RU2304582C1 - Method for preparing octa-4,5-carboxyphthalocyanine cobalt sodium salt - Google Patents

Abstract

FIELD: chemistry of metalloorganic compounds, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of octa-4,5-carboxyphthalocyanine cobalt sodium salt, or 2,3,9,10,16,17,23,24-octacarboxylic acid of phthalocyanine cobalt (terephthal) of the formula (I)

. Terephthal is a synthetic preparation used in catalytic ("dark") therapy of cancer based on generation of oxygen reactive species in tumor directly by chemical manner and in combination with ascorbic acid being without using the physical effect. Method for preparing octa-4,5-carboxyphthalocyanine cobalt sodium salt involves melting pyromellitic acid dianhydride with cobalt salt in the presence of urea followed by alkaline hydrolysis of prepared octa-4,5-carboxyphthalcyanine cobalt tetraimide. Salt formed after hydrolysis is purified from impurities, in particularly, from oligomeric compounds by column chromatography method on aluminum oxide, following precipitation of octacarboxylic acid, its, its washing out, concentrating and purifying from residual inorganic salts by washing out with distilled water and by neutralization with sodium hydroxide aqueous solution also, treatment with apyrogenic activated carbon, filtration and drying the end substance. Purification of octa-4,5-carboxyphthalocyanine cobalt from residual inorganic salt is carried out preferably by electrodialysis method after its partial neutralization to pH 5.2-5.5 at current density 0.15-0.25 A/dm², temperature 20-35°C and the concentration 1.5-3.0% followed by complete neutralization to pH 8.7, treatment of obtained octacarboxy-PcCo salt solution with activated carbon, filtration and drying filtrate in a spray drier. Proposed method provides preparing octa-4,5-carbocyphthalocyanine cobalt salt of high purity degree and free of oligomeric compounds and residual chlorides.

EFFECT: improved method of synthesis.

5 ex

Description

The invention relates to the field of chemical technology, and in particular to a method for producing sodium salt of octa-4,5-carboxyphthalocyanine cobalt (terafthal), which is a synthetic preparation for catalytic ("dark") cancer therapy (A.B.Syrkin, O.S. Zhukova, B.S. Kikot, L.G. Gatinskaya, et al. Ross. Chem. Journal. 1998 (5), pp. 140-146). This method is based on the generation in combination with ascorbic acid of active oxygen species directly in the tumor without the use of physical exposure.

Cobalt octa-4,5-carboxyphthalocyanine itself (2,3,9,10,16,7,23,24-octacarboxylic acid cobalt phthalocyanine, or octacarboxy-PcCo) can be obtained by reacting cobalt octacyanophthalocyanine with potassium hydroxide in aqueous ethylene glycol in a temperature of 160 ° C for 24 hours, the selection of the target product in an acidic environment and its subsequent purification [Y. Orihashi, M. Nishikawa, H. Ono, E. Tsuchida. Bull. Chem. Soc. Jpn. 1987, Vol.60, No. 10, pp. 3731-3738]. However, this method is complicated by the difficulty of synthesizing pyromellitonitrile - the starting compound for the preparation of cobalt octacyanophthalocyanine.

There is also known a method for producing octacarboxy-PcCo from pyromellitic dianhydride by fusing it with a cobalt salt in the presence of urea, alkaline hydrolysis of the resulting tetraimide to form the octacarboxy-PcCo salt and its subsequent acidification (DRBoston, JCBailar, Jr. 1972 Inorg Chem. .11, pp. 1578-1584). Its disadvantage is the low purity of the target products - both salt and acid itself, due, in particular, to the presence of organic impurities in them,

impurities, including oligomeric nature, resulting from further interaction of octa-4,5-carboxyphthalocyanine tetraimide with pyromellitic acid dianhydride, as well as inorganic salts.

