A novel method for producing N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide

Abstract

A process for producing N,N'-bis[2-(1H-imidazole-4-yl)ethyl]malonamide of formula (I) by reacting dimethyl malonate with histamine in a polar organic solvent at a temperature of 85°C to 120°C, the process comprising a step of crystallization from water and / or a polar organic solvent. The process makes it possible to produce a product with a purity of 99.0% by weight and suitable for the production of substances in the pharmaceutical industry.

Description

Technical Field

[0001] The present invention relates to organic compound chemistry, pharmacology and medicine, and to a method for producing N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide, wherein the purity of the N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide is higher than 99.0% and does not contain more than 0.1% of other single impurities, and is suitable for use as a pharmaceutical agent in the production of various types of dosage forms. Background Art

[0002] The preparation of malonamide from malonic acid or its esters has been described repeatedly in the literature. Since malonic acid is unstable at typical reaction temperatures for direct amidation of carboxylic acids, various reactive acid derivatives (isolated or obtained in situ) are usually used for the synthesis of its amide. Common methods for the preparation of malonamide, classified by the type of acylating agent, are listed below:

[0003] Methods for activating esters;

[0004] A method for acylation of amines with acid halides;

[0005] Method for acylation of carboxylic acid imidazolides with amines;

[0006] A method for acylation of amines with acid esters.

[0007] Let us consider in more detail embodiments of implementing each of the above methods described in the art:

[0008] Method for activating esters

[0009] This method uses specific compounds with which malonic acid reacts to form highly reactive intermediates that can then react rapidly with amines to convert them to the target amides in high yields. The following can be used as activating agents:

[0010] 1)(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine )-3-oxide salt in anhydrous dimethylformamide at room temperature. (See 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, pp. 2825-2830).

[0011] 2) O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethylurea salt in anhydrous dimethylformamide at room temperature (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, pp. 2302-2309).

[0012] 3) Dicyclohexylcarbodiimide in various solvents at room temperature (Cipolla, Laura; Sgambato, Antonella; Forcella, Matilde; Fusi, Paola; Parenti, Paolo; Cardona, Francesca; Bini, Davide-CarbohVdrate Research, 2014, volume 389, #1, pages 46-49; Wu, Hua; He, Yu-Ping; Xu, Lue; Zhang, Dong-Yang; Gong, Liu-Zhu-Angewandte Chemie-International Edition, 2014, volume 53, #13, pages 3466-3469; Angew. Chem., 2014, volume 126, #13, pages 3534-3537). The reaction can also be carried out 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, pp. 2976-2979). In some cases, the use of benzotriazole-1-ol results in an increased yield of the target product.

[0013] 4) (1-(3-dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride in dimethylformamide in the presence of a base at 25° C. (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.). The reaction can also be carried out with dicyclohexylcarbodiimide in the presence of benzotriazole-1-ol (SANOFI-AVENTIS-US2009 / 69368, 2009, A1). As in the case of using dicyclohexylcarbodiimide, in some cases, the use of benzotriazole-1-ol results in an increased yield of the target product.

[0014] 5) 1-Methyl-2-chloropyridine Salts in various solvents in the presence of bases (Tyler; Webster - Chemical Communications, 2014, Vol. 50, #73, pp. 10665-10668; Evans, Vikki; Mahon, Mary F.; Webster, Ruth L. - Tetrahedron, 2014, Vol. 70, #41, pp. 7593-7597).

[0015] However, as shown during this study, the method of activated esters does not allow the preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide with a purity greater than 99% and acceptable yields, thus limiting the use of this method in industry.

[0016] Method for acylation of amines with acid halides

[0017] The reaction between malonic acid dichloride and amine is usually carried out in a wide range of solvents in the presence of a base (or using an excess of acylated amine as a base) under cooling. (Lei, Shan; Jin, Bo; Zhang, Qingchun; Zhang, Zhichao; Wang, Xiaofang; Peng, Rufang; Chu, Shijin-Polyhedron, 2016, Vol. 119, pp. 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, pp. 193-199). However, as has been shown in the course of the studies, this process does not allow high yields of the target product to be achieved due to the presence of a malonyl chloride hydrolysis side reaction in addition to the main reaction. Furthermore, the use of chlorinated derivatives is undesirable for industrial processes for safety reasons.

