JPH09255682A - Optically active porphyrin derivative bearing trifluoromethyl substituent and its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new derivative subject to former accumulation onto carcinoma tissue and to rabid excretion from the other biological tissues, and useful for cancer diagnoses/therapies with combined use of laser beams. SOLUTION: This new optically active porphyrin derivative (salt) bearing trifluoromethyl substituents is expressed by the formula [R is Na or CH3 ; R<1> and R<2> are such that when one party thereof is (R)-CH(OH)-CF3 or (S)-CH(OH)- CF3 , the other is H or CHO], being subject to firmer accumulation onto carcinoma tissue and to rapid excretion from the other biological tissues, and useful for cancer diagnoses/trerapies with combined use of laser beams. This new compound is obtained by reaction of e.g. 3-(2,2,2-trifluoro-1-hydroxyetheyl) deuteroporphyrin dimethyl ester with (-)-camphornyl chloride followed by optical resolution of the reaction product and then conducting a hydrolysis.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an optically active porphyrin derivative having a trifluoromethyl (CF ₃ ) substituent and a salt thereof, which are useful for diagnosis and treatment of cancer.

[0002]

2. Description of the Related Art In order to carry out so-called photochemotherapy for cancer, which destroys cancer tissue by utilizing electromagnetic wave energy such as laser beam or ultrasonic wave, laser beam or the like is irradiated from the outside. It is indispensable to administer a substance capable of converting the light energy into energy that destroys biological tissues to the living body in advance, and to accumulate it in a portion requiring treatment for cancer or the like. As this substance, a porphyrin body is currently considered useful and is being developed.

As a porphyrin body used for this purpose,
The hematoporphyrin derivative (HPD) is currently licensed for its manufacture as a drug of this type, but HPD is a mixture of compounds polymerized with hematoporphyrin (HP), and the individual structures have not been determined. Furthermore, HPD is known to cause skin irritation when exposed to sunlight after administration, which is a practical problem when performing this treatment. This side effect occurs when the administered HPD accumulates in the skin, and in order to avoid this, it is desired to develop a porphyrin body that is selectively taken up by cancer as compared with other biological tissues such as skin. .

Considering that this drug is usually used for diagnosis as well, it is necessary to minimize side effects due to uptake into living tissues other than the skin rather than the skin. It can be said that the discovery of a substance that accumulates in cancer more selectively as compared with the used HPD determines the success or failure of this treatment method. Furthermore, to clarify the pharmacological effect that the administered porphyrin body accumulates in cancer, it is urgently required that the administered porphyrin body be promptly excreted from biological tissues such as the skin. However,
HPD is a mixture of polymers, and it cannot be expected to be excreted promptly as compared with a single substance such as HP.

In order to overcome the disadvantages of HPD due to such a polymer, many porphyrin derivatives as a simple substance have been synthesized and their structure and pharmacology have been elucidated. However, the basis for the specific accumulation of HPD in cancer remains unclear. Its specificity is not expressed from a simple planar structure, but rather is that HP, which is a compound that is easily polymerized, has constructed a specific three-dimensional structure having pharmacological activity with a certain polymerization ratio. It is reasonable to think. Therefore, attempts have been made to separate the compounds having a certain degree of polymerization degree and to extract the fractions having a strong pharmacological activity to reveal the specificity of HPD, and have succeeded to some extent. However, it is difficult to isolate a polymer having a certain degree of polymerization, and due to the fact that it is a polymer, the occurrence of side effects due to the deposition on living tissues such as the skin still remains.

[0006] For the purpose of avoiding such side effects and elucidating the mechanism of the pharmacological action manifested in HPD, the synthesis of various derivatives having a basic skeleton of protoporphyrin existing in the living body and the pharmacological action of the derivatives. Has been studied. In the course of that research, it has been discovered so far that a compound in which methanol is added to the vinyl group at the 3-position of protoporphyrin is selectively accumulated in cancer. Focusing on the asymmetric carbons of the substituents at the 3- and 8-positions, which are the bases of pharmacological activity, and separating the stereoisomers, the selectivity of the drug effect due to the so-called "key and keyhole" relationship can be elucidated. It will be possible, and it is considered possible to create a drug effective in performing this treatment method.

[0007] In the present invention, a model compound which is considered to be easily excreted from living tissues while maintaining the specific accumulation property of HPD is designed, and the so-called "key and keyhole" in the pharmacological action of HPD is designed. We aimed to find a relationship. In the process, we paid attention to the existence of optical isomers of HP which is a raw material of HPD, and tried to synthesize model compounds and separate each isomer.

[0008]

Embedded image

As described above, hematoporphyrin (HP) has two asymmetric carbons (*) in one molecule, and the presence of these optical isomers is considered to be deeply related to the expression of pharmacological action.
Naturally, it would be good if the optical isomers could be separated and their pharmacological effects could be studied, but HP is easily polymerized and it is difficult to optically separate HP itself. However, it is difficult to administer it stably to a living body.

On the other hand, if hydrogen in the active center is replaced with a fluorine atom, it is expected that not only a chemically stable compound but also pharmacological activity will be increased. This is known as the "pseudo-effect" in the broad sense of the fluorine atom, and is one of the leading methods for drug development. The basis of the improvement is
It is said that by substituting with fluorine, the three-dimensional shape does not change so much, the lipophilicity of the molecule increases, and the absorption rate to the biological membrane increases.

Further, since the background of the nuclear magnetic resonance spectrum of fluorine is much smaller than that of hydrogen, by introducing a fluorine atom into a porphyrin body having the property of accumulating in cancer, the fluorine-containing porphyrin body becomes cancerous. When it is accumulated in, it is considered that cancer can be detected nondestructively by measuring the nuclear magnetic resonance spectrum of fluorine with a small background, and a clearer image of cancer can be obtained without using an endoscope. It has been thought that diagnosis will be easier. Further, it is considered that fluorination of porphyrin, administration of the obtained fluorine porphyrin to a living body, and measurement of nuclear magnetic resonance of fluorine throughout the living body may enable more accurate diagnosis of cancer. In order to realize this, naturally, it is an essential condition to administer a fluoroporphyrin that selectively accumulates in the cancer tissue. The present invention seeks this selectivity for an optically active fluoroporphyrin.

From the above consideration, it was attempted to obtain a compound in which the methyl group of the hydroxyethyl group, which is considered to be the active center of HP, was substituted with the CF ₃ group, one of which was (R) -CH (OH) -CF ₃ Alternatively, when (S) -CH (OH) -CF ₃ , the other is represented by —H 2 or —CHO, and an optically active porphyrin derivative having a CF ₃ substituent is synthesized.

A porphyrin derivative having this purpose is represented by the following formula:

[0014]

Embedded image In, when R is -CH ₃ or -Na, (*)-CH (OH) -CF ₃
In which * is (R) or (S) and R ¹ is -H or -CHO (3- (R) TFDP, 3- (S) TFDP, 3- (R) TFADP, 3- ( S) TFAD
P), or

[0015]

Embedded image In, when R is -CH ₃ or -Na, (*)-CH (OH) -CF ₃
In which * is (R) or (S) and R ¹ is -H or -CHO (8- (R) TFDP, 8- (S) TFDP, 8- (R) TFADP, 8- ( S) TF
ADP) was stably taken out.

The amount of uptake of 3-TFDP and 8-TFDP to hepatoma cells before optical separation was found from the cultured cell experiment to be such that the derivative in which both methyl groups were replaced with -CF ₃ groups was at only one 3-position or 8-position methyl group is known that more than derivatives substituted on a -CF ₃ group. On the other hand, 3-TFDP, 8-TF
From an experiment in which the other hydrogen of DP was changed to another substituent, it is known that the aldehyde group has the highest affinity to the cancer tissue.

In the present invention, in order to obtain a porphyrin derivative which is a simple substance and selectively accumulates in cancer, in order to obtain a porphyrin derivative, an optically active —CH (0H) -CF at one of the 3-position and the 8-position of the porphyrin body.
A derivative having _three groups and at the same time, the other substituents at the 3- and 8-positions were replaced with hydrogen or an aldehyde group was synthesized as a camphor derivative through optical separation, and each was obtained from the obtained optical isomers. Eight kinds of optically active hydroxyethyl compounds were obtained in total, and the accumulation property in cancer was examined.

[0018]

The present invention has been made based on the above-mentioned findings and ideas described above.
The following formula useful for the diagnosis and treatment of cancer

[0019]

Embedded image In the formula, when R is -CH ₃ or -Na, ^one of R ¹ and R ² is (R) -CH (OH) -CF ₃ or (S) -CH (OH) -CF ₃ , the other is Is -H or -CHO, trifluoromethyl (CF
₃ ) to provide an optically active porphyrin derivative having a group and a salt thereof.

[0020]

Example 1 3- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) deuteroporphyrin dimethyl ester: 3-CAMPOTFE-1 [1] and 3-CAMPOTFE-2 [ Synthesis of 2] Under argon atmosphere, 3- (2,2,2-trifluoro-1-human-rooxyethyl) deuteroporphyrin dimethyl ester (1.00 g, 1.57 mmol) and (-)-camphanyl chloride (0.41 g) , 1.89 mmol) in anhydrous CH ₂ Cl ₂ solution (80 ml)
-(Dimethylamino) pyridine (0.67 mg, 5.50 mmol) anhydrous CH ₂ Cl ₂
The solution (20 ml) was slowly added dropwise under ice cooling, and the mixture was stirred for 10 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with a 10% aqueous hydrochloric acid solution, extracted with CH ₂ Cl ₂ , and the CH ₂ Cl ₂ layer was washed with water,
It was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 97: 3).
Separated and purified with 3-CAMPOTFE-1 ([1], 0.57g, 45%) and
3-CAMPOTFE-2 ([2], 0.59g, 46%) was obtained. [1]: mp 218 to 219 ° C. MS m / z: 816 (M ⁺ ). HRMS Calcd C ₄₄ H ₄₇ F ₃ N ₄ O ₈ (M ⁺ ): 816.335. Found: 81
6.335. ¹ H-NMR (CDCl ₃ ) δ: 10.56 (1H, s), 10.20 (1H, s), 10.04
(1H, s), 10.01 (1H, s), 9.16 (1H, s), 7.89 (1H, q, J =
7.3 Hz), 4.45 (2H, t, J = 7.8 Hz), 4.33 (2H, t, J = 7.8
Hz), 3.86 (3H, s), 3.82 (3H, s), 3.69 (3H, s), 3.66 (3
H, s), 3.63 (3H, s), 3.55 (3H, s), 3.29 (2H, t, J = 7.8
Hz), 3.27 (2H, t, J = 7.8 Hz), 2.43 (1H, ddd, J = 16.
0, 12.5, 4.0 Hz), 1.94 (1H, dd, J = 12.5, 4.0 Hz),
1.91 (1H, dd, J = 12.5, 4.0 Hz), 1.67 (1H, ddd, J = 1
6.0, 12.5, 4.0 Hz), 1.24 (3H, s), 1.19 (3H, s), 1.12
(3H, s), -3.80 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -74.09 (3F,
d, J = 7.3 Hz). [2]: mp 215-216 ° C. MS m / z: 816 (M ⁺ ). HRMS Calcd C ₄₄ H ₄₇ F ₃ N ₄ O ₈ (M ⁺ ): 816.335. Found: 816.3
34. ¹ H-NMR (CDCl ₃ ) δ: 10.49 (1H, s), 10.19 (1H, s), 10.0
3 (1H, s), 9.99 (1H, s), 9.15 (1H, s), 7.91 (1H, q, J =
7.3 Hz), 4.43 (2H, t, J = 7.8 Hz), 4.31 (2H, t, J = 7.8
Hz), 3.83 (3H, s), 3.82 (3H, s), 3.68 (3H, s), 3.65 (3
H, s), 3.62 (3H, s), 3.53 (3H, s), 3.28 (2H, t, J = 7.8
Hz), 3.25 (2H, t, J = 7.8 Hz), 2.68 (1H, ddd, J = 13.
4, 10.6, 4.3 Hz), 2.21 (1H, ddd, J = 13.4, 9.1, 4.3
Hz), 1.99 (1H, ddd, J = 13.4, 10.6, 4.3 Hz), 1.77
(1H, ddd, J = 13.4, 9.1 4.3 Hz), 1.11 (3H, s), 1.05
(3H, s), 0.56 (3H, s), -3.80 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -73.94 (3F,
d, J = 7.3 Hz).

