The method of producing sodium 10-methylanthracene-9-acridone or 10-metrocable-9-acridone from acridone

 

(57) Abstract:

The invention relates to an improved method for obtaining 10-methylanthracene-9-acridone or 10-metrocable-9-acridone intended for the synthesis of drug substances or preparation of dosage forms (sodium 10-methylanthracene-9-acridone) used in medical and veterinary practice as antiviral agents. Offered technologically acceptable method of obtaining sodium 10-methylanthracene-9-acridone or 10-metrocable-9-acridone by alkylation of acridine ethylparathion in the presence of carbonates of sodium or potassium in conditions allowing to obtain technical ester 10-metrocable-9-acridone with high yield and high content of basic substance, and translate it by alkaline hydrolysis and separation of the original product in the target products of high purity. The technical result consists in increasing the yield and purity of the target product. 9 C.p. f-crystals, 1 table.

The present invention relates to chemistry acridone, in particular, to an improved method for the synthesis of sodium 10-methylanthracene-9-acridone and 10-metrocable-9-acridone, the General formula

< / BR>
where R = Na, (I is prigotovleniya dosage forms, salt (I) is used in medical and veterinary practice as antiviral agents: the inducer of interferon has antiviral activity against both DNA-and RNA-containing viruses that due to its ability to dramatically stimulate the formation of interferon. Proposed as an anti-plague funds for animals (Patent 2031650, the Russian Federation, 1995, Szule And B. at al.//Arch. Immun. Therapie.. 1985. Vol. 33. P. 287-297).

All known methods of obtaining products (I, Ia) based on alkaline hydrolysis of the ester 10-metrocable-9-acridone (II) when they are processed with caustic soda or sodium alcoholate in the alcohol and subsequent selection of salt (I) as the target product or the acidification of its solution with acid secretion (Ia). Because the last stage is the selection of the acid (Ia) is quite simple, the decisive stages of the chain are getting ether (II) and its hydrolysis with the formation of the salt (I).

Ether (II) is usually synthesized in the alkylation of 10-methoxyacridine [Lyakhov S. A. at al.//Pharmazie. 1994. Vol. 45. N 5. P. 367-3683] or alkaline salts acridone (III) esters of chloro - or bromoxynil acid, using in the case of acridone the overall scheme of [U.S. Pat. 3681360. USA, 1972, Postescu J. et al. // J. Prakt. Chem. 1977. Bd. 319. N 2. S. 347-352; Patent 2033413. The Russian Federation, 1995, Inglot F. D. et al. //Arch. Immun. Therapie E1977. Bd. 319. N 2. S. 347-352. Patent 2029764. Of the Russian Federation. 1995].

The method of obtaining the product (I) through 9-methoxyacridine is heated (120oC) last methylbromide in nitrobenzene. In this embodiment, instead of substitution in position 10 with the formation of O-methylated analogue ether (II) took place N9-alkylation by heteroatom cycle with the formation of the intermediate Quaternary salt, which upon basic hydrolysis with sodium methylate in methanol gave the target salt (I) /60%/ [S. A. Lyakhov, etc. // Pharmazie. 1994. Vol. 45. N 5. P. 367-3683], this method is not practically feasible due to inaccessible 9-ethoxyaniline and use of nitrobenzene, sodium methylate and methanol.

More promising in terms of technology, the methods based on the alkylation of acridine (III) acylhalogenides when heated in a solvent in the presence of bases.

The method of obtaining the target salt (I) of the ester (II) is described in [Postescu J. et al. // J. Prakt. Chem. 1977. Bd. 319. N 2. S. 347-352; Inglot F. D. etc. // Arch. Immun. Therapie.. 1985. Vol. 33. P. 275-285. Patent 2029764. Of the Russian Federation. 1995] . In the last two papers of the previous stage - alkylation, is not considered at all, although, as experience shows, it is the quality of the product of this stage determines the way of its transformation into zelenoy acid with the release of >90%.

Methods of synthesis of salt (I) on the basis of the ether (II) [//J. Prakt. Chem. 1977. Bd. 319. N 2. S. 347-352 7] close: a hot solution of ester (II) in absolute alcohol is treated with excess concentrated aqueous solution of caustic soda, the output of technical substance 85%, recrystallized from a mixture of DMF/methanol - 70%.

