RU2445307C1 - Method of producing trans-urocanic acid - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, particularly to a method of producing trans-urocanic acid, which involves treating D-glucose with aqueous ammonia and formalin in molar ratio D-glucose: aqueous ammonia: formalin equal to 1:24:2.7, in water in the presence of basic copper carbonate at temperature 85-90°C for 3 hours to form (1S,2S,3S)-1-(1H-imidazol-4-yl)-butane-1,2,3,4-tetrazole, which is extracted in form of a hydrochloride. Through periodate splitting in water, the obtained (1S,2S,3S)-1-(1H-imidazol-4-yl)-butane-1,2,3,4-tetrazole is converted at room temperature to 1H-imidazole-4-carbaldehyde, condensation of which, in acetic anhydride in the presence of anhydrous potassium acetate at temperature 120°C for 2 hours, leads to formation of trans-urocanic acid with subsequent extraction thereof from the reaction mass.

EFFECT: novel method of producing trans-urocanic acid which is based on use of cheap and readily available initial reagents.

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Description

The invention relates to organic chemistry, specifically to a method for producing trans-urocanoic acid [(2E) -3- (1H-imidazol-4-yl) prop-2-enoic acid] (1).

trans-Urocanic acid (1), which has versatile biological activity, is formed in living organisms as a result of histidine metabolism. It exhibits an immunosuppressive effect, which finds application in surgical operations on transplantation of organs and tissues, as well as the treatment of skin diseases. In addition, the study of E / Z photoisomerization of urocanic acid revealed the possibility of using it to protect human skin from solar radiation [S.Franceschi, V.Andrew, N.Viguerie, M. Riviere, A. Lattes, A. Moisand, Synthesis and aggregation behavior of two-headed surfactants containing the urocanic acid moiety // New J. Chem., 1998, p. 225]. The N-methyl derivative of trans-urocanoic acid is included in the structure of diterpenic esters of eleutherobin and sarcodiktiin - metabolites of soft corals Eleutherobia sp and Sarcodictyon roseum, which have a taxol-like mechanism of cytotoxic action [R. Britton, M. Roberge, N. Berisch, J. Andersen, Antimitotic diterpenoids from Erythropodium caribaeorum: isolation artifacts and putative biosynthetic intermediates // Tet. Lett. 2001, v. 42, p. 2953]. During the creation of the combinatorial library of sarcodictines, it was found that removing the N-methylurocanoic acid residue or replacing its imidazole ring with an oxazole, thiazole or phenyl critically affects the cytotoxic activity of the compound [K.C. Nicolaou, N.Winssinger, D.Vourlomis, T. Ohshima , S. Kim, J. Pfefferkorn, Solid and Solution Phase Synthesis and Biological Evaluation of Combinatorial Sarcodictyin Libraries // J.Am. Chem. Soc. 1998, v.l20, p.l0814].

The results of the invention can be used in chemistry, biology and medicine.

Known methods for producing trans-urocanoic acid are based on the deamination of histidine.

trans-Urocanic acid is obtained as a result of the action of microorganisms [T. Shibatani, N. Nishimura, K. Nabe, T. Kakimoto, I. Chibata. Enzymatic Production of Urocanic Acid by Achromobacter liquidum II Appl. Microbiol. 1974, v.27 No. 4, p.688], and chemically.

Chemical synthesis of trans-urocanoic acid [S. Edlbacher, N. Bidder // Z. Physiol. Chem. 1942, v.276, p.126 (The preparation of urocanic acid, CA. 1943, v.37, p.5404)] was carried out by diazotization of histidine in concentrated hydrochloric acid in the presence of NaNO ₂ and dehydrochlorination of the obtained α-chloro-β- imidazolpropionic acid with triethylamine in an autoclave at 60 ° C. The total yield was 31% in terms of trans-urocanoic acid dihydrate.

Another more effective method for producing trans-urocanoic acid [Sh.M. Salikhov, O.Yu. Krasnoslobodtseva, B.T. Sharipov, F.A. Valeev, G.A. Tolstikov, Synthesis of N-methylurocanoates of isocembrol hydroxy derivatives // Chemistry of Natural Compounds, 2007, No. 2 p.119] based on Hoffmann histidine cleavage. In this case, treatment of histidine with a four-fold excess of methyl iodide with KOH in methanol, followed by elimination of trimethylamine, leads to trans-urocanoic acid in two stages with a total yield of 66%.

The main disadvantages of the considered methods is the high cost of the initial histidine. In addition, in the second case, a large amount of expensive methyl iodide is used for deamination.

