RU2679636C1 - New method of the n,n'-bis[2-(1h-imidazol-4-yl)ethyl]malonamide obtaining - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: method of the N,N'-bis[2-(1H-imidazol-4-yl) ethyl]malonamide of formula (I) obtaining by the dimethyl malonate with histamine reaction in the polar organic solvent at a temperature of 85–120 °C, comprising crystallization from the water and/or the polar organic solvent..EFFECT: method allows to obtain a product with a purity of 99 wt% and is suitable for the substance production in the pharmaceutical industry.6 cl, 6 dwg, 4 ex, 4 tbl

Description

Technical field

This invention relates to the chemistry of organic compounds, pharmacology and medicine, and relates to a method for producing N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide with a purity above 99.0% and not containing a single impurity above 0 , 1% suitable for use as a pharmaceutical substance in the production of various types of dosage forms.

State of the art

The preparation of malonic acid amides from the acid itself or its esters has been repeatedly described in the literature. Since malonic acid is not stable at temperatures characteristic of the direct amidation of carboxylic acids, the synthesis of its amides, as a rule, uses more reactive derivatives, with isolation or obtained in situ . The following are the main methods for producing malonic acid amides classified by type of acylating agent:

The method of activated esters.

Method of acylation of amines with acid halides.

The method of acylation of amines with imidazolidides of carboxylic acids

Method of acylation of amines with acid esters.

Consider the implementation options for each of the above methods described in detail in the literature:

Activated Ether Method

This method involves the use of special excipients, reacting with which, malonic acid forms highly reactive intermediates, which, in turn, can quickly and in high yields interact with amines, turning into target amides. As activating agents can be used:

1) Salts of (1- [bis (dimethylamino) methylene] -1 H -1,2,3-triazolo [4,5-b] pyridinium) -3-oxide at room temperature in absolute dimethylformamide. (Tan, Guanhai; Yao, Yuchao; Gu, Yunjing; Li, Shuai; Lv, Mengjiao; Wang, Kerang; Chen, Hua; Li, Xiaoliu Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 13, p. 2825 -2830).

2) Salts of O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium at room temperature in absolute dimethylformamide (Koval, Vasiliy S .; Arutyunyan, Albert F .; Salyanov, Victor L .; Klimova, Regina R .; Kushch, Alla A .; Rybalkina, Ekaterina Yu .; Susova, Olga Yu .; Zhuze, Alexei L. - Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 9, p. 2302-2309) .

3) Dicyclohexylcarbodiimide at room temperature in various solvents (Cipolla, Laura; Sgambato, Antonella; Forcella, Matilde; Fusi, Paola; Parenti, Paolo; Cardona, Francesca; Bini, Davide - Carbohydrate Research, 2014, vol. 389, # 1, p. 46-49. Wu, Hua; He, Yu-Ping; Xu, Lue; Zhang, Dong-Yang; Gong, Liu-Zhu - Angewandte Chemie - International Edition, 2014, vol. 53, # 13, p. 3466 -3469, Angew. Chem., 2014, vol. 126, # 13, p. 3534-3537). It is also possible to conduct a reaction with dicyclohexylcarbodiimide in the presence of benzotriazole-1-ol (Burghardt, Stephan; Hirsch, Andreas; Schade, Boris; Ludwig, Kai; Boettcher, Christoph-Angewandte Chemie - International Edition, 2005, vol. 44, # 19, p. 2976-2979). The use of benzotriazole-1-ol allows, in some cases, to increase the yield of the target product.

4) (1- (3-Dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride in dimethylformamide at 25 ° С in the presence of a base (Goldberg, Joel; Jin, Qing; Ambroise, Yves; Satoh, Shigeki; Desharnais, Joel; Capps , Kevin; Boger, Dale L. - Journal of the American Chemical Society, 2002, vol. 124, # 4, p. 544-555.) It is also possible to carry out a reaction with dicyclohexylcarbodiimide in the presence of benzotriazole-1-ol (SANOFI-AVENTIS - US2009 / 69368, 2009, A1). As in the case of dicyclohexylcarbodiimide, the use of benzotriazole-1-ol allows, in some cases, to increase the yield of the target product.

