RU2577039C2 - Substance having combined antiaggregant, anticoagulant and vasodilator activity, and method of producing n, n '-substituted piperazines - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to N, N′-substituted piperazines of formula I and a method of producing compounds of formula II. Said compounds affect hemostasis system and exhibit antiplatelet, anticoagulant and vasodilatory properties. In general formula (I) R¹ - linear or branched alkyl C₁-C₄, R² - linear or branched alkyl C₅-C₁₂, G - mineral or organic C₁-C₄ acid or water, in general formula II R¹ - linear or branched alkyl C₁-C₄, R² - linear or branched alkyl C₁-C₁₂, G - mineral or organic C₁-C₄ acid or water.

EFFECT: disclosed method enables to obtain compounds of formula II with purity of over 99 % and content of individual impurities not more than 1/10 % and sum of impurities of not more than 5/10 %.

11 cl, 2 dwg, 6 tbl, 13 ex

Description

The invention relates to the field of pharmaceutical chemistry, namely, to new N, N′-substituted piperazines - compounds affecting the hemostatic system, exhibiting antiplatelet, anticoagulant and vasodilatory properties and a method for producing N, N′-substituted piperazines.

In particular, the invention relates to new organic compounds, namely to N, N′-substituted piperazines of the general formula I:

where R ¹ is a linear or branched alkyl C ₁ -C ₄ ;

R ² is a linear or branched C ₅ -C ₁₂ alkyl _;

G is a mineral or organic C ₁ -C ₄ acid or water,

possessing increased combined antiplatelet, antithrombolytic and vasodilatory activity, and methods for producing both the above compounds and compounds with a shorter chain of radicals, that is, to the General method for producing N, N′-substituted piperazines of formula II:

where R ¹ is a linear or branched alkyl C ₁ -C ₄ ;

R ² is a linear or branched alkyl C ₁ -C _12;

G is a mineral or organic C ₁ -C ₄ acid or water.

Diseases of the hemostatic system are the main cause of disorders of the coronary and cerebral circulation, which makes the task of treating these diseases quite relevant. In particular, it has been shown that effective treatment of diseases of the hemostatic system helps to reduce the risk of developing cardiovascular events, nonfatal myocardial infarction, nonfatal stroke, vascular death [McConnel N. // Br. Med. J. 2002. V. 324. P. 71-86]. So, the appointment of antithrombotic drugs reduces the total risk of cardiovascular events by a quarter, non-fatal myocardial infarction - by a third, non-fatal stroke - by a quarter, vascular death - by one sixth [McConnel N. // Br. Med. J. 2002. V. 324. P. 71-86].

The main directions of antithrombotic therapy are inhibition of platelet aggregation, targeted action on the hemocoagulation system, decrease in platelet activity of the endothelium, vasodilation. In particular, [Cardiovascular Drug Reviews. 2008. V18. N3. R. 222-231; Life Scinece. 1997. V. 60. N18. P. 1583-88] use drugs - thromboxane blockers - Ridogrel, Ozagrel, Pyrmagrel, which have antihypertensive and vasodilating properties, are safe and effective for myocardial infarction, and are also able to relieve bronchospasm.

The disadvantages of this group of drugs are their relatively low effectiveness with oral administration.

As an antiplatelet drug, aspirin is widely used. However, the well-known pronounced side effects of the drug, for example platelet dysfunction, hypoprothrombonemia [Temple AR. Acute and Chronic effects of aspirin toxicity and their treatment. Archives of Internal Medicine, 1981; 141: 367], aspirin resistance in patients with insulin-dependent diabetes mellitus [Trevor A. Mori, at all. Differential Effect of Aspirin on Platelet Aggregation in IDDM Diabetes, vol. 41, p. 261-266, March 1992].

To overcome the disadvantages of existing drugs, previously [RU 2469029, 2010], the authors synthesized compounds of the general formula IIa:

where R ₁ , R ₂ - linear or branched alkoxy (C ₁ ÷ C ₄ ), CH ₃ C (= O) O;

n is 1-5; m is 0-3; Z-C = O, SO ₂ ; XC (= NH) NH ₂ ; C (= NH) NHC (-NH) NH ₂ ;

G is a low molecular weight organic or mineral acid, sodium, potassium, ammonium or water cations,

which showed high efficiency in various types of thrombosis and vasoconstriction, and a method for producing these compounds was developed. This group of inventions is the closest analogue in technical essence to the claimed invention. According to patent RU 2469029, 2010, a method for the synthesis of N, N′-substituted piperazines of the general formula IIb:

where R ₁ , R ₂ - linear or branched alkoxy (C ₁ ÷ C ₄ );

n is 1-5; m is 0-3; ZC = O; XC (= NH) NH ₂ ;

G is a low molecular weight organic or mineral acid, sodium, potassium, ammonium or water cations,

includes the following stages (the synthesis scheme is shown in Fig. 1):

- Bromine treatment of 3,4,5-trialkoxybenzoic acid of general formula III in boiling chloroform, which leads to the formation of 2-bromo-3,4,5-trialkoxybenzoic acid of general formula IV.

- Treatment of 2-bromo-3,4,5-trimethoxybenzoic acid of the general formula IV with sodium alcoholate in the corresponding alcohol in the presence of a 50% mole. copper iodide, followed by acidification with hydrochloric acid, leading to the formation of 2,3,4,5-tetraalkoxybenzoic acid of the general formula IX.

- Treatment of 2,3,4,5-tetraalkoxybenzoic acid of the general formula IX with thionyl chloride in a solution of methylene chloride in the presence of N, N-dimethylformamide, which leads to the formation of 2,3,4,5-tetraalkoxybenzoyl chloride of the general formula X

- Treatment of 2,3,4,5-tetraalkoxybenzoyl chloride of general formula X with tert-butoxycarbonylpiperazine in methylene chloride in the presence of triethylamine, which leads to the formation of 1- (tert-butoxycarbonyl) -4- (2,3,4,5-tetraalkoxybenzoyl) piperazine general formula XI;

- Treatment of 1- (tert-butoxycarbonyl) -4- (2,3,4,5-tetraalkoxybenzoyl) piperazine of general formula XI with trifluoroacetic acid in boiling methylene chloride, which leads to the formation of trifluoroacetate 1- (2,3,4,5 -tetraalkoxybenzoyl) piperazine of the general formula XII;

- Treatment of trifluoroacetate 1- (2,3,4,5-tetraalkoxybenzoyl) piperazine of general formula XII with an aqueous solution of 1H-pyrazole-1-carboximidamide hydrochloride in the presence of sodium carbonate, which leads to the formation of 4- (2,3,4,5- tetraalkoxybenzoyl) piperazine-1-carboximidamide of general formula XIII;

- Treatment of 4- (2,3,4,5-tetraalkoxybenzoyl) piperazine-1-carboximidamide of the general formula XIII with acetic acid, which leads to the formation of salts of 4- (2,3,4,5-tetraalkoxybenzoyl) piperazine-1-carboximide- amide of the general formula II.

The disadvantages of the method described in the patent analogue [RU 2469029, 2010] are the inability to achieve a purity of the target substance of more than 99%, with an individual impurity content of not more than 0.1%, which is a new requirement for the developed pharmaceutical substances [Q3A (R2). Impurities in New Drug Substances]. In addition, this method does not allow to obtain N, N′-substituted piperazines with an alkyl radical length of R ² greater than C ₄ in high yield due to the difficulty of working with alcohol alcohols with a carbon chain longer than C ₄ at the stage of 2-bromo-3 conversion, 4,5-trialkoxybenzoic acid of general formula IVc 2,3,4,5-tetraalkoxybenzoic acid of general formula IX, while experiments to evaluate their biological activity showed that the antithrombolic activity of N, N′-substituted piperazines increases with increasing length alkyl radical and R ² in the compounds of General formula II.

The technical problem solved by the authors was the creation of new derivatives of N, N′-substituted piperazines with enhanced anti-aggregate, anticoagulant and vasodilating properties and the development of a new method for producing N, N′-substituted piperazines of general formula II with a purity of more than 99%, the content of an individual impurity is not more than 0.1% and the amount of impurities not more than 0.5% [Q3A (R2). Impurities in New Drug Substances] using commercially available starting compounds.

The creation of a new production method was based on the results of the authors' work to increase the degree of purity above 99% according to the scheme proposed earlier in the patent analogue [RU 2469029, 2010], which showed that the main impurities polluting the final product are salts 4- (3,4,5 -trialkoxybenzoyl) piperazine-1-carboximidamide.

These impurities are formed at the reaction stage by alkoxylation of 2-bromo-3,4,5-trialkoxybenzoic acid of the general formula III with sodium alkoxides in the presence of copper (I) iodide. The reaction is accompanied by a side reaction leading to the reduction of bromo-substituted benzoic acids to benzoic acids, i.e., according to FIG. 1 - the formation of the starting 3,4,5-trialkoxybenzoic acids of the general formula III. An admixture of 3,4,5-trialkoxybenzoic acids of the general formula III is not removed by recrystallization due to the related chemical nature of the compounds of the general formula II and VIII. After further chemical processes and isolation of the target product, the target product — N, N′-substituted piperazines of the general formula II, that is, salts of 4- (2,3,4,5-tetraalkoxybenzoyl) piperazine-1-carboximidamide — contains an admixture of salts 4 - (3,4,5-trialkoxybenzoyl) piperazine-1-carboximidamide practically inseparable from the target product by conventional methods (recrystallization, chromatography) without significant loss of the target product.

The technical result in relation to the method was achieved by obtaining N, N′-substituted piperazines of the general formula I with a purity of more than 99%, individual impurity content of not more than 0.1%, as a result of the method, the scheme of which is shown in FIG. 2. The method includes the following steps:

- Treatment of 3,4,5-trialkoxybenzoic acids of the general formula III with bromine in an organic solvent, which leads to the formation of 2-bromo-3,4,5-trialkoxybenzoic acids of the general formula IV. As 3,4,5-trialkoxybenzoic acids, acids are used that contain linear or branched C ₁ -C ₄ alkyl as a substituent. Ethyl acetate or chloroform, or acetic acid, is used as the organic solvent.

- Treatment of 2-bromo-3,4,5-trialkoxybenzoic acids of the general formula IV with alkalis in water or in a water-alcohol solvent in the presence of copper or its salts or oxides in a molar ratio of 2-bromo-3,4,5-trialkolsibenzoic acid formula IV with copper or its salts or its oxides not more than 1: 0.1. Copper (I) chloride is used as copper (I) chloride, copper (I) iodide, copper (I) acetate, copper (II) salts are used copper (II) sulfate, copper (II) chloride, copper (II) acetate ), copper oxide is copper oxide (I), copper oxide (II). Methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol are used as alcohols.

- Processing the reaction mixture with copper (II) salts at a molar ratio of 2-bromo-3,4,5-trialkolsibenzoic acid of the general formula IV with copper (II) salts is not less than 1: 0.5; separation and washing of the precipitate formed with an aqueous solution of alkali; treating the precipitate with acid, separating and washing the resulting 2-hydroxy-3,4,5-trialkoxybenzoic acids of the general formula V with water. As copper (II) salts, copper (II) sulfate, copper (II) chloride, copper (II) acetate are used. As alkaline reagents, potassium or sodium hydroxides are used in water or alcohols, or in a water-alcohol solvent.

- Treatment of 2-hydroxy-3,4,5-trialkoxybenzoic acids of the general formula V with alcohols in the presence of sulfuric acid or with alcohols in a solution of methylene chloride in the presence of dicyclohexylcarbodiimide or dialkyl sulfates in a polar aprotic solvent in the presence of sodium carbonate, which leads to the formation of 2-hydroxy -3,4,5-trialkoxybenzoates of the general formula VI. Methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-o are used as alcohols, dimethyl sulfate is used as dialkyl sulfates, and acetone, methyl ethyl ketone, acetonitrile, N, N- are used as a polar aprotic organic solvent. dimethylformamide.

- Treatment of 2-hydroxy-3,4,5-trialkoxybenzoates of the general formula VI with compounds of the general formula VII in a polar aprotic solvent in the presence of potassium carbonate or a mixture of potassium carbonate and potassium iodide, which leads to the formation of 2,3,4,5-tetraalkoxybenzoates of the general formula VIII; or treating 2-hydroxy-3,4,5-trialkoxybenzoic acids of the general formula V with dialkyl sulfates in a polar aprotic solvent in the presence of potassium carbonate, which leads to the formation of 2,3,4,5-tetraalkoxybenzoates of the general formula VIII. Dimethyl sulfate is used as dialkyl sulfates, and acetone, methyl ethyl ketone, acetonitrile, N, N-dimethylformamide are used as a polar aprotic organic solvent. As compounds of the general formula VII, compounds of the general formula R ² —Y are used, where R ² is a linear or branched alkyl C ₁ -C ₁₂ , Y-Cl, Br.

- Treatment of 2,3,4,5-tetraalkoxybenzoates of the general formula VIII with sodium or potassium hydroxides in water or alcohols or in a water-alcohol solvent; and then treating the resulting reaction mixture with acids, which leads to the formation of 2,3,4,5-tetraalkoxybenzoic acids of the general formula IX. As acids, trifluoroacetic, sulfuric, perchloric, hydrochloric acids, and metal sulfonic acids are used. Methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol are used as alcohols.

- Treatment of 2,3,4,5-tetraalkoxybenzoic acids of the general formula IX with thionyl chloride in a solution of methylene chloride or with thionyl chloride without solvents, which leads to the formation of 2,3,4,5-tetraalkoxybenzoyl chlorides of the general formula X.

- Treatment of 2,3,4,5-tetraalkoxybenzoyl chloride of general formula X with tert-butoxycarbonylpiperazine in the presence of amines in a polar aprotic solvent or in methylene chloride, which leads to the formation of 1- (tert-butoxycarbonyl) -4- (2,3,4, 5-tetraalkoxybenzoyl) piperazines of the general formula XI. As amines, triethylamine, N-methylmorpholine, diisopropylethylamine are used.

- Treatment of 1- (tert-butoxycarbonyl) -4- (2,3,4,5-tetraalkoxybenzoyl) piperazines of the general formula XI with acids in water or in a water-alcohol solvent or in methylene chloride, which leads to the formation of salts 1- (2,3,4,5-tetraalkoxybenzoyl) piperazines of the general formula XII. Methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol are used as alcohols.

- Treatment of salts of 1- (2,3,4,5-tetraalkoxybenzoyl) piperazines of the general formula XII 1H-pyrazole-1-carboximidamide with hydrochloride in the presence of amines, or sodium or potassium carbonates or bicarbonates in water, or in a water-alcohol solvent or in polar aprotic solvent, which leads to the formation of 4- (2,3,4,5-tetraalkoxybenzoyl) piperazine-1-carboximidamide of the general formula XIII. As amines, triethylamine, N-methylmorpholine, diisopropylethylamine are used.

- Treatment of 4- (2,3,4,5-tetraalkoxybenzoyl) piperazine-1-carboximidamide of the general formula XII with mineral or organic C ₁ -C ₄ acid in water, or alcohols, or methylene chloride, or acetone or mixtures thereof, which leads to the formation of N, N′-substituted piperazines of the general formula II. Phosphoric acid, hydrochloric acid and the like are used as a mineral acid, acetic acid, fumaric acid, methanesulfonic acid and the like are used as organic C ₁ -C ₄ acids.

Treatment of 3,4,5-trialkoxybenzoic acids of the general formula III with bromine in an organic solvent leads to the formation of 2-bromo-3,4,5-trialkoxybenzoic acids of the general formula IV. Acetic acid, chloroform or ethyl acetate can be used as organic solvents. When carrying out the reaction in acetic acid, the reaction is carried out at room temperature, when chloroform or ethyl acetate are used as solvents - the process is carried out at elevated temperature, while the reaction is most expediently carried out by boiling.

One of the key steps in the process for producing N, N′-substituted piperazines of general formula II is the step of producing 2-hydroxy-3,4,5-trialkoxybenzoic acids of general formula V. For hydrolysis of 2-bromo-3,4,5-trialkoxybenzoic acid of general Formulas IV use sodium or potassium hydroxides, carbonates or phosphates. These substances must be introduced into the reaction in at least a 3-fold molar excess with respect to 2-bromo-3,4,5-trialkoxybenzoic acid of the general formula IV. The reaction can be carried out in an aqueous or in an aqueous-alcoholic solution, moreover, methanol, ethanol, propan-1-ol, propan-2-ol, ibutan-1-ol can be used as alcohols. The reaction is carried out at elevated temperature, it is most advisable to carry it out when boiling. The reaction should be carried out in the presence of copper, its salts or oxides. Moreover, copper salts can be used: copper (I) chloride, copper (I) iodide, copper (I) acetate, copper (II) sulfate, copper (II) chloride, copper (II) acetate; as copper oxides, copper oxide (I) or copper oxide (II). The molar ratio of 2-bromo-3,4,5-trialkoxybenzoic acid of the general formula IV and copper, or copper salts or copper oxides, used for carrying out the reaction is not more than 1: 0.1. A larger amount of copper, or its salts, or its oxides does not affect the reaction rate and the purity of 2-hydroxy-3,4,5-trialkoxybenzoic acid of the general formula V, however, it significantly complicates the technical execution of the process. So, with a molar ratio of 2-bromo-3,4,5-trialkoxybenzoic acid of the general formula IV and copper, or copper salts or copper oxides greater than 1: 0.1, during its conversion to 2-hydroxy-3,4,5 β-trialkoxybenzoic acid of the general formula V precipitation of copper compounds with 2-hydroxy-3,4,5-trialkoxybenzoic acids of the general formula V is observed, which leads to a strong foaming of the reaction mixture, which complicates the further reaction.

After completion of the reaction for the conversion of 2-bromo-3,4,5-trialkoxybenzoic acid of general formula IV to 2-hydroxy-3,4,5-trialkoxybenzoic acid of general formula V, copper (II) salts are added to the reaction mixture to obtain copper compounds ( II) with 2-hydroxy-3,4,5-trialkoxybenzoic acids of the general formula V, precipitated from the reaction mixture. As the salts of copper (II) in the isolation of sparingly soluble compounds of copper (II) with 2-hydroxy-3,4,5-trialkoxybenzoic acids of the general formula V, any water-soluble salts of copper (II) can be used, for example, copper (II) sulfate, chloride copper (II). For precipitation, it is necessary to use a molar ratio of 2-bromo-3,4,5-trialkoxybenzoic acid of the general formula IV, taken into the reaction, to the salts of copper (II), which would be at least 1: 0.5. An important condition for the precipitation of the copper (II) compound with 2-hydroxy-3,4,5-trialkoxybenzoic acids of the general formula V is the alkaline reaction of the solution, which must be maintained even after the addition of the entire amount of copper (II) salts. To comply with this condition, it is advisable to add alkali to the reaction mixture after the reaction in a molar ratio to copper (II) salts of at least 2: 1.

The preparation and isolation of sparingly soluble copper (II) compounds with 2-hydroxy-3,4,5-trialkoxybenzoic acids of the general formula V allows their further purification from impurities, including 3,4,5-trialkoxybenzoic acid of the general formula III. Purification is carried out by washing the copper (II) compounds with 2-hydroxy-3,4,5-trialkoxybenzoic acids of the general formula V with an alkali solution. As alkalis, solutions of sodium or potassium hydroxides in water are used. Next, an acid treatment is carried out. As the acid used: hydrochloric, sulfuric, perchloric, trifluoroacetic acids. Other strong acids that form water-soluble copper salts can be used.

The process at this stage leads to the preparation of an intermediate product, namely 2-hydroxy-3,4,5-trialkoxybenzoic acid of general formula V containing at least 99% of the basic substance.

Further interaction of 2-hydroxy-3,4,5-trialkoxybenzoic acid of general formula V with alcohols in the presence of sulfuric acid or with alcohols in a solution of methylene chloride in the presence of dicyclohexylcarbodiimide or with dialkyl sulfate in a polar aprotic solvent in the presence of sodium carbonate leads to the formation of 2-hydroxy -3,4,5-trialkoxybenzoates of the general formula VI. When carrying out the reaction in dicyclohexylcarbodiimide, the reaction is carried out at room temperature, and when it is carried out in the presence of sulfuric acid or with dialkyl sulfate at an elevated temperature, it is most advisable in this case to carry out the reaction by boiling. As polar aprotic solvents, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide can be used.

The interaction of 2-hydroxy-3,4,5-trialkoxybenzoates of the general formula VI with compounds of the general formula VII (namely, alkyl halides or dialkyl sulfates) in a polar aprotic solvent in the presence of potassium carbonate leads to the formation of 2,3,4,5-tetraalkenesibenzoates of the general formula VIII . Also, the interaction of 2-hydroxy-3,4,5-trialkoxybenzoic acid of the general formula V with dialkyl sulfate in a polar aprotic solvent in the presence of potassium carbonate results in the formation of 2,3,4,5-tetraalkenesibenzoates of the general formula VIII. The reaction is carried out at elevated temperature. If the solvent used is: acetone, methyl ethyl ketone, acetonitrile, it is advisable to carry out the reaction by boiling. The following can be used as polar aprotic solvents: acetone, methyl ethyl ketone, acetonitrile, dimethylformamide.

The hydrolysis of 2,3,4,5-tetraalkenesibenzoates of the general formula VIII is carried out with sodium or potassium hydroxides in water or alcohols, or in a water-alcohol solvent. As alcohols, methanol, ethanol, propan-1-ol, propan-2-ol butan-1-ol are used. Hydrolysis is carried out at elevated temperature (the most appropriate reaction is carried out by boiling). Further processing of the reaction mixture with acids gives 2,3,4,5-tetraalkoxybenzoic acid of the general formula IX. As the acids used: trifluoroacetic, sulfuric, perchloric, hydrochloric acid, methyl sulfonic acid.

The reaction of 2,3,4,5-tetraalkenesibenzoic acid of the general formula IX with thionyl chloride in a methylene chloride solution or without solvent thionyl chloride with catalytic amounts of N, N-dimethylformamide gives 2,3,4,5-tetraalkoxybenzoyl chloride of the general formula X.

The reaction is carried out at elevated temperature (the most appropriate reaction is carried out by boiling). After completion of the reaction, the solvent and excess thionyl chloride were removed under reduced pressure, and the resulting 2,3,4,5-tetraalkoxybenzoyl chloride of general formula X was used in the next step without further purification.

2,3,4,5-Tetraalkoxybenzoyl chloride of general formula X, when reacted with tert-butoxycarbonylpiperazine in the presence of amines in a polar aprotic solvent or in methylene chloride, gives 1- (tert-butoxycarbonyl) -4- (2,3,4,5-tetraalkoxybenzoyl ) piperazine of the general formula XI. The following can be used as polar aprotic solvents: acetone, methyl ethyl ketone, acetonitrile, N, N-dimethylformamide. As amines, triethylamine, N-methylmorpholine, diisopropylethylamine are used. The isolation of 1- (tert-butoxycarbonyl) -4- (2,3,4,5-tetraalkoxybenzoyl) piperazines of the general formula XI is carried out using conventional organic synthesis methods.

Deprotection of 1- (tert-butoxycarbonyl) -4- (2,3,4,5-tetraalkoxybenzoyl) piperazines of the general formula XI is carried out with acids in water or in an aqueous-alcoholic solvent or in methylene chloride with the formation of salts 1- (2,3,4,5-tetraalkoxybenzoyl) piperazines of the general formula XII. As acids can be used: trifluoroacetic, sulfuric, hydrochloric acids, methyl sulfonic acid. The reaction is carried out at elevated temperature, for example, by boiling. As the alcohols used: methanol, ethanol, propan-1-ol, propan-2-ol ibutan-2-ol. Isolation of the intermediate is carried out by distillation of the solvent.

The reaction of salts of 1- (2,3,4,5-tetraalkoxybenzoyl) piperazines of the general formula XII with 1H-pyrazole-1-carboximidamide hydrochloride leads to the formation of 4- (2,3,4,5-tetraalkoxybenzoyl) piperazine-1-carboximidamide formulas XIII. The reaction is carried out at a temperature below 50 ° C. Water, a water-alcohol solvent are used as solvents (methanol, ethanol, propan-1-ol, propan-2-ol, butan-2-ol or polar aprotic solvent: acetone, methyl ethyl ketone, acetonitrile, N, N-dimethylformamide). The reaction is carried out in the presence of amines (triethylamine, N-methylmorpholine, diisopropylethylamine) are used as amines), sodium or potassium carbonates or bicarbonates. The isolation of 4- (2,3,4,5-tetraalkolsibenzoyl) piperazine-1-carboximidamides of the general formula XIII is carried out using traditional methods of organic synthesis.

The reaction of 4- (2,3,4,5-tetraalkolsibenzoyl) piperazine-1-carboximide amide of the general formula XIII with mineral or organic C ₁ -C ₄ acid is carried out in water, alcohols, methylene chloride, acetone, or mixtures thereof, which leads to the formation of N, N′-substituted piperazines of the general formula II. The isolation of N, N′-substituted piperazines of the general formula II is carried out using traditional methods of organic synthesis.

The degree of reactions and the purity of intermediates at each stage of synthesis are controlled by TLC on Merck "TLC Silica gel 60 F ₂₅₄ " or Macherey-Nagel "ALUGRAM SIL G / UV ₂₅₄ " plates in cyclohexane / acetic acid / isopropyl alcohol systems (20: 2 : 3) and cyclohexane / tert-butyl methyl ether (10: 3).

