A method of obtaining a triterpene glycopeptides

 

(57) Abstract:

The invention relates to organic chemistry, specifically to a method for producing triterpene glycopeptides derived glycyrrhizic acid (GA) using unprotected glycoside (carboxy-component) and free amino acids or dipeptides (aminoquinones AK). In the proposed method, glycyrrhizinic acid is treated with a complex of F in a medium of dimethylformamide at 0oC 1 h, at room temperature for 4 h, incubated overnight at 4-80oC and get activated Tris-pentafluorophenyl ester Ledger, in which the solution is injected into the reaction with amino acids or dipeptides in the presence of 1N NaOH solution at a ratio of reagents QA/complex F/AK 1:3-3,5/3-4 mmol. The yield of the target compounds 62,5-90,9%.

The invention relates to method of getting free triterpene glycopeptides derived glycyrrhizic acid (GA) (I) of General formula (II) interest for medicine as immunomodulators and anti-HIV funds

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A method of obtaining carboxy-protected glycopeptides Ledger, consisting in condensing glycoside (carboxy-component) with esters of amino acids (methyl and tert-butyl),closeclicked (DCGK) in the environment, tetrahydrofuran or dioxane in the presence of triethylamine (tea) (prototype), serial maintaining the reaction mass at a temperature of 0-5oC 3 h, room 6 h, 4-8oC 12 h followed by interaction of the formed triaxialities ether with AK at 0-5oC and maintaining the reaction mass at room temperature for 24 h with a molar ratio of reagents GC/HOSu/DCHC/AK/OCH= 2/10-10,4/6-6,4/6-7/9,8-10,8 mmol, yield carboxyamide glycopeptides Ledger (IY) 46-86% (scheme 1).

The disadvantage of this method is the occurrence of side reactions of education succinimidylester alanine, which reduces the yield of the target products (in this case, glycopeptides CC):

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In addition, the main disadvantage of the proposed method previously is used as a reagent (aminocompounds) esters of amino acids or dipeptides in the form of salts (HCI), resulting in the final product of the reaction are carboxyaldehyde glycopeptides of formula (IY), containing fragments of methyl and tert-butyl esters of amino acids or dipeptides. To get fully released glycopeptides of formula (II), where R is the fragments of free amino acids, it is necessary to conduct additional phase synthesis associated with paying carboxyamide ester group is or NaOH in methanol) in the case of methyl esters.

As shown by our research, the release of protected glycopeptides Ledger, containing fragments of methyl esters of amino acids by alkaline hydrolysis leads to a complex mixture of products resulting from the cleavage of glycosidic linkages. When processing triperoxonane acid glycopeptides Ledger, containing fragments of tert-butyl esters of amino acids, the free outputs of the glycopeptides was 43-47% (examples 8, 9). As an example, we present two methods of obtaining the target glycopeptides (IV,C) in the method prototype. So getting free triterpene glycopeptides Ledger formula (II) interest for medicine as a potential immunomodulatory and anti-virus tools, suitable for injection forms, is an important task. In the proposed technical solution is simplified technology for free glycopeptides Ledger formula II, thanks to the principle of "minimum protection", excluding the release process.

Glycopeptides Ledger formula (II) are formed by condensation of the activated intermediate KG (VI) with amino acids or dipeptides in DMF medium in the presence of 1N NaOH solution. To produce an activated ester group (VI) (scheme 2) CC opr>C in DMF. The molar ratio of the reagents QA /complex F/ aminocompounds is 1/3/3-4 mmol

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How is that glycyrrhizinic acid (I) (1 mmol) is treated at 0 -5oC under stirring complex F (3 mmol) in DMF medium for 1 h, at room temperature for 4h, receiving the activated intermediate (VI), after which the precipitate of N, N' -dicyclohexylmethane subjected to interaction with aminocompounds (AK) (amino acids or dipeptides) formula RNH2where

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in DMF medium in the presence of 1N NaOH solution at a molar ratio of reagents QA/complex F/AK equal 1/3/3-4 mmol at 0oC, followed by keeping the reaction mixture at room temperature for 24 hours Target glycopeptides P (a-W) was isolated by dilution of the reaction mixture Kolodny water and acidification with citric acid to pH3. The precipitate is filtered off and periostat from a mixture of chloroform methanol (5:1) ether. The output of glycopeptides (P-W) was 62.5-90,9% After purification column chromatography, the yield of products is 44,4-57,9%

Differences between the proposed method are as follows.

