JPH0352470B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula (Here, n is 1 to 20, m is 1 to 6, l is 1 to 6
A novel iron-5,10,15,20-tetra[α,α,α,α-o-(substituted amido)phenyl] having a hydroxyl group represented by an integer of and X is a halogen atom)
Concerning porphine complexes. 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). etc. However, these iron-porphine complexes have the disadvantage that they are immediately oxidized when even a small amount of water coexists, and cannot produce oxygen complexes. Moreover, these complexes also have the problem of not being soluble in water. It has been reported that a very stable oxygen complex can be formed in anhydrous aprotic solvents, especially under room temperature conditions. −(pivalamide)phenyl]
Porphin complexes (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 purpose of the present invention is to make a poorly soluble iron-tetraphenylporphin derivative water-soluble while retaining its oxygen adsorption/desorption function, or to make it possible to make a slightly soluble iron-tetraphenylporphin derivative water-soluble, or to use a small amount of surfactant, phospholipid, synthetic water-soluble polymer, polysaccharide, etc. The object of the present invention is to provide a novel nonionic hydrophilic and hydrophobic iron-tetraphenylporphine complex of the general formula () which has been improved so that it can be easily and uniformly dissolved in an aqueous solution containing water-soluble proteins. 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. 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, By treatment with hydroiodic acid, etc., a complex corresponding to the intermediate of general formula () coordinated with bromide ion, chloride ion, or iodine ion is obtained, and then α, ω- of formula () or () is added to this complex. Dicarboxylic acid anhydride or dichloride (where m is the same as defined above) in the presence of a base catalyst It is obtained by reacting and further reacting with one-terminated amino oligoethylene glycol of formula () (where l is the same as defined above). The starting material of the general formula H ₂ N(-CH ₂ CH ₂ O)- _l H () was synthesized by the following method.
George ω-benzyloxyalkyl halide
The dilithium anion of 2-methylpropionic acid produced according to the report of R. Newkome et al. Synthesia, 1975 , 517. Made it react. The reaction mixture is then decomposed with cold dilute hydrochloric acid and the solvent extracted crude product is recrystallized in a non-polar solvent such as petroleum ether, n-hexane, n-heptane and ω-benzyloxy-2,2- Dimethylalkanoic acid was obtained 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 Socie´te Che´mique 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 and extracted with chloroform. The extract was washed with water and then with a 4% aqueous sodium bicarbonate solution. The separated chloroform layer was dried with Glauber's salt, and the residue obtained by evaporating the chloroform was dissolved in benzene or dichloromethane. - Recrystallized from a mixed solvent of 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 is obtained which is in the valent state. reacting an excess amount of α,ω-dicarboxylic acid anhydride or chloride of formula () or () with respect to the -OH units of this complex in the presence of dimethylaminopyridine in CHCl ₃ at 0 to 5 °C, Wash with water with 1% hydrochloric acid, hydrobromic acid, or hydroiodic acid (acids with the same halogen as the type of Elution with water yields a carboxylic acid-terminated intermediate. This was reacted with an excess amount of triethylamine and ethyl chloroformate relative to the carboxylic acid unit in dehydrated DMF at 0 to 5°C, further reacted with one-terminal aminooligoethylene glycol of the formula, and separated using the gel column described above. The general formula for the purpose ()
The complex is obtained. 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, 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 novel nonionic hydrophilic and hydrophobic iron-tetraphenylporphine complex represented by the general formula of the present invention acts as a useful oxygen adsorbent/desorber. 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, analytical 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 (CHCl 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 the porphyrin ring
H), -0.23 (24H,s, -C( _CH3 ) _2CONH- ),
3.46 (8H, t, PhcH ₂ OC H ₂ −), 4.50 (8H, s,
Phami CH ₄ 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
-dimethyldodecaneamide) phenylporphine was obtained in a yield 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 to 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 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 bromo{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. Approximately 200 mg of this substance in 1.5 g of anhydrous chloroform
of succinic anhydride and 1.0 g of dimethylaminopyridine for 10 hours. After washing with a 1% HBr aqueous solution, the product was purified by Sephadex LH-60 gel column chromatography to obtain a terminal carboxylic acid type complex in a yield of 85%. Elemental analysis: C ₁₁₆ H ₁₅₂ N ₈ O ₂₀ Calculated value as FeBr (%); C69.31, H7.62, N5.57, analytical value (%);
