The method of obtaining carboxyamide glycopeptides glycyrrhizic acid

 

(57) Abstract:

Usage: in medicine as immunomodulators. The inventive product is carboxyamide glycopeptides derived from glycyrrhizic acid (GA) without prior protection of the hydroxyl groups of the carbohydrate part of the molecule. In the proposed method the group treated with N-hydroxybenzotriazole and N,N-dicyclohexylcarbodiimide at 0 - 5oFrom among tetrahydrofuran or dioxane for 1 h, at room temperature 6 to 7 hours, getting activated Tris-oxibendazole ether Ledger, in which the solution is injected into reaction with aminocompounds - esters of L-amino acids (methyl, benzyl, n-nitrobenzylamine or tributyl) in the form of their hydrochloride, tozilaty or mesosulfuron in the presence of a tertiary base (N-methylmorphine, triethylamine, tributylamine) at 0 - 5oC, followed by keeping the mixture at room temperature for 24 h, the Yield of the target compounds 82 - 94%.

The invention relates to a new process for the production of glycopeptides triterpene glycoside glycyrrhizic acid (GA) (I) of General formula (II) interest for medicine as immunomodulators [1 3]

< / BR>L-Phe(OMe);

G R CH= L-Ala (OMe);

D R MeCOOCH2CH= L-Glu (OMe)2;

G R CHAla (OBZl);

S R C6H5CHPhe (OBZl);

I R (CH3)2CHCH(ONB);

C HOC R6H4CHONB);

L R (CH3)2CHCH - Leu (OtBu);

M R C6H5CH2COOCH2CH

< / BR>
< / BR>
consisting in condensing Ledger (carboxy-component) with esters of L-amino acids (methyl, ethyl and benzyl), taken in the form of their hydrochloride (amino component (AC) in the General formula

RNH2HCl (III), where

R=CH3-), CH3-b)

CH-CH2-) CH2using N,N'-dicyclohexylcarbodiimide (DCGK) in the presence of triethylamine (tea) in methylene chloride (CH2Cl2) at room temperature for 48 h at a molar ratio of reagents GK:AK:DCGK:tea 1,0:4,5:3,0:4.5 mmol (scheme 1) [4]

Outputs are the products of the reaction are 74-79% (mixture glycopeptides V and N-allodapini VI).

The disadvantage of this method of obtaining glycopeptides Ledger is the formation during the reaction side N-allodapini (VI) (scheme 1), the resulting rearrangement of the activated intermediate is-0-utilization (IV) formed from HK (I) and DCGK during the reaction, N-allocating (VI) generally, sustainable and Nochnoi chromatography. A limitation of this method is that the original compound glycyrrhizin acid is not soluble in methylene chloride, which complicates the process because of the heterogeneity of the reaction mixture. Method unsuitable for holding narabotany syntheses (ethnological).

A method of obtaining glycopeptides Ledger formula (VIII) [7] according to the following scheme (2) (prototype):

Scheme 2

< / BR>
H

< / BR>
VIIIa R L-Val(OMe);

VIII R L-Val(OtBu);

Viiic R Gly-L-Leu(OMe);

VIII R L-Glu(OMe)2consisting in processing GK (I) N-hydroxysuccinimide (HOSu) in the presence of N,N'-dicyclohexylcarbodiimide (DCGK) in the solvent (THF or dioxane) at a ratio of chemicals VOC:HOSu:DCGK 2: (10-10,4): (6-6,4) mmol at 0-5aboutC for 3 h, at 20-22aboutC for 6 h, 4-8aboutWith 12 h and subsequent interaction of the formed Tris-oxysuccinimide ester (VII) with hydrochloride methyl (tert-butyl) esters of amino acids or dipeptides (aminocompounds) of the formula R-NH2HCl, where

R (CH3)2CH) (CH3)2CH-,

(CH3)2CH-CO-CH2- (),- H2)2-COOMe (g) in the presence of base of triethylamine (tea) at a ratio of aminocompounds to the base (6-7):(9,8-10,8) mmol at 0-15aboutWith posledstvijam 75-86%

The disadvantage of this method is that when using N-hydroxysuccinimide in the presence DCGK possible occurrence of side reactions leading to the formation of succinimidylester--alanine (IX) [5, 6] which can react with aminocompounds (esters of amino acids), forming succinimidylester- -alaninemia, as well as derivatives of urea-alanine, which reduces the yield of the target products (glycopeptides of the civil code).

N-OH + N-Io_

< / BR>
_____ N-O-CHON

This tendency to the formation of by-products has led to the search for a new method of obtaining glycopeptides Ledger, which allows to obtain pure products with a higher yield.

The purpose of the invention is to develop a new selective method for obtaining glycopeptides Ledger using as a starting substance of glycoside without prior protection of the hydroxyl groups of the carbohydrate part of the molecule, allowing to obtain the target products with a higher yield in the individual condition.

