The method of obtaining l-carnosine and its homologues

 

(57) Abstract:

Usage: in medicinal chemistry. Entity: an improved method of obtaining L-carnosine and its homologues total f-crystals of NH2(CH2)nCO-HiS, where n is 2-5. Reagent 1: derived T-protected amino acids f-crystals I. Reagent 2: hydrochloride methyl ester L-gistirina. The process is conducted in an aprotic organic solvent, the obtained N-protected trailvoy group methyl ether derivative of L-carnosine is washed with an alkaline aqueous solution at a pH of 7.5 to 11, extracted with an acidic aqueous solution at a pH of 0.5 to 3, will unlock. Output 82-97%. Product of high purity LD5010000-12000 mg/kg 1 tab.

The invention relates to the field of synthesis of biologically active peptides, specifically to an improved chemical process for the preparation of L-carnosine and its homologues General formula I:

< / BR>
where n= 2-5.

L-carnosine is a natural dipeptide structure-AlaHis and has antitumor /1/, antihistamines /2/, immunomoduliruushimi /3/, anti-stress /4/, antiulcer /5/ activity and wound healing /6/ and antineoplastics /7/ action. One of the homologues of L-carnosine L - homocarnosine (n=3), containing instead of b-alanine 4-am is Holocene L-carnosine, based on the interaction of N-protected derivative of b-alanine or b-substituted propionic acid with L-histidine or its methyl ether. Thus, L-carnosine is produced by interaction of b-iodopropionic with L-histidine with subsequent treatment with ammonia /9/, by the reaction of N-phthaloyl-b-Albergaria with L - histidine with the subsequent removal of the protective group /10/, the interaction of N-carbamasepine with methyl ester of L-histidine with the subsequent release of the obtained peptide /11/, the interaction of L-histidine with tetrahydro-1,3-triazine-2,4-dione in aqueous medium at pH of 8.5 to 9.5 /12/ and other Homologues of L-carnosine get methods commonly used for the synthesis of carnosine without essential modification /13/. So, homocarnosine produced by the method of mixed anhydrides of N-carbobenzoxy-4-aminobutanoic acid and methyl ester of L-histidine /14/.

The closest in technical essence to the described is a method of obtaining L-carnosine /15/ based on the interaction of the methyl ester of L-histidine with paranitrophenyl ether N-phthaloyl-b-alanine in chloroform followed by recrystallization of the protected dipeptide, removing the methyl group under alkaline conditions, the removal of phthaloyl what hodom 54%

The disadvantage of all previously described methods of obtaining synthetic L-carnosine and its homologues is the inability to obtain pure peptides without related structure impurities and high yield. This is due both to the presence of side reactions mainly involving imidazole cycle histidine /16/ and the impossibility of separating L-carnosine and its homologues from toxic impurities (their racemic forms, N-imidazole isomers and other) due to similar physico-chemical properties of these impurities and free or protected L-carnosine and its homologues. In the presence of impurities synthetic L-carnosine and its homologues begin to show toxicity, is not peculiar to pure drugs /17/.

The proposed method of producing L-carnosine and its homologues General formula I is the hydrochloride of the methyl ester of L-histidine formula II:

HisOMe2l (II)

condense with N-trityl - b-alalalalalalala or its homolog General formula III:

< / BR>
where n has the values specified in the environment aprotic organic solvent, the obtained protected dipeptide washed away impurities aqueous alkaline solution at a pH of 7.5 to 11, extracted with acidic water restore from known /15/, in the present method uses other starting compound: N-trityl- -alanine or its homolog, activated C-end-imidazole (or similar imidazole) and the hydrochloride of the methyl ester of L-histidine. The result is a new intermediate product Trit-NH(CH2)nCO-HisOMe (n=2-5), which before releasing first washed of impurities aqueous alkaline solution at a pH of 7.5 to 11, and then extracted with an acidic aqueous solution at a pH of 0.5 to 3. Use in the described method, the source and intermediate compounds of different structure than in the known method, as well as other conditions for granting interim protected dipeptides prevent numerous impurities and pollution of their target products.

