JPH0352471B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula (Here, n is an integer of 1 to 20, m is an integer of 1 to 6, and X is a halogen atom).
[alpha]-o-(substituted amido)phenyl]porphine complex. Many reports have been made of iron-porphine complexes that can form oxygen complexes in organic solvents at room temperature. Examples include J.P.Collman, Accounts of
Chemical Research, 10 , 265 (1977) or F.
Basolo, BMHoffman and JAIbers, ibid.
8, 384 (1975). and so on. However, these iron-porphine complexes have the disadvantage that they are immediately oxidized when even a small amount of water is present, and cannot produce oxygen complexes. Moreover, there is also the problem that these complexes do not dissolve in water. It has been reported that a very stable oxygen complex can be formed in anhydrous aprotic solvents, especially under room temperature conditions. o-(pivalamide)phenyl]porphine complex (JP Collman et al., Journal
of the American Chemical Society, 97 , 1427
(1975)) is immediately oxidized as it is when it comes into contact with water, but by embedding it in a liposome membrane formed from an appropriate phospholipid, it can reversibly adsorb and desorb oxygen in water at room temperature. It is possible to obtain a liposome-dispersed aqueous solution of a porphin complex.
E. Hasegawa et al., Biochemical and Biophysical
Research Communications, 105 , 1416 (1982).
was reported. The object of the present invention is to make it possible to water-solubilize a dissolvable iron-tetraphenylporphine derivative while retaining its oxygen adsorption/desorption function, or to make it possible to water-solubilize a dissolvable iron-tetraphenylporphin derivative while retaining its oxygen adsorption/desorption function, or to use a small amount of surfactant, phospholipid, synthetic water-soluble polymer, polysaccharide, The object of the present invention is to provide a novel iron-tetraphenylporphine complex which has been improved so that it can be easily and uniformly dissolved in an aqueous solution containing water-soluble proteins.
Furthermore, many natural phospholipids have unsaturated bonds, and after encapsulating the complex of the general formula () in the liposome-like aggregates formed by these, appropriate means such as light irradiation can be applied. It has the characteristic that the encapsulated state can be stabilized by cleavage and crosslinking of the unsaturated bonds in the phospholipid part and the complex (). The compound of the general formula forms an oxygen complex in a homogeneous aqueous solution at room temperature in the presence of a suitable basic ligand, preferably a substituted imidazole ligand, with the central iron in a divalent state, and reversibly absorbs oxygen. It is a very useful oxygen adsorbing/desorbing agent or oxygen carrier because it can be desorbed.
For the above reasons, the novel iron-tetraphenylporphine complex having a hydroxyl group represented by the general formula of the present invention has value as an important synthetic intermediate. According to the invention, novel complexes of the formula (where n is an integer from 1 to 20) and J.P. Collman et al., Journal of the
American Chemical Society, 97 , 1427 (1975)
The expression reported in 5, 10, 15, 20-tetra (α, α,
α,α-o-aminophenyl)porphin (hereinafter referred to as
Abbreviated as H ₂ TamPP. ) in the presence of a base, the obtained formula is (where n is the same as defined above), the benzyl group was removed with anhydrous aluminum chloride in the presence of anisole, and the resulting formula (where n is as defined above) is reacted with ferrous bromide in the presence of pyridine, and a suitable mineral acid such as 48% hydrobromic acid, concentrated hydrochloric acid, iodide A terminal hydroxy-type complex coordinated with bromide, chloride, or iodine ions is obtained by treatment with hydrogen acid, and this is treated with itaconic anhydride to form a terminal carboxylic acid-type complex, which is then treated with triethylamine and ethyl chloroformate. After the treatment, _H2N ( _-CH2CH2O ) _-nH () is further reacted with a terminal amino oligoethylene glycol represented by the formula (where m is the same as _defined above). New complexes with the desired general formula can be synthesized. The starting materials of the general formula were synthesized by the following method.