The purity of the obtained compounds was evaluated by HPLC on an Alliance chromatograph (Waters) —Zorbax Eclipse XDB-C18 column, 3.5 μm, 3 * 100 mm (Agilent Technologies), mobile phase — a mixture of a buffer solution containing 0.01 M sodium octanesulfonate and 0.03 M sodium dihydrogen phosphate (pH 3.0) with acetonitrile (75:25 v / v) in the isocratic mode, or 0.05 M solution of phosphoric acid and acetonitrile in a linear gradient mode from 5% acetonitrile to 70%. Detection is carried out at 210 nm.

The structure of the intermediate and final compounds is confirmed by ¹ H and ¹³ C NMR spectroscopy (Bruker DPX 300 instrument, frequency 300 and 75 MHz, respectively). When registering the spectra of compounds in CDCl ₃ , DMSO or D ₂ O, the signals of residual protons for ¹ N (7.28 ppm, 2.50 ppm and 4.79 ppm, respectively) and the signals of the carbon atoms of the solvent for ¹³ C (77.16 ppm and 39.52 ppm) are used as internal standards. KSSW (constant of spin-spin interaction) in proton spectra was estimated in the first order approximation. Mass spectra of N, N′-substituted piperazines were recorded on a Bruker AmaZon mass spectrometer (electrospray ionization).

In FIG. 1 is a diagram of the preparation of N, N′-substituted piperazines according to patent RU 2469029, 2010. FIG. 2 shows the claimed scheme for the production of N, N′-substituted piperazines, which provides the target product with a purity of more than 99% and an individual impurity content of not more than 0.1%.

Physical and pharmacobiological studies have shown that the synthesized N, N′-substituted piperazines of the general formula 1 have good solubility in water, compared with the known analogues of -N, N′-substituted piperazines according to the patent RU 2469029, 2010, have a wider therapeutic interval, a lower average effective dose of the EU ₅₀ when inhibiting platelet aggregation, and a stronger vasodilator and anticoagulant effect. This allows them to be widely used as drugs that affect the hemostatic system and combine antiplatelet, anticoagulant and vasodilatory activity.

In particular, in the treatment of pathologies of the hemostasis system, studies have shown that the introduction of N, N′-substituted piperazines into the body at a dose of 0.001 mM / kg or more leads to a decrease in pathological platelet aggregation, a positive effect on the fibrinolysis system, and vasodilation of blood vessels, which confirmed by the examples below.

N, N′-substituted piperazines can be introduced into the body in compositions containing a mixture of physiologically active (active) substances with excipients. As excipients, substances permitted by the Pharmacopoeia are used that improve the conditions for the preparation, storage or use of a medicinal product, for example, solvents, fillers, flavors, flavorings, stabilizers, etc.

The essence and advantages of the claimed N, N′-substituted piperazines and a method for producing N, N′-substituted piperazines are illustrated by the following examples.

Example 1. Obtaining 1-carbimidamido-4- (2,3,4,5-tetramethoxybenzoyl) piperazine acetate

2.1. 2-bromo-3,4,5-trimethoxybenzoic acid

To a suspension of 3,4,5-trimethoxybenzoic acid (100.0 g, 0.471 M) in ethyl acetate (500 ml) was added 2 ml of water. The reaction mixture is heated to boiling point. To the boiling reaction mixture, bromine (26.6 ml, 0.519 M) was added dropwise with stirring for 30 minutes. The mixture was refluxed for 2 hours. Volatile components from the mixture are removed on a rotary film evaporator under reduced pressure. The intermediate product, crystals of a pale cream color, obtained in quantitative yield (137.2 g, 100%), used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.92 (3H, CH ₃ O-), 3.93 (3H, CH ₃ O-), 3.98 (3H, CH ₃ O-), 7.42 (1H, s. , H-Ar), 11.00 (1H, br.s.CO ₂ H ). The purity of the intermediate according to ¹ H NMR and TLC spectroscopy is 95%.

2.2. 2-hydroxy-3,4,5-trimethoxybenzoic acid

To a hot solution of 2-bromo-3,4,5-trimethoxybenzoic acid (33.2 g, 0.114 M) and sodium hydroxide (18.25 g, 0.456 M) in a mixture of water (100 ml) and methanol (100 ml) are added copper (I) chloride (0.56 g, 5.7 mmol). The reaction mixture was refluxed with stirring for 8 hours. Water (100 ml) and sodium hydroxide (4.56 g, 0.114 M) are added to the hot reaction mixture, after which a hot solution of copper (II) dihydrate chloride (9.72 g, 0.057 M) in water (100 ml) is added with stirring. ) The precipitate formed is filtered off. The precipitate is suspended in a 5% sodium hydroxide solution (100 ml), stirred for 1 hour, and then separated by filtration (the operation is repeated twice). The precipitate was suspended in water (100 ml), acidified with concentrated hydrochloric acid (25 ml, 0.3 M), the precipitate was filtered off, washed with water (3 × 100 ml), and dried in vacuo. Intermediate - crystals of a pale cream color (7.80 g, 30%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.87 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.05 (3H, CH ₃ O-), 5.5 (1H, br. s., HO-Ar), 7.17 (1H, s, H-Ar), 10.31 (1H, s. CO ₂ H ).

According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate - 2-hydroxy-3,4,5-trimethoxybenzoic acid - 99.5%.

2.3. 2-hydroxy-3,4,5-trimethoxybenzoic acid

To a hot solution of 2-bromo-3,4,5-trimethoxybenzoic acid (33.2 g, 0.114 M), sodium hydroxide (18.25 g, 0.456 M) in a mixture of water (100 ml) and propan-2-ol ( 100 ml) add copper (I) iodide (0.23 g, 1.2 mmol, 1% mol.). The reaction mixture was refluxed with stirring for 10 hours. Water (100 ml) and sodium hydroxide (13.70 g, 0.342 M) are added to the hot mixture, after which a hot solution of copper (II) sulfate pentahydrate (42.70 g, 0.171 M) in water (150 ml) is added with stirring. ) The precipitate formed is filtered off, suspended in a 5% solution of sodium hydroxide in water (100 ml), stirred for 1 hour, separated by filtration (the operation is repeated three times). The precipitated precipitate was suspended in 100 ml), acidified with concentrated hydrochloric acid (25 ml, 0.3 M), the precipitate was filtered off, washed on the filter with water (3 × 100 ml) and dried in vacuo. The intermediate product is obtained in the form of crystals of a pale cream color (7.28 g, 28%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.87 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.05 (3H, CH ₃ O-), 5.5 (1H, br. s, HO-Ar), 7.17 (1H, s, H-Ar), 10.31 (1H, s. CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate - 2-hydroxy-3,4,5-trimethoxybenzoic acid - 99.5%.

2.4. 2-hydroxy-3,4,5-trimethoxybenzoic acid

To a hot solution of 2-bromo-3,4,5-trimethoxybenzoic acid (37.55 g, 0.129 M) and sodium carbonate (34.20 g, 0.323 M) in water (200 ml), copper (II) sulfate pentahydrate ( 3.22 g, 0.013 M, 10 mol%), the mixture is refluxed with stirring for 6 hours. Sodium hydroxide (5.20 g, 0.130 M) was added to the hot reaction mixture, and a hot solution of copper (II) sulfate pentahydrate (16.10 g, 0.065 M) in water (50 ml) was added with stirring. The precipitate formed is filtered off, suspended in a 5% sodium hydroxide solution (100 ml), stirred for 1 hour, after which the precipitate is separated by filtration (the operation is repeated three times), suspended in water (100 ml), acidified with concentrated hydrochloric acid (25 ml, 0.3 M). The precipitate formed is filtered off, washed on the filter with water (3 × 100 ml) and dried in vacuo. The intermediate product is obtained in the form of crystals of a pale cream color (9.13 g, 31%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.87 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.05 (3H, CH ₃ O-), 5.5 (1H, br. s, HO-Ar), 7.17 (1H, s, H-Ar), 10.31 (1H, s. CO ₂ H ).

According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate - 2-hydroxy-3,4,5-trimethoxybenzoic acid - 99.5%.

2.5. 2-hydroxy-3,4,5-trimethoxybenzoic acid

To a hot solution of 2-bromo-3,4,5-trimethoxybenzoic acid (33.2 g, 0.114 M) and sodium hydroxide (18.25 g, 0.456 M) in water (150 ml), copper (II) oxide is added (4 , 53 g, 0.057 M, 50% mol.). The reaction mixture was refluxed with stirring for 7 hours. Water (100 ml) and sodium hydroxide (4.56 g, 0.114 M) are added to the hot mixture, after which a hot solution of copper (II) sulfate pentahydrate (14.23 g, 0.057 M) in water (100 ml) is added with stirring. . The precipitate formed is filtered off. The precipitate is suspended in a 5% aqueous solution of sodium hydroxide (100 ml), stirred for 1 hour, the precipitate is separated by filtration (operation is repeated three times). The precipitate isolated is suspended in water (100 ml) and acidified with concentrated hydrochloric acid (25 ml, 0.3 M). The precipitate formed is filtered off, washed on the filter with water (3 × 100 ml), squeezed and dried in vacuo. The intermediate product is obtained in the form of crystals of a pale cream color (11.70 g, 45%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.87 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.05 (3H, CH ₃ O-), 5.5 (1H, br. s, HO-Ar), 7.17 (1H, s, H-Ar), 10.31 (1H, s. CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate - 2-hydroxy-3,4,5-trimethoxybenzoic acid - 99.5%.

2.6. 2,3,4,5-Tetramethoxybenzoic acid methyl ester

To a boiling solution of 2-hydroxy-3,4,5-trimethoxybenzoic acid (31.0 g, 0.136 M) in acetone (250 ml), anhydrous potassium carbonate (61.0 g, 0.442 M) is added with stirring, then dimethyl sulfate (38 6 g, 0.306 M). The reaction mixture was refluxed with stirring for 6 hours. The precipitated salts are separated from the cooled reaction mixture by filtration and discarded. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate was obtained in quantitative yield (35.0 g, 100%) as a light brown viscous liquid, and was used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.79 (6H, s, CH ₃ O- and CH ₃ O ₂ C), 3.81 (3H, CH ₃ O-), 3.87 (3H, CH ₃ O-) 6.10 (1H, s., H-Ar)

2.7. 2,3,4,5-tetramethoxybenzoic acid

To a 2,3,4,5-tetramethoxybenzoic acid methyl ester (35.0 g, 0.136 M), a 5 M aqueous solution of potassium hydroxide (200 ml) was added dropwise with stirring and heating in a boiling water bath for 20 minutes. The reaction mixture was stirred under heating for 1 hour, acidified with concentrated hydrochloric acid (130 ml, ~ 1.5 M) while cooling with ice. The precipitate was separated by filtration, washed with water (2 × 100 ml).

The precipitate was dissolved in methylene chloride (250 ml), the solution was washed with water (1 × 200 ml), saturated sodium chloride solution (~ 100 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, crystals of light beige color (31.0 g, 94%), are used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.89 (3H, CH ₃ O-), 3.93 (3H, CH ₃ O-), 3.99 (3H, CH ₃ O-), 4.08 (3H, CH ₃ O-), 7.40 (1H, s, H-Ar), 10.40 (1H, s. CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the reaction product - 2,3,4,5-tetramethoxybenzoic acid - 99.8%.

2.8. 2,3,4,5-tetramethoxybenzoyl chloride

To a solution of 2,3,4,5-tetramethoxybenzoic acid (31.0 g, 0.128 M) in methylene chloride (50 ml) was added thionyl chloride (30.9 g, 0.260 M) and N, N-dimethylformamide (0.05 ml). The mixture was stirred at room temperature for 1 hour, refluxed for 2 hours. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The intermediate, a viscous liquid of light brown color, obtained in quantitative yield (33.4 g, 100%), used in the next step without further purification.

2.9. 1- (tert-butoxycarbonyl) -4- (2,3,4,5-tetramethoxybenzoyl) piperazine

To a solution of 1- (tert-butoxycarbonyl) piperazine (25.7 g, 0.138 M) and triethylamine (28.4 ml, 0.204 M) in acetone (100 ml) was added dropwise with stirring and external cooling in an ice-salt bath, 3,4,5-tetramethoxybenzoyl chloride (33.4 g, 0.128 M) in acetone (40 ml). The reaction mixture was stirred while cooling for 10 minutes, then at room temperature for 2 hours. The reaction mixture was poured into water (2000 ml) with vigorous stirring. The precipitate was separated by filtration, washed on the filter with water (2 × 200 ml). The precipitate was dissolved in methylene chloride and washed successively with a saturated solution of ammonium chloride (2 × 50 ml), water (2 × 50 ml), saturated sodium bicarbonate solution (2 × 50 ml), water (2 × 50 ml), saturated chloride solution sodium (50 ml), dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate product, a light yellow liquid (49.0 g, 93%), crystallized upon standing in pale cream crystals, is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 1.47 (9H, s, (CH ₃ ) ₃ C-), 3.0-4.0 (20H, m, 4xC H ₃ O-, C H ₂ piperazine fragment) 6.54 (1H, s., H-Ar).

2.10. 1- (2,3,4,5-tetramethoxybenzoyl) piperazine trifluoroacetate

To a solution of 1- (tert-butoxycarbonyl) -4- (2,3,4,5-tetramethoxybenzoyl) piperazine (49.0 g, 0.119 M) in methylene chloride (200 ml) was added trifluoroacetic acid (27.1 g, 0.238 M). The reaction mixture was refluxed with stirring for 5 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The intermediate product is obtained in quantitative yield (50.6 g, 100%) and is used without further purification in the next step. ¹ H NMR Spectrum (DMSO), δ, ppm (J, Hz): 2.5-4.1 (20H, m, 4xC H ₃ O-, C H ₂ -piperazine fragment), 6.71 (1H, s, H-Ar), 9.63 (2H, br.s, N ⁺ H ₂ ).

2.11. 1-carbimidamido-4- (2,3,4,5-tetramethoxybenzoyl) piperazine acetate

), 3,24 (2Н, м., СH ₂-пиперазинового фрагмента), 3,37 (2Н, м., СH ₂-пиперазинового фрагмента) 3,50 (2Н, м., СH ₂-пиперазинового фрагмента), 3,68 (2Н, м., СH ₂-пиперазинового фрагмента), 3,70 (3Н, м., CH ₃O-), 3,76 (3Н, м., CH ₃O-), 3,78 (3Н, м., CH ₃O-), 3,83 (3Н, м., CH ₃O-), 6,66 (1Н, с., H-Ar), 8,95 (4Н, ш.с., C(NH ₂)(N⁺ H ₂)). Масс-спектр: МН⁺ найдено - 353,21, МН⁺ вычислено - 353,18. Чистота продукта по данным ВЭЖХ 99,56%, максимальная неидентифицированная примесь 0,08%, сумма неидентифицированных примесей 0,44%.To a solution of 1- (2,3,4,5-tetramethoxybenzoyl) piperazine trifluoroacetate (50.6 g, 0.119 M) and 1H-pyrazole-1-carboximidamide hydrochloride (19.2 g, 0.131 M) in water (200 ml) sodium carbonate (26.5 g, 0.250 M) was added in portions. The reaction mixture was stirred at 50 ° C for 24 hours, cooled and washed with tert-butyl methyl ether (3 × 40 ml), made basic with sodium hydroxide (15 g, 0.375 M), extracted with methylene chloride (4 × 30 ml). The combined organic extracts were washed with water (30 ml), dried over anhydrous potassium carbonate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The remainder of 1-carbimide-amido-4- (2,3,4,5-tetramethoxybenzoyl) piperazine was dissolved in acetone (200 ml). Insoluble impurities are separated by filtration of the suspension at a temperature of 50 ° C through celite. Glacial acetic acid (6.1 ml, 0.107 M) was added to the filtrate. The precipitate was filtered off, washed with acetone (2 × 20 ml), and refluxed with stirring in a mixture of acetone: water (200 ml: 20 ml) for 90 minutes. The precipitate was filtered off, washed with acetone (2 × 100 ml) and dried in vacuo. Intermediate, small colorless crystals (39.2 g, 80%). ¹ H NMR spectrum (DMSO), δ, ppm (J, Hz): 1.64 (3H, s, $$C{\underset{\_}{H}}_{3}C{O}_2^{-}$$

), 3.24 (2H, m, C H ₂ piperazine fragment), 3.37 (2H, m, C H ₂ piperazine fragment) 3.50 (2H, m, C H ₂ piperazine ), 3.68 (2H, m, C H ₂ piperazine fragment), 3.70 (3H, m, C H ₃ O-), 3.76 (3H, m, C H ₃ O-) 3.78 (3H, m, C H ₃ O-), 3.83 (3H, m, C H ₃ O-), 6.66 (1H, s, H-Ar), 8.95 (4H, br.s, C (N H ₂ ) (N ⁺ H ₂ )). Mass spectrum: MH ⁺ found, 353.21; MH ⁺ calculated, 353.18. The purity of the product according to HPLC 99.56%, the maximum unidentified impurity of 0.08%, the sum of unidentified impurities of 0.44%.

Example 2. Obtaining 1-carbimidamido-4- (2,3,4,5-tetramethoxybenzoyl) piperazine hemi-fumarate monohydrate

2.1 Carbimidamido-4- (2,3,4,5-tetramethoxybenzoyl) piperazine hemifumarate

1-Carbimidamido-4- (2,3,4,5-tetramethoxybenzoyl) piperazine acetate (39.0 g, 0.095 M), prepared as described in Example 1, was dissolved in hot water (125 ml, ~ 60 ° C). A hot (~ 60 ° C) solution of fumaric acid (5.2 g, 0.045 M) in water (75 ml) is added to the solution. The precipitate formed is filtered off and washed on the filter with water (3 × 75 ml). The precipitate was recrystallized from hot water to give 1-carbimidamido-4- (2,3,4,5-tetramethoxybenzoyl) piperazine hemi-fumarate monohydrate as colorless crystals (30.3 g, 78%). ¹ H NMR Spectrum (DMSO), δ, ppm (J, Hz): 3.25 (2H, m, C H ₂ piperazine fragment), 3.39 (4H, m, C H ₂ piperazine fragment and H ₂ O), 3.51 (2H, m., C H ₂ piperazine fragment), 3.65 (5H, m., C H ₂ piperazine fragment and C H ₃ O-), 3.76 (3H, m, C H ₃ O-), 3.78 (3H, m., C H ₃ O-), 3.83 (3H, m., C H ₃ O-), 6.21 (1H, s., HO ₂ CC H = C H CO ₂ H), 6.67 (1H, s, H-Ar), 9.43 (4H, br.s, C (N H ₂ ) (N ⁺ H ₂ )). ¹³ C NMR (DMSO), δ, ppm .: 40,64 (CH ₂ -piperazine fragment), 44,29 (CH ₂ -piperazine fragment), 44,82 (CH ₂ -piperazine fragment), 45, 63 (CH ₂ piperazine fragment), 56.17 (CH ₃ O-), 60.68 (CH ₃ O-), 61.06 (CH ₃ O-), 61.52 (CH ₃ O-), 105 43 (С6, Ar), 124.54 (С1, Ar), 136.56 (НО ₂ С С Н = С НСО ₂ Н), 143.04 (С2, Ar), 143.20 (С5, Ar) , 146.48 (C4, Ar), 149.51 (C3, Ar), 157.43 ( C (NH ₂ ) (N ⁺ H ₂ )), 166.16 ( C ON), 172.12 (HO ₂ C CH = CH C O ₂ H). Mass spectrum: MH ⁺ found, 353.20; MH ⁺ calculated, 353.18. The purity of the product according to HPLC 100%, unidentified impurities were not found.

Example 3. Obtaining 1-carbimidamido-4- (2- [1-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine acetate

3.1. 2-bromo-3,4,5-trimethoxybenzoic acid

Water (10 ml) was added to a solution of 3,4,5-trimethoxybenzoic acid (106.0 g, 0.50 M) in chloroform (500 ml). The reaction mixture is heated to boiling point, a solution of bromine (99.8 g, 0.626 M) in chloroform (100 ml) is added dropwise to the boiling reaction mixture for 30 minutes. The reaction mixture was refluxed for 10 hours, cooled, washed with water (3 × 200 ml) and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate product is obtained in the form of pale cream crystals (120.8 g, 83%), used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.92 (3H, CH ₃ O-), 3.93 (3H, CH ₃ O-), 3.98 (3H, CH ₃ O-), 7.42 (1H, s. , H-Ar), 11.00 (1H, br.s.CO ₂ H ). The purity of the intermediate according to ¹ H NMR and TLC spectroscopy is 95%.

3.2. 2-hydroxy-3,4,5-trimethoxybenzoic acid

To a hot solution of 2-bromo-3,4,5-trimethoxybenzoic acid (60.0 g, 0.206 M) and sodium hydroxide (50.0 g, 1.25 M) in water (400 ml), copper sulfate ( II) pentahydrate (51.4 g, 0.206 M, 100% mol.), The mixture is boiled for 3.5 hours (2 hours after the start of boiling, butan-1-ol (10 ml) is added to suppress foaming). Then the reaction mixture is cooled, the precipitate is separated by filtration. The precipitate is suspended in a 5% sodium hydroxide solution (200 ml), stirred for 1 hour, and then separated by filtration (operation is repeated three times). The precipitate was suspended in water (200 ml and acidified with concentrated hydrochloric acid (50 ml, 0.6 M). The precipitate was separated by filtration, washed with water (3 × 100 ml) on the filter, squeezed and dried in vacuo. The product was obtained in the form of crystals pale cream color (8.46 g, 18%). ¹ NMR spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.87 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.05 (3H, CH ₃ O-), 5.5 (1H, br s, HO-Ar), 7.17 (1H, s, H-Ar) , 10.31 (1H, s, CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate, 2-hydroxy-3,4,5-trimethoxybenzoic acid, is 99.5%.

From the alkaline filtrate, acidification with concentrated hydrochloric acid (200 ml, 2.4 M) and subsequent filtration isolate the crude unreacted 2-bromo-3,4,5-trimethoxybenzoic acid, which is recrystallized from water. After air drying, 2-bromo-3,4,5-trimethoxybenzoic acid (28.8 g, 48%) is obtained. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.92 (3H, CH ₃ O-), 3,93 (3H, CH ₃ O-), 3,98 (3H, CH ₃ O-), 7.42 (1H, s. , H-Ar), 11.00 (1H, br.s.CO ₂ H ).

3.3. 2-hydroxy-3,4,5-trimethoxybenzoic acid

To a hot solution of 2-bromo-3,4,5-trimethoxybenzoic acid (60.00 g, 0.206 M) and sodium hydroxide (50.0 g, 1.25 M) in water (400 ml), copper acetate ( II) monohydrate (2.06 g, 10.4 mmol, 5% mol.). The reaction mixture was refluxed for 7 hours. A hot solution of copper (II) dihydrate chloride (17.0 g, 0.10 M) in water (100 ml) is added to the hot reaction mixture with stirring. The precipitate formed is filtered off, suspended in a 5% sodium hydroxide solution (200 ml), stirred for 1 hour, separated by filtration (the operation is repeated three times). The precipitate isolated is suspended in water (500 ml) and acidified with trifluoroacetic acid (44.6 ml, 0.6 M). The precipitate was separated by filtration, washed with water (3 × 100 ml), dried in vacuum. The intermediate product is obtained in the form of crystals of a pale cream color. (18.80 g, 40%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.87 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.05 (3H, CH ₃ O-), 5.5 (1H, br. s, HO-Ar), 7.17 (1H, s, H-Ar), 10.31 (1H, s. CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate - 2-hydroxy-3,4,5-trimethoxybenzoic acid - 99.5%.

3.4. 2-Hydroxy-3,4,5-trimethoxybenzoic acid methyl ester

To a boiling solution of 2-hydroxy-3,4,5-trimethoxybenzoic acid (18.2 g, 0.080 M) in acetone (150 ml), anhydrous sodium carbonate (20.4 g, 0.192 M), dimethyl sulfate (12) are added in portions. 1 g, 0.096 M). The reaction mixture was refluxed with stirring for 3 hours. The precipitate was separated from the cooled reaction mixture by filtration and discarded. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The residue was dissolved in ethyl acetate (200 ml) and washed successively with saturated sodium hydrogen carbonate solution (2 × 50 ml), water (2 × 50 ml), saturated sodium chloride solution (50 ml), and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The resulting residue is crystallized from heptane. The intermediate product is obtained in the form of large crystals of sand color (11.6 g, 60%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.84 (3H, s, CH ₃ O ₂ C-), 3.93 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.01 ( 3H, CH ₃ O-), 7.08 (1H, s, H-Ar), 10.68 (1H, s, HO-Ar).