It is known that in the course of the synthesis histidinemia peptides, as a rule, formed a number of side products, such as diketopiperazine and connection type:

< / BR>
where n 2 5 and X TritNH(CH2)n-

However, in our case, the formation of such impurities is either not happening, or they are separated by extraction, which was confirmed by TLC, NMR1H-spectra and studies of toxicity target peptides.

Used in the synthesis of N-trityl- -Alenia and use in the synthesis of such compounds seemed doubtful, because steric hindrance created trailvoy group may partially or completely inhibit the synthesis of the dipeptide and N-trityl - b-alalalalalalala and its homologues. Even more doubtful seemed the possibility of separating the intermediate dipeptide from close in physico-chemical properties of impurities by using a simple extraction.

According to this invention, L-carnosine and its homologues General formula I get the following scheme:

< / BR>
First conduct the activation of N-trityl- -alanine or homolog timelimitaction or other derivatives of imidazole or benzimidazole in the environment aprotic organic solvent at -5oC +40oC for 10 to 90 minutes In the solvent used dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dimethylformamide, etc., Then to the reaction mixture of the hydrochloride of the methyl ester of L-histidine, triethylamine and stirred for 36 h at room temperature to complete the reaction. The solution containing the protected dipeptide IV, filtered off from the precipitated salts, the precipitate washed. A solution of the protected dipeptide IV washed several times in water with an alkaline solution at pH 7.5 to 11, for example, the bicarbonate solution is an aqueous solution at pH 0.5 to 3, for example, 20% acetic acid. This will release dipeptide IV under standard conditions and the target product is recrystallized.

The invention is illustrated in the following examples.

Example 1. L-garnison (NH2(CH2)2CO-His).

3 g (44 mmol) of Imidazole and 7 ml (50 mmol) of triethylamine dissolved in 10 ml of dichloromethane for 20 min add a mixture of 5 ml of dichloromethane with a 1.46 ml chloride tiomila and stirred at 20oC 50 minutes Then to the resulting reaction mass is added 8 g (24 mmol) N-trityl - b-alanine in 5 ml of DMF, stirred for 1 h, type of 5.24 g (21,7 mmol) of methyl ester hydrochloride, L-histidine and 7 ml of triethylamine and stirred for 36 hours Precipitated salt is filtered off, washed on the filter with 3 x 10 ml dichloromethane, then the combined filtrates are washed with 3 x 10 ml of water and 2 x 10 ml saturated NaHCO3(the pH to 8.6). Extracted dipeptide Trit b AlaHisOMe 20% solution of acetic acid (pH 2.3) and leave at 85oC until complete removal of trailvoy group. Trailovic alcohol is extracted with 3 x 10 ml of ethyl acetate, the reaction mixture is evaporated to dryness, add 40 ml of water, evaporated again, mixed with a solution of 4.2 g LiOHH2O in 100 ml of water and allowed to mix for 2 hours and Then che is ablaut 100 ml of methanol and filtered the precipitation of Li2CO3. To a methanol solution was added 300 ml of isopropanol, evaporated methanol and residual water on the rotor to volume of 100 ml, which results in a precipitate of L-carnosine. Yield 4.5 g (92%).

Example 2. L-carnosine ( NH2(CH2)2CO-His).

