RU2162843C2 - Method of preparing sodium 10-methylene carboxylate-9-acridone or 10- methylenecarboxy-9-acridone from acridone - Google Patents

Abstract

FIELD: medicine and veterinary practice. SUBSTANCE: described is improved method of preparing 10- methylenecarboxylate-9-acridone or 10-methylenecarboxy-9-acridone intended for synthesis of medicinal substances or medicinal forms useful in medical and veterinary practice as antiviral agent. Sodium 10-methylenecarboxylate-9- acridone or 10-methylenecarboxy-9-acridone is prepared or 10-methylenecarboxy-9- acridone is prepared by alkylation of acridone with ethylchloro acetate in the presence of sodium or potassium carbonates under conditions that enable one to prepare industrial ether of 10-methylene carboxy-9-acridone with high yield and high content of main substance and to convert it into desired products of high purity by alkaline hydrolysis and isolation of original product. EFFECT: increased yield and higher purity of the desired products. 10 cl, 9 ex, 1 tbl

Description

где R = Na, (I), H (Ia),
являющихся полупродуктами для синтеза фармацевтических препаратов (I, Ia) или субстанциями (I) для приготовления лекарственных форм, соль (I) применяется в медицинской и ветеринарной практике в качестве противовирусного средства: индуктор интерферона обладает противовирусным действием в отношении как ДНК-, так и РНК-содержащих вирусов, что обусловлено его способностью резко стимулировать образование интерферона. Предложен в качестве противочумного средства для животных (Патент 2031650, РФ, 1995, Szule B. И at al.//Arch. Immun. Therapie Exper. 1985. Vol. 33. P. 287-297).The present invention relates to the chemistry of acridone, in particular, to an improvement of the method for the synthesis of sodium 10-methylenecarboxylate-9-acridone and 10-methylenecarboxy-9-acridone, of the General formula

where R = Na, (I), H (Ia),
being intermediates for the synthesis of pharmaceutical preparations (I, Ia) or substances (I) for the preparation of dosage forms, salt (I) is used in medical and veterinary practice as an antiviral agent: the interferon inducer has an antiviral effect against both DNA and RNA -containing viruses, due to its ability to dramatically stimulate the formation of interferon. It is proposed as an anti-plague agent for animals (Patent 2031650, RF, 1995, Szule B. And at al.//Arch. Immun. Therapie Exper. 1985. Vol. 33. P. 287-297).

 All known methods for producing products (I, Ia) are based on alkaline hydrolysis of 10-methylenecarboxy-9-acridone (II) esters when they are treated with sodium hydroxide or sodium alcoholate in alcohols and subsequent isolation of salt (I) as the target product or acidification of its solution with the release of acid (Ia). Since the last stage, the isolation of acid (Ia), is quite simple, the determining steps in the general chain are the production of ether (II) and its hydrolysis with the formation of salt (I).

 Ether (II) is usually synthesized by alkylation of 10-methoxyacridine [Lyakhov S. A. at al.//Pharmazie. 1994. Vol. 45. N 5. P. 367-3683] or the alkaline salt of acridone (III) with chloro- or bromoacetic acid esters, using the general scheme in the case of acridone [US Pat. 3681360. USA, 1972, Postescu J. et al. // J. Prakt. Chem. 1977. Bd. 319. N 2. S. 347-352; Patent 2033413. RF, 1995, Inglot F.D. et al. // Arch. Immun. Therapie Exper. 1985. Vol. 33. P. 275-285]. Acid (Ia) is obtained by treating a salt (I) solution with a mineral acid [Postescu J. // J. Prakt. Chem. 1977. Bd. 319. N 2. S. 347-352. Patent 2029764. RF. 1995].

The method of obtaining product (I) through 9-methoxyacridine consists in heating (120 ^o C) the latter with methyl bromoacetate in nitrobenzene. In this embodiment, instead of the planned substitution at position 10 with the formation of the O-methylated analogue of the ester (II), there was an N ⁹ -alkylation at the heteroatom of the ring with the formation of an intermediate quaternary salt, which, upon alkaline hydrolysis with sodium methylate in methanol, gave the target salt (I) / 60 % / [Lyakhov SA et al. // Pharmazie. 1994. Vol. 45. N 5. P. 367-3683], this method is not technologically advanced due to the use of inaccessible 9-ethoxyacridine and the use of nitrobenzene, sodium methylate and methanol.

 More promising in terms of technology are methods based on the alkylation of acridone (III) with ethyl halogen acetate when heated in a solvent in the presence of bases.