George omega-benzyloxyalkyl halide
The dilithium anion of 2-methylpropionic acid was prepared according to the report of R. Nowkome et al., Synthesia, 1975 , 517. The dilithium anion of 2-methylpropionic acid was initially heated at a low temperature (-70℃ to 20℃) and then heated to 30 to 45℃. I reacted with The reaction mixture is then decomposed with cold dilute hydrochloric acid and the crude product extracted with a solvent is added to a non-polar solvent such as petroleum ether, n-
Recrystallization in hexane and n-heptane gave ω-benzyloxy-2,2-dimethylalkanoic acid as colorless crystals. This is reacted with an excess amount of thionyl chloride in a nonpolar solvent, preferably benzene or carbon tetrachloride, or without a solvent, and then concentrated under reduced pressure to form a ω-benzyloxy-
2,2-dimethylalkanoyl chloride was obtained. raw material formula (Here, n has the same meaning as defined earlier,
X' represents chlorine or bromine. ) denoted by ω−
Benzyloxyalkyl halide is n=1, X
=Cl, AJHill et al., Journal of the
American Chemical Society, 48 , 257 (1926)
According to the report of , when n = 2 and X' = Br, P.
Cresson, Bulletin de la Societe Chimique de
It can be synthesized according to the report of France, 1964, 2629.
Also, for n = 3 to 20 and X' = Br, α, ω-
It is obtained by refluxing dibromoalkane with 1 equivalent of sodium benzyl oxide in benzene. An excess amount of the carboxylic acid chloride of the general formula is mixed with a known substance, H ₂ TamPP, in an anhydrous aprotic solvent, preferably tetrahydrofuran, dichloromethane,
Residue obtained by reacting in chloroform, N,N-dimethylformamide or acetone solution in the presence of excess triethylamine or pyridine at 0°C to room temperature, pouring into water and extracting with chloroform, and evaporating the separated extract. A compound represented by the general formula can be obtained by purifying it by silica gel column chromatography. In order to remove the benzyl group of the benzyl ether represented by this general formula, dichloromethane:
The mixture was reacted with excess anhydrous aluminum chloride in a mixed solvent of nitromethane in the presence of an excess amount of anisole at -5°C to 30°C, preferably 15°C to 25°C for 2 to 12 hours. The reaction mixture was poured into ice water, extracted with chloroform, the extract was washed with water, and then
After washing with a % sodium bicarbonate aqueous solution, the separated chloroform layer was dried with sodium sulfate, and the residue obtained by evaporating the chloroform was recrystallized from benzene or a mixed solvent of dichloromethane-benzene. To introduce iron into the resulting compound of general formula, J.P. Collman et al., Journal of the American
The reaction was carried out with excess ferrous bromide in the presence of pyridine in refluxed anhydrous tetrahydrofuran under a nitrogen atmosphere, following the method reported in Chemical Society, 97 , 1427 (1975). Purification by column chromatography using alumina or silica gel, and treatment of the resulting eluate with hydrochloric acid, hydrobromic acid, or hydroiodic acid, results in the formation of chlorine, bromine, or iodine as a counter ion, and the central iron is
A complex of terminal hydroxyl type is obtained which is in the valent state. This was reacted with an excess amount of itaconic anhydride in the presence of dimethylaminopyridine in chloroform at room temperature, treated with a 1% aqueous solution of hydrohalic acid having the same X as the counter ion, and the solvent was replaced with methanol. , and developed with methanol on a Sephadex LH-60 column to obtain a terminal carboxylic acid type complex.
This was treated with an excess amount of triethylamine and methyl chloroformate in anhydrous DMF at 0 to 5°C,
Next, an excess amount of one-terminal amino-oligoethylene glycol of formula () was applied to Sephadex LH.
Develop with methanol or water on a -60 column to obtain the desired complex of formula (). This complex is transferred to an aqueous medium (e.g. water, buffer solution (PH4).
pH 10 to 10), physiological saline, etc.), and a basic ligand, preferably a substituted imidazole ligand, is dissolved in
A 1000 to 1000 times equivalent amount, preferably a 5 to 200 times equivalent amount was added, and nitrogen was bubbled to form a deoxygenated aqueous solution. To reduce the central iron from trivalent to divalent, 1
A method of adding 1 to 10 times the amount of sodium dithionite, sodium borohydride, or ascorbic acid, and a method of reducing with hydrogen gas in the presence of a palladium black or palladium carbon catalyst. E.
