EA040924B1 - A NEW METHOD FOR OBTAINING N,N'-BIS[2-(1H-IMIDAZOL-4-YL)ETHYL]MALONAMIDE - Google Patents

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 typical for the reaction of direct amidation of carboxylic acids, for the synthesis of its amides, as a rule, more reactive derivatives are used, isolated or obtained in situ. The following are the main methods for the preparation of malonic acid amides, classified according to the type of acylating agent:

method of activated esters, method of acylation of amines with acid halides, method of acylation of amines with imidazolides of carboxylic acids, method of acylation of amines with acid esters.

Let us consider the options for implementing each of the above methods described in detail in the literature.

Activated ester method.

This method involves the use of special excipients, reacting with which malonic acid forms highly reactive intermediates, which, in turn, are able to 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]-1H-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) O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium salts at room temperature in absolute dimethylformamide (Koval, Vasiliy S.; Arutyunyan, Albert F.; Salyanov, Victor L.; Klimova, Regina R.; Kushch, Alia 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, pp. 3534-3537). It is also possible to carry out the reaction with dicyclohexylcarbodiimide in the presence of benzotriazol-1-ol (Burghardt, Stephan; Hirsch, Andreas; Schade, Boris; Ludwig, Kai; Boettcher, Christoph - Angewandte Chemie - International Edition, 2005, vol. 44, # 19, pp. 2976-2979). The use of benzotriazol-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°C in the presence of 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, pp. 544-555.) It is also possible to carry out the reaction with dicyclohexylcarbodiimide in the presence of benzotriazol-1-ol 2009/69368, 2009, A1). As in the case of dicyclohexylcarbodiimide, the use of benzotriazol-1-ol allows, in some cases, to increase the yield of the target product,

5) 1-methyl-2-chloropyridinium salts 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, pp. 7593-7597).

However, as was shown in the course of research, 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 using the process in industry. 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 the acylated amine as the base), in a wide range of solvents. (Lei Shan; Jin, Vo; 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 K.J.; Dimmock, Jonathan R. - European Journal of Medicinal Chemistry, 2012, vol. 51, p 193-199). However, as shown in the course of research, this method does not allow achieving high yields of the target product, due to the presence, in addition to the main reaction, of a side reaction of malonyl chloride hydrolysis. In addition, for industrial syntheses, the use of chlorinated derivatives is undesirable for safety reasons. Method for acylation of amines with carboxylic acid imidazolides Malonic acid imidazolide can be obtained from malonic acid by reaction with 1,1'-carbonyldiimidazole, in

- 1 040924 various solvents (Nguyen, M. V. D.; Nicolas, L.; Gaudemer, A.; Brik, M. E. - Bioorganic & Medicinal Chemistry Letters, 1998, vol. 8, # 3, p. 227-232).

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

Method of acylation of amines with acid esters.

This method involves the interaction of the amine with esters of malonic acid. These compounds are relatively low-reactive, but due to their thermal stability, they allow the reaction to be carried out at relatively high temperatures (150-180°C). As acylating agents, the use of malonic acid diethyl ester is described in the literature (Devarasetty, Kiran; Tharikoppula, Giri; Sridhar, Tailor; Eppakayala, Laxminarayana; Kyasani, Mahesh; Arumugam, Premkumar; Pusuluri, Srinivas - Synthetic Communications, 2016, vol. 4 6 , # 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 C. M. .; 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 the preparation of malonic acid amides is associated with 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.

Obviously, the ease of purification and isolation is especially important in the case of obtaining substances that are pharmaceutical substances, since 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 technology of production of pharmaceutical substances.

Thus, there is a need to develop a process for the preparation of such compounds that is commercially viable for the preparation of significant amounts of pharmaceutically useful product.

Based on the analysis of literature sources, it has been shown that various synthetic approaches can be applied to obtain N,N'-6uc[2-(1Himidazol-4-yl)ethyl]malonamide. A specific synthetic strategy that provides the target product with a high yield and a 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 obtaining N,N'-bis[2-(1H-imidazol4-yl)ethyl]malonamide of formula (I)

(I) allowing to obtain the target product 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.

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

The technical result of this invention is to provide a method that allows you to get N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide of formula (I) with a purity above 99.0 wt.%, this product does not contain a single impurities 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 obtaining N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide may additionally 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 the method for its preparation by the interaction of malonic acid diethyl ester and histamine are described in the patent for invention RU 2 665 688. Reproducing the procedure described therein makes it possible to obtain a sample of N,N'bis[2-(1H-imidazol-4-yl)ethyl]malonamide with a purity of less than 90%.