[0018] Acylation of amines with carboxylic acid imidazolides

[0019] Malonate imidazolides can be prepared from malonic acid by reacting malonic acid with 1,1'-carbonyldiimidazole in a variety of solvents (Nguyen, MVD; Nicolas, L.; Gaudemer, A.; Brik, ME - Bioorganic & Medicinal Chemistry Letters, 1998, Vol. 8, #3, pp. 227-232).

[0020] As in the case of the process using activated esters, the low yield of the product is due to the need to remove the imidazole, which has comparable solubility in water and alcohol, from the reaction mixture.

[0021] Amine acylation with acid esters

[0022] The process involves the interaction of amines with malonates. These compounds are relatively unreactive, however, due to their thermal stability, they allow the reaction to be carried out at relatively high temperatures (150° C. to 180° C.). The use of diethyl malonate and 2,4,6-trichlorophenylmalonate as acylating agents is described in the prior art (see Devarasetty, Kiran; Tharikoppula, Giri; Sridhar, Tailor; Eppakayala, Laxminarayana; Kyasani, Mahesh; Arumugam, Premkumar; Pusuluri, Srinivas - Synthetic Communications, 2016, Vol. 46, #3, pp. 263-274 and 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, pp. 2670-2677).

[0023] A wide variety of known processes for the preparation of malonamides are associated with the desired selectivity of the reaction process, the yield of the target product and the ease of product isolation and purification, depending on the nature of the amine being acylated.

[0024] Obviously, since the requirements for the chemical purity of pharmaceutical substances are particularly high, the ease and simplicity of their purification and isolation are particularly important in the case of obtaining substances as pharmaceutical substances. For this reason, the optimization of synthesis methods is an important goal of pharmaceutical substance production technology.

[0025] Therefore, there is a need to develop processes for the preparation of such compounds which can be carried out on an industrial scale and which are capable of producing large quantities of pharmaceutically useful products.

[0026] As shown by the analysis based on the prior art, a variety of methods can be used to obtain N, N'-bis [2- (1H-imidazol-4-yl) ethyl] malonamide. No specific synthesis strategy has been found in the prior art to provide the target product with high yield and purity higher than 99.0% and no other single impurity exceeding 0.1% on an industrial scale. Summary of the invention

[0027] The object of the present invention is to develop a process for preparing N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide of formula (I)

[0028]

[0029] The method enables obtaining a target product with a purity higher than 99.0% and no other single impurities exceeding 0.1%, which is suitable for use as a pharmaceutical substance in the production of various types of dosage forms.

[0030] "Single impurity" in the present invention means any individual chemical compound that may be formed during the implementation of the synthesis method according to the present invention.

[0031] The technical object of the present invention is to provide a process allowing to obtain N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide of formula (I) with a purity higher than 99.0% by weight, wherein this particular product does not contain more than 0.1% by weight of a single impurity, wherein this particular product is suitable for use as a pharmaceutical substance to produce various types of dosage forms.

[0032] The specific technical result is achieved by heating dimethyl malonate (2) with histamine (1) in butanol at a temperature of 90°C to 110°C:

[0033]

[0034] The protocol for the preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide may also include a purification step comprising crystallization from water or an organic solvent.

[0035] Patent RU2665688 describes the compound of formula (I) (N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide and its preparation by contacting / reacting diethyl malonate with histamine. Following the process procedure described therein leads to the obtaining of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide samples with a purity of less than 90%.

[0036] Attempts to synthesize N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide by heating a reaction mixture having stoichiometric ratios of diethyl malonate and histamine to 170°C resulted in significant resinification of the reaction mixture and substantial (up to 38%) formation of by-products.

[0037] Unexpectedly found that, replacing diethyl malonate with dimethyl malonate makes the reaction temperature reduce and makes it possible to realize high conversion. In addition, in the technology of new design, use solvent (butanols) to make it possible to scale up the technology for preparing formula (I) compound with industrial quantity. As the result of described optimization, the total yield of target compound can be increased to 60% from 44%, and simultaneously, according to HPLC data, product does not contain any impurity.