3 g (44 mmol) of Imidazole and 7 ml (50 mmol) of triethylamine dissolved in 10 ml of methylene chloride for 20 min with stirring mixture of 5 ml of methylene chloride with a 1.46 ml chloride tiomila and stirred at 18oWith 50 minutes Then to the resulting reaction mass is added 8 g (24 mmol) N-trityl - b-alanine in 5 ml of DMF, stirred for 1 h, type of 5.24 g (21,7 mmol) of methyl ester hydrochloride, L-histidine and ml of triethylamine and stirred for 36 hours Precipitated salt is filtered off, washed on the filter with 4 x 5 ml of methylene chloride, then the combined filtrates washed with 2 x 10 ml of 10% aqueous solution of Na2CO3(pH of 10.9). Extracted dipeptide Trit b AiaHisOMe 5% aqueous HCl solution (pH 0,3) at 0oC and allowed to mix at room temperature overnight until complete removal of trailvoy group. Trailovic alcohol is extracted with 3 x 10 ml of ethyl acetate, the reaction mixture is evaporated to dryness, add 100 ml of water,re-evaporated to dryness, add 200 ml Dowe I-B>2to neutral pH grains resin, L-carnosine wash of 0.2 m solution of NH4HCO3water evaporated and L-carnosine is recrystallized from ethanol. The output of 4.45 g (90.7 percent).

Example 3. L-carnosine (NH2(CH2)2CO-His).

3 g (44 mmol) of Imidazole and 7 ml (50 mmol) of triethylamine dissolved in 10 ml of dichloromethane for 20 min add a mixture of 5 ml of dichloromethane with a 1.46 ml chloride tiomila and stirred at 20oC 50 minutes Then to the resulting reaction mass is added 8 g (24 mmol) N-trityl - b-alanine in 5 ml of DMF, stirred for 1 h, type of 5.24 g (22.7 mmol) of methyl ester hydrochloride, L-histidine and 12 ml of triethylamine and stirred for 36 hours Precipitated salt is filtered off, washed on the filter with 3 x 5 ml dichloromethane, then the combined filtrates are washed with 3 x 10 ml of water and 2 x 10 ml saturated KHCO3(pH of 9.8). Extracted dipeptide Trit b AlaHisoMe 3 x 20 ml of 20% aqueous solution of acetic acid (pH 2.3) and leave at 85oC until complete removal of trailvoy group. Trailovic alcohol is extracted with 3 x 10 ml of ethyl acetate, the reaction mixture is evaporated to dryness, add 40 ml of water, evaporated again, mixed with a solution of 4.2 g LiOHH2O in 100 ml of water and allowed to mix for 2 hours and Then in a solution Pronoia and filtered the precipitation of Li 2CO3. The filtrate is applied to the column 50 x 8 c 50 ml of Dowex 50 (H+form, elute L-carnosine 2M solution of NH4OH, the fractions containing L-carnosine unite, evaporated and recrystallized from isopropanol. Yield 4 g (82%).

Example 4. L-homocarnosine (NH2(CH2)3CO-His).

3 g (44 mmol) of Imidazole and 12 ml (85 mmol) of triethylamine dissolved in 10 ml of methylene chloride for 20 min with stirring mixture of 5 ml of methylene chloride with a 1.46 ml chloride tiomila and stirred at 18oC 50 minutes Then to the resulting reaction mass is added 8 g (24 mmol) N-trityl-4-aminobutanoic acid in 5 ml of DMF, stirred for 1 h, type of 5.24 g (21,7 mmol) of methyl ester hydrochloride, L-histidine and 7 ml of triethylamine and stirred for 6 hours Precipitated salt is filtered off, washed on the filter with 4 x 5 ml of methylene chloride, then the combined filtrates are washed with 3 x 10 ml of water, 2 x 10 ml of 10% aqueous solution of NaHCO3(pH 8,6). Extracted dipeptide Trit-NH(CH2)3CO-HisOME 4 x 20 ml 25% aqueous solution of acetic acid (pH 2,4) at 0oC and allowed to mix at room temperature overnight until complete removal of trailvoy group. Trailovic alcohol is extracted with 3 x 10 ml of ethyl acetate, Rea is UP>OH-form, and stirred at 50oC for 4 h until complete removal of the methyl group. The resin is saturated with CO2to neutral pH grains resin, L-homocarnosine wash of 0.2 m solution of NH4HCO, the water evaporated and L-homocarnosine recrystallized from isopropanol. Output 4,56 g (87,5%).

