JPH06271577A - Metal complex of tetraphenylporphyrin containing side chain at two-position and its production - Google Patents

Abstract

PURPOSE:To provide a new compound excellent in safety and liposolubility and useful as an artificial oxygen carrier, a gas adsorbent, etc. CONSTITUTION:There is provide a compound of formula I [R1 is an alkyl; R2 is a substituent group; M is a transition metal (ion) belonging to the fourth to fifth period in the periodic table; X is a halogen ion; The number of X<-> is the remainder obtained by reducing 2 from the valence number of the metal ion], e.g. 2-hydroxymethyl-5,10,15,20-tetrakis(alpha,alpha,alpha,alpha-0-pivalami dophenyl)- porphinate iron. In addition, the compound of formula I can be obtained, e.g. by refluxing the compound of formula II together with >= equimolar cupric halide in dry chloroform and reacting them.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a tetraphenylporphyrin metal complex having a 2-position side chain having an oxygen transporting function, which is useful for medical purposes and the like, and a method for producing the same.

[0002]

2. Description of the Related Art Iron (II) porphyrin complexes present in hemoglobin and myoglobin have a function of reversibly adsorbing and desorbing oxygen molecules. Heretofore, many studies have been reported to try to realize an oxygen adsorption / desorption function similar to such a natural porphyrin iron (II) complex with a synthetic complex. As an example, J. P. Collma
n, Accounts of Chemical Re
search, 10, 265 (1977); Bas
olo, B. M. Hoffman and J.M. A. Ibe
rs, ibid, 8, 384 (1975).
In particular, a porphyrin iron (II) complex is known as a compound capable of forming a stable oxygen complex under room temperature conditions, and specifically, iron (II) 5,10,15,20-tetra (α,
An α, α, α-o-pivalamidophenyl) porphyrin complex (hereinafter, referred to as TpivPP complex) has been reported (JP Collman et al., J. Am. Chem.
Soc. , 97, 1427 (1975).

The TpivPP complex is an axial base, for example 1
When -alkyl imidazole, 1-alkyl-2-methyl imidazole and the like coexist, benzene, toluene,
Molecular oxygen can be reversibly bound in a greenhouse in an organic solvent such as N, N-dimethylformamide. In addition, by embedding this complex in a bilayer membrane vesicle composed of phospholipids, physiological conditions (aqueous phase, pH 7.4, ≤40 ° C)
However, the same function is exerted (E.Tsuc
hida et al. Chem. Soc. , Dalton
Trans. , 1984, 1147).

However, in order for the TpivPP complex to exhibit an oxygen adsorption function, it is necessary to externally add a large excess molar number of axial bases. In general, imidazole derivatives widely used as axial bases have a pharmacological action, and often have high in vivo toxicity. For this reason, development of a method for reducing the addition amount of the axial base to the utmost is strongly demanded from the viewpoint of safe use of the TpivPP complex.

From the viewpoint of safe use of the TpivPP complex described above, the present inventors have earnestly studied a method for reducing the externally added amount of the axial base, and have made some proposals. That is, the present inventors believe that when an imidazole derivative as an axial base is integrated with a TpivPP complex, a stable oxygen carrier can be provided without externally adding the axial base, and the position 2 is previously selected. Tpi having a substituent
A vPP complex was synthesized, and its reversible adsorption and desorption of oxygen was clarified (JP-A-59-164791). Furthermore, it has been found that by embedding these iron porphyrin complexes in a lipid bilayer, they function as an effective oxygen carrier in an aqueous phase system (JP-A-59-16292).
No. 4).

However, the above-mentioned Japanese Patent Application Laid-Open No. 59-164791 and Japanese Patent Application Laid-Open No. 59-164791 proposed by the present inventor.
In the invention of No. 162924, a substituent is introduced into the TpivPP complex via a urethane bond or an amide bond. For this reason, it is unavoidable to go through an unstable intermediate in the synthesis process, that is, not only the synthesis method is complicated, but also biodegradability and metabolism when this is administered to a living body as an artificial oxygen carrier leave anxiety. It leaves room for improvement.

[0007]

DISCLOSURE OF THE INVENTION The present inventors have investigated a method for introducing a substituent into the 2-position of a TpivPP complex under more convenient, high yield, and mild conditions, and formed a stable oxygen complex. We have conducted extensive studies on the molecular design and functional expression of possible metalloporphyrin complexes. As a result, 2-
Hydroxymethyl-5,10,15,20-tetra [α, α, α, α-o- (alkylamido) phenyl]
By introducing into the porphyrin metal complex a substituent necessary for effectively exhibiting the oxygen adsorbing ability, for example, an imidazole derivative which is a basic axial ligand by an ester bond at a ratio of 1 mol per 1 mol of porphyrin. Therefore, it was found that a stable oxygen carrier can be obtained by using a porphyrin compound having an axial base in the molecule, and completed the present invention. The above-mentioned ester bond is also highly biodegradable and advantageous for biological administration. According to the present invention, the tetraphenylporphyrin metal complex as an oxygen carrier having a 2-position side chain is highly safe, and its productivity is improved. A manufacturing method is provided.