The goal achieved by a method of obtaining carboxyamide glycopeptides glycyrrhizic acid of General formula (II-m) without prior protection of the hydroxyl groups of the glycoside, namely, that the glycoside food dry tetrahydrofuran (THF) or dioxane at 0-5aboutC for 1.0 h at room temperature for 6-8 h at a molar ratio of reagents Ledger:HOBt:DCGK equal 1:(3,5-4,0):(3,4-4,0) mmol, and subjected to interaction with compounds of the General formula R1NH2H-X (XI), where

R1= CH3SCH2CHa), (CH3)2The NSS), C6H5Start)

CH(g), MeOOCCH2DNS), CH

C6H5CH), (CH3)2CHCH

HOC6H4CH (CH3)2CHCH,

C6H5CH2COOCH2CHX Cl ((XI) a-d, h-l); SO3C6H5((XI), K); SO3C6H4CH3((XI) W, m) (esters of L-amino acids:methyl, benzyl, n-nitrobenzylamine or tert-butyl, taken in the form of their hydrochloride, tozilaty or benzosulfimide) (aminocompounds) in the presence of a tertiary base (core) (N-methylmorpholine, tributylamine, triethylamine) at a molar ratio of reagents R1NH2HX OCH equal(3,5-4,0):(4,2-7,2) mmol, at 0-5aboutC, followed by keeping the mixture at room temperature for 24 h (scheme 3).

Scheme 3

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< / BR>
N

How is that glycyrrhizinic acid (I) (carboxy-component) (1 mmol) is treated with stirring snache dioxane at 0-5aboutC for 1.0 h at room temperature for 6-8 h, receiving the activated intermediate (X), after which the precipitate of N,N'-dicyclohexylmethane subjected to interaction with the amino component (AC) in the General formula R1-NH2HX (XI) (methyl, benzyl, n-nitrobenzylamine or tert-butyl esters of L-amino acids in the form of their hydrochloride, tozilaty or benzosulfimide) in the presence of a tertiary base (core) (N-methylmorpholine, tributylamine, triethylamine) in a molar ratio AK:core, equal(3,5-4,0):(4,2-7,2) mmol at 0-5aboutC, followed by keeping the reaction mixture at room temperature for 24 hours Target glycopeptides (II) a-m) was isolated by diluting the reaction mixture with cold water and acidification with citric acid to pH 3. The precipitate is filtered off, washed with water and dried. To obtain analytically pure samples of products periostat or recrystallized from chloroform alcohol-ether, acetone-hexane or methanol-ether. The output of glycopeptides (II-m), homogeneous by TLC, is 82,3-94,4%

Significant differences of the proposed method are as follows.

To activate carboxyl groups glycyrrhizic acid ipolish in the method-prototype (scheme 2).

As the activated intermediate is formed during this Tris-oxibendazole ether GK (X).

The advantages of the proposed method:

high selectivity, does not form by-products as in method-prototype;

the yield of the target glycopeptides (II) above (82-94%) than in the method-prototype (75-86%);

the time of formation of the activated intermediate (X) (scheme 3) is 7-8 h in the proposed method, while the method prototype is spent 20-22 hours to obtain an activated oxysuccinimide ether GC (VII) (scheme 2).

P R I m e R 1. 1-0-[(3,20)-11,30-dioxo-30-deoxy-(N-L-methionine methyl ester)-Olean-2-EN-3-yl] -2-0-[ -D-6-oxo-6-deoxy-6-6(N-L-methionine methyl ester)-glyukopiranozil]- -D-6-oxo-6-deoxy-6- (N-L-methionine methyl ester)-glucopyranosid (IIA).

a) To a solution of 0.82 g (1 mmol) of ha in 25 ml of dry dioxane at 0-5aboutWith added with stirring to 0.47 g (3.5 mmol) of HOBt, 0,72 g (3.5 mmol) DCGK and stirred at this temperature for 1 h, at room temperature for 6 h, filtered, the precipitate of dicyclohexylamine, and to the filtrate, cooled in a bath with ice, added to 0.80 g (4 mmol) of methyl ester hydrochloride L-methionine L-Met(OMe) HCl (XIa) and 0.5 ml (5 mmol) N-methylmorpholine, stood Renai water (+10aboutC), acidified with citric acid to pH 3. The precipitate was filtered of glycopeptide (IIa), washed several times with water, dried, received 1,11 g (88.1 percent) of product, homogeneous by TLC. To obtain analytically pure sample of the product perioadele from acetone-hexane. Rfof 0.68 (chloroform-methanol-water 45:10:1), []D20+28,5about(from 0.03; alcohol). IR , cm-1: 3600-3200 (HE, NH); 1740 (COOR); 1660 (C=O); 1540 (CONH).

UVmaxEtOH(lg ): 249,5 nm (4,12).

Found, 57,22; N. Of 7.35; N 3,53.

C60H95N3O19S3. M. C. 1258,8.