The problem to which the claimed invention is directed, is to reduce the cost of the process for producing trans-urocanoic acid.

In the claimed method for producing trans-urocanoic acid, readily available D-glucose is used as the starting compound. The result of the invention is to obtain trans-urocanoic acid in three stages with a total yield of 23% based on D-glucose.

The invention consists in the following. The necessary imidazole ring with a substituent in the 4-position is formed by treating D-glucose (2) with aqueous ammonia and formalin at a molar ratio of components of 1: 24: 2.7 in water at 85-90 ° C in the presence of basic copper carbonate for 3 hours, as a result of which (1S, 2S, 3S) -1- (1H-imidazol-4-yl) butan-1,2,3,4-tetraol is formed in the form of hydrochloride with a yield of 47%. The resulting tetraol (3) is periodically cleaved with KIO ₄ (or NalO ₄ ) in water at room temperature and converted to 1H-imidazole-4-carbaldehyde (4). Further condensation of aldehyde (4) at 120 ° C in acetic anhydride in the presence of anhydrous potassium acetate for 2 hours leads to trans-urocanoic acid with a total yield of 23%.

Thus, the proposed method allows to reduce the cost of the process of obtaining trans-urocanoic acid through the use of inexpensive and readily available reagents.

The invention is confirmed by the following examples.

Example 1. Synthesis of (1S, 2S, 3S) -1- (1H-imidazol-4-yl) butane-1,2,3,4-tetraol hydrochloride (3).

222 g (1 mol) of basic carbon dioxide of copper are placed in the flask and 1500 ml of water and 800 ml (12 moles) of 28% aqueous ammonia are added to it. Then, 100 ml (1.35 mol) of 37% formalin and 90 g (0.5 mol) of glucose (2) are added to the contents of the flask. The solution was thoroughly mixed and heated for 3 hours at 90 ° C. The mixture is cooled, and then the olive-brown precipitate is filtered off of a poorly soluble copper complex of imidazole derivatives. The precipitate is washed with cold water, suspended in a wet state in 1250 ml of diluted hydrochloric acid (1: 4). Then, with stirring, hydrogen sulfide is passed through the suspension until copper is completely precipitated. After that, the precipitate is filtered off and washed with hot water. The precipitated crystals after evaporation of the light brown solution are poured into 200 ml of ethanol and the suspension is boiled for 1 hour, then the precipitate is filtered off, washed with 100 ml of hot ethanol. The remaining precipitate is dissolved in a minimum amount of water, three times the amount of isopropanol is added, the solution is heated until the precipitate is completely dissolved. When the solution was cooled to -5 ° C, crystals precipitated, which were filtered off and washed with isopropanol.

The mother liquor is evaporated and crystallization is repeated two more times. After three crystallizations, 53 g (47%) of 1,2,3,4-tetrahydroxybutylimidazole hydrochloride are isolated (3).

R _f 0.30 (EtOH: H ₂ O, 5: 1). Mp 179-181 ° C. [α] _D ²⁰ −18.6 ° (s 1.0, H ₂ O). IR spectrum (ν, cm ^-1 ): 3315, 3230, 3136, 2922, 2852, 1624, 1458, 1051, 623. ¹ H NMR spectrum (D ₂ O, δ, ppm): 3.60-3.90 m (4H, C ² H, C ³ H, C ⁴ H), 5.21 s (1H, C ¹ H), 7.45 s (1H, C ⁵ H), 8.69 s (1H, C ² H). ¹³ C NMR spectrum (D ₂ 0, δ, ppm): 65.42 (C ⁴ ), 66.42 (C ¹ ), 72.88 (C ³ ), 74.96 (C ² ), 118.23 (C ⁵ ), 135.76 (C ² ), 136.02 (C ⁴ ). Mass spectrum: m / z 189 [M-C1] ⁺ . Found (%): C 37.62; H 5.48; C1 15.65; N, 12.49. C ₇ H ₁₃ ClN ₂ O ₄ . Calculated (%): C 37.43; H 5.83; C1 15.78; N, 12.47.

Example 2. Synthesis of 1H-imidazole-4-carbaldehyde (4).