The present invention is to obtain a salt of octacarboxy-PcCo of high purity, not containing impurities of an oligomeric nature and inorganic salts. To solve this problem, use the method for its preparation, consisting of the following technological stages:

- obtaining tetraimide octacarboxy-PcCo by fusion of pyromellitic acid dianhydride with cobalt salt in the presence of urea;

- production of octacarboxy-PcCo salt by alkaline hydrolysis of tetraimide;

- purification of octacarboxy-PcCo salt from organic impurities, including oligomeric products, by column chromatography on alumina;

- precipitation of octacarboxy-PcCo, its purification from inorganic salts;

- neutralization of octacarboxy-PcCo with an aqueous solution of caustic soda, treatment of the sodium salt solution (terataphthalum) with pyrogen-free activated carbon, its filtration and drying in a spray dryer.

The problem of the invention can be solved by purification of residual inorganic salts by washing with distilled water and by electrodialysis of octacarboxy-PcCo solutions. To carry out the latter, octacarboxy-PcCo obtained after concentration is partially neutralized with an aqueous solution of caustic soda to pH 5.2-5.5, and the octacarboxy-PcCo tetrasodium salt resulting from this is subjected to electrodialysis purification of residual inorganic salts. At a higher pH value, the solubility of octacarboxy-PcCo increases due to the neutralization of the remaining free carboxyl groups, however, the multiply charged octacarboxy-PcCo anions formed in this case poison the anion-exchange membranes, reducing the efficiency of the cleaning process.

The electrodialysis process is carried out at a current density of 0.15-0.25 A / dm ² , a temperature of 20-35 ° C and an octacarboxy-PcCo salt concentration of 1.5-3.0%. Increasing the current density above 0.25 A / dm ² reduces the current efficiency due to the participation of salt anions in the transfer of electricity, which leads to blocking the working surface of anion-exchange membranes and the deterioration of their work. Thus, with an increase in current density from 0.15 to 0.4 A / dm ² , the current efficiency decreases from 19.5 to 4.5%, and the energy consumption of the process increases from 3.5 to 9.5 kWh / kg. The temperature at which the electrodialysis process is carried out in accordance with the invention is limited from above by the thermal stability of the anion-exchange membranes, and at a temperature below 20 ° C the mobility of the suspension decreases, and the voltage on the electrodialyzer increases, which leads to an increase in the energy intensity of the process.

The optimal concentration of solutions for electrodialysis purification of octacarboxy-PcCo salt is 1.5-3.0%. With it, the best energy intensity of the process is achieved - 3.5-4.7 kWh / kg and the specific productivity of the apparatus - 250-320 g / m ² · h in comparison with more dilute solutions (0.7%): 7.5 kWh / kg and 160 g / m ² · h respectively. At a concentration above 3.0%, the mobility of the suspension decreases, which reduces the productivity of the process. So, at a current density of 0.25 A / dm ² and an octacarboxy-PcCo salt concentration of 4.0%, the energy consumption of the cleaning process is 8.8 kWh / kg, and the unit's specific productivity is 126 g / m ² · h.

After electrodialysis, the purified octacarboxy-PcCo salt solution is neutralized with sodium hydroxide to a pH of 8.5-8.6, treated with pyrogen-free activated carbon, sterilized by ultrafiltration, and terafthal is isolated by drying in a spray dryer. The terataphthal yield at the electrodialysis purification stage is 94.0-95.0%, the chloride content in the isolated product is no more than 0.1%, and the purification time is 3.5-7.0 hours.

The proposed method is illustrated by the following examples.

Example 1

Tetraimide octacarboxy-PcCo.

A mixture of 2.39 M pyromellitic anhydride, 23.6 M urea, 0.41 M cobalt chloride and 16.0 g of ammonium molybdate are heated with stirring for 1.5 hours at 140-150 ° C and 3 hours at 200-205 ° C. The melt is cooled, crushed and boiled with 30 l of water for about 3 hours, then boiled with 10% hydrochloric acid, the suspension is filtered, the precipitate is washed with water to a pH of wash water of at least 6.5, then with alcohol, squeezed and dried. 1.3 kg of tetraimide are obtained (molar extinction coefficient in DMSO of at least 50,000).

Potassium salt of octacarboxy-PcCo.