[0008]

SUMMARY OF THE INVENTION The present invention will be outlined. The present invention relates to a tetraphenylporphyrin metal complex having a 2-position side chain represented by the following general formula (1). General formula (1)

[0009]

[Chemical 4] (In the formula, R ₁ is an alkyl group, R ₂ is a substituent, and M is a fourth group.
The transition metal atom or metal ion of the fifth period, X ⁻ represents a halogen ion, and the number of X ⁻ represents the number obtained by subtracting 2 from the valence of the metal ion. )

In the present invention, the substituent (R ₂ ) at the 2-position in the general formula (1) has an important meaning as described above. In the present invention, examples of the substituent (R ₂ ) at the 2-position include those represented by the following general formula (2). General formula (2)

[0011]

[Chemical 5] , R ₃ is a C ₁ -C ₁₈ alkyl group, or a general formula (3)
It is shown by. ) General formula (3)

[0012]

[Chemical 6] (In the formula, R ₄ represents a group that does not hinder the coordination of the imidazole to which it is bound to the central metal, and R ₅ represents an alkylene group.)

In the above general formulas (1) to (3), R ₁
Is a C ₁ -C ₁₈ alkyl group, R ₄ is hydrogen,
Alternatively, a lower alkyl group such as a methyl group, an ethyl group, or a propyl group, and R ₅ is a C _{1 to} C ₁₀ alkylene group.

The tetraphenylporphyrin metal complex having a 2-position side chain represented by the general formula (1) of the present invention is a transition of the 4th to 5th periods with respect to the porphyrin compound represented by the following general formula (4). It has a structure in which metal ions are coordinated. General formula (4)

[Chemical 7]

Next, a synthesis example of the tetraphenylporphyrin metal complex having a 2-position side chain represented by the general formula (1) of the present invention will be described. The tetraphenylporphyrin metal complex of the present invention is produced using a porphyrin compound represented by the following general formula (5) as a starting material. In addition, as compared with the porphyrin compound represented by the general formula (4), the compound represented by the general formula (5) does not have a substituent (R ₂ ) at the 2-position. General formula (5)

[0016]

[Chemical 8]

In the above general formula (5), for example, a hydrophobic porphyrin compound in which R ₁ is a C ₁ -C ₁₈ alkyl group is synthesized according to JP-A-58-21379. That is, 5,10,15,20-tetrakis (α,
α, α, α-o-amidophenyl) porphyrin and 2,
2-Dimethylalkanoic acid chloride and a suitable aprotic anhydrous solvent such as tetrahydrofuran, acetone,
5,10,15,20-tetrakis (α, α, which is the starting material of the present invention, is subjected to a condensation reaction in the presence of pyridine in dichloromethane, chloroform, dimethylformamide.
α, α-o-alkylamidophenyl) porphyrin is obtained. In the present invention, the hydrophobic 5,10,
15,20-Tetrakis (α, α, α, α-o-alkylamidophenyl) porphyrin is added to a suitable dry organic solvent, for example, dry chloroform, in a metal ion selected from the fourth cycle, preferably a divalent cation. After adding equimolar amount or more of copper in the form of acetate or halide, refluxing for about 20 minutes or more, and purifying with a silica gel column to prepare the metal complex of porphyrin. Furthermore, in the present invention, a tetraphenylporphyrin derivative having a 2-position side chain and a transition metal complex are produced from the metal complex of porphyrin by the method described below.

In order to introduce a formyl group at the 2-position of this hydrophobic tetraphenylporphyrin metal complex such as a copper complex, a Vilsmeier reagent is generally used. That is, a Vilsmeier complex prepared by adding an equimolar amount of sulforyl chloride, thionyl chloride, or phosgene to dimethylformamide or methylformamide under ice-cooling in an organic solvent such as dichloromethane, chloroform, benzene, dichloroethane, or dimethylformamide. , 5,10,15,20-tetrakis (α, α,
A 2-formyl-hydrophobic porphyrin copper complex is produced by a method of reacting with an α, α-o-alkylamidophenyl) porphyrin copper complex and hydrolyzing the immonium salt formed. As a method for desorbing copper ions from this complex, for example, after stirring in concentrated sulfuric acid at room temperature, it is poured into a mixed solution of an aqueous solution containing sodium carbonate or ammonia and dichloromethane under ice cooling and purified by a silica gel column. To do. 2-formyl-5,10 thus obtained
15,20-Tetrakis (α, α, α, α-o-amidophenyl) porphyrin is dissolved in a mixed solvent of chloroform and methanol, isopropanol, ethanol, or diglyme, preferably a mixed solvent of chloroform and methanol, and dissolved in 10 to 10 parts thereof. Add 20 times the molar equivalent of NaBH ₄ . After the reaction is completed, the product is purified with a silica gel column,
Induction to hydroxymethyl-5,10,15,20-tetrakis (α, α, α, α-o-amidophenyl) porphyrin. By reacting this 2-hydroxymethyl hydrophobic porphyrin derivative with a suitable acid in the presence of a suitable acid chloride or a condensing agent, preferably dicyclohexylcarbodiimide, a tetraphenylporphyrin derivative having a desired 2-position side chain is obtained. Manufactured.
The transition metal complex of tetraphenylporphyrin having the 2-position side chain thus prepared in the 4th to 5th periods is obtained by adding an equimolar amount or more of an acetate salt or a halide of the above metal to chloroform, tetrahydrofuran, or dimethylformamide. It can be obtained by reacting in an organic solvent such as.

