JPS58113198A - Porphyrin compound bonded with cyclodextrin - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI[R1 is OH, ORa (Ra is 1-7C hydrocarbon group), etc.; R2 is vinyl, CH2CH2COORf (Rf is H or Ra), etc.; R3 is OH, NH2, etc.; R4 is H, hydrocarbon group, etc.; -XY- is group of formula II, formula III, etc.; n is 6-8]. EXAMPLE:An iron (III) complex of porphyrin derivative consisting of protoporphyrin IX monoethyl ester and 6A,6B,6C,6D,6E,6F,6G-aminomethyl-6A,6B, 6C,6D,6E,6F, 6G-deoxy-beta-cyclo-dextrin bonded to the ester at one point through the group of formula III. USE:Blood substitute for transfusion. PROCESS:The objective compound is prepared, e.g. by reacting monoethyl ester derived from protoporphyrin IX, 2Na salt with an amine (e.g. 6A,6B,6C,6D,6E,6F, 6G-heptaminomethyl-6A,6B,6C,6D,6E,6F,6G-heptadeoxy-beta-cyclodextrin) in the presence of a peptide bonding agent (e.g. diethylphosphoric acid cyanide).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to porphyrin derivatives, and particularly to porphyrin compounds to which cyclodextrino is attached.

In general, iron porphyrin complexes (heme) represented by the formula have the ability to adsorb and desorb oxygen molecules in the presence of an appropriate axial base ligand to form so-called oxygen complexes when the central iron is in a divalent state. That is what is being said.

However, this complex is rapidly oxidized in the presence of water and loses its ability to adsorb and desorb oxygen.

On the other hand, hemoglobin and myoglobin in living bodies stably adsorb and desorb oxygen in the presence of water and are unlikely to be oxidized. A basic ligand is coordinated to only one of the axial coordination sites of the central iron of the porphyrin, and the other axial coordination site (sixth coordination dust) is left empty as a coordination field for oxygen molecules. This is because the reeds are surrounded by a suitable hydrophobic environment and can effectively prevent the approach of water molecules.

Therefore, if one axial coordination site of the central iron in the iron porphyrin complex shown by A or its derivative is surrounded by a hydrophobic environment that can exclude the approach of water molecules, a compound capable of stably adsorbing and desorbing oxygen molecules can be provided. It seems possible.

This invention was made based on the above-mentioned viewpoint, and is 14- to provide a porphyrin compound in which one axial coordinate site of the central iron is surrounded by a suitable hydrophobic environment, thereby preventing the approach of water molecules. With the goal.

In order to achieve the above object, the present invention provides the formula (A)
The iron porphyrin complex or its derivative represented by is bound to cyclodextrin (α-1β- or r-cyclodextrin).

That is, according to the present invention, a porphyrin compound having a porphyrin ring in which iron is coordinated at the center and having at least one functional group as a ring substituent has an amide bond with the functional group and/or a urethane bond. In a compound in which a cyclodextrin is bound by a bond, if the porphyrin compound has a free functional group that does not survive the bond, the free functional group is protected or coordinated to the central iron. A porphyrin compound is provided which may be covalently bonded to the resulting imidazole derivative.

As is well known, cyclodextrin is a cyclic product derived from starch with 6 (α-form),
It has seven (β-form) and eight (1-form) glucose residues, and has a hollow truncated cone-shaped molecular structure. In this hollow truncated cone-shaped molecular structure, the lower surface side where the secondary hydroxyl group is present is -
The cavity diameter is larger than that on the top side where the class hydroxyl groups are present.

Compounds obtained by bonding such cyclodextrins with porphyrin compounds according to the present invention can be roughly divided into two types: structures in which the upper surface of the cyclodextrin faces the plane of the porphyrin compound, and structures in which the lower surface thereof faces the plane of the porphyrin compound. . If we further divide these structures according to the number of bonds between Ilufilin and cyclodextrin, we can see that the structure of this invention is different from that of this invention. The Schiff-41J compound will include a structure represented by the following formulas.

(1) Here, R1 is 10H group, -0Ra M- or -NH
Rb group, R8 is a hydrocarbon group having 1 to 7 carbon atoms, Rb is a hydrocarbon group having 1 to 7 carbon atoms, or R;

17- hydrogen or methyl group, m is an integer of 3 or more, R2 is each independently -C) I=CH24, -CH2CH2COO
J group or -CH2CH2CONHRb group, Rf is hydrogen or Ra, R5 is 10H group, -NH2 group, -NHCH
3 groups or their acylated products, R4 is each independently hydrogen, a hydrocarbon group or -OCRg group, Rg is a hydrocarbon group, -XY- is 18- (II) where R2 is each independently , -CH=CH2 group,
-CH2CH2COOR4 group or -CH2CH2CO
NHRb group, Rf is an aqueous group or a hydrocarbon group having a prime number of 1 to 7, Rb is a hydrocarbon group having 1 to 7 carbon atoms or a 1q-aqueous group, or a methyl group, m is 3 or more =W, and R3 is a 〇H group, -N112 group, -NHCH5 group or their acylated products, R4 is hydrogen, hydrocarbon group or -
OCRg group, Rg is a hydrocarbon group, -xy is n is 6.7 or 8° (■), where R2 is each independently a -CH=CH2 group,
-CH2CH2COORf group or -Cf(2CH2C
ONHRb group, Ftf is hydrogen or a hydrocarbon group having 1 to 7 carbon atoms, Rb is a hydrocarbon group having 1 to 7 carbon atoms, hydrogen or methyl group, m is an integer of 3 or more, R3 is a 10H group, -NH2 group, -NHCH3 group or an acylated product thereof, R4 is each hydrogen or a hydrocarbon group 22- Here, R3 is -01 (group, -N13 group, -NHCH,
group or an acylated product thereof, R4 is each hydrogen, a hydrocarbon group or -OCRg group, Rg is a hydrocarbon group, and n it: 6.7 or 8° (V) +1 where R2 company, each -cu =cn2 group, -CH2
CH2C00R4 group 1: or -CH2CH2CONHR
1) group, Ftf is an aqueous or C1 to C7 hydrocarbon group, Rb is a C1 to C7 hydrocarbon group, dihydrogen or methyl group, m is an integer of 3 or more, 'R6 is a 10H group , -N13 group, -tmcH5 group or their acylated products, R4 is hydrogen, hydrocarbon group or -o
ca, group, Rg are hydrocarbon groups, -X'Y' are each 25- (Vl), where R2 is -CtL-(I (2 groups, -CHzCH2
COOR (group or -CH2CH2CONHRb group, F
tf is hydrogen or a hydrocarbon group having 1 to 7 carbon atoms, Rb
is a hydrocarbon group having 1 to 7 carbon atoms, 726-hydrogen or methyl group, m is an integer of 3 or more, R3 is -O
H group, -NH2 group, -NHCI (5 groups or acylated products thereof, R4 is hydrogen, hydrocarbon group, respectively,
R3 is a 10H group, -NH2 group, -NHCHs group or an acylated product thereof, R4 is each hydrogen, hydrocarbon group or -OCRg group, Rg is a hydrocarbon group, -xly/ is each n is 6.7 Or 8. In order to produce the cyclodextrin-bonded porphyrin compound of the present invention, the functional group that is the ring substituent of the porphyrin compound and the primary or secondary hydroxyl group of the cyclodextrin are bonded via a urethane bond. Alternatively, the amine group of a cyclodextrin amino compound (a derivative in which all primary hydroxyl groups of cyclodextrin are converted to primary or secondary amines) is bonded with an amide.

Specifically, the compounds represented by the formulas (I) to (■) can be produced, for example, by the methods shown below.

=29- (i-a) After suspending the disodium salt of glotoporphyrin (formula) in dichloromethane, hydrogen chloride gas is blown into the suspension to convert free dicargen into dicargen. To this, alcohol ft.
A half molar amount of nocarboxylic acid is added to aOH, and the mixture is reacted at room temperature. Thin layer chromatography (silica gel; chloroform/methanol/triethylamine (20/2/1
) After determining the maximum production time of the component with the second highest Rf value using the mixed heating medium), the reaction is stopped by neutralizing with an appropriate amount of trienylamine. This product was set in a silica dull column, and the components were first drained using chloroform, and then chloroform/methanol/triethylamine (20/2/1
) The desired protoporphyrin monoester is obtained by eluting with a mixed solvent and crystallizing the colored first component of the porphyrin from a mixed solvent of triethylamine and water and acetic acid. Yield is 25-30%.

)! Lotoporphyrin ■ Monoester with N,N-dimethylformamide/dichlormeth/triethylamine (
70/30/1) dissolved in a mixed solvent, a heftide binder such as diethyl phosphate cyanide and an amine Rb-NH2
1 mol to 1 mol to 1 mol of monoester, respectively.
．． The mixture was added at a ratio of 2 moles, and the mixture was stirred and reacted overnight at room temperature. This reaction product is made into a dichloromethane solution, washed with water, dried and recrystallized from dichloromethane-petroleum ether to obtain glotoporphyrin monoester monoamide. The yield is over 90%. (Note that the amine used is R.

After catalytic hydrogenation of the produced cyano bodies in the presence of a Raney nickel catalyst or hydrazine decomposition followed by a known process ('IJ, Schwa
n, J, Haterocycle, +cham1 [6
33 (1967), etc.].

).

(The protoporphyrin monoester monoamide obtained in this way was mixed with an aqueous solution containing a small molar amount of potassium hydroxide relative to the monoester monoamide in methanol or N,N-dimethylformamide solvent and kept at room temperature for one day. After the reaction product is made into an alkaline aqueous solution, it is diluted with hydrochloric acid and the precipitate is collected. In this way, almost pure protoporphyrin monoamide is obtained.

f) Glotoporphyrin ■ A stone made by adding a diethyl ether solution of osmium tetroxide to a sooxane solution of monoester and adding water. Next, metaperiodic acid (IJ) is added in small portions over several hours, followed by stirring at room temperature for 3 days in the dark.

Add the same amount of water to this reaction solution, collect the precipitate,
2,4-diformyldeetheroporphyrin monoester is obtained by recrystallizing from a suitable solvent if necessary.

(B) After dissolving the above 2.4-diformyl deuteroporphine I) monoester in pyridine containing a small amount of piperidine at the boiling point, the malonic acid monoester HOOC-CH2 was dissolved at 33-95°C. -COORa (2,4-diformyl f niteroporphyrin ■ About 200% for monoester
x -1 = Louis II) and a small amount of a solution of piperidine dissolved in pyridine is added dropwise over several hours. Subsequently, the above malonic acid monoester (2,4-diformyldeetheroporphyrin
°) and a small amount of a solution of piperidine in pyridine are further added at boiling point over a period of 1 hour. After cooling the reaction mixture to 60'C, add a large amount of petroleum ether, leave it overnight under water cooling, collect the precipitated crystals, and add a small amount of nomethanol as necessary, for example using a silica dull column. Elution with chloroform yields 2,4-noacrylic acid ester-deuteroborphyrin monoester. Yield is 60-80%. .

(C) The 2,4-noacrylic acid ester-f''z-froporphyrin monoester obtained by the process was mixed with A'34-radium black or activated carbon-supported radium catalyst in methanol containing 2% triethylamine. The desired 2,4
-Dipropionate ester-deuteroborphyrin■
Monoester can be obtained quantitatively.

(A) After dissolving the 2.4-noformyl deuteroporphyrin monoester in pyridine containing a small amount of piperidine at the boiling point, the malonic acid monoamide HOOC-CH2-CONHRg (2,4- Noformyl r niteroporphyrin ■About 2 for monoester
00 times the molar amount) and a small amount of a solution of piperidine dissolved in pyridine are added dropwise over several hours. Subsequently, a brood solution prepared by dissolving the above malonic acid monoamide (approximately 60 times the molar amount of 2,4-diformyl deuteroporphyrin monoester) and a small amount of piperidine in pyridine was further separated at boiling point for 1 hour. I can do it.

After cooling the reaction mixture to 60°C, add a large amount of petroleum ether, leave it overnight under water cooling, collect the precipitated crystals, and if necessary, use a silica gel column for example. Elution with methanol in chloroform yields 2,4-noacrylamide-rneeteroporphyrin monoester. Yield is 50-60
It is Chi.

(B) The thus obtained 2,4-noacrylamide deuteroporphyrin ■monoester In methanol containing 2 parts of triethylamine, 2,4-noacrylamide deuteroporphyrin ■several times to ten times as much palladium black as the monoester. In the presence of hydrogen pressure of 10 atm or more, 50 to 6
React at 0°C for several hours. Thereafter, the catalyst is filtered off under nitrogen in the dark, and the solvent is distilled off under reduced pressure. Nitrogen saturated water containing a small amount of iodine is added to the residue, and while the solution changes from green to reddish brown, a small amount of cysteine is added to eliminate the iodine coloration. Furthermore, a small amount of acetic acid is added and the precipitate is collected. Thus the desired 2,4
- Dinolobionic acid amide deuteroporphyrin ■ monoester is obtained quantitatively.

(ib) In formula (C), n is 6 or 7, and all R3
is a monomethylamino group or an amino group J
For example, R. Breslow et al., J.

Amer, Chem, Soc, 102, 76
2 (1980) and He1v, Chin, Ac.
ta #61 (6), 2190 (1978), and the compound of formula (B) can also be produced according to that method, for example, as follows.

(A) Cyclodextrin and p-)luenesulfonyl chloride (1.1 for cyclodextrin)
<n mol iL n is 6 if the cyclodextrin is α-integrated, 7 if it is β-integrated, and 8 if it is r-integrated, and the mixture is added to pyridine and stirred at room temperature for - days. Then, after standing at 5°C for 18 hours, the reaction solution was poured into a large amount of ice water.

Collect the precipitated crystals, wash thoroughly with water, and then with noethyl ether. The washed crystals are dried under reduced pressure under high heat and recrystallized from methanol to obtain a derivative in which all of the primary hydroxyl groups of cyclodextrin are tosylated. Yield is 3
It is in charge of 0-35.

(B) The cyclodextrin tosylated product thus obtained is added to a 50% methylamine/methanol solution, and heated and stirred at 70° C. for 3 days in a metal sealed tube. The reactants were transferred to an ion exchanger column (caloxymethyl cellulose, 5%
By treatment with NH4HCO3 water bath i), a desired cyclodextrin derivative in which all the primary hydroxyl groups of cyclodextrin are monomethylaminated is obtained.

(ib-2) R5=-NH2 (5) Cyclodextrin tosylated product N, N -3
8- Dissolve in dimethylformamide and add sodium azide (2Xn times molar amount to cyclodextrin tosylated product,
(h is as described above) was heated to 90°C at 90°C.
Allow to react for 12 hours. After cooling, the reaction mixture is poured into ice water and the precipitate precipitated is collected. In this way, a derivative in which all the primary hydroxyl groups of cyclodextrin are azidated is obtained. Yield is 85-90%.

(B) Cyclodextrin tosylate and triphenylphosphine (approximately 1,2
A molar amount of n (n is as defined above) is dissolved in pyridine and stirred at room temperature for 1 to 2 days. Next, ammonia-saturated methanol is added and the mixture is further stirred at room temperature for 2-3 days. Dilute this reaction solution about 10 times with ethyl acetate, and collect all the precipitate that has precipitated. Extract this precipitate with dilute hydrochloric acid,
When the extract is poured into 50 to 100 times the volume of ethanol, the hydrochloride salt of a derivative in which all of the primary hydroxyl groups of cyclodextrin have been aminated is precipitated as a white precipitate. Yield is 70-80%.

(11) Porphyrin derivative represented by formula (B), porphyrin derivative represented by formula (B), and formula (C)
The cyclodextrin derivative represented by is added in equimolar proportions at a dilute concentration in dimethyl sulfoxide, and a small amount of triethylamine is added.

Add diethyl phosphate cyanide as a condensing agent to this,
Stir at room temperature in the dark for several days. This reaction solution was diluted with the same amount of chloroform, poured into diethyl ether, and the precipitate precipitated was collected. This precipitate, 1
Porous packing material that can separate molecules within the molecular weight range of 00 to 2700 (e.g. BIO-RAD Rapora) IJ-
Biobeads S As a result, the desired compound, in which one molecule of the porphyrin derivative and one molecule of the cyclodexide derivative conductor are amide bonded at one site, has a dark porphyrin color.
components, followed by some unreacted components and other low-molecular impurities flowing out. By repeating this purification process, the desired amide bonding compound can be produced in a yield of 80 to 90%.The above amide bonding reaction was performed in a dilute bath solution, and both reactants were steric. Because they are highly damaging molecules, it is difficult to produce a compound that is a multimolecular condensation of a porphyrin derivative and a siphrobukis derivative. This means that near the excluded volume in the above purification process? This is evidenced by the almost absence of coloring components.

The porphyrin derivative represented by formula (B) and cyclodextrin were dissolved in equimolar proportions in N,N-dimethylformamide at a dilution of 3 degrees, followed by a small amount of 41-triethylamine, followed by a small amount of cyclodextrin with respect to the porphyrin derivative. Add diphenyl phosphoryl azide (condensing agent) to the lid and stir. This converts the porphyrin derivative into an acid azide. Then, when the reaction mixture is stirred at 70° C. for 12 hours, the acid azide decomposes to convert into isocyanate, and the highly active primary hydroxyl group of the coexisting cyclodextrin reacts with it to form a urethane bond. For this reaction mixture, the above (li-1
), the desired purified urethane-bonded compound is obtained. Yield is 45-60%.

(11θ, Next Introduction (Production of Iron Complex 3) The conjugate of cyclodextrin and porphyrin derivative obtained by the above method is dissolved in N,N-dimethylformamide and placed under an inert gas (nitrogen, argon, etc.) atmosphere. Add more than an equimolar amount of ferrous chloride to the combined product and react at 60 to 80°C for several hours. After cooling, a small amount of concentrated hydrochloric acid is added to the reaction bath solution, making it weakly acidic or neutral. A Biobeadi 42-SX-2 glucolumn was developed with N,N-dimethylformamide. As a result, the desired I[l complex was separated from unreacted ferrous chloride and the hemin-colored column first effluent component can be obtained quantitatively as

When the iron ([1) complex obtained in (+ii) above, which has a propionic acid ester group on the top of the porphyrin, is to be esterolyzed to convert the ester group into a propionic acid group, the iron ([ 11) The complex is dissolved in N,N-dimethylformamide, an aqueous solution containing a small molar excess of potassium hydroxide relative to the ester is added, and the mixture is stirred overnight at room temperature.