3.5. 2- (1-Methylpropyl) hydroxy-3,4,5-trimethoxybenzoic acid methyl ester

Dissolve 2-hydroxy-3,4,5-trimethoxybenzoic acid methyl ester (4.95 g, 0.020 M), 2-bromobutane (2.74 ml, 3.43 g, 0.025 M), anhydrous potassium carbonate (4.15 g, 0.030 M) and potassium iodide (0.33 g, 0.002 M) in N, N-dimethylformamide (15 ml). The reaction mixture is heated with stirring at a temperature of 65 ° C for 5 hours. To the reaction mixture was added 2-bromobutane (1.71 g, 0.012 M) and anhydrous potassium carbonate (2.00 g, 0.015 M each), heated with stirring at a temperature of 65 ° C for 5 hours (the operation was repeated twice). The cooled reaction mixture was poured into water (50 ml), acidified with concentrated hydrochloric acid (20 ml, ~ 0.240 M) and extracted with tert-butyl methyl ether (3 × 25 ml). The combined extracts were washed successively with water (2 × 30 ml), saturated sodium bicarbonate solution (2 × 30 ml), 10% sodium thiosulfate solution (2 × 20 ml), saturated sodium chloride solution (30 ml), dried over anhydrous calcium chloride. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure.

The intermediate, a yellow liquid (5.90 g, 97%), is used in the next step without further purification.

3.6. 2- (1-Methylpropyl) hydroxy-3,4,5-trimethoxybenzoic acid

To a solution of 2- (1-methylpropyl) hydroxy-3,4,5-trimethoxybenzoic acid methyl ester (5.90 g, 0.020 M) in 95% aqueous ethanol (20 ml), potassium hydroxide (1.40 g, 0.025 M ) The reaction mixture was refluxed with stirring for 1 hour. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The resulting residue was treated with boiling diethyl ether (50 ml). The precipitate was isolated by filtration of a cooled suspension, washed with diethyl ether (40 ml each), and dried in air. The resulting cream-colored precipitate was dissolved in water (50 ml), acidified with concentrated hydrochloric acid (3 ml, 0.036 M) and extracted with diethyl ether (2 × 25 ml). The combined extracts were washed with water (2 × 20 ml), saturated sodium chloride solution (20 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a yellow liquid (5.17 g, 89%), is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 1.06 (3H, t. 6 Hz, C H ₃ CH ₂ С * НCH ₃ ), 1.29 (3Н, d., 6 Hz, CH ₃ CH ₂ С * НС Н ₃ ), 1.8 (2H, m, CH ₃ C H ₂ C * HCH ₃ ), 3.90 (6H, s, 2x CH ₃ O-), 4.00 (3H, s, CH ₃ O -), 4.73 (1H, m, CH ₃ CH ₂ C * H CH ₃ ), 7.45 (1H, s, H-Ar), 11.56 (1H, br.s.CO ₂ H ) ¹³ C NMR Spectrum (CDCl ₃ ), δ, ppm: 9.92 ( C H ₃ CH ₂ C * HCH ₃ ), 19.01 (CH ₃ CH ₂ C * H C H ₃ ), 29.54 (CH ₃ C H ₂ C * HCH ₃ ), 56.19 (CH ₃ O-), 61.22 (CH ₃ O-), 61.33 (CH ₃ O-), 83.51 (CH ₃ CH ₂ C * HCH ₃ ), 108.00 (C1, Ar), 117.20 (C6, Ar), 144.49 (C2, Ar), 145.96 (C5, Ar), 147.92 (C3, Ar) 149.70 (C4, Ar); 165.36 ( C O ₂ H). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate - 2- (1-methylpropyl) hydroxy-3,4,5-trimethoxybenzoic acid - is 99.8%.

3.7. 2- (1-Methylpropyl) hydroxy-3,4,5-trimethoxybenzoyl chloride

To a solution of 2- (1-methylpropyl) hydroxy-3,4,5-trimethoxybenzoic acid (5.0 g, 0.018 M) in methylene chloride (25 ml) was added thionyl chloride (4.18 g, 0.035 M) and N, N-dimethylformamide (0.01 ml). The mixture was stirred at room temperature for 1 hour, after which it was refluxed for 2 hours, and the volatiles were removed on a rotary film evaporator under reduced pressure. The intermediate, a yellow liquid, was obtained in quantitative yield (5.32 g, 100%) and was used in the next step without further purification.

3.8. 1- (tert-butoxycarbonyl) -4- (2- [1-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine

To a solution of 1- (tert-butoxycarbonyl) piperazine (3.76 g, 0.02 M) and triethylamine (4.20 ml, 0.030 M) in methylene chloride (25 ml), a solution of 2- (1-methylpropyl) was added dropwise with stirring hydroxy-3,4,5-trimethoxybenzoyl chloride (5.32 g, 0.018 M) in methylene chloride (25 ml), after which the reaction mixture was stirred for 3 hours. The reaction mixture is filtered, the precipitated precipitate of triethylamine hydrochloride is separated. The filtrate is washed successively with water (2 × 20 ml), saturated ammonium chloride solution (2 × 20 ml), water (2 × 20 ml), saturated sodium bicarbonate solution (2 × 20 ml), saturated sodium chloride solution (20 ml), dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a viscous yellow-brown liquid, slowly crystallizing upon standing in cream-colored crystals, was obtained in quantitative yield (7.95 g, 100%), and was used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz) (hindered rotation around the amide bond in the NMR spectrum shows two isomers): 0.87 and 1.01 (two t, 7.4 and 7.6 Hz, respectively, total 3H, C H ₃ CH ₂ C * HCH ₃ ) 1.09 and 1.27 (two doublets, 5.9 and 5.9 Hz, respectively, 3H, CH ₃ CH ₂ C * NS H ₃ ), 1.49 (9H, s, (C H ₃ ) ₃ C-), 1.66 (2H, m, CH ₃ C H ₂ C * HCH ₃ ), 3.0-4.0 (17H, m, 4xC H ₂ piperazine fragment and 3xC H ₃ O- ), 4.19 (1H, m, CH ₃ CH ₂ C * H CH ₃ ), 6.60 and 6.62 (two s., Total 1H, H-Ar).

3.9. 1- (2- [1-Methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine hydrochloride

Mix 1- (tert-butoxycarbonyl) -4- (2- [1-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine (7.95 g, 0.018 M) with concentrated hydrochloric acid (50 ml, ~ 0, 6 M). The reaction mixture was stirred at room temperature until complete homogenization (3 hours).

The volatile components of the mixture are removed on a rotary film evaporator under reduced pressure, twice adding 20 ml of water to the residue to remove excess hydrogen chloride. The residue was heated with propan-2-ol (100 ml), after which insoluble impurities were separated by filtration through celite. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The resulting intermediate (6.63 g, 97%) was used in the next step without further purification.

3.10. 1-Carbimidamido-4- (2- [1-methylpropyl1oxy-3,4,5-trimethoxybenzoyl) piperazine acetate

To a solution of 1- (2- [1-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine hydrochloride (6.48 g, 0.017 M) and 1H-pyrazole-1-carboximidamide hydrochloride (3.66 g, 0.025 M ) in N, N-dimethylformamide (20 ml) while heating to a temperature of 50 ° C, diisopropylethylamine (8.00 ml, 0.046 M) is added. The reaction mixture was stirred at 50 ° C for 10 hours. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The residue was dissolved in water (120 ml) and extracted with tert-butyl methyl ether (3 × 30 ml). The organic extracts are discarded. The aqueous layer was made alkaline with a 50% sodium hydroxide solution (35 ml), extracted with methylene chloride (3 × 30 ml). The combined organic extracts were washed with water (2 × 20 ml), dried over anhydrous potassium carbonate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The residue, 1-carbimidamido-4- (2- [1-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine (3.90 g, 0.010 M), was dissolved in methylene chloride (20 ml), glacial acetic acid was added. (0.59 g, 0.010 M). The precipitate was separated by filtration, washed successively with methylene chloride (2 × 5 ml) and tert-butyl methyl ether (3 × 10 ml), suspended in a mixture of acetone (20 ml) and water (2 ml).

$$(C{\underset{\_}{H}}_{3}C{O}_2^{-})$$

, 30,16 (CH₃ CH₂С*НCH₃), 41,50 (CH₂-пиперазинового фрагмента), 45,05 (CH₂-пиперазинового фрагмента), 45,63 (CH₂-пиперазинового фрагмента), 46,27 (CH₂-пиперазинового фрагмента), 56,99 (CH₃O-), 61,49 (CH₃O-), 61,72 (CH₃O-), 81,38 (CH₃CH₂ С*НCH₃), 106,84 (С6, Ar), 126,32 (С1, Ar), 141,43 (С2, Ar), 144,31 (С5, Ar), 147,59 (С4, Ar), 150,18 (С3, Ar), 158,42 (C(NH₂)(N⁺H₂)), 167,44 (CON), 176,66 (CH₃ CO₂Н). Масс-спектр: МН⁺ найдено - 395,18, МН⁺ вычислено - 395,23. Чистота продукта по данным ВЭЖХ составляет 99,74%, максимальная неидентифицированная примесь 0,1%, сумма неидентифицированных примесей 0,26%.The suspension is refluxed with stirring for 1 hour, and then cooled. The precipitate was separated by filtration, washed on the filter with acetone (2 × 5 ml) and dried in vacuum. Product, small colorless crystals (4.00 g, 53%). ¹ H NMR Spectrum (DMSO), δ, ppm (J, Hz): 0.90 (3H, t. 6 Hz, С Н ₃ CH ₂ С * НCH ₃ ), 1,09 (3Н, d., 6 Hz, CH ₃ CH ₂ С * НС Н ₃ ), 1.64 (5H, m, CH ₃ C H ₂ C * HCH ₃ and C H ₃ CO ₂ -), 3.0-4.0 (17H, m, 4xC H ₂ piperazine fragment and 3xC H ₃ O-), 4.12 (1H, m, CH ₃ CH ₂ C * H CH ₃ ), 6.62 (1H, s, H-Ar), 8.20 (4H, br.s. , C (N H ₂ ) (N ⁺ H ₂ )). ¹³ C NMR spectrum (DMSO), δ, ppm: 10.31 ( C H ₃ CH ₂ C * HCH ₃ ), 20.02 (CH ₃ CH ₂ C * H C H ₃ ), 25.83 $$$$

$$(C{\underset{\_}{H}}_{3}C{O}_2^{-})$$

30.16 (CH ₃ C H ₂ C * HCH ₃ ), 41.50 (CH ₂ piperazine fragment), 45.05 (CH ₂ piperazine fragment), 45.63 (CH ₂ piperazine fragment), 46 27 (CH ₂ -piperazine fragment), 56.99 (CH ₃ O-), 61.49 (CH ₃ O-), 61.72 (CH ₃ O-), 81.38 (CH ₃ CH ₂ C * HCH ₃ ), 106.84 (C6, Ar), 126.32 (C1, Ar), 141.43 (C2, Ar), 144.31 (C5, Ar), 147.59 (C4, Ar), 150 18 (C3, Ar), 158.42 ( C (NH ₂ ) (N ⁺ H ₂ )), 167.44 ( C ON), 176.66 (CH ₃ C O ₂ H). Mass spectrum: MH ⁺ found, 395.18; MH ⁺ calculated, 395.23. The purity of the product according to HPLC is 99.74%, the maximum unidentified impurity is 0.1%, the sum of unidentified impurities is 0.26%.

Example 4. Obtaining 1-carbimidamido-4- (2- [2-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine hydrochloride.

4.1. 2-bromo-3,4,5-trimethoxybenzoic acid.

3,4,5-Trimethoxybenzoic acid (53.0 g, 0.25 M) was suspended in glacial acetic acid (150 ml). Bromine (60.7 g, 0.38 M) was added dropwise to the reaction mixture with stirring, the reaction mixture was stirred at room temperature for 16 hours, poured into cold water (2000 ml). The precipitate was separated by filtration, washed on the filter with water (3 × 500 ml) and dried at atmospheric pressure at a temperature of 50 ° C.

The intermediate, sandy yellow crystals (44.8 g, 62%), is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.92 (3H, CH ₃ O-), 3.93 (3H, CH ₃ O-), 3.98 (3H, CH ₃ O-), 7.42 (1H, s. , H-Ar), 11.00 (1H, br.s.CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate is 99.8%.

4.2. 2-hydroxy-3,4,5-trimethoxybenzoic acid

Red metal copper (0.49) is added to a hot solution of 2-bromo-3,4,5-trimethoxybenzoic acid (22.4 g, 0.077 M) and potassium phosphate (16.35 g, 0.077 M) in water (150 ml). g, 7.7 mmol, 10 mol%). The reaction mixture was refluxed with stirring for 10 hours. Potassium hydroxide (2.20 g, 0.039 M) is added to the hot mixture with stirring, followed by a hot solution of copper (II) sulfate pentahydrate (4.81 g, 0.02 M) in water (50 ml). The precipitate was separated by filtration, suspended in a 5% solution of potassium hydroxide in water (100 ml), stirred for 1 hour, separated by filtration (the operation is repeated three times). The precipitate was suspended in water (100 ml), acidified with concentrated sulfuric acid (15 ml, 0.28 M), the precipitate was filtered off, washed on the filter with water (3 × 100 ml), squeezed and dried in vacuo. Intermediate, crystals of a pale cream color (5.62 g, 32%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.87 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.05 (3H, CH ₃ O-), 5.5 (1H, br. s, HO-Ar), 7.17 (1H, s, H-Ar), 10.31 (1H, s. CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate - 2-hydroxy-3,4,5-trimethoxybenzoic acid - 99.5%.

4.3. 2-hydroxy-3,4,5-trimethoxybenzoic acid

To a hot solution of 2-bromo-3,4,5-trimethoxybenzoic acid (22.4 g, 0.077 M) and potassium carbonate (21.30 g, 0.154 M) in a mixture of water (50 ml) and ethanol (50 ml) are added copper oxide (I) (0.55 g, 3.9 mmol, 5% mole). The reaction mixture is boiled with stirring for 8 hours. Water (100 ml), potassium hydroxide (8.6 g, 0.154 M), and a hot solution of copper (II) sulfate pentahydrate (19.23 g, 0.077 M) in water (100 ml) are added to the hot reaction mixture. The precipitate formed is filtered off, suspended in a 5% potassium hydroxide solution (100 ml), stirred for 1 hour, and then filtered off (the operation is repeated three times). The precipitated precipitate was suspended in water (100 ml), acidified with concentrated sulfuric acid (15 ml, 27.0 g, 0.28 M), the precipitate was filtered off, washed on the filter with water (3 × 100 ml) and dried in vacuum. Intermediate, pale cream crystals (3.55 g, 20%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.87 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.05 (3H, CH ₃ O-), 5.5 (1H, br. s, HO-Ar), 7.17 (1H, s, H-Ar), 10.31 (1H, s. CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate is 2-hydroxy-3,4,5-trimethoxybenzoic acid - 99.5%.

4.4. 2-Hydroxy-3,4,5-trimethoxybenzoic acid methyl ester

To a solution of 2-hydroxy-3,4,5-trimethoxybenzoic acid (9.13 g, 0.040 M) in methanol (20 ml), concentrated sulfuric acid (1.6 ml, 0.03 M) was added with stirring. The reaction mixture was refluxed for 7 hours, cooled, poured with stirring into a mixture of ice (50 g), water (50 ml) and sodium bicarbonate (10.0 g, 0.119 M), and then extracted with tert-butyl methyl ether ( 3 × 50 ml). The combined organic extracts were washed successively with a saturated solution of sodium bicarbonate in water (2 × 25 ml), water (25 ml) and a saturated solution of sodium chloride (25 ml), and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate is obtained in the form of a light yellow liquid (8.42 g, 87%), which crystallizes upon standing, and is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.84 (3H, s, CH ₃ O ₂ C), 3.93 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.01 ( 3H, CH ₃ O-), 7.08 (1H, s, H-Ar), 10.68 (1H, s, HO-Ar).

4.5. 2- (2-Methylpropyl) hydroxy-3,4,5-trimethoxybenzoic acid methyl ester

2-Hydroxy-3,4,5-trimethoxybenzoic acid is dissolved in methyl ether (4.95 g, 0.020 M), 2-methyl-1-chloropropane (5.30 ml, 0.05 M), anhydrous potassium carbonate (8, 30 g, 0.060 M) and potassium iodide (0.66 g, 0.004 M) in N, N-dimethylformamide (15 ml). the reaction mixture is heated with stirring at a temperature of 70 ° C for 24 hours. Then, 2-methyl-1-chloropropane (2.65 ml, 0.025 M each) and anhydrous potassium carbonate (4.15 g, 0.030 M each) are added to the reaction mixture and the reaction mixture is heated with stirring at 70 ° C for 24 hours (the operation is repeated twice). The cooled reaction mixture was poured into water (100 ml), acidified with concentrated hydrochloric acid (25 ml, ~ 0.300 M), extracted with tert-butyl methyl ether (3 × 30 ml). The combined organic extracts are washed successively with water (2 × 30 ml), saturated sodium bicarbonate solution (2 × 30 ml), 10% sodium thiosulfate solution (3 × 30 ml), saturated sodium chloride solution (30 ml), dried over anhydrous potassium carbonate . The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate is obtained in the form of a yellow liquid (4.73 g, 78%), used in the next step without further purification.

4.6. 2- (2-Methylpropyl) hydroxy-3,4,5-trimethoxybenzoic acid

To a solution of 2- (2-methylpropyl) hydroxy-3,4,5-trimethoxybenzoic acid methyl ether (4.73 g, 0.016 M) in 95% aqueous ethanol (20 ml), potassium hydroxide (1.65 g, 0.029 M). The reaction mixture was refluxed with stirring for 3 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The residue was treated with boiling tert-butyl methyl ether (30 ml). The suspension is filtered, the precipitate is washed with tert-butyl methyl ether (2 × 25 ml), dried in air, dissolved in water (50 ml), acidified with concentrated hydrochloric acid (10 ml, 0.12 M), extracted with tert-butyl methyl ether (3 × 25 ml). The combined extracts were washed with water (2 × 30 ml), saturated sodium chloride solution (20 ml), dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure, the residue is dissolved in methylene chloride (10 ml), passed through a layer of silica gel (60 mesh, 20 g), eluted with methylene chloride. Volatile components are removed on a rotary film evaporator under reduced pressure. The intermediate product is obtained in the form of a yellow liquid (2.31 g, 51%); it is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 1.06 (3H, doublet, 6 Hz, (C H ₃ ) ₂ CHCH ₂ -), 2.14 (1H, m, (CH ₃ ) ₂ C H CH ₂ -), 3.86 (3H, s, CH ₃ O-), 3.87 (3H, s, CH ₃ O-), 3.96 (5H, s, CH ₃ O- and (CH ₃ ) ₂ CHC H ₂ -), 7.38 (1H, s, H-Ar), 11.02 (1H, br.s.CO ₂ H ). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 18.98 ( C H ₃ ) ₂ CHCH ₂ -), 28.93 (CH ₃ ) ₂ C HCH ₂ -), 56.19 (CH ₃ O-), 61.22 (CH ₃ O-), 61.33 (CH ₃ O-), 82.39 (CH ₃ ) ₂ CH C H ₂ -), 108.85 (C1, Ar), 115, 87 (C6, Ar), 146.00 (C2, Ar), 146.53 (C5, Ar), 147.92 (C3, Ar), 149.80 (C4, Ar), 165.15 ( C O ₂ H). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate was 2- (2-methylpropyl) hydroxy-3,4,5-trimethoxybenzoic acid - 99.8%.

4.7. 2- (2-Methylpropyl) hydroxy-3,4,5-trimethoxybenzoyl chloride

To a solution of 2- (2-methylpropyl) hydroxy-3,4,5-trimethoxybenzoic acid (2.21 g, 0.008 M) in methylene chloride (10 ml) was added thionyl chloride (1.85 g, 0.015 M) and N, N-dimethylformamide (0.01 ml). The mixture was stirred at room temperature for 1 hour, after which it was refluxed for 2 hours.

Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The intermediate, a moving dark yellow oil, was obtained in quantitative yield (2.35 g, 100%), used in the next step without further purification.

4.8. 1- (tert-butoxycarbonyl) -4- (2- [2-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine

To a solution of 1- (tert-butoxycarbonyl) piperazine (1.66 g, 0.009 M) and triethylamine (1.85 ml, 0.013 M) in methylene chloride (10 ml), a solution of 2- (2-methylpropyl) oxy- 3,4,5-trimethoxybenzoyl chloride (2.35 g, 0.008 M) in methylene chloride (10 ml). The reaction mixture was stirred for 3 hours.

The precipitate of triethylamine hydrochloride was filtered off and discarded. The filtrate was washed with water (2 × 15 ml), a saturated solution of ammonium chloride (2 × 15 ml), water (2 × 15 ml), a saturated solution of sodium bicarbonate (2 × 15 ml), a saturated solution of sodium chloride (10 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure.

The intermediate, a yellow liquid, is obtained in quantitative yield (3.52 g, 100%), used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.98 (6H, t. 6 Hz, (C H ₃ ) ₂ CHCH ₂ -), 1.48 (9H, s., (C H ₃ ) ₃ C-), 1, 98 (1H, m, (CH ₃ ) ₂ С Н CH ₂ -), 3.0-4.0 (19Н, m, 4хCH ₂ piperazine fragment, (СН ₃ ) ₂ СНС Н ₂ - and 3хC H ₃ O-), 6.55 (1H, s, H-Ar).

4.9. 1- (2- [2-Methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine hydrochloride

1- (tert-Butoxycarbonyl) -4- (2- [2-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine (3.52 g, 0.008 M) was mixed with concentrated hydrochloric acid (20 ml, 24.0 g, ~ 0.24 M). The reaction mixture was stirred at room temperature for complete homogenization for 3 hours. Volatile components are removed on a rotary film evaporator under reduced pressure, twice adding 10 ml of water to the residue to more effectively remove hydrogen chloride. The residue was heated with propan-2-ol (40 ml), insoluble impurities were separated by filtration through celite. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, colorless crystals (2.92 g, 97%), are used in the next step without further purification.

4.10. 1-Carbimidamido-4- (2- [2-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine hydrochloride

To a solution of 1- (2- [2-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine hydrochloride (2.82 g, 0.007 M) and 1H-pyrazole-1-carboximidamide hydrochloride (1.60 g, 0.011 M ) in N, N-dimethylformamide (10 ml), diisopropylethylamine (3.50 ml, 0.020 M) is added while heating to a temperature of 50 ° C. The reaction mixture was stirred at 50 ° C for 10 hours. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The residue was dissolved in water (50 ml), extracted with tert-butyl methyl ether (3 × 30 ml). The organic extracts are discarded. The aqueous layer was alkalinized with a 50% solution of sodium hydroxide in water (20 ml), extracted with methylene chloride (3 × 15 ml). The combined organic extracts were washed with water (2 × 10 ml) and dried over anhydrous potassium carbonate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The residue, which is 1-carbimidamido-4- (2- [2-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine (2.90 g, 0.007 M), is dissolved in acetone (25 ml) and acidified with concentrated hydrochloric acid acid (0.60 ml, 0.007 M). The precipitate formed is filtered off, washed successively on the filter with acetone (2 × 5 ml) and tert-butyl methyl ether (2 × 10 ml) and dried in vacuo. The product was obtained as small colorless crystals (2.28 g, 73%). ¹ H NMR Spectrum (DMSO), δ, ppm (J, Hz): 0.92 (3H, d, 6 Hz, (C H ₃ ) ₂ CHCH ₂ -), 1.90 (1 H, m, (CH ₃ ) ₂ C H CH ₂ -), 3.0-4.0 (19H, m., 4xC H ₂ piperazine fragment, (CH ₃ ) ₂ CHC H ₂ - and 3xC H ₃ O-), 6.65 (1H, s, H-Ar) 7.76 (4H, br.s, C (N H ₂ ) (N ⁺ H ₂ )). ¹³ C NMR spectrum (DMSO), δ, ppm: 18.93 ( C H ₃ ) ₂ CHCH ₂ -), 28.45 (CH ₃ ) ₂ C HCH ₂ -), 40.41 (CH ₂ - piperazine fragment), 44.46 (CH ₂ piperazine fragment), 45.08 (CH ₂ piperazine fragment), 45.31 (CH ₂ piperazine fragment), 56.12 (CH ₃ O-), 60.60 (CH ₃ O-), 61.02 (CH ₃ O-), 80.26 ((CH ₃ ) ₂ CH C H ₂ -), 105.47 (C6, Ar), 124.70 (C1, Ar) , 142.24 (C2, Ar), 143.24 (C5, Ar), 146.52 (C4, Ar), 149.42 (C3, Ar), 156.67 ( C (NH ₂ ) (N ⁺ H ₂ )), 166.25 ( C ON). ¹ H NMR spectrum (D ₂ O), δ, ppm (J, Hz): 0.99 (3H, doublet, 6 Hz, (C H ₃ ) ₂ CHCH ₂ -), 2.00 (1H, m, (CH ₃ ) ₂ C H CH ₂ -), 3.0-4.0 (19H, m., 4xC H ₂ -piperazine fragment, (CH ₃ ) ₂ СНС Н ₂ - and 3хC H ₃ O-), 6.81 (1H, s, H-Ar) . ¹³ C NMR spectrum (D ₂ O), δ, ppm: 18.76 ( C H ₃ ) ₂ CHCH ₂ -), 28.92 (CH ₃ ) ₂ C HCH ₂ -), 41.68 (CH ₂ piperazine fragment), 44.34 (CH ₂ piperazine fragment), 45.42 (CH ₂ piperazine fragment), 45.77 (CH ₂ piperazine fragment), 56.81 (CH ₃ O-), 61 87 (CH ₃ O-), 61.10 (CH ₃ O-), 82.39 ((CH ₃ ) ₂ CH C H ₂ -), 106.22 (C6, Ar), 124.37 (C1, Ar), 142.73 (C2, Ar), 144.03 (C5, Ar), 146.09 (C4, Ar), 150.19 (C3, Ar), 156.97 ( C (NH ₂ ) (N ⁺ H ₂ )), 169.77 ( C ON). Macc spectrum: MH ⁺ found, 395.21; MH ⁺ calculated, 395.23. The purity of the product according to HPLC 99.51%, the maximum unidentified impurity of 0.1%, the sum of unidentified impurities of 0.49%.