5) Salts of 1-methyl-2-chloropyridinium in the presence of a base in various solvents (Tyler; Webster - Chemical Communications, 2014, vol. 50, # 73, p. 10665-10668. Evans, Vikki; Mahon, Mary F .; Webster , Ruth L. - Tetrahedron, 2014, vol. 70, # 41, p. 7593-7597).

However, as was shown during the studies, the activated ester method does not allow obtaining N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide with a purity of more than 99% with an acceptable yield for industrial use.

Method for Acylation of Amines with Acid Halides

The reaction between malonic acid dichloride and amines is usually carried out under cooling in the presence of a base (or using an excess of an acylated amine as a base) in a wide range of solvents. (Lei, Shan; Jin, Bo; Zhang, Qingchun; Zhang, Zhichao; Wang, Xiaofang; Peng, Rufang; Chu, Shijin - Polyhedron, 2016, vol. 119, p. 387-395. Das, Swagatika; Das, Umashankar ; Sakagami, Hiroshi; Umemura, Naoki; Iwamoto, Shoko; Matsuta, Tomohiko; Kawase, Masami; (...) Gorecki, Dennis KJ; Dimmock, Jonathan R. - European Journal of Medicinal Chemistry, 2012, vol. 51, p. 193 -199). However, as was shown in the course of research, this method does not allow to achieve high yields of the target product, due to the presence, in addition to the main reaction, of an adverse reaction of hydrolysis of malonyl chloride. In addition, for industrial syntheses, it is undesirable to use chlorinated derivatives for safety reasons.

The method of acylation of amines with imidazolidides of carboxylic acids

Malonic acid imidazolid can be obtained from malonic acid by reaction with 1,1'-carbonyldiimidazole in various solvents (Nguyen, MVD; Nicolas, L .; Gaudemer, A .; Brik, ME - Bioorganic & Medicinal Chemistry Letters, 1998, vol. 8, # 3, p. 227-232).

The low yield of the product, as well as in the case of the activated ester method, is explained by the need to remove imidazole from the reaction mixture, which has comparable solubilities in water and alcohols.

Method of acylation of amines with acid esters

This method involves the interaction of an amine with esters of malonic acid. These compounds are relatively unreactive, but due to their thermal stability, they allow the reaction to be carried out at relatively high temperatures (150-180 ° C). The use of malonic acid diethyl ester (Devarasetty, Kiran; Tharikoppula, Giri; Sridhar, Tailor; Eppakayala, Laxminarayana; Kyasani, Mahesh; Arumugam, Premkumar; Pusuluri, Srinivas - Synthetic Communications, 2016, 4. , # 3, p. 263-274) and 2,4,6-trichlorophenyl malonic acid ester (Barbeau, Olivier R .; Cano-Soumillac, Celine; Griffin, Roger J .; Hardcastle, Ian R .; Smith, Graeme CM ; Richardson, Caroline; Clegg, William; Harrington, Ross W .; Golding, Bernard T. - Organic and Biomolecular Chemistry, 2007, vol. 5, # 16, p. 2670-2677.).

The existence of a wide variety of methods for producing malonic acid amides is related to the dependence of the selectivity of the reaction, the yield of the target product, as well as the ease of its isolation and purification from the nature of the acylated amine.

It is obvious that the ease of purification and isolation is especially important in the case of obtaining substances that are pharmaceutical substances, because The requirements for the chemical purity of pharmaceutical substances are particularly high. For this reason, the optimization of the synthesis method is an important task for the production technology of pharmaceutical substances.

Thus, there is a need to develop a method for producing such compounds, which is marketable under industrial conditions, suitable for producing significant quantities of a product suitable for use in pharmaceuticals.

As was shown on the basis of literature analysis, various synthetic approaches can be used to obtain N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide. A specific synthetic strategy that provides the target product with high yield and purity above 99.0%, as well as not containing a single impurity above 0.1% on an industrial scale, was not found by the applicant in the prior art.

Disclosure of invention

The objective of the present invention is to develop a method for producing N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide of the formula (I)

allowing to obtain the target product with a purity higher than 99.0% and not containing a single impurity higher than 0.1%, suitable for use as a pharmaceutical substance in the production of various types of dosage forms.