The preparation examples of the tetraphenylporphyrin metal complex of the present invention, for example, the copper complex will be specifically described below. First, dimethylformamide is cooled with ice water, phosphorus oxychloride is added, and the mixture is stirred in a greenhouse for 0.5 to 4 hours to prepare a Vilsmeier reagent. 5,1 dissolved in a suitable dry organic solvent such as dry dichloromethane
0,15,20-Tetrakis (α, α, α, α-o-alkylamidophenyl) porphinato copper is added dropwise in a greenhouse and reacted at 30-60 ° C for 5-30 hours. As the reaction progresses, it becomes a dark green solution (iminium salt). After allowing to cool, add gradually to a saturated aqueous solution of sodium acetate,
After allowing to cool at 60 ° C for 0.5 to 6 hours, it is gradually added to a saturated aqueous solution of sodium acetate, and at 20 to 60 ° C,
The solution becomes magenta upon stirring for 0.5-6 hours. This is washed with water, dried and filtered, and then the solvent is removed under reduced pressure. This was purified by silica gel column chromatography and 2
-Formyl-5,10,15,20-tetrakis (α,
α, α, α-o-alkylamidophenyl) porphinato copper is obtained.

The above-mentioned 2-formyl-5, 10, 15, 20
-Tetrakis (α, α, α, α-o-alkylamidophenyl) porphinato copper is dissolved in a suitable organic solvent such as dichloromethane, chloroform, etc., concentrated sulfuric acid in the same amount as the solvent is added, and the mixture is vigorously stirred at room temperature for 5 minutes. Allow reaction for ~ 30 minutes. The solution immediately becomes a dicationic green color. When the reaction solution is slowly added to a two-phase solvent of dichloromethane / ice water and neutralized with sodium carbonate, the solution turns purple. This is washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure. Purified by silica gel column chromatography, 2-formyl-5,10,15,
20-Tetrakis (α, α, α, α-o-alkylamidophenyl) porphyrin is obtained.

The above-mentioned 2-formyl-5, 10, 15, 20
-Tetrakis (α, α, α, α-o-alkylamidophenyl) porphyrin is dissolved in a mixed solvent of dichloromethane and dehydrated methanol, and sodium borohydride (10 times or more moles of porphyrin) is added. After stirring at room temperature in an argon atmosphere for 5 to 30 minutes, water is added to stop the reaction. This is washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure. Purified by silica gel column chromatography, 2-hydroxymethyl-5,1
This gives 0,15,20-tetrakis (α, α, α, α-o-alkylamidophenyl) porphyrin. The carboxylic acid derivative is introduced into the 2-position hydroxymethyl group of the porphyrin derivative thus obtained through an ester bond.
Applicable carboxylic acids include fatty acids, substituted fatty acids, various amino acid derivatives, and the like, and as a method for forming an ester bond, an acid halogenation method, an acid anhydride method, or the like is effective, and a desired yield can be easily obtained with a high yield. A porphyrin compound is obtained.

For example, (N-imidazolyl) alkanoic acid is dissolved in tetrahydrofuran, acetonitrile, preferably dimethylformamide to give 2-hydroxymethyl-5,10,15,20-tetrakis (α, α, α, α).
-O-Alkylamidophenyl) porphyrin, 4-dimethylaminopyridine, dicyclohegexylcarbodiimide (large excess) were added, and the mixture was allowed to stand at room temperature for 12 hours to 12 in the dark.
Stir for 0 hours. The solvent is removed under reduced pressure, redissolved in a non-polar solvent, preferably benzene, the insoluble component is filtered, and the solvent is removed under reduced pressure. This is purified by silica gel column chromatography to obtain the desired porphyrin.

The porphyrin having a substituent at the 2-position represented by the general formula (4) prepared as described above can be prepared by a conventional method (eg, D. Dolphin ed., The Porph).
Yrins, 1978, Academic Press, Inc., etc.) introduced the central metal to the general formula (1) of the present invention.
A tetraphenylporphyrin metal complex represented by is obtained. Generally, in the case of iron complexes, porphinato iron (III
When the complex is a cobalt complex, a porphinatocobalt (II) complex is obtained.

Among the tetraphenylporphyrin metal complexes represented by the above general formula (1), in the case of having an iron (III) complex, a suitable reducing agent (sodium dithionite,
Oxygen-binding activity can be imparted by reducing the central iron from trivalent to divalent by a conventional method using ascorbic acid or the like). Is the tetraphenylporphyrin metal complex represented by the above general formula (1) of the present invention embedded in a bilayer vesicle composed of a lipid in an organic solvent (toluene, benzene, tetrahydrofuran, etc.) or in neutral water? By encapsulating it in a phospholipid-coated fat emulsion, a stable oxygen complex is promptly produced when it comes into contact with oxygen. Further, these complexes adsorb and desorb oxygen according to the oxygen partial pressure. This oxygen adsorption / desorption can be reversibly repeated, and it functions as an oxygen adsorption / desorption agent and an oxygen carrier.