[0038] Without wishing to be bound by theory, applicants believe that the combination of the discovered starting compounds and the solvent used in the reaction allows the reaction to be carried out efficiently under milder conditions and thus slows down the rate of side reactions including by-product formation due to thermal degradation (resinification) and also leads to the elimination of local hot spots which promote resinification, making it difficult to extract the reaction mass from the reactor. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 HPLC analysis curve 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 the hot solution with activated carbon.

[0040] Figure 2 HPLC analysis curve 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 the hot solution with activated carbon.

[0041] Figure 3 HPLC analysis curve 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 the hot solution with activated carbon.

[0042] Figure 4 .NMR spectrum of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide sample 1 H (BrukerDRX500.13, 500.13MHz, DMSO-d6).

[0043] Figure 5 .NMR spectrum of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide sample 13 C (BrukerDRX500.13 125.76MHz, DMSO-d6).

[0044] Figure 6.High-resolution mass spectrum of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide sample. DETAILED DESCRIPTION

[0045] According to the prior art data, in order to solve the problem of obtaining N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide of formula (I) with a purity higher than 99.0% and without more than 0.1% of other single impurities, the synthesis of this compound was carried out according to all the known methods mentioned, in order to determine the yield of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide and to evaluate the methods for isolating and purifying it, and to compare the known methods with the method according to the present invention.

[0046] HPLC analysis of samples was performed on a liquid chromatography apparatus with an autosampler, UV detector equipped with a 4.6 x 250 mm, 5 μm Gemini C18 column.

[0047] Sample analysis by NMR was performed at 500.13 MHz in DMSO-d6 on a Bruker DRX instrument operating at a frequency of 500.13.

[0048] Sample analysis by mass spectrometry was performed on a Bruker micrOTOF-Q instrument with electrospray ionization.

[0049] Example 1 (Comparative) Synthesis of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide by activated ester method

[0050] In the presence of (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine )-3-oxido hexafluorophosphate (method a1), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea Tetrafluoroborate (method a2), (1-(3-dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (method a4) and 1-methyl-2-chloropyridine The reaction between histamine and malonic acid in the case of (method a5) is carried out in dimethylformamide, which is a polar aprotic solvent that can completely dissolve histamine and is the most commonly used solvent for this type of transformation. The reaction is carried out at room temperature according to the following procedure:

[0051] Under continuous stirring, 10.4 g (0.1 mol) of vacuum-dried malonic acid, 35 ml (about 0.25 mol) of anhydrous triethylamine and 0.22 mol of activator were added to a solution of 22.2 g (0.2 mol) of histamine in 120 ml of anhydrous degassed dimethylformamide. The reaction mixture was stirred for 4 hours, the solvent was removed in a vacuum, and the residue was suspended in 100 ml of cold water, the precipitate was filtered out and washed with water until the by-products as monitored by HPLC analysis were removed.

[0052] Despite the high conversion of the starting material (measured by HPLC analysis), the overall yield of the N,N'-bis[2-(1H-imidazole-4-yl)ethyl]malonamide product is extremely low. This is due to the fact that, although the byproducts formed by the activator have a higher water solubility than N,N'-bis[2-(1H-imidazole-4-yl)ethyl]malonamide, a large amount of water is required to completely remove it (to a level of less than 5%), resulting in a significant loss of the target substance. At the same time, due to the poor solubility of the target product in water-immiscible solvents (dichloromethane, benzene, hexane), the product cannot be isolated by extraction from the aqueous phase.

[0053] The reaction that causes amide formation (target product of formula (I)) is also carried out in the presence of dicyclohexylcarbodiimide, because it is known that the solubility of dicyclohexylurea formed by it in water is low during the building-up process. The reaction is carried out in tetrahydrofuran and dimethylformamide without adding other alkali (for example, triethylamine, diisopropylethylamine). As a result, high-yield N, N'-bis [2-(1H-imidazoles-4-yl) ethyl] malonamide is obtained, but the product comprises dicyclohexylurea impurities that can not be removed even after the aqueous solution is subjected to twice hot filtration. The experimental study results of preparing N, N'-bis [2-(1H-imidazoles-4-yl) ethyl] malonamide by the method for activated ester are shown in Table 1.