Then, N,N-trimethylformamide was distilled off under reduced pressure,
Dissolve the residue in water. A small amount of hydrochloric acid is added dropwise to this aqueous solution to make it neutral to weakly acidic, and the precipitate precipitated is collected by centrifugation. In this way, the desired four iron (Ill) bodies having a free propionic acid group in the porphyrin ring are obtained.

(v) Acylation 1. I? When acylating and protecting the amino group, monomethylamino group, or secondary hydroxyl group of cyclodextrin that is not participating in the bond with lufilin, dissolve the complex in pyridine and add a large excess of carboxylic acid anhydride to it. 1 in °C
Drip over time. Then, after stirring at room temperature in a dark place for one day, the mixture was poured into a large amount of diethyl ether, and the precipitate precipitated as the desired product was collected.

(I 1) R2=-CH=CH2 One tray of pharmaceutical zolotoporphyrin disodium is dissolved in an appropriate amount of water at room temperature, and then acetic acid is added to make it acidic. After collecting the precipitated reddish-brown precipitate and thoroughly washing it with water,
By drying under reduced pressure at 0°C for 1 day, zolotoporphyrin (2) can be obtained quantitatively.

(A) Disodium salt of f-rotoporphyrin is suspended in a large amount of dichloromethane. Benzyl alcohol is added to this suspension and chlorine gas is introduced. After stirring overnight at room temperature in the dark, the mixture is washed with an ice-water solution of 100 ml of bicarbonate and dried over 11 ml of anhydrous carbonic acid.

The solvent was then distilled off under reduced pressure, and the residue was recrystallized from a methane-petroleum ether system to obtain protoporphyrin.
Dibenzyl ester is obtained. Yield is 84 cm.

(B) The ester obtained in (A) above is dissolved in a large amount of oxane, and a diethyl di-45-ethyl solution of osmium tetroxide is added. Next, after adding water, sodium metaperiodide, which is about 2.5 times heavier than the ester, is added little by little over several hours, and the mixture is stirred at room temperature in the dark for 2 to 3 days. A large amount of water is added to this, and the precipitated dark purple crystals are collected, washed successively with water, methanol and diethyl ether, and dried under reduced pressure while heating. Thus 2,4-
Diformyl deuteroporphyrin dibenzyl ester is obtained in a yield of 77%.

(C) Deuteroporphyrin obtained in (B) above ■
The ester was dissolved in a large amount of pyridine containing a small amount of bi(lysine) under the boiling point, and malonic acid (300 times heavier than the ester) and a small amount of piperidine were dissolved in a solution of 95 ml of pyridine.
Add dropwise at °C. In addition, Maron #! A solution of pyridine (10 times heavier than the ester) and a small amount of piperidine is added dropwise at the boiling point. Then, this reaction solution was heated to 60
After cooling to ℃, add a large amount of petroleum ether and leave overnight under water cooling. The precipitated crystals are collected, thoroughly washed with chloroform/noethyl ether (3/2), and dried under reduced pressure while heating. In this way, 2,4-diarylic acid deuteroporphyrin dibenzyl ester is obtained.

Yield is 87 cm.

(D) The ester obtained in the above (Q) was dissolved in N,N-dimethylformamide containing a small amount of triethylamine by fByW.
and amine Rb/ -NH2 (6 times molar M of ester)
and diethyl phosphoric cyanide (3 times the molar amount of the ester) are added, and the mixture is stirred at room temperature in the dark for 1 day. This reaction solution is subjected to column analysis (silica dal, chloroform/methanol mixed solvent), and a second component colored by porphyrin that flows out of the column is collected. This is dissolved in chloroform, and this solution is washed successively with water, a 5% carbonic acid aqueous solution, and water. After treatment in a conventional manner, 1. recrystallization from chloroform/petroleum ether yields a porphyrin derivative of the formula. Yield is 28-3
It is 2%.

(Smell) The porphyrin derivative obtained in (D) above was dissolved in methanol containing a small amount of triethylamine. The reaction is allowed to proceed for several hours at ℃.Then, the catalyst is filtered off under nitrogen in a dark place, and the solvent is distilled off under reduced pressure.Nitrogen hydrated water containing a small molar excess of iodine is added to the residue, and the solution is While the color changes from green to reddish brown, a small amount of cysteine is added to eliminate the iodine color.Furthermore, a small amount of acetic acid is added and the precipitate precipitated is collected.In this way, 2, 4 as shown by the formula
-Dizolobionylamide deuteroporphyrin (■) is obtained in good yield.

(A) In the reaction (1-2) (C) above, malonic acid monoester HOOC-CH2-
After reacting in the same manner using COORf (Rf is a C1 to C7 hydrocarbon, excluding the benzyl group), petroleum ether is added to the reaction solution kept at about 60°C, and the precipitate precipitated is collected. This precipitate is eluted using a silica gel column with chloroform/methanol (20/l) to collect the colored first component of ruphyrin. This is recrystallized from chloroform/petroleum ether to obtain 2,4-diarylic acid ester-pnieteroporphyrin dibenzyl ester. Yield is 60-80%.

(B) The porphyrin derivative obtained in (A) above is dissolved in a suitable solvent (e.g. triethylamine-methanol, N,
Dissolved in N-dimethylformamide), ? Water accumulation treatment is carried out in the presence of radium black under a hydrogen pressure of 1 to 3 atm at room temperature for 5 to 6 hours. Thereafter, when treated in a conventional manner, 2,4-dizolopionic acid ester-deuteroporphyrin ■
It can be obtained with a yield of 0.0% or more.

(11) Binding with cyclodextrin (1-1)
) to (i-3) and the cyclodextrin derivative represented by formula (C), the steps described in (1) above except for using twice the amount of each condensing agent
The reaction may be carried out in the same manner as in (ii). In this way, a desired compound is obtained in which each molecule of the porphyrin derivative and the Schiffrobukis IJ derivative is bonded with amide or urethane at the 50-position. The yield is 75-80% for amide bonds and 30-45% for urethane bonds.

These methods can be carried out in exactly the same manner as in (1) (ii+) to (V) above. In this way, the compound represented by formula (II) is obtained in good yield.

[■] Method for producing a compound of formula (ωI) (Shu Formula (II)
) The formula % obtained in the step of obtaining the compound represented by CU3 is dissolved in N,N-methylformamide (where R is a C1 to C7 hydrocarbon). Then, add an aqueous potassium hydroxide solution, stir under a hood, and then evaporate the solvent under reduced pressure. Dissolve the residue in water, add the same amount of a7ton as this aqueous solution, and then dropwise add a small amount of dilute hydrochloric acid. Centrifuge the precipitated sediment. In this way, the glycine ester group in the above formula (G) is hydrolyzed and the corresponding free cal? A compound having an acid group is obtained.

(B) Add the compound obtained in (4) above to [■] (11
) by subjecting it to the same reaction conditions using a condensing agent (t may be half), the compound is further intramolecularly condensed at one site to obtain a compound in which cyclodextrin and porphyrin are bonded at three sites. .

(C”l) For the compound obtained in (B) above, m(
By introducing iron or acylating gold by the method of iiD and (ψ), a compound represented by formula (g) is obtained.

[■] Method for producing a compound of formula (transformation) (N formula ([[
) in the step of obtaining the compound represented by (formerly (ii)) except that the compound represented by the formula (where R is a C1-C7 hydrocarbon group) is double-digested with potassium hydroxide. [1
(The two zoropionic acid ester groups are converted to free noropionic acid groups by hydrolysis in the same manner as At.

(B) The compound obtained in (A) above [■, l (
By subjecting the compound to the same reaction conditions using the condensing agent in i), the compound is further intramolecularly condensed at two locations, and a compound in which cyclodextrin and porphyrin are bonded at four locations is obtained. It will be done.

(C) In (B) above, the m (
iii) Iron introduction or acylation by methods b- and Q) yields a compound of formula □□□.

Cyclodextrin and benzoic anhydride in a molar amount 1.2 times the number of primary aqueous groups of the cyclodextrin are dissolved in an appropriate amount of pyrinone at a total temperature of 60°C, and stirred at the same temperature for 24 hours. After cooling, the reaction solution was added to 10 volumes of diethyl ether and left standing at room temperature for several hours. After washing the precipitated precipitate with diethyl ether and water,
Drying under reduced pressure at 0°C and recrystallization from methanol/diethyl ether yields cyclodextrin in which all primary hydroxyl groups are benzoylated.

Cyclodextrin and 5 to 6 times the molar amount of trityl chloride are dissolved in an appropriate liter of pyridine at 100°C and stirred at the same temperature for 4 hours. After cooling to room temperature, the reaction bath solution was added to the 15-ml ice water. The precipitated white starch is collected by the white method, washed with water and diethyl ether, and then dried under reduced pressure at 60 to 70°C. In this way, a cyclodextrin in which several or more of the -class hydroxyl groups are tritylated is obtained.

(ib) Above (t-a-1) or (ia-2)
) The cyclodextrin derivative obtained in ) is dissolved in a mixed solvent of dimethyl sulfoxide and dioxane, and triethylamine is added. This was completely cooled on ice, and ethyl chlorocarbonate was added dropwise at a temperature of 15°C. After standing for a predetermined period of time, concentrated hydrochloric acid is poured into this solution while cooling with water to bring it to a weak level. This was added to a large amount of ice water, the precipitate precipitated was collected, washed with cold water and diethyl ether, and dried under reduced pressure over phosphorus pentoxide.
A cyclodextrin derivative represented by - (ie, a compound* in which two or more carnate groups are introduced into or between cyclodextrin molecules) is obtained.

(ie) the cyclodextrin derivative obtained in (ib) above is treated with N,N-dimethylformamide pvcms,
This solution was added to a mixed solvent of ethylene amine y/N,N-trimethylformamide (1/1), and the mixture was stirred overnight under sealing. Then, the reaction solvent was distilled off under reduced pressure, and the residue was purified with N
, reprecipitated from N-dimethylformamide/diethyl ether. In this way, a cyclodextrin derivative of formula (J) is obtained.

(10) The cyclodextrin derivative of formula (J) and the porphyrin derivative represented by the above formula CD were dissolved in equimolar amounts in diluted N,N-dimethylformamide, and 2.4 times molar amount of diethyl phosphorus was dissolved in diluted N,N-dimethylformamide. Add acid cyanide and triethylamine and stir in the dark for 6 days. This reaction solution was diluted with the same amount of chloroform and added to 58-ether, and the precipitated precipitate was dissolved in a total dull column (Bi
5X-2, solvent: N,N-trimethylformamide) to collect the porphyrin colored first component. In this way, one molecule of the cyclodextrin derivative of formula (J) and one molecule of the porphyrin derivative of formula (D) are
A compound with an amide bond at the site is obtained.

(11D) The amide F% conjugate obtained in (11) above is subjected to iron introduction, ester decomposition, or acylation according to the method of CI) ([1) to (■), so that XY becomes amide in the formula The desired compound is obtained.

(lψ Deacylation Compounds obtained in 010 above whose primary hydroxyl groups are protected with benzoyl or trityl groups and whose secondary hydroxyl groups are free) were dissolved in chloroform/methanol and diluted with hydrochloric acid. The mixture was stirred at room temperature in the dark. After neutralization, the solvent was distilled off under reduced pressure, and the residue was purified using a gel column (Biobeads 5X-2, solvent: N, N
The -nomethylfortrityl group is removed, yielding a compound in which all hydroxyl groups on the cyclodextrin are in free form.

CB) Urethane conjugate (1) The porphyrin derivative of the formula (D) and the cyclodextrin derivative of the formula (K) (M) 4 are added to N,N-trimethylpolamide at a dilute concentration in a +-namol ratio.
Then, 2.4 times molar amount of nophenyl phosphate at-p and triethylamine are added, and the mixture is stirred at room temperature. After that, 90
Heat at ℃ for 24 hours or more and add the reaction solution to diethyl ether. The precipitated precipitate total dull column (Bi
ObadsSX-2, dd: N,N-trimethylformamide) was prepared at 1nI, and the entire first component of porphyrin color was collected. In this way, a compound is obtained in which each molecule of cyclodextrin and porphyrin are bonded at two locations via urethane bonds.

(11) The desired product can be obtained by subjecting the precipitate obtained in (1) above to the above-mentioned ≧9 reactions, deacylation, or acylation.

[VI] Method for producing the compound of formula (b) [Route (1)
)) Compounds of the formula (where Bi and R'' are -CH2COOH and the other is Rb) which are intermediate products in obtaining compounds of formula (to) 'i N,N-methyl Dissolve in formamide and react at 90°C for 24 hours or more with the addition of a small amount of triethylamine and diphenyl phosphate.This reaction solution 61- is poured into 10 times the amount of diethyl ether, and the precipitate is 9 column (BiobeadsSX-2
, N, N-dimethylformamide), the compound (M) is further intramolecularly condensed in the first ρ of porphyrin coloring, and the cyclodextrin and porphyrin become 3
- Urethane-bonded porphyrin derivatives can be produced in good yield. After introducing iron into the obtained porphyrin derivative in exactly the same manner as in the production of compound (V), the desired porphyrin derivative (RO) can be obtained by removing tritylation, removing benzoyl or acyl protection of the cyclodextrin hydroxyl group as required. ) is manufactured.

[Roo] (2)) For the porphyrin derivative (b) in which cyclodextrin and porphyrin are bonded with urethane at three points on the secondary hydroxyl group side of the cyclodextrin, the following manufacturing process may be used, for example. That is, to explain in detail each manufacturing process, 62- Glotoluphyrin D (5 g to 25 HBr/AcOH
The mixture was stirred at room temperature in a dark place for 4 days in a 50 ml volume, and then poured into 10 times the volume of diethyl ether. After removing F, the precipitate was washed with ethyl ether until the irritating odor disappeared. Drying over potassium hydroxide in the dark at room temperature under reduced pressure yields almost pure hematoporphyrin fupromide 2HBr salt (N) quantitatively.

(B) Add an appropriate amount of the compound (N) obtained in (4) above to
The solution was dissolved in N-trimethylformamide, and heated and stirred in the dark at 60° C. for 20 hours in the presence of 1.5 times the molar amount of biperazone. Next, the solvent was distilled off under reduced pressure, and the residue was dissolved in an appropriate amount of ethanol containing a catalytic amount of sulfuric acid, and the mixture was stirred at room temperature for 24 hours. Add 10 times the volume of the reaction solution to 10% -Na2COx
Pour it into an aqueous solution/sochloromethane, collect one component of nochloromethane, remove the component that flows out with chloroform using a silica force ram, and collect the component that flows out with chloroform/methanol - 4/1. 64 of 0)
- Compounds are produced with a yield of 30-35%.

(C) Porphyrin derivative (0) and cyclodextrin derivative (J) ffi in equimolar proportions of 4 warm N, N-
Dissolve in methylformamide and heat at 600°C for 20 hours. After cooling, water containing 10 times the molar amount of sodium hydroxide relative to the porphyrin derivative (0) was added at a ratio of N,N-methylformamide to Yotsuya, and the mixture was stirred at room temperature overnight. After adjusting the concentration to 1-4.0 with dilute hydrochloric acid, the solvent was distilled off under reduced pressure, leaving a residue of 1r.
Rukaramuk O Mad (Biobeads 5X-2, N,
A hydrolyzed product of the porphyrin propionic acid ester in formula (P) is prepared by preparing the porphyrin with N-methylformamide) and collecting the porphyrin color component.

(D) The porphyrin derivative obtained in (C) above was dissolved in N,N-trimethylformamide, and 10 to 10
-5 mol/l solution. To this, 2.4 times the molar amount of attenuate diphenyl phosphate and triethylamine were added, and the mixture was stirred at 80 to 90° C. for 24 hours or more. Five times the amount of diethyl ether was added to this reaction solution, and the precipitate was collected using a glu column (Biobead).
The product is purified with sSX-2,N,N-methylformamide (I) to obtain a porphyrin derivative in which (P) is further intramolecularly condensed at two positions as the component (2) with a deep porphyrin layer color.

(@ The above (orally prepared porphyrin derivatives) were introduced with iron in exactly the same manner as was done in the preparation of compound (7), followed by detritylation or acylation of the hydroxyl group of Schiffrobuchstri I if necessary. By performing the following steps, the desired porphyrin derivative (b) is produced.

Production method of (■) When the porphyrin derivative represented by the general formula (AI) is R,=R2=CH2Ck42C(4)H, it is prepared as an intermediate product in the production process of compound (V). . This was carried out in exactly the same manner as the method for producing compound (b) (however, nophenyl phosphate az' was used as the cyclization condensation agent).
(double the amount for the production of r and triethylamine tl)
After condensation, the desired porphyrin derivative (Vll) is produced by introducing iron and, if necessary, detritylating the cyclodextrin hydroxyl group or r-syl protection.

When reducing a cyclodextrin-bound porphyrin compound having the form of a p-, iron-saliva complex to the form of an iron-valent complex, it is necessary to This is possible by adding nithionic acid in an amount of 1 to 20 times the molar equivalent.

In particular, when the above-mentioned porphyrin does not have a vinyl group in its side chain, it is also possible to add a heterogeneous reduction catalyst of a very small acid under a hydrogen gas atmosphere, such as ♀Lasoum black, iR radium supported on activated carbon, etc.

The porphyrin derivative of this invention is mainly composed of biological components and quasi-biological components such as polysaccharides, and has a structure that tends to exist stably under physiological conditions. In addition, although it has poor water solubility, it can be easily dispersed in water at a high concentration using a solubilizing agent because it contains sugars. Since it is a polyfunctional substance, it can be easily made water-soluble by covalent bonding to a water-soluble substance. It is a compound with excellent structural stability when dissolved in water at Km, for example, even when solubilized in water around -27.4, it is essentially important for the oxygen scavenging ability of the porphyrin center iron. Some cyclodextrin-porphyrin ring bonds are broken and fragile. Regarding the stability of the oxygen complex in water, there is a clear difference between the naturally occurring iron-glotoporphyrin (2) complex and the porphyrin derivative of the present invention. For example, in the case of the former, B
is an axial base, X is for example a water molecule). Also, n' is difficult to approach, and the stability of the oxygen complex is unlikely to be lost.