The resulting tetraimide (1.3 kg) is boiled with a 25% alcohol solution of potassium hydroxide (30 L), the hot suspension is filtered, the precipitate is washed on the filter with alcohol to a colorless filtrate, squeezed and dried.

The resulting salt is purified from impurities, in particular from oligomeric products, by column chromatography. For this, a salt solution (concentration of 8-10%) in deionized water is acidified with 10% hydrochloric acid to pH 8.0-8.3, loaded onto columns (diameter 80 mm, height 75 cm) with 4 kg of aluminum oxide (TU 6-09- 426-75) and elute with phosphate buffer, pH 8). A fraction with R _f 0.9 (one spot on the silofol plate) is taken, which is filtered through FSB glass paper. To increase the yield of the target product, a second fraction containing an admixture of oligomers is also taken, from which an additional amount of the target product is recovered by chromatography.

Sodium salt of octacarboxy-PcCo.

A suspension of tetraimide melt (300 g) in 6 L of a 10% aqueous solution of sodium hydroxide is boiled with stirring, the hot suspension is filtered, the precipitate is washed on the filter with a hot 10% aqueous solution of sodium hydroxide, the paste is squeezed, then washed with alcohol and dried. The resulting sodium salt is purified by column chromatography similarly to potassium salt.

Oktakarboxi-RsSo.

A solution of the purified salt (potassium or sodium) is acidified with conc. hydrochloric acid to a pH of about 2, the resulting acid precipitate is repeatedly decanted with deionized water after 20-30 minutes of stirring and complete suspension of the suspension (about 12 hours). The washing is repeated until the electrical conductivity is 75-80 × 10 ^-2 S / m. After the last decantation, the suspension is concentrated in a centrifuge, then the resulting paste is placed on a suction filter and washed with distilled water with repulpation to obtain a 3-5% aqueous suspension.

Sodium salt of octacarboxy-PcCo (Terafthal).

Obtained by neutralizing a suspension of purified octacarboxy-PcCo with a 10% aqueous solution of sodium hydroxide to a pH of 8.5-8.6. For complete neutralization, the mixture is stirred at 20-25 ° C, the pH of the solution is checked and, if necessary, titrated, the solution is treated with pyrogen-free activated carbon, filtered through FSB glass paper, then through a Vladipor filter (0.2 μm), dried on a Mobile minor type spray dryer 2000 "at an inlet temperature of 170 ± 10 ° C and an output temperature of 90 ± 5 ° C. Draining is carried out in an oven at 105-110 ° C. The yield of Terafthal obtained is 19-20% based on pyromellitic acid dianhydride. Electronic absorption spectrum (in water, pH 7.3-8.3), λ _max , nm: 674 ± 2, 332 ± 2. The content of the main substance is 97.0%, the coefficient of specific absorption is 1200 cm ^-1 g ^-1 , the chloride content is 0.08%. Found,%: C 42.60, 42.54; H 1.04, 1.03; N 9.97, 9.79. Calculated,%: C ₄₀ H ₈ CoN ₈ Na ₈ O ₁₆ . C 43.70; H 0.73; N 10.19.

Example 2

In a glass container equipped with a stirrer, 900 g of crude octacarboxy-PcCo paste obtained after centrifugation (Example 1) are loaded, 3000 ml of distilled water are added, and a 10% aqueous solution of sodium hydroxide is added with stirring to pH 5.5. At this pH value, a mobile, close to solution, suspension of octacarboxy-PcCo tetrasodium salt is formed, containing 2.15% phthalocyanine and 1.0-1.5% sodium chloride, which is subjected to electrodialysis purification in a multi-chamber filter-type electrodialyzer, consisting of MA-type ion-exchange membranes 40 and MK-40 with intermediate frames made of paronite and turbulent separators. The cathode and anode are plates made of stainless steel grade X18H10T with a working surface of 4 dm ² . The electrodialyzer consists of three anion-exchange and five cation-exchange membranes with a working surface of 4 dm ² , forming three “cleaning” chambers and four “concentration” chambers, as well as two electrode chambers.