Example 5. Obtaining 1-carbimidamido-4- (2- [2-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine methanesulfonate

5.1. 1-Carbimidamido-4- (2- [2-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine methanesulfonate

), 3,25-4,0 (19Н, м, 4хСН ₂-пиперазинового фрагмента, (СН₃)₂CHCH ₂- и 3хCH ₃O-), 6,66 (1Н, с., H-Ar), 7,50 (4Н, ш.с., C(NH ₂)(N⁺ H ₂)). Спектр ЯМР ¹³С (DMSO), δ, м.д.: 19,83 (CH₃)₂СНCH₂-), 29,35 (CH₃)₂ СНCH₂-), 40,59 ( $$C{\underset{\_}{H}}_{3}S{O}_3^{-}$$

) 41,30 (CH₂-пиперазинового фрагмента), 45,40 (CH₂-пиперазинового фрагмента), 46,03 (CH₂-пиперазинового фрагмента), 46,13 (CH₂-пиперазинового фрагмента), 57,00 (CH₃O-), 61,52 (CH₃O-), 61,93 (CH₃O-), 81,18 ((CH₃)₂СНCH₂-), 106,36 (С6, Ar), 125,59 (С1, Ar), 143,16 (С2, Ar), 144,15 (С5, Ar), 147,43 (С4, Ar), 150,33 (С3, Ar), 157,23 (C(NH₂)(N⁺H₂)), 167,16 (CON). Масс-спектр: МН⁺ найдено - 395,19, МН⁺ вычислено - 395,23. Чистота вещества по данным ВЭЖХ 99,83%, максимальная неидентифицированная примесь 0,08%, сумма неидентифицированных примесей 0,17%.1-Carbimidamido-4- (2- [2-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine hydrochloride (0.714 g, 1.81 mmol) obtained according to the description of Example 4 is treated with a 20% solution of sodium hydroxide in water ( 20 ml). The reaction mixture was extracted with methylene chloride (2 × 20 ml). The combined organic extracts were washed with 20% sodium hydroxide in water (20 ml), water (20 ml) and dried over anhydrous potassium carbonate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The residue, which is 1-carbimidamido-4- (2- [2-methylpropyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine (0.70 g, 1.77 mmol, 98% yield), is dissolved in t -butyl methyl ether (30 ml), methylene chloride (10 ml) is added, acidified with a solution of methyl sulfonic acid (0.170 g, 1.77 mmol) in tert-butyl methyl ether (5 ml). The precipitate formed is filtered off, washed on the filter with tert-butyl methyl ether (2 × 10 ml), and dried in vacuo. Product, colorless crystals (0.86 g, 97%). ¹ H NMR Spectrum (DMSO), δ, ppm (J, Hz): 0.92 (3H, d, 6 Hz, (C H ₃ ) ₂ CHCH ₂ -), 1.89 (1 H, m, (CH ₃ ) ₂ C H CH ₂ -), 2.36 (3H, s., $$C{\underset{\_}{H}}_{3}S{O}_3^{-}$$

), 3.25-4.0 (19Н, m, 4хС Н ₂ -piperazine fragment, (СН ₃ ) ₂ CHC H ₂ - and 3хC H ₃ O-), 6.66 (1Н, s., H-Ar ), 7.50 (4H, br.s, C (N H ₂ ) (N ⁺ H ₂ )). ¹³ C NMR spectrum (DMSO), δ, ppm: 19.83 ( C H ₃ ) ₂ CHCH ₂ -), 29.35 (CH ₃ ) ₂ C HCH ₂ -), 40.59 ( $$C{\underset{\_}{H}}_{3}S{O}_3^{-}$$

) 41.30 (CH ₂ piperazine fragment), 45.40 (CH ₂ piperazine fragment), 46.03 (CH ₂ piperazine fragment), 46.13 (CH ₂ piperazine fragment), 57.00 (CH ₃ O-), 61.52 (CH ₃ O-), 61.93 (CH ₃ O-), 81.18 ((CH ₃ ) ₂ CH C H ₂ -), 106.36 (C6, Ar), 125.59 (C1, Ar), 143.16 (C2, Ar), 144.15 (C5, Ar), 147.43 (C4, Ar), 150.33 (C3, Ar), 157.23 ( C (NH ₂ ) (N ⁺ H ₂ )), 167.16 ( C ON). Mass spectrum: MH ⁺ found, 395.19; MH ⁺ calculated, 395.23. The purity of the substance according to HPLC 99.83%, the maximum unidentified impurity of 0.08%, the sum of unidentified impurities of 0.17%.

Example 6. Obtaining 1-carbimidamido-4- (3,4,5-tributoxy-2-ethoxybenzoyl) piperazine acetate

6.1. 2-bromo-3,4,5-tributoxybenzoic acid

Water (0.1 ml) was added to a solution of 3,4,5-tributoxybenzoic acid (10.20 g, 0.030 M) in ethyl acetate (50 ml). The reaction mixture is heated to boiling with stirring, and bromine (5.27 g, 0.033 M) is added dropwise with stirring for 20 minutes. The reaction mixture was refluxed for 90 minutes. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The intermediate product, an orange-brown liquid, hardens when standing in a mass of light sand color, obtained in quantitative yield (12.66 g, 100%), used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 1.01 (9H, m, C H ₃ CH ₂ CH ₂ CH ₂ ), 1.54 (6H, m, CH ₃ C H ₂ CH ₂ CH ₂ ), 1.84 (6H, m, CH ₃ CH ₂ C H ₂ CH ₂ ), 4.04 (6H, m, CH ₃ CH ₂ CH ₂ C H ₂ , 7.39 (1H, s. H-Ar), 11.05 (1H , br.s. CO ₂ H ). The purity of the intermediate according to ¹ H NMR and TLC spectroscopy is 95%.

6.2. 3,4,5-tributoxy-2-hydroxybenzoic acid

To a hot suspension of 2-bromo-3,4,5-tributoxybenzoic acid (12.10 g, 0.030 M) in a 3 M solution of sodium hydroxide in water (40 ml), copper (II) oxide (0.12 g, 1, 5 mM, 5% mole). The reaction mixture was refluxed with stirring for 5 hours. Water (60 ml) and sodium hydroxide (2.40 g, 0.06 M), a hot solution of copper (II) sulfate pentahydrate (3.74 g, 0.015 M) in water (25 ml) are added to the hot reaction mixture with stirring. . The precipitate formed is filtered off, suspended in a 5% sodium hydroxide solution (200 ml), stirred for 1 hour, and then filtered off (the operation is repeated twice). The precipitate was suspended in water (200 ml), acidified with concentrated hydrochloric acid (20 ml, 0.24 M), extracted with methylene chloride (2 × 100 ml). The combined organic extracts were washed with 3% hydrochloric acid solution (2 × 50 ml), water (2 × 50 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. Intermediate, liquid, hardening when standing. (5.57 g, 54%).

¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.98 (9H, m, C H ₃ CH ₂ CH ₂ CH ₂ ), 1.53 (6H, m, CH ₃ C H ₂ CH ₂ CH ₂ ), 1.79 (6H, m, CH ₃ CH ₂ C H ₂ CH ₂ ), 3.96 (2H, t, 6.5 Hz, CH ₃ CH ₂ CH ₂ C H ₂ ), 4.06 (2H, t, 6.5 Hz, CH ₃ CH ₂ CH ₂ C H ₂ ) 4.17 (2H, t, 6.5 Hz, CH ₃ CH ₂ CH ₂ C H ₂ ), 7.15 (1H, s, H-Ar) 10.22 (2H, br.s.CO ₂ H , HO-Ar). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate is 3,4,5-tributoxy-2-hydroxybenzoic acid - 99.5%.

6.3. 3,4,5-Tributoxy-2-hydroxybenzoic acid propyl ether.

To a solution of 3,4,5-tributoxy-2-hydroxybenzoic acid (5.34 g, 0.015 M), propan-1-ol (4.50 ml, 0.06 M) and 4-dimethylaminopyridine (0, 07 g, 0.6 mmol) in methylene chloride (30 ml) are added with stirring N, N′-dicyclohexylcarbodiimide (3.31 g, 0.016 M). The reaction mixture was stirred while cooling for 10 minutes, stirred at room temperature for 5 hours. The precipitate formed is filtered off and discarded.

The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure.

The residue was dissolved in tert-butyl methyl ether (25 ml). Insoluble impurities are separated by filtration and discarded. The filtrate is washed successively with a 0.5 M solution of hydrochloric acid in water (2 × 20 ml), water (2 × 20 ml), saturated sodium bicarbonate in water (2 × 20 ml), saturated sodium chloride solution (20 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. Intermediate, light brown liquid (5.91 g, 99%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 1.02 (12H, m, 3xC H ₃ CH ₂ CH ₂ CH ₂ and C H ₃ CH ₂ CH ₂ ), 1.56 (6H, m, 3xCH ₃ C H ₂ CH ₂ CH ₂ ), 1.73 (8H, m, 6 Hz, 4xCH ₃ CH ₂ C H ₂ CH ₂ ), 3.94 (2H, t. 6 Hz, CH ₃ CH ₂ CH ₂ C H ₂ ), 4.05 (2H, t. 6 Hz, CH ₃ CH ₂ CH ₂ C H ₂ ), 4.12 (2H, t. 6 Hz, CH ₃ CH ₂ CH ₂ C H ₂ ), 4.30 (2H, t ., 7 Hz, CH ₃ CH ₂ C H ₂ ), 7.08 (1H, s. H-Ar), 10.70 (1H, s. H O-Ar).

6.4. 3,4,5-Tributoxy-2-ethoxybenzoic acid propyl ether

Propyl ether (5.60 g, 0.014 M), bromoethane (2.10 ml, 0.028 M), anhydrous potassium carbonate (3.59 g, 0.029 M), potassium are dissolved in 3,4,5-tributoxy-2-hydroxybenzoic acid. iodide (0.23 g, 0.001 M) in N, N-dimethylformamide (15 ml). The reaction mixture was stirred while heating at 50 ° C for 4 hours, bromoethane (3.07 g, 0.028 M), anhydrous potassium carbonate (3.59 g, 0.029 M) were added, after which the reaction mixture was stirred at 50 ° C within 4 hours (the operation is repeated twice). The cooled reaction mixture was poured into water (50 ml), extracted with ethyl acetate (3 × 25 ml). The combined organic extracts are washed with water (2 × 15 ml), 0.5 M hydrochloric acid solution (2 × 20 ml), water (2 × 20 ml), saturated sodium bicarbonate solution (2 × 20 ml), 10% sodium thiosulfate solution (2 × 20 ml), saturated sodium chloride solution (20 ml), dried over anhydrous potassium carbonate. Volatile components are removed on a rotary film evaporator under reduced pressure. Intermediate - a bright orange liquid (5.75 g, 96%) is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 1.00 (12H, m, 3xC H ₃ CH ₂ CH ₂ CH ₂ and C H ₃ CH ₂ CH ₂ ), 1.40 (3H, t. 6 Hz, C H ₃ CH ₂ ), 1.56 (6H, m, 3xCH ₃ C H ₂ CH ₂ CH ₂ ), 1.73 (8H, m, 6 Hz, 2xCH ₃ CH ₂ C H ₂ CH ₂ and C H ₃ CH ₂ CH ₂ ) 4.00 (8H, m., 3xCH ₃ CH ₂ CH ₂ C H ₂ and CH ₃ C H ₂ , 4.27 (2H, t. 6 Hz, CH ₃ CH ₂ C H ₂ , 7.10 ( 1H, s. H-Ar).

6.5. 3,4,5-tributoxy-2-ethoxybenzoic acid

To a solution of 3,4,5-tributoxy-2-ethoxybenzoic acid methyl ester (4.9 g, 0.012 M) in propan-2-ol (20 ml), sodium hydroxide (0.75 g, 0.019 M) was added with stirring. The reaction mixture was stirred at 75 ° C for 3 hours. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The residue is treated with a mixture of heptane with tert-butyl methyl ether (10: 1, 50 ml). The resulting suspension was separated by filtration. The precipitate was washed with a mixture of heptane with tert-butyl methyl ether (10: 1, 20 ml), dried in vacuo, suspended in water (25 ml), acidified with concentrated hydrochloric acid (3.0 ml, 0.036 M), extracted with ethyl acetate (2 × 15 ml).

The combined organic extracts were washed with water (2 × 15 ml), saturated sodium chloride solution (15 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a light yellow liquid (2.92 g, 66%), was used in the next step without further purification.

¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (7, Hz): 0.99 (9H, m, 3xC H ₃ CH ₂ CH ₂ CH ₂ ), 1.35 (3H, t. 6 Hz, C H ₃ CH ₂ ), 1.76 (6H, m, CH ₃ CH ₂ C H ₂ CH ₂ ), 4.03 (4H, m, 2xCH ₃ CH ₂ CH ₂ C H ₂ ), 4.11 (2H, t, 6.3 Hz, CH ₃ CH ₂ CH ₂ C H ₂ ), 4.35 (2H, q, 7 Hz, CH ₃ C H ₂ ), 7.40 (1H, s. H-Ar), 11.63 (1H, br.s.CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate is 3,4,5-tributoxy-2-ethoxybenzoic acid - 99.8%.

6.6. 3,4,5-tributoxy-2-ethoxybenzoyl chloride

3,4,5-Tributoxy-2-ethoxybenzoic acid (2.89 g, 7.6 mmol) was mixed with thionyl chloride (2.70 g, 22.7 mmol), N, N-dimethylformamide (~ 0.01 ml). The reaction mixture is boiled for 1 hour. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The intermediate, a brown liquid, was obtained in quantitative yield (3.03 g, 100%), used in the next step without further purification.

6.7. 1- (tert-butoxycarbonyl) -4- (3,4,5-tributoxy-2-ethoxybenzoyl) piperazine

To a solution of 1- (tert-butoxycarbonyl) piperazine (1.55 g, 8.32 mmol) and diisopropylethylamine (1.95 g, 15.12 mmol) in N, N-dimethylformamide (10 ml) with stirring, cooling to a temperature (-) 10 ° C, a solution of 3,4,5-tributoxy-2-ethoxybenzoyl chloride (3.03 g, 7.6 mmol) in N, N-dimethylformamide (10 ml) was added dropwise. The reaction mixture was stirred while cooling for 30 minutes, at room temperature for 3 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The residue was emulsified in water (40 ml) and extracted with ethyl acetate (3 × 30 ml). The combined extracts were washed with water (2 × 25 ml), saturated solution of ammonium chloride (2 × 25 ml), water (2 × 25 ml), saturated sodium bicarbonate solution (2 × 25 ml), water (2 × 25 ml), saturated a solution of sodium chloride (20 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure.

The intermediate is obtained in the form of a yellow liquid (4.12 g, 99%), used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.96 (9H, t, 9 Hz, 3xC H ₃ CH ₂ CH ₂ CH ₂ ), 1.28 (3H, t. 6 Hz, C H ₃ CH ₂ ), 1.50 (15H, m., 3xCH ₃ C H ₂ CH ₂ CH ₂ and (C H ₃ ) ₃ C), 1.72 (6H, m., CH ₃ CH ₂ C H ₂ CH ₂ ), 3.0-4 2 (16H, m, 3xCH ₃ CH ₂ CH ₂ C H ₂ , CH ₃ C H ₂ , and the 4xC H ₂ piperazine fragment), 6.51 (1H, s. H-Ar).

6.8. 1- (3,4,5-Tributoxy-2-ethoxybenzoyl) piperazine

To a solution of 1- (tert-butoxycarbonyl) -4- (3,4,5-tributoxy-2-ethoxybenzoyl) piperazine (4.12 g, 7.48 mmol) in 95% aqueous ethanol (5 ml) was added concentrated sulfuric acid (0.74 g, 7.55 M). The reaction mixture was stirred at 50 ° C for 1 hour. Volatile components are removed on a rotary film evaporator under reduced pressure.

The residue was dissolved in water (20 ml), treated with a 5 M solution of potassium hydroxide in water (10 ml), extracted with methylene chloride (3 × 30 ml). The combined organic extracts were washed successively with water (20 ml), saturated sodium chloride solution (20 ml) and dried over anhydrous potassium carbonate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate product is obtained in the form of a waxy mass of light yellow color (3.00 g, 89%), used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.97 (9H, t., 8 Hz, 3xC H ₃ CH ₂ CH ₂ CH ₂ ), 1.31 (3H, m, 6 Hz, C H ₃ CH ₂ ), 1, 50 (6H, m., 3xCH ₃ C H ₂ CH ₂ CH), 1.73 (6H, m., CH ₃ CH ₂ C H ₂ CH ₂ ), 2.6-4.2 (16H, m, 3xCH ₃ CH ₂ CH ₂ C H ₂ , CH ₃ C H ₂ , and 4xC H ₂ piperazine fragment), 6.53 (1H, s. H-Ar).

6.9. 1-carbimidamido-4- (3,4,5-tributoxy-2-ethoxybenzoyl) piperazine acetate

), 3,1-4,2 (16Н, м., 3xCH₃CH₂CH₂CH ₂, CH₃CH ₂, и 4хCH ₂-пиперазинового фрагмента), 6,53 (1Н, с. H-Ar), 8,55 (4Н, ш.с., C(NH ₂)(N⁺ H ₂)). Спектр ЯМР ¹³С (CDCl₃), δ, м.д.: 14,17 (CH₃CH₂CH₂CH₂), 14,25 (CH₃CH₂CH₂CH₂), 14,28 (CH₃CH₂CH₂CH₂), 16,27 (CH₃CH₂), 19,54 (CH₃ CH₂CH₂CH₂), 19,56 (CH₃ CH₂CH₂CH₂), 19,64 (CH₃ CH₂CH₂CH₂), 25,18 $$(C{\underset{\_}{H}}_{3}C{O}_2^{-})$$

, 31,73 (CH₃CH₂ CH₂CH₂), 32,68 (CH₃CH₂ CH₂CH₂), 32,79 (CH₃CH₂ CH₂CH₂), 41,52 (CH₂-пиперазинового фрагмента), 45,10 (CH₂-пиперазинового фрагмента), 45,69 (CH₂-пиперазинового фрагмента), 46,47 (CH₂-пиперазинового фрагмента), 69,08 (CH₃ CH₂), 70,77 (CH₃CH₂CH₂ CH₂), 73,90 (CH₃CH₂CH₂ CH₂), 74,13 (CH₃CH₂CH₂ CH₂), 106,44 (С6, Ar), 124,40 (С1, Ar), 143,05 (С2, Ar), 144,59 (С5, Ar), 147,16 (С4, Ar), 150,54 (С3, Ar), 157,97 (C(NH₂)(N⁺H₂)), 168,40 (CON), 178,59 $$(C{\underset{\_}{H}}_{3}C{O}_2^{-})$$

. Масс-спектр: МН⁺ найдено - 493,37, МН⁺ вычислено - 493,34. Чистота продукта по данным ВЭЖХ - 99,54%, максимальная неидентифицированная примесь 0,09%, сумма неидентифицированных примесей 0,46%.To a solution of 1- (3,4,5-tributoxy-2-ethoxybenzoyl) piperazine (3.37 g, 7.48 mmol) and 1H-pyrazole-1-carboximidamide hydrochloride (1.64 g, 11.22 mmol) in acetonitrile (25 ml) was added N-methylmorpholine (1.64 ml, 1.51 g, 14.96 mmol). The reaction mixture was stirred at 50 ° C for 3 hours. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The residue was dissolved in water (30 ml), the emulsion was basified with potassium hydroxide (1.0 g, 17.9 mmol), extracted with methylene chloride (3 × 30 ml). The combined extracts were washed with 5% potassium hydroxide in water (3 × 20 ml), dried over anhydrous potassium carbonate. The desiccant is separated by filtration. Volatile components are removed on a rotary film evaporator under reduced pressure. The residue, 1-carbimidamido-4- (3,4,5-tributoxy-2-ethoxybenzoyl) piperazine (3.52 g, 7.14 mmol, 95%), was dissolved in tert-butyl methyl ether (100 ml), acidified with ice-cold acetic acid (0.41 ml, 0.43 g, 7.16 mmol). The precipitate formed is filtered off, dissolved in methylene chloride (50 ml) and tert-butyl methyl ether (50 ml) is added. The resulting solution was slowly evaporated on a rotary film evaporator under reduced pressure, while when most of the methylene chloride was removed and a precipitate formed in the distillation cube, heptane (100 ml) was added and volatile components were distilled off. The resulting crystalline residue was dried in vacuo. The product is small cream-colored crystals (2.71 g, 66%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.97 (9H, t., 8 Hz, 3xC H ₃ CH ₂ CH ₂ CH ₂ ), 1.28 (3H, t. 6 Hz, C H ₃ CH ₂ ), 1, 50 (6H, m., 3xCH ₃ C H ₂ CH ₂ CH), 1.73 (9H, m., CH ₃ CH ₂ C H ₂ CH ₂ and $$C{\underset{\_}{H}}_{3}C{O}_2^{-}$$

), 3.1-4.2 (16H, m, 3xCH ₃ CH ₂ CH ₂ C H ₂ , CH ₃ C H ₂ , and a 4xC H ₂ piperazine fragment), 6.53 (1H, s. H- Ar) 8.55 (4H, br.s, C (N H ₂ ) (N ⁺ H ₂ )). ¹³ C NMR Spectrum (CDCl ₃ ), δ, ppm: 14.17 ( C H ₃ CH ₂ CH ₂ CH ₂ ), 14.25 ( C H ₃ CH ₂ CH ₂ CH ₂ ), 14.28 ( C H ₃ CH ₂ CH ₂ CH ₂ ), 16.27 ( C H ₃ CH ₂ ), 19.54 (CH ₃ C H ₂ CH ₂ CH ₂ ), 19.56 (CH ₃ C H ₂ CH ₂ CH ₂ ), 19.64 (CH ₃ C H ₂ CH ₂ CH ₂ ), 25.18 $$(C{\underset{\_}{H}}_{3}C{O}_2^{-})$$

, 31.73 (CH ₃ CH ₂ C H ₂ CH ₂ ), 32.68 (CH ₃ CH ₂ C H ₂ CH ₂ ), 32.79 (CH ₃ CH ₂ C H ₂ CH ₂ ), 41.52 ( CH ₂ piperazine fragment), 45.10 (CH ₂ piperazine fragment), 45.69 (CH ₂ piperazine fragment), 46.47 (CH ₂ piperazine fragment), 69.08 (CH ₃ C H ₂ ) 70.77 (CH ₃ CH ₂ CH ₂ C H ₂ ), 73.90 (CH ₃ CH ₂ CH ₂ C H ₂ ), 74.13 (CH ₃ CH ₂ CH ₂ C H ₂ ), 106.44 ( C6, Ar), 124.40 (C1, Ar), 143.05 (C2, Ar), 144.59 (C5, Ar), 147.16 (C4, Ar), 150.54 (C3, Ar), 157.97 ( C (NH ₂ ) (N ⁺ H ₂ )), 168.40 ( C ON), 178.59 $$(C{\underset{\_}{H}}_{3}C{O}_2^{-})$$

. Mass spectrum: MH ⁺ found, 493.37; MH ⁺ calculated, 493.34. The purity of the product according to HPLC is 99.54%, the maximum unidentified impurity is 0.09%, the sum of unidentified impurities is 0.46%.