This is due to the molecular sieve IF-use of cyclodextrin in the compound of this invention. This is because water and other polar molecules can enter the sixth ruphyrin iron conformation site, making it easier for oxygen molecules to approach. Therefore, should an axial base such as an imidazole derivative with a heavy substituent be added externally, or m-, j? Due to the presence of a base covalently bonded to the luphyrin ring, only one molecule of the axial base is coordinated to the central iron of the porphyrin, and the sixth coordination site and its vicinity to which acid mole is bound become aqueous, so that in vivo -\Mogro69 − Bin, the same requirements as for myoglobin will be met. so that the hydrophobic cavity within the cyclodextrin is well located near the porphyrin center iron sixth coordination locus,
The same cyclodextrin covers the bottom or top surface,
The fact that it covers the dolphin surface well is that /
If clogakistrin and porphyrin are bonded at three or four points, it is geometrically clear.

Even when the number of bonds between cyclodextrin and porphyrin is small, the same thing can be easily proven by a method using carbon-13 nuclear magnetic resonance. In other words, when electrons move through the μ-conjugated system in macrocyclic conjugated compounds such as porphyrins, a ring current is generated, which creates a magnetic field, which causes the influence of the magnetic field on nearby molecules (ring bending current). It is generally known that the relative configuration of porphyrin, which is a substance constituting a macrocyclic conjugated system, and substances in its vicinity can be specified in detail. For example, the chemical shift (δ) of each carbon atom of the cyclodextrin of a porphyrin derivative shown in The chemical shift (δ') of each carbon atom in cyclodextrin and the chemical shift difference (δ'-δ) of each carbon atom in the wick is ■ 104.08 1+) 1.85
2.23■ 84.78
82.73 2.05■ 74
．． 78 71.22 3.56■
74.28 71.22 3.
06 ■ 70.48 61.29
9.19■ 42°78
15.79 26.99 (here, each chemical shift is calculated using tetramethylsilane in dimethylsulfoxide solvent as an internal standard), but cyclodextrin is expected to be close to porphyrin. The carbon atom species are strongly influenced by the magnetic field due to the ring current, and the value of δ−θ' becomes large. The same carbon species are also affected by a uniform magnetic field. These facts indicate that the configuration degree structure shown by 72-73- (here, the cylindrical proboscis described as β-CD represents all I-cyclodextrin) is maintained. This proves that even when the number of bonds between cyclodextrin and porphyrin is small, the porphyrin center iron hexagonal conformation and the hydrophobic environment in its vicinity are maintained.

In general, it is known that the hydrophobicity of the cavity near the entrance of the cyclodextrin cavity is higher on the secondary hydroxyl group side than on the primary hydroxyl group side, and that the cavity entrance size is also larger.1. When porphyrin and cyclodextrin are covalently bonded on this secondary hydroxyl group side, the hydrophobic environment near the porphyrin center iron sixth coordination site is further secured. In a covalent bond between porphyrin and cyclodextrin, if the hydroxyl group and amino group of the cyclodextrin part are protected, it becomes possible to exclude water molecules that are strongly hydrogen bonded near the cyclodextrin. Provides stronger IF to prevent water from entering the seat.

When covalently bonding a cyclodextrin having a car♂xyl group and a rimilphyrine hydroxyl group, esterification methods such as the acid chloride method and the nocyclohexylcardiimide/4-nomethylaminopyrison method are direct and simple. However, in the case of esters, stability against acids and alkalis is poor. For example, quasi-physiological conditions (room temperature, pH=
In order to stably maintain the structure in 7.4), an amide bond is preferable, followed by a urethane bond.

Table 1 When the two are combined, it is possible to perform the synthesis reaction and post-treatment under relatively harsh conditions, and it is not only possible to synthesize elaborate cyclodextrin and porphyrin combinations and their derivatives, but also to There are also fewer problems with the stability of objects. /Clodextrin secondary hydroxyl side functional group that does not participate in the bond between cyclodextrin and porphyrin,
For example, when an imidazole or Jj derivative having an amino group is appropriately condensed to the noropionic acid residue of porphyrin, only the 11 group of the molecule coordinates to the central iron of 4 ruphyrin without adding an extra axial base from the outside. A complex is formed. Moreover, the sixth coordination site is empty because it is covered with a cyclodextrin cavity that has a shielding effect against polar molecules such as water, providing favorable conditions for the formation of oxygen complexes in water.

As mentioned above, the porphyrin derivative of this invention itself has poor water solubility, but it can be made water-soluble at a high concentration with a solubilizing agent such as a water-soluble polymer, and it can be covalently bonded to a water-soluble polymer. Water solubilization using this method is also effective. Therefore, for example, if it is used in combination with dextran, hydroxyethyl starch, and hegelatin, which are frequently used as plasma expanders, it can also be used as a blood substitute.

The porphyrin derivative of the present invention utilizes the above-mentioned properties, and can be used for: ・Blood substitute for brass blood, I'lAg9 preservation solution K 1f
Not only can it be used as fl, but it can also be used as an oxygen adsorbent, oxygenation reaction catalyst, and redox catalyst.

The present invention will be described in detail below with reference to Examples.

Production contract example 1 of the compound of formula (1) ■) Protoporphyrin ■, disodium salt □(
Hamari Pharmaceutical Co., Ltd. 4 pharmaceutical “Nagropol”) 1og dichloromethane 500mA! After suspending the suspension, hydrogen chloride is bubbled in it for 5 minutes a little more strongly than a commercially available pump. Next, add 20 ml of ethanol, check the maximum production time of the component with the second highest Rf value using thin layer chromatography (silica dal, chloroform/methanol/triethylamine = 20/2/1), and then add an appropriate amount of triethylamine. The reaction is stopped by neutralization. The product was set in a silica gel column (diameter 6 m x length 22 columns), and after first letting out the chloroform component, the porphyrin colored i-component flowing out was treated with chloroform/methanol/trini-L-thylamine-20/2/1 with triethylamine. Saturated water
Crystallized from acetic acid. The separated end crystals were thoroughly washed with water and then dried under reduced pressure at 80°C to obtain 2.6p of Groto, J″!Luphyrin ■monoethyl ester [1].

IR (KBr) 3330 (νNH* 'roll NH), 1735 (νc=o+ester), 1710
(C=o, carboxylic acid) Crn-'NMR (CDC/
=3/d-pyrinone-10,/1, TMS)
9.79 (-double line, 2H, meso), 9.63
(- double line, 2H.

Meso), 8.08 (multi-wire, 2H, -C■
-CH2J, 6°39~6.09 (multi-wire, 4
H, -CH=CH2), 4.30 (triplet line.

4H, β-cH2), 4.23 (four-layer warehouse, 2
H, C00C and 2CH3).

3.51 (-double line, 3H, 4-Cf(s)
, 3.50 (- double line, 3H.

Ring -CH3), 3.45 (- double line, 6H, ring -
CH3), 3.19 (triple edge, 4H1α-CH2
), 1.13 (triple line, 3■.

-COOCH2CH3) FDMS m/e 590 (M-)2)! -Cyclodextrin17. ! +? , 21.7 g of p-toluenesulfonyl chloride was added to Virinone 100 Inl and stirred at room temperature for 24 hours. After being allowed to stand at 5°C for 18 hours, the reaction liquid was poured into ice water containing Gold 21. Precipitated crystal kW
and water (11).

After washing with diethyl ether (1 liter) and drying under reduced pressure at 70°C, this was recrystallized from 600 rnl of methanol.
A16”16c16DI6”16F16°-! Methosyl-β-cyclodextrin [2) 111! Fc4ru.

IR (KBr) 3400 (νon), 2
930 (νCH>CH21-CH5), 160
0 (νc=c phenyl ring), 1360.

1175 (νs=o), 1200~1000
Noroton ratio of (C-o + C-OH + C-0-C) Otsu M-1 NMR (DMSO-d6. TMS ) ppm) = 3/2 Elemental analysis (as C91H112042S7) (calculated value) C49,36H5,09S 10.13 Chi (Amakawa 111 shift) C49, 47H5, 31S
10.13 Chi 3) 6A, 6B, 6c16DI6
1'16'16°-hebutatosyl-β-cyclorkistrin 2.2. ! Add to 407 nl of 50% methylamine/methanol solution and heat and stir at 70°C for 3 days in a 100% ml metal sealed tube. □ Distill the methylamine/methanol under reduced pressure and leave the residue 'e1/ 10
htl'tsukal? oxymethylcellulose column (diameter 3
, cm x length 100 cm), and 5%-NH4H
Elute the target component with a CO3 aqueous solution and freeze-dry, mL, 6
A+68+bc+6D+bg+6'+66-! 1.1 g of taaminomethyl-6,6,6,6,6,6,6-begtadeoxy-β-cyclodextrin [3] is obtained.

IR (KBr)) Absorption due to sil group completely disappears Ninhydrin color reaction positive NMR (DMSO-d6, TMS)-NHCH3
(2,32ppm) and 1st place C once (4,82ppm
) noroton ratio = 3/1 4) 7'rotoporphyrin ■ Monoethyl ester [
[] 413Ily, 6A, 6”+6c+61616
-tl-”'Ivy7 Mi/Me-y-/l/-6AI
6B16c16DI6'+6'16°-thioxy-β-
Cyclodextrin 86019'jy: dissolved in nomethylsulfoquind 701a, triethylamine 1 +J
, after adding 0.14 g of diethyl phosphate cyanide 7
Stir at room temperature in the dark for 2 hours. Next, chloroform 70mA
! and then poured into 80-1 liter of diethyl ether. The precipitated reddish-brown precipitate was washed with soethyl ether after P was collected, and dried under reduced pressure at 60°C.

The obtained crude proboscis 10011+p was dissolved in a small amount of N,N-methylformamide and placed in Biobeads 5X-
Set in a 2'y' column (diameter 4IIM x length 80 cm). Next, the mixture was developed with N,N-methylformamide solvent, and the first effluent component, which was slightly colored with a porphyrin layer, was collected. After crystallization from N,N-methylformamide-diethyl ether, this was taken out and dried under reduced pressure at 70°C for over 24 hours to form zolotoporphyrin monoethyl ester 6.6.6.6.6,6.6 -Amitumenaloo 6.6
．． 6.6.6.6.6-y"oυ. Repeat the above operation to obtain 1.1g as the total sound pickup.

IR (KBr) 3400 (νOHrνNH),
2940 (C-HrCH2, -CH5), 1
735 (ν(:=Q + ester).

81- Predictable spectrum (N,N-trimethylformamide) λ
m,, 401, 501 + 535 + 572
+627 nm5) The porphyrin derivative obtained above (
4) 180””ilN, N-trimethylformamide 2
After 6 solutions to 0Inl, nitrogen atmosphere FFeCt2・nH2O
Add 150ml and heat the reaction at 80°C for 3 hours. After cooling, slightly crushed concentrated hydrochloric acid was added to the reaction solution to make a weakly acidic to neutral solution, and the solution was poured into 200 ml of diethyl ether. Collect the precipitated yellow precipitate by centrifugation. This is B%
obeads 5X-2 dull column (diameter 4 tyn
When developed with N,N-trimethylformamide P using a polymer with a length of 80 ttn, one iron complex [5] of the porphyrin derivative [4] can be separated from the excess unreacted iron component. After completing the first interval of the hemin-containing column, N, N −
When crystallized from trimethylformamide P-noethyl ether and dried under reduced pressure at 70°C for more than 24 hours, [5] becomes 1.
407/1iiJ is obtained.

IR(KRr) 3400 (νOHIνNH)
+ 2940 (C-H, CH2r -CH3)
, 1735 (C-0. ester), 1640
(νC=0 No. amide), 1200-100
0 town vision spectrum (N,N-trimethylformamide) λ
398 558 590 ax Example 2 Porphyrin complex 3 produced in Example 1 97,
3 In9 was dissolved in 5 ml of N,N-dimethylformamide, 1 ml of water containing 41 hydroxide was added, and the mixture was stirred until the final stage. After the solvent was completely distilled off under reduced pressure, the residue was dissolved in 5 ml of water, neutralized with a small amount of diluted hydrochloric acid, and the precipitate was collected by centrifugation. After washing with water, drying under reduced pressure at 70° C. for 24 hours yields 67.2 m9 of Chi(II) porphyrin complex [6] in which globionic acid ethyl ester is hydrolyzed in the porphyrin complex [5].

IR (KBr) 3400 (shiH1shiNH)
, 2940 (C-H1>CH2, -CH5),
1710 (vc=or-COOH).

1640 (νc=o, W, T: i amide), 12
00~1000 (C-0°C-OH, C-0-C)
cm-' Visible spectrum (N,N-trimethylformamide) λ
398 558 590, nax Example 3 B Noro),? Lufirin ■ Monoenal ester [
IJ 413 mg and α-cyclorgistrin 681
! Meeting N, i-Tumedelformamide °70 IILl
Trietheramine 0.15mA! Then, Nophenylic Acid Asodo 235 JIQ was added and the mixture was stirred for 1 hour. This was followed by a 71D heat stirring reaction at 70°C for 12 hours.

After cooling, it was poured into 700 ml of diethyl ether, and the precipitated crystals were collected by F. Wash diethyl nityl and water in sequence and dry under reduced pressure.

100 ml of the obtained M' color powder was dissolved in MF4 in 3 ml of N,N-dimethylformamide, and bio
beadsSX-2F” column (diameter 4 cm
80α). After collecting the colored first fraction of bornoirin flowing out with N + N-dimethylformamide, it was crystallized from N,N-nometumeformamide soethyl ether and dried under reduced pressure at 70°C for 24 hours to yield α-cyclodextrin and glotoporphyrin. Urethane bond 84- (-〇-C-N-) l, porphyrin derivative [7] with monoethyl ester in one place
Get 5301 da.

IR(KBr) 34(10(νOH),
2940 (νCH+nCH2, -CH3)
, 1735 (C-O, Nisder).

1700 (νC=OI urethane), 1
200~1000 (C-o +C-OH, C-0-
C) crrL al 'fM spectrum (N, N-trimethylformamide) λ, n4z 4t) 1 + 501 + 535
+ 572 + 627 nm2] Porphyrin derivative [73180"fi' is obtained in exactly the same manner as described in 5) of Example 1 to obtain iron complex 162m9 of [7].

IR (KBr) 3400 (νOH), 29
40 (νCH1 CH2, -CH5), 17
35 (νC=Ol ester).

1700 (νC=0 1 urethane), 1
200~1000 (C-o + C-OH*C-0
-C) cm-'λmax 398 557 590
nm Example 4 1) After dissolving 27.2 N of imidazole crystals by force heating to 95° C., 50 ml of acrylonitrile was added dropwise over 3 hours. After cooling, excess acrylonitrile was distilled off under reduced pressure, and the residue was cooled with dry ice-methanol and stirred overnight at room temperature.
-1 Migsol [8] is 46.3. ! 9 obtained.

IR (KBr) 2250z (νc=s)NMR
(CD(43, TMS) 7.47, 7.02, 6.95 (respectively - heavy, urine,
3■, imidazole ring-H), 4.20 (triple line, 2H1CI-12cH2cN), 2.80 (
Triple line, 2H, CH2CH2NH22m MS mle 121 (M±) 2) 1-(2-cyanoethyl)imidazole [8] 7
0.3,! 9, 400Tnl of benzene and 30g
A catalyst obtained by developing a Noun-Nisokel alloy (Ni: 48%) by the W-7 method was sealed in a 1 liter autoclave, and a pressurized hydrogenation reaction was carried out at 60°C for 3 hours at an initial pressure of 128 kg/cyn. . After removing the catalyst and distilling off penzene under reduced pressure, the residue was subjected to total distillation to obtain 1-(3-aminozorobyl)-imidazole [9] (55.1%).

NMR (CDC1,,'rMS) 7.55, 7.16, 6.83 (respectively - heavy line,
3H, imidazole ring -H), 3.96 (triple line, 2H, -Cdan2CH2CH2NH2).

2.42 (multiplet, 2H, -CH2CH2CH
2NH2), 1.70 (broad, 2H, -N
H2), 1.68 (triple line, 2H1-CH2
CH2CH2NH2) p pmMS mle 1
25 (,M −) element cumulative analysis (zivicrate c12
As H14N6o7) (1 paralysis in total) C37
゜06 H2,94N 21.61% (
Actual measurement end) C37, 03H2, 89N 21.77
%3) Norotoborphyline ■ Monoethyl ester [1]
2.36g N,N-dimethylformamide/dichloromethane/triethylamine = 70/30/l5oul
After dissolving in 1-(3-aminonorovir)-iotasol 5
501n9. Noethyl phosphate cyanide 718#ll1l
Add and stir overnight at room temperature. After removing the reaction solvent under reduced pressure, dichloromethane was added at 200 mA! Dissolve in water, wash with water, and remove sodium chloride.
Dry over 2SO4. By distilling off the chloromethane and recrystallizing the residue in dichloromethane-petroleum ether color, the monoethyl ester 7-N-(
-(1-imidazolyl)zolopyl)amide [10]2.
Obtain 6II.

IR (KBr) 3340 (νNH+ Virol book).

1735 (C-On ester), 1660
(Amide first absorption).

1540 (Amide No. 1 absorption) cm-'NMR (CDC
l3, TMS) 9.76, 9.72
, 9.56, 9.49 (respectively - double line, 4H,
meso).

8.22-7.83 (multiplet, 2H, -CH-C
H2), 6.80.

6.10, 6.05 (respectively - heavy line, 3H, imidazole ring -H).

6.61 (Mie 15, H, C0NH),
6.34~6.05 (multiple@, 4H, -CH2
CH2'), 4.04 (triple line, 4H1β-
CH2), 3.81 (quartet, 2H, -C
See 2CH3).

3.42, 3.31, 3.29, 3
．． 26 (each - double line, 121 (.

Ring -CH5), 3.06 (triple line, 4H, α-
CH2), 2.81 (triple line, 2H, -Cf(
zcf(2GHzNHco), 1.93 (multiplet.