[0021]

Example 2 8- (1-(-)-Campanyloxy-2,2,2-trifluoroethyl) deuteroporphyrin dimethyl ester 8-CAMPOTFE-1 [3] and 8-CAMPOTFE-2 [4 ] In an argon atmosphere, 8- (2,2,2-trifluoroethyl) deuteroporphyrin dimethyl ester (0.98g, 1.54mmol) and (-)-camphanyl chloride (0.40
g, 1.85 mmol) in anhydrous CH ₂ Cl ₂ solution (80 ml) in 4- (dimethylamino) pyridine (0.66 g, 5.41 mmol) in anhydrous CH ₂ Cl ₂ solution (2
(0 ml) was slowly added dropwise under ice cooling, and the mixture was stirred for 10 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with a 10% hydrochloric acid aqueous solution and then extracted with CH ₂ Cl ₂ , and the CH ₂ Cl ₂ layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure,
The residue was separated and purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 97: 3) to give 8-CAMPOTFE-1 ([3], 0.55g, 44%) and
8-CAMPOTFE-2 ([4], 0.49g, 39%) was obtained. [3]: mp 198-199 ° C. MS m / z: 816 (M ⁺ ). HRMS Calcd C ₄₄ H ₄₇ F ₃ N ₄ O ₈ (M ⁺ ): 816.335. Found: 816.
335. ¹ H-NMR (CDCl ₃ ) δ: 10.54 (1H, s), 10.13 (1H, s), 10.
09 (1H, s), 10.05 (1H, s), 9.17 (1H, s), 7.88 (1H, q, J
= 7.3 Hz), 4.48 (2H, t, J = 7.8 Hz), 4.34 (2H, t, J = 7.8
Hz), 3.79 (3H, s), 3.78 (3H, s), 3.75 (3H, s), 3.67 (3
H, s), 3.66 (3H, s), 3.56 (3H, s), 3.30 (2H, t, J = 7.8
Hz), 3.27 (2H, t, J = 7.8 Hz), 2.43 (1H, ddd, J = 14.
5, 11.5, 4.5 Hz), 1.91 (2H, m), 1.66 (1H, ddd, J = 1
4.5, 10.5 4.5 Hz), 1.25 (3H, s), 1.20 (3H, s), 1.13
(3H, s), -3.83 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -74.06 (3F,
d, J = 7.3 Hz). [4]: mp 163-165 ° C. MS m / z: 816 (M ⁺ ). HRMS Calcd C ₄₄ H ₄₇ F ₃ N ₄ O ₈ (M ⁺ ): 816.335. Found: 816.3
35. ¹ H-NMR (CDCl ₃ ) δ: 10.46 (1H, s), 10.14 (1H, s), 10.
10 (1H, s), 10.07 (1H, s), 9.18 (1H, s), 7.92 (1H, q, J
= 7.3 Hz), 4.49 (2H, dt, J = 7.8, 2.5 Hz), 4.35 (2H,
t, J = 7.8 Hz), 3.79 (3H, s), 3.76 (3H, d, J = 2.5 Hz),
3.75 (3H, s), 3.67 (3H, s), 3.66 (3H, s), 3.58 (3H,
s), 3.31 (2H, t, J = 7.8 Hz), 3.27 (2H, t, J = 7.8 Hz),
2.69 (1H, ddd, J = 13.5, 10.5, 4.5 Hz), 2.21 (1H, d-
dd, J = 13.5, 9.0, 4.5 Hz), 2.01 (1H, ddd, J = 13.5,
10.5, 4.5 Hz), 1.78 (1H, ddd, J = 13.5, 9.0, 4.5 H
z), 1.13 (3H, s), 1.08 (3H, s), 0.62 (3H, s), -3.81 (2
H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -73.97 (3F,
d, J = 7.3 Hz).

[0022]

Example 3 3- (2,2,2-trifluoro-1-hydrooxy) deuteroporphyrin dimethyl ester:
Synthesis of 3- (R) TFDP [5] Under argon atmosphere, 3-CAMPOTFE-1 ([1], 0.62g, 0.76mmol)
Solution of sodium bis (trimethylsilyl) amido in a mixed solvent of tetrahydrofuran (15 ml) and methanol (15 ml).
(5 ml, 7.55 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with a 10% hydrochloric acid aqueous solution and then extracted with CH ₂ Cl ₂ , and the CH ₂ Cl ₂ layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et).
₂ O, 97: 3 to 95: 5), and separated and purified to give 3- (R) TFDP ([5], 0.42
g, 88%) was obtained. The solid of [5] was determined by the Mosher method. [5]: mp 203-204 ° C. MS m / z: 636 (M ⁺ ). HRMS Calcd C ₃₄ H ₃₅ F ₃ N ₄ O ₅ (M ⁺ ): 636.256. Found: 636.
257. ¹ H-NMR (CDCl ₃ ) δ: 10.70 (1H, s), 10.12 (1H, s), 9.9
8 (1H, s), 9.93 (1H, s), 9.19 (1H, s), 6.96 (1H, dq,
J = 7.3, 4.9 Hz), 6.65 (1H, d, J = 4.9 Hz), 4.22 (2H, t,
J = 7.3 Hz), 4.20 (2H, t, J = 7.3 Hz), 3.77 (3H, s), 3.
74 (3H, s), 3.60 (3H, s), 3.57 (3H, s), 3.50 (3H, s),
3.45 (3H, s), 3.19 (4H, t, J = 7.3 Hz), -4.13 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -75.41 (3F,
d, J = 7.3 Hz).

[0023]

Example 4 Synthesis of 3- (2,2,2-trifluoro-1-hydrooxy) deuteroporphyrin dimethyl ester: 3- (S) TFDP [6] In an argon atmosphere, 3-CAMPOTFE-2 ( [2], 0.49g, 0.60mmo
l) Tetrahitofurofuran (24 ml) and methanol (24 ml) in a mixed solvent of sodium bis (trimethylsilyl) amido in a 1.0 M tetrahitofurofuran solution (6.
(00 ml, 6.00 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After completion of the reaction, the reaction mixture was poured into ice water, neutralized with 10% hydrochloric acid solution and extracted with CH ₂ Cl _2, washed with water CH ₂ Cl ₂ layer was dried over anhydrous sulfate macro Bu Neshiumu. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et).
₂ O, 97: 3 to 95: 5) and separated and purified to give 3- (S) TFDP ([6], 0.3
7g, 98%) was obtained. The solid of [6] was determined by the Mosher method. [6]: mp 203-204 ° C. MS m / z: 636 (M ⁺ ). HRMS Calcd C ₃₄ H ₃₅ F ₃ N ₄ O ₅ (M ⁺ ): 636.256. Found: 636.
256. ¹ H-NMR (CDCl ₃ ) δ: 10.71 (1H, s), 10.15 (1H, s), 10.0
1 (1H, s), 9.98 (1H, s), 9.21 (1H, s), 6.96 (1H, dq,
J = 7.3, 4.9 Hz), 6.67 (1H, d, J = 4.9 Hz), 4.25 (2H, t,
J = 7.3 Hz), 4.22 (2H, t, J = 7.3 Hz), 3.78 (3H, s), 3.
74 (3H, s), 3.60 (3H, s), 3.58 (3H, s), 3.53 (3H, s),
3.47 (3H, s), 3.21 (4H, t, J = 7.3 Hz), -4.08 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -75.41 (3F,
d, J = 7.3 Hz).

[0024]

[Example 5] Synthesis of 8- (2,2,2-trifluoro-1-hydrooxy) deuteroporphyrin dimethyl ester: 8- (R) TFDP [7] In an argon atmosphere, 8-CAMPOTFE-1 ( [3], 0.50g, 0.61mmol)
In a mixed solvent of tetrahitofurofuran (24 ml) and methanol (24 ml) of a 1.0 M solution of sodium bis (trimethylsilyl) amido in tetrahitofurofuran (6.13 m
(6.13 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with a 10% aqueous hydrochloric acid solution, extracted with CH ₂ Cl ₂ , and the CH ₂ Cl ₂ layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O).
, 97: 3 to 95: 5), and purified by 8- (R) TFDP ([7], 0.35
g, 90%) was obtained. The solid of [7] was determined by the Mosher method. [7]: mp 243-245 ° C. MS m / z: 636 (M ⁺ ). HRMS Calcd C ₃₄ H ₃₅ F ₃ N ₄ O ₅ (M ⁺ ): 636.256. Found: 636.
256. ¹ H-NMR (CDCl ₃ ) δ: 10.67 (1H, s), 10.17 (1H, s), 10.0
7 (1H, s), 9.92 (1H, s), 9.13 (1H, s), 6.96 (1H, dq,
J = 7.3, 4.9 Hz), 6.67 (1H, d, J = 4.9 Hz), 4.38 (2H, t,
J = 7.8 Hz), 4.22 (2H, t, J = 7.8 Hz), 3.75 (3H, s), 3.
66 (3H, s), 3.61 (3H, s), 3.60 (3H, s), 3.59 (3H, s),
3.43 (3H, s), 3.29 (2H, t, J = 7.8 Hz), 3.21 (2H, t, J =
7.8 Hz), -4.09 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -75.42 (3F,
d, J = 7.3 Hz).

[0025]

Example 6 Synthesis of 8- (2,2,2-trifluoro-1-hydrooxy) deuteroporphyrin dimethyl ester: 8- (S) TFDP [8] In an argon atmosphere, 8-CAMPOTFE-2 ( [4], 0.44g, 0.54mmol)
In a mixed solvent of tetrahitofurofuran (21 ml) and methanol (21 ml) of a 1.0 M solution of sodium bis (trimethylsilyl) amido in tetrahitofurofuran (5.39 m
(1, 39.39 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After completion of the reaction, the reaction mixture was poured into ice water, neutralized with 10% hydrochloric acid solution and extracted with CH ₂ Cl _2, washed with water CH ₂ Cl ₂ layer was dried over anhydrous sulfate macro Bu Neshiumu. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O).
, 97: 3 to 95: 5) and purified. 8- (S) TFDP ([8], 0.33g,
96%). The solid of [8] was determined by the Mosher method. [8]: mp 243-245 ° C. MS m / z: 636 (M ⁺ ). HRMS Calcd C ₃₄ H ₃₅ F ₃ N ₄ O ₅ (M ⁺ ): 636.256. Found: 636.
256. ¹ H-NMR (CDCl ₃ ) δ: 10.67 (1H, s), 10.18 (1H, s), 10.0
8 (1H, s), 9.92 (1H, s), 9.13 (1H, s), 6.96 (1H, dq,
J = 7.3, 4.9 Hz), 6.67 (1H, d, J = 4.9 Hz), 4.38 (2H, t,
J = 7.8 Hz), 4.22 (2H, t, J = 7.8 Hz), 3.76 (3H, s), 3.
66 (3H, s), 3.61 (3H, s), 3.60 (3H, s), 3.59 (3H, s),
3.43 (3H, s), 3.29 (2H, t, J = 7.8 Hz), 3.21 (2H, t, J =
7.8 Hz), -4.09 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -75.41 (3F,
d, J = 7.3 Hz).

[0026]

Example 7 3- (2,2,2-trifluoro-1-hydrooxy) deuteroporphyrin sodium sodium:
Synthesis of 3- (R) TFDPNa [9] 3- (R) TFDP, ([5], 24.4mg, 0.038mmol) was dissolved in 50ml of toluene and 300mg of NaOH was dissolved in 100ml of methanol.
Add ml and stir for 1 hour. After the reaction was completed, methanol was distilled off, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 3- (R) T.
FDPNa ([9], 24 mg, 92%) was obtained.

[0027]

Example 8 3- (2,2,2-trifluoro-1-hydrooxy) deuteroporphyrin sodium sodium: 3
-Synthesis of (S) TFDPNa [10] 3- (S) TFDP, ([6], 24.4mg, 0.038mmol) was dissolved in 50ml of toluene, and 300ml of NaOH was dissolved in 100ml of methanol. 1.5ml
And boil and stir for 1 hour. After completion of the reaction, methanol was distilled off and the precipitated crystals were collected by filtration and dried under reduced pressure to give 3- (S) TFDPN.
a ([10], 26.4 mg, 101.1%) was obtained.

[0028]

Example 9 8- (2,2,2-trifluoro-1-hydrooxy) deuteroporphyrin disodium:
Synthesis of 8- (R) TFDPNa [11] 8- (R) TFDPNa, ([7], 23.4mg, 0.036m mol) in toluene 50ml
A solution prepared by dissolving 100 mg of NaOH in 100 ml of methanol.
Add 1.5 ml and boil for 1 hour. After completion of the reaction, methanol was distilled off, and the precipitated crystals were collected by filtration, dried under reduced pressure and treated with 8- (R) TF.
DPNa ([11], 21.1 mg, 105.5%) was obtained.

[0029]

Example 10 8- (2,2,2-trifluoro-1-hydrooxy) deuteroporphyrin disodium:
Synthesis of 8- (S) TFDPNa [12] 8- (S) TFDP, ([8], 20.4mg, 0.032mmol) was dissolved in 50 ml of toluene and a solution of 100 mg of NaOH in 100 ml of methanol was added.
Add ml and stir for 1 hour. After completion of the reaction, methanol was distilled off, and the precipitated crystals were collected by filtration, dried under reduced pressure and treated with 8- (S) TFDPN.
a ([12], 16.2 mg, 74.3%) was obtained.

[0030]

Example 11 3- (1-(-)-Campanyloxy-2,2,2-trifluoroethyl) deuteroporphyrin
Synthesis of Dimethyl Ester-Copper Complex: 3-CAMPOTFE-Cu-1 [13] 3- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) deuteroporphyrin
Dimethyl ester: 3-CAMPOTFE-1, ([1], 677 mg, 0.83 mmol)
And copper acetate (319 mg, 1.60 mmol) in methanol (6.2 ml) -CH ₂ Cl
_{The 2} (45 ml) suspension was heated to reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure, and column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et
₂ O, 95: 5) isolated and purified, 3-CAMPOTFE-Cu-1, ([13], 668
mg, 92%) was obtained. mp 103-105 ° C.