 A method of obtaining the target salt (I) from ether (II) is described in [Postescu J. et al. // J. Prakt. Chem. 1977. Bd. 319. N 2. S. 347-352; Inglot F.D. et al. // Arch. Immun. Therapie Exper. 1985. Vol. 33. P. 275-285. Patent 2029764. RF. 1995]. In the last two works, the previous stage - alkylation, is not considered at all, although, as experience shows, it is the quality of the product of this stage that determines the way it is converted to the target salt or acid and the purity of the latter. Acid (Ia) is isolated by acidifying a solution of pure salt (I) with mineral acid in a yield of> 90%.

 Methods for the synthesis of salt (I) based on ether (II) according to [// J. Prakt. Chem. 1977. Bd. 319. N 2. S. 347-352 7] are close: a hot solution of ether (II) in absolute alcohol is treated with an excess of concentrated aqueous sodium hydroxide solution, the yield of technical substance is 85%, recrystallized from a mixture of DMF / methanol - 70%.

The disadvantages of this method:
1) the use of absolute alcohol in large quantities / per 1 g of salt (I) up to 35 ml /.

2) the need to use purified ether free from acridone, since the latter, under the accepted conditions of alkaline hydrolysis, will go into the target products (I, Ia) almost completely;
3) low yield of purified substance.

 Method [Patent 2029764. RF. 1995] uses alkaline hydrolysis of ether (II) by boiling the latter in aqueous alkali, which is simpler and more economical, but the authors use catalysts - porous aluminosilicates (zeolites, molecular sieves with a pore size of 3-9 A); the target salt (I) after evaporation of the filtered solution is precipitated with acetone, yield> 90%. 10-Methylenecarboxy-9-acridone (Ia), if necessary, is isolated by acidification of an unpaired solution of salt (I) with dilute hydrochloric acid.

The disadvantages of this option are:
1) the use of additional catalysts - molecular sieves with a specific pore size;
2) the need for large-scale synthesis of regeneration or utilization of the catalyst;
3) the synthesis of ether (II) is not considered in the patent, but it is intended to use a product of only high quality (mp. 176-178 ^o C); the conversion of a technical product, the content of acridone in which is significantly higher than 2% for this option is not proposed; note that even in the case of a positive result, the return of unreacted acridone to the cycle will be problematic and, at a minimum, the development of a technique for separating it from the catalyst will be required. The stage preceding the target synthesis of ether (II) is considered by the same authors separately in the patent [Patent 2033413. RF. 1995].

Here, 10-methylenecarboxy-9-acridone esters were prepared by boiling acridone with monochloracetic acid esters in dimethylacetamide (DMAA) in the presence of an interphase transfer catalyst (quaternary ammonium salts) and using only 0.5-4 equivalents of anhydrous alkali metal carbonate. Preliminarily, the mixture of acridone, carbonate and catalyst was boiled (165 ^° C), followed by distillation of a part of the solvent, after which ethyl chloroacetate was dosed and the mixture was kept under boiling; the reaction mass, cooled to 60-70 ^o C, was poured into ice water, the precipitated target product was washed on the filter with ethanol and hexane and dried at 120 ^o C; the admixture of acridone in technical ether, according to the patent, was not higher than 2%, it did not require, in the authors' opinion, additional purification, and its yield was 82-88%.