Calculated, 57,24; N A 7.62; N 3,34.

b) In terms of experience (example 1A) from 0,83 g (1 mmol) Ledger of 0.54 g (4 mmol) of HOBt, of 0.82 g (4 mmol) DCGK, 0.8 g (4 mmol) of L-Met(OMe) HCl (XIa) and 0.5 ml (5 mmol)N-methylmorpholine obtained 1.19 g (94,4%) glycopeptide (IIA) with Rfof 0.68 (chloroform-methanol-water 45:10:1). After recrystallization from chloroform-ethanol-ether to yield 0.96 g (76.6 percent). []D20+27,5about(From 0.07; alcohol). Powder with a yellowish tinge. So pl. 169-171aboutC (with decomp.).

in terms of experience (example 1A) from 0,82 g (1 mmol) Ledger of 0.47 g (3.5 mmol) of HOBt, 0,72 g (3.5 mmol) DCGK, 0,80 g (4 mmol) of L-Met(OMe) HCl (XIa) and 1.0 ml (4.2 mmol) of tributylamine got 1,05 g (82,3%) glycopeptide (IIa), homogeneous by TLC. To obtain ainol-water 45:10:1), []D20+33about(from 0.02; alcohol).

P R I m e R 2. 1-0-[(3 ,20 )-11,30-dioxo-30-(N-L-valine methyl ester)-Olean-12-EN-3-yl] -2-0-[ -D-6-oxo-6-deoxy-6-(N - L-valine methyl ester)- glucopyranosid (IIB).

To a solution of 1.64 g (2 mmol) of ha in 50 ml of dry tetrahydrofuran at 0-5aboutWith added 0,94 g (7 mmol) of HOBt, 1.44 g (7 mmol) DCGK and stirred at this temperature for 1 h, 7 h at room temperature. The precipitate was filtered of dicyclohexylamine, to the filtrate, cooled in a bath with ice, added to 1.36 g (8 mmol) of L-Val(OMe) HCl (HB) and 1 ml (10 mmol) of N-Me-the research that has withstood the reaction mixture at room temperature for 24 h, poured into 400 ml of cold water, acidified with citric acid to pH 3. The precipitate was filtered, washed with water, dried. The output of glycopeptide (IIB) 2.16 g (93.1%) are. To obtain analytically pure sample of the product was recrystallize from a mixture of acetone-hexane, got 1.70 g (73,3%) glycopeptide (IIB) in the form of a white powder, []D20= +31about(from 0.02, ethanol), Rfof 0.62 (chloroform-ethanol 5: 1); of 0.54 (chloroform-alcohol 7:1); of 0.68 (chloroform-ethanol 4:1). IR , cm-1: 3600-3200 (HE, NH); 1740 (COOMe); 1670 (C11=O); 1550 (ONH), UV,maxEtOH(lg ): 250 nm (4,23).

Found, 61,63; N 8,24; N Was 4.02.

C60H95N3O19< the methyl ether)-Olean-12-EN-3-yl]-2-0-[(-D-6-oxo-6-DESA - XI-6-(N-L-phenyl - alanine methyl ester)-glyukopiranozil] -D-6-oxo-6-deoxy-6-(N-L-phenylalanine methyl ester)-glucopyranosid (IIB).

To a solution of 1.64 g (2 mmol) of glycyrrhizic acid in 50 ml of dry dioxane at 0-5aboutWith added 1.0 g (7.4 mmol) of HOBt, 1.40 g (6.8 mmol) DCGK and stirred at this temperature for 1 h, at room temperature for 7 h, the precipitate was filtered of dicyclohexylamine, to the filtrate was added 1.50 g (7 mmol) of L-Phe(OMe) HCl (XIVc) and 1.0 ml (10 mmol) of N-Me-the research, were able to mix with periodic stirring at room temperature for 24 h, poured into 400 ml of cold water, acidified with citric acid to pH 3, the precipitate was filtered, washed with water, dried. Received of 2.45 g (93.9 per cent) glycopeptide (IIB). To obtain analytically pure sample of the product was recrystallized from acetone-hexane. White powder. []D20+30about(from 0.02; ethanol). Rf0,69 (chloroform-methanol-water 45:10:1); 0,67 (chloroform-ethanol 5: 1). IR , cm-1: 3600-3200 (OH, NH); 1740 (COOMe), 1650 (C11=O); 1520 (CONH). UVmaxEtOH(lg ): 251 nm (4,11).

Found, 65,68; N 7,66; N 3,65.

C72H15N3O19. M. C. 1306,75.

Calculated With 66,17; N 7,34; N 3,22.

P R I m e R 4. 1-0-[(3 -20)-11,30-dioxo-30-(N-L-alanine methyl ester)-Olean-12-EN-3-yl]-2-0-[ -D-6-oxo-6-deoxy-6-(N-L - alanine methyl ester)-glyukopiranozil] -D-6-oxo-6-deoxy-6-(N-L-alanine methyl ester)-g,5 mmol) HOBt, 0.7 g (3.4 mmol) DCGK and stirred at this temperature for 1 h, 7 h at room temperature, the precipitate was filtered of dicyclohexylamine, to the filtrate, cooled in a bath of ice, was added 0.7 g (4 mmol) of the hydrochloride of the methyl ester of L-alanine L-Ala(OMe) HCl (Hg), dropwise 0.5 ml (5 mmol) N-methylmorpholine and withstood the mixture with periodic stirring 24 hours Poured the mixture into 200 ml of cold water, acidified with citric acid to pH 3, the precipitate was separated, washed with water and dried. Obtained 0.9 g (82.5 per cent) glycopeptide (G).