Example 7. Obtaining 1-carbimidamido-4- (3,4,5-tributoxy-2-ethoxybenzoyl) piperazine trihydrogen phosphate

7.1. 1-Carbimidamido-4- (3,4,5-tributoxy-2-ethoxybenzoyl) piperazine trihydrogen phosphate

). Спектр ЯМР ¹³С (CDCl₃), δ, м.д.: 14,25 (3хCH₃CH₂CH₂CH₂), 16,17 (CH₃CH₂), 19,54 (2хCH₃ CH₂CH₂CH₂), 19,67 (CH₃ CH₂CH₂CH₂), 31,78 (CH₃CH₂ CH₂CH₂), 32,73 (CH₃CH₂ CH₂CH₂), 32,82 (CH₃CH₂ CH₂CH₂), 41,89 (CH₂-пиперазинового фрагмента), 45,15 (CH₂-пиперазинового фрагмента), 45,79 (CH₂-пиперазинового фрагмента), 46,36 (CH₂-пиперазинового фрагмента), 69,14 (CH₃ CH₂), 70,57 (CH₃CH₂CH₂ CH₂), 73,81 (CH₃CH₂CH₂ CH₂), 74,07 (CH₃CH₂CH₂ CH₂), 106,51 (С6, Ar), 124,71 (С1, Ar), 143,02 (С2, Ar), 144,30 (С5, Ar), 147,05 (С4, Ar), 150,26 (С3, Ar), 157,58 (C(NH₂)(N⁺H₂)), 168,47 (CON). Масс-спектр: МН⁺ найдено - 493,44, МН⁺ вычислено - 493,34. Чистота продукта по данным ВЭЖХ 99,66%, максимальная неидентифицированная примесь 0,10%, сумма неидентифицированных примесей - 0,34%.1-Carbimidamido-4- (3,4,5-tributoxy-2-ethoxybenzoyl) piperazine acetate (1.0 g, 1.81 mmol), obtained as described in example 6, is treated with a 20% solution of sodium hydroxide in water (20 ml), extracted with methylene chloride (2 × 20 ml). The combined organic extracts were washed with 20% sodium hydroxide solution (20 ml), water (20 ml), dried over anhydrous potassium carbonate. The desiccant is separated by filtration. Volatile components are removed on a rotary film evaporator under reduced pressure. The residue, 1-carbimidamido-4- (3,4,5-tributoxy-2-ethoxybenzoyl) piperazine (0.81 g, 1.64 mmol, 91% yield), was dissolved in tert-butyl methyl ether (40 ml), acidified with 85% phosphoric acid (0.190 g, 1.64 mmol) in tert-butyl methyl ether (5 ml). The precipitate formed is filtered off, then dissolved in methylene chloride (30 ml), tert-butyl methyl ether (20 ml) and heptane (20 ml) are added. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The resulting crystalline residue was dried in vacuo. Product, yellow crystals (0.99 g, 93%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz) (all signals are broadened): 0.95 (9Н, m, 3хС Н ₃ CH ₂ CH ₂ CH ₂ ), 1.19 (3Н, m, C H ₃ CH ₂ ), 1.47 ( 6H, m, 3xCH ₃ C H ₂ CH ₂ CH), 1.71 (6H, m, CH ₃ CH ₂ C H ₂ CH ₂ ), 3.1-4.2 (16H, m, 3xCH ₃ CH ₂ CH ₂ C H ₂ , CH ₃ C H ₂ , and the 4xC H ₂ piperazine fragment), 6.49 (1H, s. H-Ar), 7.99 (6H, br.s, C (N H ₂ ) (N ⁺ H ₂ ) and $$H_{2}P{O}_{\mathrm{four}}^{-}$$

) ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 14.25 (3x C H ₃ CH ₂ CH ₂ CH ₂ ), 16.17 ( C H ₃ CH ₂ ), 19.54 (2x CH ₃ C H ₂ CH ₂ CH ₂ ), 19.67 (CH ₃ C H ₂ CH ₂ CH ₂ ), 31.78 (CH ₃ CH ₂ C H ₂ CH ₂ ), 32.73 (CH ₃ CH ₂ C H ₂ CH ₂ ), 32.82 (CH ₃ CH ₂ C H ₂ CH ₂ ), 41.89 (CH ₂ piperazine fragment), 45.15 (CH ₂ piperazine fragment), 45.79 (CH ₂ piperazine fragment) , 46.36 (CH ₂ piperazine fragment), 69.14 (CH ₃ C H ₂ ), 70.57 (CH ₃ CH ₂ CH ₂ C H ₂ ), 73.81 (CH ₃ CH ₂ CH ₂ C H ₂ ), 74.07 (CH ₃ CH ₂ CH ₂ C H ₂ ), 106.51 (C6, Ar), 124.71 (C1, Ar), 143.02 (C2, Ar), 144.30 (C5 , Ar), 147.05 (C4, Ar), 150.26 (C3, Ar), 157.58 ( C (NH ₂ ) (N ⁺ H ₂ )), 168.47 ( C ON). Mass spectrum: MH ⁺ found, 493.44; MH ⁺ calculated, 493.34. The purity of the product according to HPLC 99.66%, the maximum unidentified impurity is 0.10%, the sum of unidentified impurities is 0.34%.

Example 8. Obtaining 1-carbimidamido-4- (3,4,5-tri [1-methylethyl] hydroxy-2-propoxybenzoyl) piperazine acetate

8.1. 2-bromo-3,4,5-tri (1-methylethyl) hydroxybenzoic acid

Water (0.1 ml) was added to a solution of 3,4,5-tri (1-methylethyl) hydroxybenzoic acid (4.50 g, 0.015 M) in ethyl acetate (40 ml). The reaction mixture is heated to boiling. A solution of bromine (2.52 g, 0.015 M) in ethyl acetate (5 ml) was added dropwise to the boiling mixture with stirring for 10 minutes. The mixture is boiled for 1 hour. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The intermediate, a brown liquid, was obtained in quantitative yield (5.70 g, 100%), used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 1.34 (18H, m, 3x (C H ₃ ) ₂ CH-), 4.56 (3H, m, (CH ₃ ) ₂ C H -), 7.35 (1H, s.p. H-Ar) 8.5 (1H, br.s.CO ₂ H ). The purity of the intermediate according to NMR spectroscopy ¹ H and TLC 95%.

8.2. 2-Hydroxy-3,4,5-tri (1-methylethyl) hydroxybenzoic acid

To a hot solution of 2-bromo-3,4,5-tri (1-methylethyl) hydroxybenzoic acid (4.61 g, 0.012 M) in a 3 M solution of sodium hydroxide in water (25 ml), copper (II) oxide is added (0 , 10 g, 1.2 mmol, 10% mol.). The reaction mixture was refluxed with stirring for 6 hours. Water (30 ml) and a hot solution of copper (II) sulfate pentahydrate (1.53 g, 0.006 M) in water (10 ml) are added to the hot mixture with stirring. The precipitate formed is filtered off, suspended in a 5% sodium hydroxide solution (50 ml), stirred for 1 hour, separated by filtration (the operation is repeated three times). The precipitate isolated is suspended in water (20 ml), acidified with concentrated hydrochloric acid (5 ml, 0.06 M). The solution was extracted with ethyl acetate (2 × 10 ml), the combined organic extracts were washed with 3% hydrochloric acid (2 × 10 ml), water (2 × 10 ml), saturated sodium chloride solution (10 ml), dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. Intermediate - peach-pink crystals (1.34 g, 35%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 1.34 (18Н, m, (C H ₃ ) ₂ СН-), 4,50 (2Н, m, 2х (CH ₃ ) ₂ С Н -), 4,65 (1Н, m., (CH ₃ ) ₂ C H -), 7.19 (1H, s. H-Ar), 10.1 (2H, s. H O-Ar). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate, 2-hydroxy-3,4,5-tri (1-methylethyl) hydroxybenzoic acid is 99.5%.

8.3. 2-Hydroxy-3,4,5-tri (1-methylethyl) hydroxybenzoic acid butyl ether

To a solution of 2-hydroxy-3,4,5-tri (1-methylethyl) hydroxybenzoic acid (1.33 g, 0.004 M), butan-1-ol (1.26 g, 0.017 M) and 4- dimethiaminopyridine (0.02 g, 0.16 mmol) in methylene chloride (10 ml) was added with stirring N, N-dicyclohexylcarbodiimide (0.93 g, 0.004 M). The reaction mixture was stirred while cooling for 10 minutes, after which it was stirred at room temperature for 5 hours. The precipitate formed is filtered off and discarded. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The residue was dissolved in tert-butyl methyl ether (15 ml). Insoluble impurities are separated by filtration and discarded. The filtrate is washed successively with a 0.5 M hydrochloric acid solution (2 × 10 ml), water (2 × 10 ml), saturated sodium hydrogen carbonate solution (2 × 10 ml), saturated sodium chloride solution (10 ml) and dried over anhydrous magnesium sulfate . The desiccant is separated by filtration, the solvent is removed on a rotary film evaporator under reduced pressure. The residue was dissolved in a mixture of heptane with methylene chloride (5: 2, 10 ml), passed through a layer of silica gel (60 me1H, 20 g), eluted with a mixture of heptane with methylene chloride (5: 2). The intermediate is obtained as a colorless liquid (0.87 g, 55%). ¹ H NMR spectrum (CDCl ₃ ), δ, ppm (J, Hz): 1.00 (3H, t, 6 Hz C H ₃ CH ₂ CH ₂ CH ₂ ), 1.27 (20H, m. , 3x (C H ₃ ) ₂ CH and CH ₃ C H ₂ CH ₂ CH ₂ ), 1.77 (2H, m, CH ₃ CH ₂ C H ₂ CH ₂ ), 4.34 (2H, t. 7 Hz, CH ₃ CH ₂ CH ₂ C H ₂ , 4.52 (3H, m, 3x (CH ₃ ) ₂ C H ), 7.11 (1H, s. H-Ar), 10.67 (1H, c. H O-Ar).

8.4. 3,4,5-Tri (1-methylethyl) hydroxy-2-propyloxybenzoic acid butyl ether

2-hydroxy-3,4,5-tri (1-methylethyl) hydroxybenzoic acid butyl ether (0.87 g, 2.4 mmol), 1-bromopropane (1.22 g, 9.9 mmol), anhydrous potassium carbonate are dissolved (1.30 g, 9.4 mmol) and potassium iodide (0.04 g, 0.24 mmol) in acetone (20 ml). The reaction mixture is refluxed with stirring for 8 hours, 1-bromopropane (0.90 ml, 9.9 mmol), anhydrous potassium carbonate (1.30 g, 9.4 mmol) are added to the reaction mixture, and the reaction mixture is boiled under reflux with stirring for 8 hours. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The residue was dissolved in water (20 ml) and extracted with ethyl acetate (3 × 20 ml). The combined organic extracts were washed successively with water (2 × 20 ml), saturated sodium chloride solution (20 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration, the solvent is removed on a rotary film evaporator under reduced pressure. The intermediate, a yellow liquid (0.97 g, 100%), is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 1.01 (6H, m., C H ₃ CH ₂ CH ₂ and C H ₃ CH ₂ CH ₂ CH ₂ ), 1.27 (12H, m, 2x (C H ₃ ) ₂ CH ), 1.30 (6H, d, 6.3 Hz, (C H _{3) 2} CH), 1.35 (6H, d, 6.3 Hz, (C H _{3) 2} CH), 1.45 ( 2H, m, CH ₃ C H ₂ CH ₂ CH ₂ ), 1.78 (4H, m, CH ₃ C H ₂ CH ₂ and CH ₃ CH ₂ C H ₂ CH ₂ ), 3.96 (2H, t ., 7 Hz, CH ₃ CH ₂ C H ₂ ), 4.30 (2Н, t, 6.9 Hz, CH ₃ CH ₂ CH ₂ С H ₂ O ₂ С), 4.54 (3Н, m, 3х (CH ₃ ) ₂ C H ), 7.09 (1H, s. H-Ar).

8.5. 3,4,5-Tri (1-methylethyl) hydroxy-2-propyloxybenzoic acid

To a solution of 3,4,5-Tri (1-methylethyl) hydroxy-2-propyloxybenzoic acid butyl ether (0.97 g, 2.4 mmol) in 95% aqueous ethanol (10 ml), potassium hydroxide (0, 34 g, 6.1 mmol). The reaction mixture was refluxed with stirring for 1 hour. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The residue was suspended in water (30 ml), acidified with dilute sulfuric acid (2.0 ml, ~ 7.5 mmol) and extracted with ethyl acetate (3 × 20 ml). The combined organic extracts were washed with water (2 × 10 ml), saturated sodium chloride solution (20 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate is obtained in the form of a light yellow liquid (0.73 g, 87%); it is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 1.07 (3H, t. 7.4 Hz, C H ₃ CH ₂ CH ₂ ), 1.29 (6H, d, 6.3 Hz, (C H ₃ ) ₂ CH ), 1.32 (6H, d, 6.3 Hz, (C H ₃ ) ₂ CH), 137 (6H, d, 6.3 Hz, (C H ₃ ) ₂ CH), 1.89 ( 2H, m, CH ₃ C H ₂ CH ₂ ), 4.23 (2H, t, 7 Hz, CH ₃ CH ₂ C H ₂ ), 4.57 (3H, m, 3x (CH ₃ ) ₂ C H ), 7.40 (1H, s. H-Ar), 11.55 (1H, br.s.CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the degree of purity of the intermediate — 3,4,5-tri (1-methylethyl) hydroxy-2-propyloxybenzoic acid — is 99.8%.

8.6. 3,4,5-Tri (1-methylethyl) hydroxy-2-propyloxybenzoyl chloride

3,4,5-Tri (1-methylethyl) -oxy-2-propyloxybenzoic acid (0.73 g, 2.1 mmol) was mixed with thionyl chloride (0.74 g, 6.2 mmol) and N, N was added. dimethylformamide (~ 0.01 ml). The reaction mixture is boiled for 1 hour. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The intermediate, a brown liquid, was obtained in quantitative yield (0.77 g, 100%), used in the next step without further purification.

8.7. 1- (tert-butoxycarbonyl) -4- (3,4,5- (1-methylethyl) hydroxy-2-propyl-hydroxybenzoyl) piperazine

To a solution of 1- (tert-butoxycarbonyl) piperazine (0.42 g, 2.27 mmol) and triethylamine (0.42 g, 4.12 mmol) in acetonitrile (5 ml) with stirring and a temperature of (-10) ° C dropwise a solution of 3,4,5- (1-methylethyl) hydroxy-2-propyloxybenzoyl chloride (0.77 g, 2.1 mmol) in acetonitrile (5 ml). The reaction mixture was stirred while cooling for 30 minutes, stirred at room temperature for 3 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure.

The residue was dissolved in water (20 ml), extracted with ethyl acetate (3 × 20 ml). The combined extracts were washed with water (20 ml), saturated ammonium chloride solution (20 ml), water (20 ml), saturated sodium hydrogen carbonate solution (20 ml), water (20 ml), saturated sodium chloride solution (20 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate is obtained in the form of a yellow liquid (1.02 g, 94%), used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.97 (3H, t. 6 Hz, C H ₃ CH ₂ CH ₂ ), 1.28 (18H, m, 3x (C H ₃ ) ₂ CH), 1.47 ( 9H, s, (C H ₃ ) ₃ C), 1.67 (2H, m, CH ₃ C H ₂ CH ₂ ), 2.8-4.5 (13H, m, 4xC H ₂ piperazine fragment CH ₃ CH ₂ C H ₂ , 3x (CH ₃ ) ₂ C H ), 6.51 (1H, s. H-Ar).

8.8. 1- (3,4,5- (1-Methylethyl) hydroxy-2-propyloxybenzoyl) piperazine hydrochloride

To a solution of 1- (tert-butoxycarbonyl) -4-3,4,5-1-methylethyl) hydroxy-2-propyl-hydroxybenzoyl) piperazine (1.00 g, 1.91 mmol) in propan-2-ol ( 2.0 ml) concentrated hydrochloric acid (0.8 ml, ~ 9.6 mmol) is added. The reaction mixture was stirred at 50 ° C for 30 minutes. Volatile components of the reaction mixture are removed on a rotary film evaporator. The residue was dissolved in methylene chloride (40 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The resulting intermediate (0.74 g, 84%) was used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.96 (3H, t. 6 Hz, C H ₃ CH ₂ CH ₂ ), 1.29 (18 H, m, 3x (C H ₃ ) ₂ CH), 1.67 (2 H , m, CH ₃ C H ₂ CH ₂ ), 3.0-4.1 (13Н, m, 4хC H ₂ -piperazine fragment, CH ₃ CH ₂ C H ₂ , 3х (CH ₃ ) ₂ С Н ) 6.49 (1H, s. H-Ar), 10.06 (2H, br.s, N ⁺ H ₂ ).

8.9. 1-Carbimidamido-4- (3,4,5- (1-methylethyl) hydroxy-2-propyloxybenzoyl) piperazine acetate

), 3,1-3,8 (8Н, 4хCH ₂-пиперазинового фрагмента), 4,07 (2Н, м., CH₃CH₂CH ₂), 4,48 (3Н, м., 3х(CH₃)₂СН), 6,52 (1Н, с. H-Ar), 8,57 (4Н, ш.c., С(NH ₂)(N⁺(H ₂)). Спектр ЯМР ¹³С (CDCl₃), δ, м.д.: 10,95 (CH₃CH₂CH₂), 22,41 ((CH₃)₂СН), 22,60 ((CH ₃)₂СН), 22,79 ((CH₃)₂СН), 23,02 ((CH₃)₂СН), 24,01 ((CH₃)₂СН), 25,04 ((CH₃)₂СН), 41,45 (CH₂-пиперазинового фрагмента), 45,06 (CH₂-пиперазинового фрагмента), 45,55 (CH₂-пиперазинового фрагмента), 46,48 (CH₂-пиперазинового фрагмента), 71,38 (CH₃ CH₂), 75,54 ((CH₃)₂ CH), 76,16 ((CH₃)₂ CH), 76,46 ((CH₃)₂ CH), 108,01 (С6, Ar), 124,09 (С1, Ar), 143,83 (С2, Ar), 144,65 (С5, Ar), 146,14 (С4, Ar), 149,45 (С3, Ar), 157,88 (C(NH₂)(N⁺H₂)), 168,55 (CON), 178,47 (CH ₃CO₂). Масс-спектр: МН⁺ найдено - 465,33, МН⁺ вычислено - 465,31. Чистота продукта по данным ВЭЖХ 99,62%, максимальная неидентифицированная примесь 0,08%, сумма неидентифицированных примесей 0,38%.To a solution of 1- (3,4,5- (1-methylethyl) oxy-2-propyloxybenzoyl) piperazine hydrochloride (0.74 g, 1.61 mmol) and 1H-pyrazole-1-carboximidamide hydrochloride (0.35 g, 2.42 mmol) in 95% aqueous ethanol (12 ml) triethylamine (0.67 ml, 4.83 mmol) is added. The reaction mixture was stirred at 50 ° C for 5 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The residue was emulsified in water (15 ml), made basic with potassium hydroxide (0.5 g, 8.9 mmol) and extracted with methylene chloride (3 × 20 ml). The combined organic extracts are washed with a ~ 5% solution of potassium hydroxide in water (3 × 20 ml), dried over anhydrous potassium carbonate. The desiccant is separated by filtration. Volatile components are removed on a rotary film evaporator under reduced pressure. The resulting residue, which is 1-carbimidamido-4-3,4,5- (1-methylethyl) oxy-2-propyloxybenzoyl) piperazine (0.62 g, 1.33 mmol, 83% yield), is dissolved in tert-butylmethyl ether (50 ml) and acidified with glacial acetic acid (0.08 g, 1.33 mmol). The precipitate formed is filtered off, dissolved in methylene chloride (20 ml) and tert-butyl methyl ether (20 ml) is added. Volatile components are removed on a rotary film evaporator under reduced pressure. The resulting crystalline residue was dried in vacuo. The product was obtained as small colorless crystals (0.60 g, 71%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.96 (3H, t. 6 Hz, C H ₃ CH ₂ CH ₂ ), 1.28 (18H, m, 3x (C H ₃ ) ₂ CH), 1.66 ( 2H, m, CH ₃ C H ₂ CH ₂ ), 1.78 (3H, s, $${\text{CH}}_{\text{3}}{\text{ÑO}}_{\text{2}}^{\text{-}}$$

), 3.1-3.8 (8H, 4xC H ₂ -piperazine fragment), 4.07 (2H, m, CH ₃ CH ₂ C H ₂ ), 4.48 (3H, m, 3x (CH ₃ ) ₂ C H ), 6.52 (1H, s. H-Ar), 8.57 (4H, bc.c., C (N H ₂ ) (N ⁺ ( H ₂ )). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 10.95 ( C H ₃ CH ₂ CH ₂ ), 22.41 (( C H ₃ ) ₂ CH), 22.60 ((C H ₃ ) ₂ CH) , 22.79 (( C H ₃ ) ₂ CH), 23.02 (( C H ₃ ) ₂ CH), 24.01 (( C H ₃ ) ₂ CH), 25.04 (( C H ₃ ) ₂ CH), 41.45 (CH ₂ piperazine fragment), 45.06 (CH ₂ piperazine fragment), 45.55 (CH ₂ piperazine fragment), 46.48 (CH ₂ piperazine fragment), 71.38 (CH ₃ C H ₂ ), 75.54 ((CH ₃ ) ₂ C H), 76.16 ((CH ₃ ) ₂ C H), 76.46 ((CH ₃ ) ₂ C H), 108.01 (C6, Ar), 124.09 (C1, Ar), 143.83 (C2, Ar), 144.65 (C5, Ar), 146.14 (C4, Ar), 149.45 (C3, Ar) , 157,88 (C (NH ₂₎ (N ⁺ H _2)), 168,55 (C oN) , 178,47 (C H ₃ CO ₂₎ Mass spectrum. MH ⁺ for Deno - 465.33, calculated MH ⁺ - 465.31 Purity by HPLC analysis: 99.62%, maximum 0.08% unidentified impurity, the amount of unidentified impurities 0.38.%.

Example 9. Obtaining 1-carbimidamido-4- (2,4-dibutoxy-3,5-diethoxybenzoyl) piperazine acetate

9.1. 2-bromo-4-butoxy-3,5-diethoxybenzoic acid

Water (0.1 ml) was added to a solution of 4-butoxy-3,5-diethoxybenzoic acid (2.09 g, 0.007 M) ethyl acetate (10 ml). The reaction mixture is heated to boiling. A solution of bromine (0.40 ml, 1.24 g, 0.008 M) in ethyl acetate (3 ml) is added dropwise to the boiling reaction mixture with stirring for 20 minutes. The reaction mixture is refluxed for 1 hour, the volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The intermediate was obtained in quantitative yield (2.68 g, 100%) as pale yellow crystals and was used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.99 (3H, t. 7 Hz, C H ₃ CH ₂ CH ₂ CH ₂ ), 1.46 (8H, t. 6 Hz, 2xC H ₃ CH ₂ and CH ₃ C H ₂ CH ₂ CH ₂ ), 1.76 (2H, m, CH ₃ CH ₂ C H ₂ CH ₂ ), 4.11 (6H, m, 2xCH ₃ C H ₂ and CH ₃ CH ₂ CH ₂ C H ₂ ), 7.38 (1H, s. H-Ar), 8.15 (1H, br.s.CO ₂ H ). The purity of the intermediate according to ¹ H NMR and TLC spectroscopy is 95%.

9.2. 4-butoxy-2-hydroxy-3,5-diethoxybenzoic acid

To a hot solution of 2-bromo-4-butoxy-3,5-diethoxybenzoic acid (2.68 g, 7.4 mmol) in a 3 M solution of potassium hydroxide in water (10 ml), copper (II) oxide is added (0.03 g, 0.37 mmol, 5% mol.). The reaction mixture was refluxed with stirring for 15 hours. Water (10 ml), potassium hydroxide (0.84 g, 0.015 M) and a hot solution of copper (II) sulfate pentahydrate (0.92 g, 3.7 mmol) in water (10 ml) are added to the hot reaction mixture with stirring. . The precipitate was separated by filtration, suspended in a 5% solution of potassium hydroxide in water (50 ml), stirred for 1 hour and separated by filtration (the procedure was repeated three times). The precipitate was suspended in water (20 ml), acidified with concentrated hydrochloric acid (15 ml, 0.06 M), extracted with ethyl acetate (2 × 25 ml). The combined organic extracts are washed successively with 3% hydrochloric acid in water (2 × 15 ml), water (2 × 15 ml), saturated sodium chloride solution (20 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. Intermediate, light yellow liquid (1.15 g, 52%), hardening upon standing. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.98 (3H, t. 7 Hz, C H ₃ CH ₂ CH ₂ CH ₂ ), 1.45 (6H, t, 6 Hz, 2xC H ₃ CH ₂ ), 1.74 (2H, m, CH ₃ C H ₂ CH ₂ CH ₂ ), 1.78 (2H, m, CH ₃ CH ₂ C H ₂ CH ₂ ), 4.04 (2H, q, 7 Hz, CH ₃ C H ₂ ) 4.19 (4H, m, CH ₃ C H ₂ and CH ₃ CH ₂ CH ₂ C H ₂ ), 7.16 (1H, s. H-Ar), 10.22 (2H, br s . CO ₂ H, H O-Ar).

According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate product of -4-butoxy-3,5-diethoxybenzoic acid is 99.5%.

9.3. 4-Butoxy-2-hydroxy-3,5-diethoxybenzoic acid ethyl ester

To a solution of 4-butoxy-2-hydroxy-3,5-diethoxybenzoic acid (1.12 g, 3.7 mmol), absolute ethanol (0.88 ml, 15.0 mmol) and 4- dimethiaminopyridine (0.02 g, 0.16 mmol) in methylene chloride (10 ml) was added with stirring N, N′-dicyclohexylcarbodiimide (0.82 g, 3.9 mmol). The reaction mixture was stirred while cooling for 10 minutes, then at room temperature for 48 hours. The precipitate formed is filtered off and discarded. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The residue was dissolved in tert-butyl methyl ether (25 ml). The resulting solution was washed successively with 0.5 M hydrochloric acid (2 × 12 ml), water (2 × 12 ml), saturated sodium bicarbonate solution (2 × 12 ml), saturated sodium chloride solution (15 ml) and dried over anhydrous sulfate magnesium. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The residue was dissolved in a mixture of heptane with methylene chloride (5: 2, 10 ml), passed through a layer of silica gel (60 mesh, 20 g), eluting with a mixture of heptane with methylene chloride (5: 2). Intermediate, yellow liquid (0.89 g, 73%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.98 (3H, t. 7 Hz, C H ₃ CH ₂ CH ₂ CH ₂ ), 1.45 (11H, m, 2xC H ₃ CH ₂ , C H ₃ CH ₂ O C ₂ and C H ₃ CH ₂ CH ₂ CH _2), 1.57 (2H, m, CH ₃ CH ₂ C H ₂ CH _2), 4.03 (2H, q., 7Hz, CH ₃ C H ₂ ) 4.15 (6H, m, CH ₃ C H ₂ and CH ₃ CH ₂ CH ₂ C H ₂ ), 4.41 (2H, q, 7 Hz, CH ₃ C H ₂ O ₂ C-) 7.10 (1H, s. H-Ar); 10.72 (1H, s., HO- Ar).