The disadvantages of this method:

1) the use of absolute ethanol in a large number of /on 1 g of salt (I) to 35 ml/.

2) the need to use purified ether, free from acridone as the last in the accepted conditions of alkaline hydrolysis go into target products (I, Ia) almost completely;

3) low yield of purified substances.

The Way [The Patent 2029764. Of the Russian Federation. 1995] uses alkaline hydrolysis of the ester (II) by boiling the latter in aqueous alkali, which is easier and more economical, but the authors make use of the catalysts, porous aluminosilicates (zeolites, molecular sieves with pore size 3-9 (A); target salt (I) after evaporation of the filtered solution discharges acetone, yield >90%. 10-Metrocable-9-acridone (Ia), if necessary, isolated by acidification neuverennogo solution of salt (I) dilute hydrochloric acid.

The disadvantages of this option:

1) primesearchteam synthesis of regeneration or recycling of the catalyst;

3) synthesis of ester (II) in the patent is not considered, but it is assumed the application of the product to be of high quality (so pl. 176-178oC); the transformation of a technical product, the content of acridone which significantly above 2% for this option is not available; note that even in the case of a positive return unreacted acridone in the cycle will be problematic and, as a minimum, will require the development of methods of separation from the catalyst. Pre-target - synthesis of ester (II), considered by the same authors separately in the patent [Patent 2033413. Of the Russian Federation. 1995].

Here esters 10-metrocable-9-acridone received by boiling acridone with esters of monochloracetic acid in the environment dimethylacetamide (DMAA) in the presence of phase transfer catalyst (Quaternary ammonium salt), and the use of only 0.5 to 4 equivalents of anhydrous carbonate of an alkali metal. Pre-mix acridone, carbonate and catalyst were heated (165oC) followed by distillation of part of the solvent, and then spent the dosage of ethylchloride and gave an extract by boiling; the reaction mass is cooled to 60-70oC, poured into water with ice, fallen target product was washed on the had been no higher than 2%, he did not require, according to the authors, additional cleaning, and its output was 82-88%.

The disadvantages of this method include:

1) introduction preliminary boiling of the base and catalyst in a solvent and distillation 1/3 DMAA; this is an additional operation that ethnologica, with the safety of the catalyst at this stage dubious;

2) use very harsh reaction conditions, in particular high-temperature synthesis 165oC, which requires extra energy, but most importantly, promotes the decomposition of metastability catalyst and ethylchloride and leads to partial resinification mass. It should be noted that in other cases the alkylation of acridine other alkylating agents when using potassium carbonate was carried out under relatively mild conditions by introducing Quaternary ammonium salts; in this case, however, with the introduction of the catalyst applied unreasonably harsh conditions of alkylation - DMF changed to the higher boiling DMAA, and the reaction is carried out at boiling last (165oC);

3) use very high for technological purposes in the concentration of reagents (1.43 g of reagent to 1 ml of the solvent at the start, more than 0.7 g of the target ester in 1 ml of DMAA s of acridone (or its salt) in a small amount of solvent at the start, but it is important for faster and target consumption, metastabile at such high temperatures of ethylchloride; b/ reaction mass is mixed and difficult very quickly thickens when cooled, making it drain even when 70oC; this leads to significant mechanical losses at the end of the synthesis;

4) the low quality of ether (II); and the product is very dark, due to the high concentration reagent and the extremely high (165oC, boiling DMAA) the reaction temperature at that are used insufficiently thermally stable catalyst and ethylchloride; the resulting product requires repeated cleaning with the use of activated carbon.y.), that leads to more and greater losses; washing the product on the filter with ethanol, as proposed in the patent, does not give a significant increase quality, but leads to a considerable drop in output; b/ ether includes an appreciable amount of unreacted acridone when technical product 85%, it contains more than 10% of acridone (1. TLC; 2. hydrolysis of the alkali in the water 58% salt (I). UV spectroscopy); the output from acridone in terms of the target substance when it is less than 50%;

5) the number of soda, introduced in the synthesis of ester (II) in particular PTSA.