By a single impurity in this invention is meant any individual chemical compound that may be formed during the synthesis process of the invention.

The technical result of this invention is the provision of a method that allows you to get N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide of the formula (I) with a purity higher than 99.0 wt.%, The specified product does not contain a single impurities of more than 0.1 wt.%, the specified product is suitable for use as a pharmaceutical substance for the production of various types of dosage forms.

The specified technical result is achieved by heating dimethyl ester of malonic acid (2) with histamine (1) in butanol at a temperature of 90-110 ° C.

The scheme for producing N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide may further include a purification step by crystallization from water or an organic solvent.

The compound (N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide of formula (I) and a method for its preparation by reacting malonic acid diethyl ester and histamine are described in patent RU 2 665 688. Reproduction of the procedure described in it allows you to get a sample of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide with a purity of less than 90%.

Attempts to synthesize N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide by heating the stoichiometric ratios of diethyl malonate and histamine to 170 ° C led to a significant resinification of the reaction mixture and the formation of a significant amount (up to HPLC) 38%) by-products.

It was unexpectedly found that the replacement of diethyl malonate with dimethyl malonate, allowed to lower the reaction temperature, to achieve high conversion. In addition, the use of a solvent (butanol) in the developed procedure allowed us to make the procedure scalable to obtain industrial compounds of the formula (I). As a result of the optimization, it was possible to increase the total yield of the target compound from 44% to 60%, while the product according to HPLC does not contain any impurities.

Not wanting to be bound by theory, the Applicant suggests that the combination of the starting compounds used and the solvent used by him allows one to efficiently carry out the reaction under milder conditions and, as a result, slow down the rate of side reactions, including the formation of thermal degradation products (resins) and leads to the absence of local overheating (they also contribute to resinification, which makes it difficult to extract the reaction mass from the reactor).

Brief Description of the Figures

FIG. 1. HPLC curves for analysis of a sample of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide obtained by the interaction of dimethyl malonate and histamine in butanol at 100 ° C and recrystallization from ethanol with treatment of a hot solution with activated carbon.

FIG. 2. HPLC curves for analysis of a sample of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide obtained by the interaction of dimethyl malonate and histamine in butanol at 100 ° C and recrystallization from methanol with treatment of a hot solution with activated carbon.

FIG. 3. HPLC curves for analysis of a sample of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide obtained by the interaction of dimethyl malonate and histamine in butanol at 100 ° C and recrystallization from water with treatment of a hot solution with activated carbon.

FIG. 4. ¹ H nuclear magnetic resonance spectrum (Bruker DRX500.13, 500.13 MHz, DMSO-d6) of sample N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide.

FIG. 5. ¹³ C nuclear magnetic resonance spectrum (Bruker DRX500.13 125.76 MHz, DMSO-d6) of sample N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide.

FIG. 6. High-resolution mass spectrum of a sample of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide.

Detailed Disclosure of Invention

To solve the problem of obtaining N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide of the formula (I) with a purity higher than 99.0% and not containing a single impurity higher than 0.1%, based on published data , this compound was synthesized according to all the described methods in order to determine the yield and evaluate methods for the isolation and purification of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide and a comparison was made with the method of the invention.

Analysis of the samples by HPLC was carried out on a liquid chromatograph with an autosampler, a UV detector equipped with a Gemini C18 column, 4.6 × 250 mm, 5 μm.

NMR analysis of the samples was carried out on a Bruker DRX instrument with an operating frequency of 500.13, 500.13 MHz, in DMSO-d6.

The analysis of samples by mass spectrometry was carried out on a Bruker micrOTOF-Q instrument with electrospray ionization.