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

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

Without wishing to be bound by theory, the Applicant assumes that the combination of starting compounds and solvent he has found makes it possible to effectively carry out the reaction under milder conditions and, as a result, to slow down the rate of side reactions, including the formation of thermal degradation products (tarring) as well as leads to the absence of local overheating (they also contribute to gumming, which makes it difficult to remove the reaction mass from the reactor).

Brief description of the figures

Fig. Fig. 1. HPLC analysis curves of a sample of N,N'-bis[2-(III-imidazol-4-yl)ethyl]malonamide obtained by the reaction of dimethylmalonate and histamine in butanol at 100°C and recrystallization from ethanol with treatment of the hot solution with activated charcoal.

Fig. Fig. 2. HPLC analysis curves of a sample of N,N'-bis[2-(III-imidazol-4-yl)ethyl]malonamide obtained by the reaction of dimethylmalonate and histamine in butanol at 100°C and recrystallization from methanol with treatment of the hot solution with activated charcoal.

Fig. Fig. 3. HPLC analysis curves of a sample of ^^-bis[2-(1H-imidazol-4-yl)ethyl]malonamide obtained by the reaction of dimethylmalonate and histamine in butanol at 100°C and recrystallization from water with treatment of the hot solution with activated charcoal.

Fig. 4. 1H nuclear magnetic resonance spectrum (Bruker DRX500.13, 500.13 MHz, DMSO-d ₆ ) of a K,K'-bis[2-(Nm-imidazol-4-yl)ethyl]malonamide sample.

Fig. 5. ¹³ C nuclear magnetic resonance spectrum (Bruker DRX500.13 125.76 MHz, DMSO-d ₆ ) of a sample of K,K'-bis[2-(Nm-imidazol-4-yl)ethyl]malonamide.

Fig. 6. High resolution mass spectrum of a sample of ^^-bis[2-(1H-imidazol-4-yl)ethyl]malonamide.

Detailed disclosure of the invention

To solve the problem of obtaining K,K'-bis[2-(III-imidazol-4-yl)ethyl]malonamide of formula (I) with a purity above 99.0% and not containing a single impurity above 0.1%, based on the literature data , the synthesis of this compound was carried out according to all the described methods in order to determine the yield and evaluate the methods for isolating and purifying N-Ni-bis[2-(1H-imidazol-4-yl)ethyl]malonamide and compared with the method according to 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, 4.6x250 mm, 5 μm.

Analysis of the samples by NMR was carried out on a Bruker DRX instrument with an operating frequency of 500.13, 500.13 MHz, in DMSO-d ₆ .

Samples were analyzed by mass spectrometry 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 О-( benztriazol-1-yl)-N,N,N',N'-tetramethyluronium (method a2), (1-(3dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (method a4), and 1-methyl-2-chloropyridinium hydroiodide (method a5) was carried out in the medium of dimethylformamide, which is a polar, aprotic solvent capable of well dissolving histamine and being the most used solvent in this type of transformations. 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 was added with stirring 10.4 g (0.1 mol) of vacuum-dried malonic acid, 35 ml (~0.25 mol) of anhydrous triethylamine and 0.22 mol of an activating agent. The reaction mixture was stirred for 4 h, the solvents were removed in a vacuum, the residue was suspended in 100 ml of cold water, the precipitate was filtered off and washed with water until the by-products of the reaction disappeared according to HPLC.

Despite the high conversion (according to HPLC) of the starting materials, the overall yield of N,N'-6uc[2(1H-imidazol-4-yl)ethyl]malonamide as a product turned out to be extremely low. This is due to the fact that the reaction by-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%) turned out to be 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 isolate the product by extraction from the aqueous phase.

A reaction was also carried out to form an amide (target product of formula (I)) under the action of dicyclohexylcarbodiimide, since it is known that dicyclohexylurea formed from it as a result of synthesis has a low solubility in water. The reaction was carried out in tetrahydrofuran and dimethylformamide without adding additional bases (eg triethylamine, diisopropylethylamine). As a result, N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide was obtained in high yield, which, however, even after double hot filtration of the aqueous solution, contained an impurity of dicyclohexylurea. The results of experimental studies on the preparation of N,N'-6uc[2(1H-imidazol-4-yl)ethyl]malonamide by the activated ester method are given in Table 1. 1.