[0054] Table 1

[0055]

[0056]

[0057] As can be seen from the data obtained, the method of activated esters does not allow obtaining N,N′-bis[2-(1H-imidazol-4-yl)ethyl]malonamide in a purity exceeding 99% and in acceptable yields.

[0058] Example 2 (Comparative) Synthesis of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide by acylation of histamine with malonyl chloride

[0059] Initially, the acylation of histamine with malonyl chloride was carried out in the presence of a concentrated aqueous histamine solution (about 20% by weight) under cooling. The experiment was carried out in two forms: in the first form, we used stoichiometric reagents and in the second form, we used a two-fold excess of histamine. In both cases, even when carried out with the amounts of substances usually used on a laboratory scale, the reaction mixture thickened rapidly, making further stirring impossible and, therefore, making it impossible to ensure sufficient mass and heat transfer.

[0060] This process results in low conversion of histamine and the formation of many by-products that are difficult to separate.

[0061] Attempts to carry out the reaction in a diluted solution (approximately 5% by weight) demonstrated that in this case the hydrolysis of malonyl chloride rather than the acylation of histamine proceeds as the main reaction.

[0062] The attempt to use dimethylformamide as the medium for the acylation, although it allows to provide high conversion of histamine and achieve high yields of product, leads to the formation of many impurities which are difficult to remove, in particular N-formylhistamine and the bisdimethylamide of malonic acid. The formation of these impurities is apparently related to the relatively high reactivity of dimethylformamide towards strong nucleophiles. Despite the low reaction temperature (-5°C to (-)10°C) and vigorous stirring, local overheating leads to the occurrence of these side reactions.

[0063] Therefore, the separation of the product obtained by this method is complicated by the formation of impurities that are difficult to separate due to close solubility values. Therefore, the recrystallization of the N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide sample prepared by this method from water or ethanol has practically no effect on the content of sample impurities.

[0064] This method is also considered unsatisfactory in view of the need to further use a heterogeneous ion exchange support for the isolation of the free base of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide. The results of experimental studies on 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.

[0065] Table 2

[0066]

[0067] Example 3 (Comparative) Acylation of Histamine with Bisimidazole Malonic Acid

[0068] Malonate imidazolide was prepared in situ from malonic acid and carbonyldiimidazole and was not isolated.

[0069] The acylation was carried out according to the following procedure: 34.0 g (0.21 mol) of carbonyldiimidazole were 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 at room temperature for 30 minutes and then at 50° C. for another 2 hours. The reaction mixture was cooled and 22.2 g (0.2 mol) of histamine were added and stirred for 18 hours. The solvent was removed in vacuo, 100 ml of cold water were added to the residue, the precipitate was filtered off and washed with 3×50 ml of cold water. The yield of N,N′-bis[2-(1H-imidazol-4-yl)ethyl]malonamide was 13.6 g (47%).

[0070] As in the case of the process using activated esters, the low yields of the products can be explained by the necessity of removing the imidazole from the reaction mixture and by the fact that imidazole has similar solubility values ​​in water and alcohols.

[0071] Furthermore, based on HPLC analysis, bis(2-ethyl-4(5)-imidazolyl)urea was found to be formed as a by-product in the reaction.

[0072] Summary of the data obtained demonstrates the infeasibility of using this approach to achieve the objectives of the present invention.

[0073] Example 4. Acylation of histamine with various malonates

[0074] As described above, a method for preparing the compound of formula (I) by reacting diethyl malonate with histamine in the absence of a solvent is already known.

[0075] The applicant has studied the interaction of diphenyl and dimethyl esters of malonic acid with histamine. The reaction was carried out in a variety of solvents. The results of the experimental study on the interaction of malonic esters with histamine to obtain N, N'-bis[2-(1H-imidazole-4-yl)ethyl]malonamide are shown in Table 3.

