The method of obtaining complex compounds of aluminum with tetracapsuloides

 

(57) Abstract:

The invention relates to a method for producing complex compounds with phthalocyanine, in particular complex aluminium tetrabromophthalimide, and can be used in the production of compounds used in medicine for diagnosis and photodynamic therapy of cancer.

With the aim of obtaining complex soluble in water and organic solvents, as well as to improve product yield and reduce process time method for obtaining complex aluminium phthalocyanine by the interaction of an aluminum salt with dicyano-benzo-15-crown-5, and the process is preferably carried out in an environment of urea in the presence of ammonium molybdate.

The method allows a 2 - 2.5 times, to shorten the process time by 10 to 20% to increase the product yield, as well as receive a set of aluminium tetrabromophthalimide, soluble in water and some organic solvents.

The resulting complex has an intense absorption in the region of 600 to 900 nm. 1 Il., table 1.

The invention relates to a method for producing complex compounds of aluminum phthalocyanine, in particular complex aluminium tetrabromophthalimide, iscoe cancer therapy.

Currently, phthalocyanines and their derivatives are considered as promising drugs for the diagnosis and photodynamic therapy of cancer due to the presence of intense absorption in the red and near infrared regions [1]

Most suitable for these purposes are diamagnetic complexes AlIII, GaIIIand ZnIIwith phthalocyanines with significant time and high energy triplet state, ensuring the generation of singlet oxygen with high quantum yield [2]

The main requirements of such compounds are selective accumulation in the tumor, intense absorption in the region of 600 to 900 nm, and solubility in water. In practice, when selecting real fotohimioterapiei agents are able to perform only part of the requirements. Therefore, it is highly important to search for new effective photosensitizers and methods for their preparation.

A method of obtaining complex of aluminum with the unsubstituted phthalocyanine and its derivatives interact phthalimide (phthalic acid and others), urea and the corresponding metal salt at a temperature of approximately 200oC for 6 to 11 hours in the presence of alcalali, not soluble in water [3]

The closest solution of the problem to the technical essence and the achieved result is a method of producing a complex of aluminum phthalocyanine by the interaction of phthalonitrile and aluminium chloride in a molar ratio Al: phthalonitrile 1:3.5 in the solution of quinoline at 175oC for 5.5 hours. The yield was 35% [4]

The disadvantages of this method are the low yield of products, the duration of the process and, most importantly, the insolubility of the resulting complex aluminium phthalocyanine in water and low solubility in organic solvents, which limits its use in medicine.

The aim of the invention is to obtain a complex of aluminum phthalocyanine, soluble in water and in many organic solvents, increasing the yield of the final product, as well as the reduction of the process time.

According to the invention this goal is achieved by the fact that the complex aluminium phthalocyanine is produced by the interaction of an aluminum salt with dicyano-benzo-15-crown-5 (DCBC). When this process is carried out in an environment of urea in the presence of ammonium molybdate.

A distinctive feature of this method is the use of as, and preferably, in the environment of urea in the presence of molybdenum ammonium.

The complex of aluminum (Fig.) produced by interaction of sulphate or aluminium chloride with DCBC in a molar ratio of Al DCBC 1:(2 5). The synthesis is carried out in an environment of urea in the presence of catalytic amounts of molybdenum aluminum. The reaction mixture is carefully stirred and heated at 160 - 180oC for 1.5 to 2.0 hours. The reaction product is a dark green color is treated with chloroform and pyridine and purified chromatographically on a column of Al2O3(eluent ethanol chloroform 1 10 and 1 1). The product yield up to 55%

The elemental composition of the compounds on the content of C, H, N and S determined by standard methods. The Al content determined by the method of flame atomic absorption analysis. Data analysis to answer the formula AlCRPcXH2O (where CR 15-crown-5; Pc C32H16N8; X SO4H-for complex I and X Cl-for complex II).

The decomposition temperature of the complex I 290oC _, and complex II - 295oC. the Complex decomposes without melting.

The purity and composition of the compounds is controlled by electronic and infrared spectroscopy, which allows to judge about the structure of the obtained compounds.