1. To activate carboxyl groups glycyrrhizic acid is used Kashima 1). As the activated intermediate is formed during this Tris-pentafluorophenyl ester GL (VI).

2. The solvent used is N, N-dimethylformamide (DMF).

3. As aminocompounds (AK) are free amino acids or dipeptides.

4. As the base used 1N NaOH solution instead of the tertiary amine (triethylamine) in a known way.

Example 1. Tris-pentafluorophenyl ester glycyrrhizic acid (VI).

To a solution of 0.82 g (1 mmol) of glycyrrhizic acid in 30 ml of dimethylformamide (DMF) at 0oC added with stirring 2.28 g (3 mmol) of the complex F and the mixture was stirred at this temperature for 1 h, at room temperature (20-22oC) 4 hours Withstood the reaction mixture in the refrigerator (4 -8oC) during the night and the precipitate was filtered of dicyclohexylamine. The resulting solution of pentafluorophenyl ester group (VI) used in the condensation reaction with aminoacetophenone.

Example 2. 3-0-2-0-[N - (D-glyukopiranozil of urinal)- L-alanine-N-(b - D-glucopyranosyloxy) L-alanine} (3, 20), -11-oxo-30-(N-carbonyl-L-alanine) -30 - norolean - 12-ene (ll).

To a solution of 0.36 g (4 mmol) of L-alanine in 10 ml of I N NaOH solution was added 10 ml of DMF, cooled the FA (example 1), stirred the mixture for 30 minutes under cooling and kept at room temperature for 24 hours with periodic mixing. Diluted the reaction mixture with 200 ml of cold water, acidified with citric acid to pH3. The precipitation was filtered, washed with water and dried. Received of 1.03 g (99,4%) crude glycopeptide ll that perioadele from a mixture of chloroform methanol (5:1, Y/Y) ether. Yield 0.8 g (77.2 percent). Rf of 0.47 (Chloroform methanol-water, 45:10:1); []2D0+55cm-1: 3600-3200 (OH,NH); 1720 (COOH); 1670 (C110); 1540 (CONH). UV-range,MeOmaxH, nm (lg) 248,5 nm (4,00). Found, C 58,93; H 7,10; N 3,74. C51H77N3O19. M. C. 1036,3. Calculated C 59,11; H 7,50; N 4,05.

Example 3. 3-0-{ 2-0-[N-(b-D-glucopyranosyloxy)-L-valine] -N- (b-D-glucopyranosyloxy)-L-valine} 3, 20-11-oxo-30-(N-carbonyl-L-valine)-30-norolean-12 - ene (ll).

To a solution of 0.35 g (3 mmol) of L-valine in 10 ml of IN NaOH solution was added 10 ml of DMF, cooled to 0oC and with stirring was added dropwise a solution of 1 mmol of pentafluorophenyl ester group (VI)(example 1) in 30 ml of DMF, the mixture was stirred at 0oC for 30 min and kept at room temperature for 24 hours Diluted the reaction mixture with 200 ml of cold water, acidified with citric acid to pH 2. The precipitate was filtered, prom the od of 0.9 g (80,4%). Rf 0.5 (chloroform-methanol-water, 45:10:1); []2D0+42,5cm-1: 3600-3200 (OH, NH); 1710 (COOH); 1670 (C110); 1530 (CONH), UV spectrum,MeOmaxHnm (lg): 248 nm (3,93). Found, C 61,46; H of 7.96; N 3,23; C57H89N3O19. M. C. 1120,49. Calculated C 61,09; H 8,02; N 3,75.

