JP3385469B2 - Efficient synthesis of extended porphyrins consisting of even pyrrole units - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to extended porphyrins, particularly a group in which 6 to 12 even-numbered pyrrole rings have the hydrogen of the methine group substituted by an Ar group at the α-position (hereinafter, referred to as C-
It may be called one unit. ) And a method for efficiently producing expanded porphyrins having macrocycles alternately bonded to each other.

[0002]

BACKGROUND OF THE INVENTION There has been considerable interest in the synthesis and research of porphyrins and other tetrapyrrolic macrocycles, but with regard to large aromatic pyrrole-containing systems, so-called expanded porphyrins. The fact is that is not well understood. In the extended porphyrin system, multiple π electrons are included as much as the extended portion and a larger central binding core is formed, so that multiple metal ions are coordinated and conventional porphyrins are not coordinated. It is of great interest because it can provide new properties not found in conventional porphyrins, such as coordination of metal ions with a large ionic radius.

Under such circumstances, all-pyrrole category extended porphyrins having 6 pyrrole rings in the ring (Sessler, JL et al., 1991 and Gossaue)
r, A., 1983) are provided as rubyrin and pentaphyrin, which are used to produce various cells by utilizing the recognition properties of expanded porphyrins such as various cells and cell membrane permeability (lipid). In connection with the development of a drug delivery system that is stable in the body and the design of diagnostic agents and the like, much attention has been paid to it as a compound that constitutes the skeletal structure of the agent. Furthermore, the development of all-pyrrole category expanded porphyrins having 10 pyrrole rings in the ring has been developed, and these have been developed to the conventional porphyrins with the expansion of π electrons. Complex-forming compounds which form chelate compounds with novel metals [eg, gadolinium Gd useful as MRI diagnostic agents] (Forms a stable complex with (III)]] (WO 96/2166
5, published internationally on July 18, 1996). However, in these prior arts, in order to promote the formation of an expanded porphyrin skeleton, not only each pyrrole is crosslinked with a C-1 unit but also pyrroles are often directly bonded to each other, and thus all pyrrole-type expanded porphyrins are Almost none of them consisted of C-1 units.

By the way, as a conventional method for producing porphyrins, porphyrins are reacted by reacting an aldehyde with pyrrole in CHCl ₃ or CHCl ₂ using an acid catalyst to produce porphyrin in an equilibrium state and then oxidizing the porphyrins. The method of obtaining the class is widely established as the Lindsey method. Specifically, the Journal of Organic
Chemistry (J. Org. Chem.) Vol. 52, 5
No. 827-836 (1987), an aldehyde and pyrrole are reacted with boron trifluoride or trifluoroacetic acid (TFA) as an acid catalyst to form a tetraalkylporphyrinogen, and then oxidation of p-chloranil or the like is performed. Oxidation by agents to synthesize porphyrins is described. Thus, until now, equilibrium compounds of cyclic tetramer porphinogen and linear oligomers mainly exist in the reaction solution before oxidation, and porphine is produced by the oxidation of porphinogen. It was believed that the oxidation of linear oligomers produces a polymeric material. Therefore, it is not expected to produce the expanded porphyrins of interest, particularly the all-pyrrole type (there is no vinylene repeating unit) expanded porphyrins, which are of interest from the above-mentioned synthetic method of porphyrins.

Therefore, the present inventor has tried to synthesize a novel extended porphyrin compound, particularly a novel extended porphyrin compound in which a pyrrole ring is alternately bonded to a methylene group at the α-position to form a macrocycle. In studying synthetic methods by modifying various basic methods for synthesizing compounds, steric hindrance such as aromatic aldehydes having substituents at both ortho positions of formyl group, 9-formylanthracene, cyclohexanecarbaldehyde, etc. When a large aldehyde is used as the substrate and the concentration of the substrate is made considerably higher than the conventional synthetic concentration of porphyrins, that is, about 6 times higher, the hydrogen of the methine group is substituted with the Ar group at the α position in 6 or more pyrrole rings. It was discovered that new extended porphyrins have been formed which are alternately bonded to the above groups to form macrocycles.