9.4. 2,4-Dibutoxy-3,5-diethoxybenzoic acid ethyl ester

4-Butoxy-2-hydroxy-3,5-diethoxybenzoic acid is dissolved in ethyl ether (0.86 g, 2.6 mmol), 1-bromobutane (1.13 ml, 10.5 mmol), anhydrous potassium carbonate (1 , 45 g, 10.5 mmol) and potassium iodide (0.04 g, 0.26 mmol) in acetonitrile (20 ml). The reaction mixture was refluxed with stirring for 16 hours. The precipitate from the cooled mixture was separated by filtration, washed with acetonitrile (2 × 5 ml), discarded. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The residue was dissolved in ethyl acetate (25 ml), washed with water (2 × 10 ml), 0.5 M hydrochloric acid solution (2 × 10 ml), water (2 × 10 ml), saturated sodium bicarbonate solution (2 × 10 ml) saturated sodium chloride solution (15 ml), dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. Volatile components are removed on a rotary film evaporator under reduced pressure. The intermediate, a light yellow liquid (0.94 g, 93%), is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.99 (6H, m, 2xC H ₃ CH ₂ CH ₂ CH ₂ ), 1.45 (14H, m, 2xC H ₃ CH ₂ , C H ₃ CH ₂ O ₂ C- and 2xCH ₃ C H ₂ CH ₂ CH ₂ ), 1.76 (4H, m, 2xCH ₃ CH ₂ C H ₂ CH ₂ ), 4.09 (8H, m, 2xCH ₃ C H ₂ and 2xCH ₃ CH ₂ CH ₂ C H ₂ ), 4.37 (2H, q, 7 Hz, CH ₃ C H ₂ O ₂ C-), 7.10 (1H, s. H-Ar).

9.5. 2,4-Dibutoxy-3,5-diethoxybenzoic acid

Sodium hydroxide (0.19 g, 4.8 mmol) was added to a solution of 2,4-dibutoxy-3,5-diethoxybenzoic acid ethyl ester (0.93 g, 2.4 mmol) in methanol (25 ml). The reaction mixture was refluxed with stirring for 3 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The residue was suspended in water (10 ml), acidified with concentrated hydrochloric acid (1.0 ml, 0.012 M) and extracted with ethyl acetate (2 × 20 ml). The combined organic extracts were washed with water (2 × 10 ml) and a saturated solution of sodium chloride (15 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a yellow liquid (0.74 g, 86%), is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.99 (6H, m, 2xC H ₃ CH ₂ CH ₂ CH ₂ ), 1.45 (10H, m, 2xC H ₃ CH ₂ , and 2xCH ₃ C H ₂ CH ₂ CH _2), 1.76 (4H, m., 2hCH ₃ CH ₂ C H ₂ CH _2), 4.10 (6H, m., 2hCH ₃ C H ₂ and CH ₃ CH ₂ CH ₂ C H ₂₎ 4 27 (2H, t, 7 Hz, CH ₃ CH ₂ CH ₂ C H ₂ ), 7.39 (1H, s. H-Ar), 10.11 (1H, br.s.CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate product - 2,4-dibutoxy-3,5-diethoxybenzoic acid - 99.8%.

9.6. 2,4-Dibutoxy-3,5-diethoxybenzoyl chloride

2,4-Dibutoxy-3,5-diethoxybenzoic acid (0.74 g, 2.09 mmol) was mixed with thionyl chloride (0.45 ml, 6.27 mmol) and N, N-dimthylformamide (~ 0.01 ml). The reaction mixture is boiled for 1 hour. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The intermediate is obtained in quantitative yield (0.78 g, 100%) as a liquid and is used in the next step without further purification.

9.7. 1- (tert-butoxycarbonyl) -4- (2,4-dibutoxy-3,5-diethoxybenoyl) piperazine

To a solution of 1-tert-butoxycarbonyl) piperazine (0.43 g, 2.30 mmol) and N-methylmorpholine (0.58 ml, 4.18 mmol) in methylene chloride (5 ml) with stirring and cooling to (-) A solution of 2,4-dibutoxy-3,5-diethoxybenzoyl chloride (0.78 g, 2.09 mmol) in methylene chloride (5 ml) was added dropwise at 10 ° C. The reaction mixture was stirred while cooling for 30 minutes, after which it was stirred at room temperature for 3 hours. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure.

The residue was dissolved in water (20 ml) and the product was extracted with ethyl acetate (3 × 20 ml). The combined organic extracts were washed successively with water (20 ml), saturated ammonium chloride solution (20 ml), water (20 ml), saturated sodium hydrogen carbonate solution (20 ml), water (20 ml), saturated sodium chloride solution (20 ml), and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a yellow liquid (1.01 g, 92%), is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.97 (6H, m, 2xC H ₃ CH ₂ CH ₂ CH ₂ ), 1.30-1.80 (23H, m, 2xC H ₃ CH ₂ , 2xCH ₃ C H ₂ CH ₂ CH ₂ , (CH ₃ ) ₃ C and 2x CH ₃ CH ₂ C H ₂ CH ₂ ), 3.0-4.5 (16H, m, 4xC H ₂ piperazine fragment, 2x CH ₃ CH ₂ CH ₂ C H ₂ and 2xCH ₃ C H ₂ ), 6.52 (1H, s. H-Ar).

9.8. 1- (2,4-Dibutoxy-3,5-diethoxybenzoyl) piperazine hydrochloride

To a solution of 1-tert-butoxycarbonyl) -4- (2,4-dibutoxy-3,5-diethoxybenzoyl) piperazine (1.00 g, 1.91 mmol) in 95% aqueous ethanol (2.0 ml) was added concentrated hydrochloric acid acid (0.8 ml, ~ 9.6 mmol). The reaction mixture was stirred at 50 ° C for 1 hour. Volatile components of the reaction mixture are removed on a rotary film evaporator. The residue was dissolved in methylene chloride (40 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The resulting intermediate (0.73 g, 83%) was used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.97 (6H, m, 2xC H ₃ CH ₂ CH ₂ CH ₂ ), 1.30-1.80 (14H, m, 2xC H ₃ CH ₂ , 2xCH ₃ C H ₂ CH ₂ CH ₂ and 2xCH ₃ CH ₂ C H ₂ CH ₂ ), 3.0-4.5 (16H, m, 4xC H ₂ piperazine fragment, 2xCH ₃ CH ₂ CH ₂ C H ₂ and 2xCH ₃ C H ₂ ), 6.50 (1H, s. H-Ar), 10.08 (2H, br.s, N ⁺ H ₂ ).

9.9. 1-Carbimidamido-4- (2,4-dibutoxy-3,5-diethoxybenzoyl) -piperazine acetate To a solution of 1- (2,4-dibutoxy-3,5-diethoxybenzoyl) piperazine hydrochloride (0.73 g, 1.59 mM) and 1H-pyrazole-1-carboximidamide hydrochloride (0.35 g, 2.39 mm) in propan-2-ol (12 ml) N-methylmorpholine (0.52 ml, 4.77 mm) was added. The reaction mixture was stirred at 50 ° C for 5 hours. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The residue was emulsified in water (15 ml), made basic with potassium hydroxide (0.5 g, 8.9 mmol) and extracted with methylene chloride (3 × 20 ml). The combined extracts were washed with ~ 5% potassium hydroxide solution (3 × 20 ml), dried over anhydrous potassium carbonate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The residue, 1-carbimidamido-4- (2,4-dibutoxy-3,5-diethoxybenzoyl) piperazine (0.74 g, 1.59 mmol, 100% yield), was dissolved in tert-butyl methyl ether (50 ml) and acidified glacial acetic acid (0.095 g, 1.33 mmol). The precipitate formed is filtered off, then tert-butyl methyl ether (20 ml) is added in methylene chloride (20 ml). Volatile components are removed on a rotary film evaporator under reduced pressure. The resulting crystalline residue was dried in vacuo. The product was obtained in the form of cream-colored crystals (0.53 g, 63%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.97 (6H, m, 2xC H ₃ CH ₂ CH ₂ CH ₂ ), 1.30-1.80 (14H, m, 2xC H ₃ CH ₂ , 2xCH ₃ C H ₂ CH ₂ CH ₂ and 2hCH ₃ CH ₂ C H ₂ CH _2), 1.82 (3H, s, C H ₃ CO _2), 3,1-4,5 (16H, m., ₂ H 4hC -piperazine fragment , 2xCH ₃ CH ₂ CH ₂ C H ₂ and 2xCH ₃ C H ₂ ), 6.53 (1H, s. H-Ar), 8.58 (4H, bc.c., C (N H ₂ ) (N ⁺ H ₂ )). ¹³ C NMR Spectrum (CDCl ₃ ), δ, ppm: 14.22 ( C H ₃ CH ₂ CH ₂ CH ₂ ), 15.26 ( C H ₃ CH ₂ CH ₂ CH ₂ ), 16.06 ( C H ₃ CH ₂ ), 15.26 ( C H ₃ CH ₂ ), 19.51 (2x CH ₃ C H ₂ CH ₂ CH ₂ ), 24.99 ( C H ₃ CO ₂ -), 32.67 (CH ₃ CH ₂ C H ₂ CH ₂ ), 32.79 (CH ₃ CH ₂ C H ₂ CH ₂ ), 41.47 (CH ₂ piperazine fragment), 45.03 (CH ₂ piperazine fragment), 45.62 ( CH ₂ piperazine fragment), 46.44 (CH ₂ piperazine fragment), 65.05 (CH ₃ C H ₂ ), 69.88 (CH ₃ C H ₂ ), 73.83 (CH ₃ CH ₂ CH ₂ C H ₂ ), 74.95 (CH ₃ CH ₂ CH ₂ C H ₂ ), 106.71 (C6, Ar), 124.24 (C1, Ar), 143.47 (C2, Ar), 144.75 (C5, Ar), 146.74 (C4, Ar), 150.24 (C3, Ar), 157.93 ( C (NH ₂ ) (N ⁺ H ₂ )), 168.34 ( C ON), 178 42 ( C H ₃ CO ₂ ). MS: MH ⁺ found - 465.34, calculated MH ⁺ - 465.31. The purity of the product according to HPLC 99.59%, the maximum unidentified impurity 0.10%, the sum of unidentified impurities 0.41%.

Example 10. Obtaining 1-carbimidamido-4- (2-heptyloxy-3,4,5-trimethoxybenzoyl) piperazine acetate

10.1. 2-bromo-3,4,5-trimethoxybenzoic acid

To a suspension of 3,4,5-trimethoxybenzoic acid (53.0 g, 0.25 M) in glacial acetic acid (150 ml), bromine (19.6 ml, 0.38 M) was added dropwise with stirring. The reaction mixture was stirred at room temperature for 16 hours, poured into cold water (2000 ml). The precipitate formed is filtered off, washed on the filter with water (3 × 500 ml) and dried at 50 ° C at atmospheric pressure. Intermediate, sandy yellow crystals (44.9 g, 63%) and used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.92 (3H, CH ₃ O-), 3.93 (3H, CH ₃ O-), 3.98 (3H, CH ₃ O-), 7.42 (1H, s. , H-Ar), 11.00 (1H, br.s.CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate is 99.8%.

10.2. 2-hydroxy-3,4,5-trimethoxybenzoic acid

To a hot solution of 2-bromo-3,4,5-trimethoxybenzoic acid (33.2 g, 0.114 M) and sodium hydroxide (18.25 g, 0.456 M) in water (150 ml), copper (II) oxide is added (4 , 53 g, 0.057 M, 50 mol%). The reaction mixture is refluxed with stirring for 7 hours, 3 hours after the start of boiling, the reaction mixture begins to foam very much, which makes mixing difficult. Water (100 ml), sodium hydroxide (4.56 g, 0.114 M) and a hot solution of copper (II) sulfate pentahydrate (14.23 g, 0.057 M) in water (100 ml) are added to the hot mixture with stirring. The precipitate formed is filtered off, suspended in a 5% aqueous sodium hydroxide solution (100 ml), stirred for 1 hour, separated by filtration (the operation is repeated three times). The precipitate isolated is suspended in water (100 ml) and acidified with concentrated hydrochloric acid (25 ml, 0.3 M). The precipitate formed is filtered off, washed on the filter with water (3 × 100 ml), squeezed and dried in vacuo. The intermediate product is obtained in the form of crystals of a pale cream color (11.70 g, 45%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.87 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.05 (3H, CH ₃ O-), 5.5 (1H, br. s, HO-Ar), 7.17 (1H, s, H-Ar), 10.31 (1H, s. CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate of -2-hydroxy-3,4,5-trimethoxybenzoic acid is 99.5%.

10.3. 2-Hydroxy-3,4,5-trimethoxybenzoic acid methyl ester

To a solution of 2-hydroxy-3,4,5-trimethoxybenzoic acid (9.13 g, 0.040 M) in methanol (20 ml), concentrated sulfuric acid (1.6 ml, 0.03 M) was added with stirring, the mixture was boiled with reflux for 7 hours, cooled, poured into a mixture of ice (50 g), water (50 ml) and sodium bicarbonate (10.0 g, 0.119 M), extracted with tert-butyl methyl ether (3 × 50 ml). The combined organic extracts were washed successively with saturated sodium bicarbonate solution (2 × 25 ml), water (25 ml), saturated sodium chloride solution (25 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a light yellow liquid (8.42 g, 87%), crystallized upon standing, was used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.84 (3H, s, CH ₃ O ₂ C), 3.93 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.01 ( 3H, CH ₃ O-), 7.08 (1H, s, H-Ar), 10.68 (1H, s, HO-Ar).

10.4. 2-heptyloxy-3,4,5-trimethoxybenzoic acid methyl ester

2-hydroxy-3,4,5-trimethoxybenzoic acid methyl ester (4.95 g, 0.020 M), heptyl bromide (8.95 g, 0.05 M), anhydrous potassium carbonate (8.30 g, 0.060 M) are dissolved. potassium iodide (0.66 g, 0.004 M) in N, N-dimethylformamide (15 ml). The reaction mixture was stirred at 70 ° C for 24 hours. The cooled reaction mixture was poured into water (100 ml), acidified with concentrated hydrochloric acid (25 ml, ~ 0.300 M) and extracted with tert-butyl methyl ether (3 × 30 ml). The combined organic extracts were washed successively with water (2 × 30 ml), saturated sodium bicarbonate solution (2 × 30 ml), 10% sodium thiosulfate solution (3 × 30 ml), saturated sodium chloride solution (30 ml), and dried over anhydrous carbonate potassium. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a yellow liquid (5.08 g, 75%), is used in the next step without further purification.

10.5. 2-heptyloxy-3,4,5-trimethoxybenzoic acid

To a solution of 2-heptyloxy-3,4,5-trimethoxybenzoic acid methyl ester (5.08 g, 0.015 M) in 95% aqueous ethanol (20 ml), potassium hydroxide (1.65 g, 0.029 M) is added, the mixture is boiled with under reflux with stirring for 3 hours. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The residue was treated with boiling tert-butyl methyl ether (30 ml). The resulting suspension was separated by filtration. The precipitate was washed with tert-butyl methyl ether (2 × 25 ml), dried in air, dissolved in water (50 ml), acidified with concentrated hydrochloric acid (10 ml, 0.12 M), extracted with tert-butyl methyl ether (3 × 25 ml) . The combined organic extracts were washed with water (2 × 30 ml), saturated sodium chloride solution (20 ml), dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a yellow liquid (3.83 g, 81%), is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.91 (3H, t. 6.7 Hz, C H ₃ (CH ₂ ) ₄ CH ₂ CH ₂ -), 1.3 (8H, m, CH ₃ (C H ₂ ) ₄ CH ₂ CH ₂ -), 1.85 (2Н, m, CH ₃ (CH ₂ ) ₄ C H ₂ CH ₂ -), 3,90 (3Н, s, C H ₃ О), 3, 92 (3H, s, C H ₃ O), 3.99 (3H, s, C H ₃ O), 4.25 (2H, t, 7 Hz, CH ₃ (CH ₂ ) ₄ CH ₂ C H ₂ -), 7.43 (1H, s, H-Ar), 11.54 (1H, ss, CO ₂ H). According to ¹ H NMR spectroscopy and TLC purity precursor - 2-heptyloxy-3,4,5-trimethoxybenzoic acid - 99.7%.

10.6. 2-heptyloxy-3,4,5-trimethoxybenzoyl chloride

To a solution of 2-heptyloxy-3,4,5-trimethoxybenzoic acid (3.8 g, 0.012 M) in methylene chloride (10 ml) was added thionyl chloride (1.85 g, 0.015 M) and N, N-dimethylformamide (0 , 01 ml). The reaction mixture was stirred at room temperature for 1 hour, refluxed with stirring for 2 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The intermediate product is obtained in quantitative yield (4.15 g, 100%) as a dark yellow liquid, used in the next step without further purification.

10.7. 1- (tert-butoxycarbonyl) -4- (2-heptyloxy-3,4,5-trimethoxybenzoyl) piperazine

To a solution of 1- (tert-butoxycarbonyl) piperazine (1.66 g, 0.009 M) and triethylamine (1.85 ml, 0.013 M) in methylene chloride (10 ml), a solution of 2-heptyloxy-3,4,5 is added dropwise with stirring. -trimethoxybenzoyl chloride (2.77 g, 0.008 M) in methylene chloride (10 ml). The reaction mixture was stirred at room temperature for 3 hours.

The precipitate formed is filtered off and discarded. The filtrate was washed successively with water (2 × 15 ml), a saturated solution of ammonium chloride (2 × 15 ml), water (2 × 15 ml), a saturated solution of sodium bicarbonate (2 × 15 ml), a saturated solution of sodium chloride (10 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a yellow liquid, is obtained in quantitative yield (3.92 g, 100%), and is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.90 (3H, t, 6 Hz, C H ₃ (CH ₂ ) ₄ CH ₂ CH ₂ ), 1.35 ( ₈ H , m, CH ₃ (C H ₂ ) ₄ CH ₂ CH ₂ ), 1.48 (9H, s, (C H ₃ ) ₃ C), 1.69 (2H, m, CH ₃ (CH ₂ ) ₄ CH ₂ CH ₂ ), 3.0-4.3 (19H, m, 4xC H ₂ piperazine fragment, CH ₃ (CH ₂ ) ₄ CH ₂ C H ₂ and 3xC H ₃ O-), 6.56 (1H, s, H-Ar).

10.8. 1- (2-Heptyloxy-3,4,5-trimethoxybenzoyl) piperazine hydrochloride

1- (tert-Butoxycarbonyl) -4- (2-heptyloxy-3,4,5-trimethoxybenzoyl) piperazine (3.92 g, 0.008 M) was mixed with concentrated hydrochloric acid (20 ml, ~ 0.24 M). The reaction mixture was stirred at room temperature until completely homogenized for 3 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator, adding 10 ml of water twice to the residue to effectively remove excess hydrogen chloride. The residue was dissolved in hot propan-2-ol (50 ml). Insoluble impurities are separated by filtration through celite. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, colorless crystals (3.40 g, 98%), are used in the next step without further purification.

10.9. 1-carbimidamido-4- (2-heptyloxy-3,4,5-trimethoxybenzoyl) piperazine acetate

), 28,36 (CH₃CH₂CH₂ CH₂CH₂CH₂CH₂), 29,61 (CH₃CH₂CH₂CH₂ CH₂CH₂CH₂), 31,21 (CH₃CH₂CH₂CH₂CH₂ CH₂CH₂), 40,57 (CH₂-пиперазинового фрагмента), 44,11 (CH₂-пиперазинового фрагмента), 44,72 (CH₂-пиперазинового фрагмента), 45,48 (CH₂-пиперазинового фрагмента), 56,09 (CH₃O-), 60,60 (СН₃О-), 60,98 (CH₃O-), 73,95 (CH₃ (CH₂)₄CH₂ CH₂), 105,45 (С6, Ar), 124,83 (С1, Ar), 142,18 (С2, Ar), 143,18 (С5, Ar), 146,55 (С4, Ar), 149,44 (С3, Ar), 157,46 (C(NH₂)(N⁺H₂)), 166,23 (CON), 175,83 (CH₃ CO₂H).To a solution of 1- (2-heptyloxy-3,4,5-trimethoxybenzoyl) piperazine hydrochloride (3.40 g, 0.008 M) and 1H-pyrazole-1-carboximidamide hydrochloride (1.60 g, 0.011 M) in N, N -dimethylformamide (10 ml) at a temperature of 50 ° C add diisopropylethylamine (3.50 ml, 0.020 M). The reaction mixture was stirred at 50 ° C for 10 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The residue was dissolved in water (50 ml) and extracted with tert-butyl methyl ether (3 × 15 ml). The organic layer is folded. The clear aqueous layer was made basic with 50% sodium hydroxide solution (20 ml) and extracted with methylene chloride (3 × 15 ml). The combined organic extracts were washed with water (2 × 10 ml) and dried over anhydrous potassium carbonate. The desiccant is separated by filtration. Volatile components are removed on a rotary film evaporator under reduced pressure. The resulting residue, 1-carbimidamido-4- (2-heptyloxy-3,4,5-trimethoxybenzoyl) piperazine (3.49 g, 0.008 M), was dissolved in acetone (25 ml) and acidified with glacial acetic acid (0.45 ml) , 0.008 M). The precipitate was separated by filtration, washed with acetone (2 × 5 ml) and tert-butyl methyl ether (2 × 10 ml), dried in vacuum. The product is small, colorless crystals (2.61 g, 69%). ¹ H NMR Spectrum (DMSO), δ, ppm (J, Hz): 0.87 (3H, m., C H ₃ (CH ₂ ) ₄ CH ₂ CH ₂ ), 1.35 (8H, m, CH ₃ (CH ₂ ) ₄ CH ₂ CH ₂ ) 1.64 (5H, m, CH ₃ (CH ₂ ) ₄ C H ₂ CH ₂ and C H ₃ CO ₂ -), 3.5-4.2 (19H, m, 4xC H ₂ piperazine fragment , CH ₃ (CH ₂ ) ₄ CH ₂ C H ₂ and 3xC H ₃ O -), 6.64 (1H, s, H-Ar), 8.84 (4H, br.s, C (N H ₂ ) (N ⁺ H ₂ )). ¹³ C NMR Spectrum (DMSO), δ, ppm: 13.90 ( C H ₃ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ), 22.02 (CH ₃ C H ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ), 24.96 (CH ₃ CH ₂ C H ₂ CH ₂ CH ₂ CH ₂ CH ₂ ), 25.36 ( $$\underset{\_}{\text{C}}{\text{H}}_{\text{3}}{\text{ÑO}}_{\text{2}}^{\text{-}}$$

), 28,36 (CH ₃ CH ₂ CH ₂ C H ₂ CH ₂ CH ₂ CH _2), 29,61 (CH ₃ CH ₂ CH ₂ CH ₂ C H ₂ CH ₂ CH _2), 31,21 (CH ₃ CH ₂ CH ₂ CH ₂ CH ₂ C H ₂ CH ₂ ), 40.57 (CH ₂ piperazine fragment), 44.11 (CH ₂ piperazine fragment), 44.72 (CH ₂ piperazine fragment), 45, 48 (CH ₂ piperazine fragment), 56.09 (CH ₃ O-), 60.60 (CH ₃ O-), 60.98 (CH ₃ O-), 73.95 (CH ₃ (CH ₂ ) ₄ CH ₂ C H ₂ ), 105.45 (C6, Ar), 124.83 (C1, Ar), 142.18 (C2, Ar), 143.18 (C5, Ar), 146.55 (C4, Ar ), 149.44 (C3, Ar), 157.46 ( C (NH ₂ ) (N ⁺ H ₂ )), 166.23 ( C ON), 175.83 (CH ₃ C O ₂ H).