In the electronically the results indicate the following absorption bandsmax(lg) 689 (5,14): 652(4,61): 621(4,34): 432(4,30): 361(4,91): PL. (4,77), and in the spectrum of complex II 689(5,10); PL. 622(4,22) 333(4,89).

In the infrared absorption spectra of the complexes I and II (table). observed absorption bands, assigned to the stretching vibrations of benzene ringBCabout 1600 cm-1and 1500 cm-1and etilenglikolevykh parts of crown-ethers (SOS) in the area of 1280 1090 cm-1. Broad absorption band around 3330 3400 cm-1and a weak band at 1640 cm-1indicate the presence of H2O and belong to n (OH) and d (H2O), respectively.

Example 1.

A mixture of 42.8 mg (0.125 mmol) of Al2(SO4)3, 318,0 mg (1.0 mmol) DCBC, 240,2 mg (4.0 mmol) of urea and 6.0 mg of molybdenum ammonium rubbed and heated at 160oC for 2 hours. The ratio of Al DCBC 1 4. The reaction product is a dark green color after cooling, is treated with chloroform and pyridine. The resulting solution is filtered and purified chromatographically on a column of alumina (eluent C2H5OH CHCl31 10 and 1:1). Received for 194.3 mg (was 0.138 mmol) AlCRPcSO4HH2O.

Yield 55%

The solubility of the resulting complex in water is 10-4mol/L. in Addition, the complex is soluble in pyridine, chloroform,g (0,250 mmol) Al2(SO4)3, 318,0 mg (1.0 mmol) DCBC, 240,2 mg (4.0 mmol) of urea and 6.0 mg of ammonium molybdate rubbed and heated at 170oC for 1.5 hours. The ratio of Al DZBC= 1 2. The reaction product is purified analogously to example 1. Received 176,6 mg (0.125 mmol) AlCRPcSO4H2O. Output 50%

Example 3. A mixture of 44,4 mg (0.33 mmol) AlCl3, 318,0 mg (1 mmol) DCBC, 240,2 mg (4 mmol) of urea and 6 mg of ammonium molybdate are heated at 180oC for 1.5 hours. The ratio of Al:DCBK 1:3. The reaction product highlight analogously to example 1. Received 142,2 mg AlCRPcClH2O. Exit 42%

The solubility of the resulting complex in water is 10-4mol/L.

The complex is soluble in pyridine, chloroform, alcohols, dimethylsulfoxide, dimethylformamide, etc.

Example 4.

For the synthesis of complex take 26.9 mg (0.20 mmol) AlCl3, 318,0 mg (1 mmol) DCBC, 240,2 mg (4.0 mmol) of urea and 6.0 mg of ammonium molybdate. The ratio of Al DCBC 1:5. The reaction time is 2 hours. The example is carried out analogously to example 1. Received mg 148, 8 persons (0,111 mol) AlCRPcClH2O. Exit 45%

As seen from the above examples, the proposed method allows to obtain a compound of aluminum with tetrabromophthalimide, soluble in water (RASTAM, alcohols, dimethylsulfoxide, dimethylformamide. The resulting complex, as well as other compounds of the phthalocyanine has an intense absorption in the region of 600 to 900 nm (lgmax~5) that, because of its good solubility in water, makes a promising its use in medicine.

The method allows significantly (by 10 to 20%) compared with the prototype to improve the yield of the obtained product, as well as to reduce the synthesis time is 2 to 2.5 times, that is, to improve the performance of the process.

The proposed method is simple to perform and does not require complex hardware design.

Literature

1. Rosenthal I. // Photochemi Photobiol 1991. V. 53, n 6, p. 859 870.

2. Mironov A. F. the Results of science and technology. Ser.Sovr. problems of laser physics. 1990. So 3, S. 5 -62.

3.U.S. patent N2647127, CL 260-314.5, 1953.

4. Owen J. E, Kenney M. E. Inorg. Chem. 1992, V. 1, N2, R. 331 333.

The method of obtaining complex compounds of aluminum with tetrabromophthalimide, characterized in that dicyano-benzo-15-crown-5 is subjected to interaction with the salt of aluminum in the environment of urea in the presence of ammonium molybdate.

 

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