[0031]

Example 12 3- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) -8-formyl-deuteroporphyrin dimethyl ester-copper Complex- (1): 3-CAMPOTFE -8-CHO
Synthesis of -Cu-1 [14] Under argon atmosphere, 3-CAMPOTFE-Cu-1, ([13], 100 mg, 0.
11 mmol) and CH (OMe) ₃ (240 μl, 2.19 mmol) anhydrous CH ₂
SnCl ₄ (66 μl, 0.56 mmol) was slowly added dropwise to the Cl ₂ (2.0 ml) solution under ice cooling, the ice cooling was stopped, and the mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, pour the reaction solution into ice water and
The solution was neutralized with an aHCO ₃ aqueous solution, the CH ₂ Cl ₂ layer was washed with water, and dried with anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, the residue was isolated and purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 92: 8), and 3-CAMPOTFE-8-CHO-Cu-1 ( [14], 92 mg, 89%)
I got mp 154-155 ° C.

[0032]

Example 13 3- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) -8-formyl-deuteroporphyrin dimethyl ester- (1): 3-CAMPOTFE-8- Synthesis of CHO-1 [15] 3-CAMPOTFE-8-CHO-Cu-1 ([14], 147 mg, 0.16 mmol)
CF ₃ COOH (3.0 ml) and concentrated H ₂ SO ₄ (0.3 ml) were added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water, neutralized with 5% NaOH solution, extracted with CH ₂ Cl _2, washed CH ₂ Cl ₂ layer was dried over anhydrous sulfate macro Bu Neshiumu.
After filtration, the solvent was removed under reduced pressure, and the residue was subjected to column chromatography (S
iO ₂ , CH ₂ Cl ₂ -Et ₂ O, 93: 7) isolated and purified, 3-CAMPOTFE-8
-CHO-1 ([15], 105 mg, 77%) was obtained. mp 127-130 ° C. ¹ H-NMR (CDCl ₃ ) δ: 11.42 (1H, s), 10.68 (1H, s), 10.
61 (1H, s), 10.00 (1H, s), 9.71 (1H, s), 7.93 (1H, q, J
= 7.3 Hz), 4.23 (2H, t, J = 7.3 Hz), 4.21 (2H, t, J = 7.3
Hz), 4.04 (3H, s), 3.84 (3H, s), 3.63 (3H, s), 3.62 (3
H, s), 3.52 (3H, s), 3.48 (3H, s), 3.20 (2H, t, J = 7.3
Hz), 3.16 (2H, t, J = 7.3 Hz), 2.42 (1H, ddd, J = 13.
0, 11.0, 4.0 Hz), 1.93 (1H, ddd, J = 13.0, 11.0, 4.
0 Hz), 1.89 (1H, ddd, J = 13.0, 10.0, 4.0 Hz), 1.67
(1H, ddd, J = 13.0, 10.0, 4.0 Hz), 1.31 (3H, s), 1.
22 (3H, s), 1.16 (3H, s), -3.63 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ internal standard) ppm: -74.22 (3F, d,
J = 7.3 Hz).

[0033]

Example 14 Synthesis of 3- (2,2,2-trifluoroethyl) -8-formyl-deuteroporphyrin dimethyl ester- (1): 3- (R) TFADP [16] In an argon atmosphere, 3 -CAMPOTFE-8-CHO-1 ([15], 80mg, 0.0
95 mmol) anhydrous tetrahitofurofuran (3.8 ml) and anhydrous MeOH (3.
To a mixed solution of 8 ml), a 1.0 M solution of sodium bis (trimethylsilyl) amido in tetrahylrofuran (0.95 ml, 0.95 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with 10% aqueous hydrochloric acid solution, and extracted with CH ₂ Cl _2.
The CH ₂ Cl ₂ layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ ,
CH ₂ Cl ₂ -Et ₂ O, 90:10) separated and purified, 3- (R) TFADP ([1
6], 63 mg, 100%) was obtained. The solid of [16] was determined by the Mosher method. mp 235-237 ° C. MS m / z: 664 (M ⁺ ). HRMS Calcd C ₃₅ H ₃₅ N ₄ O ₆ F ₃ (M ⁺ ): 664.251. Found: 664.
251. ¹ H-NMR (acetone-d ⁶ ) δ: 11.36 (1H, s), 10.57 (1H,
s), 10.22 (1H, s), 9.91 (1H, s), 9.50 (1H, s), 7.66 (1
H, bs), 7.02 (1H, q, J = 7.3 Hz), 4.13 (2H, t, J = 7.3 H
z), 4.12 (2H, t, J = 7.3 Hz), 3.88 (3H, s), 3.84 (3H,
s), 3.59 (3H, s), 3.56 (3H, s), 3.45 (3H, s), 3.35 (3H,
s), 3.13 (2H, t, J = 7.3 Hz), 3.09 (2H, t, J = 7.3 Hz),
-4.80 (2H, bs). ¹⁹ F-NMR (acetone-d ⁶ , CFCl ₃ internal standard) ppm: -75.36
(3F, d, J = 7.3 Hz).

[0034]

Example 15 3- (1-(-)-Campanyloxy-2,2,2-trifluoroethyl) deuteroporphyrin
Dimethylester-Copper Complex- (2): Synthesis of 3-CAMPOTFE-Cu-2 [17] 3- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) deuteroporphyrin
Dimethyl ester-(2): 3-CAMPOTFE-2, ([2], 549 mg, 0.67 m
mol) and copper acetate (259 mg, 1.30 mmol) in MeOH (5.0 ml)
It was heated to reflux -CH ₂ Cl ₂ (36.5 ml) suspension 1 hour. After cooling, the solvent was distilled off under reduced pressure, and column chromatography (SiO ₂ , C
H ₂ Cl ₂ -Et ₂ O, 95: 5) isolated and purified, 3-CAMPOTFE-Cu-2
([17], 590 mg, 100%) was obtained. mp 110-112 ° C.

[0035]

Example 16 3- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) -8-formyl-deutero
Porphyrin Dimethyl Ester-Cu Complex- (2): 3-CAMPOTFE-8-CHO
Synthesis of -Cu-2 [18] In an argon atmosphere, 3-CAMPOTFE-Cu-2 ([17], 100 mg, 0.11
 mmol) and CH (OMe)_Three (240 μg, 2.19 mmol) anhydrous CH_TwoC
l_Two(2.0 ml) solution with SnCl_Four (66 μl, 0.56 mmol) under ice cooling
Slowly drop the mixture with ice, stop the ice cooling, and stir at room temperature for 2.5 hours.
Stirred. After the reaction was completed, the reaction solution was poured into ice water and saturated NaHCO 3 was added.
_Three Neutralize with aqueous solution, CH_TwoCl_Two Extracted with CH _TwoCl_Two Wash the layers with water
And dried over anhydrous magnesium sulfate. After filtration, solvent under reduced pressure
Column chromatograph (SiO 2)_Two, CH_TwoCl_Two-Et_TwoO,
92: 8) isolated and purified, 3-CAMPOTFE-8-CHO-Cu-2 ([18], 7
4 mg, 72%) was obtained. mp 144-146 ° C.

[0036]

Example 17 3- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) -8-formyl-deuteroporphyrin dimethyl ester- (2): 3-CAMPOTFE-8- Synthesis of CHO-2 [19] 3-CAMPOTFE-8-CHO-Cu-2 ([18], 119 mg, 0.13 mmol)
CF ₃ COOH (2.0 ml) and concentrated H ₂ SO ₄ (0.2 ml) were added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the reaction solution was poured into ice water, neutralized with a 5% aqueous NaOH solution, the CH ₂ Cl ₂ layer was washed with water, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et).
₂ O, 93: 7) isolated and purified, 3-CAMPOTFE-8-CHO-2 ([19],
69 mg, 62%) was obtained. mp 133-135 ° C. ¹ H-NMR (CDCl ₃ ) δ: 11.44 (1H, s), 10.74 (1H, s), 10.
56 (1H, s), 10.03 (1H, s), 9.78 (1H, s), 7.94 (1H, q, J
= 7.3 Hz), 4.24 (2H, t, J = 7.3 Hz), 4.22 (2H, t, J = 7.3
Hz), 4.02 (3H, s), 3.84 (3H, s), 3.63 (3H, s), 3.62 (3
H, s), 3.53 (3H, s), 3.49 (3H, s), 3.21 (2H, t, J = 7.3
Hz), 3.18 (2H, t, J = 7.3 Hz), 2.67 (1H, ddd, J = 13.
5, 11.0, 4.0 Hz), 2.28 (1H, ddd, J = 13.5, 9.0, 4.5
Hz), 2.00 (1H, ddd, J = 13.5, 11.0, 4.5 Hz), 1.80 (1
H, ddd, J = 13.5, 9.0, 4.0Hz), 1.06 (3H, s), 1.04 (3
H, s), 0.48 (3H, s), -3.52 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ internal standard) ppm: -4.03 (3F, d,
J = 7.3 Hz).

[0037]

Example 18 Synthesis of 3- (2,2,2-trifluoroethyl) -8-formyl-deuteroporphyrin dimethyl ester- (2): 3- (S) TFADP [20] In an argon atmosphere, 3 -CAMPOTFE-8-CHO-2 ([19], 53 mg, 0.
063 mmol) of anhydrous tetrahitofurofuran (2.5 ml) and anhydrous MeOH
(2.5 ml) of mixed solution of sodium bis (trimethylsilyl) amido.
A 0M tetrahitofurofuran solution (0.63 ml, 0.63 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After the reaction was completed, the reaction solution was poured into ice water and neutralized with a 10% aqueous hydrochloric acid solution, and then CH ₂ Cl ₂
Extraction was performed, the CH ₂ Cl ₂ layer was washed with water, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, the residue was separated and purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 90:10), and 3-
(S) TFADP ([20], 39 mg, 94%) was obtained. The solid of [20]
Determined by the Mosher method. mp 235-237 ° C. MS m / z: 664 (M ⁺ ). HRMS Calcd C ₃₅ H ₃₅ N ₄ O ₆ F ₃ (M ⁺ ): 664.251. Found: 664.
250. ¹ H-NMR (acetone-d ⁶ ) δ: 11.38 (1H, s), 10.59 (1H,
s), 10.33 (1H, s), 9.95 (1H, s), 9.61 (1H, s), 7.39 (1
H, bs), 7.03 (1H, q, J = 7.3 Hz), 4.19 (2H, t, J = 7.8 H
z), 4.16 (2H, t, J = 7.8 Hz), 3.88 (3H, s), 3.84 (3H,
s), 3.59 (3H, s), 3.57 (3H, s), 3.48 (3H, s), 3.41 (3H,
s), 3.15 (2H, t, J = 7.8 Hz), 3.13 (2H, t, J = 7.8 Hz),
-4.61 (2H, bs). ¹⁹ F-NMR (acetone-d ⁶ , CFCl ₃ internal standard) ppm: -5.56 (3
F, d, J = 7.3 Hz).

[0038]

Example 19 8- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) deuteroporphyrin
Dimethylester-Copper Complex- (1): Synthesis of 8-CAMPOTFE-Cu-1 [21] 8- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) deuteroporphyrin
Dimethyl ester-(1): 8-CAMPOTFE-1 ([3], 256 mg, 0.31 m
mol) and copper acetate (121 mg, 0.61 mmol) in MeOH (2.3 ml)-
The CH ₂ Cl ₂ (17 ml) suspension was heated under reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure, and column chromatography (SiO ₂ , CH ₂
Cl ₂ -Et ₂ O, 95: 5) isolated and purified, and 8-CAMPOTFE-Cu-1 ([2
1], 248 mg, 90%) was obtained. mp 220-221 ° C.

[0039]

Example 20 8- (1-(-)-Campanyloxy-2,2,2-trifluoroethyl) -3-formyl-deuteroporphyrin dimethyl ester-copper Complex- (1): 3-CHO -8-CAMPOTFE-
Synthesis of Cu-1 [22] 8-CAMPOTFE-Cu-1 ([21], 146 mg, 0.17
mmol) and CH (OMe) ₃ (360 μl, 3.29 mmol) anhydrous CH ₂ Cl
SnCl ₄ (100 μl, 0.86 mmol) was slowly added dropwise to the ₂ (3.0 ml) solution under ice cooling, the ice cooling was stopped, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the reaction solution was poured into ice water and saturated NaH
The solution was neutralized with a CO ₃ aqueous solution, the CH ₂ Cl ₂ layer was washed with water, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, the residue was isolated and purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 90:10), and 3-CHO-8-CAMPOTFE-Cu-1 ( [22], 124 mg, 82%) was obtained. mp 148-150 ° C.

