Method for preparing 5-aminolevulinic (5-amino-4-oxopentanoic) acid hydrochloride
FIELD: organic chemistry, chemical technology, medicine.
SUBSTANCE: invention relates to a method for preparing the synthetic 5-aminolevulinic (5-amino-4-oxopentanoic) acid hydrochloride (5-ALA) representing an endogenous substance (metabolite). Method for preparing 5-ALA involves electrochemical reduction of 5-nitrolevulinic acid methyl ester in acid aqueous medium on graphite cathode at temperature 60-75°C and the current density value 2-10 A/dm2. 5-ALA can be used in medicine for photodiagnosis and photodynamic therapy of malignant tumors of different localization and for treatment of diseases of non-tumor nature also. Invention provides simplifying technology of synthesis of 5-ALA, improved economy indices and provides ecological safety of the process.
EFFECT: improved preparing method.
The present invention relates to a method of obtaining synthetic hydrochloride of 5-aminolevulinic (5-amino-4-oxopentanoate) acid, HCl.NH2CH2COCH2COOH (5-ALA)is an endogenous substance is a biological precursor of porphyrins in living organisms and plants. 5-ALA is able to accumulate in tumor cells, turning them into protoporphyrin IX - photosensitizer that generates singlet oxygen upon irradiation with visible light, allowing its use in medicine for photodiagnosis and photodynamic therapy (PDT) of malignant tumors of different localization, as well as for the treatment of skin diseases non-neoplastic nature [Q.Peng, Kogd, J.Moan et al. Photochem. Photobiol. 1997, 65, 235-251]. Also of interest is the use of 5-ALA as immunostimulant (RF Patent 2160587, a 61 K 31/195, 2000).
In addition, 5-ALA is used as a growth promoter, plant and herbicides and other (European patent EP 514776, A 01 N 37/44, 1992). A wide range of use of 5-ALA is of great interest to its production in many countries of the world.
The number of known methods for obtaining 5-ALA. So, the most frequently used source for intermediate it is aired 5-problevpontai acid, in which the replacement of the bromine on the amino group is carried out either by the action of phthalimide with subsequent hydrolysis phthalimidopropyl or h is cut stage obtain the corresponding azide [..Morton, ..Leanna. Tetrahedron Lett. 1993, 34(28), 4481-4484]. In recent years there have been publications on the synthesis of 5-ALA derivative of pyridine, piperidine, furan, tetrahydrofuran (European patent 718405, 12 P 13/00, 1996). However, all these methods either ethnologica and time-consuming, or require the use of hard-to-reach source of substances, and thus outputs 5-ALA in them low, which complicates the development of these methods of obtaining 5-ALA in the industry.
A method of obtaining 5-ALA by hydrogenation diluted (0.18-1.5%) solution of 5-nitro-4-oxopentanoic acid or its salts in the environment 2M hydrochloric acid on the catalyst 10% Pd/C at a temperature of(-20)-(+110)°and a hydrogen pressure of 1-3 at (JP 09316041, C 07 C 229/22, 19.12.97). This method is also technologically complex and its use in industrial production difficult.
Closest to the present invention is a method for 5-ALA by hydrogenation of the methyl ester 5-nitrolingual acid, NO2CH2COCH2CH2COOH (me-5-NLC), on the catalyst 5% Pd/C in acidic methanolic medium at a temperature of 5-30°and pressure of 10-20 at (Patent RF 2146667, C 07 C 229/22, 2000). The disadvantages of this process are complex and expensive instrumentation process, the use of expensive catalyst, the need for additional stages of the hydrolysis of the methyl ester of 5-ALA and stage filtration races the thief from the catalyst, technological complexity and environmental risk of the process due to the use of explosive hydrogen, high pressure and poisonous methyl alcohol.
The task of the invention is to simplify the technology and the exclusion of the environmental hazards of the process of obtaining 5-ALA.
To solve this problem, a method in which the restoration of the me-5-NLC carried out electrochemically in an acidic aqueous solution on graphite cathode at a temperature of 60-75°and a current density of 2-10 A/DM2.
At temperatures below 60°With the reduction of yield of 5-ALA on the substance and current, probably due to the decreased solubility of the initial me-5-NLC. In addition, at these temperatures the selectivity decreases due to the more electronegative potentials implemented in these conditions, which leads to the recovery of ketogroup. At temperatures above 75°With possibly a side acceleration of chemical reactions leading to the reduction of the target product.
The increase in current density above 10 A/DM2impractical because it leads to lower current output and, consequently, to the increase of energy consumption, as well as to the increase of the electrode potential, which causes the occurrence of adverse reactions. So, with increase in current density of 15 a/DM2the current output is reduced to 31.0%. When the density of t is ka less than 2.0 A/DM 2reduced cell capacity.
The choice of the cathode material was determined by the highest selectivity of the recovery process, high corrosion resistance under the conditions of electrolysis and low cost material. Studied cathode materials (copper, Nickel, titanium, platinum, platinized titanium, graphite) to a greater extent, all these requirements are satisfied graphite.