), 28,84 (CH₃CH₂CH₂ CH₂CH₂CH₂CH₂), 30,01 (CH₃CH₂CH₂CH₂ CH₂CH₂CH₂), 31,79 (CH₃CH₂CH₂CH₂CH₂ CH₂CH₂), 41,67 (CH₂-пиперазинового фрагмента), 44,56 (CH₂-пиперазинового фрагмента), 45,63 (CH₂-пиперазинового фрагмента), 45,86 (CH₂-пиперазинового фрагмента), 56,73 (CH₃O-), 61,49 (CH₃O-), 61,70 (CH₃O-), 75,56 (CH₃ (CH₂)₄CH₂ CH₂), 106,15 (С6, Ar), 124,60 (С1, Ar), 142,69 (С2, Ar), 144,00 (С5, Ar), 147,01 (С4, Ar), 150,23 (С3, Ar), 157,00 (C(NH₂)(N⁺H₂)), 169,25 (CON), 181,67 (CH₃ СO₂Н). Масс-спектр: МН⁺ найдено - 437,25, МН⁺ вычислено - 437,28. Чистота продукта по данным ВЭЖХ 99,61%, максимальная неидентифицированная примесь - 0,1%, сумма неидентифицированных примесей - 0,39%NMR ¹ H (D ₂ O), δ, ppm (J, Hz): 1.05 (3H, m., C H ₃ (CH ₂ ) ₄ CH ₂ CH ₂ ), 1.50 (8H, m, CH ₃ (C H ₂ ) ₄ CH ₂ CH ₂ ), 1.84 (2H, m, CH ₃ (CH ₂ ) ₄ C H ₂ CH ₂ ), 2.11 (3H, s, C H ₃ CO ₂ -), 3.5-4.5 ( 19H, m., 4xC H ₂ -piperazine fragment, CH ₃ (CH ₂ ) ₄ CH ₂ C H ₂ and 3xC H ₃ O-), 6.95 (1H, s, H-Ar). ¹³ C NMR spectrum (D ₂ O), δ, ppm: 13.96 ( C H ₃ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ), 22.60 (CH ₃ C H ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ), 23.75 (CH ₃ CH ₂ C H ₂ CH ₂ CH ₂ CH ₂ CH ₂ ), 25.90 ( $$\underset{\_}{\text{C}}{\text{H}}_{\text{3}}{\text{ÑO}}_{\text{2}}^{\text{-}}$$

), 28.84 (CH ₃ CH ₂ CH ₂ C H ₂ CH ₂ CH ₂ CH ₂ ), 30.01 (CH ₃ CH ₂ CH ₂ CH ₂ C H ₂ CH ₂ CH ₂ ), 31.79 (CH ₃ CH ₂ CH ₂ CH ₂ CH ₂ C H ₂ CH ₂ ), 41.67 (CH ₂ piperazine fragment), 44.56 (CH ₂ piperazine fragment), 45.63 (CH ₂ piperazine fragment), 45, 86 (CH ₂ piperazine fragment), 56.73 (CH ₃ O-), 61.49 (CH ₃ O-), 61.70 (CH ₃ O-), 75.56 (CH ₃ (CH ₂ ) ₄ CH ₂ C H ₂ ), 106.15 (C6, Ar), 124.60 (C1, Ar), 142.69 (C2, Ar), 144.00 (C5, Ar), 147.01 (C4, Ar ), 150.23 (C3, Ar), 157.00 ( C (NH ₂ ) (N ⁺ H ₂ )), 169.25 ( C ON), 181.67 (CH ₃ C O ₂ H). Mass spectrum: MH ⁺ found, 437.25; MH ⁺ calculated, 437.28. The purity of the product according to HPLC 99.61%, the maximum unidentified impurity is 0.1%, the sum of unidentified impurities is 0.39%

Example 11. Obtaining 1-carbimidamido-4- (2-dodecyloxy-3,4,5-trimethoxybenzoyl) piperazine methanesulfonate

11.1. 2-bromo-3,4,5-trimethoxybenzoic acid

To a suspension of 3,4,5-trimethoxybenzoic acid (100.0 g, 0.471 M) in ethyl acetate (500 ml) was added 2 ml of water. The reaction mixture is heated to boiling point. To the boiling reaction mixture, bromine (82.6 g, 0.519 M) was added dropwise with stirring for 30 minutes. The reaction mixture was refluxed for 1 hour. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The intermediate, a pale cream colored precipitate, was obtained in quantitative yield (137.2 g, 100%), used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.92 (3H, CH ₃ O-), 3.93 (3H, CH ₃ O-), 3.98 (3H, CH ₃ O-), 7.42 (1H, s. , H-Ar), 11.00 (1H, br.s.CO ₂ H ). The purity according to ¹ H NMR spectroscopy and TLC is 95%.

11.2. 2-hydroxy-3,4,5-trimethoxybenzoic acid

To a hot solution of 2-bromo-3,4,5-trimethoxybenzoic acid (37.55 g, 0.129 M) and sodium carbonate (34.20 g, 0.323 M) in water (200 ml), copper (II) sulfate pentahydrate ( 3.22 g, 0.013 M, 10 mol%), the mixture is refluxed with stirring for 6 hours. Sodium hydroxide (5.20 g, 0.130 M) is added to the hot mixture, then a hot solution of copper (II) sulfate pentahydrate (16.10 g, 0.065 M) in water (50 ml) is added with stirring. The precipitate formed is separated by filtration, suspended in a 5% solution of sodium hydroxide in water (100 ml), stirred for 1 hour and separated by filtration (the operation is repeated twice). The precipitate isolated is suspended in water (100 ml) and acidified with concentrated hydrochloric acid (25 ml, 0.3 M). The precipitate was filtered off, washed on the filter with water (3 × 100 ml) and dried in vacuo. Intermediate, pale cream crystals (9.13 g, 31%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.87 (3H, C H ₃ O-), 3.95 (3H, C H ₃ O-), 4.05 (3H, C H ₃ O-), 5.5 (1H , br.s, H O-Ar), 7.17 (1H, s, H- Ar), 10.31 (1H, s. CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate - 2-hydroxy-3,4,5-trimethoxybenzoic acid - 99.5%.

11.3. 2-Hydroxy-3,4,5-trimethoxybenzoic acid methyl ester

To a solution of 2-hydroxy-3,4,5-trimethoxybenzoic acid (9.13 g, 0.040 M) in methanol (20 ml), concentrated sulfuric acid (1.6 ml, 0.03 M) was added with stirring.

The reaction mixture is boiled for 7 hours, cooled, poured into a mixture of ice (50 g), water (50 ml) and sodium bicarbonate (10.0 g, 0.119 M). The solution was extracted with tert-butyl methyl ether (3 × 50 ml). The combined extracts were washed successively with saturated sodium hydrogen carbonate solution (2 × 25 ml), water (25 ml), saturated sodium chloride solution (25 ml), dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a light yellow liquid (8.42 g, 87%), crystallized upon standing, was used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.84 (3H, s., C H ₃ O ₂ C), 3.93 (3H, C H ₃ O-), 3.95 (3H, C H ₃ O-), 4 01 (3H, C H ₃ O-), 7.08 (1H, s, H- Ar), 10.68 (1H, s, H O-Ar).

11.4. 2-Dodecyloxy-3,4,5-trimethoxybenzoic acid methyl ester

2-hydroxy-3,4,5-trimethoxybenzoic acid was dissolved in methyl ether (4.95 g, 0.020 M), dodecyl bromide (12.45 g, 0.05 M), anhydrous potassium carbonate (8.30 g, 0.060 M) and potassium iodide (0.66 g, 0.004 M) in N, N-dimethylformamide (15 ml). The reaction mixture was stirred at 70 ° C for 24 hours, cooled, poured into water (100 ml), acidified with concentrated hydrochloric acid (25 ml, ~ 0.300 M) and extracted with tert-butyl methyl ether (3 × 30 ml). The combined organic extracts were washed successively with water (2 × 30 ml), saturated sodium bicarbonate solution (2 × 30 ml), 10% sodium thiosulfate solution (3 × 30 ml), saturated sodium chloride solution (30 ml) and dried over anhydrous potassium carbonate . The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a yellow liquid (6.65 g, 81%), is used in the next step without further purification.

11.5. 2-docecyl-3,4,5-trimethoxybenzoic acid

Potassium hydroxide (1.65 g, 0.029 M) is added to a solution of 2-dodecyl-3,4,5-trimethoxybenzoic acid methyl ester (6.65 g, 0.016 M) in 95% aqueous ethanol (20 ml). The reaction mixture was refluxed with stirring for 3 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator. The residue is treated with boiling tert-butyl methyl ether. (30 ml). The resulting suspension was separated by filtration. The precipitate was washed with tert-butyl methyl ether (2 × 25 ml), dried in air, dissolved in water (50 ml), acidified with concentrated hydrochloric acid (10 ml, 0.12 M), extracted with tert-butyl methyl ether (3 × 25 ml) . The combined extracts were washed with water (2 × 30 ml), saturated sodium chloride solution (20 ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a yellow liquid (4.51 g, 71%), is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.9 (3H, t. 6.7 Hz, C H ₃ (CH ₂ ) ₉ CH ₂ CH ₂ -), 1.3 ( ₂₀ H , m, CH ₃ (C H ₂ ) ₉ CH ₂ CH ₂ -), 1.86 (2Н, m, CH ₃ (СН ₂ ) ₉ C H ₂ CH ₂ -), 3,90 (3Н, s, C H ₃ O), 3, 92 (3H, s, C H ₃ O), 4.00 (3H, s, C H ₃ O), 4.25 (2H, t, 7 Hz, CH ₃ (CH ₂ ) ₉ CH ₂ C H ₂ -), 7.43 (1H, s, H-Ar), 11.53 (1H, bs, CO ₂ H). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate - 2-heptyloxy-3,4,5-trimethoxybenzoic acid - 99.5%.

11.6. 2-dodecyl-3,4,5-trimethoxybenzoyl chloride

To a solution of 2-dodecyl-3,4,5-trimethoxybenzoic acid (4.51 g, 0.011 M) in methylene chloride (10 ml) was added thionyl chloride (1.12 ml, 1.85 g, 0.015 M) and N, N-dimethylformamide (0.01 ml). The reaction mixture was stirred at room temperature for 1 hour, refluxed for 2 hours. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The intermediate product is obtained in quantitative yield (4.65 g, 100%), in the form of a dark yellow liquid, and is used in the next step without further purification.

11.7. 1- (tert-butoxycarbonyl) -4- (2-dodecyl-3,4,5-trimethoxybenzoyl) piperazine

To a solution of 1- (tert-butoxycarbonyl) piperazine (2.21 g, 0.012 M), triethylamine (1.85 ml, 0.013 M) in methylene chloride (10 ml), a solution of 2-dodecyl-3,4,5- is added dropwise with stirring trimethoxybenzoyl chloride (4.65 g, 0.011 M) in methylene chloride (10 ml). The mixture is stirred for 6 hours. The precipitate was filtered off and discarded. The filtrate was washed with water (2 × 15 ml), a saturated solution of ammonium chloride (2 × 15 ml), water (2 × 15 ml), a saturated solution of sodium bicarbonate (2 × 15 ml), a saturated solution of sodium chloride (10 ml), dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a yellow liquid, was obtained in quantitative yield (6.21 g, 100%), and was used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.89 (3H, t, 6 Hz, C H ₃ (CH ₂ ) ₉ CH ₂ CH ₂ ), 1.27 (18 H, m, CH ₃ (C H ₂ ) ₉ CH ₂ CH ₂ ), 1.48 (9H, s, (C H ₃ ) ₃ C), 1.68 (2H, m, CH ₃ (CH ₂ ) ₉ C H ₂ CH ₂ ), 3.3-4, 1 (19H, m., 4xC H ₂ piperazine fragment, CH ₃ (CH ₂ ) 9CH ₂ C H ₂ and 3xC H ₃ O -), 6.55 (1H, s, H-Ar).

11.8. 1- (2-Dodecyl-3,4,5-trimethoxybenzoyl) piperazine hydrochloride

1- (tert-Butoxycarbonyl) -4- (2-dodecyl-3,4,5-trimethoxybenzoyl) piperazine (6.21 g, 0.011 M) was mixed with concentrated hydrochloric acid (20 ml, ~ 0.24 M). The reaction mixture was stirred at room temperature until completely homogenized for 3 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator, adding 10 ml of water to the concentrated mixture twice to effectively remove hydrogen chloride. The residue was heated with spropan-2-ol (40 ml). Insoluble impurities are separated by filtration through celite. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, colorless crystals (4.85 g, 85%), are used in the next step without further purification.

11.9. 1-Carbimidamido-4- (2-dodecyl-3,4,5-trimethoxybenzoyl) methyl sulfonate

To a solution of 1- (2-dodecyl-3,4,5-trimethoxybenzoyl) piperazine hydrochloride (4.85 g, 0.009 M) and 1H-pyrazole-1-carboximidamide hydrochloride (1.60 g, 0.011 M) in N, N -dimethylformamide (10 ml) is added at a temperature of 50 ° C diisopropylethylamine (3,50 ml, 0,020 M). The reaction mixture was stirred at 50 ° C for 10 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The residue was dissolved in water (50 ml), extracted with tert-butyl methyl ether (3 × 15 ml). The organic extracts are discarded.

), 3,3-4,1 (19Н, м., 4хCH ₂-пиперазинового фрагмента, CH₃ (CH₂)₉CH₂CH ₂ и 3хCH ₃O-), 6,65 (1Н, с., H-Ar), 7,53 (4Н, ш.с, C(NH ₂)(N⁺ H ₂)). Спектр ЯМР ¹³С (DMSO), δ, м.д.: 13,89 (CH₃CH₂CH₂CH₂ (CH₂)₄CH₂CH₂CH₂), 22,05 (CH₃ CH₂CH₂CH₂ (CH₂)₄CH₂CH₂CH₂), 25,37 (CH₃CH₂ CH₂CH₂ (CH₂)₄CH₂CH₂CH₂), 28,68 (CH₃CH₂CH₂ CH₂ (CH₂)₄CH₂CH₂CH₂), 28,98 (CH₃CH₂CH₂CH₂ (CH₂)₄CH₂CH₂CH₂), 29,57 (CH₃CH₂CH₂CH₂ (CH₂)₄ CH₂CH₂CH₂), 31,26 (CH₃CH₂CH₂CH₂ (CH₂)₄CH₂ CH₂CH₂), 39,67 ( $$\underset{\_}{\text{C}}{\text{H}}_{\text{3}}{\text{SO}}_{\text{3}}^{\text{-}}$$

), 40,49 (CH₂-пиперазинового фрагмента), 44,53 (CH₂-пиперазинового фрагмента), 45.16 (CH₂-пиперазинового фрагмента), 45,31 (CH₂-пиперазинового фрагмента), 56,10 (CH₃O-), 60,59 (CH₃O-), 60,96 (СН₃О-), 73,96 (CH₃ (СН₂)₉CH₂ CH₂), 105,49 (С6, Ar), 124,74 (С1, Ar), 142,21 (С2, Ar), 143,23 (С5, Ar), 146,55 (С4, Ar), 149,44 (С3, Ar), 156,37 (C(NH₂)(N⁺H₂)), 166,25 (CON). Масс-спектр: МН⁺ найдено - 507,44, МН⁺ вычислено - 507,35. Чистота продукта по данным ВЭЖХ 99,51%, максимальная неидентифицированная примесь 0,10%, сумма неидентифицированных примесей 0,49%.The aqueous layer was made basic with 50% sodium hydroxide solution (20 ml) and extracted with methylene chloride (3 × 15 ml). The combined organic extracts were washed with water (2 × 10 ml) and dried over anhydrous potassium carbonate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The resulting residue, 1-carbimidamido-4- (2-heptyloxy-3,4,5-trimethoxybenzoyl) piperazine (3.49 g, 0.008 M), was dissolved in acetone (25 ml) and acidified with methyl sulfonic acid (0.89 g, 0.008 M). The precipitate formed is filtered off, washed successively with acetone (2 × 5 ml), tert-butyl methyl ether (2 × 10 ml) and dried in vacuo. Product, small colorless crystals (3.13 g, 65%). ¹ H NMR Spectrum (DMSO), δ, ppm (J, Hz): 0.85 (3H, m., C H ₃ (CH ₂ ) ₉ CH ₂ CH ₂ ), 1.24 (18H, m, CH ₃ (C H ₂ ) ₉ CH ₂ CH ₂ ), 1.58 (2H, m, CH ₃ (CH ₂ ) ₉ C H ₂ CH ₂ ), 2.38 (3H, s, $$\text{C}{\underset{\_}{\text{H}}}_{\text{3}}{\text{SO}}_{\text{3}}^{\text{-}}$$

), 3.3-4.1 (19H, m., 4xC H ₂ -piperazine fragment, CH ₃ (CH ₂ ) ₉ CH ₂ C H ₂ and 3xC H ₃ O-), 6.65 (1H, s. , H-Ar) 7.53 (4H, br s, C (N H ₂ ) (N ⁺ H ₂ )). ¹³ C NMR spectrum (DMSO), δ, ppm: 13.89 ( C H ₃ CH ₂ CH ₂ CH ₂ (CH ₂ ) ₄ CH ₂ CH ₂ CH ₂ ), 22.05 (CH ₃ C H ₂ CH ₂ CH ₂ (CH ₂ ) ₄ CH ₂ CH ₂ CH ₂ ), 25.37 (CH ₃ CH ₂ C H ₂ CH ₂ (CH ₂ ) ₄ CH ₂ CH ₂ CH ₂ ), 28.68 (CH ₃ CH ₂ CH ₂ C H ₂ (CH ₂ ) ₄ CH ₂ CH ₂ CH ₂ ), 28.98 (CH ₃ CH ₂ CH ₂ CH ₂ ( C ₂ ) ₄ CH ₂ CH ₂ CH ₂ ), 29.57 (CH ₃ CH ₂ CH ₂ CH ₂ (CH ₂ ) ₄ C H ₂ CH ₂ CH ₂ ), 31.26 (CH ₃ CH ₂ CH ₂ CH ₂ (CH ₂ ) ₄ CH ₂ C H ₂ CH ₂ ), 39.67 ( $$\underset{\_}{\text{C}}{\text{H}}_{\text{3}}{\text{SO}}_{\text{3}}^{\text{-}}$$

), 40.49 (CH ₂ piperazine fragment), 44.53 (CH ₂ piperazine fragment), 45.16 (CH ₂ piperazine fragment), 45.31 (CH ₂ piperazine fragment), 56.10 (CH ₃ O-), 60.59 (CH ₃ O-), 60.96 (CH ₃ O-), 73.96 (CH ₃ (CH ₂ ) ₉ CH ₂ C H ₂ ), 105.49 (C6, Ar) , 124.74 (C1, Ar), 142.21 (C2, Ar), 143.23 (C5, Ar), 146.55 (C4, Ar), 149.44 (C3, Ar), 156.37 ( C (NH ₂ ) (N ⁺ H ₂ )), 166.25 ( C ON). Mass spectrum: MH ⁺ found, 507.44; MH ⁺ calculated, 507.35. The purity of the product according to HPLC 99.51%, the maximum unidentified impurity 0.10%, the sum of unidentified impurities 0.49%.

Example 12. Obtaining 1-carbimidamido-4- (2- [3-methylbutyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine acetate

12.1. 2-bromo-3,4,5-trimethoxybenzoic acid

To a suspension of 3,4,5-trimethoxybenzoic acid (33.0 g, 0.156 M) in ethyl acetate (200 ml) was added 1 ml of water, the mixture was heated to boiling point, bromine was added dropwise to the boiling reaction mixture with stirring for 30 minutes (8 8 ml, 0.171 M). The reaction mixture was refluxed for 2 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The intermediate product, crystals of a pale cream color, obtained in quantitative yield (45.2 g, 100%), used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.92 (3H, CH ₃ O-), 3.93 (3H, CH ₃ O-), 3.98 (3H, CH ₃ O-), 7.42 (1H, s. , H-Ar), 11.00 (1H, br.s.CO ₂ H ). The purity of the intermediate according to ¹ H NMR and TLC spectroscopy is 95%.

12.2. 2-hydroxy-3,4,5-trimethoxybenzoic acid

To a hot solution of 2-bromo-3,4,5-trimethoxybenzoic acid (42 g, 0.144 M) and sodium hydroxide (14.4 g, 0.36 M) in water (200 ml), copper (II) oxide is added (1 , 14 g, 0.014 M, 10% by mol.). The reaction mixture was refluxed with stirring for 6 hours. Sodium hydroxide (5.76 g, 0.144 M) was added to the hot reaction mixture, after which a hot solution of copper (II) sulfate pentahydrate (17.9 g, 0.072 M) in water (50 ml) was added with stirring. The precipitate was separated by filtration. The precipitate isolated is suspended in a 5% sodium hydroxide solution (100 ml), stirred for 1 hour, separated by filtration (the operation is repeated three times), the precipitate is suspended in water (100 ml), acidified with concentrated hydrochloric acid (25 ml, 30.0 g, 0.3 M). The precipitate formed is filtered off, washed on the filter with water (3 × 100 ml) and dried in vacuo. Intermediate, pale cream crystals (13.5 g, 41%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.87 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.05 (3H, CH ₃ O-), 5.5 (1H, br. s, HO-Ar), 7.17 (1H, s, H-Ar), 10.31 (1H, s. CO ₂ H ). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate - 2-hydroxy-3,4,5-trimethoxybenzoic acid - 99.5%.

12.3. 2-Hydroxy-3,4,5-trimethoxybenzoic acid methyl ester

To a boiling solution of 2-hydroxy-3,4,5-trimethoxybenzoic acid (13.2 g, 0.058 M) in methanol (150 ml), 98% sulfuric acid (8.7 g, 0.087 M) was added in portions with stirring. The reaction mixture was refluxed with stirring for 9 hours. After cooling, it is poured into a solution of sodium bicarbonate, filtered to remove inorganic salts, the volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The residue was dissolved in ethyl acetate (200 ml), washed with saturated sodium hydrogen carbonate solution (2 × 50 ml), water (2 × 50 ml), saturated sodium chloride solution (50 ml), dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. Volatile components of the filtrate are removed on a rotary film evaporator. The residue was recrystallized from heptane. Intermediate, large sand-colored crystals (11.6 g, 82%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 3.84 (3H, s, CH ₃ O ₂ C), 3.93 (3H, CH ₃ O-), 3.95 (3H, CH ₃ O-), 4.01 (3H , CH ₃ O-), 7.08 (1H, s, H-Ar), 10.68 (1H, s, HO-Ar).

12.4. 2- (3-Methylbutyl) hydroxy-3,4,5-trimethoxybenzoic acid methyl ester

2-Hydroxy-3,4,5-trimethoxybenzoic acid is dissolved in methyl ether (11.5 g, 0.047 M), 1-bromo-3-methylbutane (12.1 ml, 0.095 M), anhydrous potassium carbonate (19.86 g , 0.095 M) in N, N-dimethylformamide (30 ml). The reaction mixture was stirred at 85 ° C for 5 hours, 1-bromo-3-methylbutane (3.58 g, 0.024 M), anhydrous potassium carbonate (3.28 g, 0.024 M) were added and stirred at 65 ° C within 5 hours (the operation is repeated twice). The cooled reaction mixture was mixed with tert-butyl methyl ether (100 ml). The precipitate was filtered off and discarded. The filtrate is washed with 10% sodium bicarbonate solution (2 × 25 ml) and water (3 × 50 ml). The organic layer was dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate is obtained in the form of a yellow liquid (14.8 g, 100%), used in the next step without further purification.

12.1. 2- (3-Methylbutyl) hydroxy-3,4,5-trimethoxybenzoic acid

To a solution of 2- (3-methylbutyl) hydroxy-3,4,5-trimethoxybenzoic acid methyl ester (14.00 g, 0.045 M) in 95% aqueous ethanol (20 ml), potassium hydroxide (10.5 g, 0.179 M). The reaction mixture was refluxed for 1 hour. Volatile components are removed on a rotary film evaporator under reduced pressure. The residue was treated with boiling tert-butyl methyl ether (50 ml). The precipitate was filtered off, washed with tert-butyl methyl ether (2 × 40 ml), dried in air, dissolved in water (50 ml), acidified with concentrated hydrochloric acid (20 ml, 0.24 M) and extracted with tert-butyl methyl ether (2 × 25 ml). The combined extracts were washed with water (2 × 20 ml), saturated sodium chloride solution (20 ml) and dried over anhydrous magnesium sulfate.

The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a yellow liquid (12.03 g, 90%), slowly crystallizing over time, is used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.97 (6H, d, OCH ₂ CH ₂ CH (C H ₃ ) ₂ ), 1.70-1.76 (2H, m. OCH ₂ C H ₂ CH (CH ₃ ) ₂ ), 1.76-1.87 (1H, m.OCH ₂ CH ₂ С Н (CH ₃ ) ₂ ), 3.88 (3Н, s. ОС H ₃ ), 3.91 (3Н, s. ОС H ₃ ), 3.97 (3H, s. OC H ₃ ), 4.27 (2H, t. J = Ar-OC H ₂ CH ₂ ), 7.4 (1H, s. H-Ar), 11, 53 (1H, br.s.CO-O N ). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 22.42 ( C H ₃ ) ₂ CHCH ₂ CH ₂ -), 24.24 (CH ₃ ) ₂ C H CH ₂ CH ₂ -), 38 , 54 (CH ₃ ) ₂ CH C H ₂ CH ₂ -), 55.91 (CH ₃ O-), 60.62 (CH ₃ O-), 61.03 (CH ₃ O-), 72.57 ( CH ₃ ) ₂ CHCH ₂ C H ₂ -), 107.98 (C1, Ar), 120.88 (C6, Ar), 145.64 (C2, Ar), 146.55 (C5, Ar), 147, 26 (C3, Ar), 148.57 (C4, Ar), 166.69 ( C O ₂ H). According to ¹ H NMR and TLC spectroscopy, the purity of the intermediate is 2- (3-methylbutyl) hydroxy-3,4,5-trimethoxybenzoic acid - 99.7%.