To obtain analytically pure sample of the product perioadele from chloroform-ethanol-ether. The amorphous substance of a yellowish color. Rf0,75 (chloro - form alcohol 7:1). []D20+33about(0,06; MeOH). IR , cm-1: 3600-3200 (HE, NH); 1745 (COOMe); 1665 (C=O); 1550 (CONH, amide II), 1230 (CONH, amide III). UVmaxEtOH(lg ): 249 nm (3,93).

Found, 59,77; N To 7.67; N 3,52.

C54H83N3O19. M. C. 1078,22.

Calculated With 60,15; N. Of 7.75; N 3,90.

P R I m e R 5. 1-0-[(3 ,20 )-11,30-dioxo-30-(N-L-glutamic acid dimethyl ester)-Olean-12-EN-3-yl] -2-0-[-D-6 - oxo - 6-deoxy-6-(N-L-glutamic acid dimethyl ester)-glyukopiranozil] -D-6-oxo-6-deoxy-6-(N-L-glutamic acid dimethyl ester)-Gluckman) HOBt, 0.7 g (3.4 mmol) DCGK and stirred at this temperature for 1 h, at room temperature 6 hours the precipitate was Filtered of dicyclohexylamine, to the filtrate, cooled in a bath with ice, added 0.72 g (4 mmol) of the dimethyl ester hydrochloride L-glutamic acid L-Glu(OMe)2HCl (HD), dropwise 0.7 g (7.2 mmol) of dry tea. Withstood the mixture with periodic stirring at room temperature for 24 hours Poured the mixture into cold water, acidified with citric acid to pH 3, the precipitate was separated, washed with water, dried, and weighed. Received 1.10 g (84,5%) glycopeptide (D) in the form of an amorphous substance of a yellowish color. To obtain analytically pure sample of the product perioadele from a mixture of chloroform-methanol-ether. Rf0,65 (chloroform-ethanol 10:1), []D20+42about(from 0.02, MeOH). IR , cm-1: 3600-3200 (HE, NH); 1740 (COOMe); 1660 (C11=0); 1540 (CONH, amide II); 1230 (CONH, amide III). UVmaxEtOH(lg ): 249 nm (4,05).

Found, 58,11; N 7,40; N 3,14.

C63H99N3O25. M. C. 1298,4.

Calculated, 58,48; N. Of 7.35; N 3,25.

P R I m e R 6. 1-0-[(3 ,20 )-11,30-dioxo-30-(N-L-alanine benzyl ester)-Olean-12-EN-3-yl] -2-0-[ -D-6-oxo-6-deoxy - 6-(N-L-alanine benzyl ester)-glyukopiranozil] -D-6-oxo-6-deoxy-6-(N-L-alanine ansilove is or 1.0 g (7.4 mmol) of HOBt, 1.4 g (6.8 mmol) DCGK, stirred at this temperature 1,0 h, at room temperature for 7 h, the precipitate was filtered of dicyclohexylamine, the filtrate is cooled in a bath of ice and added 2,53 g (8 mmol) of tosylate benzyl ester of L-alanine L-Ala(OBzI) CH3C6H4SO3H (Hi), dropwise 1.2 ml (12.4 mmol) of triethylamine (tea) and passed with periodic stirring at room temperature for 24 hours Poured the mixture into 400 ml of cold water was added citric acid to pH 3, the precipitate was filtered, washed with water, dried. Got to 2.55 g (97,3%) glycopeptide (I) containing an admixture of n-toluenesulfonic acid. After recrystallization from methanol-ether got a 2.45 g (93.5 per cent) of the net glycopeptide (J) (yellow powder). Rf0,67 (chloroform-methanol-water 37:10:1); of 0.56 (chloroform-ethanol 4:1). []D20+40,5about(from 0.01; ethanol). IR , cm-1: 3600-3200 (OH, NH); 1740 (COOR), 1660 (C=O); 1550 (CONH); 1500 (Ph). UVmaxMeOH(lg ): 250 nm (4,14).

Found, With 65,50; N 7,86; N 2,78.

WITH72H95N3O19.

Calculated With 66,19; N 7,33; N 3,22. M. C. 1306,49.

