The method of obtaining esters of l-carnosine and their salts

 

(57) Abstract:

The invention relates to a method for producing esters of L-carnosine and their salts, including the interaction of L-carnosine with the lower alcohol in an anhydrous environment of the corresponding alcohol by cooling, in the presence of an acid catalyst, followed by the selection of the target product and its purification. All stages are conducted in an atmosphere of inert gas, and as the acid catalyst used chloride thionyl, hydrogen chloride or sulfuric acid. The method allows to obtain the target products, which have high biological activity and relatively high L-carnosine hydrophobicity, with a stable release of carnosine any origin. 4 C.p. f-crystals, 1 table.

The invention relates to organic chemistry, and more specifically to methods of producing biologically active derivatives histidinemia of dipeptides, namely, esters and salts of esters of natural dipeptide L-carnosine.

L-carnosine is a natural neuropeptide that exerts a variety of biological activity, including high efficiency in protecting neurons in conditions of oxidative stress (ischemia of the brain and heart, Hypobank lifetime in the body, subjected to cleavage by carnosinase (Gulyaeva N.In., Abidin A. B., Levshin, I. P. et al. // Bul. exp. Biol. the honey. 1989. So 107. 2. C. 144-147). So urgent is the problem of chemical modification of L-carnosine order to obtain compounds weakly split by carnosinase and characterized with respect to L-carnosine hydrophobicity. Such compounds can be its esters and their salts.

Known methods of esterification of peptides in the presence of dry hydrogen chloride (herskowitz A. A., Kibirev C. K., Chemical synthesis of peptides. Kiev, "Naukova Dumka", S. 198, 1992) and sulfuric acid (Guttman road S., R. A. Boissonnas , Helv. Chim. Acta, v. 41, 6, pp. 1852-1867, 1958), but esters of carnosine is not described here.

A method of obtaining Vos-substituted esters of L-carnosine (patent Spain ES 496892, CL C1 C 07 C 103/52, 1981) in the interaction of the substituted amino acids BOC-protected --alanine hydrochloride and methyl ester of L-histidine. The resulting substituted ester of L-carnosine in two stages fully zablokirovala (beginning with the removal of the BOC-protective group, and then removing ester metal group) with the formation of the actual L-carnosine. This known method for the synthesis of esters of L-carnosine complex technologist is on ether of L-carnosine using ion-exchange resins (Yamashita S., Ishikawa N., Experientia, V. 24, 10, pp. 1079-1080, 1968), which is too complicated and is suitable primarily for the receipt of ether in preparative purposes.

Closest to the proposed method of producing methyl ester of L-carnosine, including the interaction of carnosine with methyl alcohol in its anhydrous medium in the presence of chloride tiomila at temperatures below zero, followed by exposure at zero temperature. The target product emit after removal of the solvent, purified by re-dissolving in methanol and its removal by evaporation (Pietta, P. G., A. Chersi, Gazz. Chim. Ital., v. 98, 12, pp. 1503-1510, 1968). However, according to our data, this method leads to not getting the methyl ester of L-carnosine and its dihydrochloride. In addition, this method is reproduced with good results only when used as the source connection of high-purity natural L-carnosine. When using synthetic L-carnosine, as an initial matter, the esterification in the presence of chloride tiomila leads to a noticeable resinification reaction mixtures, which makes it difficult to clean and reduces the yield of the desired esters or their salts.

The objective of the invention is to develop an automated way to obtain esters of L-carnosine and >The objective of the invention is implemented the proposed method of obtaining esters of L-carnosine and their salts, which comprises the interaction of L-carnosine with the lower alcohol in an anhydrous environment of the corresponding alcohol by cooling in the presence of an acid catalyst, followed by the selection of the target product and its purification. All operations is carried out in an inert gas environment. As the lower alcohols use of methyl or ethyl alcohol. As the acid catalyst used, for example, chloride thionyl, hydrogen chloride or sulfuric acid. To obtain free of esters obtained salt is treated with alkaline reagents such as hydroxides, carbonates, bicarbonates of alkali metals, aqueous ammonia, pyridine. Purification of salts of esters is carried out by their resultant deposition rates anhydrous diethyl ether from the corresponding alcohol.

The structure of the obtained esters of L-carnosine and their salts described by the formulas a and b, respectively:

(structure prototroph imidazole fragment molecules is depicted in accordance with the recommendations of the Merck Index, 10thEd., 1983, R. 1834)

< / BR>
For example, the methyl ether of carnosine, R=CH3(I) ethyl ester card ethyl ester carnosine, R= C2H5, henna=2hcl (IV), sulfate, ethyl ester carnosine, R=C2H5, henna=H2SO4(V).

The invention is illustrated by the following examples.