12.2. 2- (3-Methylbutyl) hydroxy-3,4,5-trimethoxybenzoyl chloride

To a solution of 2- (1-methylbutyl) hydroxy-3,4,5-trimethoxybenzoic acid (10.00 g, 0.034 M) was added thionyl chloride (12.0 g, 0.035 M) and N, N-dimethylformamide (0.05 ml), stirred at room temperature for 1 hour, refluxed for 2 hours. Volatile components of the mixture are removed on a rotary film evaporator under reduced pressure. The intermediate, a tan liquid, was obtained in quantitative yield (10.6 g, 100%), and was used in the next step without further purification.

12.3. 1- (tert-butoxycarbonyl) -4- (2- [3-methylbutyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine

To a solution of 1- (tert-butoxycarbonyl) piperazine (7.49 g, 0.04 M) and triethylamine (7.0 ml, 0.05 M) in methylene chloride (50 ml), a solution of 2- (3- methylbutyl) oxy-3,4,5-trimethoxybenzoyl chloride (10.62 g, 0.034 M) in methylene chloride (25 ml). The reaction mixture was stirred for 3 hours at room temperature. The precipitate of triethylamine hydrochloride was collected by filtration and discarded. The filtrate is washed successively with water (2 × 20 ml), 3% phosphoric acid solution (2 × 20 ml), water (2 × 20 ml), saturated sodium hydrogen carbonate solution (2 × 20 ml), saturated sodium chloride solution (20 ml ) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The intermediate, a yellow-brown liquid, was obtained in quantitative yield (15.64 g, 100%), used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.84-0.93 (6H, m, (C H ₃ ) ₂ CHCH ₂ CH ₂ -), 1.43 (9H, s, (C H ₃ ) ₃ C-) 1.48-1.60 (2H, m, (CH ₃ ) ₂ CHS H ₂ CH ₂ -)), 1.65-1.84 (1H, m, (CH ₃ ) ₂ C H CH ₂ CH ₂ -)), 3.09-4.11 (19H, m, 4xC H ₂ piperazine fragment, (CH ₃ ) ₂ CHCH ₂ C H ₂ - and 3xC H ₃ O-), 6.51 (1H , H-Ar).

12.4. 1- (2- [3-Methylbutyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine hydrochloride

1- (tert-butoxycarbonyl) -4- (2- [3-methylbutyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine (15.0 g, 0.032 M) and propan-2-ol (50 ml) are mixed with concentrated hydrochloric acid (14 ml, ~ 0.168 M). The reaction mixture was stirred at 65 ° C until complete homogenization for 3 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator, twice adding 20 ml of water to the concentrated mixture to remove hydrogen chloride. The residue was partially dissolved in water (75 ml) and extracted with tert-butyl methyl ether (3 × 20 ml). The organic extracts are discarded. Volatile components of the aqueous solution are removed on a rotary film evaporator under reduced pressure. The resulting intermediate (12.8 g, 99%) was used in the next step without further purification. ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.88-0.93 (6H, m, (C H ₃ ) ₂ CHCH ₂ CH ₂ -), 1.47-1.60 (2H, m, (CH ₃ ) ₂ CHC H ₂ CH ₂ -)), 1.65-1.84 (1H, m, (CH ₃ ) ₂ С Н CH ₂ CH ₂ -)), 2.70-4.53 (19Н, m, 4xC H ₂ piperazine fragment, (CH ₃ ) ₂ CHCH ₂ C H ₂ - and 3xC H ₃ O-), 6.71 (1H, H-Ar), 9.74 (2H, br.s, N ⁺ H ₂ ). ¹³ C NMR spectrum (DMSO), δ, ppm: 22.34, ( C H ₃ ) ₂ CHCH ₂ CH ₂ -), 24.24 (CH ₃ ) ₂ C HCH ₂ CH ₂ -), 38, 54 (CH ₃ ) ₂ CH C H ₂ CH ₂ -), 37.78 (CH ₂ piperazine fragment), 42.40 (CH ₂ piperazine fragment), 42.68 (CH ₂ piperazine fragment), 43, 28 (CH ₂ piperazine fragment), 56.14 (CH ₃ O-), 60.64 (CH ₃ -), 61.07 (CH ₃ O-), 72.37 ((CH ₃ ) ₂ CHCH ₂ C H ₂ -), 105.49 (C6, Ar), 124.39 (C1, Ar), 142.21 (C2, Ar), 143.27 (C5, Ar), 146.59 (C4, Ar), 149.55 (C3, Ar); 166.17 ( C ON).

12.5. 1-Carbimidamido-4- (2- [3-methylbutyl] hydroxy-3,4,5-trimethoxybenzo-yl) piperazine acetate

), 1,70-1,77 (1Н, м., (CH₃)₂СНCH₂CH₂-)), 2,70-4,34 (19Н, м, 4×CH ₂-пиперазинового фрагмента, (CH₃)₂СНCH₂CH ₂- и 3х×CH ₃O-), 6,63 (1Н, H-Ar), 8,54 (4Н, ш.с., C(NH ₂)(N⁺ H ₂)). Спектр ЯМР ¹³С (DMSO), δ, м.д.: 22,32, (CH₃)₂СНCH₂CH₂-), 24,33 (CH₃)₂ СНCH₂CH₂-), 24,78 ( $$\underset{\_}{С}{H}_3СO_2^{-}$$

), 38,59 (CH₃)₂СНCH₂CH₂-), 37,82 (CH₂-пиперазинового фрагмента), 44,17 (CH₂-пиперазинового фрагмента), 44,79 (CH₂-пиперазинового фрагмента), 45,42 (CH₂-пиперазинового фрагмента), 56,34 (CH₃O-), 60,60 (CH₃O-), 60,95 (CH₃O), 72,43 ((CH₃)₂СНCH₂ CH₂-), 105,86 (С6, Ar), 124,87 (С1, Ar), 142,40 (С2, Ar), 143,49 (С5, Ar), 146,60 (С4, Ar), 149,49 (С3, Ar), 157,71 (C(NH₂)(N⁺H₂)), 166,40 (CON), 175,40 (CH₃СO₂). Чистота продукта по данным ВЭЖХ 99,70%, максимальная неидентифицированная примесь 0,10%, сумма неидентифицированных примесей 0,3%.

To a solution of 1- (2- [3-methylbutyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine hydrochloride (12.5 g, 0.031 M) and 1H-pyrazole-1-carboximidamide hydrochloride (12.5 g, 0.031 M ) in water (100 ml) sodium carbonate (8.42 g, 0.0794 M) is added at room temperature, then propan-2-ol (25 ml) is added at a temperature of 50 ° C. The reaction mixture was stirred at 50 ° C for 10 hours. Volatile components of the reaction mixture are removed on a rotary film evaporator under reduced pressure. The residue was dissolved in water (120 ml) and extracted with tert-butyl methyl ether (3 × 30 ml). The organic extracts are discarded. The aqueous layer was made alkaline with a 50% sodium hydroxide solution (35 ml), extracted with methylene chloride (3 × 30 ml). The combined organic extracts were washed with water (2 × 20 ml) and dried over anhydrous potassium carbonate. The desiccant is separated by filtration. The volatile components of the filtrate are removed on a rotary film evaporator under reduced pressure. The obtained residue, 1-carbimidamido-4- (2- [1-methylbutyl] hydroxy-3,4,5-trimethoxybenzoyl) piperazine (12.66 g, 0.031 M), was dissolved in methylene chloride (50 ml), acidified with ice-cold acetic acid (2.1 ml, 0.0366 M). The precipitate formed is filtered off, washed on the filter with methylene chloride (2 × 10 ml), acetone (2 × 50 ml), suspended in a mixture of acetone (60 ml) and water (5 ml), the suspension is refluxed with stirring for 1 hour. The precipitate was filtered off, washed with acetone (2 × 25 ml) on the filter and dried in vacuo. Product, small colorless crystals (8.42 g, 43%). ¹ H NMR Spectrum (CDCl ₃ ), δ, ppm (J, Hz): 0.90 (6H, d.,. J = 6.2 Hz, (C H ₃ ) ₂ CHCH ₂ CH ₂ -), 1.47-1.57 (2H, m, ( CH ₃ ) ₂ CHC H ₂ CH ₂ -)), 1.66 (3H, s, $$\mathrm{FROM}{\underset{\_}{H}}_3\mathrm{FROM}{O}_2^{-}$$

), 1.70-1.77 (1H, m, (CH ₃ ) ₂ С Н CH ₂ CH ₂ -)), 2.70-4.34 (19Н, m, 4 × C H ₂ piperazine fragment , (CH ₃ ) ₂ CHCH ₂ C H ₂ - and 3x × C H ₃ O-), 6.63 (1H, H-Ar), 8.54 (4H, br.s., C (N H ₂ ) (N ⁺ H ₂ )). ¹³ C NMR spectrum (DMSO), δ, ppm: 22.32, ( C H ₃ ) ₂ CHCH ₂ CH ₂ -), 24.33 (CH ₃ ) ₂ C HCH ₂ CH ₂ -), 24, 78 ( $$\underset{\_}{\mathrm{FROM}}{H}_3\mathrm{FROM}{O}_2^{-}$$

), 38.59 (CH ₃ ) ₂ CH C H ₂ CH ₂ -), 37.82 (CH ₂ piperazine fragment), 44.17 (CH ₂ piperazine fragment), 44.79 (CH ₂ piperazine fragment) ), 45.42 (CH ₂ piperazine fragment), 56.34 (CH ₃ O-), 60.60 (CH ₃ O-), 60.95 (CH ₃ O), 72.43 ((CH ₃ ) ₂ CHCH ₂ C H ₂ -), 105.86 (C6, Ar), 124.87 (C1, Ar), 142.40 (C2, Ar), 143.49 (C5, Ar), 146.60 (C4 , Ar), 149,49 (C3, Ar), 157,71 (C ( NH ₂₎ (N ⁺ H _2)), 166,40 (C ON) , 175,40 (C H ₃ CO _2). The purity of the product according to HPLC 99.70%, the maximum unidentified impurity 0.10%, the amount of unidentified impurities 0.3%.

Example 13. The study of the antiplatelet properties of N, N′-substituted piperazines in vitro.

Blood for the study was taken from donors, persons of both sexes, who did not receive drugs that affect blood function for 10 days in the morning after a light breakfast. In order to exclude contact activation of platelets, all blood manipulations were carried out in plastic dishes. Blood stabilization was carried out with a 3.8% solution of trisubstituted basic sodium citrate (pH = 7.4) in the ratio of citrate: blood 1: 9. Blood was obtained by puncture of the ulnar vein with a dry, sharp, short needle without a syringe. A 1 ml sodium citrate was placed in a plastic centrifuge tube. The first drops of blood were left on a cotton swab, then freely flowing blood was collected in a test tube to a mark of 10 ml. Immediately mixed blood with sodium citrate, avoiding the formation of air bubbles.

The study of induced platelet aggregation was carried out within 3 hours after receiving blood.

Platelet counts were determined on a Coulter LH500 hematology analyzer (Beckman Coulter Inc., USA).

Induced platelet aggregation was studied on a 4-channel aggregator company CHRONO-LOG, model 590, which allows to study platelet function in whole blood.

Temperature in sample preparation cells: 37 ° C, measuring cell: + 37 ° C, magnetic stirrer rotation speed: 1200 rpm.

ADP-induced reversible platelet aggregation: Chrono-parADPreagent (CHRONO-LOG, USA, was dissolved in 5 ml of physiological saline, the solution was packaged in 50 μl Eppendorf microtubes, stored at (-) 20 ° C. Platelet aggregation was evaluated by reaction to adding 10.0 μl of ADP to 1 ml of whole blood (final concentration - 10 μM).

Collagen-induced platelet aggregation: Chrono-parCollagen (CHRONO-LOG, USA) was packaged in 10 μl Eppendorf microtubes and stored at 4 ° C. Platelet aggregation was evaluated by the reaction of adding 2 μl of collagen to 1 ml of whole blood (final concentration - 2 μg / ml).

Ristocetin-induced platelet aggregation: Chrono-parRISTOCETIN reagent (CHRONO-LOG, USA) was dissolved in 0.5 ml of sterile water, the solution was packaged in 50 μl Eppendorf type microtubes and stored at (-) 20 ° C. Platelet aggregation was evaluated by the reaction of adding 8 μl of ristocetin to 1 ml of whole blood (final concentration - 1 mg / ml).

Platelet aggregation with arachidonic acid: Chrono-parArachidonicAcid reagent (CHRONO-LOG, USA). Albumin previously diluted in sterile saline was mixed with arachidonic acid, brought to a volume of 700 μl, transferred to a microtube, and shaken on a vortex for 5 min. The resulting mixture was packaged in 100 μl Eppendorf type microtubes, stored at a temperature of (-) 20 ° C. Before use, it was thawed, shaken on a vortex for 2 minutes.

Platelet aggregation was evaluated by the reaction of adding 10 μl of arachidonic acid to 1 ml of whole blood (final concentration of -0.5 mm).

Thrombin-induced platelet aggregation: Chrono-par Thrombinreagent reagent (CHRONO-LOG, USA) was dissolved in 1.0 ml of sterile physiological saline, the solution was packaged in 500 μl Eppendorf microtubes, and stored at (-) 20 ° C. Platelet aggregation was evaluated by the reaction of adding 100 μl of thrombin solution to 1 ml of whole blood (final concentration - 1.0 Unit / ml).

Epinephrine-induced platelet aggregation: Chrono-par Epinephrinereagent reagent (CHRONO-LOG, USA) was dissolved in 5.0 ml of sterile water, the solution was packaged in Eppendorf microtubes of 500 μl and stored at (-) 20 ° C.

Platelet aggregation was evaluated by the reaction of adding 10 μl of an epinephrine solution to 1 ml of whole blood (final concentration -100 μM).

A portion of the compound was dissolved in 0.05 M Tris-HCl buffer, pH = 7.4. Received solutions with a concentration of from 0.05 to 15 mm. 0.1 ml of the resulting solution was mixed in a cuvette with a stirrer with 0.9 ml of blood, incubated for 5 min at + 37 ° C, aggregation inducers were introduced. In the control, 0.1 ml of Tris-HCl buffer was mixed with 0.9 ml of blood, incubated as described above, an aggregation inducer was added.

Aggregation was recorded before the curve reached a plateau. The inhibitory ability (Q,%) was calculated by the formula: Q = [A ₀ -A _x ]: A ₀ × 100, where A ₀ and A _x are the amplitudes of aggregation in the control and the solution of the compound in the blood, respectively.

According to the results of a study of the dependence of the inhibitory ability of compounds on their concentration, the concentration was calculated that suppressed platelet aggregation in whole blood by 50% - EC ₅₀ (table 2).

As follows from the data in Table 2, a directed change in the structure of N, N′-substituted piperazines, namely the presence of R ² radicals with a carbon chain length of 5 atoms and more R ² with a carbon chain length of 1-4 atoms as substituents in the aromatic cycle [ patent RU 2469029, 2010], leads to a change in the spectrum of their activity in the test induced platelet aggregation.

Compounds of general formula I containing R ² with a carbon chain length of 5-12 atoms have 3-5 times higher EC ₅₀ values when induced by arachidonic acid aggregation, which increases the safety of compounds of R ² with a carbon chain length of 5 atoms or more due to their lesser effect on cyclooxygenase activity [Schjerning Olsen A, FosbølL, Lind-hardsen J, et al. Long-term cardiovascular risk of NSAID use according to time passed after first-time myocardial infarction. A nation wide cohortstudy. Circulation, September 10, 2012].

At the same time, the activity of N, N′-substituted piperazines of the general formula I in the thrombin and collagen-induced aggregation test increased by 1.5 times, and the activity in the epinephrine-induced aggregation test increased by 2 times compared with the compounds of the patent RU 2469029, 2010.

Example 14. The study of the anticoagulant and antiplatelet properties of N, N′-substituted piperazines in vivo.

The fact that the replacement in the aromatic cycle of N, N′-substituted piperazines of the radical R ² with a carbon chain length of 1-4 atoms by the radical R ² with a carbon chain length of 5-12 atoms leads to a significant increase in their anticoagulant and antiplatelet properties was shown in experiment invivo.

In vivo studies of N, N′-substituted piperazines were performed on male Wistar rats (weight at the beginning of the experiment 250 ± 15 g, age 10-12 weeks). The animals were kept on unlimited feed and water consumption, distributed into groups by a randomization method, 12 animals in each group.

Intravenous administration (iv): 1 ml of a solution of N, N′-substituted piperazine was injected bolus into the tail vein of non-anesthetized rats 1 time in the light period of the day, course - 7 days.

Intragastric administration (w / w): 15 g of a composition containing N, N′-substituted piperazine (Table 3) was mixed with 40 ml of water for 10 minutes. 2 ml of the suspension was injected into the rat iv with a rigid metal probe, once during the daylight hours for 30 days.

The dose of the active substance was calculated in μM per 1 kg of rat weight. In a control rat, 2 ml of water was similarly administered.

Blood was taken by cardiopuncture in all animals a day after the last administration of the drug, to assess necropsy using CO ₂ euthanasia, to assess aggregation parameters and coagulograms.

Blood was collected in test tubes containing a 3.8% sodium citrate solution, centrifuged to obtain a plasma, in which the following indicators were determined using the RA-50 semi-automatic analyzer (Bayer, Germany): activated partial thromboplastin time (APTT), prothrombin time (PV), fibrinogen content.

To determine the indicators used standard kits for coagulological tests (LLC "Technology Standard", Russia).

The parameters of induced aggregation were measured as described in example 13.

Example 15. The study of the vasodilating activity of N, N′-substituted piperazines in vivo. The effect of N, N′-substituted piperazines on the vascular reactivity of the microvasculature.

The study was performed on male Wistar rats weighing 250-300 g (laboratory animal nursery "Rappolovo" RAMS). The animals were kept on unlimited feed and water consumption, divided into groups by randomization.

The studied composition was injected bolus into the tail vein of non-narcotic animals (at the rate of 5 ml per 1 kg). In the control, physiological saline (5 ml / kg) was administered.

30 minutes after drug administration, the animals were anesthetized (thiopental sodium, 60 mg / kg, subcutaneously). Through the lower middle access, a loop of the small intestine adjacent to the mesoappendix was removed to study blood circulation in the venules and arterioles of the mesentery in transmitted light, and the rat was placed on a thermostatic microscope stage. The change in microcirculation was evaluated by the number of functioning capillaries. The mesentery was constantly moistened with saline (20 drops / min). A noradrenaline solution was applied directly to the mesentery [Furness J. B., Marshall J. M., Correlation of the directly observed responses of mesentericves sels of the rattonervestimulation and noradrenalie with the distribution of adrenergicnerves J. Physiol. (1974), 239, pp. 75-88]. Before applying norepinephrine, the intake of saline was stopped, the field of view was dried for 20 s.

After evaluating the vascular response, the mesentery was washed with saline until the initial blood flow was completely restored. The intestinal tracts removed from the study were wrapped with a wet gauze to prevent drying out. In experiments to visually determine the effect of the drug on the microvasculature, rats were anesthetized first, femoral artery catheterized, and then 1 ml of the drug was injected within 1 minute. Using a video camera (Optics and Electronics ISTA Ltd), video was recorded on a personal computer, the Video-Test 4.0 software package (ISTA Ltd., Russia). The following parameters were determined: diameter of the vascular wall (D, μm) before and after the application of norepinephrine, the time of the onset of deceleration of blood flow in the vessels under the action of norepinephrine (observation was performed for 1 min after application). The final concentration of norepinephrine was 10 ^-6 g / ml. The results are shown in table 6.

Pharmaco-biological tests showed that N, N′-substituted piperazines of the general formula I possess antiplatelet, anticoagulant and vasodilating properties and exceed the activity of the compounds of the patent RU 2469029, 2010.

Compositions based on N, N′-substituted piperazines of the general formula I have a positive effect on the restoration of the hemostatic system.

Claims (11)

1. N, N′-substituted piperazines of the general formula I

where R ¹ is a linear or branched alkyl C ₁ -C ₄ ,
R ² is a linear or branched alkyl C ₅ -C ₁₂ ,
G is a mineral or organic C ₁ -C ₄ acid or water,
as a substance with combined antiplatelet, antithrombotic and vasodilator activity. 2. The method of obtaining N, N′-substituted piperazines of General formula II

where R ¹ is a linear or branched alkyl C ₁ -C ₄ ,
R ² is a linear or branched alkyl C ₁ -C ₁₂ ,
G is a mineral or organic C ₁ -C ₄ acid or water,
by treating 3,4,5-trialkoxybenzoic acid with bromine in an organic solvent, isolating 2-bromo-3,4,5-trialkoxybenzoic acid, further converting 2-bromo-3,4,5-trialkoxybenzoic acid to 2,3,4, 5-tetraalkoxybenzoic acid, treatment of 2,3,4,5-tetraalkoxybenzoic acid with thionyl chloride, isolation of 2,3,4,5-tetraalkoxybenzoyl chloride, treatment of 2,3,4,5-trialkoxybenzoyl chloride with tert-butoxycarbonylpiperazine in a polar aprotic solvent in the presence of amines allocation of 1- (tert-butoxycarbonyl) -4- (2,3,4,5-tetraalkoxybenzoyl) Iperazine, treating 1- (tert-butoxycarbonyl) -4- (2,3,4,5-tetraalkoxybenzoyl) piperazine with acids, isolating 1- (2,3,4,5-tetraalkoxybenzoyl) piperazine salts, treating 1- (2 , 3,4,5-tetraalkoxybenzoyl) piperazine 1H-pyrazole-1-carboximidamide hydrochloride, isolation of 4- (2,3,4,5-tetraalkoxybenzoyl) piperazine-1-carboximidamide, treatment of 4- (2,3,4,5 -tetraalkolsibenzoyl) piperazine-1-carboximidamide acid and isolating N, N′-substituted piperazines, characterized in that 2,3,4,5-tetraalkoxybenzoic acid is obtained by treating 2-bromo-3,4,5-trialkoxybenzo acid with alkalis in water or an aqueous-alcoholic solvent in the presence of copper, or copper salts, or copper oxides at a molar ratio of 2-bromo-3,4,5-trialkoxybenzoic acid with copper, or its salts, or its oxides, subsequent addition into the reaction mixture of copper (II) salts at a molar ratio of 2-bromo-3,4,5-trialkolsibenzoic acid with copper (II) salts of at least 1: 0.5, separating the precipitate formed, washing the precipitate with an alkali solution, treating the precipitate with acid, rinsing with water or an aqueous organic solvent, isolation of 2-hydroxy-3, 4,5-trialkoxybenzoic acid of the general formula

where R ¹ is a linear or branched alkyl C ₁ -C ₄ ,
treatment of 2-hydroxy-3,4,5-trialkoxybenzoic acid with alcohols in the presence of sulfuric acid, or alcohols in a solution of methylene chloride in the presence of dicyclohexylcarbodiimide, or dimethyl sulfate in a polar aprotic solvent in the presence of sodium carbonate, 2-hydroxy-3,4,5 -trialkoxybenzoate of the general formula

where R ¹ is a linear or branched alkyl C ₁ -C ₄ ,
R ³ is linear alkyl C1-C4,
treating 2-hydroxy-3,4,5-trialkoxybenzoate with compounds of the general formula R ² -Y
where R ² is a linear or branched alkyl C ₁ -C ₁₂ ,
Y - Cl, Br, I,
in a polar aprotic solvent in the presence of potassium carbonate or a mixture of potassium carbonate and potassium iodide, or treatment of 2-hydroxy-3,4,5-trialkoxybenzoic acid with dimethyl sulfate in a polar aprotic solvent in the presence of potassium carbonate, the release of 2,3,4,5-tetraalkoxybenzoate total formulas

where R ¹ is a linear or branched alkyl C ₁ -C ₄ ,
R ² is a linear or branched alkyl C ₁ -C ₁₂ ,
R ³ is linear alkyl C ₁ -C ₄ ,
treating 2,3,4,5-tetraalkenesibenzoate with sodium or potassium hydroxides in water, or alcohols, or a water-alcohol solvent, and then treating the reaction mixture with acids. 3. The method according to p. 2, characterized in that the organic solvent used is ethyl acetate or chloroform or acetic acid. 4. The method according to p. 2, characterized in that as alkaline reagents use sodium or potassium hydroxides, carbonates or phosphates of sodium or potassium. 5. The method according to p. 2, characterized in that as the salts of copper (I) use copper chloride (I), copper iodide (I), copper acetate (I). 6. The method according to p. 2, characterized in that the copper (II) salts are copper (II) sulfate, copper (II) chloride, copper acetate (I). 7. The method according to p. 2, characterized in that the copper oxide is copper oxide (I), copper oxide (II). 8. The method according to p. 2, characterized in that methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol are used as alcohols. 9. The method according to p. 2, characterized in that the acids used are trifluoroacetic, sulfuric, perchloric, hydrochloric acids, methane sulfonic acid. 10. The method according to p. 2, characterized in that the polar aprotic organic solvent is acetone, methyl ethyl ketone, acetonitrile, N, N-dimethylformamide. 11. The method according to p. 2, characterized in that as amines use triethylamine, N-methylmorpholine, diisopropylethylamine.

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