In the tetraphenylporphyrin metal complex represented by the above general formula (1) of the present invention, a complex which can specifically bind oxygen has a central metal (M) in a +2 valent state and one base. These are coordinated complexes, and these are represented by the following general formula (6) or general formula (7). General formula (6)

[0026]

[Chemical 9] In the general formula (6), L represents a nitrogen-based axial ligand such as imidazole derivative. General formula (7)

[0027]

[Chemical 10]

In the tetraphenylporphyrin metal complex represented by the general formula (1) of the present invention, as the above-mentioned effective oxygen adsorbing / desorbing agent or oxygen carrier, the central metal (M) is a +2 valent complex structure. belongs to. In the case of an imidazole derivative in which the substituent at the 2-position itself functions as an axial base, the intramolecular imidazole can be coordinated to the porphyrin central metal (M), so that it does not need to add a large excess of the axial base itself. The oxygen binding ability can be demonstrated with. In other words, in the porphyrin compound in which the axial base is intramolecularly bonded, it is not necessary to add a large amount of the imidazole derivative as the axial base, and in consideration of in vivo administration, the useful concentration of the axial base is greatly reduced. Becomes

Further, the tetraphenylporphyrin metal complex of the present invention has a 2-hydroxymethyl-metal complex as described above.
5,10,15,20-Tetrakis (α, α, α, α-
It is produced by using o-alkylamidophenyl) porphyrin as a precursor. Then, a functional substituent (—CH ₂ OH group) that allows the precursor to easily bond with other substances
The present invention can easily provide a porphyrin metal complex having some useful properties because it has 2 in the 2-position. For example, by increasing the lipophilicity of the porphyrin metal complex by covalent bond to a highly lipophilic substance (specifically, ester bond with fatty acid, etc.),
It can be dissolved in animal or vegetable oils and fats and synthetic oils and fats of low polarity at high concentrations. Such a complex is more advantageous for embedding in the hydrophobic region of phospholipid vesicles. Further, these are extremely convenient for dissolving porphyrin in water in the form of oil droplet dispersion or phospholipid vesicle dispersion, and when porphyrin is a complex of a metal ion belonging to, for example, the 4th cycle, a redox reaction, It has a great added value as a catalyst for an oxygen oxidation reaction or an oxygen addition reaction. In particular, it is an effective oxygen transporter when it is a porphyrin metal complex of divalent iron.

The tetraphenylporphyrin metal complex of the present invention is produced not only by having a function as an oxygen carrier as described above but also by using a precursor having a functional substituent at the 2-position (precursor). Therefore, conversion to a hydrophilic, hydrophobic, or amphipathic porphyrin metal complex is possible. If the substituents are coordinating to the porphyrin center metal, they themselves become the active compound without the addition of excess axial ligand. Therefore, the porphyrin metal complex of the present invention can be applied not only as a redox reaction catalyst in a homogeneous system, a heterogeneous system, or a non-aqueous system and a gas adsorbent, but also in the case of an iron (II) or cobalt (II) complex. It is an excellent artificial oxygen carrier that can eliminate the presence of free imidazole, which is widely used as an axial base but has high toxicity in vivo.

As described above, the porphyrin metal complex of the present invention itself serves as an artificial oxygen carrier, and also as a gas adsorbent, an oxygen adsorption / desorption agent, a redox catalyst, an oxygen oxidation reaction catalyst, an oxygen addition reaction catalyst, and the like. It is useful.

[0032]

EXAMPLES The present invention will now be described in more detail with reference to examples. Needless to say, the present invention is not limited to the examples.

Reference Example 1 (1) J.P. Collman et al., J. Am. Chem. So
c. , 97, 1427 (1975) and JP-A-59-
According to the method described in 164761, 5, 10,
15,20-Tetrakis (α, α, α, α-o-pival
Amidophenyl) porphinato copper (CuTpivPP)
A complex was obtained. Meanwhile, add 3.5 ml of dimethylformamide to ice.
Cooled with water, phosphorus oxychloride 3.5 ml (37.3 mmol)
Was added and stirred at room temperature for 1 hour, and the Vilsmeier reagent was added.
Prepared. The above dissolved in 40 ml of dichloromethane
CuTpivPP 0.20g (0.19mmol) in a greenhouse
The mixture is added dropwise and refluxed at the boiling point for 15 hours. As the reaction progresses
It becomes a dark green solution (iminium salt). After cooling, the reaction melts
The solution was added dropwise to 50 ml of a saturated aqueous solution of sodium acetate, and
After stirring at 40 ° C. for 3 hours, the solution becomes magenta. This
It is washed with water, dried over anhydrous sodium sulfate, filtered,
The solvent is removed under reduced pressure. Silica gel column (chloroform
/ Fraction purification with ethyl acetate (6/1) (volume / volume))
Collect the desired product and vacuum dry. Thus, purple 2-ho
Rumil-5,10,15,20-tetrakis (α, α,
α, α-o-pivalamidophenyl) porphinato copper
(CuTpivPP-CHO) yield 0.16 g (yield
78%). The above-mentioned porphinato copper (CuTpi
The results of analysis of (vPP-CHO) are as follows: Elemental analysis value (% by weight): C71.1 (70.9), H
6.31 (6.04), N10.47 (10.17)
(However, the value in parentheses is C₆₅H₆₄N₈O_FiveTotal for Cu
Indicates the calculated value). FAB-mass spectrum: 1100
[M]⁺. Thin layer chromatography (Merck silica gel
Plate, chloroform / ethyl acetate (4/1) (volume
/ Volume)): Rf: 0.33 (mono spot). Infrared absorption
Collection spectrum (cm ^-1): 1690 (υc = o (Ami
)), 1674 (υc = o (formyl)). Visible absorption
Spectrum (CHCl₃, Λmax: 587, 545
424 nm).