C69.26, H7.58, N5.62 Infrared absorption spectrum (KBr): ν3600~3200
(broad), 3440, 3020, 2950, 2860, 1770,
1720, 1705, 1590, 1520, 1450, 1180, 1020,
820,770cm ^-1 . ¹ HNMR spectrum ( _CDCl3 ); -CH3 _1.25
(24H), alkyl chain _-CH2 -1.30~3.30 (88H),
Alkyl chain _-CH2 -O-4.22(8H), succinyl- _CH2-4.1,4.8 (16H), oxyethylene- _CH2
-3.8, 4.4, 4.3 (total 32H), o-phenyl-H8.50
(4H), p-phenyl-H12.8 (4H), m-phenyl-H17.0 (8H), pyrrole β-H90.0 (8H), phenylamide NH7.5 (4H). The entire amount of this terminal carboxylic acid type complex was reacted with 1.0 ml of triethylamine and 1.0 ml of ethyl chloroformate in anhydrous chloroform for 1.5 hours at 5°C or lower, and then 2.0 ml of one-terminal aminodiethylene glycol was added and reacted for 10 hours. Ta. Purified by Sephadex LH-60 gel column chromatography, and in the general formula (), n=10, m=2, l=
Complex No. 2 was obtained in a yield of 75%. Elemental analysis: Calculated value (%) as C ₁₃₂ H ₁₈₈ N ₁₂ O ₂₄ FeBr; C64.38, H7.69, N6.82, analytical value (%);
C64.29, H7.73, N6.80. Infrared absorption spectrum (KBr); ν3600~3100
(broad), 3440, 3400, 3020, 2945, 2860,
1770, 1720, 1645, 1590, 1550, 1520, 1450,
1200 (broad), 1180, 1030, 820, 770 cm ^-1 . 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 is, for example, 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 resulting oily substance was mixed with 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 C29H50O3} (%) _;
C77.97, H11.28, 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 colorless solid 20-benzyloxy-2,2-dimethyleicosanoic acid chloride. 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 OCH ₂ CH ₂ −), 4.49 (8H, s, PhCH 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 voluphyrin 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 product was reacted with 5 g of adipic acid dichloride and 2 g of dimethylaminopyridine in anhydrous chloroform at 0 to 5°C for 10 hours, washed with 1% hydrobromic acid solution, and separated on a gel column in the same manner as in Example 1. A terminal carboxylic acid type complex was obtained in a yield of 82%. Elemental analysis: C ₁₅₆ H ₂₃₂ N ₈ O ₂₀ Calculated value as FeBr (%); C70.04, H8.74, N4.19, analytical value (%);
C70.01, H8.67, N4.22. The IR spectrum (KBr) is the n obtained in Example 1.
= 10, m = 2 terminal carboxylic acid type complex, especially ester ^and -
Absorption based on COOH was confirmed. The entire amount was mixed with 1.0 ml of triethylamine and 1.0 ml of ethyl chloroformate in anhydrous DMF.
React at ℃ for 1.5 hours, then add 5 g of aminotetraethylene glycol at one end and react for 10 hours.
Thereafter, gel column separation was performed in the same manner as in Example 1 to obtain a complex of general formula () with n=18, m=4, and l=4 in a yield of 76%. Elemental analysis: Calculated value (%) as C ₁₈₈ H ₃₀₀ N ₁₂ O ₃₂ FeBr: C66.88, H8.96, N4.98, analytical value (%);
C66.85, H8.99, N5.02. The IR spectrum (KBr) is the n obtained in Example 1.
= 10, m = 2, l = 2.
cm ^-1 (broad), 1645 based on the first and second amides,
1550cm ^-1 , based on C-O-C of oxyethylene
An absorption band of 1200 cm ^-1 (broad) was confirmed. The complex thus obtained exhibited a solubility similar to that of the complex of 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, _{PhCH2OCH22C ( 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-o-
Yield: 1.92 g of (3-benzyloxy-2,2-dimethylpropanamido)phenyl]porphin.
Obtained with a yield of 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 chloroform/
It was purified with a mixed solvent of methanol = 50/1 and recrystallized from benzene/methanol to obtain 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 product was reacted with 5 g of α,ω-octanedionic acid chloride and 1 g of dimethylaminopyridine in anhydrous chloroform at room temperature for 20 hours, and then treated in the same manner as in Example 1 to obtain a terminal carboxylic acid type complex. obtained with a rate of 64%. Elemental analysis: Calculated value (%) as C ₉₆ H ₁₁₂ N ₈ O ₂₀ FeBr; C62.88, H6.16, N6.11, analytical value (%);
C62.94, H6.11, N6.17. The IR spectrum (KBr) is the n obtained in Example 1.
= 10, m = 2 terminal carboxylic acid type complex, especially ester and -COOH at 1720 and 1705 cm ^-1
Absorption based on The entire amount of this product was reacted with 2 ml of triethylamine and 2 ml of ethyl chloroformate in anhydrous DMF at 0 to 5° C. for 2 hours, and 7 g of aminohexaethylene glycol at one end was added and reacted for 24 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain a complex having the general formula () with n=1, m=6, and l=6 in a yield of 54%. Elemental analysis: Calculated value (%) as C ₁₄₄ H ₂₁₂ N ₁₂ O ₄₀ FeBr; C59.91, H7.40, N5.82, analytical value (%);
C59.93, H7.44, N5.79. The IR spectrum (KBr) was obtained in Example 1 with n=
10, is very similar to that of the complex with m = 2, l = 2, especially ν3600 to 3200 cm ^-1 based on terminal -OH etc.
(broad), 1650, 1550 based on the 1st and 3rd amides
cm ^-1 , 1200cm based on C-O-C of oxyethylene
^-1 (broad) absorption band was confirmed. This complex is water soluble.

Claims (1)

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