2H, -CH2CH2O), t t9 (triple line, 2H1-CH2C, 2CH2-), 0.
82 (triple line + 3H, -CH2CH5L-4,6
0 (-' line, 2H, virol N-H) ppmFD
MS mle 697 (M,)88- 4) Norotoporphyrin ■ Monoethyl nistermo/-
N-((1-imidazolyl)zorobyl)amide 2.4
49'e Dissolve in 50 ml of N,N-trimethylformamide and add 5 ml of 5% aqueous potassium hydroxide solution.
tl-added 7 Jl], after stirring at room temperature in the dark for - days,
Remove the solvent under reduced pressure. Add 50 ml of water to the residue, dissolve 1 barley, and add all of the diluted hydrochloric acid dropwise. The precipitate was collected, washed with water, and then dried under reduced pressure at 6 () to 70°C for 20 hours! Lotoporphyrin ■ Mono N-(3-(1-imidacyl)-norobil)amide [11] 2.27,! get i'.

IR(KBr) 3340 (vNH, virol NH).

1710t*-'(1'c=o ・-C00)I
), 1655 (amito first absorption), 154
0 (Amide No. ■ absorption) 閤-1 elemental analysis (CaaH4
sNyOs) (calculated value) C71,73H6,
47N 14.64 Section (Actual 4J [) C71,
,51H6,53N 14.4315) 6.6
+6.6.6.6 +6-hezotatosol-β-cyclodextrin [2] 4.439 was added to 70 ml of N,N-
Dissolved in dimethylformamide, 89-NaN33.65. li' k dissolved in 3 ml of water, Jn thermal reaction at 90° C. for 9 hours after addition of ffi. The total number of white precipitates precipitated by pouring the cooled drained water into the water, washing with water at 70°C, 24 R or more, d pressure i, drying L -c 6A, f
il', 6'16D16'+6'16°-henotaasodo-b A+ 6' + 6°, 611.6°, 6P1
66-hebutadeoxy-β-cyclodextrin (12
] Obtain 2.30 g.

IR (KBr) 3400 (νOH) -294
0 (C-H1; CHz), 2120 (νNS
), 1200~1000 (C-o+C-OH*
c-o-c) tyn-'6) 6A, 68, 6
c, 6D+6', 6'+6°-H: 7' Ta 7 So 1'-6
A+6B+6c+6°, 6°, 6', 6°-heta r*cy 1-cyclodextrin 1.97,9. ) 3.3 g of liphenylphosphine was dissolved in 60 ml of pyridine and stirred at room temperature for 24 hours. Next, 201 nl of ammonia-saturated methanol was added, and the mixture was further stirred at room temperature for 72 hours.

After adding 8001 nl of ethyl acetate to the reaction solution and allowing it to stand overnight, the precipitate deposited was collected by F. Diluted hydrochloric acid extract 20
Officials 1a in 11 ethanol. The precipitated white precipitate was collected, washed with ethanol, and dried under reduced pressure at 80°C for 48 hours to obtain 6A+6"+6°+bD+bE+6'+6 low hectaminol 6A, 61', 6c, 61), 6E, 6F, 6.
To a-! Tadeoxy-β-cyclorkistrin・7HC
A.4H204[13) is obtained at 1.60.9.

IR (KBr) 3700~2300 (νnt
3 1 νOH, broad), 1620 (δa3)
, 1200~1000 (C-o IC-OH, C
-0-C) Test NMR (DMSO-d6.TMS) 8.26
(Broad, 21H.

-HH5CL), 5.84 (broad,
14H, -OH).

5.05 (-double line, 7H, C(1)-1()
, 4.01 (Broad.

7H, C(5)-H), 3.56-3.34
(Multiple, glandular (broad).

351(, C(2)-H, C(3)-H, C(4)-H
, C(6)-H)94m"C-NMR (D20, CH3CO0H) 78.1
0 (C(1)), 58.80 (C(4))
, 4s, 8゜(C(3)) , 48.30(
C(2)), 44.50 (C(5)).

16.80 (C(6J) ppm Elemental analysis (as C42H92N7032Ct7)
Calculated value) C34,66H6,37N 6.74chi (actual value) C34,70H6,62N 6.49
Section 6) Noroto, Melphyrin ■ Mono-N-((1-imidazolyl)f-ropyl)amide [llco468~, b,
6. 6.6.6.6-hetutamino6.6°6°
, 6°+6'+b', to 6°-! Rideoxy-β-cyclodextrin ・7HCL-4H20 salt c1:o
A total of 102 onywo was dissolved in 701 nl of dimethyl sulfoxide containing 1 ml of triethylamine, and 140 η of soethyl phosphate cyanide was cooled. After stirring in the dark at room temperature for 3 days, the same amount of chloroform as the reaction solution was added and then poured into 1 liter of diethyl ether. After washing the precipitate with diethyl ether.

Dry under reduced pressure at 70°C for 3 hours. 100 out of 100 compositions for hemorrhoids
Each column (m9) was set in a Biobeads 5X-2't' column (diameter 4 x length 80 cm) and developed with N,N-methylformamide solvent. After separating the colored tip fraction of melphilin, it was crystallized from N,N-nometumeformamidozoethyl ether and dried under reduced pressure at 70°C for more than 24 hours. Lotoporphyrin ■Mono N-
(-(1-imidazolyl)-glopyr)abad [11]
and 6.6.6.

92- 6.6.6.6-hebutamino-6,6,6,6,6°6'+6'-hegetadeoxy-β-7 talodextri conductor [14] 9 i 4 mg is obtained.

IR (KBr) 3400 (shiOH+shi, H),
294(1(νC-H+CH2, -CH3),
1660 (amide first absorption), 1550 (
Amide 9th ■ absorption), 1200-1000 (
C-o + C-0LC-0-C) cm-' Visible spectrum (N,N-trimethylformamide) λr
nax 400, 501, 532, 572,
626 nm7) Porphyrin derivative [14] 180
rn? 'i After dissolving in 20 ml of N,N-methylformamide, 150 m9 of FeCl2.nH2O was added under nitrogen atmosphere.
was added and reacted by heating at 80°C for 5 hours. After cooling, add a small amount of crushed hydrochloric acid to the reaction solution to adjust pd = 5.5 to 6 V. Next, the precipitate precipitated by adding diethyl ether was collected, used in a Biobeads SX-2 Dull column (4 columns in diameter x 80 cm in length), and developed with N,N-dimethylformamide 9 to give a hemin-colored tip. The iron complex [15] of the -C porphyrin derivative [14] is released in 93 minutes, and ? After crystallization of J,N-nomethitumerumamidesoenalethytel, 170Tn9 [15] is obtained by drying under reduced pressure at 70°C for 24 hours.

IR (KBr) 3400 (νOHlνNH) 1
2940 (C-H*=CH2, -cm3)
, 1655 (amide I absorption), 1550 (amide II absorption), 1200-1000 (C-c-
o * C-0HIC-0-C) C1n-' Capable spectrum (ISJ, N-methylformamide) 407 635 nm 8) Porphyrin derivative 15J 146.7 rI
Solve q with birinone 25mA'vCM and 3.31 with OC.
NL acetic anhydride was added dropwise over 1 hour. Then, stir at room temperature in the dark for 24 hours or add 500ml of diethyl ether! Inserted into the instep. The deposited precipitate is thoroughly washed with diethyl ether, P is removed, and dried under reduced pressure at room temperature for 12 hours to obtain a porphyrin derivative [15] in which all the secondary hydroxyl groups and amino groups of the cyclodextrin are acetylated [16].
Hemorrhoids 21OIng.

IR (KBr) 1750 (νC=Ol ester), 1660 (amide I absorption La, 1540
(Amide No. ■ absorption), 1375 (C-o-
c) Based on νOH and νNH (absorption band at 3400 m-' completely disappears).

1'T 11 spectrum (N,N-methylformamide) λmax 407 635 nm Dog Example 5 ■) Glotoborphyrin■・Ninatriwam 109'C After suspending in 500n/dichloromethane, hydrogen chloride was added from commercially available Dempe for 5 minutes. degree of bubbling.

Next, 20 ml of methanol was added, and after determining the maximum amount production time of the component with the second highest Rf value by thin layer chromatography (silica dal, chloroform/methanol/triethylamine-20/2/1), 4 amounts of After adding triethylamine and removing all the solvent in the reaction under reduced pressure, the residue was transferred to a silica dull column (diameter 6 cm x length 20 tt).
n), and remove the tip component (f rotoporphyrin ■ dime) with chloroform.
・Rinse out the nal ester). Next, change the solvent to chloroform/methanol/triethylamine = 20/2/1 and collect the first fraction that flows out. After distilling the hot medium under reduced pressure, the shallow residue is triethylamine #LL! Crystallized from in water-acetic acid. After setting this aside and washing it thoroughly with water,
Depressurize + km at ℃ for 10 hours, and remove Groto and Melphilin ■
A total of 2.5 g of monomethyl ester [17J was obtained.

IR(KBr) 3330 (νN)l
l pyrrole NH).

1735 (νC=+Q ester), 1710 (
cyc=ocarboxylic acid), -1 NMR (CDCl3/d''-biIJ syn=10/1
, TMS) 9.80 (-double line, 2H, men), 9.63 C-type set, 2H.

(men), 8.10 (multiplet, 2H, -CH
=Cf(z), 6.41-6.10 (multiplet, 4H, -CH=CH2), 4.30 (triplet.

4f (, #-GHz), 3.58 (-wire,
3f(,-COOCdan5).

3.50 (-ton line, 6H1 ring-CH3),
3.45 (-double line.

6H, Yong-CH3), 3.19 (triple line, 4H
, α-C)I2)29m FDMS m/e 576 (M-)2) Glototerphyrin ■ Monomethyl ester [17] 2.3g/
Add 2°di of 96-osmium tetraate 2001Q/zoethyl ether to the SOOXAN 20On+J solution. Next, water 2 (14) was added, and then 6 g of sodium methano-14 iodate was added over 2 hours, and the reaction was stirred at a constant temperature for 3 days in the dark. The same amount of water was added to the reaction solution, and the precipitate was separated by p.
After drying under reduced pressure at 70°C for 6 hours, pure 2.4
-diformyl r niteroporphyrin ■ 1.6I of monomethyl ester [18] is obtained.

IR(KBr) 3330 (νN1(, Virol N-H).

1740 (C-0 * ester),
1710 (νC=Or Cal?nba), 16
70 (νc=o, aldehyde) cm', 1620cIn'' due to vinyl group νc=c, δC-H
The absorption at 990°910m-1 completely disappears.

FDMS rn/e 580 (M ±) Elemental analysis (as Cs5Hs2NaOb) (calculated value) C6
8,26, H5,56, N 9.65% (actual value)
C68,02, H5,34, N 9.60% 3) Commercially available diethyl malonate 50]t-ethanol 200'I
n! ! After stirring at the same temperature for 3 hours, a solution of 17.5 fl of potassium hydroxide/200 ethanol of potassium hydroxide was added at room temperature for 30 minutes.
Yono Ii + (it, melt the precipitated crystals under the boiling point with heat of υ0, and remove the insoluble components when heated. After cooling the P solution, the precipitated crystals 'ice' were washed with a small amount of ethanol and diethyl ether. Dry under reduced pressure.1J et al. malonic acid monoethyl ester mononotrium 34409 total diethyl ether 3
After adding 00ml/60ynl of ice water, add 21ml of hydrochloric acid.
．． Add 5 ml, shake, and separate the liquids.

The diethyl ether layer was dried over anhydrous sodium sulfate overnight and then dried under reduced pressure at 40C for 20 hours to obtain malonic acid monoethyl ester't 1/2 hydrate.

IR (solution i) 1760~1700 (νC=O
+ ester.

Carbon Clay〕m-m-1N (CDC1s, TMS) 7.
12 (-heavy, fitting, 2H2-COOH4/2HzO)
, 4.20 (quartet, 2H, -CH2CH3
)+3.38 (-double line, 2H, -CH2=n,
1.31 (Three Prisoners.

3H, -COOCH3) MS +n/e 132 (HOOC-CH2CO
M of OCH2CH4,)4) 2.4-ノ*/L'
Mil7” :L-71:I rH! Lua (Rin ■
Monomethyl ester [18) 290 dat piperidone 0.
Malonic acid monoethyl ester 13.2,9 was dissolved in 2 ooml of birinone containing 06wLt above the boiling point and then heated at 95°C.
．． A solution of 0.2 ml of biperisone in 120 tnl of pyridine was added dropwise over 6 hours. Next, a solution of 4.5 g of malonic acid monoethyl ester and 0.04 ml of viverison in 40 ml of pyridine was added under the line over 1 hour. After cooling to 60℃, apply petroleum needle 1.61'e 7Jl] and then under water cooling, -
Set up the device at night and collect all the crystals that precipitate. Set this in a 7' column (diameter 25 t, m x length 40 tm) and t' with chloroform/methanol-10/l.
When all the first fractions to be discharged from FL are collected, 308 m9 of 2,4-noacrylic acid ethyludet-telo, 4-hilfilin monomethyl ester [19] is obtained.

IR(KBr) 3320on' (νN1(,
Virol N-H).

1740 (νc=o, -COOCH3) 171
0 (νc=o r -C00H*-CH=CH-C0
0CH2CH3), 1625 (C-c.

-C1F-=CH-COOCH2CH3) cm-'F
DMS mle 720 Elemental analysis (as Ct+H44N40a) (1 shift of calculation) C68,32, H6,15, N 7.7
7 tlb (actual value) C68,44, H6,07,
N 7.72%5) 2+4--)7 Acrylic acid f
Luphyrin 7”Nitero,! Luphyrin ■Motumenal ester C19J 72〃1fz Pd black 5007%l in 500ml methanol containing 10ml triethylamine
A hydrogenation reaction was carried out for 1 () hour at a constant (M' pressure) in the presence of a catalyst. After stopping the introduction of hydrogen gas and stirring roughly at room temperature overnight, the catalyst was removed, and all four solvents were distilled off under reduced pressure. The residue was crystallized from chloroform-petroleum ether and dried under reduced pressure at 80°C for 24 hours to obtain ethyl 2.4-nonorobionate 7J1-.
Telo 7 Melfilin ■ Monomethyl ester [20] 68
．． Get 5 Da.

IR (KBυ 3330 (νNHr virol NH), 1740 (νC=0 1 ester),
1710 (νc=Q l -COOH)trn
*C=C Cal? 1625th lesson-1's atonement absorption disappears due to nil co-transformation.

FDMS (n/e 724 Elemental analysis (C41f (as 48N408) (calculated value) C67,94tl 6.67 N 7.73 Chi10()- (actual value) C68,00H6,60N 7.67
%6) γ-cyclorkistrin 4.25. S', p-
Toluenesulfonyl chloride 5.4 g total i(,N-
Tsumethylformamide 100 +//bilinone 50 m
1 and stirred at room temperature for 24 hours. Then, after being left at 5°C for 18 hours, the reaction solution was poured into ice water in Step 21.

The precipitate was collected, washed with water (11) and diethyl ether (11), and then dried under reduced pressure at 70°C. This was recrystallized from 200 ml of methanol to give 0 +6 *b, 6
+b +6 +b + 6-octatogyro-γ-7 clodegistrin (21) 2.49 is obtained.

IR (KBr) 3400 (νOH)
, 2930 (νGHz nCH2.

-Cf(a), 160t') (νC=C+
)z-rui), 1360.

1175 (ν8=o) 1120θ~1000 (shi co-o
, c-oLC-0-C) sub-1 NMR (DMSO-d6.TMS) ppm) proton ratio = 3/2 Elemental analysis ((+o4H+zaO4asa)) 10
1- (4111 in total) C49,36, t(5,t)9,
S 10.13% (41 hours shift) C49,
15, H5, 21, 810, 01%7) 6A+6”
+6c+6°+6"+b'+6°* b"-A-cutatosyl-γ-cisolodextrin 2.2g at 50% -
Methylamine/methanol bath D 81) In addition to mi,
Heat and stir at 70'C for 5 days in a 100 ml metal sealed tube. The solvent was distilled off under reduced pressure and the barley residue was 1/10 Lit-J”
Oh.

Cal? Set on a oxymethylcellulose column (3 tm diameter x 100 cm) and add 5%-NH4HCOs.
The target component was washed out with an aqueous solution and lyophilized to produce 6A.

6.6.6.6.6.6.6-octaaminomethyl-6
,6,6,6,6,su,6.6-octadeoxy-γ-
Cyclodextrin [22] 1.09 is obtained.

IFt<K13r) Absorption based on tosyl group completely disappeared Ninhydrin color reaction positive NMI ((DMSO-d6, TMS)-NHCH
s (2,32 ppm) and I vinegar C-! ! (4,8
Groton ratio of ppm) = 3/1 8) 6A16816c16n161'16'16°
, 6H-octaami/Mef Roux 6A+6”+6c
+6D+6°+6'16°, 6H-yFtadeoxy-γ-cyclodextrin [22] 98.3n19.2
．． Ethyl 4-diglobionate-f-L-teloporphyrin ■ Monomethyl ester [20] To 50.7 ml of total trimethyl sulfoxide, add 0.1 ml of triethylamine and 15~ of diethyl phosphate cyanide / 72 hours after IQ Stir at room temperature in the dark.

Next, after adding 10 di of chloroform, it was poured into 200 mA' of noethyl ether. After the precipitated reddish-brown precipitate was completely destroyed, it was washed with diethyl ether and dried under reduced pressure at 60°C for 5 hours.
The obtained citrus fruit was dissolved in 4 ml of N,N-trimethylformamide and set in a BiobeadliSX-2 glu column (diameter 4 cm x length 80 ttn).

Next, the mixture is developed with N,N-methylformamide solvent to collect the first component which is deeply colored with porphyrin. N, N-
After crystallization from methylformamide-diethyl ether, this was collected by F, thoroughly washed with diethyl ether, and then dried under reduced pressure at 7oC for 40 hours to obtain [2o] and [22].
A porphyrin derivative [23] 1132I in which -C-N-i is combined at one position of H6 is obtained.

IR (KBr) 3400 (νOH, νNH)
, 2940 (νC1(+;CH2, -CH3)
, 1735 (νC=Ol ester).