Table 1

No. Activating Reagent histamine conversion, product output, Comments % % 1 (1[bis(dimethylamino)methylene]-\H-1,2,3 triazolo[4,5b]pyridinium)-3-oxide hexafluorophosphate (method al) 97 27 The low yield of the product is associated with a comparable solubility of the reaction products in water. 2 O(benzotriazol-1-yl)-N tetrafluoroborate, N,N',N'tetramethyluronium (method a2) 92 24 3 (1-(3dimethylamino)propyl)-3 ethyl carbodiimide hydrochloride (method a4) 90 31 4 1-methyl-2-chloropyridinium hydroiodide (method a5) 78 16 5 Dicyclohexylcarbodiimide 93 86 (42) Initially, with a yield of 86%, a product containing 0.73% dicyclohexylurea was obtained. In parentheses is the yield of the product after two recrystallizations combined with hot filtration of the solution. The content of dicyclohexylurea in this case was 0.57%

As can be seen from the obtained data, the method of activated esters does not allow one to obtain 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 acylation reaction of histamine with maloyl chloride was carried out with a concentrated aqueous solution of histamine (~20% (wt.)) Under cooling. This experiment was carried out in two versions: in the first, a stoichiometric ratio of reagents was used, and in the second, a twofold excess of histamine. In both cases, even at amounts of the substance typically used on a laboratory scale, the reaction mixture rapidly thickened, making it impossible to further mix it and, as a result, ensure adequate mass and heat transfer.

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

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

An attempt to use dimethylformamide as a medium for acylation, although it made it possible to ensure high histamine conversion and product yield, led to the formation of a number of impurities that are difficult to remove, 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 reaction temperature (-5-(-)10°C) and intensive stirring, local overheating led to the occurrence of these side reactions.

Thus, the isolation of the product obtained by this method was complicated by the formation of difficult-to-separate impurities due to close solubility values. Thus, the recrystallization of a sample of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide obtained by this method from water or ethanol had practically no effect on 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 production of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide by the interaction of malonyl chloride with histamine are given in table. 2.

table 2

No. Solvent The content of histamine in the solution,% Stoichiometric ratio of histamine: Note (mass) malonyl chloride 6 Water 20 2:1 Due to the strong thickening of the reaction mixture, it was possible to add only a third of the calculated amount of malonyl chloride 4:1 Due to the strong thickening of the reaction mixture, it was possible to add only half of the calculated amount of malonyl chloride 5 2:1 The main reaction is the hydrolysis of malonyl chloride 4:1 The main reaction is the hydrolysis of malonyl chloride 7 Dimethylformamide 10 2:1 Formation of hard-to-separate impurities of N-formylhistamine and bis-dimethylmalonamide

Example 3 (comparative). Acylation of histamine with bisimidazolide malonic acid.

Malonic imidazolide was prepared from malonic acid and carbonyldiimidazole in situ and was not isolated.

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 min at room temperature and then for another 2 h 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

- 5 040924 vacuum, 100 ml of cold water was added to the residue, the precipitate was filtered off and washed with cold water 3x50 ml. Yield of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide 13.6 g (47%).

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

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

The totality of the data obtained indicates the inexpediency of using this method to solve the problem of the present invention.

Example 4 Acylation of histamine with various malonic acid esters.

As indicated above, a method has been 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 diphenyl and dimethyl esters of malonic acid. The reaction was carried out in various solvents. The results of experimental studies of obtaining N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide by the interaction of esters of malonic acid with histamine are given in table. 3.

Table 3

No. Reagent Solvent Reaction time, hours T, °C Histamine conversion, % Impurity content - (comparative) 3 170 92 Impurities over 30% methanol 12 65 20 Analysis is not was carried out from 10 Dimethylmalonate ethanol 12 80 34 due to low histamine conversion Butanol 6 100 96 Impurities less than 5% 4 120 99 Impurities over 10% - (comparative) 3 170 67 Impurities over 10% Diethylmalonate methanol 12 65 <5 Analysis is not eleven ethanol 12 80 8 was carried out from for low Butanol 12 120 21 conversions histamine No. Reagent Solvent Reaction time, hours T, °С Histamine conversion, % Impurity content (comparative) 3 170 82 Impurities over 10% methanol 12 65 15 Analysis is not 12 Diphenylmalonate ethanol 12 80 47 carried out due to low conversions histamine Butanol 4 100 97 Impurities less than 5%

As can be seen from the data presented, it seems most promising to carry out the reaction of diphenyl- and dimethylmalonate 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-imidαzol-4yl)ethyl]malonamide, which does not contain a significant amount of impurities. In order to solve the problem of this invention, the possibility of further purification of samples of N,N'-bis[2-(1H-imidazol-4yl)ethyl]malonamide obtained from diphenyl- and dimethylmalonate 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.