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

In this embodiment, the synthesis of salt (I) was carried out at alkylation of acridine (III) ethylparathion boiling reagents in DMF and the use of KOH as base, with subsequent transfer of the resulting ester (II) in the target product (I) in the processing of his warm solution in absolute alcohol conc. the alkali solution; Sol (I) stood out, was dissolved in water, and its solution upon acidification gave the acid (Ia); however, in the synthesis of ester (II):

1) pre-prepared K-salt acridone in DMF (10 minutes in boiling DMF of acridone with a 2.5-fold amount of KOH, followed by distillation of the water in the form of its azeotrope with DMF);

2) to a cooled suspension of salt was dotirovala ethylchloride, the reaction mass was heated to the boil, boiled 20 min, poured into ice water, the product was filtered off;

3) after drying, the residue was twice extracted with chloroform, after evaporation which received technical ether with a yield of 79% (product quality not assessed); most likely it is the introduction of this time-consuming operation pozvoliali of alcohol with very high so pl. (182.5-183oC); at the stage of synthesis of the target product (I): received broadcast (II) was dissolved in absolute alcohol and treated with a concentrated solution of alkali; to obtain the product (Ia) Sol (I) was dissolved in water and acidified with 5% HCl.

The disadvantages of the method include:

1. the use of KOH under alkylation, leading to the formation of water during the synthesis of K-salts acridone, the removal of which is necessary and is accomplished by distillation in the form of its azeotrope with DMF; controlled distillation of part of the solvent - reception, significantly complicating technology; used in the synthesis of 2.5 times the amount of alkali - its large surplus remaining in the reaction mass, inevitably causing adverse reactions: the conversion of ethylchloride and ether (II) into the corresponding salt (RCOOOEt + KOJ ---> RCOOK + EtOH), which contaminates the product of this stage /ether (II)/ and reduces its output; when testing option marked foaming of the reaction mixture with a threat of release, the development side of the process, and impurities due to the use of KOH, complicated isolation and purification of the ester (II), which dramatically reduced its output (about 50%);

2. a noticeable admixture of acridone technical ester (II) 30%;

3. introduction to advanced operations - extraction is here applied only purified ether (II) when translating it into the target salt (I) and then acid (Ia);

5. the use of absolute alcohol at high module on the operation of the hydrolysis of ester (II) in the target salt (I).

All this makes the technology is complex, time consuming and ineffective.

Thus,

1. received the prototype for the alkylation of acridine technical ester (II) is not useful to translate it into the target products (I, Ia) according to the method proposed in the prototype; therefore, it requires treatment with chloroform, and then repeated crystallization obtained after distillation of the chloroform the product with the corresponding loss in yield, and the high cost of solvents and their regeneration;

2. the proposed option of alkaline hydrolysis in alcohol consuming absolute alcohol, and therefore, its regeneration, but it does not solve the problem of application of the technical product (II) to obtain the target substance (I, Ia).

As follows from the above, the defining stage of the multistep synthesis of compounds (I, Ia) from acridone (III) is receiving ether (II), the quality of which determines the yield and purity of Pharmacopoeia drugs (I, Ia). Despite the seeming simplicity of the scheme of application accepted for NH-acids options - alkylation of acrida ether - all these methods have drawbacks: they are not always feasible and the results are often difficult reproducible (first of all, it concerns the quality of the intermediate product (II)).

The task to be solved by the invention is to remedy these disadvantages and to develop technologically acceptable method of obtaining sodium salt of 10-metrocable-9-acridone (I) or a 10-metrocable-9-acridone (Ia) from acridone (III) to synthesize the target drugs (I, Ia) Pharmacopoeia purity with high yield.

The task can be solved with:

1) finalization phase alkylation of acridine to ensure a high yield (>90%) technical ester (II) with a low content of acridone (not >10%);

2) develop ways of translating technical ester (II) sodium salt of 10-metrocable-9-acridone for removing residual acridone from it and the synthesis of the target drugs (I, Ia) high quality.

