The method of producing tetradecapeptide

 

(57) Abstract:

Describes a new method of obtaining tetradecapeptide General formula (I) H-Thr-Glu-Lys-Lys-Arg-Arg-Glu-Thr-Val-Glu-Arg-Glu-Lys-Glu-OH. Pentapeptide of the formula Z-Thr(But)-Glu(But)-Lys(Boc)-Lys(Boc)-Arg-OH is subjected to condensation with a nonapeptide of the formula Arg-Glu(But)-Thr(But)-Val-Glu(But)-Arg-Glu(But)-Lys(Boc)-Glu(But)-OBut, then the resulting intermediate to remove the protective group and receive the final product. The technical result is to simplify the process and increase the yield of the target product. 1 C.p. f-crystals.

The invention relates to the field of chemistry of peptide compounds, and also to the field of pharmaceutical industry, namely to the new way of getting tetradecapeptide (HEP-I) of the formula (I)

H-Thr-Glu-Lys-Lys-Arg-Arg-Glu-Thr-Val-Glu-Arg-Glu-Lys-Glu-OH

which can find application in medicine.

The peptide can be used, in particular, in the treatment of AIDS and other diseases. Drugs to treat AIDS can't be cured of AIDS after infection. The main problem is that the human immunodeficiency virus rapidly mutates, leading to changes in the proteins that are the target of antiviral drugs.

Thus, creating a new way of obtaining perspectivehere of tetradecapeptide (HEP-I) of the formula (I) (Patent of the Russian Federation, EN 2127599), which is that its synthesis is carried out by solid-phase method by stepwise extension of the peptide chain, starting with the C-terminal glutamic acid associated with a polymeric matrix, using the appropriate N-tert.butyloxycarbonyl in the presence of a condensing agent with subsequent processing of the received protected peptidylarginine debateroom agents.

The disadvantage of this method is the low yield of the target product, the inability of analytical control in the process of multi-stage synthesis, as well as the inability of a significant scale-up synthesis.

The above-described synthesis method is the only and thus the closest to the technical essence and the achieved result of the proposed method.

The objective of the invention is to simplify the process and increase the yield of the target product.

The proposed method solves this problem is condensation Pentapeptide formula (II)

Z-Thr(But)-Glu(But)-Lys(Boc)-Lys(Boc)-Arg-OH

with the nonapeptide of the formula (III)

Arg-Glu(But)-Thr(But)-Val-Glu(But)-Arg-Glu(But)-Lys(Boc)-Glu(But)-OBut

Received protected tetradecapeptide formula (IV)

Z-Thr(But)-Glu(But)-Ly) triperoxonane acid

b) with hydrogen in the presence of palladium catalyst

and the target product was then purified and isolated in pure form or in the form of acetate salt.

The intermediates can be obtained in different ways.

Intermediate protected Pentapeptide of the formula (II) used in the method may be obtained by conventional methods of peptide synthesis, for example stepwise condensation of amino acids with the use of activated esters.

In this case, the Pentapeptide of formula (II) receive, on the basis of arginine in the form of a free base sequential accession to N-carbobenzoxy - N-tert-butyloxycarbonyl-L-lysine, N-carbobenzoxy - N-tert-butyloxycarbonyl-L-lysine, N-carbobenzoxy - tert-butyl-glutamic acid and N-carbobenzoxy-O-tert-butyl-threonine. The condensation is carried out using activated esters. Carbobenzoxy group from the protected intermediate peptide is removed by catalytic hydrogenolysis. Intermediate the protected nonapeptide of the formula (III) used in the method may be obtained by conventional methods of peptide synthesis, for example stepwise condensation of amino acids with the use of activated esters.

the uly (V)

Z-Glu(But)-Thr(But)-Val-Glu(But)-Arg-OH

with the Tripeptide of formula (VI)

Glu(But)-Lys(Boc)-Glu(But)-OBut

using dicyclohexylcarbodiimide get protected oktapeptid formula (VII)

Z-Glu(But)-Thr(But)-Val-Glu(But)-Arg-Glu(But)-Lys(Boc)-Glu(But)-OBut

2. Oktapeptid formula (VII) is subjected to catalytic hydrogenolysis to obtain oktapeptid formula (VIII)

Glu(But)-Thr(But)-Val-Glu(But)-Arg-Glu(But)-Lys(Boc)-Glu(But)-OBut

3. Oktapeptid formula (VIII) is condensed with carbobenzoxy using dicyclohexylcarbodiimide, receiving the protected nonapeptide of the formula (IX)

Z-Arg-Glu(But)-Thr(But)-Val-Glu(But)-Arg-Glu(But)-Lys(Boc)-Glu(But)-OBut

4. Using catalytic hydrogenolysis protected nonapeptide of the formula (IX) is converted into a nonapeptide of the formula (III).