P R I m e R 7. 1-0-[(3 ,20 )-11,30-dioxo-30-(N-L-phenylalanine benzyl ester)-Olean-12-EN-3-yl]-2-0-[ -D-6-oxo-6-deoxy-6-(N-L-phenylalanine benzyl ester)-glyukopiranozil] -D-6-OCP dioxane at 0-5aboutWith added 1.0 g (7.4 mmol) of HOBt, 1.40 g (6.8 mmol) DCGK, stirred at this temperature for 1 h, at room temperature for 7 h, the precipitate was filtered of dicyclohexylamine, the filtrate is cooled in a bath of ice and added 2,33 g (8 mmol) of the hydrochloride benzyl ester of L-phenylalanine L-Phe(OBzI) HCl (HS) and dropwise 1.2 ml (12.4 mmol) of dry triethylamine and stood at room temperature with periodic mixing 24 hours Poured the mixture into 400 ml of cold water, added citric acid to pH 3, the precipitate was filtered, washed with water, dried, received 2,77 g (90,8%) glycopeptide (S), which perioadele from a mixture of chloroform-alcohol-ether. Received of 2.68 g (87,9%) of pure product (S) in the form of a yellow powder, so pl. 123-125aboutC. []D20+35about(from 0.01; methanol). Rf0,70 (chloroform-methanol-water 45:10:1); IR , cm-1: 3500-3200 (HE, NH); 1740 (SOON2WITH6H5); 1660 (C=O), 1530 (ONH); 1505 (Ph). UVmaxEtOH(lg ): 251 nm (4,29).

Found, 62,96; N. Of 7.23; N 2,72.

C89H107N3O19. M. C. 1522,76.

Calculated With 70,19; N 7,08; N Was 2.76.

P R I m e R 8. 1-0-[(3 ,20 )-11,30-dioxo-30-(N-L-leucine nitrobenzyloxy ether)-Olean-12-EN-3-yl]-2-0-[ -D-6-oxo-6-DESA - XI-6-(N-L-leucine nitrobenzyloxy ether)-glucopyranose the) CC in 30 ml of dry dioxane at 0-5aboutWith added 0,47 g (3.5 mmol) of HOBt, 0,72 g (3.5 mmol) DCGK and stirred at this temperature for 1 h, at room temperature for 6 h, filtered, the precipitate of dicyclohexylamine, to the filtrate, cooled in a bath of ice, was added 1.65 g (4 mmol) of benzosulfimide nitrobenzyl ester of L-leucine L-Leu(ONB) C6H5SO3H (Hee) and added dropwise to 0.5 g (5 mmol) N-methylmorpholine and withstood the mixture with periodic stirring at room temperature for 24 hours Poured the mixture into 200 ml of cold water, acidified with citric acid to pH 3, the precipitate was filtered, washed with water, dried, received 1.45 g (92.4 per cent) glycopeptide (I). To obtain analytically pure sample of the product perioadele from acetone-hexane. Amorphous yellow powder. Rf0,69 (chloroform-methanol-water 45:10:1); []D20+35about(from 0.01; MeOH). IR , cm-1: 3600-3200 (OH, NH); 1740 (COOR); 1640 (C=O); 1610 (Ph), 1530 (ONH). UVmaxEtOH(lg ): 255 nm (4,24).

Found, 61,73; N 7,41; N 4,87.

C91H110N6O25. M. C. 1567,62.

Calculated With 62,05; N 7,07; N Are 5.36.

P R I m e R 9. 1-0-[(3 ,20 )-11,30-dioxo-30-(N-L-tyrosine n-nitrobenzyloxy ether)-Olean-12-EN-3-yl] -2-0-[ -D-6-oxo-6-deoxy-6-(N-L-tyrosine n-nitrobenzyloxy ether)-glyukopiranozil] -D-6-oxo - 6-misinformation THF at 0+5aboutWith added 0,47 g (3.5 mmol) of HOBt, 0,72 g (3.5 mmol) DCGK and stirred at this temperature for 1 h, at room temperature for 7 h, the precipitate was filtered of dicyclohexylamine, to the filtrate was added 1.75 g (3.7 mmol) of benzosulfimide n-nitrobenzyl ester of L-tyrosine L-Tyr(OBzI-NO2) C6H5SO3H (HC) and 0.5 ml (5 mmol) of N-Me-the research that has stood the mixture at room temperature for 24 h with occasional stirring and poured into 200 ml of cold water, acidified with citric acid to pH 3, the precipitate was filtered, washed with water, dried, received 1,72 g glycopeptide (C) with an admixture of C6H5SO3H, which perioadele from a mixture of chloroform-alcohol-ether. The yield of pure product 1.45 g (83.6 percent) (amorphous yellow substance), []D20+32about(0,025, ethanol), Rfof 0.66 (chloroform-methanol-water 45: 10:1). IR , cm-1: 3600-3200 (OH, NH); 1760, 1745 (COOR); 1660, 1650, 1640 (C=O); 1610 (Ph); 1540 (CONH). UVmaxEtOH(lg ): 228 nm (4,08); 262 nm (4,42).

Found, 61,93; N. Of 6.25; N 4,37.

C90H104N6O26. M. C. 1717,8.

Calculated With 62,92; N 6,10; N 4,89.

