JPH0526791B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides 5,10,15-tri [α, α, α-(o
-pivalamide) phenyl]-20-mono{α-[o-
The present invention relates to a (2-substituted-2-methyl)propanamide]phenyl}porphyrin compound and an oxygen adsorbing/desorbing agent. 5, 10, 15, 20-tetra [α, α, α, α-
(o-pivalamido)phenyl]porphyrin (hereinafter referred to as picketophenesporphyrin) is a known compound, which is active when in the form of an iron divalent complex, and in excess of N-alkylimidazole, e.g. The presence of methylimidazole reversibly binds oxygen molecules at room temperature in aprotic solvents such as benzene, toluene, N,N-dimethylformamide (DMF), or tetrahydrofuran (THF) (JP Collman et al. J.Am.Chem.Soc., 97-, 1427
(1975). ). Furthermore, when embedded in liposomes made of phosphatidylcholine-type phospholipids, they exhibit similar functions even under semi-physiological conditions (E.
Hasegawa et al., Biochem.Biophys.Res.
Commun., 105-, 1416 (1982). ). An object of the present invention is to provide a compound that not only retains the activity of the above-mentioned picketophensporphyrin but also has several other effective properties. According to this invention, [Here, M is an ion pair of two hydrogen atoms, an iron divalent ion, or an iron trivalent ion with X ^- (here, X is a halogen atom or OH), and R is a substituent other than methyl] Porphyrin compounds are provided. In addition to the properties of conventional picketophensporphyrins, the compounds of this invention have the following useful properties. (1) Porphyrin in the form of a divalent iron complex can have an axial ligand in its molecule, which is essential for maintaining its activity, and free imidazole is generally considered to have high in vivo toxicity. No need for addition of similar compounds. (2) Linkage to lipophilic or water-soluble substances is possible by ester or amide condensation, and the resulting increased lipophilic or water solubility can be used to embed triglyceride in oil droplets as a constituent. It is convenient for dispersion in water as a whole or by embedding it in liposomes containing phosphatidylcholine phospholipids as a constituent, and it can also be a completely water-soluble substance. Therefore, the porphyrin compound of the present invention not only has high added value as an artificial oxygen carrier, but also has strong potential as a redox reaction catalyst in a homogeneous or heterogeneous aqueous solution or as a catalyst involving oxygen. The porphyrin compound of this invention (hereinafter referred to as M-
(abbreviated as PFP(R)) is, for example, the above-mentioned J.
According to the literature examples of P. Collman et al.5, 10, 15,
After obtaining 20-tetra(o-aminophenyl)porphyrin (4-isomer mixture), J. Lindsey, J.
Org.chem., 45-45, 5215 (1980). Produced by the following method using 5,10,15,20-tetra[α,α,α,α-(o-amino)phenyl]porphyrin [1] as a raw material prepared according to the method described in . That is, the above raw material porphyrin [1] is dissolved in, for example, THF, ether, acetone, or dichloromethane, and 1.0 to 1.5 times the molar equivalent of 2-alkoxycarbonyl (or 2-alkoxycarbonylalkyl)-2-methylpropanoyl is dissolved under ice cooling. Chloride (here, the alkoxy carbon number is 1 to 7,
A base such as pyridine or triethylamine is added dropwise in an amount equal to or more than twice the mole of the alkyl carbon (having 1 or 2 carbon atoms). After reacting at 0 to 5°C for 1 to 16 hours, 5,
10,15-Tri[α,α,α-(o-amino)phenyl]-20-mono{α-[o-(2-alkoxycarbonyl (or alkoxycarbonylalkyl)-2-methyl)propanamide]phenyl}
Porphyrin [2] is obtained. In addition, 2-alkoxycarbonyl (or 2-alkoxycarbonylalkyl)-2-methylpropanoyl chloride [CH ₃ CH (CH ₃ ) ((CH ₂ ) _n COOR ₂ ) COCl (where m is 0 to 2, R ₂ is a lower hydrocarbon having 1 to 7 carbon atoms] is a monoester monocarboxylic acid prepared by a method known per se, for example, by saponification of a diester portion or partial alcoholysis of an acid anhydride. The acids are prepared using acid chloride methods known per se, such as the thionyl chloride method or oxalyl chloride. 5,10,15-tritridine was obtained by adding pivaloyl chloride and pyridine in an amount of 3 times the mole or more to the above-mentioned porphyrin [2] obtained, using exactly the same solvent and reaction temperature and time conditions as those in which it was produced. [α,
α,α-(o-pivalamido)phenyl]-20-mono{α-[o-(2-alkoxycarbonyl (or alkoxycarbonylalkyl)-2-methyl)
Propanamide〔phenyl〝porphyrin〔3〕
is manufactured. 5, 10, 15, 20-tetra [α, α, α, α-
(o-amino)phenyl]porphyrin [1] by methods known per se, e.g. J.P.Collman
et al., J.Am.Chem.Soc., 102-102, 4182 (1980).
5,10,15-tri[α,
After preparing α,α-(o-pivalamido)phenyl]-20-mono{α-[o-amino)phenyl}porphyrin [4], it is added with at least an equimolar amount of 2-alkoxycarbonyl (or 2-alkoxycarbonyl). Porphyrin [3] can also be produced in exactly the same manner as the above-mentioned production method, except that alkyl)-2-methylpropanoyl chloride and pyridine are allowed to interact with each other. Porphyrin [3] is dissolved in a good solvent such as acetone, and a dilute alkali aqueous solution containing at least the equivalent molar amount of sodium hydroxide is added to the porphyrin [3], followed by reaction for 1 to 20 hours. Next, an aqueous solution containing more than the equivalent mole of acetic acid based on the above amount of alkali was added and gradually concentrated under reduced pressure.
-tri[α,α,α-(o-pivalamido)phenyl]-20-mono{α-[o-(2-carboxy(or carboxyalkyl)-2-methyl)propanamide]phenyl}porphyrin[5] Produced almost quantitatively. Should be bound to porphyrin [5]