(2) CuTpivPP-CHO 0.1
5 g (0.14 mmol) was dissolved in 10 ml of dichloromethane, 10 ml of concentrated sulfuric acid was added, and the mixture was vigorously stirred and reacted at room temperature for 10 minutes. The solution immediately becomes a dicationic green color. The reaction solution is slowly added to a biphasic solution of 100 ml of dichloromethane and 300 ml of ice water and neutralized with sodium acetate to give a purple color. This is washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure. Fractional purification is performed using a silica gel column (chloroform / ethyl acetate (6/1) (volume / volume)), and the desired product is collected and vacuum dried. Thus, 0.12 g (yield 85%) of purple 2-formyl-5,10,15,20-tetrakis (α, α, α, α-o-pivalamidophenyl) porphyrin (2HTpivPP-CHO) was obtained. Got with. The analysis results of the aforementioned porphyrin (2HTpivPP-CHO) are as follows: Elemental analysis value (% by weight): C75.52 (75.12),
H6.75 (6.40), N11.05 (10.78)
(However, the values in parentheses are calculated values for C ₆₅ H ₆₆ N ₈ O ₅ Cu). FAB-mass spectrum: 1039
[M] ⁺ . Thin layer chromatography (Merck silica gel plate, chloroform / ethyl acetate / (4/1) (volume / volume)): Rf: 0.33 (monospot). Infrared absorption spectrum (cm ^-1 ): 1690: (νc = o (amide)), 1674 (νc = o (Hokumil)). Visible absorption spectrum (CHCl ₃ , λmax: 655, 598,
559, 520, 428 nm).

(3) 2HTpivPP-CHO 0.
11 g (0.11 mmol) was dissolved in 2 ml of dichloromethane and 6 ml of dehydrated methanol, and sodium borohydride 41.
5 mg (1.10 mmol) are added. After stirring at room temperature in an argon atmosphere for 15 minutes, water is added to stop the reaction. This is washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure. Silica gel column (chloroform /
Fractional purification with methanol (10/1) (volume / volume)),
Collect the desired product and vacuum dry. Thus, the yield of purple 2-hydroxymethyl-5,10,15,20-tetrakis (α, α, α, α-o-pivalamidophenyl) porphyrin (2HTpivPP-CH ₂ OH) was 0.1.
Obtained in 1 g (94% yield). The porphyrin (2
The analysis result of HTpivPP-CH ₂ OH) is as follows; Elemental analysis value (% by weight): C74.97 (74.97),
H6.32 (6.58), N10.81 (10.76)
(However, the values in parentheses are calculated values for C ₆₅ H ₆₈ N ₈ O _5. ) FAB-mass spectrum: 1040 [M]
⁺ . Thin layer chromatography (Merck silica gel plate, chloroform / ethyl acetate (4/1) (volume / volume)): Rf: 0.18 (monospot). Infrared absorption spectrum (cm ^-1 ): 1690 (νc = o (amide)).
Visible absorption spectrum (CHCl ₃ , λmax: 640,
585, 542, 511, 417 nm).

Example 1 To a tetrahydrofuran solution (5 ml) of 0.21 ml (3.0 mmol) of acetyl chloride was added 2HTpivPP-CH _2.
A solution of 62.4 mg (0.06 mmol) of OH and 0.42 ml (3.0 mmol) of triethylamine in tetrahydrofuran (15 ml) was added dropwise to precipitate a white hydrochloride. The reaction is carried out at room temperature for 1 hour, the reaction solution is poured into a two-phase solution of water (300 ml) and chloroform (100 ml), and the mixture is stirred for another hour. Wash with water, dry over anhydrous sodium sulfate, filter,
The solvent is removed under reduced pressure. Fractional purification is performed using a silica gel column (chloroform / ethyl acetate (10/1) (volume / volume)), and the desired product is collected and vacuum dried. Thus, purple 2
-Acetoxymethyl-5,10,15,20-tetrakis (α, α, α, α-o-pivalamidophenyl) porphyrin was obtained in a yield of 51.3 mg (79% yield). The analysis results of the porphyrin described above are as follows: Elemental analysis value (% by weight): C74.61 (74.28),
H6.22 (6.51), N10.51 (10,34)
(However, the value in the parenthesis shows the calculated value for C ₆₇ H ₇₀ N ₈ O _5. ) FAB-mass spectrum: 1083 [M]
⁺ . Thin layer chromatography (Merck silica gel plate, chloroform / ethyl acetate (5/1) (volume / volume)): Rf: 0.32 (monospot). Infrared absorption spectrum (cm ^-1 ): 1742: (νc = o (ester)) 1690 (νc = o (amide)). Visible absorption spectrum (CHCl ₃ , λmax: 670, 630, 57
3,500,415 nm. ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , TMS standard), δ (ppm)) 8.9
(7H, s, pyrrole), 8.8 to 7.4 (16
H, m, phenyl-H), 5.3 (2H, t, Po
_{r-CH 2 OC (= 0} ) -), 2.0 (3H, s, -O
_{C (= 0) CH 3)} , 0.0 (36H, s, -C (CH
₃ ) ₃ ), -2.6 (2H, s, inner-H).

