The method of purification of all e - or 13z-retinoic acid

 

(57) Abstract:

The inventive product - all - E - retinoic acid. BF C20H26O2. The basic substance content of 97.8%. Stability in air at 20C for 7 days. Reagent 1: all = E - or 13Z-retinoic acid. Reagent: aqueous solution of alkali. Reaction conditions: boiling in the presence of alcohol C1-C3normal or ISO-structure at pH 12 - 14 with the subsequent removal of activated carbon by acidification and extraction of methylene chloride and evaporation, dissolution of the residue in hexane or methylene chloride at 18 - 25C and low temperature kristallizatsiei at 25 and 15C. table 2.

The invention relates to organic chemistry, namely the method of purification of isomeric all-E - 13Z-retinoic acid and can be used in the production of pharmaceuticals.

All-E - 13Z-retinoic acid is very effective in the treatment of severe skin diseases, not amenable to treatment with modern dermatological preparations [1] , and can be used in Oncology and rheumatology for the treatment of leukemia and arthritis [2].

Isomeric all-E - 13Z-retinoic acid is rapidly oxidized under the action of atmospheric oxygen. Most lability Atherstone forms. Studies have shown that traces of contaminants that pollute all-E - 13Z-retinoic acid, are able to greatly accelerate the process of oxidation of these compounds in the air.

Known methods for cleaning retinoic acid - recrystallization from ethanol or isopropanol [3], low-temperature crystallization from chloroform [4] , however, these methods do not produce stable to the action of oxygen drugs (examples 12, 20, 25 - comparative).

The closest in technical essence to the present invention is a cleaning method [5] , which 13Z-retinoic acid is first boiled with activated carbon in ethyl acetate, after filtration of coal excess ethyl acetate is removed in vacuum at 75-80aboutWith the solution 13Z-retinoic acid in ethyl acetate stored in the refrigerator at a temperature of -10 to -15aboutC. the Precipitated crystals are filtered and dried in vacuum.

The disadvantage of this method is that although 13Z-retinoic acid is obtained in high purity, it is not stable during storage in the presence of oxygen (example 13).

The proposed method can achieve much more resistant to the action of oxygen drugs all-E - 13Z-pet is tigerbunny coal in aqueous-alcoholic medium, using alcohols WITH1-C3normal or ISO-structure, in the presence of sodium hydroxide at pH 12 to 14 and the boiling temperature of the solvent, followed by separation of the activated carbon by acidification of the resulting solution, extraction with methylene chloride removal of solvent, the products obtained by dissolving in hexane or methylene chloride at 18-25aboutWith and carrying out the crystallization at a temperature of 18-25aboutWith and carrying out the crystallization at a temperature of -25--15aboutC.

A significant feature of the proposed method is a combination of processing coal in aqueous alcoholic alkaline medium at pH 12-14 with low-temperature crystallization from methylene chloride or hexane at a temperature of from -25 to -15aboutAfter dissolution of the treated coal product at 18-25aboutC. Only boiling with charcoal in aqueous alcoholic alkaline environment, and not in ethyl acetate, as in the prototype (example 13 comparative), or only low-temperature crystallization (examples 6.19 - comparative) only slightly increases the stability of isomeric retinoic acid and does not result in stable compounds.

Boiling with activated charcoal should be carried out in water and the ethyl acetate not result in retinoic acid, stable when stored (example 13 comparative).

As a solvent in the processing of coal used lower alcohols containing from 1 to 3 carbon atoms, normal or ISO-structure, such as methanol, ethanol, propanol or isopropanol.

Treatment of activated carbon in aqueous alcoholic alkaline environment should be conducted at pH 12-14. At pH below 12 potassium salt of retinoic acid unstable, which leads to the production of retinoic acid less resistant to oxygen (examples 10, 23 - comparative).

Processing in aqueous alcoholic alkaline environment with a pH value above 14, on the one hand does not increase the sustainability of retinoic acid (examples 11, 24 - comparative), and, on the other hand, requires a greater consumption of alkali and therefore uneconomical.