The aminoalkylimidazole represented by the formula (where n is 11 to 16) is
For example, the following method is selected.

【table】

[Table] From the hydroxyalkylimidazole thus obtained, n = 13 to 16 by the method described above.

[Formula] is synthesized in exactly the same way. All intermediate or final stage compounds mentioned above are purified by silica gel column chromatography using a chloroform-methanol mixed solvent or by recrystallization. (Here, p and q are each independently 11 to 16), for example, obtained above.

[Formula] and half equivalent of

Mix [formula] and react at 80 to 100 °C for more than 1 hour, or

[Formula] (where r is 11 to 15) in ethanol or bezene at room temperature to 100
After adding Raney-nickel under conditions of 50 to 100 atm of hydrogen and reacting for over 1 hour, the product can be purified and isolated in exactly the same manner as the above-mentioned compound. Preferred methods for bonding these imidazole compounds and the above porphyrin [5] include, for example, an acid chloride method, a diethyl phosphate cyanide method, or a mixed acid anhydride method. In the case of the acid chloride method, porphyrin [5] is added with an equivalent mole or more of thionyl chloride in benzene or dichloromethane, reacted at room temperature to 50°C for 1 to 12 hours, and then dried under reduced pressure. Next, the imidazole compound and a base, preferably triethylamine or pyridine, are added in an equimolar amount or more after redissolving in the same solvent. 0℃
A method of purifying by silica gel column chromatography using a chloroform-methanol mixed solvent after reacting at ~room temperature for 1 hour or more is selected. In the case of the diethyl phosphate cyanide method or the mixed acid anhydride method, the above imidazole compound, a base (triethylamine or pyridine), and a condensing agent (for example, diethyl phosphate cyanide, ethyl chlorocarbonate, etc.) are added in an amount equal to or more than the porphyrin [4]. A method is selected in which the mixture is mixed in dichloromethane, THF, benzene, DMF, or a mixed solvent thereof, reacted at 0° C. to room temperature for several hours or more, and then purified in exactly the same manner as the acid chloride method. The obtained porphyrin [6] is dissolved in THF or DMF containing an equimolar amount or more of pyridine or 2,6-lutidine, and after adding an equimolar amount or more of ferrous halide under a nitrogen, argon, or helium stream. , react at 50-80°C for several hours, and purify in exactly the same manner as to obtain porphyrin [5] to obtain trivalent iron complex [7] of porphyrin [6]. A complex in which the trivalent iron counterion is OH ^- can be obtained by shaking a solution of porphyrin [7] in benzene or dichloromethane with, for example, a dilute aqueous solution of sodium hydroxide and then performing a conventional operation. The method for reducing the iron trivalent complex thus obtained to the iron divalent form includes, for example, using a small amount of a heterogeneous reduction catalyst in an organic solvent such as benzene, toluene, dichloromethane, THF or DMF, under a hydrogen gas stream, Preferably, a small amount of palladium on activated carbon or palladium black is added or TG
Traylor et al., Bioinorg.chem., 9-9, 409 (1978).
Accordingly, a method is selected in which the complex of 18-crown-6 with Na ₂ S ₂ O ₄ is added in an equimolar amount or more. When dispersed in water in the form of phosphatidylcholine embedded in liposomes, for example, E. Hasegawa et al.
et al., Biochem.Biophys.Res.Commun., 104~
104, 793 (1982). According to the method described in , NADP (sodium salt) and glucose-6 were added to the above aqueous solution.
- phosphate, glucose-6-phosphate dehydrogenase ferredoxin, ferredoxin-NADP-reductase and catalase can be converted into iron divalent complexes. In the compounds of the invention, oxygen, iron, imidazole are of the formula [Here, m is 0 to 2, n is 11 to 16, R' is a hydrogen atom or