1 1640 (νc=o, -C-N-), 1200
~1000 (C-0 + CH3 C-OH, C-0-C) Confucian-1 oT visible spectrum (N,N-methylformamide)
λmax 396 * 497, 530 + 56
8 + 622 nm9) Porphyrin derivative [23J
1061ψ is N・N-thumenalformamide 20Tr
After dissolving the LlK bath, a nitrogen atmosphere of 1 'l' FeCl2 ・
Add nH2O100m9 f and heat at 80℃ for 5 hours JJ
O thermal reaction. The reaction solution was treated in the same manner as in item 7) of Example 4, and 105η of the iron valence complex [24] of the porphyrin collar conductor [23] was added.

IR (KBr) 3400 (νOHI νNH)
, 2940 (νCHI; CH2, -Ct(5)
, 1735 (νC=Or ester).

C-tOH, C-0-C) tyn-1104-0]'y spectrum (N,N-methylformamiton λmax 392 552 584 nm 10) Porphyrin derivative with iron-citron complex form [24] 9
7. Dissolve 5111p in pyridine 2oTnlVc, 0
Add 2.1 lnl of acetic anhydride to IQ at ℃. After stirring in the dark for 24 hours, diethyl ether 30
The precipitate was thoroughly washed with diethyl ether and dried under reduced pressure at room temperature. A completely acetylated porphyrin derivative [25] (13619) was obtained.

IR (KBr) 2950 (C-H, 2CH
2+ -CH3).

1755 (vc=0, x steal) + 16
45 (+'c=orH3 -C-N-), 1380 (δcu5) + 1
250 (C-011 ester), 1045 (C-o-c)
on-' visible spectrum (N,N-methylformamide) λmax 392 5 ri 2 585 nm formula (
Production Example 6 of compound II) 1) Pharmaceutical protoporphyrin ■ disodium salt 5
g was added to water in Step 11 at room temperature and stirred for 1 hour. After removing the insoluble components, acidify with acetic acid and use the apparatus overnight. After removing the supernatant, the brown precipitate was collected and washed with water (500 ml), methanol/L, (5 (10 ml)).
Protoporphyrin IX was dried at ℃ for 24 hours under reduced pressure.
[26] 4.48.9 Get money.

IR (KBr) 3330 (SiNH Virol N-H)
, 1710 (νC=O1-C0OH), 1620 (c
-c, 2.4-Bull), 990.

910 (δC-H52,4-vinyl) cm-1 elemental analysis (as C34H3404N4) (calculated value) C72
, 58, H6,09, N9.96% (actual measurement IIfL)
C72,45, H6,08, N9.78%2) 7'0 Toborfili 71X [26) 56.3/lI &, 6
Ar1 B, 6C, 6D, 6g, 6F,
6°-hair' evening 7mi/-6, 6, 6.

6°, 6°, 6', 6°-hegetadeoxy-β-7 clodextrin 77HC2.4H20 salt [13] 145.
Dissolve in 61 mg'k triethylamine 0.151111/20 ml of trimethyl sulfoxide and add diethyl phosphate cyanide 39Tn9. After stirring for 4 days in the dark 2
C) Dilute with 200 ml of chloroform, thoroughly wash with diethyl ether, and heat at 70°C for 3
Time vacuum drying. Biobeads 5
Separate it into an X-2 glu column (diameter 4 cm x length 80 cFn), and add N. Developed with N-methylformamide 4 medium. After fractionating the porphyrin-colored tip fraction, N.
crystallized from N-methylformamide-diethyl,
When dried under reduced pressure at 70°C for 24 hours or more, protoporphyrin ■ [26'' Toro A. 6B. 6c. 6D. 6°. 6'
．． 6°-he fp 7 mi/-6A.

611, 6°. 6D. 6'', 6'.6°-1 Tadeoxy-β-71 Chlodextrin [13] is 10-N-bonded at three positions to obtain a porphyrin derivative (273 1 2 6~).

IR (KBr) 3400 (shiNH0shiOH),
2940 (C-H, Nyu.-CHb), 1fi
60 (Amide No. 2 absorption), 1550 (Amide No. 11 absorption), 1 2 0 0 ~ 1000 (C + C
-0H1C-0-C) cm-' 1 7 1 0 cm-' due to νc=o of one COOH
absorption disappears (IR spectrum diagram is shown in Figure 1)1
3C-NMEt (DMSO-d6.TMS)1
1, 24, 1 2.44 (porphyrin ring-C
1(s)-1 6.0 3.

15, 79 (cyclodextrin C(6)), 21.5
2 (7 ruphyrin α-9H2), 36.87<porphyrin β-lyH2), 61.29 (cyclodextrin CC 5)), 71, 22 (cyclodextrin, C
(3)-c(2)), 82, 73 (cyclodextrin C (4)), 97.05-95, 46 (porphyrin meso carbon) 1u1.58 (cyclodextrin C (1)), 121.3 (Porphyrin-CH=
CH2 ), 130.10 (porphyrin-CH=
CH2) 137, 67, 136.27, 135.
68 (3.4-position carbon of porphyrin pyrrole ring), 1
43.55 (porphyrin virol ring 2,5-position carbon)
, 169.20 (cyclodextrin-porphyrin bond-CONH-) 99m 1087 Visible spectrum (N.N-dimethylformamide) λ
mix 4 0 1 5 0 5 5 3 8
5 7 6 6 3 1 nm3) Porphyrin derivative (2731 1 5.8 ~ was dissolved in 20 ml of N.N-dimethylformamide and then dissolved in FeCt2.nH under nitrogen atmosphere.
Add 100 mg of 2O and heat reaction at 80°C for 6 hours. The reaction product was treated in the same manner as in Example 4 (7) to obtain iron valence complex [28] of porphyrin derivative [27].

IR (KBr) 3400 (shiNH0shioh), 294
0(νCHI'-CH2.

-CH3), 1660 (amide first absorption), 155
0 (Amide No. 11), 1200-1000 (C
-0. C-OH.

C-0-C) sub-1 oT visible spectrum (N,N-trimethylformamide)
λmix 398 557 590 nm Example 7 1) Porphyrin derivative in the form of iron valence complex [28
) 1 1 3.4 7n9'i Dissolved in 20 ml of birinone and heated to 0°C. 3 mi of 10 pionic anhydride to 1
Drip over time. Subsequently, the mixture was stirred in the dark at 40°C for 30 hours.

The reaction solution was poured into 400ml of diethyl ether, and the precipitate was poured into 400ml of diethyl ether (200rnl).
). When dried under reduced pressure at room temperature for 12 hours, a porphyrin derivative [28] in which all the secondary hydroxyl groups and amino groups of noclodegistrin are propynylated is obtained.
9) Obtain 176.2 JLQ.

IR (KBr), 2950 (C-u, 'JH
2, -CH3), 1750 (νC=01 ester), 1
6F15 (amide ml absorption) 1545 (7mi I'm
kl absorption), 1250 (Vc-o-ester),
1045 (C-0-C) cm~1oJ visual spectrum (N,N-dimethylformamide) λmax 39
8 557 592 nm Example 8 1) f rotoborphyrin ■ disodium salt 15
9 Suspended in 1 liter of total isochloromethane. After adding 100 ml of pennol alcohol to this, aerate hydrogen chloride gas a little more strongly than a commercially available tank for about 1 minute. - After stirring at room temperature in the dark at night, the reaction solution was washed several times with a water-cooled 11 um sodium bicarbonate bath solution, and dried over anhydrous carbon dioxide. The solvent was then distilled off under reduced pressure, and the residue was recrystallized from sochloromethane-petroleum ether to give protoporphyrin dibennorester [30] 15.4.1-4.

IR (KBr) 3330 (νNHl virol),
1735 (C-o.

ester), 1620 (νc,, c, 2.4-vinyl), 1155 (C-01 ester), 990.91
0 (δC-H+vinyl) cm-' N1vlR (CI) CI3, TMS) 10.103,1
0.044.9.932 (each - heavy line, 4H, meso) 8
．． 265 (multiplet, 2H.

-CH=CH2), 7.003 (- double line, 101(
, ♂) , 6.226 (multiplet, 4H, -CH=C
H2), 5.020 (- double line.

4H, -CH2-@ ), 4.355 (triple line, 4H1
α-CH2) 3.647 (-double line, 6H1 ring-CH5)
, 3.524 (-lane, 6H1 ring-CH5), 3.27
9 (triplet, 4H1β-CH2), -3,887<-doublet, 2H, virol N-H) ppm F"DlviS rrv/e 742 (M", )
2)7'0)yj? Luphyrin ■ Dibenzyl ester [
30] 12 g was dissolved in 1.21 g of Nooxane
After drying, 100 mJ of diethyl ether solution containing osmium tetroxide lI was added. Then, after adding 100 mJ of water,
Add 25 g of sodium metaperiodate little by little over 3 hours, and stir in the dark at room temperature for 3 days. Next, water 1
P was extracted from the dark purple crystals that precipitated. This was washed with water, methanol, and diethyl ether, and then dried under reduced pressure at f&80°C for 6 hours.
Get 1.

NMR (CD C1, TMS) 10.947
, 10.868 (double line, 2H2-CHO), 9,9
55, 9.591.9.272 (each - double line.

41 (, men), 7.012 (- double line, IOH, ge)
, 5.034(-double line, 4)I , -CI(2@
), 4.265 (Mikumahi, 4H1α-CH2), 3.5
01.3.382, 3.237 (each - lane, 12
H, ring-CH3), 3.400 (triplet, 4H1β-C
1(2), -4,998 (- double line, 2H.

Virol N-h) ppm IR (KBr) 3320 (νNHl Virol N-H),
1740 (C-=Q + ester), 1670 (ν
C=Ol aldehyde) cm-1 FDMS n1/e 746 (M'?) 112- 3) 2.4-Noformylde 1-teloporphyrin■
Nopendyl ester (3136 g was dissolved at boiling point in 1.5 l of birinone containing 0.91 ml of piperinone, 9
Leave to cool to 5℃. A solution of 180 g of malonic acid, 3 nLt of piperidine, and 0.91 g of f-bilinone at the same temperature? 6
Drip over time. Subsequently, a solution prepared by dissolving 0.6 ml of malonic acid 6011 piperidine below the boiling point in 0.31 ml of pyridine was cooled for 1 hour and then allowed to cool to 60°C. petroleum ether 12
In addition to 1', the crystals precipitated after being left overnight under water cooling were collected,
After washing thoroughly with chloroform/noenal ether = 372 and drying under reduced pressure at 80°C for 4 hours, 2,4-diarylic acid tuteloporphyrin ■nobenzyl ester [32
] 5.8, obtain F.

IR(KBr) 3330 (νNHl Virol N
-H), 2950°2870(shiC-H・';C1(2
・-CH5)・1735 (νc=o・ester), 1
695 (νc=o, -CH=CH-C0OH), 1
625 (νc = c, -CI-I=CH-Coon
), 1600 (νc=c + phenyl ring), 1460.
1380(δc-ii, ”:, CH2, CH3)c
rn-1 elemental analysis (as C30H46N4013)
-113-L (Calculated value) C72,27, H5,58, N6.74 Chi (actual value) C72,09, H5,64, N6.64 Coefficient 4
) 2.4-noacrylic acid rnyzoloporphyrin ■
Dibenzyl ester [32] 4g Otriethylamine 4
ml/N,N-dimethylformamide 200ml
2g of glycine ethylnisder hydrochloride and]
Add 1.8 g of -(3-aminozorobyl)imidazole and 2.359 g of noethyl phosphate cyanide. In the dark 1
Stir at room temperature for several days.

After that, the reaction solvent was distilled off under reduced pressure, and the residue was placed on a silica gel column (diameter 4 cm x length 70 cm).
Chloroform/methanol - 1o/l Separate the porphyrin colored copper component that flows out with the solvent. Section 5 - citric acid aqueous solution, water, 5% Na2CO3 aqueous solution and water were washed in sequence and then dried overnight on anhydrous sodium sulfate. After all the solvent was distilled off under reduced pressure, the residue was recrystallized from chloroform-petroleum ether to give 2(4)-N-(ethoxycarbonylmethyl)acrylamide 4(2)-N-((1-imidazolyl)propyl)acrylamide. Teloporphyrin ■Sopennor IR (KBr) 3320 (νNH=Biol N-
H), 2940°2870 (C-H,;CH2,-
CH3), 1740 (νC-Iestyl), 1660
(amide first absorption), 162° (νc=c, -C
H-CH-C0NH-), 1540 (amide No. 2 absorption), 1450.1380 (δC-H, ;CH2, -CH
5) 1230-1150 (C-01 ester) sub-1
NMR (CDCt5/CD50D=9/1, TMS
) 9.88 to 9.51 (multiplet, 4H, meso), 9.
30-8.98 (multiplet, 2H, -CH=CH-C0
NH-), 7.78.7.32°7.20,7.15(
Multiplet, 5H, imidazole ring -Hl-CH=CJ (
-CONH-), 695 (- double line, 10H, zu), 4.
99 (-double line, 4H, -CH2@), 4.44 (double line.

2H, -CONHCI(2COO-), 4.29 (triplet, 4H1β-CH2), 4.04 (quartet, 4H,
C00CH2CH3)-□3.50, 3.40 (each - doublet, 12H, ring-CH5), 324 (triplet,
4H8α-CH2), 2.32 (multiplet.

2) I, -CONHCH2CH2CH2-), 1.8
8 (Mie line, 2H9-CONHCH2CH2Cdan2-)
, 1.42 (triple line, 2H.

-CONHCH2CH2CH2-), 1.34. (Triple line, 3H9-COOCH2CH3)I)pm FDMS m/e l 022 (Mri5) 2(
4) -N-(ethoxycarbonylmethyl)acrylamide-4(2)-N-((1-imidazolyl)propyl)
Acrylamitopeneeteroporphyrin ■Dibenzyl ester (33) 1o 2.3ZV't l& pd
Triethylamine lQm7/methanol-k in the presence of black catalyst
Catalytic hydrogenation in 400 ml at 60°C and 80 atm for 4 hours.

The catalyst was removed in the dark under nitrogen, and all the solvent was distilled off under reduced pressure. Nitrogen-saturated aqueous water containing 301 ny of iodine was added to the residue, and while the color of the solution changed from green to reddish-brown, a small amount of cysteine was added.

Next, acetic acid was added, and the precipitate was collected by centrifugation, washed with water, and dried under reduced pressure at 80°C for 12 hours.2(4)-
N-(ethoxycarbonylmethyl)propionylamide-4(2)-N-((1-imidazolyl)propyl)globionylamide dueroborphyrin IX [3
4) is served in 82A1v.

IR (KBr) 3330 (νNHl virol N-H),
2940.2870 (CH2, -C
I(3), 1740116- (C-0, ester), 1710 (C-0, ester),
C00H), 1655 (amide first absorption), 154
5 (Amide No. ■ absorption) cln-' Elemental analysis (as C46H54N80B) (calculated value)
C65,23, H6,43, N13.23 (actual value) C65,30, H6,29, N 13.23 tyro) 2(4)-N-(ethoxycarbonylmethyl)
Propionylamide-4(2)-N-((1-imidazolyl)711 lobil) 10 pionylamide-deuzoloporphyrin D ([34] 67.8■, β-7 clodextrin 90.8 ny with N,N- After dissolving in dimethylformamide 15 mA', triethylamine 0.0
N,N-trimethylpolamide solution g 2 with 35 mA
ml and nophenyl phosphoryl azide to 1
Stir at temperature for 4 hours. Subsequently, the reaction was heated at 70°C for 15 hours, and after cooling, the mixture was poured into 0OIItl.
The precipitated crystals were collected by F. Diethyl ether 50ml, water 5
After sequentially washing with 0ml, drying under reduced pressure at 70°C for 4 hours. The entire amount of the obtained brown powder was mixed with 3 N,N-dimethylformamide.
Dissolve 117-mL in Inl and add Biobeads SX-2 Dull column (diameter 4
cm x length 80 saw). Porphyrin coloring first 7 effluent with N,N-methylformamide solvent
After collecting the lactone, an appropriate amount of diethyl ether was added to it to precipitate crystal 'eP*, which was dried under reduced pressure at 70°C for 24 hours to give β-cyclodextrin)') 7(!:
2(4)-N-(ethoxycarbonylmethyl)fropionyl-4(2)-N-((1-imidazolyl)frobyl)propionylamide-deuteroporphyrin IX
Porphyrin derivative [35
] is obtained in an amount of 68.5m9.

IR (KBr) 3400 (νon), 2940 (Si c
-H9]CH2゜-CH5), 1740 (C-01 ester), 1695 (C-E) l urethane), 16
55 (amide 1st absorption), 154.0 (amide 2nd absorption), 1200-1000 (C-o, C-OH, C
-0-C) tyn-'i visual spectrum (N,N-tmethylformamide) λmax 394. 495
, 528. 566. 620 nm7) Porphyrin derivative [35] After dissolving 57.31n9 in N,N-methylformamide 1OrIL/F under nitrogen atmosphere
eCl2 ・nH2O501TQ f was added, and the reaction was heated at 80°C for 5 hours. The reaction product was treated in exactly the same manner as in (7) of Example 4 to obtain an iron-valent complex [36358, 1m9] of the porphyrin derivative [35].

IR (KBr) 3400 (νon), 294
0 (C-H1]CI(2, -Cf(3), 1740
(c-01 ester), 1695 (νc=o l
urethane), 1655 (amide first absorption), 1545
(amide No. Ⅰ absorption), 1200-1000 (shi c-o
-C-OH,C-0-C)crn-”visible spectrum (
N,N-trimethylformamide) λmaz 391
+ 552 + 585 nm Example 9 Porphyrin derivative in the form of an iron value complex (36)
Pyridino 10m1 of 501119! Dissolve at 0℃
Dusk.

Add 0.97 ml of acetic anhydride dropwise over 30 minutes. Subsequently, after stirring in the dark for 24 hours, 150 m/! of Noethyl Edel was added.
Throw it inside. After the precipitated crystals were subjected to PN, they were thoroughly washed with soethyl ether and then dried under reduced pressure at room temperature for 15 hours. [36]
The porphyrin derivative [37] in which all the hydroxyl groups of cyclodextrin are acetylated is 67.3 m
9 obtained.