In turn, the Pentapeptide of formula (V) and the Tripeptide of formula (VI) are obtained by the sequential condensation of amino acids, one amino acid starting from the C-Terminus, using activated esters of protected amino acids, removing the N-protective group by catalytic hydrogenolysis.

The final product was obtained as follows.

Received protected Pentapeptide of the formula (II) condense with the nonapeptide of the formula (III) with dicyclohexylcarbodiimide, receiving high yield (over 90%) zashishayut triperoxonane acid, then using catalytic hydrogenolysis to remove carbobenzoxy-protective group.

Through the use of readily available, obtained with a high yield of Pentapeptide formula (II), as well as the use of the nonapeptide of the formula (III), the proposed method can obtain the target product with a higher yield compared to the synthesis of any other intermediates.

Example.

Abbreviations:

DMF - dimethylformamide

CBI - dicyclohexylcarbodiimide

HOBT IS N-hydroxybenzotriazole

A General method of removing carbobenzoxy group by catalytic hydrogenation:

The protected peptide is dissolved in methanol based 15-50 ml solvent per 1 g of the peptide, add 0.1 g of 10% palladium catalyst on coal and miss when mixing a weak stream of hydrogen until the disappearance of the original product. The control is carried out by thin layer chromatography. The solution is filtered to remove the catalyst and evaporated.

Thin-layer chromatography.

Is carried out on glass plates Merck-Kieselgel systems:

the ethyl acetate-hexane 1:1 (system 1)

Chloroform-methanol-acetic acid-water 60:45:7:13 (system 2)

n-Butanol-acetic € 28.5 g (110 mmol) of H-Glu(But)-OBut. After 4 hours, checked with TLC (system 1) the absence of an activated ester, dilute the reaction mixture of 400 ml of ethyl acetate, washed with 200 ml of 10% acetic acid, 100 ml of water, 200 ml of 3% sodium carbonate, evaporated. The oil obtained (71.2 g) used without further purification. The quantitative output. Rf0.43 (1).

Z-Glu(But)-Lys(Boc)-Glu(But)-OBut (b)

Hydronaut 71.2 g of untreated (a) in 700 ml of methanol, filtered, evaporated, the residue of H-Lys(Boc)-Glu(But)-OBut dissolved in 200 ml of DMF and added 45.6 g (105 mmol) of Z-Glu(But)-OSu. After two hours, add 3 ml of Me2N(CH2)3NH2to remove excess activated ester. After 30 minutes, dilute the reaction mixture with 500 ml of ethyl acetate, washed with a mixture of 300 ml of water and 150 ml of saturated NaCl solution, 200 ml of 2% sulfuric acid, 100 ml of water, 200 ml of 3% sodium carbonate, evaporated. Rf0.90 (1).

HClH-Glu(But)-Lys(Boc)-Glu(But)-OBut ()

Dissolve all the protected Tripeptide (b) in 500 ml of methanol, hydronaut over palladium catalyst, the solution is filtered and added dropwise with stirring a 10% solution of hydrogen chloride in dioxane to pH 4 (control with indicator paper). The solution is evaporated in vacuum, the residue is dried in a vacuum oil pump with cold trap. Dry amorphous OS is varaut 56.4 g (130 mmol) of Z-Glu(But)-OSu in 150 ml of DMF, add 21.8 g (140 mmol) of arginine and stirred at 30-35oin the course of the day. Transparent viscous solution was diluted with 500 ml of n-butanol, add 300 ml of water and 100 ml saturated NaCl solution. The organic phase is washed with 200 ml of water, evaporated, the residue triturated with 400 ml of ether, filtered and Privat ether. Output 62,1, 97%. (126 mmol). Rf0.58 (2).

Z-Val-Glu(But)-Arg-OH (d)

Dissolve to 62.1 g (g) 600 methanol, hydronaut, evaporated, the residue is dissolved in 200 ml of DMF and add 150 mmol (52,2 g) Z-Val-OSu. After 6 hours added to the reaction mixture, 400 ml of ether and 400 ml of water and incubated for a day at 0o. The precipitation was washed with water, ether and dried in air. Output 61,5 was 87%. (104 mmol). Rf0.61 (2).

Z-Thr(But)-Val-Glu(But)-Arg-OH(e)

Dissolve of 56.4 g (is 95.2 mmol) of the protected Tripeptide (g) in 500 ml of methanol, hydronaut, evaporated, the residue is dissolved in 150 ml of DMF and added to 44.6 g (95 mmol) of Z-Thr(But)-ONB.

After 6 hours the solution was diluted with 500 ml of n-butanol, add 300 ml of water and 100 ml saturated NaCl solution. The organic phase is washed with 200 ml of water, evaporated, the residue triturated with 400 ml of ether, filtered and washed with ether. Output 62,6 was 87%. (83.5 mmol). Rf0.69 (2).