[0006]

The object of the present invention is basically to provide a method for obtaining the expanded porphyrins more selectively, and in order to solve the problem, the synthetic reaction is further detailed. In the study, the dipyrromethane formed in the middle of the synthetic reaction was isolated, purified, and reacted with equimolar aldehydes to produce extended porphyrins. It has been discovered that novel extended porphyrins can be obtained in which the hydrogens of the methine group at positions are alternately bonded with groups substituted with Ar groups to form macrocycles. Thereby, by establishing a method for obtaining expanded porphyrins in which even-numbered pyrrole rings are alternately bonded at the α-position with a group in which hydrogen of a methine group is substituted with an Ar group to form a macrocycle, Part of the problem has been solved (in the sense that we have not reached the point of selectively synthesizing only specific extended porphyrins).

[0007]

DISCLOSURE OF THE INVENTION The present invention is directed to an aldehyde represented by Formula 1 ArCHO .. Formula 1 (In Formula 1, Ar may have a substituent at another position. Di-substituted phenyl group, which may have a substituent 9
-Anthranyl group or a cyclohexyl group which may have a substituent. Further, the substituents at the 2 and 6 positions are
Independently selected from fluoro, chloro, bromo, iodo, lower alkyl having 1 to 4 carbon atoms, or lower alkoxy,
Substituents of the 3- to 5-position, 9-anthranyl group, and cyclohexyl group include, in addition to the substituents of the 2- and 6-positions, substituted or unsubstituted alkyl, alkenyl, alkynyl, substituted and unsubstituted aryl having 5 or 6 carbon atoms. , Alkyl or aryl sulfonyl, alkyl or aryl cyano, cyano, nitro, amino, carboxy, carbalkoxy,
Or their esters, are independently selected from amides and salts or Ranaru group. Each Ar may be different. ) And pyrrole with an acid catalyst by reaction 1 to obtain dipyrromethanes, and the dipyrromethanes are reacted with an equivalent amount of ArCHOs in the presence of an acid catalyst and an oxidizing agent to give 6 or more 12
This is a method for producing expanded porphyrins in which up to an even number of pyrrole rings are alternately bonded at the α-position with a hydrogen atom of the methine group substituted with the Ar group to form a macrocycle.

[0008]

[Chemical 3]

(In Reaction 1, Ar has the same meaning as in Formula 1.)

Preferably, the aldehyde compound is 2,6
-Difluorobenzaldehyde, 2,3,6-trifluorobenzaldehyde, 2,4,6-trifluorobenzaldehyde, 2,3,4,5,6-pentafluorobenzaldehyde, 2,6-dichlorobenzaldehyde,
2,3,6-trichlorobenzaldehyde, 2,4,6
-Trichlorobenzaldehyde, 2,3,4,5,6-
Pentachlorobenzaldehyde, 2,6-dimethylbenzaldehyde, 2,4,6-trimethylbenzaldehyde, cyclohexanecarbaldehyde or 9-formylanthracene is a method for producing the expanded porphyrins, which is more preferable, Is
Expanded porphyrins in which 6 to 12 even-numbered pyrrole rings are alternately bonded to a group in which hydrogen of methine group is substituted with Ar group at α position to form a macrocycle are represented by the following compound group A. A method for producing the expanded porphyrins, which is a compound,

[0011]

[Chemical 4]

More preferably, an equivalent amount of dipyrromethanes is used.
By reacting with ArCHOs in the presence of an acid catalyst and an oxidizing agent, an even number of six or more pyrrole rings is alternately bonded to a group in which hydrogen of the methine group is substituted with the Ar group at the α position to form a macrocycle. The extended porphyrins formed are used as a substrate , that is, ArCH.
A method for producing the expanded porphyrins, wherein the reaction is allowed to proceed under the condition that the O concentration is 3 × 10 ⁻² mol / liter or more. More preferably, boron trifluoride and trifluoroacetic acid are used as the acid catalyst. And at least one selected from boron trifluoride etherate is used for producing the expanded porphyrins.
The compound obtained by the above method is a biochemically effective group similar to the known extended porphyrins and extended porphyrins by forming coordination compounds with various metals similarly to the known extended porphyrins. By introducing a functional group, a compound useful for various uses can be obtained, and thus the present invention has a remarkable effect in that it can provide a method for producing the intermediate or the like more efficiently. To bring.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail.
A. Dipyrromethane is obtained by the following reaction 1,

[0014]

[Chemical 5]