The essence of the decision is that

at the stage of alkylation of acridine ethylparathion in DMF is proposed to use the carbonates of potassium or sodium, conducting the process with a ratio of acridan-DMF and the temperature of the dosage of these is isharesoft at a temperature of 100-130oC), and using the reagents, the ratio of acridan:carbonate:ethylchloride = 1:2-3:2-3 (mol), followed by exposure at temperatures below the boiling point of DMF (130-140oC) and the allocation of broadcast 10-metrocable-9-acridone in the usual way;

at the stage of alkaline hydrolysis of the resulting ester 10-metrocable-9-acridone (II) is proposed to handle technical ether aqueous alkali and separating the resulting solution of the target sodium salt from unreacted acridone, for example, be filtered; the filtrate is a solution of the target product, further processed sorbent, such as activated carbon, followed by filtration, the filtrate is proposed to be used for preparation of aqueous solutions of the desired product, the desired concentration (and in this form it is used as a substance in the drug [1]), and on its basis:

a/ to obtain sodium 10-methylanthracene-9-acridone in crystalline form by adding alcohols (ethyl, isopropyl) to its concentrated aqueous solution;

b/ extract the 10-methylanthracene-9-acridone upon acidification with mineral acid.

The proposed solution when SUB>):

and/ carbonate, in particular potassium carbonate, unlike KOH, in the formation of salts acridone and its alkylation turns into MeHCO3and MeCl (KHCO3, KCl), i.e., does not produce water, and the stage of the azeotropic distillation of water with the solvent is removed altogether;

b/ potassium carbonate is a good drying agent, and the application of its surplus (III: K2CO3= 1:2-3) provides the removal of water, the introduction of which is possible with the original 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 unlike KOH intensive translation available in the reaction mixture of the target and alkylating esters in salt even when a prolonged stay in a high temperature environment (salt at the final stage in the application of KOH certainly go with the spent aqueous solvent, but it will significantly affect the output stage alkylation).

T. O. application of potassium carbonate in excess provides a synthesis of K-salts acridone, removing the moisture binding HCl and provides the reduced alkalinity of the environment and, consequently, the degree of transmission of adverse reactions, which together leads to increase in the yield and purity of products alkilirovan is ethylchloride at elevated temperature (up to 37oC) and the application of its surplus (III: ClCH2COOEt = 1:2-3) achieved the highest salt concentration of acridine in solution by the time the dosage that provides fast flow metastabile at an elevated temperature of ethylchloride mainly on the target direction and almost for the time, with no need for prolonged boiling of the reaction mixture, which usually leads to its partial resinification; but the introduction of the phase transfer catalyst does not accelerate or increase in the yield or quality of the broadcast.

These techniques provide a fast and high conversion acridone in ether (II), and therefore, its high output and sufficient purity of the technical product (yield ether (II) >90%, the content of acridone (III) it is <10%).

Hence it is necessary to work out the conditions of hydrolysis technical ester, which provides separation of acridone and education pure sodium salt.

When spirit and alkaline hydrolysis technical ester (II) acridan (III) enters the target salt actually completely. And this stage should provide Pharmacopoeia purity of the target drugs. Therefore alcoholic version of the hydrolysis of the prototype is not acceptable for technical aired at all.

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

In this decision, the Department of acridone are encouraged to migrate to the stage of hydrolysis of the ester, holding the latter in an aqueous-alkaline medium: process ether aqueous alkali or soda when heated and filter unreacted acridan, and the resulting filtrate or acidified with filtration of the precipitated target acid (Ia), or to reach the desired concentration of salt in the water, or give the target product (I) in crystalline form.

It is proposed conditions for the stages of the alkylation and hydrolysis of the complex allow you to use Si and remaining technical broadcast acridan, to clean an aqueous solution of sodium salt sorbent, to exclude the application of absolute alcohol, to reduce the amount of solvent in the cleaning operations, and selection and get clean target drugs with high output.

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

Example 1. Synthesis of ethyl ether 10 metrocable-9-acridone (II). To 150-180 ml DMF sprinkled 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 soda), the mixture is heated with stirring to boiling, boil for 15-20 minutes, cool and add 16-24 ml (0.15-0.23 mol) of ethylchloride so that the temperature in the reactor was maintained at the level 100-130oC. after dosing the reaction mass is maintained at 130-140oC for 0.5-1 h and control the content of the original acridone /TLC, the system chloroform:methanol = 95:5). If necessary, give additional exposure. The reaction mass is then cooled, poured with stirring into water, the precipitated product is filtered and washed on the filter with water. On stage alkaline hydrolysis product arrives without purification.