[0040]

Example 21 8- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) -3-formyl-deuteroporphyrin dimethyl ester- (1): 3-CHO-8- Synthesis of CAMPOTFE-1 [23] To 3-CHO-8-CAMPOTFE-Cu-1 ([22], 268 mg, 0.30 mmol)
CF ₃ COOH (3.0 ml) and concentrated H ₂ SO ₄ (0.3 ml) were added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the reaction solution was poured into ice water, neutralized with a 5% aqueous solution of NaOH, the CH ₂ Cl ₂ layer was washed with water, and dried with anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂
O, 93: 7) isolated and purified, 3-CHO-8-CAMPOTFE-1 ([23], 23
3 mg, 93%) was obtained. mp 118-120 ° C. ¹ H-NMR (CDCl ₃ ) δ: 10.80 (1H, s), 10.47 (1H, s), 10.
45 (1H, s), 9.68 (1H, s), 8.63 (1H, s), 7.98 (1H, q, J =
7.3 Hz), 4.32 (2H, t, J = 7.8 Hz), 4.12 (2H, t, J = 7.8 H
z), 3.85 (3H, s), 3.72 (3H, s), 3.70 (3H, s), 3.60 (3
H, s), 3.28 (2H, t, J = 7.8 Hz), 3.10 (2H, t, J = 7.8 H
z), 3.06 (3H, s), 2.89 (3H, s), 2.51 (1H, ddd, J = 1
5.0, 11.5, 4.5 Hz), 2.02 (1H, ddd, J = 15.0, 9.5,
4.5 Hz), 1.97 (1H, ddd, J = 14.0, 11.5, 4.5 Hz), 1.
72 (1H, ddd, J = 14.0, 9.5, 4.5 Hz), 1.35 (3H, s),
1.25 (3H, s), 1.20 (3H, s), -4.47 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ internal standard) ppm: -74.06 (3F,
d, J = 7.3 Hz).

[0041]

Example 22 Synthesis of 8- (2,2,2-trifluoroethyl) -3-formyl-deuteroporphyrin dimethyl ester-(1): 8- (R) TFADP [24] In an argon atmosphere, 3 -CHO-8-CAMPOTFE-1 ([23], 209 mg,
0.24 mmol) anhydrous tetrahylfurofuran (9.9 ml) and anhydrous MeOH
(9.9 ml) mixed solution with 1.0% sodium bis (trimethylsilyl) amide
A solution of M tetrahydrofurofuran (2.5 ml, 2.5 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with a 10% hydrochloric acid aqueous solution and then extracted with CH ₂ Cl ₂ , and the CH ₂ Cl ₂ layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was separated and purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 90:10) to give 8- (R) TF.
ADP ([24], 164 mg, 100%) was obtained. The solid of [24] is Mos
It was determined by the her method. mp 118-120 ° C. MS m / z: 664 (M ⁺ ). HRMS Calcd C ₃₅ H ₃₅ N ₄ O ₆ F ₃ (M ⁺ ): 664.251. Found: 664.
251. ¹ H-NMR (acetone-d ⁶ ) δ: 10.94 (1H, s), 10.48 (1H,
s), 10.31 (1H, s), 9.70 (1H, s), 8.89 (1H, s), 7.10 (1
H, dq, J = 5.0, 7.3 Hz), 6.95 (1H, d, J = 5.0 Hz), 4.2
7 (2H, t, J = 7.8 Hz), 4.13 (2H, t, J = 7.8 Hz), 3.74 (3
H, s), 3.67 (3H, s), 3.59 (3H, s), 3.58 (3H, s), 3.27
(2H, t, J = 7.8 Hz), 3.15 (3H, s), 3.14 (3H, s), 3.12
(2H, t, J = 7.8 Hz), -5.02 (2H, bs). ¹⁹ F-NMR (acetone-d ⁶ , CFCl ₃ internal standard) ppm: -75.59
(3F, d, J = 7.3 Hz).

[0042]

Example 23 8- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) deuteroporphyrin
Dimethylester-Copper Complex- (2): Synthesis of 8-CAMPOTFE-Cu-2 [25] 8- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) deuteroporphyrin
Dimethyl ester- (2): 8-CAMPOTFE-2 ([4], 609 mg, 0.75 mm
ol) and copper acetate (287 mg, 1.44 mmol) in MeOH (5.5 ml)-
The CH ₂ Cl ₂ (40.5 ml) suspension was heated to reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure, and column chromatography (SiO ₂ , CH ₂
Cl ₂ -Et ₂ O, 95: 5) isolated and purified, and 8-CAMPOTFE-Cu-2 ([2
5], 535 mg, 82%) was obtained. mp 113-115 ° C.

[0043]

Example 24 8- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) -3-formyl-deuteroporphyrin dimethyl ester-copper Complex- (2): 3-CHO -CAMPOTFE-C
Synthesis of u-2 [26] In an argon atmosphere, 8-CAMPOTFE-Cu-2 ([25], 50 mg, 0.057
mmol) and CH (OMe) ₃ (120 μl, 1.10 mmol) anhydrous CH ₂ Cl
SnCl ₄ (30 μl, 0.26 mmol) was slowly added dropwise to the ₂ (1.0 ml) solution under ice cooling, the ice cooling was stopped, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the reaction solution was poured into ice water and saturated NaHCO 3 was added.
_The mixture was neutralized with ₃ aqueous solution, the CH ₂ Cl ₂ layer was washed with water, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, the residue was isolated and purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 90:10), and 3-CHO-CAMPOTFE-Cu-2 ([26 ], 38 mg, 74%) was obtained. mp 183-185 ° C.

[0044]

Example 25 8- (1-(-)-camphanyloxy-2,2,2-trifluoroethyl) -3-formyl-deuteroporphyrin dimethyl ester- (2): 3-CHO-8- Synthesis of CAMPOTFE-2 [27] C in 3-CHO-CAMPOTFE-Cu-2 ([26], 168 mg, 0.19 mmol)
F ₃ COOH (3.0 ml) and concentrated H ₂ SO ₄ (0.3 ml) were added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. After the reaction was completed, the reaction solution was poured into ice water, neutralized with 5% NaOH aqueous solution, extracted with CH ₂ Cl ₂ , and extracted with C
The H ₂ Cl ₂ layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ ,
CH ₂ Cl ₂ -Et ₂ O, 93: 7) isolated and purified, 3-CHO-8-CAMPOTFE
-2 ([27], 130 mg, 83%) was obtained. mp 125-127 ° C. ¹ H-NMR (CDCl ₃ ) δ: 10.99 (1H, s), 10.75 (1H, s), 10.
36 (1H, s), 9.79 (1H, s), 9.06 (1H, s), 8.00 (1H, q, J =
7.3 Hz), 4.32 (2H, t, J = 7.3 Hz), 4.17 (2H, t, J = 7.3 H
z), 3.88 (3H, s), 3.71 (3H, s), 3.65 (3H, s), 3.62 (3
H, s), 3.27 (2H, t, J = 7.3 Hz), 3.17 (6H, s), 3.15 (2
H, t, J = 7.3 Hz), 2.73 (1H, ddd, J = 13.5, 11.0, 3.5
Hz), 2.29 (1H, ddd, J = 13.5, 9.5, 4.5 Hz), 2.04 (1
H, ddd, J = 13.5, 11.0, 4.5 Hz), 1.82 (1H, ddd, J
= 13.5, 9.5, 3.5 Hz), 1.15 (3H, s), 1.09 (3H, s), 0.66
(3H, s), -3.98 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ internal standard) ppm: -73.94 (3F,
d, J = 7.3 Hz).

[0045]

Example 26 Synthesis of 8- (2,2,2-trifluoroethyl) -3-formyl-deuteroporphyrin dimethyl ester- (2): 8- (S) TFADP [28] In an argon atmosphere, 3 -CHO-8-CAMPOTFE-2 ([27], 108 mg,
0.13 mmol) anhydrous tetrahylfurofuran (5.1 ml) and anhydrous MeOH
Add (1.0 ml) sodium bis (trimethylsilyl) amide to a mixed solution of (5.1 ml).
A solution of M tetrahydrofurofuran (1.3 ml, 1.3 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with a 10% hydrochloric acid aqueous solution and then extracted with CH ₂ Cl ₂ , and the CH ₂ Cl ₂ layer was washed with water and dried over anhydrous magnesium sulfate.
After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (S
separated and purified with iO ₂ , CH ₂ Cl ₂ -Et ₂ O, 90:10) and 8- (S) TFADP
([28], 84 mg, 99%) was obtained. The solid of [28] was determined by the Mosher method. mp 118-120 ° C. MS m / z: 664 (M ⁺ ). HRMS Calcd C ₃₅ H ₃₅ N ₄ O ₆ F ₃ (M ⁺ ): 664.251. Found: 664.
251. ¹ H-NMR (acetone-d ⁶ ) δ: 10.89 (1H, s), 10.46 (1H,
s), 10.25 (1H, s), 9.67 (1H, s), 8.81 (1H, s), 7.10 (1
H, dq, J = 5.0, 7.3 Hz), 6.96 (1H, d, J = 5.0 Hz), 4.2
6 (2H, t, J = 7.8 Hz), 4.11 (2H, t, J = 7.8 Hz), 3.73 (3
H, s), 3.67 (3H, s), 3.58 (3H, s), 3.57 (3H, s), 3.27
(2H, t, J = 7.8 Hz), 3.12 (2H, t, J = 7.8 Hz), 3.11 (3H,
s), 3.09 (3H, s), -5.08 (2H, bs). ¹⁹ F-NMR (acetone-d ⁶ , CFCl ₃ internal standard) ppm: -75.56
(3F, d, J = 7.3 Hz).

[0046]

Example 27 3- (2,2,2-trifluoro-1-hydrooxy) -8-formyl-deuteroporphyrin
Sodium: Synthesis of 3- (R) TFADPNa [29] 3- (R) TFADP, ([5], 11.2mg, 0.016mmol) was dissolved in 50ml of toluene and 300mg of NaOH was dissolved in 100ml of methanol. 0.6
Add 5 ml and stir for 1 hour. After the reaction was completed, methanol was distilled off and the precipitated crystals were collected by filtration and dried under reduced pressure to give 3- (R) TFADP.
Na ([29], 7.2 mg, 62%) was obtained.

[0047]

Example 28 Synthesis of 3- (2,2,2-trifluoro-1-hydrooxy) -8-formyl-deuteroporphyrin sodium: 3- (S) TFADPNa [30] 3- (S) A solution of TFADP, ([20], 8.0mg, 0.012mmol) dissolved in 50ml toluene and 300mg NaOH separately in 100ml methanol 0.6
Add ml and stir for 1 hour. After completion of the reaction, methanol was distilled off and the precipitated crystals were collected by filtration and dried under reduced pressure to give 3- (S) TFADPNa.
([30], 6.3 mg, 76.8%) was obtained.

[0048]

Example 29 Synthesis of 8- (2,2,2-trifluoro-1-hydrooxy) -3-formyl-deuteroporphyrin sodium: 8- (R) TFADPNa [31] 8- (S) A solution prepared by dissolving TFADP, ([24], 14.2mg, 0.021mmol) in 50ml of toluene and separately dissolving 100mg of NaOH in 100ml of methanol.
Add ml and stir for 1 hour. After completion of the reaction, methanol was distilled off and the precipitated crystals were collected by filtration and dried under reduced pressure to give 8- (R) TFA.
DPNa ([31], 11.1 mg, 76.5%) was obtained.

[0049]

Example 30 Synthesis of 8- (2,2,2-trifluoro-1-hydrooxy) -3-formyl-deuteroporphyrin sodium: 8- (S) TFADPNa [32] 8- (S) A solution of TFADP, ([28], 19.0mg, 0.028mmol) dissolved in 50ml toluene and another 100mg NaOH dissolved in 100ml methanol 1.5
Add ml and stir for 1 hour. After the reaction was completed, methanol was distilled off, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 8- (S) T.
FADPNa, ([32], 17.3 mg, 89.1%) was obtained.

[0050]

Example 31 3.5 × 10 ⁵ KATO- / ml
III- (R) TFDPNa was added to DM201 medium in which gastric cancer cells grow.
[9], 3- (S) TFDPNa [10], 8- (R) TFDPNa [11], 8- (S) TFDPNa
[12], 3- (R) TFADPNa [29], 3- (S) TFADPNa [30], 8- (R) TFA
DPNa [31], 8- (S) TFA DPNa [32] is 2.5 μ / ml
g, and cultured for 24 hours at 37 ° C. in an atmosphere of 5% carbon dioxide using Tissue Culture Flask (IWAKI GLASS).
After culturing, the cells and the supernatant were separated by centrifugation at 600 rpm for 10 minutes. Each sample was stored frozen and thawed at the time of analysis.
100 μl of each sample was collected, 900 μl of methanol containing 2.5% diisopropylamine was added, and the mixture was shaken for 5 minutes, then spun down at 3000 rpm for 10 minutes, and the supernatant was separated by HPLC. The following table shows the analysis results of each sample at the retention time of each administered porphyrin.

[0051]

[Table 1] From the above results, 3- (S) TFDPNa [10] has about 15 times as much uptake into cancer cells as its optical isomer, 3- (R) TFDPNa [9]. The three-dimensional difference appears.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] August 20, 1996

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Full text

[Correction method] Change

[Correction contents]

[Document Name] Statement

Title: Optically active porphyrin derivative having trifluoromethyl substituent and salt thereof

[Claims]

Embedded image (In the formula, R is -Na or -CH ₃ , R ¹ and R ² are either
When (R) -CH (OH) -CF ₃ or (S) -CH (OH) -CF ₃ , the other is
An optically active porphyrin derivative having a CF ₃ substituent represented by —H or —CHO) and a salt thereof.

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an optically active porphyrin derivative having a trifluoromethyl (CF ₃ ) substituent and a salt thereof, which are useful for diagnosis and treatment of cancer.