Hasegawa et al., Biochemical and Biophysical
Research Communications, 104 , 793 (1982)
The enzyme-based reduction method reported in 2010 can be used. The aqueous solution of the iron() complex obtained by reduction becomes an oxygen complex when oxygen is blown into it at room temperature, and returns to the original iron() complex when nitrogen is blown into it, confirming reversible adsorption and desorption of oxygen. As described above, the nonionic hydrophilic and hydrophobic iron-tetraphenylporphine complex having a novel polymerizable group represented by the general formula of the present invention acts as a useful oxygen adsorbent. The present invention will be explained in more detail by the following examples, which are not intended to limit the invention. Reference example 1 10-benzyloxydecanyl bromide is 1,
100 g of 10-dibromodecane and an equivalent amount of sodium benzyl oxide were refluxed in tetrahydrofuran, and the precipitate was filtered, concentrated, and then distilled under reduced pressure. yield
46g, boiling point 185-189℃/3mmHg. George R. Newkome et al., Synthesis, 1975 ,
517, the lithium dianion of 2-methylpropionic acid was generated with lithium diisopropylamide in tetrahydrofuran under a nitrogen atmosphere, and after dropping 18 g of 10-benzyloxydecanyl bromide at -20°C, the mixture was heated at 45°C. The mixture was allowed to react for 2 hours. The reaction mixture was added to cold diluted hydrochloric acid and extracted with ether, and the separated ether layer was washed with diluted hydrochloric acid and then with water, separated and dried over Glauber's salt. The crude oil obtained by evaporation to dryness was recrystallized from petroleum ether to obtain 8.4 g of colorless crystals of 12-benzyloxy-2,2-dimethyldodecanoic acid in a yield of 46%.
Melting point 53-55℃. Elemental analysis: Calculated value (%) as C ₂₁ H ₃₄ O ₃ ; C75.40, H10.25, analysis value (%):
C75.64, H10.09. Proton nuclear magnetic resonance spectrum ( _CDCl3 ) δppm: 1.18 (6H, s, _-CH3 ), 1.26
(16H, s, -CH ₂ -), 3.46 (2H, t, PhCH ₂ O
CH ₂ CH ₂ −), 4.51 (2H, s, PhC H ₂ O−), 7.33
(5H, s, phenyl proton). 3.34 g of this obtained carboxylic acid was dissolved in 5 ml of anhydrous benzene, 1.2 ml of thionyl chloride was added, and the mixture was stirred at room temperature for 12 hours.
After reacting for an hour and drying under reduced pressure, a colorless oil of 12-
Benzyloxy-2,2-dimethyldodecanoic acid chloride was obtained in a yield of 3.53 g. Infrared absorption spectrum (CCl ₄ ) ν1790cm ^-1 ([Formula]). Proton nuclear magnetic resonance spectrum ( _CDCl3 )
δppm: 1.28 (22H, s, -CH ₃ and -CH ₂ -),
3.46 (2H, t, PhCH ₂ O CH ₂ CH ₂ −), 4.50 (2H,
s, PhC H ₂ O-), 7.32 (5H, s, phenyl proton). Example 1 5,10,15,20-tetra (α, α, α, α-o
-aminophenyl) porphin (hereinafter H ₂ TamPP
It is abbreviated as ) is J.P.Collman et al., Journal of the
American Chemical Society, 97 , 1427 (1975)
Synthesized according to the literature. 1.0 g of H ₂ Tampp was added to anhydrous tetrahydrofuran (40
ml) solution, 0.81 ml of pyridine was added thereto, and 3.53 g of 12-benzyloxy-2,2-dimethyldodecanoic acid chloride obtained in Reference Example 1 was added dropwise at room temperature, followed by reaction for 3 hours. After extraction with ether and washing with water, the separated ether layer was dried with Glauber's salt and dried under reduced pressure. The crude product obtained was purified by silica gel column chromatography using a mixed solvent of benzene and ether (volume ratio 15:1) to give a brown color. 5,10,15,20-tetra [α,
α,α,α-o-(12-benzyloxy-2,2
-dimethyldodecanamido)phenyl]porphine was obtained in an amount of 1.69 g, with a yield of 60%. Infrared absorption spectrum (CCl ₃ ) ν3440, 3330,
3000, 2930, 2860, 1680, 1580, 1510, 1450,
1300, 1100, 970, 910, ^{700cm -1} . Proton nuclear magnetic resonance spectrum ( _CDCl3 )
δppm: (2.6(2H, s, N in polyphyrin ring