Example 2 0.36 g (6.49 mmol) of electrolytic iron and 2.4 of hydrobromic acid
React 2 ml under argon atmosphere at 80 ℃ for 1 hour,
After the solvent is removed by heating, white solid ferrous bromide is obtained. Next
And the 2-dehydrogen synthesized in Example 1 and degassed with argon.
Roxymethyl-5,10,15,20-tetrakis
(Α, α, α, α-o-pivalamidophenyl) porph
35.1 mg (32.5 μmol) of lin, triethylami
Dissolved in 0.06 ml (0.65 mmol) of tetrahydrofuran
The liquid (20 ml) was added dropwise and the boiling point was refluxed for 1 hour under argon.
To do. The solvent was removed under reduced pressure, redissolved in chloroform, and rare odor
Wash with hydrofluoric acid and aqueous solution, and dry with anhydrous sodium sulfate.
After drying and filtration, the solvent is removed under reduced pressure. Neutral alumina column
Fractional purification with (chloroform), collection of desired product and vacuum drying
To do. Thus, green-violet 2-hydroxymethyl-5,
10,15,20-Tetrakis (α, α, α, α-o-
Pivalamidophenyl) porphinato iron yield 36.4
g (92% yield). Porfinato iron content
The analysis results are as follows: Elemental analysis value (% by weight): C66.42 (66.06),
H5.22 (5.59), N9.51 (9.20) (however
The value in parentheses is C₆₇H₇₀N₈O₆The calculated value for
Shown). FAB-mass spectrum: 1083 [M]⁺.
Thin layer chromatography (Merck silica gel plate,
Chloroform / methanol (15/1) (volume / volume
Amount)): Rf: 0.32 (mono spot). Infrared absorption
Vector (cm ^-1): 1746 (νc = o (ester))
1692 (vc = o (amide)). Visible absorption spectrum
(CHCl₃, Λmax: 680, 651, 588, 5
09,415 nm).

Example 3 0.12 g of 2- (N-imidazolyl) acetic acid hydrochloride (0.
(74 mmol) was dissolved in 8 ml of dimethylformami and 0.2 ml (1.48 mmol) of triethylamine was added to precipitate a white hydrochloride. After 10 minutes, excess triethylamine is removed under reduced pressure. 2HTpi prepared in Reference Example 1
_{vPP-CH 2 OH 0.15g (0.14mmol} ), 4
-Dimethylaminopyridine 9.0 mg (0.08 mmol),
Dicyclohexylcarbodiimide 0.15 g (0.7
4 mmol) is added and the mixture is stirred at room temperature for 72 hours in the dark. Remove the solvent under reduced pressure, redissolve in benzene, filter insoluble components,
The solvent is removed under reduced pressure. This is fractionated and purified using a silica gel column (chloroform / methanol (30/1) (volume / volume)), and the desired product is collected and dried under vacuum. Thus, purple 2- (N-imidazolylacetoxymethyl-5,1
Yield of 0.16 g of 0,15,20-tetrakis (α, α, α, α-o-pivalamidophenyl) porphyrin
(Yield 89%). The analysis results of the porphyrin described above are as follows: Elemental analysis value (% by weight): C73.39 (73.12),
H6.62 (6.27), N12.54 (12.18)
(However, the values in parentheses are calculated values for C ₇₀ H ₇₂ N ₁₀ O _6. ) FAB-mass spectrum: 1149
[M] ⁺ . Thin layer chromatography (Merck silica gel plate, chloroform / methanol (15/1) (volume / volume)): 0.22 (monospot). Infrared absorption spectrum (cm ^-1 ): 1738: (νc = o (amide)). Visible absorption spectrum (CHCl ₃ , λmax:
641, 586, 543, 511, 417 nm. ¹ H-
Nuclear magnetic resonance spectrum (CDCl ₃ , TMS standard), δ
(Ppm)) 8.8 (7H, s, pyrrole),
8.7-7.4 (16H, m, phenyl-H),
7.3, 7.1, 6.9 (3H, s, imidazol
e ring), 5.3 (2H, t, Por-CH 2 O
C (= 0)-), 3.2 (2H, t, CH ₂ Im),
0.0 (36H, s, -C ( CH 3) 3), - 2.6
(2H, s, inner-H).