[0002]

2. Description of the Related Art In order to carry out so-called photochemotherapy for cancer, which destroys cancer tissue by utilizing electromagnetic wave energy such as laser beam or ultrasonic wave, laser beam or the like is irradiated from the outside. It is indispensable to administer a substance capable of converting the light energy into energy that destroys biological tissues to the living body in advance, and to accumulate it in a portion requiring treatment for cancer or the like. As this substance, a porphyrin body is currently considered useful and is being developed.

As a porphyrin body used for this purpose,
The hematoporphyrin derivative (HPD) is currently licensed for its manufacture as a drug of this type, but HPD is a mixture of compounds polymerized with hematoporphyrin (HP), and the individual structures have not been determined. Furthermore, HPD is known to cause skin irritation when exposed to sunlight after administration, which is a practical problem when performing this treatment. This side effect occurs when the administered HPD accumulates in the skin, and in order to avoid this, it is desired to develop a porphyrin body that is selectively taken up by cancer as compared with other biological tissues such as skin. .

Considering that this drug is usually used for diagnosis as well, it is necessary to minimize side effects due to uptake into living tissues other than the skin rather than the skin. It can be said that the discovery of a substance that accumulates in cancer more selectively as compared with the used HPD determines the success or failure of this treatment method. Furthermore, to clarify the pharmacological effect that the administered porphyrin body accumulates in cancer, it is urgently required that the administered porphyrin body be promptly excreted from biological tissues such as the skin. However,
HPD is a mixture of polymers, and it cannot be expected to be excreted promptly as compared with a single substance such as HP.

In order to overcome the disadvantages of HPD due to such a polymer, many porphyrin derivatives as a simple substance have been synthesized and their structure and pharmacology have been elucidated. However, the basis for the specific accumulation of HPD in cancer remains unclear. Its specificity is not expressed from a simple planar structure, but rather is that HP, which is a compound that is easily polymerized, has constructed a specific three-dimensional structure having pharmacological activity with a certain polymerization ratio. It is reasonable to think. Therefore, attempts have been made to separate the compounds having a certain degree of polymerization degree and to extract the fractions having a strong pharmacological activity to reveal the specificity of HPD, and have succeeded to some extent. However, it is difficult to isolate a polymer having a certain degree of polymerization, and due to the fact that it is a polymer, the occurrence of side effects due to the deposition on living tissues such as the skin still remains.

[0006] For the purpose of avoiding such side effects and elucidating the mechanism of the pharmacological action manifested in HPD, the synthesis of various derivatives having a basic skeleton of protoporphyrin existing in the living body and the pharmacological action of the derivatives. Has been studied. In the course of that research, it has been discovered so far that a compound in which methanol is added to the vinyl group at the 3-position of protoporphyrin is selectively accumulated in cancer. Focusing on the asymmetric carbons of the substituents at the 3- and 8-positions, which are the bases of pharmacological activity, and separating the stereoisomers, the selectivity of the drug effect due to the so-called "key and keyhole" relationship can be elucidated. It will be possible, and it is considered possible to create a drug effective in performing this treatment method.

[0007] In the present invention, a model compound which is considered to be easily excreted from living tissues while maintaining the specific accumulation property of HPD is designed, and the so-called "key and keyhole" in the pharmacological action of HPD is designed. We aimed to find a relationship. In the process, we paid attention to the existence of optical isomers of HP which is a raw material of HPD, and tried to synthesize model compounds and separate each isomer.

[0008]

Embedded image

As described above, hematoporphyrin (HP) has two asymmetric carbons (*) in one molecule, and the presence of these optical isomers is considered to be deeply related to the expression of pharmacological action.
Naturally, it would be good if the optical isomers could be separated and their pharmacological effects could be studied, but HP is easily polymerized and it is difficult to optically separate HP itself. However, it is difficult to administer it stably to a living body.

On the other hand, if hydrogen in the active center is replaced with a fluorine atom, it is expected that not only a chemically stable compound but also pharmacological activity will be increased. This is known as the "pseudo-effect" in the broad sense of the fluorine atom, and is one of the leading methods for drug development. The basis of the improvement is
It is said that by substituting with fluorine, the three-dimensional shape does not change so much, the lipophilicity of the molecule increases, and the absorption rate to the biological membrane increases.

Further, since the background of the nuclear magnetic resonance spectrum of fluorine is much smaller than that of hydrogen, by introducing a fluorine atom into a porphyrin body having the property of accumulating in cancer, the fluorine-containing porphyrin body becomes cancerous. When it is accumulated in, it is considered that cancer can be detected nondestructively by measuring the nuclear magnetic resonance spectrum of fluorine with a small background, and a clearer image of cancer can be obtained without using an endoscope. It has been thought that diagnosis will be easier. Further, it is considered that fluorination of porphyrin, administration of the obtained fluorine porphyrin to a living body, and measurement of nuclear magnetic resonance of fluorine throughout the living body may enable more accurate diagnosis of cancer. In order to realize this, naturally, it is an essential condition to administer a fluoroporphyrin that selectively accumulates in the cancer tissue. The present invention seeks this selectivity for an optically active fluoroporphyrin.

From the above consideration, it was attempted to obtain a compound in which the methyl group of the hydroxyethyl group, which is considered to be the active center of HP, was substituted with the CF ₃ group, one of which was (R) -CH (OH) -CF ₃ Alternatively, when (S) -CH (OH) -CF ₃ , the other is represented by —H 2 or —CHO, and an optically active porphyrin derivative having a CF ₃ substituent is synthesized.

A porphyrin derivative having this purpose is represented by the following formula:

[0014]

Embedded image In, when R is -CH ₃ or -Na, (*)-CH (OH) -CF ₃
In which * is (R) or (S) and R ¹ is -H or -CHO (3- (R) TFDP, 3- (S) TFDP, 3- (R) TFADP, 3- ( S) TFAD
P), or

[0015]

Embedded image In, when R is -CH ₃ or -Na, (*)-CH (OH) -CF ₃
In which * is (R) or (S) and R ¹ is -H or -CHO (8- (R) TFDP, 8- (S) TFDP, 8- (R) TFADP, 8- ( S) TF
ADP) was stably taken out.

The amount of uptake of 3-TFDP and 8-TFDP to hepatoma cells before optical separation was found from the cultured cell experiment to be such that the derivative in which both methyl groups were replaced with -CF ₃ groups was at only one 3-position or 8-position methyl group is known that more than derivatives substituted on a -CF ₃ group. On the other hand, 3-TFDP, 8-TF
From an experiment in which the other hydrogen of DP was changed to another substituent, it is known that the aldehyde group has the highest affinity to the cancer tissue.

In the present invention, in order to obtain a porphyrin derivative which is a simple substance and selectively accumulates in cancer, in order to obtain a porphyrin derivative, an optically active —CH (0H) -CF at one of the 3-position and the 8-position of the porphyrin body.
A derivative having _three groups and at the same time, the other substituents at the 3- and 8-positions were replaced with hydrogen or an aldehyde group was synthesized as a camphor derivative through optical separation, and each was obtained from the obtained optical isomers. Eight kinds of optically active hydroxyethyl compounds were obtained in total, and the accumulation property in cancer was examined.

[0018]

The present invention has been made based on the above-mentioned findings and ideas described above.
The following formula useful for the diagnosis and treatment of cancer

[0019]

Embedded image In the formula, when R is -CH ₃ or -Na, ^one of R ¹ and R ² is (R) -CH (OH) -CF ₃ or (S) -CH (OH) -CF ₃ , the other is Is -H or -CHO, trifluoromethyl (CF
₃ ) to provide an optically active porphyrin derivative having a group and a salt thereof.

[0020]

EXAMPLE 1 3- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) Te Bu Yuuteroho ° Rufirinshi Bu methyl ester: 3-CAMPOTFE-1 [1 ] and 3-CAMPOTFE- 2
Synthesis of [2] Under an argon atmosphere, 3- (2,2,2-trifluoro-1-humanerooxyethyl) deuteroporphyrin dimethyl ester (1.00 g, 1.57 mmol) and (-)-camphanyl chloride (0.41) g, 1.89 mmol) in anhydrous CH ₂ Cl ₂ solution (80 ml)
-(Dimethylamino) pyridine (0.67 mg, 5.50 mmol) anhydrous CH ₂ Cl ₂
The solution (20 ml) was slowly added dropwise under ice cooling, and the mixture was stirred for 10 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with a 10% aqueous hydrochloric acid solution, extracted with CH ₂ Cl ₂ , and the CH ₂ Cl ₂ layer was washed with water,
It was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 97: 3).
Separated and purified with 3-CAMPOTFE-1 ([1], 0.57g, 45%) and
3-CAMPOTFE-2 ([2], 0.59g, 46%) was obtained. [1]: mp 218 to 219 ° C. MS m / z: 816 (M ⁺ ). HRMS Calcd C ₄₄ H ₄₇ F ₃ N ₄ O ₈ (M ⁺ ): 816.335. Found: 81
6.335. ¹ H-NMR (CDCl ₃ ) δ: 10.56 (1H, s), 10.20 (1H, s), 10.04
(1H, s), 10.01 (1H, s), 9.16 (1H, s), 7.89 (1H, q, J =
7.3 Hz), 4.45 (2H, t, J = 7.8 Hz), 4.33 (2H, t, J = 7.8
Hz), 3.86 (3H, s), 3.82 (3H, s), 3.69 (3H, s), 3.66 (3
H, s), 3.63 (3H, s), 3.55 (3H, s), 3.29 (2H, t, J = 7.8
Hz), 3.27 (2H, t, J = 7.8 Hz), 2.43 (1H, ddd, J = 16.
0, 12.5, 4.0 Hz), 1.94 (1H, dd, J = 12.5, 4.0 Hz),
1.91 (1H, dd, J = 12.5, 4.0 Hz), 1.67 (1H, ddd, J = 1
6.0, 12.5, 4.0 Hz), 1.24 (3H, s), 1.19 (3H, s), 1.12
(3H, s), -3.80 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -74.09 (3F,
d, J = 7.3 Hz). [2]: mp 215-216 ° C. MS m / z: 816 (M ⁺ ). HRMS Calcd C ₄₄ H ₄₇ F ₃ N ₄ O ₈ (M ⁺ ): 816.335. Found: 816.3
34. ¹ H-NMR (CDCl ₃ ) δ: 10.49 (1H, s), 10.19 (1H, s), 10.0
3 (1H, s), 9.99 (1H, s), 9.15 (1H, s), 7.91 (1H, q, J =
7.3 Hz), 4.43 (2H, t, J = 7.8 Hz), 4.31 (2H, t, J = 7.8
Hz), 3.83 (3H, s), 3.82 (3H, s), 3.68 (3H, s), 3.65 (3
H, s), 3.62 (3H, s), 3.53 (3H, s), 3.28 (2H, t, J = 7.8
Hz), 3.25 (2H, t, J = 7.8 Hz), 2.68 (1H, ddd, J = 13.
4, 10.6, 4.3 Hz), 2.21 (1H, ddd, J = 13.4, 9.1, 4.3
Hz), 1.99 (1H, ddd, J = 13.4, 10.6, 4.3 Hz), 1.77
(1H, ddd, J = 13.4, 9.1 4.3 Hz), 1.11 (3H, s), 1.05
(3H, s), 0.56 (3H, s), -3.80 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -73.94 (3F,
d, J = 7.3 Hz).