[0076] Table 3

[0077]

[0078]

[0079] Table 3-(Continued)

[0080]

[0081] As can be seen from the data presented, the reaction of diphenyl malonate and dimethyl malonate with histamine in butanol at a temperature of about 100° C. is the most promising. These conditions provide a high degree of histamine conversion and result in the formation of N, N'-bis[2-(1H-imidazole-4-yl)ethyl] malonamide without a large amount of impurities. In order to achieve the object of the present invention, the possibility of further purifying the N, N'-bis[2-(1H-imidazole-4-yl)ethyl] malonamide sample obtained by the reaction of diphenyl malonate and dimethyl malonate with histamine in butanol at 100° C. was studied. The results of the experimental studies on the purification of N, N'-bis[2-(1H-imidazole-4-yl)ethyl] malonamide are given in Table 4.

[0082] Table 4

[0083]

[0084]

[0085] The HPLC data for product purity determined according to Test Method 13 (Table 4) were Figure 1 , 2 and 3 are shown.

[0086] Furthermore, for a prototype sample obtained by method 13 (Table 4) and purified by crystallization from water with treatment of the hot solution with activated carbon, an NMR spectrum was obtained:

[0087] N, N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide sample 1 H(Bruker DRX500.13, 500.13MHz, DMSO-d6):

[0088] ( 1 H NMR (500MHz, DMSO-d6) δ: 11.82 (s, 1H, NH 咪唑 ), 8.09 (t, J=5.6Hz, 1H, CONH), 7.51 (s, 1H, H 2 ), 6.79(s, 1H, H 5 ), 3.28 (q, J=7.2Hz, 2H, H α ), 3.01 (s, 2H, COCH2CO), 2.63 (t, J=7.2Hz, 2H, H β ).

[0089] N, N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide sample 13 C(Bruker DRX500.13125.76MHz, DMSO-d6):

[0090] δ: 166.9 (CO), 134.7 (C 5 ), 134.3(C 3 ), 116.9(C 2 ), 43.5(CH2), 39.0(C α ), 26.8(C β ).

[0091] The 1H and 13C spectra of the samples were Figure 4 and Figure 5 , see also the high resolution mass spectra of Figure 6 .

[0092] The spectroscopic analysis data of the samples confirmed the high purity of the tested samples obtained in this study.

[0093] In the course of carrying out the present invention, it was found that the reaction of histamine with dimethyl malonate in butanol at temperatures preferably up to 100° C., combined with the crystallization of this product from ethanol, methanol or water by treating its hot solution with activated carbon, allows the preparation of N,N′-bis[2-(1H-imidazol-4-yl)ethyl]malonamide (cf. Figure 1 ), which is used as a pharmaceutical substance in the production of various types of dosage forms.

[0094] Summarizing the experimental data presented, the authors would like to point out that since dimethyl malonate is currently a more commercially available reagent than diphenyl malonate and the studied samples obtained by using it have a higher purity than the samples prepared from diphenyl malonate, the use of dimethyl malonate for the acylation of histamine appears to be the most feasible approach.

Claims

1. A process for preparing N,N'-bis[2-(1H-imidazol-4-yl)ethyl]malonamide of the formula: by reacting dimethyl malonate with histamine in butanol at a temperature ranging from 85°C to 120°C, comprising a step of crystallization from water and / or a polar organic solvent:

2. The process according to claim 1, wherein the reaction is carried out in a solution comprising 3 to 30% by weight of histamine.

3. The process according to claim 1, comprising using water, methanol, ethanol, n-propanol, isopropanol, ethylene glycol and other alcohols, or mixtures thereof with water and / or with each other in the crystallization step.

4. The method according to claim 3, further comprising a seeding solution to crystallize the product of formula (I).

5. The method according to claim 1, comprising the steps of: dimethyl malonate in an amount of 0.4 to 0.55 molar equivalents is added to a 15% by weight solution of histamine in butanol, The resulting mixture is maintained at a temperature of 90° C. to 110° C. for 4 to 8 hours until the amount of histamine in the reaction mixture is less than 3% by weight, cooled, the precipitate is filtered out, the precipitate is dissolved in hot water, 1 to 10% by weight of activated carbon is added, stirred, and the hot solution is filtered, and then the solution is subjected to a crystallization process.

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