To obtain esters of carnosine and their salts in the presence of chloride tiomila used natural carnosine production in Russia (example 2 and 3). For reactions in the presence of sulfuric acid or hydrogen chloride used as a natural L-carnosine production in Russia, and synthetic L-carnosine production Spain (examples 1, 4, 5).

The degree of purity of the obtained compounds were studied by thin-layer and high performance liquid chromatography.

Thin-layer chromatography (TLC) was performed on plates "Silufol UV-254" in the solvent system isopropanol-25% aqueous ammonia - water, 7:2:1, chromatogram was shown in iodine vapor (L-carnosine and its derivatives was manifested in the form of white spots) or by using a reagent Pauli followed by treatment with a solution of soda (L-carnosine and its derivatives was manifested in the form of red spots).

High-performance liquid chromatography (HPLC) was carried out by the method obraniakowi hydrophobic chromatography under high pressure chromatographic site And, = 210 nm). As the mobile phase used 0.1 M NaH2PO4pH=2,6.

The NMR spectra of1H and13To register on the instrument Bruker AC 200-P operating frequencies 200,1 and 50.3 MHz, respectively. The assignment of the signals L-carnosinase part of the molecule is made according to (Friedrich J. O., R. Wasylishen R, Can..1. Chem., v.64. 11, pp. 2132-2138, 1986; E. Breitmaier, VoelterW. , Carbon-13 NMR Spectroscopy. VCH, p. 423, 1987).

Example 1. Ethyl ester of carnosine (II)

Chetyrehosnuju flask with a capacity of 250 ml, equipped with an efficient mechanical stirrer, enter an inert gas, and outputs the gas bubble counter, connected by means of a flexible rubber tube with a test tube, which was placed and 2.26 g (10.0 mmol) of L-carnosine. The flask was filled with argon and placed in her 40 ml of absolute ethyl alcohol. Under vigorous stirring and cooling in an ice bath to alcohol cautiously added 4 ml (7,92 g of 80.9 mmol) of concentrated sulfuric acid ( 1.98 g/ml). The instrument was let warm up to room temperature and while stirring vigorously, slowly introduced carnosine, achieving complete dissolution of each portion to avoid the formation of difficultly soluble lumps. After adding all of L-carnosine (3-4 hours) the reaction mixture was stirred for another 6 h until complete dissolution and forgive the military, under vigorous stirring, was added finely ground sodium bicarbonate to neutralize (20-25 g, pH after the addition of 7.5). The precipitated inorganic salts were separated on the filter SCHOTT and thoroughly washed with ethyl alcohol (g ml), United alcoholic solutions of double-boiled with activated charcoal. The colorless solution was filtered and parselocale a few drops of 25% aqueous ammonia to a pH of 9.5. The solution was evaporated on a rotary evaporator, dried for 1 day in a vacuum desiccator over P2ABOUT5at 0.5 mm RT.art., dissolved in 25 ml of absolute ethanol and left at -25oC. After 3 days the solution decantation with loose sediment, representing the residual carnosine and inorganic salts, was again evaporated on a rotary evaporator and dried for 1 week. in a vacuum desiccator over P2O5at 0.5 mm RT. Art. Received 2,13 g (84%) of ethyl ester of Z-carnosine in the form of a slightly coloured yellowish powder. So pl. 192-194oC (with decomp. ). According to TLC, the product contains residual L-carnosine (Rfethyl ester of L-carnosine is 0.59, RfL-carnosine is 0.22).

Example 2. The methyl ester dihydrochloride carnosine (III)

Chetyrehosnuju flask with a capacity of 250 ml, equipped with the effect of the flexible rubber tube with a test tube, in which placed and 2.26 g (10.0 mmol) of L-carnosine. The flask was filled with argon and placed in her 100 ml of absolute methyl alcohol. Under vigorous stirring and cooling to -10oWith the alcohol slowly added 2,60 ml (4.30 g, and 36.2 mmol) freshly chloride tiomila. The resulting solution was let warm up to a temperature of -50oC and slowly added thereto L-carnosine, achieving complete dissolution of each portion. After the introduction of only L-carnosine (about 8 hours) the mixture was stirred for another 2 h and left overnight at a temperature of -10oC. the resulting solution was filtered under argon from a small amount of sediment was evaporated to dryness on a rotary evaporator, the residue was again dissolved in 20 ml of absolute methanol and added to 150 ml of absolute diethyl ether. Landed the oil separated from the solution by decantation and conducted consistent drying of the product in a vacuum desiccator at 0.5 mm RT. Art. according to the following procedure:

1) the above granules of potassium hydroxide until the termination of the formation on the surface of crystals of potassium chloride to remove excess hydrogen chloride (2 days);

2) over paraffin shavings (1 day);

3) over pjatiokisi phosphorus - removal of ethanol and water (1 day).

n (Rfmethyl ester of L-carnosine to 0.60, RfL-carnosine is 0.22). According to HPLC, the content in the sample, the methyl ester of L-carnosine was 82%, the content of impurity L-carnosine 10%, histidine 8%.