IR (KBr) 2940 (C-Hl''):,
cH2, -CH3), 1755 (ν(b), ester)
, 1740-1700 (C-0, ester, urethane, 1755m-10 shoulder absorption), 1660 (amide mI
I), 1545 (7mi)'M 11 )-1380(
δC-H3), 1250 (C-01 ester), 1
045 (C-0-C) cm + visible spectrum (N,N-trimethylformamide) λm
ax 392, 554, 583 nm formula (Ill
) Production Example 10 1) 25 mJ of acetoin and 125 mJ of formamide were mixed and boiling refluxed for 4 hours. In the future, it will be fractionated under reduced pressure, bp 16
Collect components at 5°C (11 mmHg).

Recrystallized from diethyl ether-methanol in ram 4
．． 5-Tmethylimidazole [38] I 3.5.9
- Obtain 12 leaves.

MS rrVe 96 (M”,) NMR (CDCl3, TMS > 11.04 (broad, H, NH), 6.74 (-
Heavy line.

H,>H), 1.82 (-double line, 6H, -CH5)
ppm2) Potassium phthalimide 60F was suspended in 250g of pentamethylene bromide, ff1L, at 200℃ for 12 hours.
Time heating stirring reaction. In the future, unreacted pentamethylene bromide will be removed by steam distillation.

Add diethyl ether and water to the residue and shake it thoroughly.

Separate the soethyl ether layer. After extraction with water and diethyl ether two more times, the diethyl ether solution was collected, washed with water, and dried in an apparatus over anhydrous sodium sulfate overnight. After removing the desiccant f, noethyl ether was distilled off under reduced pressure,
The residue is recrystallized from ethanol to obtain N-(5-bromopentyl)phthalimide (39) 48 #.

IR(KBr)2950.2880 (C-nr>C
H2+-CH3), 1780.1720 (ν(b),
phthalimidocarbonyl) crn-' 121- MS m/e 296 (Mj) NMR (CDCl2, TMS) 8.27 (multiplet, 4H, phenyl nucleus-H), 3.66
(Triple line, 2H,)N-CH2-), 3.38 (triplet line.

2H, -CH2Br), 2.1-1.3 (multiplet,
6H1)NCH2(CH2)CH2Br)ppm3
) 4,5-dimethylimidazole [38,12,?
was dissolved in tetrahydrofuran, 1.2711% of sodium hydride was added under nitrogen, and the mixture was refluxed at boiling point for 6 hours. N-
(5-bromopentyl)phthalimide (39) 7.1
．． 9 / Tetrahydrofuran 3 Q ml f Gamma-painted for 1 hour & Boiling point refluxed for 4 hours and allowed to cool.

After removing the precipitated IJium bromide crystals, the solvent was distilled off under reduced pressure, and the residue was transferred to a silica gel column (3 m in diameter x 30 m in length).
cm). Chloroform/methanol-20
N-(1-
(4,5-methyl)imidazolyl)pentylphthalimide [40] 3°4y.

IR(KBr)2920.2860 (C-ur〉c
H2*-CH3), 1775.1720 (ν(b),
Phthalimido carbonyl) preparation-1 MS m/e 311 (resistance) NMR (CDCl2, TMS) 778 (multiplet, 4H, phenyl nucleus-H), 7.27 (
-Multiplet, H, imidazole nucleus -N), 3.71 (30] 1 1.7 (multiplet, 4H, -CH2CH2CH2CH2
CH2-), 1.35 (broad, 2H, -CH2C
H2C)12CH2CIj2-) ppm4) N
-(1-(4,5-dimethylimidazole)henthylphthalimide (41) 3.2&' Add 25 ml of soaked water, concentrate methanol under reduced pressure, add 25 ml of concentrated hydrochloric acid, and make 2.5 methanol.
Time point reflux. After cooling with water, insoluble components were removed with F, and the P solution was dried under reduced pressure, and the residue was recrystallized from gold ethanol-tethyl ether to give 5-(1-(4,5-trimethyl)imidazolyl)pentylamine dihydrochloride [42] 1 .3 Get #IR (KBr) 3200~2500 (Wyn5
+), 1645~1600.1550 (δNH3”
) cm-'NMR (DMSO-a6.TMS)8
．． 7 (Broad, 4H, -NH3+12NH”), 7
．． 72 (-double line, H, imidazole nucleus ~H), 4.0.
1 (triple line, 2H, -CH2-Nζ), 2.43 (-
Heavy line, 6H1-CI(3), 2.7 (7'0-1'
, 2H, -CI42NH3”), 1.75 (7
' o -)' ,, 4H, -CH2CH2CH2C
H2CH2), 1.40 (7' O-t, 2H, -
CH2CH2CH2CH2CH2-)ppmMS r
rV/e 181 (M± in -2HCtO form)5)
2.4-Noacrylic acid decoteroborphyrin ■Nobennorester [32] 41-) ethylamine 5
fId! / N,N-trimethylformamide 200
ml, and add glycine ethyl ester hydrochloride 2I and 5-(1-(4,5-trimethyl)imidazolyl)pentylamine dihydrochloride [42]3.7y and diethyl phosphoric acid anide 2.35.1-. After stirring at room temperature for 1 day in the dark, the reaction solvent was distilled off under reduced pressure and the residue was transferred to a silica gel column (diameter 4
cm x technique 60 cm), and fractionated the colored component #1 of ruphyrin that flowed out using chloroform/methanol-15/1 solvent. Section 5 - Citric acid water bath solution, water, 5% -
Washed with anhydrous sulfuric acid after sequentially washing with aqueous sodium carbonate solution and water)
Equipment dry on IJum overnight. After evaporating the solvent under reduced pressure, the residue was recrystallized from chloroform-petroleum ether to give 2(4
) -N -([1-(4,5-trimethyl)imidazolyl]pentyl)acrylamide-4(2)-N-(ethquincarbonylmethyl)acrylamide-deuteroporphyrin■ Dipennorester [43] 149 g is obtained .

IR (KBr) 3320 (1/NH, Virol N
-H), 2940.2880 (+'C-H, nCH2
, -CH3), 174° (C-E)l ester),
1660 (amide No. ■ absorption), 1620 (Wc=c
, -CH=CH-C0NH-), 1545 (7mi
1440.1385 (δC-H*nCH2°-cH5), 1230-115o (C-0r
ester) cnr IFDMS m/e 1078
(M) 125- Elemental analysis (as C64H7ON808) (calculated value)
C71,22, H6, F14, N 10.38
Excellent (actual...11 value) C71,10, H6,70, N
10.19 chiro) 2(4)-N-([1-(4,5
IF (f) pd black catalyst present dotrienalamine 10ml/methanol 400ml
Medium catalytic hydrogenation reaction at 60°C and 80 atm for 4 hours.

The catalyst was removed under nitrogen gas in the dark, and the solvent was distilled off under reduced pressure.

Add nitrogen-saturated water containing ~30 iodine to the residue, and the solution changes from green to reddish-brown F! ! , a minute amount of 7 Stain was added to prevent it from becoming a side dish. Next, the precipitate precipitated by adding acetic acid was collected by centrifugation, thoroughly washed with water, and then dried under reduced pressure at 80°C for 10 hours.
□ 4,5-dimethyl)imidazolyl]hentyl)zolopionylamide-4(2) -N-(ethoxycarbonylmethyl)flopionylamide-deuteroporphyrin ② [4,4: 188.5 mg is obtained.

IR (KBr) 3330 (νNHl pyrrole N-H),
2940°2970 (+'c-H; nCH2,
-CH3), 1735 (vc-o-ester), 171
0 (C-o, -COOH), 1650 (amide 1st absorption), 1540 (amide 1st absorption), -1 Elemental analysis (as C30H62N80B) (calculated value)
C66,50, H6,92, N 12.41 (actual measurement) C66,27, H7,03, N 12.41
Section 7) 2(4)-N-(Cl-<4.5-methyl)imi1'soryl]henthyl)propionylamide-
4(2) -N-(Ethoxycarbonylmethyl)telobionylamidodeetheroborphyrin [4,4,17
2,2Lng, 6A, 6', 6c, 6D, 6", 6',
6°-Hair' Tough Mi/-6, 6, 6, 6, 6, 6
, 6-Heptadeoxy-β-ZokuOf + 7F To! J
-/ ・7HC4-4H20 salt [13] 1165η was dissolved in 0.12 mJ of triethylamine/20 d of trimethyl sulfoxide, and noethyl phosphoric acid anide 3
Add 2~. After stirring at room temperature for 4 days in the dark, diluted with 20ml of chloroform and diluted with diethyl ether 200ml.
Insert into m1. The precipitate was collected, thoroughly washed with noethyl ether, and then dried under reduced pressure at 70°C for 3 hours. The obtained composition was set in a Biobeads SX-2 glucolumn (diameter 4t: rn x length! (Ocm),
Developed with N,N-dimethylformamide solvent. The porphyrin-colored tip fraction is crystallized by adding preparative ethyl ether. When dried under reduced pressure at 70°C for 28 hours, Hol 7 (') 7 M conductor C44] Toro A, 6B, 6c
, 6D.

6", 6F, 6°-hebutamino-6A, 6B, 6":
, 6'), 6°, 6-6-hebutadeoxy-β-7 clodextrin 1 is a porphyrin derivative with -C-N- bonds at three sites [4
5) Obtain 14.2η.

IR (KBr) 3400 (νNHlνOH), 2940
(1'C-H0'/CH2,-CH5), 1735
(SiC-0, ester), 1660 (amide first absorption), 1545 (amide first absorption), 1200-10
00 (C-o + C-OH+C-0-C) cm-
1 128- Visible spectrum (N,N-trimethylformamide) λm
ax 395, 495, F128, 566
, 620 nm8) Porphyrin derivative [45] 140
1V was dissolved in 10 ml of N,N-dimethylformamide, 6 ml of potassium hydroxide/1 ml of water were added, and the mixture was stirred overnight at room temperature, and then the solvent was distilled off under reduced pressure. Add 10 ml of water to the residue and ferment it, then add 10 ml of acetone, then add a small amount of diluted hydrochloric acid for 1 hour. When the deposited precipitate is collected by centrifugation, a porphyrin derivative [46] in which the ester of the porphyrin ring side chain functional group -CONHCH2COOCH2CH3 is hydrolyzed in the porphyrin derivative [45] is obtained.
Get n9.

IR (KBr) 3400 (νOH, νNH)
, 2940 (C-H.

, ff1t+2. -CH3), 1710 (1'c=o
, -Coon), 1655 (amide first absorption),
1540 (Amide 1st I absorption), 1200-1000
(Vc-o, C-OH, C-0-C), -1 visible spectrum (N,N-trimethylformamide) λm
x 396.495.528.566.620 nm9
) Porphyrin derivative (46) 118m9,
Dissolve in 10 ml of N,N-methylformamide containing 0.027+/- of 9-ethylamine, add soethyl phosphoric acid cyanide to ip, and stir at room temperature for one week. Pour the reaction solution into 200 ml of diethyl ether. After thoroughly washing the precipitate with noethyl ether, it was dried under reduced pressure at 70°C for 3 hours.
The colored porphyrin components extracted from hemorrhoids were separated using N,N-methylformamide using a S N, N-
Crystallization from trimethylformamide-diethyl ether and drying under reduced pressure at 70°C for 28 hours yielded 2(4)-
N-(C1-(4,5-tumethyl)imidazolyl]pentyl)globionylamide-4(2)-N-(cal?
xymethyl) f robionilamide deuteroborphyrin■ and 6,6°6c+6D+6"+6',6'-he'
7' Tough Mi/-6A+6B, 6c+6D+6N
, 6F, 6G-heptadeoxy-β-enclodextrin is amide-bonded at three sites to obtain porphyrin-induced aLK [47) 1041V.

IR (KBr) 34.00 (νOH1νNH)
, 2940 (C-■.

CH2, -CH5), 1ff45 (amide first absorption),
1540 (Amide No. 1 absorption), 1200-1000 (C-o, C-OH, C-0-C)6n-1 possible spectrum (N,N-trimethylformamide) λma! 3
98,496,528,567.621 nm10) Porphyrin derivative [47] After dissolving 97.51 ng in 1 ml of N,N-methylformamide, 9511%' f of FeCL2 .nH2O was added under a nitrogen atmosphere, and 80
Heat reaction at ℃ for 5 hours. The reaction solution was adjusted to pH = 5.5 with hydrochloric acid, and then the precipitate was added to P.
Take this f Biobeads 5X-2 glucolumn (
4 m in diameter x 80 cm in length) and developed with N,N-methylformamide. The hemin-colored tip fraction was collected, crystallized from N,N-trimethylformamidonoethyl ether, and dried under reduced pressure at 70°C for 24 hours to obtain an iron-valent complex [48] of the porphyrin derivative [47]. is obtained from 934.

IR (KBr) 3400 (νOHlνNH), 2940
(C-H.

]cri2. -CH6), t645 (amide 1st absorption), 1540 (amide Ⅰ absorption), 1200-1000
(C-o, C-OH, c-o=c) cm
-'Visible spectrum (N,N-dimethylformamide)
λ, na) (392-554, 586 nmExample 11 1) Porphyrin derivative in the form of iron monovalent complex [4
8, ] 81.51/Q k Virigiy15mlVcfJ
Then, 1.62 mt of acetic anhydride was added to the OC for a total of 30 minutes.

After stirring in the dark at room temperature for 24 hours, the mixture was poured into 200 ml of diethyl ether. After removing the precipitated crystals, they were washed with 200 ml of diethyl ether and dried under reduced pressure at room temperature for 20 hours. In [48], a porphyrin derivative [49] in which all the hydroxyl and amino groups of cyclodextrin were acetylated was obtained at 106.9Iv.

IR(KBr)2940 (C-H1,,CH2,-
CH3), 1755 (C-=Ol ester), 16
50 (amide first absorption), 1540 (amide first absorption)
, 1380 (δc-H, -CH5), 1250 (c
-o, ester), 1045 (c-o-c)
cm-'h viewing spectrum (N,N-dimethylformamide 132-λmax 392, F) 54, 58
6 nm Example 12 1) β-Cyclodextrin,! = 2(4)-N (
(ethoxyl is nylmethyl) f robionyl-4(2)-
N-((1-imidazolyl) 7″ pill) delobionylamide deuteroborphyrin■ Porphyrin derivative in which [34] is bonded with urethane at three sites [35) 9 4
．． 2 to N. Potassium hydroxide 4.3m9/water 0.7ml in N-methylformamide 7. After adding 7 rnl and stirring at room temperature overnight, the solvent was distilled off under reduced pressure. Add 7 ml of water to the residue and dissolve it, then add 7 ml of acetone. Next, a small amount of diluted hydrochloric acid was added and the precipitated grapes were centrifuged, resulting in a porphyrin derivative [50] in which the ester of the porphyrin ring side chain functional group -CONHCH2 COOCH2 CH5 was hydrolyzed in the porphyrin derivative [35].
]8 7. 3 119 and IR (KBr) 3400
(νOH), 2940 (SiCH.

Ju2, -CH3), 1710-1690 (C
-=o, -cooti.

urethane), 1650 (amide first absorption), 1540 (
Amide 1st absorption), 1200-1000 (Ccc.

133-C-OH, C-0-C)tm-' Visible spectrum (N,N-trimethylformamide) λy
nax 394, 495, 528, 566,
620 nm2) Porphyrin derivative [50) 83.
5 Ing of wheat dissolved in 10 ml of N,N-trimethylformamide, 0.5 Ing of triethylamine. Olmkamu N, N-
1 ml of the methylformamide bath solution was added with 161 I of nophenyl phosphoric acid azide, and the mixture was stirred at room temperature for 1 hour. Subsequently, a heating reaction was carried out at 70° C. for 17 hours, and after cooling, the precipitated crystals were poured into 70 ml of noethyl ether. Next, use a Biobeada 5X-2 glu column (diameter 4 cm).
Crystallize by adding diethyl ether to the porphyrin-colored first component bath solution discharged with 1J, N-methylformamide using X (80 an) k.

After drying under reduced pressure at 70°C for 24 hours, β-7talodextrin and 2(4)-N-(cal-oximenal)flobionyl-4(2)-N-((,1-imidazolyl)globionyl)globionyl were obtained. Amido-deuteroborphyrin (2) has a urethane bond of 62.9 to 62.9 at three points.

IR (KBr) 3400 (νOH), 2940
(shiC-H1g(2+-CH3), 1695 (shic,
, :o, urethane), 1640 (amide first absorption), 1
540 (Amide No. 2 absorption), 1200-1000 (C
-o, C-OH, C-0-C) cm "Visible spectrum (N, N-trimethylformamide) λrnax
392, 495, 528, 566, 621 n
m3) Porphyrin derivative [51] 60InIi with N
, dissolved in 10 Inl of N-trimethylformamide, added 60 ml of FeC42.nH2O under a nitrogen atmosphere, and
Heat reaction at 0°C for 5 hours. By subjecting the reactants to the same treatment as described in Example 10, 57 times the iron valence complex [52] of the porphyrin derivative [51] was obtained.

IR (KBr) 3400 (νOH), 2940
(C-H1χH2,1-CH3), 1700 (C
-C11 urethane), 1640 (A □Mid ml absorption), 1540 (7mi)'th ■absorption), 120 ()-1
000 (C-o, C-OH, C-0-C)
crn-' visible spectrum (N,N-trimethylformamide) λ, Tlax392, 554 + 586 n
Preparation Example 12 of compound of formula (IV) 1) 2.4-noformyl deuteroborphyrin ■
Dibenzyl ester 6, li' k 0.91 mi
of piperidine in 1.5 liters of pyridine at boiling point and allowed to cool to 95°C. At the same temperature, malon awakened monoethyl 21
0 g, piperidine 3 ml dissolved in birinone 0.91 g was poured over 6 hours. Then monoethyl malonate below boiling point 70. l A solution of 0.6 ml of piperidine dissolved in 0.37 ml of birinone was added for 1 hour to γ+t41'
Leave to cool to t&60℃. After adding petroleum ether 127 and leaving it to cool in water overnight, the precipitated crystals were collected and placed in a ram (diameter 6 cm x length 70 cm). to. When the first colored porphyrin component flowing out with chloroform/methanol-2071 is collected, 2,4-diacryl 1
Narrow ethyl deuteroporphyrin ■ Novennoresder [53] 21) f 5.47136- is obtained.

