2
616
Chlorophyllin Derivatives as Photosensitizers: Synthesis and Photodynamic Properties
J. Braz. Chem. Soc.
Experimental
and the solvent distilled off to obtain a green solid. The
product was purified by column chromatography over
basic alumina, (Merck: Brockmann Grade V) using
DCM/MeOH = 10:1 (v/v) as eluent, and the obtained
precipitate was crystallized with DCM and hexanes to give
compound 4 (108 mg, 0.12 mmol) in 76% yield.
All solvents and compounds were purchased from
Acros Organics Chemicals and were used as they arrived
unless otherwise specified. The trisodium salt of Cu-
chlorophyllin: copper trisodium (2S-trans)-[18-carboxy-
2
0-(carboxymethyl)-13-ethyl-2,3-dihydro-3,7,12,17-
Compound 4 was characterized by Fourier transform
infrared (FTIR), nuclear magnetic resonance (NMR) and
electrospray ionization time-of-flight mass spectrometry
tetramethyl-8-vinyl-21-H,23-H-porphine-2-propionato
was obtained from Sigma-Aldrich and used without any
purification.
-1 1
(ESI-MS-TOF). IR signature C=O at 1661 cm ; H NMR
500 MHz, CDCl ) d (ppm): −2.3 (s, 2H, H-21 and H-22),
(
3
2
+
2
6
4
Removal of Cu and esterification
1.56 (t, 3H, CH -13 ), 1.62-1.64 (m, 6H, H-2 , H-18
3
and H-20 ), 2.13 (s, 18H, 6CH , H-2 , H-18 and H-20 ),
2.39-2.41 (m, 6H, H-2 , H-18 and H-20 ), 2.99-2.86
(m, 6H, H-2 , H-18 and H-20 ), 3.37, 3.35 and 3.27 (3s,
12H, CH -3 , CH -7 and CH -17 ), 3.58 (t, 2H, J 7.7 Hz,
CH -2 ), 4.07 (t, 2H, J 7.7 Hz, CH -2 ), 4.09 (s, 2H, CH ,
5
9
7
8
3
7
5
6
5
00 mg (0.7 mol) of trisodium salt of Cu-chlorophyllin
5
3
4
was dissolved in methanol saturated with HCl and the
reactional mixture was stirred for 4 hours. The mixture was
partitioned three times with a dichloromethane (DCM)/
HCl solvent mixture, in a second step, the organic phase
was neutralized with ammonia solution and made a second
partition. The organic phase was dried with magnesium
sulfate, and the solvent was removed in rotavap, the solid
residue was purified by column chromatography using
silica gel and eluted with DCM:MeOH 50:1. The collected
fractions were analyzed by absorption spectroscopy and
the subsequent; 18-methyl formate-20-(methyl acetate)-
1
1
1
3
3
3
2
1
2
2
2
1
2
1
20 ), 6.46-6.36 (m, 2H, 8 ), 7.99 (m, 1H, 8 ), 8.77 (s,
H, CH-10), 9.67 (s, 1H, CH-20), 10.09 (s, 1H, CH-15);
13
C NMR (125.77 MHz, CDCl ) d (ppm): 12.2, 14.3, 14.4
3
1
2
1
1
1
and 19.9 (C-7 , C-13 ,C-12 and C-17 ), 22.9 (C-2 ), 29.9,
29.7 and 29.7 (C-2 , C-18 and C-20 ), 32.1 (C, CH -2 ),
38.0 (C, CH -20 ), 30.0, 30.1, and 31.0 (C-2 , C-18 and
C-20 ), 45.5, 45.3, 45.2, 45.2 and 44.9 (C-2 , C-18 and
C-20 ), 58.5, 58.3 and 58.1 (C-2 , C-18 and C-20 ), 191.6,
185.0 and 173.3 (3C, C-2 , C-18 and C-20 ); m/z 847.57
calculated for C H N O (MH ); found: 847.60.