Example 5. 6-Aminocaproyl-L-histidine (NH2(CH2)5CO-His).

3 g (44 mmol) of imidazole and 11 ml (78 mmol) of triethylamine dissolved in 10 ml of methylene chloride for 20 min with stirring mixture of 5 ml of methylene chloride with a 1.46 ml chloride tiomila and stirred at 18oC 50 minutes Then to the resulting reaction mass is added 8 g (24 mmol) N-trityl-6-aminohexanoic acid in 5 ml of DMF, stirred for 1 h, type of 5.24 g (21,7 mmol) of methyl ester hydrochloride, L-histidine and 7 ml of triethylamine and stirred for 36 hours Precipitated salt is filtered off, washed on the filter with 4 x 5 ml of methylene chloride, then the combined filtrates are washed with 3 x 10 ml of water, 2 x 10 ml of 10% aqueous solution of NaHCO3(pH 8,6). Extracted dipeptide Trit-NH(CH2)5CO-HisOMe 2 x 20 ml 25% aqueous solution of acetic acid (pH 2,4) withoC and allowed to mix at room temperature overnight until complete removal of tritium 10 ml of water, re-evaporated to dryness, add 200 ml of Dowex I-IT is the form and stirred at 50oC for 3 h until complete removal of the methyl group. The resin is saturated with CO2to neutral pH grains of the resin, the peptide NH2(CH2)5COHis wash solution of 0.2 NH4HCO3, the water evaporated and the target product is recrystallized from isopropanol. Output 4,96 g (to 85.2%).

Physico-chemical characteristics of the target and intermediate compounds are given in the table.

TLC was performed on plates Merck Art N 5724, manifestation of substances produced by a solution containing 1% NaI and 1% starch, or benzidine reagent after treatment with chlorine, and iodine for the detection of non-polar impurities. NMR1H - spectra were taken in the D2O.

These NMR1H-spectroscopy and TLC confirmed the absence of impurities in the target products (no in NMR1H-spectra of the signals in areas that are not typical for L-carnosine and its homologues and extra spots on the chromatograms).

Test acute toxicity of L-carnosine and its homologues were performed on white mice (male) line FI(Swahs) weighing 28-30 g (4-10 animals per group). The drugs were injected intraperitoneally at a dose of 75 to 500 mg/mouse in 0.5 ml physio is Petani L-carnosine (drug 1) and homocarnosine (preparation 2), obtained by the described method. Were used for comparison of synthetic L-carnosine, obtained by the method prototype (product 3), L-carnosine, obtained from preparative meat cattle Scola at the Leningrad factory of medical preparations (preparation 4), as well as the preparation of L-carnosine, produced by Serva.

It is shown that the 3 drug is toxic at a dose of 75 mg/mouse: the death of all mice was observed after 5 min after drug administration.

Preparations 1 and 4 and are of low toxicity: LD50is 10000 mg/kg 12000 mg/kg, respectively. The drug company Serva is more toxic: it LD505000 mg/kg

The introduction of the drug 2 dose of 200 mg/mouse does not affect the health of animals during the entire period of observation.

Thus, synthetic preparations of L-carnosine and homocarnosine obtained by the present method, non-toxic as well as natural L-carnosine (preparation 4), along with data TLC and NMR1H-spectroscopy confirms the purity of the peptides obtained according to the invention.

The method of obtaining L-carnosine and its homologues General formula I

< / BR>
where n 2 5,

including condensation derived N-secure is of the dipeptide and the recrystallization of the target product, characterized in that as a function of N-protected amino acid is used as a compound of General formula II

< / BR>
and as a derivative of L-histidine hydrochloride methyl ester of L-histidine formula III

His OMe 2 HCl

obtaining the protected dipeptide of the General formula IY

< / BR>
where n 2 5,

which washed away impurities aqueous alkaline solution at pH 7.5 11 and extracted with an acidic aqueous solution at pH 0.5 to 3, and then will unlock.

 

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