IR (KBr) 3330 (νNH, pyrrole N
-H), 2930°2870 (C-n,, -CH3
, -CH3), 1740(νC"'4 +-CH2CH
2COOCH2φ), 1710(νc=o.

-CH=CH-C00CH2CH3), 1625(νc
=o, -CH=CH-), 1445.1380(δ
C-H,;CH2+-CH3)cn+'NMR(C
D Ct5, TMS) 10.04-9.71 (quadruple rice, 4H, men), 9.26-9.06 (quartet,
21(,-CH=Ct(-Coo), 6.98 (multi-wire, 12H,-@", -C)(=Cdan-COO
), 5.01 (-double line, 4H1-CIll!2-@)
, 4.60 (quartet, 4H9-CH2CH3), 4.3
2 (triple line, 4H1β-CH2-), 3.60°3.
49 (each - double line, 12) 1, ring - CI (3),
3.30 (triple line, 4H1α-CH2), 1.58 (
Triplet, 6H1-CH2CH5), -4,18 (-double, 2H, Virol N-H) ppm FDMS mle 886 (M'!')2) 2
．． 4-Ethyl diacrylate deuteroporphyrin dibensol ester [Hydrogenation reaction in 137-500 ml of methanol containing 10 ml of triethylamine in 53389 m9 in the presence of Gerasium Black 5001rQ catalyst at room temperature and pressure for 14 hours. - After the night had calmed down, the catalyst was removed and the solvent was distilled off under reduced pressure. The residue was crystallized from chloroform-petroleum ether and dried under reduced pressure at 80'C for 24 hours. Ethylude 2,4-dipropionate ↓-telopornyrin ■ [54] 16.7m9.

IR (KBr) 3330 (νNH, virol N
-H, C2930°2870 (C-n, ::C
H2, -CH3), 1740 (cyc-o + ester)
, 1710 (shi c-o , -COOf(), 1445
゜1380 (den, CH2, -CH3) crn
-1 elemental analysis (as C4oH46N408) (calculated value) C67,59H6,52N 7.88 ratio (actual value) C67,40H6,49N 7.72%3)
2.4-Noglobionic acid enaludeuteroborphyrin IX [54] 64.0~. 6A16', 6°,
6°.

6°, 6', 6°-f Tough Mi/-6A, bB,
bo, 6D, 6E, 6F.

6-hebutadeoxy-β-cyclodextrin/7HC
z・4) f20 Lm, [13) Dissolve 131.0 In9 in triethylamine f), 14 ml/20 ml of trimethyl sulfoxide, and add 35 m9 of diethyl phosphate cyanide.
Added. After stirring at room temperature for 4 days in the dark, diluted with 20 m/ml of chloroporm and diluted with diethyl ether 200++.
Put it in +l. The precipitate that has separated out is dried, and then Bio
Using a beadsS, . After drying under reduced pressure at 70°C for 28 hours, 6A, 6B, 6°, 6° with 2,4-noderobionic acid ethyl deuteroporphyrin IX [54].

6°, 6', 6°-hezotamino-6A, 6B, 6°,
6°, 6°, 6F.

146 is a porphyrin derivative [55] in which 6-he1 tadeokine-β-7 clodextrin is amide bonded at three sites.
．． 7 ~ obtained.

IR (KBr) 3400 (νNHlνam)
, 2940 (C-H.

, :, cn2 , -CH3), 1735 (c-o
, ester), 1660 (amide silk ■ absorption), 155
5 (amide first absorption), 1200 to l 000 (+
'co, C-OH, C-0-C)-1 Visible spectrum (N,N-dimethylformamide) λm
ax 394.495.529, F167.621
nm4) Porphyrin derivative [55] 126.2
■ftN,N-trimethylformamide 15ml and then potassium hydroxide 12~/water 1. After adding ml of Fl and stirring at room temperature for 5 nights, the solvent was distilled off under reduced pressure. 15m of water on the residue
Add 15rnl of dissolved acetone,
Next, a very small amount of hydrochloric acid is added to the slightly acidic bath solution, and the brown precipitate deposited is collected by centrifugation. 20 at 80℃ after washing with water
After drying under reduced pressure for an hour, the ester of (55)V (: porphyrin ring side chain -CH2CH2C00C)12CH3 is dissolved.71. Porphyrin derivative [56] 113
．． 7η is obtained.

IR (KBr) 3400 (νOH, ν
NH) -2940 (C-HlCH2, -CH3)
, 1710 (νc, -Cool(), 16
40 (Abad I absorption), 1550 (Amide 11 absorption), ■200-1000 (C-o, C-OH, C
-0-C) crn-1 visible spectrum λmax 394.495.529.567.621
nm5) Porphyrin derivative [5f0104.8
m9 with triethylamine 0.09 ml/N, N-
140 methylform, dissolved in amide 20d, noethyl phosphate cyanide 25
Add rng. After stirring at room temperature for one week in the dark, 2 (1
Pour the reaction solution into 0 tnl of diethyl ether. After collecting the precipitated gold, it was collected using a BiobeadsSX-2 dull column (diameter 4 cm x length 80 cm).
rPtS. Collect the porphyrin-colored tip 7 fractions that flowed out with N,N-methylformamide, add eζ-noethyl ether, precipitate, collect by centrifugation, wash 5 times with 20 m diethyl ether, and heat at 70°C for 20 minutes.
Dry under reduced pressure for 8 hours.

2.4-dipropionate decoteroborphyrin ■ and 6
．． 6.6.6.6.6.6-to1 amino-6A.

6.6.6.6.6.6.92.0 mg of a porphyrin derivative [57] in which 6-hebutadeoxy-β-cyclodextrin is bonded with an amide bond at the 4' end is obtained.

IR (KBr) 3400 (νNH, νOH),
2940 (C-H.

[CH2, -cH5), 1640 (Amide 9th ■ absorption), 1540 (7th amide No. ■ absorption), 1200-1000
(1'c-o.

C-0f(,C-0-C)(1)-1 Town celebration spectrum (N,N-trimethylformamide) 14
1-λmax 395, 497, 530, 568.
622 nm6) Porphyrin derivative [57,185
, 5 nq was dissolved in 15 m/N of N,N-trimethylformamide, 80/n9 of FeCt2.nH2O was added under a nitrogen atmosphere, and the reaction was heated at 80°C for 7 hours. About the reactants (1
10 Production Example 1 By the same treatment as explained in item 10), 81.4 i of iron 111 complex [58] of porphyrin derivative [57] was obtained.

IR (KBr) 3400 (νNHIνon)
, 2940 (C-H.

:'CH2, -CH5), 1640 (amide 1st absorption), 1545 (amide 2nd absorption), 120 (J ~ 1
000 (C-0.

C~OR,C-0-C)α-1 Town 4M spectrum (N,N-methylformamide)λ
max 392,554.5860m Example 13 1) Porphyrin derivative C5B in the form of iron lit 1ifli complex] 72.1 In92 birinone 15ml
Stir in 1.36 ml of gold acetate anhydride at 0°C for 30 minutes (under r4).

After stirring at room temperature for 24 hours, diethyl ether 2
Insert into 00m1. The deposited precipitate was collected, washed with diethyl ether (50 ml x 4), and then dried under reduced pressure at room temperature for 20 hours. In [58], a porphyrin derivative [59] in which all the amino groups and secondary hydroxyl groups of the cyclodextrin are acetylated is obtained at 865η. 9.49 to pyridine 100
After adding all 125y of trityl chloride to this solution, the mixture was heated and stirred at 90 to 100°C for 4 hours.

Leave to cool to room temperature and pour into ice water at 1.5 liters to precipitate. Shun dried under reduced pressure over calcium chloride, finely ground and poured into soethyl ether 25 (l ml!). 2:1
After continued stirring, the harsh components of soethyl ether were removed and dried under reduced pressure for 12 hours. β-enclodextrin in which 41 -class hydroxyl groups are tritylated [60) 11.31t
get.

IR (KBr) 3400 (νon), 294
0 (CH2>, 1500.1460
< νc=C, phenyl nucleus), □1200~10
00 (C-o, C-OH, C-0-C), 765
゜705 (δtMI, phenyl nucleus) sub-1 NMR (D
MSO-d6. TMS ) Phenyl nuclear proton (7,38-7.25)/β-k of f Ki, < ) IJ n c2.3-position -OHf
o tons = 60/14 (10 tons ratio) 2) Cyclodextrin derivative [60] 10,! i”
t-methyl sulfoxide 150IrLl Nooxane 5
Dissolved in 0 ml of mixed solvent, 140 ml of trietheramine
1 After adding everything, cool with water. Ethyl chlorocarbonate 1 below 15℃
00m1 in 40 minutes. After leaving the solution for a while, the hydrochloric acid solution is reduced under water cooling to obtain a weakly acidic bath solution. reaction mixture gold 1
．． 51 into ice water and drain the precipitate. cold water,
After washing with 500 +++ l each of noethyl ether, drying under reduced pressure over phosphorus pentoxide. Methanol-ice water re-sinking coffin = 1
After drying twice, cyclodextrin G4 [
A compound [61] in which the secondary hydroxyl group of [60] is intramolecularly or intermolecularly carbonated is obtained as 9,7I. .

IR (KBr) 3400 (νOH), 2940
(C-H.

CH2), 11320 (νc=o + intramolecular carbonate), 144-1740 (νc=o intermolecular force rudenate), 14
8 Fl.

1445 (νC=Ol phenyl nucleus), 1255 (c
-o - intramolecular and intermolecular carbonates), 755.7
00 (bc-n, phenyl nucleus) crn-13) cyclodextrin derivative [61] 1.6 l/N, N-
Dissolve 10ml of enalennoamine in 10ml of N-methylformamide, drop it into 10ml of N-methylformamide, stopper tightly, and incubate overnight (+Temporarily, the solvent is distilled off under reduced pressure. After adding methylformamide and dissolving, pour it into 400 ml of noethyl engineering and reprecipitate to obtain the precipitation method Fkr. After washing with soethyl ether, dry under reduced pressure, and the secondary hydroxyl group of [6o] is 3/14-O- C-
Cyclodextrin derivative [62] substituted with N-CH2CH2NH2 at 1.3
I get it.

IR (KBr), 3350 (νNH, νOH),
1720 (C-o.

urethane), 1500.1460 (C-O, phenyl nucleus), 1200-1000 (C-O, C-OH
, C-0-C), 760.710 (δC-Hl), 1
m-nyl nucleus) using rho1145-2,4-dinitrofluorobenzene.

Cyclodextrin derivative [62] was nonitrophenylated according to the established method and used as a colorimetric tester. β-cyclodequinutrin 1
It was confirmed that 3.0 ε groups were introduced per molecule.

4) f rotoborphyrin iX [26) 56.3
%l, cyclodextrin derivative [62) (4/7 of the -Mt hydroxyl groups are tritylated, 3/14 of the secondary hydroxyl groups are 10CNHCH2CI (I-sifurobukis1 trine substituted with 2NH2) 231.5 m? i Trie Chyl Amin 0.0351+14'N,N-
Dimethylformamide 20mKiJ was dissolved and noethyl phosphoanide 40LnQ k was added. 4 days in the dark
After warm stirring, the mixture was poured into 200 ml of noethyl ether, and after removing the brown precipitate eF, it was washed with noethyl ether. next,
Dissolve 1/3 of this in N-methylformamide and add a Biobeads 5X-2 glucolumn (diameter 4 cm x length g 80crII) vc column,
, to. One component of the porphyrin colored line that flowed out was collected using N,N-methylformamide solvent, and diethyl ether was added to it to crystallize it. Similar treetop treatment was performed twice and the total amount was dried under mf pressure at 70C for 24 hours.
0 toporphyrin IX [26] and a cyclodextrin derivative [62], each of which has two molecules bonded to each other, give a porphyrin derivative [63] 221.2/I.

IR (KBr) 340 (1 (νNH, νOH),
2940 (C-H.

;cHn, -CH3), 1720 (ν(b), urethane), 1660 (amide first absorption), 1540 (amide first absorption), 1500.1460 (c-C, phenyl nucleus) 1200-1000 ( C-o, C-0)
(, C-0-C), 760°710 (δc-tt, phenyl nucleus) cm-' visible spectrum (N, N-trimethylformamide) λmax 401, 504, 5
37, 574, 6305) Porphyrin derivatives [6
3] 142. After dissolving Otda in N,N-methylformamide 3Q+m, nitrogen atmosphere FFeCl2.n
H2O120#I9'? and heat reaction at 70°C for 4 hours. After returning to room temperature, adjust the solution to PL (=5.5) with salt and then add soethyl ether to collect the precipitated crystals. Dissolve this in a small amount of N,N-methylformamide.
-2 trowels were set on a Hobeads SX-2 column (diameter 4 cm x length 80 ctn), and N, N-
Separate the hemin M color component from fnL using trimethylformamide solvent. Add diethyl ether and separate the reddish-brown precipitate by centrifugation. Dry under reduced pressure at 70°C for 24 hours to obtain the iron complex [fi4] of bornoirin [63].
J136.2) rg) is obtained.

IR (KBr) 3400 (Shima, Shi0H)-2
940 (C-111 CH2, -CH3), 1720
(C-O, urethane), 1660 (amide first absorption), 1540 (amide side absorption), 1500.14
60 (νc=c, phenyl nucleus), 1200-1O
OO (C-o, C-OH, C-0-C), 760
゜710 (+!'c-n, phenyl nucleus) m-1 town tax spectrum (N, N-trimethylformamide) λmax
398, 556, F190 nm implementation 9+115 1) Porphyrin derivative 4 complex with iron complex form [6
4J 120 ~ chloroform/methanol = 10/
415ml VCrg! ! 4L, IN-hydrochloric acid 0.2
Add 2 ml and stir at room temperature in the dark for 13 hours. IN-Sodium hydroxide aqueous solution VC to pl (=8.0) and then dried under reduced pressure.

Noethyl ether/chloroform = 77310d in the residue
Add and stir for 10 minutes. Remove insoluble components, wash with the same solvent, and dry-bulb under reduced pressure at 50C for 8 hours. Korewogurunoyamueh=7Yon Chromatography Column (Biobeads 5X
-2, diameter 4 cm x length 80 tm.

N,N-methylform bath medium) fractionation. It was a single colored band. N,N-dimethylformamide was distilled off under reduced pressure, and 201 kg of diethyl ether was added to the residue and stirred for 30 minutes. After washing with diethyl ether (20dX3), drying under reduced pressure at 80°C for 12 hours yields a porphyrin derivative [65:] in which the cyclodextrin-class hydroxyl group in the porphyrin derivative [64] has been detritylated.
Get 55.811 evenings.

IR (KBr) 3400 (νNH, νon), 2940
(C-H1'; cH2, -CH5), 1720 (ν
C#) l urethane), 1650 (amide 1st absorption)
, 1550 (amide 11 absorption), 1200-100
0 (C-o, C-OH.

149- C-0-C) cm-' Visible spectrum (N,N-trimethylformamide) λn
'IAX 398, 556, 590 nm implementation?
1116 1) Porphyrin derivative [65] 49.11n9 was dissolved in 10 ml of birinone, and 0.9 ml of acetic anhydride was added dropwise in portions at O'C. Subsequently, the mixture was poured into 150 ml of soethyl ether while stirring in the dark + W at room temperature for 24 hours, and after P was removed, the precipitated crystals were washed with 150 mA of noethyl ether and then dried under reduced pressure at room temperature for 20 hours. In [65], a porphyrin derivative [66] in which all the hydroxyl groups and amine groups of cyclodextrin are acetylated is obtained from 65.6.

IR (KBr) 2940 (c, +t, '
;CH2, -CH3), 1755 (ν(b), ester), 1715 (c-o + urethane), 1650(
1 absorption on amide side), 1540 (absorption 1 on amide side), 13
80(δC-H, -CKs), 12fiO(shic-o
.

ester), 1045 (c-o-c) cm-'visible spectrum (N,N-methylformamide) λma
x 398 , 557 , 590 nm Preparation Example 17 of compound of formula (Vl)
/Stirred at room temperature in the dark for 4 days in 50 ml of AcOH.
& Pour into 10 times the amount of noethyl ether. After removing the precipitate, clean it with ethyl ether until it has no pungent odor. Dry over granular potassium hydroxide in the dark at room temperature under reduced pressure to obtain almost pure hematoporphyrin dipromide 2HBr salt [67] 7 .64.V can be obtained.

IR (KBr) 1710 (νc==o + carboxylic acid) uniformity 1 Characteristic absorption due to vinyl group 1625 (νc=c
), 990°910(δC-H) cm-' completely disappeared.

NMR (Dorinone-a5.TMS) 11.33, 11.28, 10.89, 10.4
2 (each - heavy line.

41-1, meso), 6.95 (multiple fj, 2H,
-CH(Br)CH3), 4.70 (3l line, 4H1β
-CH2-), 3.80 to 3.60 (multiplet, 12H,
Ring -CH3), 3゜65 (triple line, 4H, +(1-C
H2-), 2.53 (2M IN , 6H, -CH
(Br)CHx), 1-2.75 (broad,
2H, virol NH) ppm elemental analysis (C54H
5BN404Br4) (calculated value) C46,08H
4,32N6.32 Excellent (actual value) C45,92H4
, 31N6.21 L42) Hematoborphyrin nopromide 2HBr salt [67) 6.2.9 was dissolved in 5 oml of N,N-trimethylformamide, and piperazine 9
After adding 001% I, the mixture was heated and stirred at 60°C for 20 hours in the dark.

Next, the solvent was distilled off under reduced pressure, and the residue was dissolved in catalytic sulfur (1 mJ).
) 100ml of ethanol! f and stirred at room temperature in the dark for 24 hours. The reaction solution was diluted with 10% -Na2CO3
/ dichloromethane-1 F1 21 under water cooling, and after separating the nochloromethane layer, it was washed twice with 500 ml of water, and then dried overnight on an apparatus over anhydrous sodium sulfate. Desiccant P
The evaporator bath IM was dried under reduced pressure @ M o 7 after addition of powder 5I. Add this to the glue column (diameter 3.5 cr)
nXSQ port) and drain with chloroform.
After removing the toborphyrin engineered methyl ester component, the first colored porphyrin component flowing out was collected with chloroform/methanol (4/1), and the solvent was distilled off under reduced pressure to form a residue.
If 52- is recrystallized from chloroform-petroleum ether, 10 toborphyrin ■ 2- (or 4-) of soethyl ester
One molecule of viperazone is added to the vinyl group in position Marknvniko.
v-added porphyrin derivative [68] in 1. ,6
Get 5.9.