In the proposed method the electrochemical recovery of the me-5-NLC is carried out in a membrane electrolysis in an acidic aqueous environment on graphite cathode at a temperature of 60-75°and a current density of 2.0-10.0 A/DM2. Selection of 5-ALA is conducted by evaporation of the solution under vacuum and subsequent processing of the obtained oily product with acetone. Get technical 5-ALA in the form of the hydrochloride with a total yield 60.0-72.0%.
The following examples illustrate the invention.
Example 1. In the controlled load capacity 125 ml of distilled water, 5.5 ml of concentrated hydrochloric acid and 3.7 g of methyl ester of 5-nitrolingual acid. The resulting suspension is heated to a temperature of 65°and served by the pump to the recovery in the electrolyzer of the filter presnogo type with separated katiana-exchange membrane MK-40 cathode and anode spaces. As cathode and anode ispolzuyushimi of graphite with the working surface 1 DM 2. In a separate intermediate thermally capacity pour 150 ml of 10% solution of sulfuric acid and serves this solution in the anode space of the cell.
After circulation of the solution through the electrode chamber to the electrolysis cell at a temperature of 65°served With DC power, providing cathodic current density : 5.0 A/DM2. The electrolysis is terminated by complete conversion of the methyl ester 5-nitrolingual acid. Catholyte is heated in vacuum and the resulting oily product was stirred with acetone, precipitated when this precipitate is filtered off, washed with acetone and dried. Obtain 2.42 g of the product, the total output stages of recovery and allocation of 72%. TPL 147-149°C (decomp.). Little 149-151°C (decomp.). The yield of the hydrochloride of 5-ALA on the stage of recovery is 84.5% substance and 62.0% of the current.
Example 2. The recovery process and selection of the target product is carried out analogously to example 1 at a current density of 2.0 A/dm. the Output of the hydrochloride of 5-ALA on substance 74.4% and current 52.0%. After separation from the solution obtain 1.98 g of the product, the total output stages of recovery and allocation of 59.0%.
Example 3. The recovery process and selection of the target product is carried out analogously to example 1 at a current density of 10.0 A/DM2and a temperature of 75°C. the Yield of the hydrochloride of 5-ALA on substance 70% and that is at 49%. After separation from the solution obtain 1.85 g of the product, the total output stages of recovery and allocation of 58.0%.
Example 4. The recovery process and selection of the target product is carried out analogously to example 1 at a current density of 5.0 A/DM2and a temperature of 60°C. the Yield of the hydrochloride of 5-ALA on substance 74.5% and current 54.0%. After separation from the solution obtain 2.02 g of the product, the total yield of 60.0%.
Thus, the proposed method allows to simplify the technology of 5-ALA by eliminating operations filtration of the catalyst and hydrolysis of the methyl ester of 5-ALA, to make the process more economical by eliminating expensive equipment and catalyst, as well as technologically simple and environmentally friendly by eliminating the use of methanol, hydrogen and high pressure.
The way to obtain hydrochloride of 5-aminolevulinic (5-amino-4-oxopentanoate) acid from methyl ester 5-nitrolingual acid recovery in acid medium, characterized in that the recovery is carried out electrochemically in an aqueous environment on graphite cathode at a temperature of 60-75°and a current density of 2-10 A/DM2.
FIELD: organic chemistry, medicine.
SUBSTANCE: invention relates to compounds designated for applying in photochemotherapy or diagnosis and indicated compounds represent 5-aminolevulinic acid aryl-substituted esters, their derivatives or pharmaceutically acceptable salts. In particular, invention provides preparing compounds of the general formula (I): R
EFFECT: valuable medicinal properties of compounds.
18 cl, 17 dwg, 2 tbl, 3 ex
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to a new method for preparing aminophenoxyphthalic acids that are monomers of type AB used for preparing polyimides. Aminophenoxyphthalic acids of the general formula (I) are given in the invention description wherein Y means trivalent radical taken among radicals row of the general chemical structure (II) or (III) given in the invention description wherein R means hydrogen atom (H), oxyphenyl, N-morpholinyl radicals. Method for their preparing involves two stages: in the first stage method involves carrying out the process of interaction of nitrophthalonitrile of the general formula (IV) given in the invention description wherein R has above indicated values with 3- or 4-acetamidophenol of the general formula (V) given in the invention description in the presence of alkaline metal carbonate in amide solvent medium. Then as alkaline metal carbonate method involves using potassium carbonate mainly and dimethylformamide or dimethylacetamide aqueous solutions are used as an amide solvent. Alkaline hydrolysis is carried out in an aqueous-methanol potassium hydroxide (KOH) solution. Prepared aminophenoxyphthalic acid is isolated as a precipitate by acidification of the reaction mass with acetic acid mainly up to pH 4-5. Aminophenoxyphthalic acids are monomers used for synthesis of polyimides comprising at least one repeated link taken among links row of the general formula (VI) given in the invention description wherein Y has above indicated values. Invention provides preparing new aminophenoxyphthalic acids, for example, oxyphenyl- or N-morpholinyl-substituted acids. Applying these compounds allows expanding possibility for preparing polyimides having substitutes and comprising hinged fragments in the main chain, in particular, oxygen atoms that as one can expect must enhance the chain flexibility and therefore to promote appearance of thermoplasticity property.
EFFECT: improved preparing method, improved and valuable properties of compounds.
5 cl, 1 sch, 6 ex