JPH0559059A - Fluorination of porphyrin - Google Patents

Abstract

PURPOSE:To provide a method for selectively fluorinating the meso-position of porphyrin in a high yield. CONSTITUTION:Porphyrin is fluorinated by reacting the porphyrin with an N-fluoropyridinium salt. An organic solvent such as acetonitrile is preferably used as the reaction solvent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for fluorinating porphyrin. More specifically, the present invention provides
The present invention relates to a method for fluorinating porphyrin using an N-fluoropyridinium salt. In particular, the present invention is
The present invention relates to a method for fluorinating porphyrin, which is capable of fluorinating the meso position of porphyrin with good selectivity and high yield using a fluoropyridinium salt.

[0002]

BACKGROUND OF THE INVENTION Porphyrins are known to play an important role in the living body. The role and metabolic process can be easily analyzed by ¹⁹ F-NMR analysis using fluorinated porphyrin, and the principle can be applied to be used as a diagnostic agent. Further, fluorinated porphyrin is also useful as an oxidation catalyst, and it is known that benzene can be efficiently converted into phenol. Conventionally, a so-called building block method for synthesizing a target fluorinated porphyrin by combining various reactions using a fluorine-containing compound having a relatively short carbon chain as a starting material, and a porphyrin already synthesized or extracted from a natural product There is a method of fluorinating using an agent. The former has the drawbacks that it requires a multi-step synthetic route, the yield is low due to the strong electron withdrawing property of fluorine, and the desired fluorinated porphyrin is difficult to obtain. The latter has been tried using a fluorinating agent such as CsSO ₄ F, but the present situation is that the reaction does not occur even with these reactants, or even if it does, the yield is extremely low at 2-3%. is there.

[0003]

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned problems, and as a result of earnest studies on improvement of the yield of porphyrin reaction using various known fluorinating agents. , Surprisingly,
It was found that the yield and the selectivity, especially the selectivity to the meso position are improved by fluorinating with the N-fluoropyridinium salt proposed in No. 07, and the present invention has been completed. is there.

[0004]

That is, the present invention is a method for fluorinating a porphyrin, which comprises reacting a porphyrin with an N-fluoropyridinium salt. -2,6-dichloropyridinium triflate,
It is a method characterized by using at least one compound selected from N-fluoro-3,5-dichloropyridinium triflate and N-fluoropentachloropyridinium triflate, and an organic solvent such as acetonitrile or fluorobenzene as a reaction solvent. The method is characterized by using a solvent, and further provides a method characterized by further adding a base such as potassium carbonate or strontium carbonate into the reaction system, if necessary. The porphyrin fluorinated according to the present invention has a basic structure represented by the following general formula (1),
Various porphyrins can be obtained depending on the kind and position of the substituent to be substituted.

[0005]

[Chemical 1]

Examples of the N-fluoropyridinium salt used in the present invention include those represented by the following general formula (2).

[0007]

[Chemical 2]

(Here, R ^{1 to} R ⁵ are hydrogen atom, halogen atom, alkyl group, aryl group, acyl group, alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, nitro group, cyano group, alkylsulfonyl group or arylsulfonyl group. is a group, X is the conjugate base of Burensutetto acid, X ^- is _{^{- OSO 2 CF 3, - PF}} 6, - SbF 6, - Cl
_{^{O 4, - OSO 2 F,}} - OCOCF 3, - OSO 2 C 4 F 9, - a BF _4, etc.. ) The N-fluoropyridinium salt used in the present invention is usually obtained by reacting a pyridine compound with a Brensted acid compound or a Lewis acid in the presence of fluorine. One specific example is shown by the following formula (3).

[0009]

[Chemical 3]

[0010] (Note) ^- OSO ₂ CF ₃ is ^- sometimes referred to as OTf. The ^- OSO ₂ CF ₃ is referred to as trifluoromethane sulfonate or triflate. Various compounds can be made by changing the substituents on the pyridine of the N-fluoropyridinium salt. For example, N-fluoro-2,6 where R ¹ and R ⁵ are Cl.
-Dichloropyridinium triflate, R ¹ and R ⁴ are Cl
When N-fluoro-3,5-dichloropyridinium triflate which is ## STR4 ## and N-fluoropentachloropyridinium triflate in which all of R ^{1 to} R ⁵ are Cl are used, all four meso positions of porphyrin, particularly octaethylporphyrin, are fluorine-containing. I was able to Especially when N-fluoropentachloropyridinium triflate was used, the yield was remarkable. Further, as the reaction solvent, it is preferable to use an organic solvent such as acetonitrile or fluorobenzene. Further, by adding a base such as potassium carbonate or strontium carbonate to the reaction system to capture an acid generated as the reaction proceeds, the decomposition of porphyrin can be suppressed.