The disadvantages of this method include:
1) the introduction of pre-boiling the base and catalyst in a solvent and distillation 1/3 DMAA; this is an additional operation, which is not technologically advanced, while the safety of the catalyst at this stage is already doubtful;
2) the use of very severe reaction conditions, in particular a high synthesis temperature of 165 ^o C, which requires unnecessary energy consumption, but most importantly, it contributes to the decomposition of unstable catalyst and ethyl chloroacetate and leads to partial resinification of the mass. It should be noted that in other cases, the alkylation of acridone with other alkylating agents using potassium carbonate was carried out under relatively mild conditions due to the introduction of quaternary ammonium salts; in this case, when the catalyst was introduced, unreasonably harsh alkylation conditions were applied - DMF was changed to a higher boiling DMAA, and the reaction was carried out at the boiling of the latter (165 ^o C);
3) the use of a very high concentration of reagents for technological purposes (1.43 g of reagents per 1 ml of solvent at the start, more than 0.7 g of the target ether per 1 ml of DMAA plus inorganic salts insoluble in DMF at the end of the synthesis); at the same time: а / the complete dissolution of acridone (or its salt) in a small amount of solvent at the start is not achieved, and this is important for a faster and more targeted flow, unstable at such a high temperature ethyl chloroacetate; b) the reaction mass is difficult to mix and very quickly thickens when cooled, which makes it difficult to drain even at 70 ^o C; this leads to significant mechanical losses at the end of the synthesis;
4) low quality of ether (II); а / the product is very dark, due to the high concentration of reagents and extremely high (165 ^o C, boiling DMAA) reaction temperature, despite the fact that thermally insufficiently stable catalyst and ethyl chloroacetate are used; the resulting product requires repeated cleaning using activated carbon (a.u.), which leads to additional and large losses; washing the product on the filter with ethanol, as proposed in the patent, does not give a significant improvement in quality, but leads to a noticeable drop in yield; b / ether includes a noticeable amount of unreacted acridone - when the technical product is 85%, it contains more than 10% acridone (1. TLC; 2. hydrolysis with alkali in water - 58% salt (I). UV spectroscopy); the yield from acridone in terms of the target substance does not reach 50%;
5) the amount of soda introduced into the synthesis of ether (II) in a specific example is insufficient even for halogen binding;
6) the synthesis of the target products (I, Ia) is not given in the patent.

 The prototype of the proposed solution is the synthesis of the sodium salt of 10-methylenecarboxy-9-acridone (I) and 10-methylenecarboxy-9-acridone (Ia) from acridone (III) via ether (II) [. // J. Prakt. Chem. 1977. Bd. 319. N 2. S. 347-352].

In this embodiment, the synthesis of salt (I) was carried out by alkylating acridone (III) with ethyl chloroacetate while boiling the reagents in DMF and using KOH as a base, followed by transferring the obtained ether (II) to the target product (I) by processing its warm solution in absolute alcohol . alkali solution; salt (I) was released, dissolved in water, and its solution upon acidification gave acid (Ia); while the synthesis of ether (II):
1) K-salt of acridone in DMF was preliminarily prepared (10-minute boiling in DMF of acridone with 2.5-fold amount of KOH followed by distillation of water as its azeotrope with DMF);
2) ethyl chloroacetate was dosed to the cooled salt suspension, the reaction mass was heated to boiling, boiled for 20 minutes, poured into ice water, the product was filtered off;
3) after drying, the precipitate was extracted twice with chloroform, after evaporation of which technical ether was obtained with a yield of 79% (product quality was not evaluated); most likely, the introduction of this laborious operation made it possible to separate the target drug from most of the unreacted acridone and to obtain ether (II) after crystallization from alcohol with a very high mp. (182.5-183 ^o C); at the stage of synthesis of the target product (I): the obtained ether (II) was dissolved in absolute alcohol and treated with a concentrated alkali solution; to obtain product (Ia), salt (I) was dissolved in water and acidified with 5% HCl.

The disadvantages of the method include:
1. the use of KOH in the alkylation stage, which leads to the formation of water in the synthesis of the K-salt of acridone, the removal of which is necessary and is carried out by distillation in the form of its azeotrope with DMF; controlled distillation of part of the solvent - a technique that significantly complicates the technology; 2.5 times the amount of alkali is used in the synthesis - its large excess, remaining in the reaction mass, inevitably causes side reactions: the conversion of ethyl chloroacetate and ether (II) into the corresponding salts (RCOOOEt + KOJ ---> RCOOK + EtOH), which pollutes the product of this stage / ether (II) / and reduces its yield; when testing the option, foaming of the reaction mass with a threat of release, the development of side processes, and impurities due to the use of KOH complicated the isolation and purification of ether (II), which sharply reduced its yield (about 50%);
2. a noticeable admixture of acridone in technical ether (II) - up to 30%;
3. introduction of an additional operation — extraction of a technical product with chloroform, followed by its removal and crystallization of the residue;
4. the need to use only purified ether (II) when converting it to the target salt (I) and then acid (Ia);
5. the use of absolute alcohol with a high modulus in the operation of hydrolysis of ether (II) to the target salt (I).

 All this makes the technology quite complex, time-consuming and inefficient.

Thus,
1. obtained from the prototype during the alkylation of acridone technical ether (II) is not very suitable for its translation into the target products (I, Ia) according to the method proposed in the prototype; therefore, it is necessary to treat it with chloroform, and then repeatedly crystallize the product obtained after distillation of chloroform, with corresponding losses in output, high costs of solvents and their regeneration;
2. the proposed version of alkaline hydrolysis in alcohol requires high costs of absolute alcohol, and therefore, its regeneration, but, most importantly, it does not solve the problem of using a technical product (II) to obtain the target substances (I, Ia).