Example 4 2- (N-imidazolylacetoxymethyl-5,10,15,20-tetrakis (α, α,) synthesized in Example 3
α, α-o-pivalamidophenyl) porphyrin is reacted with cobalt chloride in a dry tetrahydrofuran solvent containing 2,6 lutidine to give a cobalt complex 2- (N).
-Imidazolyl acetoxymethyl-5,10,15,2
0-Tetrakis (α, α, α, α-o-pivalamidophenyl) porphinatocobalt was quantitatively obtained. The analysis results of the above-mentioned porphinatocobalt are as follows; Elemental analysis value (% by weight): C69.52 (69.63),
H6.01 (5.80), N11.87 (11.61)
(However, the values in parentheses are calculated values for C ₇₀ H ₇₀ N ₁₀ O ₆ Co). FAB-mass spectrum: 1206
[M] ⁺ thin layer chromatography (Merck silica gel plate, chloroform / methanol (15/1) (volume / volume)): Rf: 0.20 (monospot). Infrared absorption spectrum (cm ^-1 ): 1738 (νc = o (ester), 1690 (νc = o (amide)). Visible absorption spectrum (CHCl ₃ , λmax: 556, 525, 40)
3 nm).

Example 5 In Example 3, 11- (N- (imidazolyl) undecanoic acid hydrochloride was used in place of 2- (N-imidazolyl) acetic acid hydrochloride, and further 2HTpivPP-CH ₂ was used.
Instead of OH, 2- (hydroxymethyl) -5,10,15,20 synthesized according to the method described in JP-A-58-2137779 and JP-A-59-16471.
2- (11 '-(N-imidazolyl) undecanoyl according to the same procedure except that tetrakis (α, α, α, α-o-2', 2'-dimethyleicosanamidophenyl) porphyrin was used. Oxymethyl) -5,10,1
5,20-Tetrakis (α, α, α, α-o-2 ′, 2
'-Dimethyleicosanamidophenyl) porphyrin was quantitatively obtained. The analysis result of the porphyrin described above is
The values are as follows; Elemental analysis value (% by weight): C79.55 (79.27),
H10, 52 (10.14), N6.02 (6.29)
(However, the value in the parenthesis shows the calculated value for C ₁₄₇ H ₂₂₄ N ₁₀ O _6. ) FAB-mass spectrum: 2227
[M] ⁺ . Thin layer chromatography (Merck silica gel plate, chloroform / methanol (15/1) (volume / volume)): Rf: 0.51 (monospot). Infrared absorption spectrum (cm ^-1 ): 1738 (νc = o (ester), 1690 (νc = 0 (amide)). Visible absorption spectrum (CHCl ₃ , λmax: 641, 585, 54)
5,512,417 nm).

Example 6 In Example 2, 2-acetoxymethyl-5,10,
2- (11 '-(N-imidazolyl) undecanoyloxymethyl) -5 prepared in Example 5 instead of 15,20-tetrakis (α, α, α, α-o-pivalamidophenyl) porphyrin , 10,15,20-Tetrakis (α, α, α, α-o-2 ′, 2′-diamidophenyl) porphyrin was used according to the same procedure except that 2-
(11 ′-(N-imidazolyl) undecanoyloxymethyl) -5,10,15,20-tetrakis (α,
α, α, α-o-2 ′, 2′-dimethyleicosanamidophenyl) porphinato iron was quantitatively obtained. The analysis results of the above-mentioned porphinato iron are as follows: Elemental analysis value (% by weight): C75.04 (74.75),
H9.25 (9.48), N5.88 (5.93 ) ( where values in parentheses indicate calculated values for _{C 147 H 222 N 10 O 6} FeBr). FAB-mass spectrum: 236
1 [M] ⁺ . Thin layer chromatography (Merck silica gel plate, chloroform / methanol (15/1)
(Volume / Volume): Rf: 0.50 (mono spot).
Infrared absorption spectrum (cm ^-1 ): 1738 (νc = o (ester), 1690 (νc = o (amide)). Visible absorption spectrum (CHCl ₃ , λmax: 680, 651)
586, 511, 417 nm).

Application Example 1 2- (11 '-(N-imidazolyl) undecanoyloxymethyl) -5,10,15 synthesized in Example 6
20-Tetrakis (α, α, α, α-o-2 ′, 2′-
1.18 mg (0.5 μmol) of dimethyleicosanamidophenyl) porphinato iron was made into 10 ml of an anhydrous toluene solution, and after nitrogen substitution, the mixture was stirred with a dithionous acid aqueous solution in a heterogeneous system to reduce to iron (II). Extract only the toluene layer under nitrogen atmosphere, dehydrate and dry with anhydrous sodium sulfate,
After separation by filtration, the obtained toluene solution was transferred to a measuring cell and sealed. Thus, iron (II) 2- (11 '-(N-imidazolyl) undecanoyloxymethyl) -5,10,1
5,20-Tetrakis (α, α, α, α-o-2 ′, 2
A toluene solution of'-dimethyleicosanamidophenyl) porphyrin complex was obtained. The visible absorption spectrum of this solution was λmax 567, 539, 434 nm, and this complex corresponds to the pentacoordinated deoxy form with one imidazole coordinated.

