydrobromide acetic acid solution. This bromide is reacted with sodium salt of monohydroxybenzaldehyde in acetone to obtain phenyl glycoside. This phenylglycoside and pyrrole are reacted in dry dichloromethane using a boron trifluoride diethyl ether complex as a catalyst to obtain an acetylated compound of the compound represented by the general formula (I). Then, it is deacetylated in methanol / dichloromethane with sodium methoxide as a catalyst to obtain the compound represented by the above general formula (I). The compound represented by the general formula (I) of the present invention is a dark red solid at room temperature and atmospheric pressure, and its visible spectrum shows the Sole band and Q band characteristic of porphyrin. It also dissolves very well in water.

The tetraphenylporphine glycoside of the present invention to which a disaccharide of lactose or maltose is bound is compared with the one to which a monosaccharide such as glucose or xylose previously invented by the present inventors is bound. It has a strong hydrogen-bonding ability due to the OH group of the sugar chain of sugar, exhibits high solubility in water, and has dramatically improved water solubility, and is very well soluble in water. Further, the metal complex of the tetraphenylporphine derivative can be easily obtained from the compound of the present invention by improving the solubility.

[0010]

[Examples] The present invention is described in more detail below with reference to Examples, but the production method of the compound represented by the general formula (I) is not particularly limited, and the production methods previously filed by the present inventors are also included. Preferably, the individual processes may be obtained by other synthetic methods.

EXAMPLE 1 10.00 g (0.278 mol) of lactose monohydrate, 5.00 g (0.610 mol) of sodium acetate and 30.60 g (0.
2998 mol) was added and the mixture was stirred at 100 ° C. for 4 hours. The reaction solution was cooled to room temperature, 5 ml of methanol was added, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, which was extracted with dichloromethane. The dichloromethane extract was washed with a saturated aqueous solution of sodium hydrogen carbonate. Further, after washing with water, the dichloromethane layer was separated. Anhydrous sodium sulfate was added to this dichloromethane solution for drying. After distilling off the solvent, it was recrystallized from ethanol. The crystals were dried under vacuum to obtain 14.94 g of octa-O-acetyllactose.

Phosphorus tribromide (5.59 g, 0.0206 mol) was added to acetic acid 14
1.01 g of water (0.056
mol) was added dropwise. After completion of dropping, stirring was continued at room temperature for 30 minutes. This solution was added to octa-O-acetyl lactose 1
4.00 g (0.0206 mol) was added to a solution of 280 ml of chloroform, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, which was extracted with dichloromethane. The extract was washed with water and then with a saturated aqueous solution of sodium hydrogen carbonate. Furthermore, after washing with water, the dichloromethane layer was separated, and anhydrous sodium sulfate was added and dried. After distilling off dichloromethane, recrystallization from acetone-diethyl ether gave 12.26 g of hepta-O-acetyllactosyl bromide.

Hepta-O-acetyllactosyl bromide
50% acetone to 10.00 g (0.0143 mol) and sodium salt of p-hydroxybenzaldehyde 3.09 g (0.0214 mol)
ml was added, and the mixture was stirred at 50 ° C. for 2 hours. Water was added to the reaction solution, which was extracted with dichloromethane. The extract was washed with a 5% aqueous sodium carbonate solution and then with a saturated aqueous sodium chloride solution. The dichloromethane layer was separated, dried over anhydrous sodium sulfate. After distilling off dichloromethane, the residue was dried in vacuum and p-formylphenylhepta-O-
A crude product of acetyl lactoside was obtained. This crude product was adsorbed on a synthetic adsorbent SP207 manufactured by Mitsubishi Kasei Co., Ltd. and then eluted with hydrous methanol. The eluent containing phenylglycoside was concentrated under reduced pressure to obtain 1.96 g of p-formylphenylhepta-O-acetyllactoside.