 As follows from the foregoing, the determining stage in the multi-stage synthesis of compounds (I, Ia) from acridone (III) is the production of ether (II), the quality of which determines the yield and purity of pharmacopeia preparations (I, Ia). Despite the seeming simplicity of the scheme for the application of the variant generally accepted for NH acids — alkylation of acridone with halogen acetate in the presence of a base in an aprotic medium and subsequent alkaline hydrolysis of the resulting ether — all the above methods have disadvantages: they are not always technologically advanced and their results are often difficult to reproduce (first of all, these are regarding the quality of intermediate (II)).

 The problem to which the invention is directed, is to eliminate these drawbacks and to develop a technologically acceptable method for producing sodium salt of 10-methylenecarboxy-9-acridone (I) or 10-methylenecarboxy-9-acridone (Ia) from acridone (III), which allows to synthesize targeted preparations (I, Ia) of pharmacopeia purity with a high yield.

The problem can be solved with:
1) finalization of the alkylation stage of acridone to ensure a high yield (> 90%) of technical ether (II) with a small content of acridone (not>10%);
2) the development of a method for the conversion of technical ether (II) to the sodium salt of 10-methylenecarboxy-9-acridone, which ensures the removal of residual acridone from it and the synthesis of high-quality target products (I, Ia).

The essence of the solution is that
at the stage of alkylation of acridone with ethyl chloroacetate in DMF, it is proposed to use potassium or sodium carbonates, carrying out the process at the ratio of acridone-DMF and the dosage temperature of ethyl chloroacetate, ensuring the complete solubility of acridone (acridone-DMF in the ratio 1: 10-12 at the dosage of ethyl chloroacetate at a temperature of 100-130 ^o C), and using reagents in the ratio - acridone: carbonate: ethyl chloroacetate = 1: 2-3: 2-3 (mol), followed by exposure to a temperature below the boiling point of DMF (130-140 ^o C) and the isolation of 10-methylenecarboxylic ester 9-acridone oba nym method;
at the stage of alkaline hydrolysis of the obtained 10-methylenecarboxy-9-acridone (II) ester, it is proposed to treat the technical ether with aqueous alkali and separate the resulting solution of the target sodium salt from unreacted acridone, for example, filter the latter; filtrate - a solution of the target product, additionally treated with a sorbent, for example, activated carbon, followed by filtration from it; the filtrate is proposed to be used for the preparation of aqueous solutions of the target product of the desired concentration (namely, in this form it is used as a substance in a medicinal product [1]), and on its basis:
a) to obtain sodium 10-methylenecarboxylate-9-acridone in crystalline form by adding alcohols (ethyl, isopropyl) to its concentrated aqueous solution;
b) isolate 10-methylenecarboxylate-9-acridone from it upon acidification with mineral acid.

As a result of the proposed solution for the alkylation of acridone with ethyl chloroacetate when heated in an DMF-alkali metal carbonate (K ₂ CO ₃ ) system:
a / carbonate, in particular potassium carbonate, in contrast to KOH, when the acridone salt is formed and its alkylation is converted to MeHCO ₃ and MeCl (KHCO ₃ , KCl), i.e. does not produce water, and the stage of azeotropic distillation of water with a solvent is removed at all;
b / potassium carbonate is a good drying agent, and the use of its excess (III: K ₂ CO ₃ = 1: 2-3) ensures the removal of water, the introduction of which is possible with the starting products or solvent.

 At the same time, the use of even a large excess of potassium carbonate in the absence of water does not cause, in contrast to KOH, intensive conversion of the desired and alkylating esters in the reaction mixture into salts even after prolonged exposure to high temperatures (salts at the final stage, when using KOH, of course spent aqueous solvent, but this will significantly affect the yield of the product of the alkylation stage).

 T.O. the use of potassium carbonate in excess provides the synthesis of the K-salt of acridone, the removal of moisture, the necessary binding of HCl and provides a reduced alkalinity of the medium and, consequently, the degree of side reactions, which together leads to an increase in the yield and purity of alkylation products.