IR (KBr) 3330 (1'NH, Virol), 3ooo~2600 (C-H, "ecH2, -C
H3), 1740 (νC=01 ester), 1680
(δNH, piperazine), 1625 (νc=c, 2
(4)-vinyl), 1160 (C-01 ester)
cm-' FDMS rrv'e 704 (M±)NMR(C
DC15, TMS) 10.78-9.95 (multiplet, 4H, men), 8.2
3 (multiplet, H, -CH=CH2), 6.25 (multiplet, 21(.

-CH=CH2), 6.05 (multiplet, )I,
-cH<cHs>Nrl”>4.19 (Mie d,
4H, β-CH2-), 4.09 (quartet.

4H, -CH2CH3), 3.58.3.53.3.1
2 (multiple lines.

12H1 ring-CH3), 3.12 (multiplet, 12H, α
-CH2゜piperazine ring), 1.9! ') (double line, 3
H1-CH(CH3) positive IH), 1.07 (multiple i
, 6H, -CH2CH3) 153- ppm Elemental analysis (C42) (as 52N604) (calculated value) C71,63H7,44N11.93 Ch (actual value) C71,37) 17.40 N11.72
%3) Porphyrin derivative [68) 70.4 n
Fu, β-7 clodextrin derivative [61] 218.2
Dissolve mQ in 25ml of N,N-dimethylformamide and heat reaction at 60°C for 20 hours. 4 Q rT after cooling
Add 25 ru of a water bath solution containing sodium hydroxide of Q and stir overnight at room temperature. After adjusting the pH to 4.0 with dilute hydrochloric acid, the solvent was distilled off under reduced pressure, and the remaining residue was purified using a Woguru permeation chromatography column (Biobeads 5X-2 (diameter 4 cm x length 80 m) N,N-methylformamide). purification. The deeply porphyrin-colored tip fraction was dyed and then crystallized from N,N-dimethylformamide noethyl ether. This was collected by centrifugation, washed repeatedly with noether ether, and then dried under reduced pressure (70°C, 25 hours).
Then, the porphyrin derivative (69) represented by the formula
(A porphyrin derivative (68,1 in the form of ester hydrolysis and a β-enclodextrin derivative [60] bonded with urethane on the secondary hydroxyl group side of the latter) were obtained in an amount of 185.2η.

IR (KBr) 3400 (νOH), 2940
(C-H.

;CH2, -CH5), 1720-1700 (νc=
o, urethane, carboxylic acid), 1500.1460 (
νc=c, phenyl nucleus), 1200-1000 (c-o, C-OH.

C-0-C), 760+710 (ac-u 17A 1-/I/Nuclear) 1-1 possible nuctor (N, N-methylformamide) λmax 398 498 532
568 622 659nm4) Porphyrin derivative (69) 136.2~ftN, dissolved in 20ml of N-trimethylformamide, 0.017ml of triethylamine
After adding J and nophenyl phosphoryl azide 33 η 9
Heat reaction at 0°C for 24 hours. After cooling, add 100111 to the reaction solution.
Add all of the soethyl ether in Step 7 and add the precipitate to Gruno+
-Mueso Yonk O Mado (Biobeads 5X-
2 (diameter 4 m x length 80 cm), purified using N,N-trimethylformamide). After separating the porphyrin colored tip fraction, it was crystallized from N,N-nometumeformamidenoether ether and dried under reduced pressure at 70°C for 28 hours. “Three-point fixed type”
113.5 mg of porphyrin derivative [70] was obtained.

IR (KBr) 3400 (νOH), 2940 (C-
H9$Hz , -CH,>, 1720 (νc=o
+ urethane), 156- 1500.1460 (νc=c:l phenyl nucleus),
1200-1000 (C-o, C-OH, C-
0-C), 760.710 (δC-H, phenyl nucleus)
cm-', 1710-1700 (c-O.

Absorption of carboxylic acid) m-1 completely disappeared.

Visible spectrum (N,N-trimethylformamide) λm
ax 399 499 532 568 622 6
60nm5) Volf 4-phosphorus derivative [70:) 100
Tn9 to N,N-methylformamide 20+++/
After dissolving FeCl2 ・nH2O under nitrogen atmosphere
Add 100 mQ f and heat reaction at 70°C for 6 hours. Return to room temperature and add dilute hydrochloric acid to the reaction solution to make pl (= 5.5). Dissolve the precipitated crystals using a zoethyl ether metal knife, dissolve them in 3-5 d of N,N-methylformamide, and then add Biobeads. 5X-2 glu column (diameter 4 cm
x length 80m). The colored components of hemin that flowed out were separated with N,N-dimethylformamide, and noethyl ether was added to precipitate the precipitated red-brown S. After isolation by centrifugation, the porphyrin derivative [70 ] to obtain an iron m-valent complex [71]97.8~tl-.

157-IR(KBr) 3400(νon)-294
0 (C-Hl; CH2, -CH3), 1720 (ν
c=o, urethane), 1500.1460 (νc=
c t phenyl nucleus), 1200-1000 (c-o
, C-OH, C-0-C), 760.710 (δC
-H, phenyl nucleus) m-1 Visible spectrum (N, N-trimethylformamide) λm
ax 396 555 588 nm Example 18 ■) Porphyrin derivative tetrad (71
) 84.3mg'echloroform/methanol""
Dissolve in 10/412ml and add 0.17 tn of 1N-hydrochloric acid.
1 was added and stirred at room temperature in the dark for 13 hours. After setting the pH to 8.0 with a 1N sodium hydroxide water bath, drying under reduced pressure,
Regarding the rest, it is exactly the same as in the case of (1) of Example 15.
fi to obtain a porphyrin derivative [72) 37.01.7 in which the primary hydroxyl group of β-cyclodextrin is detritylated in [71].

IR (KBr) 3400 (νOH>, 2940 (SiC
-H1) CI (2, -CH3), 1720 (νC=Ol
Urethane), 1200-1000 (C-0, C
-0f(, C-0-C) cm-', 1500.1460 due to trityl group (νc=o, phenyl nucleus), 7
60.710 (δC-H,)xnyl nucleus)tY++-'
absorption completely disappeared.

9-view spectrum (N,N-trimethylformamide) λm
ax 396, 556, 588 nmExample 19 1) Volf (phosphorus derivative (72327,6+11!?) was dissolved in 7 ml of birinone, and 0.51 ml of acetic anhydride was added at 0°C for 20 minutes. After stirring in the dark at room temperature for an hour, the mixture was poured into 100 ml of diethyl ether.

The precipitate tv5 collected is washed with ether and dried under reduced pressure for 20 hours to obtain 38.0 da of a porphyrin derivative [73] in which all the hydroxyl groups of β-cyclodextrin in [72] are acetylated.

IR (KBr) 2940 (Sign CH
2, -CH3).

1755 (νC=Or ester), 1720 (νC=
1380 (δC-Hl-CH5),
1250 town (+/(-o, ester), 1045 (shi c-o-c
) tm-”9 visible spectrum (N,N-methylformamide) λrnax 396, 556, 589
Preparation Example 20 of compound of nm formula (Xll) 1) 9.4I of α-cyclodextrin was dissolved with 1100ml of N,N-trimethylformamide, and 50ml of birinone was dissolved.
Add A'. To this was added 12.5% of trityl chloride. After adding the mixture, heat and stir at 90-100°C for 4 hours.

After cooling to room temperature, the precipitate precipitated by pouring it into 1.5 ml of ice water was collected as P. After drying under reduced pressure over calcium chloride, it was finely ground and poured into 250 ml of diethyl ether. After stirring for 2 hours, remove 5 volumes of noethyl ether-insoluble components and add 12
Dry under reduced pressure for a few hours. α- with three -class hydroxyl groups tritylated.
Cyclodextrin (74) 10.2 & is obtained.

IR ('KBr) 3400 (νon), 29
40 (C-H.

, ci-t2), 1500.1460 (c-c, phenyl nucleus), 1200-1000 (c-c-o, C-
OH, C-0-C), 765°705 (1Jc-H,
phenyl nucleus) cm-'NMR (DMSO-d6.T
MS ) trityl-phenyl nuclear proton (7,40-7
．． 25ppm)/C2-OH of α-7 clodextrin
and --16C)-05-OH protons-45/12 (Proton ratio) Gravimetric analysis After acid hydrolyzing tritylated α-cyclodextrin, triphenyl carbinol was collected by a conventional method and weighed.

From the weight ratio of triphenylcarbinol/tritylated α-cyclodextrin, it was confirmed that the number of trityl groups in one molecule of tritylated α-7 clodextrin was 3.04.

2) 2.4-noderobionic acid ethylide 1-teloporphyrin IK [54) 56.91 da, α-7 clodextrin derivative [74) 136.0 Iny'&
After dissolving 32 d of N,N-trimethylformamide and adding 0.028 ml of triethylamine and 53 liters of nophenyl phosphoric acid, the mixture was heated at 90° C. for 24 hours.

The reaction product [ν1] was subjected to exactly the same treatment as explained in Production Example 17 (4), and [54] and [74] were separated into two positions, one molecule each, on the secondary hydroxyl group side of [74]. Porphyrin derivative in the form of urethane condensation [75] 156.2j
get da.

IR (KBr) 3400 (νOH), 2940 (SiC
-H.

161- CH2, -CH3), 1740 (C-0. ester), 1720 (νC=01 urethane), 1500.
1460 (ν.-6, phenyl nucleus), 1200-100
0 (C-0°C-OH, C-0-C), 760.71
0 (δC-H, phenyl nucleus) cm-1 Visible spectrum (N,N-trimethylformamide) 2m
11z 400, 501, 532, 572,
626 nm3) Porphyrin derivative [75] 135.
Dissolve 0 Ing in 22a of N,N-trimethylformamide and make 2.2 m of an aqueous solution containing 35μ of sodium hydroxide.
Add lf and stir overnight at room temperature. Distill the solvent under reduced pressure and remove water 20m
Re-dissolve in 1. After adding 20 ml of acetone, diluted hydrochloric acid was added, and the precipitated crystals were dried under reduced pressure at 70°C for 30++4 minutes [75] to obtain a porphyrin derivative in which ethyl propionate in the porphyrin core was ester-hydrolyzed [76] 117. Obtain OIIQ.

IR (KBr) 3400 (νOH), 2940
(νC-)1.

) CI (2, -CH3), 1720-1710 (cylo-0, urethane, carboxylic acid), 1500.1460
(νC=CI phenyl nucleus), 1200-1000 (C-o, C-Of(.

C-0-C), 760, 710 ('!'C-H, phenyl nucleus) crn-' visible spectrum (N, N-trimethylformamide) ax 400, 501, 53
2, F172, 626 nm4) Porphyrin derivative [76:] 105.7 m9 was dissolved in 15 wLl of N,N-trimethylformamide, and triethylamine 0
．． 016ml and diphenyl phosphate at 30m? After all additions, heat reaction at 90°C for 24 hours.

The reaction product was explained in Example 17 (4) and was completely treated by co-workers 7 to produce a porphyrin derivative (77) in which [76] was further intramolecularly condensed with urethane at three positions.
Get rv.

IR (KBr) 340 (1 (νOH), 2940 (ν
C-)1.

Ck42, -CH3), 1720. (ν (b), urethane), 1500.1460 (νC=C, phenyl nucleus), 121JO~1000 (c-o, C-OH
, C-0-C), 760.710 (δC-H・7Eol nucleus) rho1 tir +i spectrum (N,N-trimethylformamide) λmaz 399.501.532.572.6
26 nm5) Porphyrin derivative [77] 70.3
After dissolving lng in 20ml of N,N-methylformamide, 70M FeCl2 .nH2O was added under a nitrogen atmosphere.
Add 9 f @ and heat reaction at 70°C for 6 hours. The reactants were treated in exactly the same manner as described in Example 17 (5) to give [77) 67.5rn9 a slight 0 IR (KBr ) 3400 (νOH), 2940
(C-H.

'AH2, -CH5) -1720(νc=o, t
/methane, 1500.14.60 (νc=c, phenyl nucleus), 1200-1000 (c-o, C-O
H, C-0-C), 760.710” C-H+ 7
x -'-le bales) cln-1 town vision spectrum (N, N
-Tmethylformamide) λmax 394 F1
54 58t) nm Example 21 ■) Porphyrin visiting z4 form which breaks down the form of iron valence complex [ri) 61 mg 2chloroform/methanol=
10/4 Dissolve in 10ml, IN-Salt K O, 14a
Add tf/+11 hours and stir at room temperature in the dark for 13 hours. reaction'
Do you get stuck with mV and carry out (Vl) production? When the purification described in 1J2 is carried out, a total of 11.81119 porphyrin derivatives [78] in which the primary hydroxyl group of α-cyclodextrin is detritylated and protected in [77] are obtained.

164-IR (KBr) 3400 (νOH), 2
940 (C-H.

1 (2, -Cf(5), 1720 (νC=O, urethane), 1200-1000 (C-o, C-0
1(,C-0-C)m-1 town vision spectrum (N,N-dimethylformamide) λmax 396 555 5
All the porphyrin derivatives (1) to (Vll) mentioned above could be prepared in the form of n-valent iron complexes in a water/sodium organic solvent in the presence of a suitable reducing agent such as dithionite. The porphyrin derivative obtained in Example 17 was prepared in the presence of a 1=1 inclusion complex of α-7 clodextrin and 1-phenethyl-2-methylimidazole in molar excess relative to the porphyrin.
p) l=7. Q water/N,N-dimethylformamide 9/
1 (V/V), when nithionic acid in a molar amount 5 to 6 times that of porphyrin is added with nitrogen F, λmax 4
The pentacoordination type iron valence complex of 28 and 553 was cleaved, and a visible absorption spectrum of λmaX of 407'540 and 570 was observed after oxygen introduction, and the formation of an oxygen bond was confirmed.

[Brief explanation of drawings]

FIGS. 1 and 2 show two 165- Infrared absorption spectrum J+L diagram of a compound. -166- Part 1 [・F Figure 2 boyfriend (cm)

Claims (1)

[Claims] (1) It has a porphyrin ring in which iron is coordinated at the center,
A compound in which a cyclodextrin is bonded to a porphyrin compound having at least one functional group as a ring substituent through an amide bond and/or urethane bond between the functional group, and the cyclodextrin is bonded to the porphyrin compound by an amide bond and/or a urethane bond between the functional group and the porphyrin compound. If there is a free functional group, the free a
A porphyrin compound in which the functional group may be protected or covalently bonded to an imidazole derivative capable of coordinating to the central iron. (2) The porphyrin compound is zolotoporphyrin■
or a derivative thereof, the compound according to claim 1. (3) General formula (where R1 is 10H group, -0Ra group or -NI(
Rb group, Ra is a hydrocarbon group having 1 to 7 carbon atoms, Rb is a hydrocarbon group having 1 to 7 carbon atoms, or R. m is an integer of 3 or more, R2 is each independently -CH2CH2 group, -CH2CH2COOR
4 group or -CH2CH2CONHRb group, Rf is hydrogen or R1, R3 is 10H group, -Nl2 group, -NHCH
3 groups or a monosilated form thereof, R4 is each independently aqueous, a hydrocarbon group or -OCRg group, R5 is a hydrocarbon group, -xy- and R3 n is 6, 7 or 8) The compound according to claim 2. (4) General formula (where R2 is each independent K, -cn=cu2
group, -CH2CH2COORf group or -CH2CH2
CONHfj4. group, R4 is hydrogen or a hydrocarbon group having 1 to 7 carbon atoms, Rb is a hydrocarbon group having 1 to 7 carbon atoms, hydrogen or methyl group, m is an integer of 3 or more, R3
are -OH group, -Nl2 group, -NHCH3 group and their acylated products, R4 is each hydrogen, and hydrocarbon group n is 6
．． 7 or 8) according to claim 2. (5) General formula (where R2 is each independently a -CH=CH2 group, a -CH2CH2COORf group, or a -CH2CH2C
ONHRb group, Ftf is hydrogen or a hydrocarbon group having 1 to 7 carbon atoms, Rb is a hydrocarbon group having 1 to 7 carbon atoms or methyl group, m is an integer of 3 or more, R3 is 10H group, -Nl2 group, -NHCH3 group or an acylated product thereof, R4 is hydrogen, a hydrocarbon group or 8), respectively, the compound according to claim 2. 6- (Here, R3 is 10H group, -Nl2 group, -NH(J(
3 groups or their acylated products, R4 is each hydrogen,
The compound according to claim 2, wherein Rg is a hydrocarbon group or -OCRg group, and n is 6.7 or 8). (Formula (where R2 is -CH=C1 (2 groups, -c
n2cu2coot'tf group or -CH2CH2CO
NHRb group, Ftf is an aqueous or cyan hydrocarbon group having 1 to 7 carbon atoms, Rb is a hydrocarbon group having 1 to 7 carbon atoms, hydrogen or methyl group, m is an integer of 3 or more, R3 is -
OH group, -Nl2 group, -NHCH3 group or acylated products thereof, R4 is each hydrogen, hydrocarbon group or 10
CR, group, and group are hydrocarbon groups, and -X'Y' are each 6.7 or 8). So, R2 is -Cl2ctI2 group, -cu2e2 group
C00Rf group or -CH2CH2CONHRb group, R
f is hydrogen or a hydrocarbon group having 1 to 7 carbon atoms, Rb is a hydrocarbon group having 1 to 7 carbon atoms, R+ 10- hydrogen or methyl group, m is an integer of 3 or more, R5 is 10H group, - NH2 group, -NHCH5 group or their acylated products % R4 is hydrogen, hydrocarbon (here, R
3 is a 10H group, -doH2 group, -NHCH5 group, or an acylated product thereof, R4 is each hydrogen, a hydrocarbon group, or an -OCRg group, and Rg is a hydrocarbon group 1, J(/Y/-
each independently, n is 6.7 or 8].