1H-NMR (D2O), M. D.: 2,73 m (2N, -Ala); 3,24 m (4H, CH2His; -Ala); 3,74 (3H, och3); 7,34 (1H, N-CH=C His); 8,65 (1H, N-CH-N His).

Example 3. The dihydrochloride of ethyl ether carnosine (IV) (method 1)

Chetyrehosnuju flask with a capacity of 250 ml, equipped with an efficient mechanical stirrer, enter an inert gas, and outputs the gas bubble counter, connected by means of a flexible rubber tube with a test tube, which was placed and 2.26 g (10.0 mmol) of L-carnosine. The flask was filled with argon and placed in her 40 ml of absolute ethyl alcohol. Under vigorous stirring and cooling to -10oWith the alcohol slowly added 2,60 ml (4.30 g, and 36.2 mmol) freshly chloride tiomila. The resulting solution was warming to -50oC and slowly added thereto L-carnosine, achieving complete dissolution of each portion. After the introduction of only L-carnosine (about 8 hours) the mixture was stirred another 2 h at room temperature and left overnight. The solution was evaporated to dryness on a rotary evaporator, the remaining oil was again dissolved in absolute is in a vacuum desiccator at 0.5 mm RT.article:

1) the above granules of potassium hydroxide until the termination of the formation on the surface of crystals of potassium chloride to remove excess hydrogen chloride (2 days);

2) over paraffin shavings to remove traces of diethyl ether (1 day);

3) over pjatiokisi phosphorus - removal of ethanol and water (1 day).

Output 2,98 g (91%). White hygroscopic electrosuisse powder, deliquescent in the air. So pl. 118-120oC. According to TLC, the product contains residual L-carnosine (Rfethyl ester of L-carnosine is 0.59, RfL-carnosine is 0.22). According to HPLC, the content of ethyl ether carnosine was 91,0%, the content of impurity carnosine 9,0%.

Found, %: C 39,69; N 6,18; CL 21, 20; N 16,27.

WITH11H18N4O32l0,25N2O.

Calculated, %: C 39,83; N 6,23; Cl 21,38; N 16,89.

1H NMR (D2O, pH 3), , M. D.: 1,28 m (3H, CH3;3J=7,1 Hz); 2,78 m (2H, CH2CO-l;3J=6,7 Hz); 3,26 m (3N, NPro-RCH2His; -Ala); 3,39 DD (1H, HPro-SCH2His;2J=15,0,3J=6,1 Hz); 4,27 Quad (2H, CH2O;3J=7,1 Hz); 7,38 (1H, N-CH=C His); 8,69 (1H, N-CH-N His).

13C-NMR (D2O), M. D. : 14,29 (CH3); 27,12 (CH2His); 32,68 (CH2CO-Ala); 36,47 ( -Ala); 52,95 (CH His); 64,08 (CH2
In chetyrehkolkoy flask with a capacity of 250 ml, equipped with an efficient mechanical stirrer, enter chloride (lower part of which must not come into contact with the reaction mixture), the input of inert gas, and outputs the gas bubble counter, suspended and 2.26 g (10.0 mmol) of L-carnosine in 100 ml of absolute ethyl alcohol. Under vigorous stirring at room temperature the mixture is passed a current of dry hydrogen chloride to dissolve carnosine. After that, the mixture was cooled to -10oWith and continued to skip chloride up to saturation of the solution. The reaction mixture is left overnight at -10oC. the Dihydrochloride of ethyl ether carnosine fell from the reaction mixture in the form of a thick white precipitate, which was filtered from the mother liquor under argon, washed with absolute ether and dried at room temperature in a vacuum of 0.5 mm RT.article:

1) the above granules of potassium hydroxide;

2) over paraffin shavings;

3) over pjatiokisi phosphorus.

The obtained white deliquescent in the air electrosuisse powder. Output 2,22 g (68%). So pl. 115-118oC.

According to HPLC, the content of the ethyl ester of L-carnosine made 90.5%, the content of impurity L-carnosine amounted to CH2His; -Ala); 3,39 DD (1H, HPro-SCH2, His); 4,25 Quad (2H, CH2O); 7,41 (1H, N-CH=C His); 8,72 (1H, N-CH-N His). 2. In DMSO-d6: 1,14 m (3H, CH3); 2.28 m 2.95 user. m 3.12 m (6N, NPro-RHPro-SCH2His, CH2CO-Ala, -Ala); 4,08 Quad (2H, CH2O); 4,56 m (1H, CH); 7.45 from (1H, N-CH=C His); 8,18 user. (3H, NH3+), 8,82 d (1H, NH); 9,04 (1H, N-CH-N His).