When alkylating using a solvent module - acridone (III): DMF = 1: 10-12, dosing ethyl chloroacetate at elevated temperature (up to 37 ^o C) and applying its excess (III: ClCH ₂ COOEt = 1: 2-3) is achieved a high concentration of acridone salt in the solution exactly at the time of dosing, which ensures the rapid consumption of ethyl chloroacetate, which is unstable at elevated temperature, mainly in the target direction and practically during the exposure time, without the need for prolonged boiling of the reaction mass, which usually leads to its partial osmol niyu; the introduction of a phase transfer catalyst does not accelerate the process or increase the yield or quality of the ether.

 It is these methods that ensure the quick and high conversion of acridone to ether (II), and therefore, its high yield and sufficient purity of the technical product (ether (II) yield> 90%, acridone (III) content in it - <10%).

 And yet, since, as a rule, complete conversion cannot be achieved, the ether may actually contain 5-10% acridone, and when diluted, these products will fall out together. Separating acridone by crystallization is difficult and uneconomical. Even with acridone impurities <5% in technical ether, it is dangerous to use the latter for the synthesis of salt (I) without additional purification, since there is always the possibility of converting acridone to the target product (the impurity content in the output preparation should not be> 1.5%).

 In large-scale practice, fluctuations in the content of acridone in technical air can be significant (from trace to 20-30% in case of malfunctions in the performance of the technology), and a method suitable for processing such “defective” batches is necessary.

 Hence, it is necessary to work out the conditions for hydrolysis of technical ether, which ensure separation of acridone and the formation of pure sodium salt.

 During the alcohol-alkaline hydrolysis of technical ether (II), acridone (III) is practically completely converted into the target salt. And this stage should ensure the pharmacopoeial purity of the target drugs. Therefore, the alcohol version of the hydrolysis of the prototype is not acceptable for technical ether at all.

 Acridone, as it turned out, is noticeably soluble in alcohol and practically insoluble in aqueous alkali.

 In this decision, the separation of acridone is proposed to be transferred to the stage of hydrolysis of the ether, carrying out the latter in an aqueous alkaline medium: treat the ether with aqueous alkali or soda when heated and filter out the unreacted acridone, and the filtrate either acidify and then filter the precipitated target acid (Ia), or bring to the desired concentration of salt in water or to isolate the target product (I) in crystalline form.

 It is the proposed conditions for the stages of alkylation and hydrolysis in the complex that allow the use of technical ether, excluding the operation of its purification, separation and return to the previous stage of unreacted and remaining in technical ether acridone, clean the aqueous solution of sodium salt with a sorbent, exclude the use of absolute alcohol, reduce solvent consumption by purification and isolation operations and receive clean, targeted products in high yield.

 For a better understanding of the essence of the invention, an example of its specific implementation is given.

Example 1. Synthesis of ethyl ester of 10-methylenecarboxy-9-acridone (II). 15 g (0.077 mol) of acridone (III) and 21-32 g (0.154-0.231 mol) of potassium carbonate (or 0.154-0.231 mol of soda) are added to 150-180 ml of DMF, the mixture is heated to boiling with stirring, boiled for 15-20 min, cool and add 16-24 ml (0.15-0.23 mol) of ethyl chloroacetate so that the temperature in the reactor is maintained at 100-130 ^o C. At the end of the dosage, the reaction mass is kept at 130-140 ^o C for 0.5-1 h and control the content of the original acridone / TLC in it, the system of chloroform: methanol = 95: 5). If necessary, give additional exposure. The reaction mass is cooled, poured into water with stirring, the precipitated product is filtered off and washed on the filter with water. At the stage of alkaline hydrolysis, the product enters without purification.

 Synthesis of sodium salt of 10-methylenecarboxy-9-acridone (I).

To a solution of 3.7 g (0.092 mol) of sodium hydroxide in 70 ml of distilled water, ether (II) obtained in the previous step is added, kept at 95-100 ^o C for 0.5-1 h, cooled, the unreacted acridone is filtered off and washed with distilled water. After drying, acridone is returned to the alkylation step. The obtained filtrate is treated with activated carbon (a.u.) when heated, cooled, filtered from a.u. and washed on the filter with distilled water; the obtained filtrate A-solution of the target product (I) in water; yield 90-94% (UV spectroscopy of the filtrate); if necessary, a.u. repeat; the solution was evaporated in vacuo, driving off the main part of water, alcohol was added to the residue, the resulting suspension was brought to a boil, it was kept at boiling for 0.5 h, filtered and the filtrate was left to crystallize. The precipitated product is filtered off, washed on the filter with alcohol and dried; yield of product (I) 90-94% (taking into account the residual product in the mother liquor). The aqueous mother liquor can be partially recycled to the salt separation step, and the residue must be regenerated. Isolation of 10-methylenecarboxy-9-acridone (Ia). The filtrate A, cooled to 5-10 ^° C, the salt solution (I) is acidified with 5% sulfuric (hydrochloric) acid to pH 1, kept at stirring at this temperature for 0.5 h, the precipitated yellow precipitate is filtered off, washed on the filter with water and dried, yield 80-87% on acridone, mp 277-279 ^o C; if necessary, the product is crystallized (DMF - water = 1/3); characteristics of the drug are identical to those described in [5].