P R I m e R 10. 1-0-[(3 ,20 )-11,30-dioxo-30-(N-L-leucine tert-butyl ester)-Olean-12-EN-3-yl]-2-0-[ -D-6-oxo-6-DESA - XI-6-(N-L-leucine tert-butyl ester)-glucopyranosyl 30 ml of dry dioxane at 0-5aboutWith added 1.0 g (7.4 mmol) of HOBt, 1.4 g (6.8 mmol) DCGK and stirred at this temperature for 1 h, at room temperature for 7 h, the precipitate was filtered of dicyclohexylamine, to the filtrate, cooled in a bath with ice, added to 1.79 g (8 mmol) of the hydrochloride tert-butyl ester of L-leucine L-Leu(OtBu) HCl (HL) and dropwise 1.2 ml (12.4 mmol) of tea and stood at room temperature with periodic mixing 24 hours Poured the mixture into 400 ml of cold water, was acidified with citric acid to pH 3, the precipitate was filtered, washed with water, dried, obtained 2.2 g (82.7 per cent) glycopeptide (L), homogeneous by TLC. To obtain analytically pure sample of the product perioadele from acetone-hexane. Rf0,79 (chloroform-alcohol 7:1). []D20+45about(from 0.02, methanol). So pl. 165-167aboutC (decomp.). IR , cm-1: 3600-3200 (OH, NH); 1740 (COOR); 1660 (C=O); 1530 (CONH). UVmaxMeOH(lg ): 251 nm (3,95).

Found, 64,73; N 9,40; N 2,73.

C72H119O19N3. M. C. 1330,68.

Calculated With 64,98; N 9,01; N 3,16.

P R I m e R 11. 1-0-[(3,20 )-11,30-dioxo-30-(N-L-glutamic acid dimensiony ether)-Olean-12-EN-3-yl] -2-0-[ -D - 6-oxo-6-deoxy-6-(N-L-glutamic acid dimensiony ether)-glyukopiranozil] -D-6-oxo-6-deoxy-6-(N-L-glutamic acid is steamboat dioxane at 0-5aboutWith added 0,94 g (7 mmol) of HOBt, 1.4 g (6.8 mmol) DCGK and the mixture was stirred at this temperature for 1 h, at room temperature 6 hours the precipitate was Filtered of dicyclohexylamine, to the filtrate, cooled in a bath with ice, added 4,10 g (8 mmol) of tosylate of dimensional ester of L-glutamic acid L-Glu(OBzI)2CH3C6H4SO3H (Hm) and 1.2 ml (1.2 mmol) of dry N-methylmorpholine. Withstood the mixture with periodic stirring at room temperature for 24 h, poured into 400 ml of cold water, acidified with citric acid to pH 3, the precipitate was filtered, washed with water and dried Got 4G product (M) mixed with TSOH, which perioadele from chloroform-ethanol-ether. Yield 3.0 g (85,7%). Rf0,70 (chloroform-methanol-water 45:10: 1), []D20+25about(from 0.02; MeOH). IR , cm-1:3600-3200 (HE, NH); 1740 (COOR); 1650 (C= O); 1620 (C6H5); 1540 (CONH); 1500 (Ph). UVmaxEtOH(lg ): 250 nm (4,11).

Found, With 67,60; N 7,15; N 2,85.

WITH99H119N3ABOUT25. M. C. 1750,96.

Calculated With 67,91; N 6,85; N, 2,40.

The METHOD of OBTAINING CARBOXYAMIDE GLYCOPEPTIDES GLYCYRRHIZIC ACID of General formula I

< / BR>
where R = L - Met(OMe), L - Val(OMe), L - Phe(OMe), L - Ala(OMe), L - Glu(OMe)2L - Ala(OBzL), L - Phe(OBzL), L - Leu(ONBz), L - Carbodiimide environment dioxane or tetrahydrofuran at 0 - 15oWith further curing at room temperature and subsequent treatment of the resulting product is a salt of ester of the amino acids in the presence of a tertiary base with 0 to 5oC for 24 h, wherein glycyrrhizinic acid is subjected to interaction with N-hydroxybenzotriazole in a molar ratio of 1 : 3.5 to 4.0 : 3.5 to 4.0, respectively, with subsequent treatment of the obtained Tris-oxibendazole ether glycyrrhizic acid compound of General formula

R1NH2HX,

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X is Cl, SO3C6H5or SO3S6H4CH3,

in a molar ratio of 3.5 to 4.0 : from 4.2 to 7.2, respectively, in the presence of tertiary bases - N-methylmorpholine, tributylamine.

 

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The invention relates to chemical-pharmaceutical industry, in particular to a method for monoammonium salt glitzirrizinova acid to glycyram used in medicine as a medicinal product

-glycyrrhizic acid with debutalbum ester of l-glutamic acid, exhibiting anti-inflammatory and antiulcer activity" target="_blank">

The invention relates to new chemical compound, specifically to glycopeptide-glycyrrhizic acid with debutalbum ester of L-glutamic acid: 3-0-[2-0[(N--D-glucopyranosyloxy-L-glutamic acid disutility ether)-N-D-glucopyranosyloxy-L-glutamic acid BEUtility ether-(3, 20)-11,30-dioxo-30-(N-D-glutamic acid disutility ether)-30-norolean-12-EN General formula I,

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where R L-Glu(OBu)2exhibiting anti-inflammatory and antiulcer activity

