Method for preparing complexes of chlorophyll (a) derivatives with transient metals

FIELD: chemistry of coordination compounds, chemical technology, medicine.

SUBSTANCE: invention relates to an improved method for synthesis of metallic complexes of chlorophyll (A) derivatives with transient metal ions (Ni2+, Zn2+, Co2+, Cu2+). Method involves boiling the parent ligand with transient metal salt followed by isolation of the end product. Method involves using methylpyropheophorbid (a) or chlorin e6 13-N-methylamide-15,17-dimethylester or 13(2)-hydroxymethlpheiphorbid (a) as a ligand, and acetyl acetonate of the corresponding metal is used as transient metal salt, and boiling is carried out in equimolar amount of reagents for 2-3 h. By alternative variant the method involves boiling the parent ligand with transient metal salt followed by isolation of the end product wherein methylpyropheophorbid (a) or chlorin e6 13-N-methylamide-15,17-dimethyl ester, or 13(2)-hydroxymethylpheophorbid (a) is used as a ligand. Acetyl acetonate of the corresponding metal is used as transient metal salt in 10-fold excess. Acetyl acetonate is added to the reaction mixture by two equal portions followed by boiling for 1-2 min after each addition. Method provides high yield and without using large excess of metal salts. Invention can be used in synthesis of antitumor and antiviral preparations used in medicine.

EFFECT: improved method of synthesis, valuable medicinal properties of complexes.

3 cl, 1 dwg, 8 ex

 

The invention relates to the field of chemistry of coordination compounds, namely to a process for the preparation of metal complexes of chlorophyll derivatives (a) with ions of transition metals (Ni2+, Zn2+With2+, Cu2+) and can be used in the synthesis of anticancer and antiviral drugs for medicine.

A known method for the synthesis of copper and Nickel complexes of chlorophyll derivatives, which consists in the interaction of the original ligand with the acetate of the corresponding metal in a mixture of chloroform with methanol (Hitoshi Tamiaki, Masaaki Amakawa, Alfred R.Holzwarth and Kurt Schaffher. Aggregation of synthetic metallochlorins in hexane. A model of chlorosomal bacteriochlorophyll self-assemblies in green bacteria. Photosynthesis Research 71: 59-67, 2002).

The disadvantage of this method is the necessity of using multiple excess metal salt and a large number of toxic solvent is methanol.

Also known is a method of obtaining zinc and Nickel complexes derived chlorophyll (a), selected for the prototype, which consists in boiling the source of the ligand with the acetate of the corresponding metal in toluene (Antitumor Agents. Part 209: Pheophorbide-a Derivatives as Photo-Independent Cytotoxic Agents. Prapai Wongsinkongman, Arnold Brossi, Hui-Kang Wang, Kenneth F. Bastow and Kuo-Hsiung Lee. Bioorganic and Medicinal Chemistry 10 (2002) 583-591).

The disadvantage of this method of synthesis is the low yield of the obtained complexes (30%), which is unacceptable when you obtain complexes in the big Mac is the tabs.

The objective of the invention is to develop an efficient method for the synthesis of complexes of chlorophyll derivatives (a) with transition metals, which allows to obtain the target compounds in high yields without the use of large excess of metal salts. This is a technical result.

The invention presented options.

The technical result according to the first embodiment is achieved in that the method of synthesis of metal complexes of derivatives of chlorophyll (a), which consists in boiling the source of the ligand with a transition metal salt, followed by separation of the target product, according to the invention as a ligand using methylpropionic (a) or chlorin e613-N-methylamide-15,17-dimethyl ether or 13(2)-hydroxymethylfurfural (a), as a salt of the transition metal take acetylacetonate of a suitable metal, boiling is carried out in toluene in 2-3 hours when equimolar quantities of the reactants.

The technical result according to the second variant is achieved by a method of synthesis of metal complexes of derivatives of chlorophyll (a), which consists in boiling the source of the ligand with a transition metal salt, followed by separation of the target product, characterized in that the ligand used methylpropionic (a) or chlorin e613-N-methylamide-15,17-dimethyl ether or 13(2)-hydroxide Infoforum (a), as the salt of the transition metal take acetylacetonate of a suitable metal in a 10-fold molar excess, with acetylacetonate was added in two equal portions and each time after adding boiled for 1-2 minutes.

The methods are as follows.

The drawing shows the reaction of formation of metal complexes of natural chlorins.

To obtain Nickel, zinc, cobalt and copper complexes of natural chlorins in the first embodiment using equimolar amounts of the original substance (acetylacetonates of copper, Nickel, zinc or cobalt and a derivative of chlorophyll (a)), the interaction is carried out by boiling equimolar amounts of chlorine and acetylacetonate in toluene for 2-3 hours. The resulting complex is recovered from the reaction mixture column chromatography.

The implementation of the method acetylacetonate Nickel are given in examples 1, 3, 4. Similarly carry out the reaction with the acetylacetonates of copper, zinc and cobalt. The advantage of the first variant of the reaction is the reduction of a metal salt.

To obtain Nickel, zinc, cobalt and copper complexes of natural chlorins on the second version uses a relatively small (10-fold) molar excess of the metal acetylacetonate, which is added in two portions and the Les of each addition, the reaction mixture is boiled for 1-2 minutes. The resulting complex is recovered from the reaction mixture column chromatography.