A suspension of the octacarboxy-PcCo salt with inorganic impurities is pumped through the desalination chambers, tap water is pumped through the concentration path, and a 5% sodium hydroxide solution is closed through the electrode chambers.

At a temperature of 20 ° C, a direct current with a density of 0.25 A / dm ^{2 is} passed through an electrodialyzer until a chloride concentration of 0.0015% is reached in the solution. The cleaning time is 4.0 hours, while the current efficiency corresponds to 14.0%, the degree of desalination is 95%.

The purified octacarboxy-PcCo tetrasodium salt solution (4000 ml) is neutralized with 120 ml of a 9.6% sodium hydroxide solution to pH 8.5-8.6. The resulting solution of the octacarboxy-PcCo salt is treated with activated carbon, filtered, and the filtrate is dried in a spray dryer. Obtain 77.0 g of the target product, yield 83.70% based on the loaded octacarboxy-PcCo. The content of the main substance is 97.8%, the coefficient of specific absorption is 1212 cm ^-1 g ^-1 , the chloride content is 0.08%.

Example 3

Analogously to example 2, the octacarboxy-PcCo paste (example 1) is subjected to electrodialysis treatment at a current density of 0.15 A / dm ² and a temperature of 35 ° C to a chloride content of 0.0014%. Moreover, the current efficiency is 18.5%, and the degree of desalination is 95.3%, the duration of electrodialysis treatment is 6 hours.

After further processing, as in example 1, get 78.1 g of the target product. The yield on the substance is 84.9%. The content of the main substance is 98.0%, the coefficient of specific absorption is 1123 cm ^-1 · g ^-1 , the chloride content is 0.075%.

Example 4

Analogously to example 2, an octacarboxy-PcCo paste with its concentration of 3.1% and a concentration of sodium chloride of 0.045% is subjected to electrodialysis treatment at a current density of 0.25 A / dm ² and a temperature of 20 ° C to a chloride content of 0.003%. In this case, the current efficiency is 20.0%, and the degree of desalination is 93.3%, the duration of electrodialysis treatment is 3.5 hours.

After further processing, as in example 1, receive 106.8 g (83.5%) of the target product. The content of the main substance is 97.7%, the coefficient of specific absorption is 1092 cm ^-1 g ^-1 , the chloride content is 0.085%.

Example 5

Analogously to example 2, an octacarboxy-PcCo paste with a concentration of 1.52% and a concentration of sodium chloride of 0.019% is subjected to electrodialysis treatment at a current density of 0.15 A / dm ² and a temperature of 20 ° C to a chloride content of 0.0004%. Moreover, the current efficiency is 9.7%, the degree of desalination is 98.0%, the duration of electrodialysis treatment is 7 hours.

After further processing, as in example 1, receive 52.1 g (82.0%) of the target product. The content of the main substance is 97.5%, the coefficient of specific absorption is 1093 cm ^-1 · g ^-1 , the chloride content is 0.095%.

Thus, the proposed method for producing octa-4,5-carboxyphthalocyanine cobalt has an advantage over the closest analogue method in that it provides purification of the target product from organic impurities, including oligomeric nature, and from residual inorganic salts, which allows receive on its basis the substance of the drug Terafthal for catalytic therapy.

Claims (1)

 The method of obtaining sodium salt of octa-4,5-carboxyphthalocyanine cobalt

fusion of pyromellitic acid dianhydride with a cobalt salt in the presence of urea followed by alkaline hydrolysis of the obtained tetraimide octa-4,5-carboxyphthalocyanine (Pc) cobalt, characterized in that the salt formed after hydrolysis is purified from impurities, in particular from oligomeric products, by column chromatography with aluminum oxide, followed by precipitation of octacarboxy-PcCo with concentrated hydrochloric acid, washing it, concentrating and purifying the residual inorganic salts by washing with distilled oh water or electrodialysis at pH 5.2-5.5, 0.15-0.25 current density A / dm ^2, a temperature of 20-35 ° C and 1.5-3.0% concentration followed by neutralization with aqueous sodium sodium, processing the solution with activated carbon, filtering and drying the target product in a spray dryer.