Z-Glu(But)-Thr(But)-Val-Glu(But)-Arg-OH (W)

Rattatak dissolved in 150 ml of DMF and add 36,9 g (85 mmol) of Z-Glu(But)-OSu. After 6 hours the solution was diluted with 500 ml of n-butanol, add 300 ml of water and 100 ml saturated NaCl solution. The organic phase is washed with 200 ml of water, evaporated, the residue triturated with 400 ml of ether, filtered and washed with ether. Output 70,6 was 90%. (75,6 mmol). Rf0.45 (2).

Z-Glu(But)-Thr(But)-Val-Glu(But)-Arg-Glu(But)-Lys(Boc)- Glu(But)-OButHCl (C)

In a mixture of 300 ml of DMF and 300 ml of DMSO dissolved 70,6 g (W) (75,6 mmol), 57 g (III) (80,4 mmol), 20.2 g of HOBT (150 mmol) of distilled off in vacuum a few milliliters of solvent to remove water, cooled with ice and add under stirring 21 g (100 mmol) of CBI.

After 3 hours, add 3 ml of N-methylmorpholine and leave overnight at room temperature. The viscous reaction mass is mixed with 600 ml of chloroform and 400 ml of n-butanol, heated to 50oadd 400 ml of water and filtered warm. The organic layer was washed with 800 ml of water, heated to 50o, evaporated to a state of a fluid gel and add 1.5 l of hexane. The precipitate is filtered off, washed with a mixture of ethyl acetate-hexane 1:3, dried in the air. Output to 114.7 was 93%. (70.5 mmol). Rf0.71 (3).

Z-Arg-Glu(But)-Thr(But)-Val-Glu(But)-Arg-Glu(But)-Lys(Boc)- Glu(But)-OBut2HClO4(and)

Dissolve by heating and 31.7 g (of 19.5 mmol) of (C) in 700 ml of methanol, hydronaut, perivenous acid and 6.5 g (48 mmol) of HOBT in 50 ml of DMF and evaporated in vacuum a few milliliters of solvent to remove the water. Add a solution of oktapeptid, cooled with ice and add under stirring 6.3 g (30 mmol) of the OED. After 2 h, add 2.2 ml of N-methylmorpholine and 2.6 g of the OED. The next day the reaction mixture was diluted with 700 ml of n-butanol, add 300 ml of water and 100 ml saturated NaCl solution. The organic phase is washed twice with a mixture of 250 ml of water and 2 ml of 8 M perchloric acid, and then with a mixture of 200 ml of water and 100 ml saturated sodium bicarbonate solution, evaporated, the residue triturated with a mixture of 400 ml of ethyl acetate and 400 ml of hexane, filtered and washed with the same solvent. Output 28,4 was 81%. (15.8 mmol). Rf0.56 (3).

Z-Lys(Boc)-Arg-OH (to)

Dissolve 23.3 g (48.8 mmol) of Z-Lys(Boc)-OSu in 70 ml of DMF, added 8.1 g (52 mmol) of arginine and stirred at 30-35oin the course of the day. Transparent viscous solution was diluted with 400 ml of n-butanol, add 300 ml of water and 100 ml saturated NaCl solution. The organic phase is washed with 200 ml of water, evaporated, the residue triturated with 400 ml of ether, filtered and washed with ether. The output of 25.2 G. of 96%. (47 mmol). Rf0.50 (2).

Z-Lys(Boc)-Lys(Boc)-Arg-OH (l)

Dissolve 25.2 r (47 mmol) (K) in 300 ml of methanol, hydronaut, evaporated, the residue is dissolved in 150 ml of DMF and added 24.8 g (52 mmol) of Z-Lys(Boc)-OSu. After 6 hours the solution was diluted with 500 ml of n-butanol, is triturated with 400 ml of ether, filtered and washed with ether. The output of 32.3 g (42.2 mmol). Rf0.72 (2).

Z-Glu(But)-Lys(Boc)-Lys(Boc)-Arg-OH (m)

Dissolve 32.3 g (42.2 mmol) of Tripeptide (l) 600 methanol, hydronaut, evaporated, the residue is dissolved in 100 ml of DMF and added 46 mmol (20) Z-Glu(But)-OSu. After 6 hours added to the reaction mixture, 400 ml of ether and 400 ml of water and incubated for a day at 0o. The precipitation was washed with water, ether and dried in air. The output 27 of 49%. (28.4 mmol). Rf0.77 (2).