[0021]

EXAMPLE 2 8- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) Te Bu Yuuteroho ° Rufirinshi Bu methyl ester 8-CAMPOTFE-1 [3] and 8-CAMPOTFE-2
Synthesis Arco Bu down atmosphere of [4], 8- (2,2,2-trifluoro-height Bu Rookishi ethyl) Te Bu Yuuteroho ° porphyrin di methyl ester (0.98 g, 1.54 mmol) and (-) - camphor sulfonyl chloride lithograph Bu (0.40 g, 1.85 4) in anhydrous CH ₂ Cl ₂ solution (80 ml)
-(Dimethylamino) pyridine (0.66g, 5.41mmol) in anhydrous CH ₂ Cl ₂
The solution (20 ml) was slowly added dropwise under ice cooling, and the mixture was stirred for 10 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with a 10% aqueous hydrochloric acid solution, extracted with CH ₂ Cl ₂ , and the CH ₂ Cl ₂ layer was washed with water,
It was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 9
7: 3) separated and purified, 8-CAMPOTFE-1 ([3], 0.55g, 44%)
And 8-CAMPOTFE-2 ([4], 0.49g, 39%) were obtained. [3]: mp 198-199 ° C. MS m / z: 816 (M ⁺ ). HRMS Calcd C ₄₄ H ₄₇ F ₃ N ₄ O ₈ (M ⁺ ): 816.335. Found: 816.
335. ¹ H-NMR (CDCl ₃ ) δ: 10.54 (1H, s), 10.13 (1H, s), 10.
09 (1H, s), 10.05 (1H, s), 9.17 (1H, s), 7.88 (1H, q, J
= 7.3 Hz), 4.48 (2H, t, J = 7.8 Hz), 4.34 (2H, t, J = 7.8
Hz), 3.79 (3H, s), 3.78 (3H, s), 3.75 (3H, s), 3.67 (3
H, s), 3.66 (3H, s), 3.56 (3H, s), 3.30 (2H, t, J = 7.8
Hz), 3.27 (2H, t, J = 7.8 Hz), 2.43 (1H, ddd, J = 14.
5, 11.5, 4.5 Hz), 1.91 (2H, m), 1.66 (1H, ddd, J = 1
4.5, 10.5 4.5 Hz), 1.25 (3H, s), 1.20 (3H, s), 1.13
(3H, s), -3.83 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -74.06 (3F,
d, J = 7.3 Hz). [4]: mp 163-165 ° C. MS m / z: 816 (M ⁺ ). HRMS Calcd C ₄₄ H ₄₇ F ₃ N ₄ O ₈ (M ⁺ ): 816.335. Found: 816.3
35. ¹ H-NMR (CDCl ₃ ) δ: 10.46 (1H, s), 10.14 (1H, s), 10.
10 (1H, s), 10.07 (1H, s), 9.18 (1H, s), 7.92 (1H, q, J
= 7.3 Hz), 4.49 (2H, dt, J = 7.8, 2.5 Hz), 4.35 (2H,
t, J = 7.8 Hz), 3.79 (3H, s), 3.76 (3H, d, J = 2.5 Hz),
3.75 (3H, s), 3.67 (3H, s), 3.66 (3H, s), 3.58 (3H,
s), 3.31 (2H, t, J = 7.8 Hz), 3.27 (2H, t, J = 7.8 Hz),
2.69 (1H, ddd, J = 13.5, 10.5, 4.5 Hz), 2.21 (1H, d-
dd, J = 13.5, 9.0, 4.5 Hz), 2.01 (1H, ddd, J = 13.5,
10.5, 4.5 Hz), 1.78 (1H, ddd, J = 13.5, 9.0, 4.5 H
z), 1.13 (3H, s), 1.08 (3H, s), 0.62 (3H, s), -3.81 (2
H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -73.97 (3F,
d, J = 7.3 Hz).

[0022]

EXAMPLE 3 3- (2,2,2-height Bu Rookishi ethyl) Te Bu Yuuteroho ° Rufirinshi Bu methyl ester: 3- (R) TFDP synthetic Arco Bu down atmosphere of [5], 3-CAMPOTFE- 1 ([1], 0.62g, 0.76mmol)
Solution of sodium bis (trimethylsilyl) amido in a mixed solvent of tetrahydrofuran (15 ml) and methanol (15 ml).
(5 ml, 7.55 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with a 10% hydrochloric acid aqueous solution and then extracted with CH ₂ Cl ₂ , and the CH ₂ Cl ₂ layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et).
₂ O, 97: 3 to 95: 5), and separated and purified to give 3- (R) TFDP ([5], 0.42
g, 88%) was obtained. The solid of [5] was determined by the Mosher method. [5]: mp 203-204 ° C. MS m / z: 636 (M ⁺ ). HRMS Calcd C ₃₄ H ₃₅ F ₃ N ₄ O ₅ (M ⁺ ): 636.256. Found: 636.
257. ¹ H-NMR (CDCl ₃ ) δ: 10.70 (1H, s), 10.12 (1H, s), 9.9
8 (1H, s), 9.93 (1H, s), 9.19 (1H, s), 6.96 (1H, dq,
J = 7.3, 4.9 Hz), 6.65 (1H, d, J = 4.9 Hz), 4.22 (2H, t,
J = 7.3 Hz), 4.20 (2H, t, J = 7.3 Hz), 3.77 (3H, s), 3.
74 (3H, s), 3.60 (3H, s), 3.57 (3H, s), 3.50 (3H, s),
3.45 (3H, s), 3.19 (4H, t, J = 7.3 Hz), -4.13 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -75.41 (3F,
d, J = 7.3 Hz).

[0023]

Example 4 3- (2,2,2-height Bu Rookishi ethyl) Te Bu Yuuteroho ° Rufirinshi Bu methyl ester: 3- (S) TFDP synthetic Arco Bu down atmosphere of [6], 3-CAMPOTFE- 2 ([2], 0.49g, 0.60mmo
l) Tetrahitofurofuran (24 ml) and methanol (24 ml) in a mixed solvent of sodium bis (trimethylsilyl) amido in a 1.0 M tetrahitofurofuran solution (6.
(00 ml, 6.00 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After completion of the reaction, the reaction mixture was poured into ice water, neutralized with 10% hydrochloric acid solution and extracted with CH ₂ Cl _2, washed with water CH ₂ Cl ₂ layer was dried over anhydrous sulfate macro Bu Neshiumu. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et).
₂ O, 97: 3 to 95: 5) and separated and purified to give 3- (S) TFDP ([6], 0.3
7g, 98%) was obtained. The solid of [6] was determined by the Mosher method. [6]: mp 203-204 ° C. MS m / z: 636 (M ⁺ ). HRMS Calcd C ₃₄ H ₃₅ F ₃ N ₄ O ₅ (M ⁺ ): 636.256. Found: 636.
256. ¹ H-NMR (CDCl ₃ ) δ: 10.71 (1H, s), 10.15 (1H, s), 10.0
1 (1H, s), 9.98 (1H, s), 9.21 (1H, s), 6.96 (1H, dq,
J = 7.3, 4.9 Hz), 6.67 (1H, d, J = 4.9 Hz), 4.25 (2H, t,
J = 7.3 Hz), 4.22 (2H, t, J = 7.3 Hz), 3.78 (3H, s), 3.
74 (3H, s), 3.60 (3H, s), 3.58 (3H, s), 3.53 (3H, s),
3.47 (3H, s), 3.21 (4H, t, J = 7.3 Hz), -4.08 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -75.41 (3F,
d, J = 7.3 Hz).

[0024]

EXAMPLE 5 8- (2,2,2-height Bu Rookishi ethyl) Te Bu Yuuteroho ° Rufirinshi Bu methyl ester: 8- (R) TFDP synthetic Arco Bu down atmosphere of [7], 8-CAMPOTFE- 1 ([3], 0.50g, 0.61mmol)
In a mixed solvent of tetrahitofurofuran (24 ml) and methanol (24 ml) of a 1.0 M solution of sodium bis (trimethylsilyl) amido in tetrahitofurofuran (6.13 m
(6.13 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with a 10% aqueous hydrochloric acid solution, extracted with CH ₂ Cl ₂ , and the CH ₂ Cl ₂ layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O).
, 97: 3 to 95: 5), and purified by 8- (R) TFDP ([7], 0.35
g, 90%) was obtained. The solid of [7] was determined by the Mosher method. [7]: mp 243-245 ° C. MS m / z: 636 (M ⁺ ). HRMS Calcd C ₃₄ H ₃₅ F ₃ N ₄ O ₅ (M ⁺ ): 636.256. Found: 636.
256. ¹ H-NMR (CDCl ₃ ) δ: 10.67 (1H, s), 10.17 (1H, s), 10.0
7 (1H, s), 9.92 (1H, s), 9.13 (1H, s), 6.96 (1H, dq,
J = 7.3, 4.9 Hz), 6.67 (1H, d, J = 4.9 Hz), 4.38 (2H, t,
J = 7.8 Hz), 4.22 (2H, t, J = 7.8 Hz), 3.75 (3H, s), 3.
66 (3H, s), 3.61 (3H, s), 3.60 (3H, s), 3.59 (3H, s),
3.43 (3H, s), 3.29 (2H, t, J = 7.8 Hz), 3.21 (2H, t, J =
7.8 Hz), -4.09 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -75.42 (3F,
d, J = 7.3 Hz).

[0025]

Example 6 8- (2,2,2-height Bu Rookishi ethyl) Te Bu Yuuteroho ° Rufirinshi Bu methyl ester: 8- (S) TFDP synthetic Arco Bu down atmosphere of [8], 8-CAMPOTFE- 2 ([4], 0.44g, 0.54mmol)
In a mixed solvent of tetrahitofurofuran (21 ml) and methanol (21 ml) of a 1.0 M solution of sodium bis (trimethylsilyl) amido in tetrahitofurofuran (5.39 m
(1, 39.39 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After completion of the reaction, the reaction mixture was poured into ice water, neutralized with 10% hydrochloric acid solution and extracted with CH ₂ Cl _2, washed with water CH ₂ Cl ₂ layer was dried over anhydrous sulfate macro Bu Neshiumu. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O).
, 97: 3 to 95: 5) and purified. 8- (S) TFDP ([8], 0.33g,
96%). The solid of [8] was determined by the Mosher method. [8]: mp 243-245 ° C. MS m / z: 636 (M ⁺ ). HRMS Calcd C ₃₄ H ₃₅ F ₃ N ₄ O ₅ (M ⁺ ): 636.256. Found: 636.
256. ¹ H-NMR (CDCl ₃ ) δ: 10.67 (1H, s), 10.18 (1H, s), 10.0
8 (1H, s), 9.92 (1H, s), 9.13 (1H, s), 6.96 (1H, dq,
J = 7.3, 4.9 Hz), 6.67 (1H, d, J = 4.9 Hz), 4.38 (2H, t,
J = 7.8 Hz), 4.22 (2H, t, J = 7.8 Hz), 3.76 (3H, s), 3.
66 (3H, s), 3.61 (3H, s), 3.60 (3H, s), 3.59 (3H, s),
3.43 (3H, s), 3.29 (2H, t, J = 7.8 Hz), 3.21 (2H, t, J =
7.8 Hz), -4.09 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ : internal standard) ppm: -75.41 (3F,
d, J = 7.3 Hz).

[0026]

Example 7 3- (2,2,2-height Bu Rookishi ethyl) Te Bu Yuuteroho ° Rufirinshi Bu Sodium: 3- (R) Synthesis of TFDPNa [9] 3- (R) TFDP, ([ 5], 24.4mg, 0.038mmol) was dissolved in 50ml of toluene, and 300mg of NaOH was dissolved in 100ml of methanol.
Add ml and stir for 1 hour. After the reaction was completed, methanol was distilled off, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 3- (R) T.
FDPNa ([9], 24 mg, 92%) was obtained.

[0027]

Example 8 3- (2,2,2-height Bu Rookishi ethyl) Te Bu Yuuteroho ° Rufirinshi Bu Sodium: 3- (S) Synthesis of TFDPNa [10] 3- (S) TFDP, ([ 6], 24.4 mg, 0.038 mmol) dissolved in 50 ml of toluene, and another 300 ml of NaOH dissolved in 100 ml of methanol 1.5 ml
And boil and stir for 1 hour. After completion of the reaction, methanol was distilled off and the precipitated crystals were collected by filtration and dried under reduced pressure to give 3- (S) TFDPN.
a ([10], 26.4 mg, 101.1%) was obtained.

[0028]

EXAMPLE 9 8- (2,2,2-height Bu Rookishi ethyl) Te Bu Yuuteroho ° Rufirinshi Bu Sodium: 8- (R) TFDPNa [11 ] Synthesis 8- (R) TFDPNa, ([ 7], 23.4mg, 0.036m mol) in 50ml of toluene
A solution prepared by dissolving 100 mg of NaOH in 100 ml of methanol.
Add 1.5 ml and boil for 1 hour. After completion of the reaction, methanol was distilled off, and the precipitated crystals were collected by filtration, dried under reduced pressure and treated with 8- (R) TF.
DPNa ([11], 21.1 mg, 105.5%) was obtained.

[0029]

Example 10 8- (2,2,2-height Bu Rookishi ethyl) Te Bu Yuuteroho ° Rufirinshi Bu Sodium: 8- (S) Synthesis of TFDPNa [12] 8- (S) TFDP, ([ 8], 20.4mg, 0.032mmol) was dissolved in 50ml toluene, and another 100mg NaOH was dissolved in 100ml methanol 1.5.
Add ml and stir for 1 hour. After completion of the reaction, methanol was distilled off, and the precipitated crystals were collected by filtration, dried under reduced pressure and treated with 8- (S) TFDPN.
a ([12], 16.2 mg, 74.3%) was obtained.

[0030]

EXAMPLE 11 3- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) Te Bu Yuuteroho ° porphyrin di methyl ester - Copper Complex: 3-CAMPOTFE-Cu- 1 [1
3 Synthesis of 3- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) Te Bu Yuuteroho ° porphyrin di methyl ester: 3-CAMPOTFE-1, ( [1], 677 mg, 0.
83 mmol) and copper acetate (319 mg, 1.60 mmol) in methanol (6.2
ml) -CH ₂ Cl ₂ (45 ml) suspension was heated to reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure, and column chromatography (SiO ₂ , C
H ₂ Cl ₂ -Et ₂ O, 95: 5) isolated and purified to give 3-CAMPOTFE-Cu-1,
([13], 668 mg, 92%) was obtained. mp 103-105 ° C.

[0031]

EXAMPLE 12 3- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) -8-formyl - Te Bu Yuuteroho ° porphyrin di methyl ester - Copper Complex- (1): 3 -CAMPO
Synthesis of TFE-8-CHO-Cu-1 [14] Under argon atmosphere, 3-CAMPOTFE-Cu-1, ([13], 100 mg, 0.
11 mmol) and CH (OMe) ₃ (240 μl, 2.19 mmol) anhydrous CH ₂
SnCl ₄ (66 μl, 0.56 mmol) was slowly added dropwise to the Cl ₂ (2.0 ml) solution under ice cooling, the ice cooling was stopped, and the mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, pour the reaction solution into ice water and
The solution was neutralized with an aHCO ₃ aqueous solution, the CH ₂ Cl ₂ layer was washed with water, and dried with anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, the residue was isolated and purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 92: 8), and 3-CAMPOTFE-8-CHO-Cu-1 ( [14], 92 mg, 89%)
I got mp 154-155 ° C.