Example 5. Sulfate ethyl ester carnosine (V)

of 1.61 g (6.3 mmol) of ethyl ester of carnosine (II) was dissolved in 20 ml of absolute ethyl alcohol and with vigorous stirring and cooling in a water bath to 5-10oWith added solution at 0.31 ml (0,62 g, 6.3 mmol) of 98% sulfuric acid in 5 ml of absolute ethyl alcohol. Immediately began to fall precipitate monosulfata ethyl ester of carnosine in the form of a white sticky mass. The sample stood at -25oC for 12 h, the precipitate was separated from the liquid by decantation, washed with 5 ml of cold absolute ethanol, and then 25 ml of anhydrous diethyl ether and passed 3 h in a vacuum of 0.5 mm RT. Art. over R2ABOUT5. The resulting powder was washed anhydrous diethyl ether protecting it from moisture in the air, pressed on the filter SCHOTT, closed-top hopper with the feed argon and again dried over P2O5and over paraffin shavings. The floor is kopeckova powder, so different. 240-245oC.

Found, %:

WITH 36,68; H OF 5.68; N 15,08.

WITH11H18N4O31,1 N2SO4.

Calculated, %: 36,48; N 5,62; N 15,47.

1H NMR (D2O), M. D.: 1,11 m (3H, CH3); 2,64 m (2H,CH2CO-Ala); and 3.16 m (3N, NPro-RCH2His; ); 3,22 m (1H, HPro-SCH2His); 4,15 Quad (2H, CH2O); 7.22 (1H, N-CH=C His); 8,54 (1H, N-CH-N His).

Despite the hygroscopic salts of esters of L-carnosine, mainly representing powders, for example of the compound (IV), (V), are also promising dosage form along with themselves esters of L-carnosine, which are syrups, for example, the compound (I), or powders, for example the compound (II). Salts of esters of carnosine stable during storage without access moisture (not less than 2 years of storage at room temperature for dihydrochloride (III) not less than 6 months of storage for sulfate (V).

Aqueous solutions of salts (III), (IV), (V) are characterized by an acidic pH, so the pH of aqueous solutions should lead to a 7.4 (phosphate buffer solution) immediately after dissolution of salts in order to avoid partial hydrolysis of the ester group.

Example 6. Enzymatic hydrolysis kachen lifetime in the body, subjected to cleavage by specific enzyme carnosinase. After 15 min after intraperitoneal administration to rats of its content in the blood reaches a maximum and then begins to decline, returning to the original low level after 30 min after injection. The brain and liver are characterized by similar kinetics of accumulation of carnosine, although the time of maximum is shifted to 30 min, and decrease to the initial level - for 45-60 min (Gulyaeva N.In., Abidin A. B., Levshin, I. P. et al. // Bul. exp. Biol. the honey. 1989. So 107. 2. C. 144-147).

The stability of these compounds in comparison with L-carnosine to action carnosinase serum donor blood was examined by high performance liquid chromatography (HPLC). The rate of accumulation of histidine was evaluated during enzymatic hydrolysis of carnosine and its derivatives. Serum was obtained from neemalirovannuyu the blood of patients.

Activity carnosinase was measured in accordance with Lenney et al (Lenney, R. P. George, A. M. Weiss, C. M. Kucera, P. W. H. Chan, G. S. Rinzler. // Clin.Chim.Acta. 1982. V. 123. P. 221-231 M. Roth // Analyt. Chem. 1971. V. 43. R. 880-882). HPLC of dipeptides and histidine were performed on the chromatograph "Altex"-334 with the column of the firm "Serva", used fluorescent detector "Schoeffel GM970" (vasb340 nmFluor455 nm).

Methyl and ethyl esters of L-carnosine are promising as the basis for creating antihypoxic drug. They are not exposed carnosinase, caracterizada longer lifetime in the bloodstream and in tissues than carnosine, and have thus the advantage over him as a potential hypoxic funds.

Thus, the proposed method is feasible and allows to obtain the esters of carnosine and their salts with stable output, using carnosine any origin.

1. The method of obtaining esters of L-carnosine and their salts, including the interaction of L-carnosine with the lower alcohol in an anhydrous environment of the corresponding alcohol by cooling, in the presence of an acid catalyst, followed by the selection of the target product and its purification, characterized in that all stages are conducted in an atmosphere of inert gas, and as the acid catalyst used chloride thionyl, hydrogen chloride or sulfuric acid.

2. The method according to p. 1, characterized in that it is about esters allocate, treating the reaction mass with an alkaline reagent.

4. The method according to PP.1-3, characterized in that as the alkaline reagent is used a hydroxide, a carbonate, a bicarbonate of an alkali metal, aqueous ammonia or pyridine.

5. The method according to PP.1-4, characterized in that the purification of esters spend presidenial anhydrous ethyl ester of the corresponding alcohol.

 

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