By purifying this and reacting the dipyrromethane with an equimolar amount of aldehydes in the presence of an acid catalyst and an oxidizing agent, an extended porphyrin is produced by a two-step process. Extended porphyrins are obtained which form macrocycles which alternately bond the hydrogen of the methine group at the position with the group substituted by the Ar group. (In reaction 1, Ar
Has the same meaning as Ar in Formula 1. ) Examples of the acid catalyst used in the reaction 1 and the oxidation reaction include boron trifluoride, trifluoroacetic acid (TFA), and boron trifluoride etherate (BF ₃ OEt ₂ ). Further, as an oxidizing agent, p-chloranil, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DD
Q) etc. can be mentioned. Further, as the reaction solvent, methylene chloride, chloroform, carbon tetrachloride, or a mixture thereof, which has been used in the conventional synthesis of porphyrins, can be used.

In the above reaction, the steric factor around the formyl group of the aldehyde, particularly the ortho-position, plays an important role. With benzaldehyde and 2-substituted benzaldehyde, the formation of extended porphyrins is extremely small, but 2 It has been found that a considerably large amount of extended porphyrins can be obtained by using a 6-substituted benzaldehyde, 9-formylanthracenes or cyclohexanecarbaldehyde.

[0017]

EXAMPLES Example 1 Pentafluorobenzaldehyde (2.5 mL, 20.
3 mmol) and pyrrole (200 mL, 284 mmo)
l) solution of trifluoroacetic acid (TFA) (487.5 μL, 6.25 mmo) under nitrogen atmosphere with stirring.
1) is added and reacted for 30 minutes. Reaction 2 shows the dipyrromethane formation reaction.

[0018]

[Chemical 6]

200 mL of CH ₂ Cl ₂ was added to the reaction solution to dilute it and then washed with an aqueous NaOH solution. After removing the solvent using a rotary evaporator, the product (dipyrromethane) was purified using silica gel column chromatography. The yield was 6.16 g, and the yield based on the pentafluorobenzaldehyde used was 96%. Pentafluorobenzaldehyde (490mg, 2.5m
mol) and the dipyrromethane (780 mg, 2.5 m
Mol) in methylene chloride (75 mL), 200
Place in a mL round bottom flask. To this is added 75 mL of 2.5 M boron trifluoride etherate (BF ₃ OEt ₂ ) with stirring. After 2 hours, 875 mg of DDQ was added and the solution was stirred overnight. The reaction solution was subjected to column chromatography after removing the solvent using a rotary evaporator. As shown in FIG. 1, it was found that an even number of extended porphyrins were produced. The produced porphyrins and extended porphyrins were analyzed by mass spectrometry [FAB (fa
st atom bombardment): A type of atom bombardment ionization mass spectrometry, MALDI TOF (Matrix-assited Laser Deposition)
absorption Ionization-Time of Flight)], yield, Soret band, Q and n band absorption spectrum characteristics are shown in Table 1.

[0020]

[Table 1]

FIG. 2 shows an absorption spectrum of the obtained expanded porphyrins. The absorption wavelength shifts to the long wavelength side due to the formation of a large π-conjugated electron system.

[0022]

As described above, in the extended porphyrins, the absorption band shifts to the long wavelength side depending on the ring size, and in the dodecaphyrin, the Soret absorption band appears around 830 nm. These expanded porphyrins are used as new optical materials such as photodynamic therapy, photochemical recording materials such as CD-R and DVD-R, and can bind various metal ions, and are used for applications such as nuclear magnetic resonance imaging and radioimaging. Useful compounds can be synthesized. Further, since the oxidation and reduction potentials can be adjusted by the incorporated metal, the excellent effect that it is promising for the synthesis of catalyst materials using this is brought about. As can be seen from FIG. 2, the strong absorption bands of compounds 10 and 12 are 80
It extends to near 0 nm and is almost transparent to human eyes. But because of their large π-conjugated electron systems,
New functions can be expected in terms of electrical conductivity, magnetism, and far infrared absorption.

The extended porphyrins are Zn, M
g, Ca, Sr, Ba, Sc, Y, La, Ce, Pr,
Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, T
m, Yb, Lu, Ti, Zr, Hf, V, Nb, Ta,
Th, U, Cr, Mo, W, Mn, Tc, Re, Fe,
Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, C
u, Ab, Au, Cd, Hg, Al, Ga, In, T
l, Si, Ge, Sn, Pb, As, Sb, Ru course der that the same may be those substituted with Bi.