Example 1. (comparative) Synthesis of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide by the method of activated esters

The reaction between histamine and malonic acid in the presence of hexafluorophosphate (1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium) -3-oxide (method a1), tetrafluoroborate O- (benztriazol-1-yl) -N, N, N ′, N′-tetramethyluronium (method a2), (1- (3-dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (method a4), and 1-methyl- hydroiodide 2-chloropyridinium (method a5) was carried out in a medium of dimethylformamide, which is a polar, aprotic solvent, capable of dissolving histamine well and being the most used solvent in this type of transformation. The reactions were carried out at room temperature according to the following procedure:

to a solution of 22.2 g (0.2 mol) of histamine in 120 ml of anhydrous, degassed dimethylformamide, 10.4 g (0.1 mol) of vacuum-dried malonic acid, 35 ml (~ 0.25 mol) of anhydrous triethylamine were added with stirring and 0.22 mol of activating agent. The reaction mixture was stirred for 4 hours, the solvents were removed in vacuo, the residue was suspended in 100 ml of cold water, the precipitate was filtered off and washed with water until the accompanying reaction products disappeared by HPLC.

Despite the high conversion (according to HPLC) of the starting materials, the overall yield of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide as a product was extremely low. This is due to the fact that the accompanying reaction products formed from the activating agent, although they have a higher solubility in water compared to N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide, however the volumes of water required for their complete removal (to a level of less than 5%) were quite large, which led to significant losses of the target substance, and the poor solubility of the target product in water-immiscible solvents (dichloromethane, benzene, hexane) did not allow the product to be isolated by extraction from water phase.

The reaction of the formation of amide (the target product of the formula (I)) under the action of dicyclohexylcarbodiimide was also carried out. it is known that dicyclohexylurea formed from it has low solubility in water. The reaction was carried out in tetrahydrofuran and dimethylformamide without the addition of additional bases (for example, triethylamine, diisopropylethylamine). As a result, N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide was obtained in high yield, which, however, even after doubly filtering the aqueous solution, contained an admixture of dicyclohexylurea. The results of experimental studies on the preparation of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide by the method of activated esters are shown in Table 1.

Table 1

No. Activating reagent The conversion of histamine,% Product yield,% Comments one hexafluorophosphate (1- [bis (dimethylamino)
methylene] -1 H -1,2,3-triazolo [4,5-b] pyridinium) -3-oxide
(method a1) 97 27 Low yield associated with comparable solubility of reaction products in water 2 tetrafluoroborate O- (benztriazol-1-yl) -N, N, N ′, N′-tetramethyluronium
(method a2) 92 24 3 (1- (3-Dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride
(method a4) 90 31 four 1-methyl-2-chloropyridinium hydroiodide
(method a5) 78 16 5 Dicycloheskyl carbodiimide 93 86 (42) Initially, in 86% yield, a product containing 0.73% dicyclohexylurea was obtained. In parentheses is the product yield after two recrystallizations combined with hot filtration of the solution. The content of dicyclohexylurea was 0.57%

As can be seen from the data obtained, the activated ester method does not allow the production of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide with a purity of more than 99% with an acceptable yield.

Example 2 (comparative) Synthesis of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide by acylation of histamine with maloyl chloride

Initially, the histamine acylation reaction with maloyl chloride was carried out with a concentrated aqueous solution of histamine (~ 20% (mass.)) Under cooling. This experiment was carried out in two versions: in the first, the stoichiometric ratio of the reagents was used, and in the second, a twofold excess of histamine. In both cases, even on quantities of a substance typically used on a laboratory scale, a rapid thickening of the reaction mixture occurred, making it impossible to further mix it, and as a result, ensuring adequate mass and heat transfer.

The consequence of this was the low conversion of histamine and the formation of a number of intractable by-products.

An attempt to carry out the reaction in a dilute solution (~ 5% (mass.)) Showed that in this case, as the main reaction, hydrolysis of malonyl chloride proceeds, rather than histamine acylation.

An attempt to use dimethylformamide as the acylation medium, although it allowed to ensure high histamine conversion and product yield, led to the formation of a number of difficult to remove impurities, in particular N-formylhistamine and malonic acid bisdimethylamide. The formation of these impurities is apparently associated with the relatively high reactivity of dimethylformamide with respect to strong nucleophiles. Despite the low temperature of the reaction (-5 - (-) 10 ° С) and vigorous stirring, local overheating led to the occurrence of these adverse reactions.

Thus, the isolation of the product obtained by this method was complicated by the formation of hardly separated impurities due to close solubility values. Thus, recrystallization of a sample of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide, obtained by this method from water or ethanol, practically did not affect the content of impurities in the sample.