When oxygen gas was blown into this solution, the spectrum immediately changed, and a spectrum of λmax 549,426 nm was obtained. This clearly indicates that it is an oxygenated complex. Nitrogen gas was added to this oxygenated complex solution in an amount of 1
It was confirmed that the visible absorption spectrum was reversibly changed from the oxygenation spectrum to the deoxy spectrum by blowing for a minute or by freezing and degassing the solution, and the adsorption and desorption of oxygen occurred reversibly. It should be noted that the operation of blowing oxygen and then blowing nitrogen was repeated, and oxygen adsorption / desorption could be continuously performed.

Application Example 2 2- (11 '-(N-imidazolyl) undecanoyloxymethyl) -5, 10, 15, synthesized in Example 6
20-Tetrakis (α, α, α, α-o-2 ′, 2′-
Dimethyl eicosanamide phenyl) porphinato iron 1. A chloroform solution of 18 mg (0.5 µmol) and dimyristoylphosphatidylcholine 68.7 mg (0.05 mmol) was dried to a thin film on a rotary evaporator. 20 ml of 1 / 15M phosphate buffer having pH 7.0 to 8.0 was added thereto, and ultrasonic wave irradiation (60w, 10 minutes)
Was done. The solution was replaced with nitrogen, a small amount of ascorbic acid aqueous solution was added, and the solution was transferred to a measurement cell and sealed. Thus
Iron (II) -2- (11 '-(N-imidazolyl) undecanoyloxymethyl) -5,10,15,20-tetrakis (α, α, α, α-o-2', 2'-dimethyl A liposome solution of the eicosanamidophenyl) porphyrin complex was obtained. The visible absorption spectrum of this solution is λm
At ax 566,538,433 nm the complex corresponds to the deoxy form.

When oxygen gas was blown into this solution, the spectrum immediately changed and a spectrum of λmax 547,426 nm was obtained. This clearly indicates that it is an oxygenated complex. Nitrogen gas was added to this oxygenated complex solution at 5
It was confirmed that the visible absorption spectrum reversibly changed from the oxygenation type spectrum to the deoxy type spectrum by blowing for a minute, and the adsorption and desorption of oxygen occurred reversibly.
In addition, the operation of blowing oxygen and then blowing nitrogen was repeated, and oxygen adsorption / desorption could be continuously performed.

[0046]

INDUSTRIAL APPLICABILITY The tetraphenylporphyrin metal complex of the present invention is a new compound that overcomes the drawbacks of metal porphyrin derivatives known as oxygen carriers. That is, in a conventional metalloporphyrin derivative having an oxygen adsorption / desorption function, a large amount of imidazole, which is highly toxic to the body from the outside, must be added in order to exert its function, but the porphyrin metal of the present invention is used. Since the imidazole derivative as an axial base is bonded and introduced at the 2-position of the complex, the amount of imidazole added externally can be reduced, and the oxygen carrier becomes an extremely safe oxygen carrier.

The tetraphenylporphyrin metal complex of the present invention can utilize the property of the substituent at the 2-position to increase the lipophilicity of the complex, for example, so that it can be encapsulated in the hydrophobic region of the phospholipid vesicle. The embedding becomes advantageous, or the porphyrin can be dissolved in water in the form of phospholipid vesicle dispersion. The porphyrin metal complex of the present invention is useful as a gas adsorbent, an oxygen adsorption / desorption agent, a redox catalyst, an oxygen oxidation reaction catalyst, etc. in addition to the artificial oxygen carrier described above.

Claims (7)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ₁ is an alkyl group, R ₂ is a substituent, and M is a fourth group.
The transition metal atom or metal ion of the fifth period, X ⁻ represents a halogen ion, and the number of X ⁻ represents the number obtained by subtracting 2 from the valence of the metal ion. ) A tetraphenylporphyrin metal complex having a 2-position side chain represented by 2. R ₁ is a C ₁ -C ₁₈ alkyl group, and R ₂ is a general formula (2): [Wherein R ₃ is a C _{1 to} C ₁₈ alkyl group, or a compound represented by the general formula (3): (Wherein, R ₄ does not inhibit this coordination to the central metal of the imidazole bonded group, R ₅ represents an alkylene group.) Tetraphenylporphyrin metal complex according to claim 1, wherein it is represented by the . 3. The tetraphenylporphyrin metal complex according to claim 2, wherein R ₄ is hydrogen, a methyl group, an ethyl group or a propyl group. 4. The tetraphenylporphyrin metal complex according to claim 2, wherein R ₅ is a C ₁ -C ₁₀ alkylene group. 5. The tetraphenylporphyrin metal complex according to claim 2, wherein M is Fe or Co. 6. The tetraphenylporphyrin metal complex according to claim 2, wherein the valence of Fe is +2 or +3. 7. The tetraphenylporphyrin metal complex according to claim 2, wherein the Co valence is +2.