Example 4. 3-0-{2-0-[N-( b-D-glucopyranosyloxy)-L-methionine]-N-( b-D-glucopyranosyloxy)-L-methionine} (3, 20) -II - oxo-30-(N-carbonyl-L-methionine)-30-norolean-12-ene (ll).

To a solution of 0.58 g (4 mmol) of L-methionine in 10 ml of DMF was added 10 ml of 1N NaOH solution, cooled to 0oC and with stirring was added dropwise a solution of 1 mmol of pentafluorophenyl ester group (VI) in 30 ml DMF (example 1). Stirred the reaction mixture at this temperature for 24 hours was Diluted in a mixture of 200 ml of cold water, acidified with citric acid to pH3. The precipitate was filtered, washed with water and dried. Received 1.07 g (87,7%) crude glycopeptide (ll), which perioadele from a mixture of chloroform methanol (5:1) ether. Output 0,86 g (70,0% ), Rf of 0.56 (chloroform-methanol-water, 45:10:1); []2D0+34cm-13600-3200 (OH, NH); 1715 (COOH); 1660 (C11=0); 1530 (CONH). UV spectrum MeOmaxHnm (lg): 249 nm (3,92). Found, C 56,18; H 7,32; N 2,82. C57H89N3O19S3. M. C. 1216,48. Calculated C 56,27; H 7, is in ( 3, 20 )-II - oxo-30-(N-carbonyl-L-isoleucine) -30 - norolean-12-ene (ll).

To a solution of 0.52 g (4 mmol) of L-isoleucine in 10 ml of DMF, cooled to 0oadded 10 ml of 1N NaOH solution and with stirring was added dropwise a solution of 1 mmol of pentafluorophenyl ester group (VI) in 30 ml DMF (example 1). The mixture was stirred 30 min at 0oC and maintained with periodic stirring at room temperature for 24 hours was Diluted in a mixture of 200 ml of cold water, acidified with citric acid to pH3. The precipitate was filtered, washed with water and dried. Got to 1.14 g (98,3%) glycopeptide (ll), which perioadele from acetone-hexane. Yield 1.0 g (86.2 per cent). Analytical pure sample is obtained with a yield of 0.6 g (51,8%) column chromatography similarly ll. Rf 0.5 (chloroform-methanol-water, 45:10:1). []2D0+45cm-1: 3600-3200 (OH, NH); 1720 (COOH); 1660 (C11=0); 1530 (CONH). UV spectrum MeOmaxHnm (lg): 248 nm (4,10). Found, C 61,76; H 8,14; N 3,57. C60H95N3O19. M. C. 1162,5. Calculated C 61,59; H 8,25; N 3,61.

Example 6. 3-0-{ 2-0-[N-(b-D-glucopyranosyloxy)-L-glutamic acid]-N-(b-D-glucopyranosyloxy)-L-glutaminolytic}-(3)-11-oxo-30-(N-carbonyl -- glutamic acid) -30 - norolean-12 Yong (ll).

To a solution of 0.59 g (4 mmol) of L put the NML a solution of 1 mmol of pentafluorophenyl ester group (VI) in 30 ml DMF (example 1). The mixture stood with periodic stirring at room temperature for 24 h and diluted with 300 ml of cold water, acidified with citric acid to pH3. The precipitate was filtered, washed with water and dried. Got 1.20 g (99,1% ) crude glycopeptide (ll), which perioadele from a mixture of chloroform-methanol (5: 1) ether. Yield 1.1 g (90,9%). Rf 0,49 (chloroform-methanol-water, 45:10:1). []2D0+49cm-1: 3600-3200 (OH, NH); 1710 (COOh); 1660 (C11=0); 1530 (CONH). UV spectrum MeOmaxHnm (lg); 248 nm (4,07). Found, C 57,06; H Of 7.23; N 3,52. C57H83N3O25. M. C. 1210,4. Calculated C 56,56; H 6,93; N 3,47.