H), -0.23 (24H,s, -C( _CH3 ) _2CONH- ),
3.46 (8H, t, _{PhcH2OCH2CH2- )} , 4.50( _8H ,
s, Ph CH ₂ O-), 7.12 (4H, s,
[Formula]), 7.32 (20H, s), 8.82 (8H, s). 5, 10, 15, 20-tetra [α, α, α, α-o
-(12-benzyloxy-2,2-dimethyldodecanamido)phenyl] 1.68 g of porphine was dissolved in a mixed solvent of 25 ml of anhydrous dichloromethane and 25 ml of nitromethane, 2 ml of anisole was added, and then 2 g of anhydrous aluminum chloride was added and kept at room temperature for 4 hours. Made it react. The mixture was poured into 100 ml of ice water to decompose excess aluminum chloride, extracted with dichloromethane, and the separated dichloromethane layer was washed with water and then with a 10% aqueous sodium bicarbonate solution, separated, dried over sodium sulfate, and concentrated under reduced pressure. . The residue was recrystallized from benzene to give purple plate-like crystals of 5,10,15,20-tetra[α,α,α,α-o-(12-hydroxy-2,2
-dimethyldodecanamido)phenyl]porphine was obtained in an amount of 1.10 g, with a yield of 80%. Melting point 127~
129.5℃. Magnetic field desorption mass spectrum: 1579 (M+1) ⁺ infrared absorption spectrum (KBr) ν3600-3350 (wide range), 3440, 3330, 2940, 2860, 1690, 1585,
1515, 1450, 1302, 1060, 970, 810, 770, 740cm
^-1 . Proton nuclear magnetic resonance spectrum ( _CDCl3 )
δppm: −2.59 (2H, s, pyrrole NH ), −0.22
(24H, s, -C(C H ₃ ) ₂ -CONH-), 3.64 (8H,
t, HOC H ₂ CH ₂ −), 7.15 (4H, s), 7.36-8.73
(16H, m), 8.82 (8H, s). Note that the absorptions at 4.50 (8H, s) and 7.32 (20H, s) derived from the benzyl group disappeared. Elemental analysis: Calculated value (%) as C ₁₀₀ H ₁₃₈ N ₈ O ₈ ;
C76.00, H8.80, N7.09: Analysis value (%); C75.62,
H8.90, N7.09. 5, 10, 15, 20-tetra [α, α, α, α-o
-(12-Hydroxy-2,2-dimethyldodecanamido)phenyl] 0.65 g of porphine was dissolved in anhydrous tetrahydrofuran (50 ml), and 0.3 g of pyridine was dissolved.
ml and after purging with nitrogen, 2.0 g of ferrous bromide tetrahydrate was added and refluxed under nitrogen for 3 hours.
After extraction with chloroform and washing with water, the separated chloroform layer was dried with Glauber's salt and the solvent was distilled off under reduced pressure. The resulting residue was purified by alumina column chromatography using a mixed solvent of chloroform/methanol (volume ratio 9/1). . Add the elution solution to 2 ml of 48% hydrobromic acid.
After stirring, drying with Glauber's salt and evaporating to dryness, a black-purple solid of promo{5,10,15,20-tetra[α,α,
α,α-o-(12-hydroxy-2,2-dimethyldodecanamido)phenyl]porphynato}iron () was obtained in a yield of 0.38 g, 54%. Melting point 76~
79℃. Magnetic field desorption mass spectrum: 1713 (M+1) ⁺ However, the molecular formula is C ₁₀₀ H ₁₃₆ N ₈ O ₈ FeBr = 1712. Infrared absorption spectrum (KBr): ν3600~3150
(broad), 3440, 2930, 2860, 1690, 1580,
1510, 1440, 1300, 1075, 1000, 805, 760, 715
cm ^-1 . Elemental analysis: Calculated value (%) as C ₁₀₀ H ₁₃₆ N ₈ O ₈・FeBr; C70.13, H8.00, N6.54, analytical value (%);
C70.37, H8.40, N6.63. 200 mg of this terminal hydroxy type complex was reacted with 5 g of itaconic anhydride and 1.5 g of dimethylaminopyridine in anhydrous chloroform at room temperature for 10 hours, washed with 1% hydrobromic acid water, and the solvent was replaced with methanol. A Sephadex LH-60 gel column was developed with methanol and the main component was separated to obtain a terminal carboxylic acid type complex in a yield of 69%. Elemental analysis: C ₁₂₀ H ₁₅₂ N ₈ O ₂₀・FeBr Calculated value (%); C66.66, H7.08, N5.18, Analysis value (%); C66.70, H7.06, N5.21 Red External absorption spectrum (KBr): ν3600~3200
(broad), 3440, 3020, 2950, 2930, 2860,
1770, 1725, 1705, 1650, 1590, 1520, 1450,
1180, 1015, 820, 770 cm ^-1 . In particular, the absorption based on itaconic acid ester, -COOH, and C= _CH2 , respectively
Found at 1725, 1705.1650cm ^-1 . In addition, 1705cm
^-1 absorption band is 1600 by adding triethylamine.