[0011]

EXAMPLES The present invention will be further described below with reference to examples. For convenience, the following description will be given with octaethylporphyrin, but the present invention is not limited to this compound and Examples. Example 1 Octaethylporphyrin 2 represented by the following chemical formula (4)
0 mg (37.5 μmol),

[0012]

[Chemical 4]

25 mg of strontium carbonate (169 μmo
l) in 10 ml of dry acetonitrile, 150 mg of N-fluoro-2,6 dichloropyridinium triflate
A solution of (473 μmol) in acetonitrile (10 ml) was added dropwise, and the mixture was heated under reflux for 2 days under an argon atmosphere. After cooling, an aqueous thiosulfate solution was added and the acetonitrile was distilled off under reduced pressure. The residue was extracted with a mixed solution of benzene-diethyl ether, washed with an aqueous sodium bicarbonate solution and dried, and then the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel flash column chromatography with a mixed solvent of hexane-methylene chloride, and the meso-position tetrafluorinated substitution product represented by the following formula (5) was obtained at a yield of 8.8%. was gotten.

[0014]

[Chemical 5]

Example 2 20 mg (37.5 μmol) of octaethylporphyrin and 25 mg (250 μmol) of potassium carbonate were placed in 10 ml of dry acetonitrile, and a solution of N-fluoropentachloropyridinium triflate (150 mg, 473 μmol) in acetonitrile (10 ml) was added dropwise. 2 under argon
The mixture was heated under reflux for a day, cooled, and an aqueous thiosulfate solution was added, and acetonitrile was distilled off under reduced pressure. The residue was extracted with a mixed solution of benzene-diethyl ether, washed with an aqueous sodium bicarbonate solution and dried, and then the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel flash column chromatography with a mixed solvent of hexane-methylene chloride, and a meso-position tetrafluorinated compound was obtained in a yield of 13%.

Example 3 Octaethylporphyrin 20 mg (37.5 μmol) and potassium carbonate 25 mg (250 μmol) were put in dry hexafluorobenzene 10 ml, and a solution of N-fluoropentachloropyridinium triflate 150 mg (473 μmol) in acetonitrile (10 ml) was added dropwise. Then, the mixture was heated under reflux for 2 days under an argon atmosphere, cooled, an aqueous thiosulfate solution was added, and acetonitrile was distilled off under reduced pressure. The residue was extracted with a mixed solution of benzene-diethyl ether, washed with an aqueous sodium bicarbonate solution and dried, and then the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel flash column chromatography with a mixed solvent of hexane-methylene chloride, and
A meso-positioned tetrafluoro-substituted product was obtained at a yield of 0%.

Example 4 20 mg (37.5 μmol) of octaethylporphyrin and 25 mg (169 μmol) of strontium carbonate were added to 10 ml of dry hexafluorobenzene, and 150 mg of N-fluoropentachloropyridinium triflate (473 μmo).
After the hexafluorobenzene solution (10 ml) of l) was added dropwise, the mixture was heated under reflux for 2 days under an argon atmosphere, cooled and an aqueous thiosulfate solution was added, and hexafluorobenzene was distilled off under reduced pressure. The residue was extracted with a mixed solution of benzene-diethyl ether, washed with an aqueous sodium bicarbonate solution, dried, and
The solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel flash column chromatography in a mixed solvent of hexane-methylene chloride, and the meso-position 4 was obtained at a yield of 18%.
A fluorine-substituted product was obtained.

[0018]

In the present invention, N is used as the fluorinating agent.
By using the -fluoropyridinium salt, it is possible to selectively fluorinate the porphyrin particularly at its meso position in a good yield, and to provide a compound useful for medical and testing purposes.

Claims (6)

[Claims] 1. A method for fluorinating a porphyrin, which comprises reacting a porphyrin with an N-fluoropyridinium salt. 2. The method according to claim 1, wherein the meso position of porphyrin is fluorinated. 3. An N-fluoropyridinium salt as N-
At least one compound selected from fluoro-2,6-dichloropyridinium triflate, N-fluoro-3,5-dichloropyridinium triflate and N-fluoropentachloropyridinium triflate is used. The method described. 4. The method according to claim 1, wherein octaethylporphyrin is used as the porphyrin. 5. The method according to claim 1 or 2, wherein an organic solvent such as acetonitrile is used as a reaction solvent. 6. The method according to claim 1 or 2, wherein a base such as potassium carbonate or strontium carbonate is added to the reaction system.