Example 7. 3-0-{2-O-(N- ( -D-glucopyranosyloxy)-glycine-L - phenylalanine] -N-(b-D-glucopyranosyloxy)-glycine-L-phenylalanine} (3, 20)-11-oxo-30-(N-carbonyl-glycine-L-phenylalanine) -30 - norolean-12-ene ll).

To a solution of 0.89 g (4 mmol) glycyl-L phenylalanine in 10 ml of 1N NaOH, cooled to 0oC, was added 10 ml of DMF and added dropwise a solution of 1 mol of pentafluorophenyl ester group (Y) in 30 ml DMF (example 1). The mixture was stirred 30 min at 0oC and maintained with periodic stirring at room temperature for 24 h the Mixture was diluted with 300 ml of cold water, acidified with citric acid to pH2-3. The precipitation was filtered, washed with water and dry the course of 0.9 g (62,5%). Analytical pure sample obtained column chromatography similarly ll with yield 0.64 g (44,4% ). Rf of 0.45 (chloroform-methanol-water, 45:10:1). []2D0+35cm-1: 3600-3200 (OH, NH); 1720 (COOH); 1660 (C11=0), 1540 (CoNH). UV spectrum MeOmaxHnm (lg); 245 nm (3,95). Found, C 61,74; H 7,51; N 5,55. C75H10N6O22. M. C. 1438,76. Calculated C 62,61; H To 7.09; N Of 5.84.

Example 8. 3-0-{2-0-[N-()-D-glucopyranosyloxy) -L-isoleucine tert-butyl ether] -N-(b-D - glucopyranosyloxy)-L-isoleucine-butyl ether} (3, 20), 11,30 deoxy-30-L-isoleucine tert-butyl ether-30-norolean-12-ene (IVd).

1. To a solution of 1.64 g (2 mmol) of glycyrrhizinic acid in 50 ml of dioxane at 0-5oC was added 1.2 g (10.4 mmol )HOSu, 1.3 g (6 mmol) DCGK and stirred at this temperature for 3 hours, 6 hours at room Stood the mixture overnight in the refrigerator, the precipitate was filtered of dicyclohexylamine and the filtrate cooled in a bath of ice, was added 1.5 g (6 mmol) of butyl methyl ether hydrochloride L-isoleucine and 1.3 ml (9.5 mmol) of triethylamine. The mixture was stirred with cooling for 1 h and kept at room temperature for 24 h the Solvent was evaporated in vacuum at 45oC, the residue was dissolved in methylene chloride (200 ml) and washed with 5% recital in vacuum at 30oC. Received 2.0 g (75.2 per cent) of the crude protected product (IVd), which perioadele from acetone-hexane. Yield 1.28 g (48.1 percent ). Rf of 0.66 (chloroform-methanol-water 45:10:1); of 0.36 (chloroform-ethanol, 10:1). []2D0+29tOH),

The infrared spectrum; cm-1; 3600-3200 (OH, NH); 1740 (COOR); 1660 (C11=0); 1530 (CONH). UV spectrumetOmaxH, (lg): 246 nm (3,93). Found, C 64,86; H 8,96; N 3,52. C72H119N3O19. Calculated C 64,98; H 9,01; N 3,16.

Releasing protected glycopeptide (Jude).

1.0 g (0.86 mmol) of the protected glycopeptide (Ius) in 20 ml of CF3COOH has stood for 30 min at 20-22oC and evaporated mixture in vacuum to dryness. The residue (0.9 g) was chromatographically on a column of silica gel L (40/100 μm/, elwira a mixture of chloroform methanol-water, 200:10:1, 100:10:1, 50:10:1, 25:10:1. A mixture of 50:10:1 was washed with 0.5 g (43%) of homogeneous product (ll) as an amorphous substance. Rf of 0.48 (chloroform-methanol-water, 45:10:1); []2D0+55tOH).