Moved to cm ^-1 (broad). The entire complex was mixed with 2 ml of triethylamine and 2 ml of ethyl chloroformate in DMF at 0-5°C.
The reaction was carried out for 1.5 hours, and further reacted with 5 g of one-terminal aminodiethylene glycol for 10 hours. The same column separation as above was performed, and in the formula (), n=
10, the target complex with m=2 was obtained in 72% yield. Elemental analysis: Calculated value (%) as C ₁₃₆ H ₁₈₈ N ₁₂ O ₂₄ FeBr; C65.06, H7.55, N6.69, Analysis value (%); C65.02, H7.59, N6.65 Red External absorption spectrum (KBr): Compared to that of the terminal carboxylic acid mentioned above, the absorption in the ν3600 to 3200cm ^-1 (broad) region is deeper due to the terminal -OH, and the absorption in the νNH3320cm ^-1 , secondary and The appearance of amide absorption bands at 1640 and 1555 cm ^-1 and 1200 cm ^-1 (broad) based on the oxyethylene unit C-O-C was observed, and the -COOH absorption band at 1705 cm ^-1 disappeared. The complex thus obtained is water-insoluble, but when stirred in an aqueous solution with, for example, egg yolk lecithin, it becomes a homogeneous and transparent solution. Reference example 2 1,18-dibromooctadecane e.g. Lester
Friedman and Arnon Shani, Journal of the
American Chemical Society, 96, 7101-7103
(1974). In the same manner as in Reference Example 1, 18.3 g (yield: 41%) of 18-benzyloxyoctatecanyl bromide was obtained from 42 g of 1,18-dibromooctadecane instead of 1,10-dibromodecane. 18 g of this was reacted with lithium dianion (equivalent mole) of 2-methylpropionic acid, and after the same extraction treatment as in Reference Example 1, the crude oil obtained was obtained using a mixed solvent of benzene:ether (volume ratio 15:
1) was purified by silica gel column chromatography to obtain colorless crystals of 20-benzyloxy-
2,2-dimethyleicosanoic acid was obtained in a yield of 5.7 g and a yield of 31%. Melting point 72-73℃. Elemental analysis: Calculated value (%) as C ₂₉ H ₅₀ O ₃ ; C,
77.97, H, 11.28, analysis value (%); C78.25,
H11.21. Infrared absorption spectrum (KBr) ν: 2930, 2860,
1705, 1470, 1130, 1120, 950, 740, 700 cm ^-1 . Proton nuclear magnetic resonance spectrum ( _CDCl3 )
δppm: 1.18 (6H, s, -C( _CH3 ) _2COOH ), 1.25
(32H, brs PhCH ₂ OCH ₂ (CH ₂ ) ₁₆ CH ₂ −), 3.46
(2H, t, J=6.5Hz, PhCH ₂ OCH ₂ CH ₂ −),
4.50 (2H, s, PhC H ₂ O-), 7.33 (5H, m, benzene ring proton). 5.2 g of this obtained carboxylic acid was reacted with 4 ml of thionyl chloride at room temperature for 4 hours and dried under reduced pressure to obtain 5.6 g of 20-benzyloxy-2,2-dimethyleicosanoic acid chloride as a colorless solid. Infrared absorption spectrum (CCl ₄ ) ν: 2930, 2860,
1790, 1460, 1365, 1100, 905, ^{700cm -1} . Example 2 5.6 g of the obtained 20-benzyloxy-2,2-dimethyleicosanoic acid chloride was mixed with 1.3 g of H ₂ TamPP.
of anhydrous tetrahydrofuran (50 ml) and pyridine (1.5 ml) under the same conditions as in Example 1.
