SU1625882A1 - Method of obtaning glycopeptides of glycyrrihisic acid - Google Patents

Abstract

The invention relates to the chemistry of trypenoid glycoendes, in particular, the preparation of glycopeptides of glycyrrhizic acid of a common fc sy / c10 q it but C (0) R where R a) L-Val (0-СНЭ); b)

Description

I ate

00 00 GS

The invention relates to the chemistry of triterpenoid glycosides and relates to an improved method for the preparation of glycopeptides of glycyrrhizic acid of the general formula

(one)

where R a) L-Val (OMe);

b) L-Val (O-rpeT-Bu);

c) Il-L-Leu (OMe);

d) L-Ilu (OMe) 2,5 with nmnomomodulatory activity.

The purpose of the invention is to increase the yield of compounds of general formula (I).

Example 1. 1-0- (3 |}, 20f5) -U, 30rdi-oxo-ZO-deoxy-30- (NL-valine methyl ester) -oleano-12-en-3-shG -2-0 - (- fi-D-6-oxo-b-deoxy-b- (NL-valine methyl ester) -glucopyranosyl-3-B-6-oxo-6-deoxy-6- (NL-valine methyl ether) -glu "oproznoside (la).

To a solution of 1.64 g of glycyrrhizic acid in 50 ml of dry THF at 0-5 ° C is added with stirring 1.15 g (10 mmol) of N-hydroxysuccinimide 2

(HOSu) and 1.3 g (6 mmol) of N, N -flHUHKno-hexylcarbodiimide (DCCG), stirred at this temperature for 3 hours and then 6 hours at room temperature, and kept the mixture overnight in a refrigerator (4- 8 ° C). The dicyclohexyl urea precipitate is filtered off and 0.68 g (b mmol) of L-valine methyl ester hydrochloride and 1.0 ml (9.8 mmol) of distilled triethylamine are added to the cooled filtrate at 0-5 ° C. Stir the reaction mixture for 1 hour at this temperature and 24 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in distilled methylene chloride (200 ml), the solution was washed with 5% HC1, water, 5% NaHC03, water, and dried over MgSO4. After evaporation of the solvent in vacuo, 1.6 g (75%) of the glycopeptide (la), homogeneous according to TLC, are obtained. To obtain an analytically pure sample, a small portion of the product is crystallized from acetone-hexane.

PRI mme R 2.,) - 11,30- -dio-oxo-30-deoxy-30- (NL-valine tertiary ester) -oleano-12-en-3- -shH} -2-0- A-1) -6-oxo-6-deoxy-6- (NL-valine tert-butyl ether) -glucopyranosyl -o-O-b-oxo-b-deoxy-b- (NL-valine tert-butyl ether) -glucopranoside (16).

1.2 g (310.4 mmol) of HOSu and 1.4 g (6.4 mmol) of DCCG were added to a solution of 1.64 g (2 mmol) of glycyrrhenic acid in 50 ml of dry dioxane. stir the mixture at this temperature for 3 hours and 6 hours at room temperature, keep the mixture overnight at 4-8 ° C in a refrigerator, filter off the dicyclohexylurea precipitate, cool the filtrate to 0-5 ° C and add 1.47 g (7 mmol) L-valine tert-butyl ester hydrochloride, 1.1 ml (10.8 mmol) of distilled triethylamine, stirred while cooling for 1 hour and kept for 24 hours at room temperature

After processing the mixture according to Example 1, 1.8 g (80%) of the glycopeptide (16) homogenous by TLC is obtained.

Example 1-0- (3p, 2Gf) -11,30-Dioxo-ZO-deoxy-ZO- -glycyl-leucine methyl ester) -oleac-.1 2-en-3 -nn -2-0 - p-D-6-oKco-6-fle30KCH-6- (N- -glycyl-leucine methyl ester) -glucopyrosyl-ixi-D-6-oxo-b-deoxy-b- - (L-glycocyl - leucine methyl ester) -glucopyracoside (1c).