Example 9. 3-0-{2-0-[N-(-D - glucopyranosyloxy)-L-valine tert-butyl ether] -N-(b-D - glucopyranosyloxy)-L-valine tert-butyl ester} (3, 20), 11,30 dioxo-30-L-valine tert-butyl ether-30-norolean-12-ene (VI).

To a solution of 1.64 g (2 mmol) of glycyrrhizic acid in 50 ml of dry dioxane at 0-5oC was added 1.2 g (argali mixture overnight at 4-6oC in the refrigerator, the precipitate of dicyclohexylamine was filtered, the filtrate was cooled to 0-5oC and added it to 1.47 g (7 mmol) of the hydrochloride tert-butyl ester L-valine, 1.3 ml (9.5 mmol) of triethylamine and stirred with cooling for 1 h, 24 h at room temperature. The solvent was evaporated in vacuo, the residue was dissolved in methylene chloride (200 ml) and washed with 5% hydrochloric acid, water, 5% solution of NaHCO3, dried MgSO4and evaporated in vacuum. Received of 1.9 g (80%) of crude glycopeptide (IV), which perioadele from acetone-hexane. Output protected glycopeptide 1.2 g (48% ). Rf of 0.48 (chloroform-ethanol, 7:1); []2D0+30cm-1: 3600-3200 (OH, NH); 1740 (COOP); 1670 (C11=0); 1540 (CONH). UV spectrumMeOmaxH, (lg): 249 nm (3,99). Found, C 63,96; H Cent To 8.85; N 3,47. C69H116N3O19. Calculated C 63,16; X 9,04; N 3,25.

Release glycopeptide (IV).

1.0 g (0.8 mmol) of the protected glycopeptide in 20 ml of CF3COOH was stirred at room temperature for 1 h and evaporated in vacuum. The residue was washed with dry ether and dried in vacuum at 40-45oC 3 o'clock Dry residue (0.84 g) was chromatographically on a column of silica gel L (40/100 μm), elwira a mixture of chloroform-methanol-water 100:10:1, 50:10:1, 25:10:1, Sveta. Rf 0.5 (chloroform methanol-water 45:10:1), []2D0+45tOH).

The advantages of the proposed method are as follows.

1. As aminocompounds (AK), the proposed method uses the free amino acids and dipeptides, not esters, as in the methods [1] and [4] which simplifies and cheapens the process of obtaining glycopeptides Ledger (for example, the cost of 1 g of the ester of the amino acids more expensive than the cost of amino acids).

2. As of end-products are formed available glycopeptides General formula (II) (with free COOH groups), i.e., there is no need for stage release [5] which also simplifies the process of obtaining glycopeptides Ledger.

3. As the Foundation of the proposed method is used 1N NaOH solution instead of a tertiary base (triethylamine) in a known method [1, 4] which also significantly reduces the process of obtaining glycopeptides Ledger.

A method of obtaining a triterpene glycopeptides derived glycyrrhizic acid of General formula

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where R is L-Ala, L-Val, L-Met, L-Ile, L-Glu, Gly L Phe

by activating carboxyl groups unprotected glycyrrhizic acid (GA) activating complex through a stage of condensation with the formation of activerow is their 24 h, wherein the glycoside is subjected to interaction with complex pentafluorophenol N,N'-dicyclohexylcarbodiimide in the ratio of 3 to 1 (complex F) at 0 - 5oC for 1 h, at room temperature for 4 h followed by keeping at 4 8oWith during the night and condensation of the activated intermediate with amino acids (AA) of the formula RNH2,

where R is CH3CH (L-Ala) (a);

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in the presence of 1 N. NaOH solution at molarnom ratio of reagents Ledger complex F AK respectively 1 3,0 3,5 3 4.

 

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