After post-treatment and purification, 5,10,15,20-tetra[α,
α,α,α-o-(20-benzyloxy-2,2
-dimethyl-eicosanamido)phenyl]porphin was obtained in an amount of 3.70 g, with a yield of 80%. Melting point 33~
35℃. Elemental analysis: Calculated value (%) as C ₁₆₀ H ₂₃₀ N ₈ O ₈ ;
C80.29, H9.68, N4.68, analysis value (%); C80.11,
H9.88, N4.77. Infrared absorption spectrum (KBr) ν: 3440, 2920,
2850, 1690, 1580, 1510, 1450, 1360, 1300,
1100, 965, 800, 750 cm ^-1 . Proton nuclear magnetic resonance spectrum ( _CDCl3 )
δppm: −2.60 (2H, s, N in the porphyrin ring
−H ), −0.22(24H,s, −C(CH ₃ ) ₂ −CONH
−), 3.45 (8H, t, J=6.4Hz, PhCH ₂ OC H ₂
CH ₂ −), 4.49 (8H, s, PhC H ₂ O−), 7.13 (4H,
s, [formula]), 7.31 (20H, s, [formula]), 8.76 (4H, d, J = 7Hz, [formula]), 8.82 (8H, s, proton at β-position of porphine ring) 5, 10, 15,20-tetra [α, α, α, α-o
-(20-benzyloxy-2,2-dimethyleicosanamido)phenyl] 3.5 g of porphine was added to dichloromethane (30 ml) in the same manner as in Example 1.
Post-treatment and extraction were performed with 6 g of anhydrous aluminum chloride in a mixed solvent of nitromethane (15 ml) and anisole (3 ml), and the resulting residue was subjected to silica gel column chromatography (solvent chloroform/methanol = 15/ 1) and refine it,
It was recrystallized from a mixed solvent of dichloromethane and methanol. 5,10,15,20-tetra[α,α,α,α-o-(20-hydroxy-2,
1.89 g of 2-dimethyleicosanamido)phenyl]porphine was obtained in a yield of 64%. Melting point 88~
90℃. Infrared absorption spectrum (KBr) ν: 3430, 3320,
2920, 2860, 1675, 1580, 1510, 1470, 1450,
1300, 970, 805, 760, 720 cm ^-1 . Proton nuclear magnetic resonance spectrum ( _CDCl3 )
δppm: −2.60 (2H, s, N in the porphyrin ring
−H ), −0.21(24H,s, −C(CH ₃ ) ₂ −CONH
−), 3.69 (8H, t, J=6.4Hz, HOC H ₂ CH ₂ −,
7.14 (4H, s, amide group - CON H -), 8.73 (4H,
d, J=7Hz, [Formula]), 8.82 (2H, s, proton at β position of porphyrin ring). Elemental analysis: Calculated value as C ₁₃₂ H ₂₀₂ N ₈ O ₈ (%);
C78.14, H9.98, N5.52, analysis value (%); C78.42,
H10.20, N5.39. 5, 10, 15, 20-tetra [α, α, α, α-o
-(20-hydroxy-2,2-dimethyleicosanamido)phenyl] 1.06 g of porphine was reacted in the same manner as in Example 1, followed by silica gel column chromatography (mixed solvent of chloroform/methanol = 15/1). ) and further recrystallized from a mixed solvent of dichloromethane/methanol. Black-purple crystal bromo {5, 10, 15, 20−
Tetra[α,α,α,α-o-(20-hydroxy-2,2-dimethyleicosanamido)phenyl]porphynato}iron () yield 0.82 g, yield
Got it with 73%. Melting point 49-50℃. Infrared absorption spectrum (KBr) ν: 3430, 2930,
2860, 1690, 1580, 1510, 1460, 1440, 1300,
1000, 800, 760, 720 cm ^-1 . Elemental analysis: C ₁₃₂ H ₂₀₀ N ₈ O ₈ FeBr: 1/2 CH ₂ Cl ₂
Calculated value (%); C72.16, H9.19, N5.08, analytical value (%); C72.41, H9.09, N4.92. 200 mg of this terminal hydroxy type complex was added to Example 1.
The reaction was carried out with itaconic anhydride in the same manner as above to obtain the corresponding terminal carboxylic acid type complex in a yield of 76%. Elemental analysis: Calculated value (%) as C ₁₅₂ H ₂₁₆ N ₈ O ₂₀ FeBr; C69.92, H8.34, N4.29, analytical value (%);
C69.90, H8.35, N4.33 IR spectrum (KBr); very similar to that of the similar terminal carboxylic acid type complex described in Example 1,
Especially esters of itaconic acid, -COOH, C=CH ₂
Absorption based on 1720, 1705, and 1650 cm ^-1 was observed, respectively. The total amount of this complex was prepared in the same manner as in Example 1, except that 55.0 g of aminotetraethylene glycol at one end was used.