To a solution of 1.64 g (2 mmol) of glycyrrhizic acid in 50 ml of dry tetrahydrofuran at 0-5 ° C was added 1.2 g (10.4 mmol) of HOSu and 4.3 g (6 mmol) of DCCA, stirred at this 3 hours and at room temperature for 6 hours, the mixture is kept in a refrigerator at 4-8 ° C overnight, the dicyclohexylurea is filtered off, the filtrate is cooled to 0-5 ° C and 0.90 g (6.5 mmol a) methyl glycyl-T leucine hydrochloride ester, and then 1.0 ml (9.8 mmol) of distilled triethylamine, stirred under cooling for 1 h and kept at room temperature 24 After processing the mixture according to Example 1, 2.5 g (96%) of the glycopeptide (1c) is obtained. To obtain an analytically pure sample, a small portion of the product is crystallized from methanol-ether.

PRI me R 4. 1-0- (3fl, 20/3) -11,30-dioxy-3-deoxy-3-g-glutamic acid dimethyl ester) -oleano-2-ene- 3-yl -2-0-Ј | 3 -lJ-6-oxo-b-deoxy-6- -1-glutamic acid dimethyl ester) -glucopyranosygH-oЈ-0-6-oKco-6-fle3OKCH- 6- (NL-rnyraMHHOBou acid dimethyl ester) -glucopyranoside (1g).

1.15 g (10 mmol) of N-hydroxysuccinimide and 1.3 g (6 mmol) of N, N HUH uioreK were added to a solution of 1.64 g (2 mmol) of glycyrrhizic acid in 50 ml of dry tetrahydrofuran at 0–5 ° C. - sil-carbodnimide, stirred at

this temperature for 3 hours, 6 hours at room temperature and incubated for 12 hours in a refrigerator at 4-8 ° C. A precipitate of dicyclohexyl urea is filtered off and to the filtrate, cooled to 0-5 ° C, 1.4 g (6.5 mmol) of hydrochloride dn-L-glutamic acid methyl ester, 1.1 ml (10.8 mmol) are added with stirring ) trieticsamine and stirred at room temperature for 24 hours. After processing the mixture as in Example 1, 2.0 g (76.9%) of the amorphous glycopeptide (1d) is obtained.

The table shows the data of the compounds obtained.

Thus, the proposed method allows to increase the yield of the target products from 74-79 to 75-86%.

Claims (1)

Invention Formula The method of obtaining glycopeptides glycyrrhizinic acid of general formula v, C (0) R O C (0) R fr0 Tn n where R a) L-Val (OMe); b) L-7a1 (O-tert-Vi); c) Il-L-Leu (OMe); d) L-Ilu (OMe),; on the basis of glycyrrhizic acid through the stage of condensation lower alkyl ester hydrochlorides of amino acids in the presence of triethylamine and N, N; -dicyclohexylcarbodiimide, which is characterized by the fact that, in order to increase the yield, glycyrrhizic acid is treated with N-hydroxy succinimndum in the presence of N, M -dicyclohexylcarbodiimide in a medium of dry tetrahydrofuran or doxane with sequential aging. -5 ° С Зh, room 6 h, 12 h with the subsequent interaction of the resulting trisoxysuccinimide ester with methyl or tert-butyl hydrochlorides of amino acids or peptides of the formulas HCHN2Y-C, where K, -CH-CH (CH3) 2, - (JH-CH (CH3h СООМеCOO- tert-Bu 30COOMe -SNGSOYNSN2CH (CH3) g in the presence of triethylamine, at 0-5dS and keeping the reaction mixture at 35 room temperature for 24 hours 1880 168-1 / 0 86 163-167 Ir77 1J3-106 + 32 (.C-0.06) 0.77 250.5 (4: 1) (3.95) + 29 ° (c-0.04) 0.50 (3, J2) V / -. 1) + 22 ° (00.1) 0.57 250 (3.88) (5: 1) +32 (.C-0.06) 0.77 250.5 (4: 1) (3.95) 1 7JO (COOMe) 1600 (c -0) 1520 (CONH) 1220 (C-0-C) 3600-320059.55 8.85 3.47 C -. ,, 59.58 8.55 3.33 (OYA.IN) 1740 (COO-trvtBu), 1665 () 1540 (CONH) 1220 (C-OC) 3600-3200 (OH.NH) 1740 (COOMv) t640 () 1550 (CONH) 1220 (C-0-C) 3650-3200 (OH.NH) 1740 (COOMe) 1660 () 1540 (COMU) 1210 (C-0-C) 59.98 7.45 5.77 C6, H, AND NS0M 60.23 8.06 6.19 58.30 7.81 3.08 58.48 7.35 3.25 a m Ul ao oo N3 00