49 71 10 3
6
4
5
2
2
3
1
5
2
4
9
7
8
7
5
6
3
1
2
1
3-ethyl-2,3-dihydro-3,7,12,17-tetramethyl-8-vinyl-21-
+
+
H,23-H-porphine-2-methyl propionate, (trimethylester
chlorophyllin, compound 2), was isolated. The process
yielded 210 mg (0.3 mol, i.e., 48% yield).
Synthesis of compound 5, 8-(3-formamido-N,N,N-
trimethylpropan-1-aminium iodide)-20-(3-acetamido-N,N,N-
trimethylpropan-1-aminium iodide)-13-ethyl-2,3-dihydro-
3,7,12,17-tetramethyl-8-vinyl-21-H,23-H-porphine-2-N,N,N-
trimethyl-3-propionamidopropan-1-aminium iodide
Synthesis of compound 4, 18-(N-(3-(dimethylamino)propyl)
formamide)-20-(N-(3-(dimethylamino)propyl)acetamide)-13-
ethyl-2,3-dihydro-3,7,12,17-tetramethyl-8-vinyl-21-H,23-H-
porphine-2-N-(3-(dimethylamino)propyl)propionamide
5
0 mg (0.05 mmol) of the compound 4 was dissolved
2
00 mg (0.3 mmol) of compound 2, was dissolved
in anhydrous DCM and excess of CH I was added to
3
in 4 mL of CHCl and added to 20 mL aqueous HCl
give compound 5 with quantitative yield. The reaction
medium was maintained with stirring for 12 hours, and the
residues were purified by recrystallization in DCM:MeOH.
Compound 5 was characterized by FTIR, NMR and
3
-1
2
mol L . After 4 h, the solvents were distilled off under
reduced pressure, thus obtaining the compound 3 (122 mg,
1
9
0
1
.2 mmol, 66%) without further purification. After that,
-1
00 mg (0.17 mmol) of the compound 3 was refluxed
ESI-MS-TOF. IR signature observed at 1657 cm (C=O);
1
under a dry nitrogen atmosphere with an excess of fresh
oxalyl chloride (2 mL) for 2 h, followed by the distillation
of the remaining oxalyl chloride, thus yielding a green
H NMR (500 MHz, DMSO-d ) d (ppm): −2.38 (s, 2H,
6
2
H-21 and H-22), 1.83 (t, 3H , J 7.0 Hz, CH -13 ), 2.06-
1.78 (m, 6H, H-2 , H-18 and H-20 ), 2.90-2.77 (m, 6H,
H-2 , H-18 and H-20 ), 3.09-3.07 (m, 6H, H-2 , H-18
and H-20 ), 3.14, 3.12 and 3.10 (3s, 12H, CH , 7 , 12 and
17 ), 3.31 (2H, H-2 ), 3.39 (s, 18H, C-2 , C-18 and C-20 ),
3.43 (2H, H-13 ), 4.02 (2H, H-2 ), 4.21 (2H, CH-20 ),
6.12-6.08 (m, 2H, H-8 ), 8.14-8.08 (m, 1H, H-8 ), 8.48 (s,
1H, H-5), 9.02 (s, 1H, H-10), 9.35 (s, 1H, H-15); C NMR
3
6
4
5
17
7
5
6
5
3
residue as a film. Finally, this last obtained compound was
stirred with an excess of 3-dimethylamino-1-propylamine
4
1
1
3
1
2
9
7
8
(
2 mL) for 2 h, under a dry nitrogen atmosphere and at
1
1
1
room temperature. The amine excess was distilled off
under reduced pressure, and the solid was dissolved in
DCM and washed with an aqueous solution of ammonium
2
1
13
-1
hydroxide (0.5 mol L ). The organic phase was separated
(125.77 MHz, DMSO-d ) d (ppm): 13.9, 14.0, 14.2 and
6