The desired complex of formula () with n=18 and m=4 was obtained in a yield of 82%. Elemental analysis: C ₁₈₄ H ₂₈₄ N ₁₂ O ₃₂ Calculated value (%) as FeBr: C66.73, H8.64, N5.07, Analysis value (%); C66.70, H8.66, N5.10 IR Spectrum (KBr): Very similar to the complex spectrum of n=10, m=2 in the similar formula () described in Example 1, especially ν3600 ~ due to terminal -OH
The absorption at 3200 cm ^-1 (broad) becomes deep, and νN-H, primary and primary amide absorption bands based on secondary amide are observed at 3220, 1640 and 1550 cm ^-1 respectively, and the oxyethylene unit C-O-C Based on 1200cm ^-1
(broad) was confirmed. The complex thus obtained showed the same solubility as in Example 1. Reference example 3 Benzyloxymethyl chloride is described by AJHill et al.
Journal of the American Chemical Society,
48, 257 (1926), and this
10.96g was converted into an equivalent amount of 2
-Methylpropionic acid was reacted with lithium dianion and purified by recrystallization from n-hexane to obtain 7.75 g of 3-benzyloxy-2,2-dimethylpropionic acid in a yield of 53%. Melting point 72-74℃. Infrared absorption spectrum (KBr) ν: 3400-2400
(broad), 1700, 1480, 1320, 1250, 1120, 940,
740,700cm ^-1 . Proton nuclear magnetic resonance spectrum ( _CDCl3 )
δppm: 1.23 (6H, s, _-CH2C ( _CH3 ) _2COOH ),
3.47 (2H, s, _PhCH2OCH2C ( _CH3 ) _2- ) _, 4.55
(2H, s, PhC H ₂ O-), 7.31 (5H, s, phenyl ring proton). Elemental analysis: Calculated value as C ₁₂ H ₁₆ O ₃ (%);
C69.20, H7.75, analysis value (%); C69.43, H7.80. Add 3.0 g of the obtained carboxylic acid to 4 ml of thionyl chloride.
was reacted in the same manner as in Reference Example 1 to quantitatively obtain 3-benzyloxy-2,2-dimethylpropionic acid chloride as an oil. Infrared absorption spectrum (CCl ₄ ) ν: 1830, 1790,
1460, 1100, 915, ^{700cm -1} . Example 3 3.4 g of 3-benzyloxy-2,2-dimethylpropionic acid chloride was added in the same manner as in Example 1.
After reacting with 1.1 g of H ₂ Tampp, it was purified by silica gel column chromatography using chloroform/ether = 15/1 as a solvent, and recrystallized from a dichloromethane-methanol mixed solvent.
5, 10, 15, 20-tetra [α, α, α, α-(3
-benzyloxy-2,2-dimethylpropanamido)phenyl]porphine yield: 1.92 g, yield
Got it with 82%. Melting point 170-172℃. Infrared absorption spectrum (KBr) ν: 3440, 3320,
2970, 2860, 1690, 1605, 1583, 1510, 1450,
1310, 1155, 1095, 1080, 970, 800, 755, 740,
700 cm ^-1 . Proton nuclear magnetic resonance spectrum ( _CDCl3 )
δppm: −2.53 (2H, s, N in the porphyrin ring
H), 0.05 (24H, s, -C( _CH3 ) ₂ -CONH-),
2.72 (8H, s, PhCH ₂ OC H ₂ ), 3.29 (8H, s,
PhC H ₂ OCH ₂ −) 6.46 to 6.56 (8H, m,
[Formula]), 6.88-6.96 (12H, m, [Formula]), 8.70 (8H, s, proton at β-position of porphyrin ring), 8.15 (4H, s,
[Formula]), 8.80 (4H, d, J=7.3 Hz, [Formula]), 7.33 to 7.90 (12H, m, [Formula]). Elemental analysis: Calculated value (%) as C ₉₂ H ₉₀ N ₈ O ₈ ;
C76.96, N6.32, H7.81, analysis value (%); C76.81,
H6.41, N7.72. 5,10,15,20-tetra[α,α,α,α-o-(3-benzyloxy-2,2-dimethylpropanamido)phenyl] in the same manner as in Example 1
1.5 g of porphine was subjected to a debenzylation reaction and recrystallized from benzene to obtain 5,10,15,20-tetra[α,α,α,α-o-(3-hydroxy-2,