The implementation of the method shown in the examples 1, 5, 6, 7, 8, 9.

The second advantage is less reaction time.

The implementation of both options allows to obtain complexes of natural chlorins with high yields and without the use of large excess of acetylacetonates of metals.

Examples.

Example 1. A mixture of 29 mg (0.05 mmol) of methylpropionamide (a), 3 ml of toluene and 15 mg (0.05 mmol) of Nickel acetylacetonate is refluxed for 3 hours. The formation of the product of the reaction is controlled by TLC on Silufol plates, CCL4: acetone - 4:1. The reaction mixture was applied on a column (silica gel L 100/400, filling the "wet" method, the solvent is carbon tetrachloride) and elute with a mixture of CCL4with acetone, gradually increasing the content of acetone in the range of volumetric ratios of from 70:1 to 1:1. The output of the complex 25 mg (78%). ESP (CHCl3; λ, nm): 652, 607, 543, 501, 422, 397.

Example 2. To a solution of 50 mg (0.08 mmol) of chlorin e613-N-methylamide-15,17-dimethyl ester in 20 ml of toluene was added 101 mg (0.40 mmol) of zinc acetylacetonate, the mixture is brought to a boil, boil for 1-2 minutes, then cooled. To the reaction mixture was added 101 mg (0.40 mmol) of zinc acetylacetonate and the mixture is again brought to a boil and boil for 2 minutes. The cooled reaction mixture is treated as described in Example 1. The output of the complex 46 mg (83%). ESP (CHCl3; λnm): 637, 592, 514, 412.

Example 3. The interaction of Nickel acetylacetonate with 13(2)-hydroxymethylfurfural (a) is conducted as described in Example 1. Action 9 mg (0.03 mmol) of Nickel acetylacetonate 19 mg (0.03 mmol) of the original ligand obtain 14 mg (65%) of the complex. ESP (CHCl3; λ, nm): 652, 610, 542, 495, 422, 394.

Example 4. The interaction of Nickel acetylacetonate with chlorin e613-N-methylamino-15,17-dimethyl ether were carried out as described in Example 1. Action 13 mg (0.05 mmol) of Nickel acetylacetonate 29 mg (0.05 mmol) of the original ligand obtain 22 mg (70%) of the complex. ESP (CHCl3; λnm): 634, 497, 409.

Example 5. The interaction of zinc acetylacetonate with methylpropionamide (a) and the processing of the reaction mixture were carried out as described in Example 2. Action 94 mg (0.36 mmol) of zinc acetylacetonate (portions 47 mg) 17 mg (0.03 mmol) of the original ligand receive 9 mg (48%) of the complex. ESP (CHCl3; λ, nm): 658, 611, 571, 524, 486, 428, 325.

Example 6. The interaction of copper acetylacetonate with methylpropionamide (a) and the processing of the reaction mixture were carried out as described in Example 2. Action 92 mg (0.35 mmol) of copper acetylacetonate (portions 46 mg) 16 mg (0.03 mmol) of the original ligand obtain 13 mg (71%) of the complex. ESP (CHCl3; λ, nm): 654, 607, 551, 50, 426, 407.

Example 7. The interaction of copper acetylacetonate with chlorin e613-N-methylamino-15,17-dimethyl ether and the treatment of the reaction mixture were carried out as described in Example 2. The action of 202 mg (0.80 mmol) of (portions at 101 mg) of copper acetylacetonate in 50 mg (0.08 mmol) of the original ligand obtain 54 mg (98%) of the complex.

ESP (CHCl3; λnm): 635, 501, 410.

Example 8. The interaction of cobalt acetylacetonate with methylpropionamide (a) and the processing of the reaction mixture were carried out as described in Example 2. Action 114 mg (0.45 mmol) of (portions 57 mg) acetylacetonate cobalt 25 mg (0.05 mmol) of the original ligand obtain 17 mg (62%) of the complex. ESP (CHCl3; λnm): 655, 421.

Thus, the proposed method of obtaining allows the synthesis of complexes of natural chlorins with transition metals with high yield and without the use of large excess of metal salt.

1. The method of synthesis of metal complexes of derivatives of chlorophyll (a), which consists in boiling the source of the ligand with a transition metal salt, followed by separation of the target product, characterized in that the ligand used methylpropionic (a) or chlorin e613-N-methylamide-15,17-dimethyl ether or 13(2)-hydroxymethylfurfural (a), as a salt of the transition metal take acetylacetonate of a suitable metal, boiling conducting the in toluene for 2-3 h with equimolar quantities of the reactants.

2. The method of synthesis of metal complexes of derivatives of chlorophyll (a), which consists in boiling the source of the ligand with a transition metal salt, followed by separation of the target product, characterized in that the ligand used methylpropionic (a) or chlorin e613-N-methylamide-15,17-dimethyl ether or 13(2)-hydroxymethylfurfural (a), as a salt of the transition metal take acetylacetonate of a suitable metal with a 10-fold molar excess, with acetylacetonate was added in two equal portions and each time after adding boiled for 1-2 minutes



 

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