1.00 g (0.00135 mol) of p-formylphenylhepta-O-acetyllactoside and 92 mg of pyrrole
(0.00133 mol) was dissolved in dry dichloromethane and then purged with nitrogen for 10 minutes. Boron trifluoride-diethyl ether complex Add 30 mg of diethyl ether solution, and let stand at room temperature for 2 hours 30
It was made to react for minutes. Chloranil (0.33 g) was added and the mixture was refluxed for 1 hour. After concentrating the reaction solution, the obtained crude product was subjected to column chromatography using silica gel, eluting with 15% acetone-dichloromethane to collect the target product.
After the solution was concentrated, the residue was dissolved in dichloromethane and poured into methanol for reprecipitation. This precipitate was filtered under reduced pressure to recover the precipitate. The precipitate was dried under vacuum, and column chromatography was again performed using the above silica gel to obtain 0.19 g of the acetylated compound of the general formula (I). 20 mg of this solid was dissolved in 2 ml of 50% methanol-dichloromethane, one drop of 28% sodium methylate methanol solution was added, and the mixture was reacted at room temperature for 10 minutes. The precipitated solid was filtered under reduced pressure and vacuum dried to obtain 15 mg of 5,10,15,20-tetrakis (p-lactosylphenyl) porphine.

Example 2 Using the sodium salt of o-hydroxybenzaldehyde instead of the sodium salt of p-hydroxybenzaldehyde, the same synthetic method as in Example 1 above was used.
5,20-Tetrakis (o-lactosylphenyl) porphine was obtained.

Example 3 Using the sodium salt of m-hydroxybenzaldehyde in place of the sodium salt of p-hydroxybenzaldehyde, the same synthetic method as in Example 1 above was used.
5,20-Tetrakis (m-lactosylphenyl) porphine was obtained.

Example 4 5,10,15,20-tetrakis (p-maltosyl) was prepared by the same synthetic method as in Example 1 except that maltose was used as a raw material instead of lactose and sodium salt of p-hydroxybenzaldehyde was used. Phenyl) porphine was obtained.

Example 5 Using the sodium salt of o-hydroxybenzaldehyde instead of the sodium salt of p-hydroxybenzaldehyde, the same synthetic method as in Example 1 above was used.
5,20-Tetrakis (o-maltosylphenyl) porphine was obtained.

Example 6 Using the sodium salt of m-hydroxybenzaldehyde in place of the sodium salt of p-hydroxybenzaldehyde, the same synthetic method as in Example 1 above was used.
5,20-Tetrakis (m-maltosylphenyl) porphine was obtained.

The physical properties of the tetraphenylporphine lactose and maltose glycosides obtained in each of the above examples are shown in FIG.
~ 6 ¹ H-nuclear magnetic resonance spectrum (NMR: heavy solvent D
MSO) chart. The glycosides obtained in each of the above Examples all showed excellent water solubility.

[Brief description of drawings]

FIG. 1 is an NMR chart of the tetraphenylporphine glycoside obtained in Example 1.

FIG. 2 is an NMR chart of the tetraphenylporphine glycoside obtained in Example 2.

FIG. 3 is an NMR chart of the tetraphenylporphine glycoside obtained in Example 3.

FIG. 4 is an NMR chart of the tetraphenylporphine glycoside obtained in Example 4.

5 is an NMR chart of the tetraphenylporphine glycoside obtained in Example 5. FIG.

FIG. 6 is an NMR chart of the tetraphenylporphine glycoside obtained in Example 6.

[Chemical 3]

[Chemical 4]

Claims (1)

[Claims] 1. A compound represented by the general formula (I): [Wherein R is the following formula (II): (However, _one of R ₁ , R ₂ and R ₃ is a lactose or maltose glycoside residue and the rest are hydrogen atoms. Further, the substitution configuration on the anomeric carbon of the glycoside residue is α- or It is either β-.)
Represents a phenylglycoside residue represented by. ] The novel tetraphenylporphine glycoside compound represented by these.