 The structure and identity of the obtained sodium salt of 10-methylenecarboxy-9-acridone was confirmed by TLC, elemental analysis, IR and UV spectroscopy.

UV spectrum (0.02 solution in a solution of 0.01 mol / L sodium hydroxide), l, nm, (Ig E): 257 (4.68), 388 (3.88), 407 (3.91);
IR, cm ^-1 : 760, 940, 1180, 1270, 1290, 1395 (COO ^- ), 1460, 1490, 1595 (CO _ar , COO ^- ), 3020;
PMR spectrum, b, ppm: 4.83 s (CH ₂ , 2H), 7.26-7.68 mm (ArH, 4H), 7.70-7.80 m (2H, 4H and 5H), 8.30 d (2H, J = 8 Hz , 1H and 8H), D ₂ O; NMR-C13, b, ppm: 50.9 (1C), 116.2, 124.4, 122.9, 127.2, 135.9 (12C - aromatics), 175.8, 180.1 (2C - carbonyl), D ₂ O + 0.01% dioxane.

TLC (Silufol-UV-254): R _f 0.34-0.36 (IPA: ethyl acetate: NH ₄ OH = 59:25:16).

Analysis
Found,%: C 65.12, 65.32; H 4.01, 3.88; N 5.23, 5.11
C ₁₅ H ₁₀ NO ₃ Na
Calculated,%: C 65.46; H 3.66; N 5.09
Similarly, alkylation of acridone was carried out by varying the process parameters with the subsequent conversion of the technical product into the target salt according to the above procedure; the results are shown in the table.

Claims (10)

 1. The method of producing sodium 10-methylenecarboxylate-9-acridone or 10-methylenecarboxy-9-acridone by alkylation of acridone with ethyl chloroacetate in dimethylformamide (DMF) by heating, followed by alkaline hydrolysis of the resulting technical ether 10-methylenecarboxy-9-acridone and the isolation of the target products, characterized in that the alkylation is carried out in the presence of potassium or sodium carbonate at the ratio of acridone-DMF and the dosage temperature of ethyl chloroacetate, ensuring the solubility of acridone using reagents in a molar ratio Achenone: potassium or sodium carbonate: ethyl chloroacetate = 1: 2 - 3: 2 - 3, followed by exposure at a temperature lower than the boiling point of DMF, isolation of 10-methylenecarboxy-9-acridone technical ether, treatment with aqueous alkali, separation of the sodium solution 10-methylenecarboxylate-9-acridone from acridone and isolation of the desired products.  2. The production method according to claim 1, characterized in that acridone-DMF is used in a ratio of 1: 10 - 12 (parts by weight: parts by weight). 3. The production method according to claim 1, characterized in that the dosage of ethyl chloroacetate is carried out at a temperature of 100 - 130 ^o C. 4. The production method according to claim 1, characterized in that the shutter speed is performed at a temperature of 130 - 140 ^o C.  5. The production method according to claim 1, characterized in that the acridone from the solution of sodium 10-methylenecarboxidate-9-acridone after alkaline hydrolysis is separated by filtration.  6. The production method according to claim 1, characterized in that the sodium 10-methylenecarboxylate-9-acridone solution is further purified by treatment with a sorbent and subsequent filtration from it.  7. The production method according to claims 1, 6, characterized in that the sodium 10-methylenecarboxylate-9-acridone is isolated in the form of an aqueous solution of the desired concentration.  8. The production method according to claims 1, 6, characterized in that the sodium 10-methylenecarboxylate-9-acridone is isolated in crystalline form.  9. The production method according to claims 1, 7, characterized in that the sodium 10-methylenecarboxylate-9-acridone is isolated from the concentrated aqueous solution by adding alcohol.  10. The production method according to claims 1, 7, characterized in that 10-methylenecarboxy-9-acridone is isolated by acidification of a solution of its sodium salt.

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