[Brief description of drawings]

1 is a column chromatograph of the product of Example 1.

FIG. 2 Spectral absorption characteristics of a compound having 6 to 12 pyrrole rings and Ar being pentafluorobenzene.

Claims (5)

(57) [Claims] 1. An aldehyde represented by Formula 1 ArCHO .. Formula 1 (In Formula 1, Ar is a 2,6-disubstituted phenyl group which may have a substituent at another position, and a substituent. You may have 9
-Anthranyl group or a cyclohexyl group which may have a substituent. Further, the substituents at the 2 and 6 positions are
Independently selected from fluoro, chloro, bromo, iodo, lower alkyl having 1 to 4 carbon atoms, or lower alkoxy,
Substituents of the 3- to 5-position, 9-anthranyl group, and cyclohexyl group include, in addition to the substituents of the 2- and 6-positions, substituted or unsubstituted alkyl, alkenyl, alkynyl, substituted and unsubstituted aryl having 5 or 6 carbon atoms. , Alkyl or aryl sulfonyl, alkyl or aryl cyano, cyano, nitro, amino, carboxy, carbalkoxy,
Or their esters, are independently selected from amides and salts or Ranaru group. Each Ar may be different. ) And pyrrole with an acid catalyst by reaction 1 to obtain dipyrromethanes, and the dipyrromethanes are reacted with an equivalent amount of ArCHOs in the presence of an acid catalyst and an oxidizing agent to give 6 or more 12
A method for producing expanded porphyrins in which up to an even number of pyrrole rings are alternately bonded to a group in which hydrogen of a methine group is substituted with the Ar group at the α position to form a macrocycle. [Chemical 1] (In Reaction 1, Ar has the same meaning as in Formula 1. Further, the substituents at the 2- and 6-positions of the 2,6-disubstituted phenyl group are fluoro, chloro, bromo, iodo, and a lower one having 1 to 4 carbon atoms. Independently selected from alkyl or lower alkoxy, 3 to
Substituents on the 5-position, 9-anthranyl group, and cyclohexyl group have 5 or 6 carbon atoms in addition to the substituents on the 2 and 6-positions.
A substituted or unsubstituted alkyl, alkenyl, alkynyl,
Substituted and unsubstituted aryl, alkyl or arylsulfonyl, alkyl or aryl cyano, cyano, nitro, amino, carboxy, carbalkoxy, or their esters, are independently selected from amides and salts or Ranaru group. ) 2. The aldehyde compound is 2,6-difluorobenzaldehyde, 2,3,6-trifluorobenzaldehyde, 2,4,6-trifluorobenzaldehyde, 2,3,4,5,6-pentafluorobenzaldehyde, 2,6-dichlorobenzaldehyde, 2,3,6
-Trichlorobenzaldehyde, 2,4,6-trichlorobenzaldehyde, 2,3,4,5,6-pentachlorobenzaldehyde, 2,6-dimethylbenzaldehyde, 2,4,6-trimethylbenzaldehyde, cyclohexanecarbaldehyde or 9-fol The method for producing expanded porphyrins according to claim 1, wherein the method is selected from milanthracene. 3. An expanded porphyrin compound in which 6 to 12 even-numbered pyrrole rings are alternately bonded to a group in which hydrogen of a methine group is substituted with an Ar group at the α-position to form a macrocycle is the following compound group: It is a compound represented by A, The manufacturing method of the extended porphyrins of Claim 1 or 2 characterized by the above-mentioned. [Chemical 2] 4. Dipyrromethanes and an equivalent amount of ArCHOs are reacted in the presence of an acid catalyst and an oxidizing agent to produce 6 or more 12
A method for producing expanded porphyrins in which up to an even number of pyrrole rings are alternately bonded at the α-position with hydrogen of a methine group substituted with the Ar group to form a macrocycle ,
The ArCHOs are allowed to proceed at a concentration of 3 × 10 ⁻² mol / liter or more, and the ArCHOs are allowed to proceed.
A method for producing the extended porphyrins according to 1. 5. The extended porphyrin according to claim 1, 2, 3 or 4, wherein at least one selected from boron trifluoride, trifluoroacetic acid and boron trifluoride etherate is used as an acid catalyst. A method of manufacturing.