Considering that the bonding state represented by the following formula (where s is 11 to 16) can be taken, it is preferable that the sum of m+n is 11 or more. In order to increase the coordination equilibrium constant between the iron ion and imidazole within the molecule and to maintain the structure represented by the above formula more stably, the sum of m+n is preferably 11 or more and not far from this number. Coordination from the top of the porphyrin is strongly suppressed due to steric hindrance, and coordination from the bottom tends to be prioritized, but when R′

In the case of [Formula], since it is easy to form a hexacoordination structure of imidazole-iron-imidazole, it is thought that there is an advantage in ensuring coordination from the bottom. In the state of the above formula where oxygen is bonded,

[Formula] is solved for coordination to iron. In this state, for example, in a liposome composed of phosphatidylcholines, the highly polar R-terminus is considered to be more likely to be incorporated into the hydrophilic region, and other portions are more likely to be incorporated into the hydrophobic region.
As a result, there is an advantage that the stability of the generated oxygen complex is improved. The porphyrin compound of the present invention has a structure that easily maintains its properties as a picketophene porphyrin, and has a substituent that can form an amide bond or an intramolecular coordination bond to other substances, so it has hydrophilic properties, Conversion to hydrophobic or hydrophilic porphyrin compounds is possible. It can be active on its own without the external addition of an imidazole compound as an axial ligand (generally highly toxic in vivo). For these reasons, the present invention not only enables application as a catalyst for redox reactions in homogeneous or heterogeneous aqueous systems or as a catalyst for other reactions involving oxygen, but also provides artificial oxygen carriers or intermediate materials therefor. I will do it. Hereinafter, this invention will be explained in detail with reference to Examples. Example 1 (i) 25 g of 2,2-dimethylglutaric anhydride
(0.176 mol) was dissolved in 200 ml of methanol, and a trace amount of phenolphthalein was added. Ice cold 0
A solution of 4.45 g (0.194 mol) of metallic sodium in 50 ml of methanol was added dropwise at °C, and after confirming the end point with phenolphthalein, the solvent was distilled off under reduced pressure. 100 ml of a saturated NaH ₂ PO ₄ solution was added to the residue to make it an acidic solution, followed by extraction with ether (100 ml x 3). After drying over magnesium sulfate, 36.8 ml (0.185 mol) of dicyclohexylamine was added and the solvent was distilled off under reduced pressure. The residue was recrystallized from ether-petroleum ether and then recrystallized again from acetone to obtain 2,2-dimethyl-4-methoxycarbonylbutyric acid in the form of dicyclohexylamine salt. Yield 35 g (56%), mp 123-125°C IR spectrum (KBr) 1740 (ν _C=O , ester), 1620, 1400 (ν _C=O , −CO ₂ ) cm ⁻¹ , etc. PMR spectrum ( _CDCl3 ) δ (ppm): 1.13
(singlet, 6H, -CH ₃ ), 1 to 2.9 (multiplet,
26H, cyclohexyl ring hydrogen, -C H ₂ C H ₂ C
(CH ₃ ) ₂ −), 3.64 (singlet, 3H, −COOCH ₃ ),
8.88 (singlet, 2H, -COO ・H -2N). (ii) 33.8 g of dicyclohexylamine salt of 2,2-dimethyl-4-methoxycarbonylbutyric acid
After dissolving (0.095 mol) in 200 ml of ethyl acetate,
200 ml of 20% citric acid aqueous solution was added and shaken. After separating the organic layer, it was washed with water (200 ml x 2), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
The mixture was then dried and desalted. After adding 25 ml of thionyl chloride to the entire amount of the obtained residue and reacting at 40°C for 2 hours, excess thionyl chloride was distilled off and 2,2
Acid chloride of -dimethyl-4-methoxycarbonylbutyric acid was obtained. Yield 17.0g (92.8%), bp102~104℃ (9mm
Hg) IR spectrum (liquid film) 1800 (ν _C=O , −COCl),
1740 (ν _C=O , ester) cm ^-1 and others. MS spectrum m/e193((M+1) ⁺

Claims (1)

[Claims] 1. General formula [Here, M is an ion pair of two hydrogen atoms, an iron divalent ion, or an iron trivalent ion with X ^- (here, X is a halogen atom or OH), and R is -
(CH ₂ ) _n COR _l {where m is 0 to 2, R ₁ is OH,
OR ₂ (where R ₂ is a lower hydrocarbon having 1 to 7 carbon atoms) or [Formula] [where R ₃ and R ₄ are each independently a hydrogen atom or [Formula] (where n is 11 to 7) 16)]} Porphyriine compound. 2 General formula [Here, m is 0 to 2, n is 11 to 16, R' is a hydrogen atom or [Formula] (here, s is 11 to 16)] An oxygen adsorption/desorption agent containing a porphyrin compound as an active ingredient .