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

the stage maintained at 95-100oC 0.5-1 h, cooled, filtered unreacted acridan and washed it with distilled water. After drying, acridan return to the stage alkylation. The resulting filtrate is treated with activated carbon.W.) when heated, cooled, and filtered from.. and washed on the filter with distilled water; the resulting filtrate is A solution of the desired product (I) in water; output 90-94% (UV-spectroscopy filtrate); if necessary, clean up operation.. I repeat; the solution is evaporated under vacuum, fending off the main part of water to the residue add the alcohol, the resulting suspension is brought to a boil, soak in boiling 0.5 h, filtered and leave the filtrate to crystallize. The precipitated product is filtered off, washed on the filter with alcohol and dried; the yield of the product (I) 90-94% (including residual product in the mother liquor). Water uterine solvent may be partially recycled to the extraction of salt, the remainder is subject to regeneration. Selection 10-metrocable-9-acridone (Ia). Cooled to 5-10oC the filtrate a solution of salt (I) acidified with 5% sulfuric (hydrochloric) acid to pH 1, then maintained under stirring at this temperature for 0.5 h, the precipitated yellow Timoti the product is crystallized (DMF - water = 1/3); product characteristics identical to those described in [5].

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

UV-spectrum (0.02 R-R 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 (COar, COO-), 3020;

Range of PMR, B., M. D.: 4.83 (CH2, 2H), 7.26-7.68 mm (ArH, 4H), 7.70-7.80 m (2H, 4H, and 5H), 8.30 (2H, J = 8 Hz, 1H and 8H), D2O; NMR C13, B., M. D.: 50.9 (1C), 116.2, 124.4, 122.9, 127.2, 135.9 (12C - aromatics), 175.8, 180.1 (2C - carbonyl),2O + 0.01% dioxane.

TLC (Silufol UV-254): Rf0.34-0.36 (IPA: ethyl acetate: NH4OH = 59:25:16).

Analysis

Found, %: C, 65.12, 65.32; H, 4.01, 3.88; N, 5.23, 5.11

C15H10NO3Na

Calculated, %: C, 65.46; H, 3.66; N, 5.09

Similarly carried out the alkylation of acridine when the variation of the process parameters with the subsequent transfer of technical product in the target salt according to the above method; the results are shown in the table.

1. The method of producing sodium 10-methylanthracene-9-acridone or 10-metrocable-9-acridone by alkylation of acridine ethylparathion in dimethylformamide (DMF) PR is the selection of target products, characterized in that the alkylation is carried out in the presence of potassium carbonate or sodium when the ratio acridan-DMF and temperature dosage ethylchloride providing solubility of acridine using the reactants in a molar ratio acridan : potassium carbonate or sodium : ethylchloride= 1 : 2 - 3 : 2 - 3, followed by exposure at temperatures below the boiling point of DMF, the allocation of technical ester 10-metrocable-9-acridone, processed aqueous alkali, separating the solution of the resulting sodium 10-methylanthracene-9-acridone from acridone and selection of target products.

2. A way of getting under item 1, characterized in that acridan-DMF used in the ratio of 1 : 10 to 12 (the weight.h. : about.h.).

3. A way of getting under item 1, characterized in that the dosage of ethylchloride carried out at a temperature of 100 - 130oC.

4. A way of getting under item 1, characterized in that the exposure is performed at a temperature of 130 - 140oC.

5. A way of getting under item 1, characterized in that acridan from a solution of sodium 10-methyltyrosine-9-acridone after alkaline hydrolysis is separated by filtration.

6. A way of getting under item 1, characterized in that a solution of sodium 10-methylanthranilate for PP.1, 6, characterized in that the sodium 10-methylanthracene-9-acridone isolated in the form of an aqueous solution of the desired concentration.

8. The way of getting PP.1, 6, characterized in that the sodium 10-methylanthracene-9-acridone isolated in crystalline form.

9. The way of getting PP.1, 7, characterized in that the sodium 10-methylanthracene-9-acridone separated from the concentrated aqueous solution by the addition of alcohol.

10. The way of getting PP.1, 7, characterized in that 10-metrocable-9-acridone allocate acidification of a solution of its sodium salt.

 

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