Z-Thr(But)-Glu(But)-Lys(Boc)-Lys(Boc)-Arg-OH (n)

Dissolve 27 g (28.4 mmol) of the protected tetrapeptide (m) in 500 ml of methanol, hydronaut, evaporated, the residue is dissolved in 150 ml of DMF and added 15 (32 mmol) of Z-Thr(But)-ONB. After 6 hours the solution was diluted with 500 ml of n-butanol, add 300 ml of water and 100 ml saturated NaCl solution. The organic phase is washed with 200 ml of water, evaporated, the residue triturated with 400 ml of ether, filtered and washed with ether. The output of 30.3 g (27,3 mmol). Rf0.80 (2).

Z-Thr(But)-Glu(But)-Lys(Boc)-Lys(Boc)-Arg-Arg-Glu(But)-Thr(But)-Val - Glu(But)-Arg-Glu(But)-Lys(Boc)-Glu(But)-OBut3HClO4(about)

Dissolve by heating 28.4 g (15.8 mmol) of the protected nonapeptide (and) in 800 ml of methanol, hydronaut, the residue is dissolved in 400 ml of DMF, add to 17.7 g (16 mmol) of Pentapeptide (h), 16 mmol of 72% perchloric acid (1.8 ml), 4.7 is Ivanyi add a 5.25 g (25 mmol) CBI, then after 2 hours, 1 ml of N-methylmorpholine. Mixed day at room temperature, evaporated to 1/3 volume under vacuum oil pump, mix the residue with 300 ml of hexane, 300 ml of ethyl acetate and 500 ml of water. The precipitate is filtered off, washed with water and a mixture of ethyl acetate-hexane, dried in the air. The output of 42.3 G. of 93%. Rf0.51 (3).

H-Thr-Glu-Lys-Lys-Arg-Arg-Glu-Thr-Val-Glu-Arg-Glu-Lys-Glu-OH nAcOH (p)

All secure tetradecapeptide (o) are dissolved in 300 ml triperoxonane acid, allowed to stand for 1 hour at 25o, evaporated, the residue triturated with 500 ml of ether, filtered off, washed with ether and dissolved in 500 ml of water. The aqueous solution was filtered, extracted with non-polar impurities with 200 ml of n-butanol. The organic phase is discarded, and the water is mixed with 200 ml of methanol, add 2 g of 10% palladium catalyst on charcoal, heated to 40oand add portions of 30 ml of saturated solution of ammonium formate in 3 hours. The solution was stirred at room temperature for 20 hours, filtered and applied to a column containing 1 l of SP-Sephadex in 0.2 M pyridylacetate buffer solution. The division performed in the gradient of 0.2 M - 1.3 M pyridylacetate buffer; the fractions containing the product, evaporated, evaporated twice with water and lyophilisate on the media with reversed phase. Yield purity of 95-97% and 13.2 g (44%).

Amino acid analysis: threonine 1.9 (2), valine 1.0 (1), lysine 3.1 (3), arginine 2.9 (3), glutamic acid 5.2 (5).

[]D-27(c = 0.5 in 95% acetic acid). The product is also characterized by a mass spectrum and the spectrum of nuclear magnetic resonance.

Retention time on HPLC 8.5 minutes

High-performance liquid chromatography (HPLC) is performed on a Gilson chromatograph (France) under the following conditions:

- ODS column size 250 x 4.6 mm, filled with sorbent with reversed phase with a particle size of 5 microns;

- mobile phase A: 0.2% acid solution triperoxonane in 0.1 M solution of sodium chloride;

- mobile phase B: acetonitrile;

gradient mode: from 35 to 45% phase B for 10 min;

a flow rate of 1.0 ml/min;

- detection at a wavelength of 220 nm;

- sensitivity of 0.1 OE.

Thin layer chromatography is carried out on the plates Merck-Kieselgel-60 systems:

(1) Chloroform-ethyl acetate-acetic acid 8:26:0.2

(2) Chloroform-methanol-acetic acid-water 75:15:5:2

(3) Chloroform-methanol 9:1.

1. The method of producing tetradecapeptide threonyl-glutamyl-lysyl-lysyl-arginyl-arginyl-glutamyl-trione the decomposing those what Pentapeptide of the formula

Z-Thr(X)-Glu(X)-Lys(Y)-Lys(Y)-Arg-OH

is subjected to condensation with a nonapeptide of the formula

Arg-Glu(X)-Thr(X)-Val-Glu(X)-Arg-Glu(X)-Lys(Y)-Glu(X)-OX,

received protected tetradecapeptide formula

Z-Thr(X)-Glu(X)-Lys(Y)-Lys(Y)-Arg-Arg-Glu(X)-Thr(X)-Val-Glu(X)-Arg-Glu(X)-Lys(Y)-Glu(X)-OX,

where X, Y, Z is hydrogen or a protective group,

subjected to interaction with triperoxonane acid, hydronaut in the presence of a catalyst and produce the final product.

2. The method according to p. 1, characterized in that X represents tertbutylphenol group (But), Y - tertbutyloxycarbonyl group (Boc), and the Z - benzyloxycarbonyl.

 

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