-glycyrrhizic acid with 6-amino-2-thio-uracil, exhibiting anti-aids activity" target="_blank">

The invention relates to new biologically active compound, particularly to Amida-glycyrrhizic acid with 6-amino-2-thio-uracil: 3-0-[2-0-(-D-glucopyranosyloxy)--D-glucopyranosyloxy] -(3, 20)-11,30-dioxo-30-(N-6-amino-2-thio-uracil)-30-norolean-12-EN Fort - mules I

exhibiting anti-AIDS activity

-glycyrrhizic acid with 6-aminouracil exhibiting anti-aids activity" target="_blank">

The invention relates to new biologically active compound, particularly, to Amida-glycyrrhizic acid with 6-aminouracil: 3-0-[2-0-(-D-glucopyranosyloxy)--D-glucopyranosyloxy] -(3, 20)-11,30-dioxo-30-(11-6-aminouracil)-30-norolean-12-ene of the formula (I)

exhibiting anti-AIDS activity

-glycyrrhizic acid dimethyl ester, l-aspartic acid, exhibiting anti-aids activity" target="_blank">

The invention relates to new chemical compound, specifically to glycopeptide-glycyrrhizic acid dimethyl ester, L-aspartic acid: 3,0-[2-0-(N--Dr. glyukopiranozil - uranyl-L-aspartic acid dimethyl ester)-N--Dr. glyukopiranozil uranyl-L-aspartic acid dimethyl ester] - (3, 20)-11,30-dioxo-30-(N-L-aspartic acid dimethyl ester)-30-norolean-12-ene of the formula I

where I R - L - Asp (OMe)2;

II R - OH manifesting anti-AIDS activity

-glycyrrhizic acid methyl ester, l - histidine, exhibiting anti-aids activity" target="_blank">

The invention relates to new biologically active compound, particularly, to Amida-glycyrrhizic acid with methyl ester of L-histidine: 3-0-[2-0-(-D-glucopyranosyloxy)--D-glucopyranosyloxy]-(3, 20)-11,30-dioxo-30-(N-L-histidine methyl ester)-30-norolean- -12-ene of the formula I

exhibiting anti-AIDS activity

-glycyrrhizic acid with methyl ether glycyl-l-valine, exhibiting anti-aids activity" target="_blank">

The invention relates to new biologically active compound, specifically, to glycopeptide-glycyrrhizic acid with methyl ether glycyl-L-valine: 1-0-[(3, 20)-11-oxo-20-oxo-20-(N-glycyl-L-valine methyl ester)-30-norolean-12-EN-3-yl] -2-0-[-D-6-oxo-6-deoxy - 6-(N-glycyl-L-valine methyl ester)-glyukopiranozil-D-6-oxo-6-deoxy-6-(N-glycyl-L-valine methyl ester)-gluco - pyranoside formula (I)

exhibiting anti-AIDS activity

FIELD: chemical technology, natural materials, medicine, pharmacy.

SUBSTANCE: invention relates to the improved method for preparing betulin from betulinic acid that can be used in preparing anti-tumor and anti-HIV medicinal preparations. Method for preparing betulinic acid involves oxidation of betulin with chrome (VI) oxide in acetic acid to betulonic acid and reduction with sodium boron hydride to betulinic acid. Betulonic acid sodium salt is reduced to betulinic acid and reduction reaction is carried out at room temperature at the concentration of sodium boron hydride 1.0-6.0 wt.-%. Invention provides simplifying method for preparing betulinic acid, reducing its cost and enhancing ecological safety of the process of it producing.

EFFECT: improved preparing method.

1 cl, 4 ex

FIELD: chemical technology.

SUBSTANCE: invention relates to methods for preparing oleanolic acid used as a standard sample (comparison samples) in carrying out standardization of medicinal vegetable raw and phytopreparations comprising triterpene saponins - derivatives of oleanolic acid. For preparing oleanolic acid method involves sum of saponins extracted by alkaline extraction from sugar or table beet root crops followed by reprecipitation in acid medium and extraction of precipitate with ethanol, chloroform. Method provides preparing oleanolic acid of high purity degree from inexpensive and available raw.

EFFECT: improved preparing method.

2 cl, 3 ex

FIELD: medicine; pharmaceutical industry; perfumery-cosmetic industry; methods production of betulin.

SUBSTANCE: the invention is pertaining to the method of extraction of betulin from the wastes products of wood-processing, in particular, a birch bark processing and may be used in medicine, pharmaceutical and perfumery-cosmetic industries. The method provides for activation of a birch bark by the shock-acoustic impulses, an alkaline hydrolysis and an extraction of betulin by an alcohol. The operations are conducted simultaneously. The technical result of the invention is simplification of the method of the process, reduction of its duration and power input.

EFFECT: the invention ensures simplification of the method of the process, reduction of its duration and power input.