1.09 g of 2-dimethyl-propanamido)phenyl]porphine was obtained in a yield of 96%. Melting point 294
~297℃. Infrared absorption spectrum (KBr) ν: 3430
(broad), 3280 (broad), 1670, 1615, 1590,
1530, 1470, 1450, 1350, 1310, 1290, 1160,
1050, 970, 820, 810, 760 cm ^-1 . Proton nuclear magnetic resonance spectrum ( _CDCl3 )
δppm: −2.89 (2H, brs, N in the porphyrin ring
H), -0.78 (2H, brs, hydrated _H2O ), 0.49 (24H,
s, -C( _CH3 ) _2CONH- ), 1.02(4H, brt.H
OCH ₂ −), 2.22 (8H, d, J = 4Hz, HOC H ₂ C
( _CH3 ) _2- ), 7.35(4H,s,-C( _CH3 ) _2- CON
H), 8.85 (8H, s, porphyrin ring β-position proton). Elemental analysis: Calculated value (%) as C ₆₄ H ₆₆ N ₈ O ₈・H ₂ O; C70.31, H6.27, N10.24, analytical value (%);
C70.60, H6.34, N9.97. 5,10,15,20-tetra [α, α, α,
0.89 g of α-o-(3-hydroxy-2,2-dimethylpropanamido)phenyl]porphine was reacted with ferrous bromide tetrahydrate and purified using a mixed solvent of chloroform/methanol = 50/1. , recrystallized from benzene/methanol to give bromo{5,
10, 15, 20-tetra [α, α, α, α-o-(3
-Hydroxy-2,2-dimethylpropanamido)phenyl]porphynato}iron () yield
Obtained 0.37 g, yield 38%. Melting point over 300℃. Infrared absorption spectrum (KBr) ν: 3420
(broad), 3250 (broad), 1670, 1610, 1585,
1525, 1440, 1330, 1050, 1000, 800, 760, 720
cm ^-1 . Elemental analysis: Calculated value (%) as C ₆₄ H ₆₄ N ₈ O ₈ FeBr・H ₂ O; C62.65, H5.42, N9.13, analytical value (%)
C62.36, H5.46, N9.01. 200 mg of this terminal hydroxy type complex was reacted with itaconic anhydride in the same manner as in Example 1 to obtain the corresponding terminal carboxylic acid type complex in a yield of 77%. Elemental analysis: Calculated value (%) as C ₈₄ H ₈₀ N ₈ O ₂₀ FeBr; C60.88, H4.87, N6.76, analytical value (%);
C60.90, H4.90, N6.72 Infrared absorption spectrum (KBr); very similar to that of the similar terminal carboxylic acid type complex described in Example 1, especially for the ester of itaconic acid, -COOH, C
Absorption based on =CH ₂ was observed at 1725, 1705, and 1650 cm ^-1 , respectively. The entire amount of this terminal carboxylic acid type complex was prepared in the same manner as in Example 1, except that 6 g of aminohexaethylene glycol at one end was used, and in the formula (), n=1, m=6
The desired complex was obtained in 92% yield. Elemental analysis: Calculated values (%) as C ₁₃₂ H ₁₈₀ N ₁₂ O ₄₀ FeBr; C58.49, H6.69, N6.20, analytical values (%); C58.53, H6.66, N6.23. Infrared absorption spectrum (KBr): very similar to the spectrum of the complex with n=10 and m=2 in the similar formula () described in Example 1, especially absorption in the range of ν3600 to 3200 cm ^-1 (broad) due to terminal -OH becomes deeper, and νN-H and primary amide absorption rates based on secondary amide are observed at 3220, 1645, and 1550 cm ^-1 , respectively,
C-O-C1200cm ^-1 based on oxyethylene units
(broad) was confirmed. The complex thus obtained is water-soluble.

Claims (1)

[Claims] 1 formula (Here, n is an integer of 1 to 20, m is an integer of 1 to 6, and
iron-5,10,15,20-tetra [α, α, α, α-o
-(Substituted amido)phenyl]porphin complex.