[0032]

EXAMPLE 13 3- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) -8-formyl - Te Bu Yuuteroho ° porphyrin di methyl ester - (1): 3-CAMPOTFE- 8-CHO-1
Synthesis of [15] To 3-CAMPOTFE-8-CHO-Cu-1 ([14], 147 mg, 0.16 mmol)
CF ₃ COOH (3.0 ml) and concentrated H ₂ SO ₄ (0.3 ml) were added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water, neutralized with 5% NaOH solution, extracted with CH ₂ Cl _2, washed CH ₂ Cl ₂ layer was dried over anhydrous sulfate macro Bu Neshiumu.
After filtration, the solvent was removed under reduced pressure, and the residue was subjected to column chromatography (S
iO ₂ , CH ₂ Cl ₂ -Et ₂ O, 93: 7) isolated and purified, 3-CAMPOTFE-8
-CHO-1 ([15], 105 mg, 77%) was obtained. mp 127-130 ° C. ¹ H-NMR (CDCl ₃ ) δ: 11.42 (1H, s), 10.68 (1H, s), 10.
61 (1H, s), 10.00 (1H, s), 9.71 (1H, s), 7.93 (1H, q, J
= 7.3 Hz), 4.23 (2H, t, J = 7.3 Hz), 4.21 (2H, t, J = 7.3
Hz), 4.04 (3H, s), 3.84 (3H, s), 3.63 (3H, s), 3.62 (3
H, s), 3.52 (3H, s), 3.48 (3H, s), 3.20 (2H, t, J = 7.3
Hz), 3.16 (2H, t, J = 7.3 Hz), 2.42 (1H, ddd, J = 13.
0, 11.0, 4.0 Hz), 1.93 (1H, ddd, J = 13.0, 11.0, 4.
0 Hz), 1.89 (1H, ddd, J = 13.0, 10.0, 4.0 Hz), 1.67
(1H, ddd, J = 13.0, 10.0, 4.0 Hz), 1.31 (3H, s), 1.
22 (3H, s), 1.16 (3H, s), -3.63 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ internal standard) ppm: -74.22 (3F, d,
J = 7.3 Hz).

[0033]

Example 14 3- (2,2,2-trifluoro-height Bu Rookishi ethyl) -8-formyl - Te Bu Yuuteroho ° porphyrin
Dimethyl ester- (1): Synthesis of 3- (R) TFADP [16] In an argon atmosphere, 3-CAMPOTFE-8-CHO-1 ([15], 80mg, 0.0
95 mmol) anhydrous tetrahitofurofuran (3.8 ml) and anhydrous MeOH (3.
To a mixed solution of 8 ml), a 1.0 M solution of sodium bis (trimethylsilyl) amido in tetrahylrofuran (0.95 ml, 0.95 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with 10% aqueous hydrochloric acid solution, and extracted with CH ₂ Cl _2.
The CH ₂ Cl ₂ layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ ,
CH ₂ Cl ₂ -Et ₂ O, 90:10) separated and purified, 3- (R) TFADP ([1
6], 63 mg, 100%) was obtained. The solid of [16] was determined by the Mosher method. mp 235-237 ° C. MS m / z: 664 (M ⁺ ). HRMS Calcd C ₃₅ H ₃₅ N ₄ O ₆ F ₃ (M ⁺ ): 664.251. Found: 664.
251. ¹ H-NMR (acetone-d ⁶ ) δ: 11.36 (1H, s), 10.57 (1H,
s), 10.22 (1H, s), 9.91 (1H, s), 9.50 (1H, s), 7.66 (1
H, bs), 7.02 (1H, q, J = 7.3 Hz), 4.13 (2H, t, J = 7.3 H
z), 4.12 (2H, t, J = 7.3 Hz), 3.88 (3H, s), 3.84 (3H,
s), 3.59 (3H, s), 3.56 (3H, s), 3.45 (3H, s), 3.35 (3H,
s), 3.13 (2H, t, J = 7.3 Hz), 3.09 (2H, t, J = 7.3 Hz),
-4.80 (2H, bs). ¹⁹ F-NMR (acetone-d ⁶ , CFCl ₃ internal standard) ppm: -75.36
(3F, d, J = 7.3 Hz).

[0034]

EXAMPLE 15 3- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) Te Bu Yuuteroho ° porphyrin di methyl ester - copper Complex- (2): 3-CAMPOTFE -Cu- 2
[17] Synthesis of 3- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) Te Bu Yuuteroho ° porphyrin di methyl ester - (2): 3-CAMPOTFE -2, ([2 ], 549 m
g, 0.67 mmol) and copper acetate (259 mg, 1.30 mmol) in MeOH
The (5.0 ml) -CH ₂ Cl ₂ (36.5 ml) suspension was heated under reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure and the residue was isolated and purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 95: 5) to give 3-CAMPOT.
FE-Cu-2 ([17], 590 mg, 100%) was obtained. mp 110-112 ° C.

[0035]

EXAMPLE 16 3- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) -8-formyl - Te Bu Yuuteroho ° porphyrin di methyl ester -Cu Complex- (2): 3 -CAMPOT
Synthesis of FE-8-CHO-Cu-2 [18] In an argon atmosphere, 3-CAMPOTFE-Cu-2 ([17], 100 mg, 0.11
mmol) and CH (OMe) ₃ (240 μg, 2.19 mmol) anhydrous CH ₂ C
SnCl ₄ (66 μl, 0.56 mmol) was slowly added dropwise to the l ₂ (2.0 ml) solution under ice cooling, the ice cooling was stopped, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the reaction solution was poured into ice water and saturated NaHCO 3 was added.
₃ was neutralized with an aqueous solution, and extracted with CH ₂ Cl ₂ and washed with water CH ₂ Cl ₂ layer was dried over anhydrous sulfate macro Bu Neshiumu. After filtration, the solvent was removed under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O,
92: 8) isolated and purified, 3-CAMPOTFE-8-CHO-Cu-2 ([18], 7
4 mg, 72%) was obtained. mp 144-146 ° C.

[0036]

EXAMPLE 17 3- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) -8-formyl - Te Bu Yuuteroho ° porphyrin di methyl ester - (2): 3-CAMPOTFE- 8-CHO-2
Synthesis of [19] To 3-CAMPOTFE-8-CHO-Cu-2 ([18], 119 mg, 0.13 mmol)
CF ₃ COOH (2.0 ml) and concentrated H ₂ SO ₄ (0.2 ml) were added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the reaction solution was poured into ice water, neutralized with a 5% aqueous NaOH solution, the CH ₂ Cl ₂ layer was washed with water, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et).
₂ O, 93: 7) isolated and purified, 3-CAMPOTFE-8-CHO-2 ([19],
69 mg, 62%) was obtained. mp 133-135 ° C. ¹ H-NMR (CDCl ₃ ) δ: 11.44 (1H, s), 10.74 (1H, s), 10.
56 (1H, s), 10.03 (1H, s), 9.78 (1H, s), 7.94 (1H, q, J
= 7.3 Hz), 4.24 (2H, t, J = 7.3 Hz), 4.22 (2H, t, J = 7.3
Hz), 4.02 (3H, s), 3.84 (3H, s), 3.63 (3H, s), 3.62 (3
H, s), 3.53 (3H, s), 3.49 (3H, s), 3.21 (2H, t, J = 7.3
Hz), 3.18 (2H, t, J = 7.3 Hz), 2.67 (1H, ddd, J = 13.
5, 11.0, 4.0 Hz), 2.28 (1H, ddd, J = 13.5, 9.0, 4.5
Hz), 2.00 (1H, ddd, J = 13.5, 11.0, 4.5 Hz), 1.80 (1
H, ddd, J = 13.5, 9.0, 4.0Hz), 1.06 (3H, s), 1.04 (3
H, s), 0.48 (3H, s), -3.52 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ internal standard) ppm: -4.03 (3F, d,
J = 7.3 Hz).

[0037]

EXAMPLE 18 3- (2,2,2-trifluoro-height Bu Rookishi ethyl) -8-formyl - Te Bu Yuuteroho ° porphyrin
Dimethyl ester- (2): 3- (S) TFADP [20] Synthesis under argon atmosphere, 3-CAMPOTFE-8-CHO-2 ([19], 53 mg, 0.
063 mmol) of anhydrous tetrahitofurofuran (2.5 ml) and anhydrous MeOH
(2.5 ml) of mixed solution of sodium bis (trimethylsilyl) amido.
A 0M tetrahitofurofuran solution (0.63 ml, 0.63 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After the reaction was completed, the reaction solution was poured into ice water and neutralized with a 10% aqueous hydrochloric acid solution, and then CH ₂ Cl ₂
Extraction was performed, the CH ₂ Cl ₂ layer was washed with water, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, the residue was separated and purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 90:10), and 3-
(S) TFADP ([20], 39 mg, 94%) was obtained. The solid of [20]
Determined by the Mosher method. mp 235-237 ° C. MS m / z: 664 (M ⁺ ). HRMS Calcd C ₃₅ H ₃₅ N ₄ O ₆ F ₃ (M ⁺ ): 664.251. Found: 664.
250. ¹ H-NMR (acetone-d ⁶ ) δ: 11.38 (1H, s), 10.59 (1H,
s), 10.33 (1H, s), 9.95 (1H, s), 9.61 (1H, s), 7.39 (1
H, bs), 7.03 (1H, q, J = 7.3 Hz), 4.19 (2H, t, J = 7.8 H
z), 4.16 (2H, t, J = 7.8 Hz), 3.88 (3H, s), 3.84 (3H,
s), 3.59 (3H, s), 3.57 (3H, s), 3.48 (3H, s), 3.41 (3H,
s), 3.15 (2H, t, J = 7.8 Hz), 3.13 (2H, t, J = 7.8 Hz),
-4.61 (2H, bs). ¹⁹ F-NMR (acetone-d ⁶ , CFCl ₃ internal standard) ppm: -5.56 (3
F, d, J = 7.3 Hz).

[0038]

EXAMPLE 19 8- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) Te Bu Yuuteroho ° porphyrin di methyl ester - Copper Complex- (1): 8-CAMPOTFE -Cu- 1
Synthesis of [21] 8- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) Te Bu Yuuteroho ° porphyrin di methyl ester - (1): 8-CAMPOTFE -1 ([3] , 256 m
g, 0.31 mmol) and copper acetate (121 mg, 0.61 mmol) in MeOH
The (2.3 ml) -CH ₂ Cl ₂ (17 ml) suspension was heated under reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure, and column chromatography (S
iO ₂ , CH ₂ Cl ₂ -Et ₂ O, 95: 5) isolated and purified to give 8-CAMPOTFE-C.
u-1 ([21], 248 mg, 90%) was obtained. mp 220-221 ° C.

[0039]

EXAMPLE 20 8- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) -3-formyl - Te Bu Yuuteroho ° porphyrin di methyl ester - Copper Complex- (1): 3 -CHO-8-C
Synthesis of AMPOTFE-Cu-1 [22] In an argon atmosphere, 8-CAMPOTFE-Cu-1 ([21], 146 mg, 0.17
mmol) and CH (OMe) ₃ (360 μl, 3.29 mmol) anhydrous CH ₂ Cl
SnCl ₄ (100 μl, 0.86 mmol) was slowly added dropwise to the ₂ (3.0 ml) solution under ice cooling, the ice cooling was stopped, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the reaction solution was poured into ice water and saturated NaH
The solution was neutralized with a CO ₃ aqueous solution, the CH ₂ Cl ₂ layer was washed with water, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, the residue was isolated and purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 90:10), and 3-CHO-8-CAMPOTFE-Cu-1 ( [22], 124 mg, 82%) was obtained. mp 148-150 ° C.

[0040]

Example 21 8- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) -3-formyl - Te Bu Yuuteroho ° porphyrin di methyl ester - (1): 3-CHO- 8-CAMPOTFE-1
Synthesis of [23] To 3-CHO-8-CAMPOTFE-Cu-1 ([22], 268 mg, 0.30 mmol)
CF ₃ COOH (3.0 ml) and concentrated H ₂ SO ₄ (0.3 ml) were added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the reaction solution was poured into ice water, neutralized with a 5% aqueous solution of NaOH, the CH ₂ Cl ₂ layer was washed with water, and dried with anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂
O, 93: 7) isolated and purified, 3-CHO-8-CAMPOTFE-1 ([23], 23
3 mg, 93%) was obtained. mp 118-120 ° C. ¹ H-NMR (CDCl ₃ ) δ: 10.80 (1H, s), 10.47 (1H, s), 10.
45 (1H, s), 9.68 (1H, s), 8.63 (1H, s), 7.98 (1H, q, J =
7.3 Hz), 4.32 (2H, t, J = 7.8 Hz), 4.12 (2H, t, J = 7.8 H
z), 3.85 (3H, s), 3.72 (3H, s), 3.70 (3H, s), 3.60 (3
H, s), 3.28 (2H, t, J = 7.8 Hz), 3.10 (2H, t, J = 7.8 H
z), 3.06 (3H, s), 2.89 (3H, s), 2.51 (1H, ddd, J = 1
5.0, 11.5, 4.5 Hz), 2.02 (1H, ddd, J = 15.0, 9.5,
4.5 Hz), 1.97 (1H, ddd, J = 14.0, 11.5, 4.5 Hz), 1.
72 (1H, ddd, J = 14.0, 9.5, 4.5 Hz), 1.35 (3H, s),
1.25 (3H, s), 1.20 (3H, s), -4.47 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ internal standard) ppm: -74.06 (3F,
d, J = 7.3 Hz).