1 cl, 2 ex

FIELD: natural compounds, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing biologically active substances from products of chemical processing vegetable biomass, in particular, to a method for preparing betulinic acid from betuline. Method is carried out by oxidation of betuline with chrome anhydride in acetic acid to betulonic acid, and reduction of betulonic acid with sodium boron hydride is carried out in diethyl ether solution being without its preliminary isolation. Invention provides enhanced yield, simplifying technology, decrease of the process time and decreasing set of solvents used.

EFFECT: improved preparing method.

1 cl, 1 ex

FIELD: chemistry of natural compounds, chemical technology, pharmaceutical industry.

SUBSTANCE: invention relates to the improved method for preparing betulinic acid from betulonic acid. Method is carried out by reduction of betulonic acid with sodium boron hydride in water. Method provides simplifying the process, declining cost of the process for preparing betulinic acid and enhancing ecological safety of the process. Invention can be used in producing antitumor and anti-HIV medicinal preparations.

EFFECT: improved preparing method.

1 cl, 2 ex

FIELD: organic chemistry of steroids, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing chemical compounds of steroid order, namely, to a method for preparing epibrassinolide representing (22R,23R,24R)-2α,3α,22,23-tetrahydroxy-B-homo-7-oxa-5α-ergostane-6-one and relating to biologically active substance - a phytostimulator regulating growth of plants. Method involves the successive carrying out the following stages: a) synthesis of ergosterol mesylate by treatment of ergosterol with methanesulfochloride in pyridine; b) synthesis of isoergosterol by boiling ergosterol mesylate in aqueous acetone in the presence of potassium (sodium) hydrocarbonate; c) synthesis of isoergosterone by oxidation of isoergosterol with chrome anhydride in pyridine; d) synthesis of 7,8-dihydroergosterol by reduction of isoergosterone with sodium dithionite in the presence of a solubilizing medium containing cationic, anionic or nonionic surface-active substances of the following order: CnH2n+1X wherein n = 9-18; X means -NMe3, -NEt3, -COOH, -SO3H, -OSO2M, -OP(O)(OM)2 wherein M means alkaline metal, polyethylene glycol, (C2-C6)-aliphatic alcohols or monoesters of ethylene glycol or diethylene glycol as a co-solubilizing agent, electrolyte and water taken in the molar ratio = 1:(5-6):(100-250), respectively; e) steroid rearrangement of 7,8-dihydroisoergosterol; f) formation of 24-epicastasterone by treatment of (22E,24R)-5α-ergosta-2,22-diene-6-one with methanesulfoneamide and potassium carbonate with using catalytic amounts of potassium ferricyanide (III) and osmium tetraoxide; g) dissolving 24-epicastasterone formed in chloroform followed by treatment with trifluoroperacetic acid forming in mixing trifluoroacetic anhydride and hydrogen peroxide in chlorinated organic solvent, and isolation of the end product of the formula (I) with high yield.

EFFECT: improved preparing method.

2 cl, 7 ex

FIELD: fine organic synthesis, in particular production of triterpene compounds, betulin, useful in pharmaceutical and cosmetic industry.

SUBSTANCE: betulin is isolated from birch bark by extraction with neutral organic solvents, namely dioxan aqueous solution containing 0-20 mass % of water.

EFFECT: accelerated extraction process, increased yield of target product, decreased concentration of ester contaminants, and simplified betulin purification.

1 cl, 7 ex, 1 tbl

FIELD: natural substances technology.

SUBSTANCE: method of preparing extractive substances from ground birch bark comprises extraction and filtration of precipitated extract. Extraction is effected with extractant condensate sprinkling ground birch bark bed in presence of ascending vapors of the same extractant. Extractant is two-component mixture of water and low-boiling solvent having boiling point below 100°C. Product is isolated by bringing extractant condensate containing dissolved extract with contents of receiver. Once extraction is completed, solvent is removed with live steam.

EFFECT: reduced consumption of extractant, increased degree of extractant regeneration, simplified isolation of product, and reduced fire and explosion risk.

1 tbl, 2 ex

FIELD: biochemistry.

SUBSTANCE: describes is new chemical compound, namely glycirrisine acid derivative with L-prolin: 3-O-{2-O-[N-(β-O-glucopyranosyluronoyl)-L-prolin-N-(β-D-glucopyranosyluronoyl)-L-prolin]}-(3β,20β)-11-oxoolean-12-en-30-oic acid, stimulating of humoral immune response. Said compound has low toxicity and increases agglutinins levels (by 3,7 times) and hemolysines level (by 3 times) in mouth blood in contrast with control while administrating of 2 mg/kg.

EFFECT: preparation with increased stimulating activity in relation to agglutinin production.

1 cl, 2 ex

FIELD: bioactive substances, in particular glycyrrhizic acid derivatives.

SUBSTANCE: invention relates to glycyrrhizic acid derivatives of general formula wherein R is formula or hydrogen atom, with the proviso that at least two of said R are . Also disclosed is inhibitor of human immunodeficiency virus reproduction, including di- and/or trinicotinates of glycyrrhizic acid.

EFFECT: new glycyrrhizic acid derivatives with high bioactive activity; anti-HIV inhibitor of improved activity.

2 cl, 14 ex, 3 tbl

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