During crystallization retinoic acids from hexane or methylene chloride, the temperature of the dissolution shall not exceed 25aboutWith, otherwise decreases the stability of retinoic acid (examples 8, 21 - comparative).

The temperature of dissolution below the 18aboutInappropriate because it greatly decreases the solubility of retinoic acid increases the consumption of solvent and decreasing curves).

Cleaning isomer of retinoic acid by this method leads not only to increase the stability of the target compounds (table. 1), but also to increase the shelf life of ready medicinal forms, such as suppositories with 13Z-retinoic acid (PL. 2).

From the data table. 1 one can see that the stability of labile 13Z-retinoic acid increases more than 10 times, the stability of all-E-retinoic acid increased more than 20 times.

Table. 2 shows that the suppositories with 13Z-retinoic acid, obtained by the claimed method, 5 times more resistant than suppositories with 13Z-retinoic acid, purified by the method of crystallization from ethyl acetate.

The proposed method retinoic acid obtained as follows: retinoic acid is boiled with activated carbon in aqueous alcoholic alkaline medium at pH 12-14 for 30 minutes After cooling the reaction mixture and removal of activated charcoal, the solution acidified with 5% sulfuric acid solution. Retinoic acid is extracted with methylene chloride, the extract is dried with sodium sulfate, the solvent is removed in vacuum, the residue is dissolved in hexane or methylene chloride at 18-25aboutWith and leave when temperature is me at a residual pressure of 1 mm RT. tbsp. at a temperature of 20aboutC.

The invention is illustrated by the following examples.

P R I m e R 1. 6 g 13Z-retinoic acid dissolved in a mixture of 170 ml of isopropanol and 170 ml of 0.5 n solution of sodium hydroxide to bring the pH of the resulting solution to 12-14 of 0.5 N. a solution of caustic potash. To the resulting solution was added 6 g of activated charcoal and boiled for 0.5 hours After removal of the activated charcoal, the solution acidified with 5% sulfuric acid solution to pH 2-3. 13Z-retinoic acid is extracted with methylene chloride, the extract washed with water, dried with sodium sulfate, the solvent is removed in vacuum. The residue is dissolved in 18 ml of methylene chloride at 20aboutWith and leave for 12 h at -20aboutC. the Precipitated crystals filtered off, washed with hexane, dried in vacuum at 20aboutC. Gain of 4.2 g 13Z-retinoic acid, the yield was 69.7%, the content of 97.8%, stability (the time during which the storage of the drug in air at a temperature of 20aboutWith the remains of at least 95% of the original substance) - 7 days.

P R I m e R s 2-13 carried out analogously to example 1. Conditions of experiments and data on the stability of the drugs 13Z-retinoic acid are presented in table. 1.

P R I m eara 12-14). The resulting solution was then treated with activated carbon as in example 1. All-E-retinoic acid is extracted with methylene chloride, after washing with water, the extract is dried with sodium sulfate, the methylene chloride removed in vacuo. The residue is dissolved in 480 ml of methylene chloride at 20aboutC and leave at -20aboutC. Obtain 4.5 g of all-E-retinoic acid; yield 70.3% of the content of 97.5%; resistance (the time during which the storage of the drug in air at a temperature of 20aboutWith the remains of at least 95% of the original substance) 12 months.

P R I m e R s 15-25 carried out analogously to example 14. Conditions of experiments and data on the stability of the preparations all-E - retinoic acid are presented in table. 1.

Thus, cleaning isomer of retinoic acid on the proposed method increases the stability of the target compounds 10-20 times that not only eliminates difficulties in working with substance, but also economically profitable, because of the loss of substances, due to their instability, can be very significant.

The economic effect is obtained also by increasing the shelf life of medicines with retinoic acid, ocimene the new coal in a solvent, followed by the separation of coal and low-temperature crystallization, characterized in that the solvent boiling using an aqueous solution of caustic potash, and the process is carried out at pH 12 - 14 in the presence of alcohol C1- C3normal or isotrate and after separation of the coal resulting solution was acidified with acid and extracted with methylene chloride, which is then evaporated, then the residue is dissolved in hexane or methylene chloride at 18 - 25oWith and carry out low-temperature crystallization at -25 15oC.

 

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