[0041]

EXAMPLE 22 8- (2,2,2-trifluoro-height Bu Rookishi ethyl) -3-formyl - Te Bu Yuuteroho ° porphyrin
Dimethyl ester-(1): Synthesis of 8- (R) TFADP [24] In an argon atmosphere, 3-CHO-8-CAMPOTFE-1 ([23], 209 mg,
0.24 mmol) anhydrous tetrahylfurofuran (9.9 ml) and anhydrous MeOH
(9.9 ml) mixed solution with 1.0% sodium bis (trimethylsilyl) amide
A solution of M tetrahydrofurofuran (2.5 ml, 2.5 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with a 10% hydrochloric acid aqueous solution and then extracted with CH ₂ Cl ₂ , and the CH ₂ Cl ₂ layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was separated and purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 90:10) to give 8- (R) TF.
ADP ([24], 164 mg, 100%) was obtained. The solid of [24] is Mos
It was determined by the her method. mp 118-120 ° C. MS m / z: 664 (M ⁺ ). HRMS Calcd C ₃₅ H ₃₅ N ₄ O ₆ F ₃ (M ⁺ ): 664.251. Found: 664.
251. ¹ H-NMR (acetone-d ⁶ ) δ: 10.94 (1H, s), 10.48 (1H,
s), 10.31 (1H, s), 9.70 (1H, s), 8.89 (1H, s), 7.10 (1
H, dq, J = 5.0, 7.3 Hz), 6.95 (1H, d, J = 5.0 Hz), 4.2
7 (2H, t, J = 7.8 Hz), 4.13 (2H, t, J = 7.8 Hz), 3.74 (3
H, s), 3.67 (3H, s), 3.59 (3H, s), 3.58 (3H, s), 3.27
(2H, t, J = 7.8 Hz), 3.15 (3H, s), 3.14 (3H, s), 3.12
(2H, t, J = 7.8 Hz), -5.02 (2H, bs). ¹⁹ F-NMR (acetone-d ⁶ , CFCl ₃ internal standard) ppm: -75.59
(3F, d, J = 7.3 Hz).

[0042]

EXAMPLE 23 8- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) Te Bu Yuuteroho ° porphyrin di methyl ester - copper Complex- (2): 8-CAMPOTFE -Cu- 2
Synthesis of [25] 8- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) Te Bu Yuuteroho ° porphyrin di methyl ester - (2): 8-CAMPOTFE -2 ([4] , 609 mg,
0.75 mmol) and copper acetate (287 mg, 1.44 mmol) in MeOH
The (5.5 ml) -CH ₂ Cl ₂ (40.5 ml) suspension was heated under reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure, and column chromatography (S
iO ₂ , CH ₂ Cl ₂ -Et ₂ O, 95: 5) isolated and purified to give 8-CAMPOTFE-C.
u-2 ([25], 535 mg, 82%) was obtained. mp 113-115 ° C.

[0043]

Example 24 8- (1-(-)-camphanyloxy-2,2,2-trifluorohydrooxyethyl) -3-formyl-deuteroporphyrin dimethyl ester-copper Complex- (2): 3 -CHO-CA
Synthesis of MPOTFE-Cu-2 [26] Under argon atmosphere, 8-CAMPOTFE-Cu-2 ([25], 50 mg, 0.057
mmol) and CH (OMe) ₃ (120 μl, 1.10 mmol) anhydrous CH ₂ Cl
SnCl ₄ (30 μl, 0.26 mmol) was slowly added dropwise to the ₂ (1.0 ml) solution under ice cooling, the ice cooling was stopped, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the reaction solution was poured into ice water and saturated NaHCO 3 was added.
_The mixture was neutralized with ₃ aqueous solution, the CH ₂ Cl ₂ layer was washed with water, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, the residue was isolated and purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ -Et ₂ O, 90:10), and 3-CHO-CAMPOTFE-Cu-2 ([26 ], 38 mg, 74%) was obtained. mp 183-185 ° C.

[0044]

EXAMPLE 25 8- (1 - (-) - camphor oxy-2,2,2-trifluoro-height Bu Rookishi ethyl) -3-formyl - Te Bu Yuuteroho ° porphyrin di methyl ester - (2): 3-CHO- 8-CAMPOTFE-2
Synthesis of [27] C in 3-CHO-CAMPOTFE-Cu-2 ([26], 168 mg, 0.19 mmol)
F ₃ COOH (3.0 ml) and concentrated H ₂ SO ₄ (0.3 ml) were added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. After the reaction was completed, the reaction solution was poured into ice water, neutralized with 5% NaOH aqueous solution, extracted with CH ₂ Cl ₂ , and extracted with C
The H ₂ Cl ₂ layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ ,
CH ₂ Cl ₂ -Et ₂ O, 93: 7) isolated and purified, 3-CHO-8-CAMPOTFE
-2 ([27], 130 mg, 83%) was obtained. mp 125-127 ° C. ¹ H-NMR (CDCl ₃ ) δ: 10.99 (1H, s), 10.75 (1H, s), 10.
36 (1H, s), 9.79 (1H, s), 9.06 (1H, s), 8.00 (1H, q, J =
7.3 Hz), 4.32 (2H, t, J = 7.3 Hz), 4.17 (2H, t, J = 7.3 H
z), 3.88 (3H, s), 3.71 (3H, s), 3.65 (3H, s), 3.62 (3
H, s), 3.27 (2H, t, J = 7.3 Hz), 3.17 (6H, s), 3.15 (2
H, t, J = 7.3 Hz), 2.73 (1H, ddd, J = 13.5, 11.0, 3.5
Hz), 2.29 (1H, ddd, J = 13.5, 9.5, 4.5 Hz), 2.04 (1
H, ddd, J = 13.5, 11.0, 4.5 Hz), 1.82 (1H, ddd, J
= 13.5, 9.5, 3.5 Hz), 1.15 (3H, s), 1.09 (3H, s), 0.66
(3H, s), -3.98 (2H, bs). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ internal standard) ppm: -73.94 (3F,
d, J = 7.3 Hz).

[0045]

EXAMPLE 26 8- (2,2,2-trifluoro-height Bu Rookishi ethyl) -3-formyl - Te Bu Yuuteroho ° porphyrin
Dimethylester- (2): Synthesis of 8- (S) TFADP [28] In an argon atmosphere, 3-CHO-8-CAMPOTFE-2 ([27], 108 mg,
0.13 mmol) anhydrous tetrahylfurofuran (5.1 ml) and anhydrous MeOH
Add (1.0 ml) sodium bis (trimethylsilyl) amide to a mixed solution of (5.1 ml).
A solution of M tetrahydrofurofuran (1.3 ml, 1.3 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred for 15 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with a 10% hydrochloric acid aqueous solution and then extracted with CH ₂ Cl ₂ , and the CH ₂ Cl ₂ layer was washed with water and dried over anhydrous magnesium sulfate.
After filtration, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (S
separated and purified with iO ₂ , CH ₂ Cl ₂ -Et ₂ O, 90:10) and 8- (S) TFADP
([28], 84 mg, 99%) was obtained. The solid of [28] was determined by the Mosher method. mp 118-120 ° C. MS m / z: 664 (M ⁺ ). HRMS Calcd C ₃₅ H ₃₅ N ₄ O ₆ F ₃ (M ⁺ ): 664.251. Found: 664.
251. ¹ H-NMR (acetone-d ⁶ ) δ: 10.89 (1H, s), 10.46 (1H,
s), 10.25 (1H, s), 9.67 (1H, s), 8.81 (1H, s), 7.10 (1
H, dq, J = 5.0, 7.3 Hz), 6.96 (1H, d, J = 5.0 Hz), 4.2
6 (2H, t, J = 7.8 Hz), 4.11 (2H, t, J = 7.8 Hz), 3.73 (3
H, s), 3.67 (3H, s), 3.58 (3H, s), 3.57 (3H, s), 3.27
(2H, t, J = 7.8 Hz), 3.12 (2H, t, J = 7.8 Hz), 3.11 (3H,
s), 3.09 (3H, s), -5.08 (2H, bs). ¹⁹ F-NMR (acetone-d ⁶ , CFCl ₃ internal standard) ppm: -75.56
(3F, d, J = 7.3 Hz).

[0046]

EXAMPLE 27 3- (2,2,2-height Bu Rookishi ethyl) -8-formyl - Te Bu Yuuteroho ° porphyrin disodium: 3- (R) Synthesis of TFADPNa [29] 3- (R ) TFADP, ([5], 11.2mg, 0.016mmol) was dissolved in 50ml of toluene, and 300mg of NaOH was dissolved in 100ml of methanol.
Add 5 ml and stir for 1 hour. After the reaction was completed, methanol was distilled off and the precipitated crystals were collected by filtration and dried under reduced pressure to give 3- (R) TFADP.
Na ([29], 7.2 mg, 62%) was obtained.

[0047]

Example 28 3- (2,2,2-height Bu Rookishi ethyl) -8-formyl - Te Bu Yuuteroho ° Rufirinshi Bu Sodium: 3- (S) Synthesis of TFADPNa [30] 3- (S ) TFADP, ([20], 8.0 mg, 0.012 mmol) was dissolved in 50 ml of toluene, and another 300 mg of NaOH was dissolved in 100 ml of methanol.
Add ml and stir for 1 hour. After completion of the reaction, methanol was distilled off and the precipitated crystals were collected by filtration and dried under reduced pressure to give 3- (S) TFADPNa.
([30], 6.3 mg, 76.8%) was obtained.

[0048]

EXAMPLE 29 8- (2,2,2-height Bu Rookishi ethyl) -3-formyl - Te Bu Yuuteroho ° porphyrin disodium: 8- (R) Synthesis of TFADPNa [31] 8- (S ) TFADP, ([24], 14.2mg, 0.021mmol) was dissolved in 50ml of toluene, and a solution of NaOH 100mg in methanol 100ml 1.0
Add ml and stir for 1 hour. After completion of the reaction, methanol was distilled off and the precipitated crystals were collected by filtration and dried under reduced pressure to give 8- (R) TFA.
DPNa ([31], 11.1 mg, 76.5%) was obtained.

[0049]

Example 30 8- (2,2,2-height Bu Rookishi ethyl) -3-formyl - Te Bu Yuuteroho ° porphyrin disodium: 8- (S) Synthesis of TFADPNa [32] 8- (S ) TFADP, ([28], 19.0mg, 0.028mmol) was dissolved in 50ml of toluene, and another 100mg of NaOH was dissolved in 100ml of methanol.
Add ml and stir for 1 hour. After the reaction was completed, methanol was distilled off, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 8- (S) T.
FADPNa, ([32], 17.3 mg, 89.1%) was obtained.

[0050]

Example 31 3.5 × 10 ⁵ KATO- / ml
III- (R) TFDPNa was added to DM201 medium in which gastric cancer cells grow.
[9], 3- (S) TFDPNa [10], 8- (R) TFDPNa [11], 8- (S) TFDPNa
[12], 3- (R) TFADPNa [29], 3- (S) TFADPNa [30], 8- (R) TFA
DPNa [31], 8- (S) TFA DPNa [32] is 2.5 μ / ml
g, and cultured for 24 hours at 37 ° C. in an atmosphere of 5% carbon dioxide using Tissue Culture Flask (IWAKI GLASS).
After culturing, the cells and the supernatant were separated by centrifugation at 600 rpm for 10 minutes. Each sample was stored frozen and thawed at the time of analysis.
100 μl of each sample was collected, 900 μl of methanol containing 2.5% diisopropylamine was added, and the mixture was shaken for 5 minutes, then spun down at 3000 rpm for 10 minutes, and the supernatant was separated by HPLC. The following table shows the analysis results of each sample at the retention time of each administered porphyrin.

[0051]

[Table 1] From the above results, 3- (S) TFDPNa [10] has about 15 times as much uptake into cancer cells as its optical isomer, 3- (R) TFDPNa [9]. The three-dimensional difference appears.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Takashi Matsumoto 1088-3 Nishioka, Uozumi-cho, Akashi-shi, Hyogo (72) Inventor Toshiyuki Takagi 1-49-7 Guntsu, Katazu, Katano-shi (72) Inventor Mayumi Koyama Osaka 4-4 Matsuya-cho, Neyagawa-shi

Claims (1)

[Claims] 1. The following formula: (In the formula, R is -Na or -CH ₃ , R ¹ and R ² are either
When (R) -CH (OH) -CF ₃ or (S) -CH (OH) -CF ₃ , the other is
An optically active porphyrin derivative having a CF ₃ substituent represented by —H or —CHO) and a salt thereof.