Taking into account the need for further use of heterogeneous ion-exchange carriers for the isolation of the free base of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide, this approach was also considered unsatisfactory. The results of experimental studies of the preparation of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide by the interaction of malonyl chloride with histamine are shown in Table 2.

table 2

No. Solvent The content of histamine in solution,% (mass.) The stoichiometric ratio of histamine: malonyl chloride Note 6 Water twenty 2: 1 Due to the strong thickening of the reaction mixture, only a third of the calculated amount of malonyl chloride was added. 4: 1 Due to the strong thickening of the reaction mixture, only half of the calculated amount of malonyl chloride was added. 5 2: 1 The main reaction is the hydrolysis of malonyl chloride 4: 1 The main reaction is the hydrolysis of malonyl chloride 7 Dimethyl formamide 10 2: 1 Formation of difficultly separated impurities of N-formylhistamine and bis-dimethyl malonamide

Example 3 (comparative) Acylation of histamine with bisimidazolid malonic acid

Malonic acid imidazolid was obtained from malonic acid and carbonyldiimidazole in situ and did not stand out.

The acylation was carried out according to the following procedure: 34.0 g (0.21 mol) of carbonyldimidazole was added to a solution of 10.4 g (0.1 mol) of malonic acid in 200 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred for 30 minutes. at room temperature, and then another 2 hours at 50 ° C. The reaction mixture was cooled and 22.2 (0.2 mol) of histamine was added and stirred for 18 hours. The solvent was removed in vacuo, 100 ml of cold water was added to the residue, the precipitate was filtered off and washed with 3 × 50 ml cold water. Yield of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide 13.6 g (47%).

The low yield of the product, as well as in the case of the activated ester method, can be explained by the need to remove imidazole from the reaction mixture, which has comparable solubilities in water and alcohols.

Also, by HPLC analysis, it was found that bis (2-ethyl-4 (5) -imidazolyl) urea was formed as a by-product in this reaction.

The totality of the data indicates the inappropriateness of the application of this method to solve the problem of the present invention.

Example 4. Acylation of histamine with various esters of malonic acid

As indicated above, a method was known for preparing a compound of formula (I) by reacting malonic acid diethyl ester with histamine in the absence of a solvent.

The applicant has studied the interaction with histamine of diphenyl and dimethyl malonic acid esters. The reaction was carried out in various solvents. The results of experimental studies on the preparation of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide by the interaction of malonic acid esters with histamine are shown in table 3.

Table 3

No. Reagent Solvent Reaction time, hours T, ° С The conversion of histamine,% Impurity content 10 Dimethyl malonate - (comparative) 3 170 92 Impurities over 30% Methanol 12 65 twenty No analysis due to low histamine conversion Ethanol 12 80 34 Butanol 6 one hundred 96 Impurities less than 5% four 120 99 Impurities over 10% eleven Diethyl malonate - (comparative) 3 170 67 Impurities over 10% Methanol 12 65 <5 No analysis due to low histamine conversion Ethanol 12 80 8 Butanol 12 120 21

Table 3 - continued

No. Reagent Solvent Reaction time, hours T, ° С The conversion of histamine,% Impurity content 12 Diphenyl malonate -
(comparative) 3 170 82 Impurities over 10% Methanol 12 65 fifteen No analysis due to low histamine conversion Ethanol 12 80 47 Butanol four one hundred 97 Impurities less than 5%

As can be seen from the data presented, the most promising is the reaction of diphenyl and dimethyl malonate with histamine in butanol at a temperature of about 100 ° C. These conditions provide a high conversion of histamine and lead to the formation of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide, which does not contain a significant amount of impurities. In order to solve the problem of the present invention, the possibility of further purification of samples of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide obtained from diphenyl and dimethyl malonate with histamine in butanol at 100 ° C was studied. The results of experimental studies on the purification of N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide are presented in table 4.