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Table 4

No. Sample Cleaning method Impurity content Product yield, % 13 Ν, ^-bis[2-(lHimide azol-Dyl)ethyl] malonamide Crystallization from ethanol with treatment of the hot solution with activated carbon 0.325% 63 obtained by the reaction of histamine with dimethylmalonate Crystallization from methanol with treatment of the hot solution with activated carbon No impurities 54 Crystallization from water with treatment of the hot solution with activated carbon No impurities 61 14 Ν, ^-bis[2-(lHimidazol-4yl)ethyl]malonamide obtained by the reaction of histamine with diphenylmalonate Crystallization from ethanol with treatment of the hot solution with activated carbon The amount of impurities is 1.67%. Of which phenol 1.10% 52 Crystallization from methanol with treatment of the hot solution with activated carbon The amount of impurities is 1.24%. Phenol admixture 0.98% 46 Crystallization from water with treatment of the hot solution with activated carbon The amount of impurities is 1.36%. Phenol impurity 1.23% 48

HPLC data confirming the purity of the products according to Experimental Method 13 (Table 4) are shown in FIG. 1, 2 and 3, respectively.

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

'n (Broker DRX500.13, 500.13 MHz, DMSOCH) sample of N,N'-6hc[2-(1H-imidazol-4yl)ethyl]malonamide. ('Н NMR (500 MHz, DMSO-d^) δ: 11.82 (s, 1H, NH„ _Mel3OJI ), 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“), 3.01 (s, 2H, COCH ₂ CO), 2.63 (t, J=7.2 Hz, 2H, Η ^β ) .

¹³ C (Broker DRX500.13 125.76 MHz, DMSO-c16) N,N'-6nc[2-( 1 H-imidazol-4yl)ethyl]malonamide sample: δ: 166.9 (CO), 134.7 (C ⁵ ) , 134.3 ( ^C3 ), 116.9 ( ^C2 ), 43.5 (CH2), 39.0 (C°), 26.8 (C ^? ).

These 'H and ^13C spectra of the sample are shown in FIG. 4 and 5, respectively, as well as in FIG. 6 shows a high resolution mass spectrum.

The data of the spectral analysis of the sample confirm the high purity of the studied prototype.

In the course of the present invention, it has been found that the reaction of histamine with dimethylmalonate in butanol at temperatures preferably up to 100°C, in combination with crystallization of the product from ethanol, methanol or water with treatment of the hot solution with activated charcoal, makes it possible to obtain Ν,Ν'bis[2-( 1H-imidazol-4-yl)ethyl]malonamide with a purity above 99.0% and not containing a single impurity above 0.1% (see Fig. 1), suitable for use as a pharmaceutical substance in the production of various types of dosage forms.

Summarizing the above experimental data, the authors note that since dimethylmalonate, unlike diphenylmalonate, is currently a more commercially available reagent, and the samples obtained using it are of higher purity than the samples obtained from diphenylmalonate, the use of dimethylmalonate for histamine acylation seems to be the most appropriate.

Claims (6)

1. Method for obtaining K,K'-bis[2-(N-imidazol-4-yl)ethyl]malonamide of the formula reaction of dimethylmalonate with histamine in a polar organic solvent at a temperature of 85-120°C, including the stage of crystallization from water and/or a polar organic solvent. 2. The method according to claim 1, including carrying out the reaction in a solution containing 3-30 wt.% histamine. 3. The method according to claim 1 or 2, including 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 of water, methanol, ethanol, npropanol, isopropanol, ethylene glycol and other alcohols, or mixtures thereof with water and/or with each other, in the crystallization step. 5. The method according to any one of claims 1 to 4, further comprising seeding the solution to crystallize the product of formula (I). 6. The method according to any one of claims 1 to 5, comprising the following steps: to a 15% (by mass) solution of histamine in butanol or isopropanol, or ethanol, optionally as a mixture with each other, while the mixture optionally contains water in an amount of up to 10 wt.%, dimethylmalonate is added in an amount of 0.4-0.55 mol equivalents, the resulting mixture is kept at a temperature of 90 to 110°C until the histamine content in the reaction mixture is less than 3% (wt.) for 4-8 hours, cooled, the precipitate is filtered off, dissolved in hot water, add 1-10 % (wt.) activated carbon, stirred, the hot solution is filtered and left to crystallize.