25 g (0.11 mol) of 1,2,3,4-tetrahydroxybutylimidazole hydrochloride (3) are dissolved in 50 ml of water and 11 g (0.13 mol) of NaHCO ₃ are gradually added with stirring, then 50 g (0.22 mol) of KIO _{4 are} added. After this, the reaction mixture is stirred for 1 hour, 50 ml of isopropanol are added and the inorganic salt precipitate is filtered off, washed with 50 ml of hot isopropanol. To separate inorganic salts, the mother liquor is evaporated, the resulting precipitate is diluted with 50 ml of isopropanol, the precipitate is filtered off and washed with 30 ml of hot isopropanol. The mother liquor is evaporated, the remaining precipitate is dissolved in 10-15 ml of hot methanol, while cooling the solution to -10 ° C, crystals of 4- (5) -carbaldehydeimidazole precipitate (4). Next, the mother liquor is evaporated, the residue is chromatographed on SiO ₂ (EtOAc), an additional small amount of aldehyde is isolated. Yield 7.8 g (73%).

R _f 0.30 (CHCl ₃ : EtOH, 10: 1). T. pl. 170-172 ° C. IR spectrum (ν, cm ^-1 ): 3118, 2940, 2729, 1699, 1635, 1450, 1373, 1101, 775. ¹ H NMR spectrum (DMFA-D7, δ, ppm): 8.05 s (1H , C ² H), 8.09 s (1H, C ⁵ H), 9.88 s (1H, CHO). ¹³ C NMR spectrum (DMFA-D7, δ, ppm): 124.60 (C ² ), 134.48 (C ⁵ ), 135.00 (C ⁴ ), 179.31 (CHO). Mass spectrum: m / z 97 [MH] ⁺ . Found (%): C 50.15; H 4.15; N 29.27. C ₄ H ₄ N ₂ O. Calculated (%): C 50.0; H 4.20; N 29.15.

Example 3. Synthesis of trans-urocanoic acid [(2E) -3- (1H-imidazol-4-yl) prop-2-enoic acid] (1).

A mixture of 7.8 g (0.081 mol) of aldehyde (4), 7.9 g (0.081 mol) of anhydrous potassium acetate and 40 ml (0.42 mol) of acetic anhydride is heated at 120 ° C for 2 hours. Then add 100 ml of water and the solution is boiled for 1 hour, evaporated, pumped under reduced pressure until the odor of acetic acid disappears. The resulting precipitate was dissolved in 15 ml of water and 7.15 ml (8.4 g) of 35% HCl, the solution was cooled to 0 ° C. The precipitated crystals of trans-urocanoic acid are filtered off, washed with cold water. To further isolate trans-urocanoic acid, the mother liquor is evaporated, the residue is diluted with 15 ml of a solution of 20% aqueous NH ₃ in EtOH (1: 7), the insoluble precipitate of inorganic salts is filtered off and washed with a solution of 20% aqueous NH ₃ in EtOH (1 : 7). The mother liquor is evaporated, water is added and re-evaporated, pumped under reduced pressure until the smell of ammonia disappears. The remaining trans-urocanoic acid precipitate is recrystallized from water. trans-Urocanic acid after the first and second crystallization is combined. Further purification is carried out by repeated crystallization from water. The obtained trans-uric acid (1) is pumped out under reduced pressure for 3 hours at a temperature of 90-100 ° C. Yield 7.62 g (68%).

R _f 0.30 (EtOH). T. pl. 210-212 ° C, decomp. IR spectrum (ν, cm ^-1 ): 3311, 3143, 2940, 2609, 1653, 1456, 1340, 1114, 974. ¹ H NMR spectrum (D ₂ O, δ, ppm): 6.50 d (1H , J 16.14 Hz, С ² Н), 7.46 d (1Н, J 16.14 Hz, С ³ Н), 7.71 s (1Н, С ² Н), 8.74 s (1Н, С ⁵ Н). Mass spectrum: m / z 139 [MH] ⁺ . Found (%): C 52.08; H 4.42; N 20.16. C ₆ H ₆ N ₂ O ₂ . Calculated (%): C 52.17; H 4.38; N, 20.28.

Claims (1)

A method of producing trans-urocanoic acid, characterized in that D-glucose is treated with aqueous ammonia and formalin in a molar ratio of D-glucose: aqueous ammonia: formalin equal to 1: 24: 2.7, in water in the presence of basic copper carbonate at a temperature of 85 -90 ° C for 3 h with the formation of (1S, 2S, 3S) -1- (1H-imidazol-4-yl) -butane-1,2,3,4-tetraol, isolated in the form of hydrochloride, which is periodically cleaved in water at room temperature it is converted to 1H-imidazole-4-carbaldehyde, the condensation of which in acetic anhydride in the presence of anhydrous acetate potassium at a temperature of 120 ° C for 2 hours leads to the formation of trans-urokanovoy acid followed by isolation from its reaction mass.