Table 4

No. Sample Cleaning method Impurity content Product yield,% 13 N, N'-bis [2- (1H-imidazol-4-yl) ethyl]
malonamide obtained by the reaction of histamine with dimethyl malonate Crystallization from ethanol with activated carbon treatment of a hot solution 0.325% 63 Crystallization from methanol with activated carbon hot solution No impurities 54 Crystallization from water with activated carbon treatment of a hot solution No impurities 61 fourteen N, N'-bis [2- (1H-imidazol-4-yl) ethyl]
malonamide obtained by the reaction of histamine with diphenyl malonate Crystallization from ethanol with activated carbon treatment of a hot solution The amount of impurities is 1.67%. Of which phenol is 1.10% 52 Crystallization from methanol with activated carbon hot solution The amount of impurities is 1.24%. An admixture of phenol 0.98% 46 Crystallization from water with activated carbon treatment of a hot solution The amount of impurities is 1.36%. Admixture of phenol 1.23% 48

HPLC data confirming the purity of the products by the experimental method 13 (tab. 4) are shown in figures 1, 2 and 3, respectively.

Also for the prototype obtained by method 13 (tab. 4), purified by crystallization from water with treatment of a hot solution with activated carbon, NMR spectra were obtained:

^one H (Bruker DRX500.13, 500.13 MHz, DMSO-d6) of sample N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide. ( ^one H NMR (500 MHz, DMSO- d ₆ ) δ : 11.82 (s, 1H, NH _imidazole ,), 8.09 (t, J = 5.6 Hz, 1H, CONH), 7.51 (s, 1H, H ² ), 6.79 (s, 1H, H ⁵ ), 3.28 (q, J = 7.2 Hz, 2H, H ^α ), 3.01 (s, 2H, COCH ₂ CO), 2.63 (t, J = 7.2 Hz, 2H, H ^β )

¹³ C (Bruker DRX500.13 125.76 MHz, DMSO-d6) sample N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide: δ : 166.9 ( C O), 134.7 ( C ⁵ ), 134.3 ( C ³ ), 116.9 ( C ² ), 43.5 ( C H ₂ ), 39.0 ( C ^α ), 26.8 ( C ^β ).

These spectra 1H and 13C of the sample are shown in figure 4 and figure 5., respectively, and also figure 6 shows the mass spectrum of high resolution.

The data of spectral analysis of the sample confirm the high purity of the test sample.

During the development of the present invention, it was found that the reaction of histamine with dimethyl malonate in butanol at a temperature preferably of up to 100 ° C, in combination with crystallization of the product from ethanol, methanol or water with the treatment of a hot solution with activated carbon, allows one to obtain N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide with a purity higher than 99.0% and not containing a single impurity higher than 0.1% (see Fig. 1), suitable for use as a pharmaceutical substance in the production of various types of dosage forms.

Summarizing the experimental data presented, the authors note that since dimethyl malonate, unlike diphenyl malonate, is currently a more commercially available reagent, and samples obtained using it are more pure than samples obtained from diphenyl malonate, the use of dimethyl malonate for histamine acylation seems most appropriate.

Claims (10)

1. The method of obtaining N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide of the formula

the reaction of dimethyl malonate with histamine in a polar organic solvent at a temperature of 85-120 ° C, including the stage of crystallization from water and / or polar organic solvent. 2. The method according to claim 1, comprising carrying out the reaction in a solution containing 3-30 wt.% Histamine. 3. The method according to claim 1 or 2, comprising carrying out the reaction in butanol, propanol, isopropanol, ethylene glycol, dioxane, or a combination of these solvents, or mixtures thereof with water. 4. The method according to claim 1, including the use at the stage of crystallization of water, methanol, ethanol, n-propanol, isopropanol, ethylene glycol and other alcohols, or mixtures thereof with water and / or with each other. 5. The method according to any one of claims 1 to 4, further comprising introducing seed in a solution for crystallization of the product of formula (I). 6. The method according to any one of claims 1 to 5, comprising the following stages: to a 15% (by weight) solution of histamine in butanol or isopropanol or ethanol, optionally as a mixture with each other, the mixture optionally containing water in an amount of up to 10 wt.%, dimethyl malonate in an amount of 0.4-0 is added, 55 mol-equiv., the resulting mixture is maintained at a temperature of from 90 to 110 ° C until the histamine content in the reaction mixture reaches less than 3% (wt.) for 4-8 hours, cooled, the precipitate is filtered off, dissolved in hot water, 1-10% (wt. ) activated carbon, stirred, the hot solution is filtered and left to crystallize.

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