The method of receiving penta-o-nicotinate glycyrrhizic acid

 

(57) Abstract:

Usage: as a drug for the treatment of rheumatoid polyarthritis and anti-HIV funds. The inventive Penta-O-nicotinate glycyrrhizic acid, which is produced through the conversion of salts of glycyrrhizic acid under the action of acid chloride of nicotinic acid in the environment of a tertiary base, characterized in that the pharmacopoeial glitsiram (substance) or TRACELEVEL salt of glycyrrhizic acid in a mixture of tributylamine and benzene is subjected to azeotropic drying at 69 - 70oC in vacuum and treated with hydrochloride acid chloride of nicotinic acid at 75-80oC for 3-4 h at a molar ratio of reagents, equal to, respectively, 1/7,4-7,6 followed by decantation of tributylamine and the spent reaction mixture, at 50oC.

The present invention relates to a thin organic synthesis, and in particular to an improved process for the preparation of Penta-O-nicotinate glycyrrhizic acid nigrizia (1), of interest as a means for the treatment of rheumatoid polyarthritis [1] and anti-HIV funds [2] the Drug has successfully passed the 1st stage of clinical trials as media as a tool for therapy of AIDS.

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A method of obtaining nigrizia Penta-O-nicotinate glycyrrhizic acid (1) by treatment with glycyrrhizic acid (IV) (CC) the hydrochloride of the acid chloride of nicotinic acid (V) in pyridine at room temperature at a molar ratio of reactants is 1:8 for 48 h (scheme I) [3]

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The output of pentatominae GK (1) was 88%

The disadvantage of this method is used as a solvent toxic pyridine, after which the reaction mixture is unable to regenerate (the way of ethnological). In addition, for carrying out synthesis needed for a long time 48 hours

There is also known a method of obtaining pentatominae Ledger [4] which consists in processing trikalinos CC salt (III) with a mixture of nicotinic acid (VI) with l5in the environment of pyridine at a molar ratio of reagents 1/3-4/1 at a temperature of 45-50oC for 3 h (scheme 2).

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The yield of the target product (1) 75%

The disadvantages of this method of obtaining Penta-O-nicotinate Ledger are also used as a solvent toxic solvent of pyridine and use as a reagent petaluridae of phosphorus, irritating to respiratory system.

In connection with the conduct of clinical ispitanika experienced parties substance nigrizia.

Both the known method [3, 4] proved to be unsuitable for holding narabotany syntheses with raw material loading more than 50 g and-low-tech, because after the reaction is unable to regenerate the solvent is pyridine, which is discharged into the drain along with the water necessary for the selection of the reaction product, when the production of pilot batches of the drug leads to the formation of large amounts of environmentally harmful waste, which is difficult to dispose of. In addition, raw material for production of Penta-O-nicotinate Ledger glycyrrhizin acid (IV) and tricalysia salt (III) the industry is not produced and are obtained only in the laboratory [5, 6] Therefore, an urgent task is to develop a technological method of obtaining a substance nigrizia on the basis of available industrial raw materials. All this prompted us to seek a new, more automated way to get the Penta-O-nicotinate GK (I) to make a trial batch of the drug substance (0.5 kg) using industrially available raw materials and regeneration of the solvent with the aim of creating further wasteless production of the drug substance.

The aim of the invention is to develop emove industrially available raw materials, allowing to obtain an experimental batch of the drug substance.

This objective is achieved in that the raw materials of pharmacopoeial glitsiram (II) (VFS 42-419-75) (monoammonium salt of glycyrrhizic acid) produced Chimkent himfarmzavod ("Cementboard") or TRACELEVEL Sol SC (III) after azeotropic drying with benzene under 69 70oWith environment tributylamine (TBA) is subjected to interaction with the acid chloride hydrochloride nicotinic acid (HHNK) (V), at a temperature of 75 80oC for 3-4 h at a molar ratio of the reagents (II) (III)/(V) equal to 1:(7,4oC7,5). The resulting mixture after separation of the solvent by decantation at the 50oWith is treated with an excess of acetone, the product is planted with water and tributylamine regenerated. The essence of the method is that the solution of glycyram (II) or trikalinos salt (III) in tributylamine subjected to azeotropic drying with benzene under 69 70oWith the vacuum, is then treated with acid chloride hydrochloride nicotinic acid (V), obtained by the method [7] and incubated the mixture at this temperature for 3-4 hours at a molar ratio of reagents, equal to, respectively, 1:(7,4oC7,5), followed by decantation of the solvent (tributylamine), oberbaumbruecke alkali. The reaction proceeds according to the scheme 3.

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Significant differences method: 1) in contrast to the known methods [3] and [4] in our proposed method uses the available industrial raw material - substance drug glitsiram corresponding VFS 42-419-75 produced Chimkent himfarmzavod; 2) uses a different solvent tributylamine as reaction medium; 3) in contrast to the known method [3] is the closest to the proposed method according to the scheme of synthesis (see scheme 1), the synthesis of Penta-O-nicotinate GK (I) proceeds in a relatively short period of time 3 4 h instead of 48 h according to the method of [3] 4) in contrast to the known methods [3] and [4] the proposed method allows to regenerate the solvent TBA (see examples) (loss 2 13%), which after the separation can be reused in the synthesis of pentacoordinate GC (see example 2), i.e. the prerequisites for the development of waste-free technology.

The output substance Penta-O-nicotinate Ledger (nigrizia) was 76 77% in terms of raw materials glitsiram with 100% content of the basic substance or 84 of 85% in terms of industrial glitsiram, the content of the basic substance in which VFS equal to 90.4% When used as a feedstock Tr is our proposed method allows narabotany syntheses with loading raw material more than 500 g (see examples).

Example 1. Getting nigrizia of the Pharmacopoeia of glycyram.

a) Azeotropic dehydration of glycyram and tributylamine.

A 5-liter flask equipped with a mechanical stirrer, a refrigerator and a separating vessel, put 2670 g tributylamine (TBA), the water content of 0.15% 1150 g of benzene (% H2O 0.04), and heated the mixture to 60oC. Turned on the mixer and added under vigorous stirring 440 g (0.52 mol) of glycyram (VFS-42-419-75, H2O 5,61). Heated the mixture to 69 70oWith and drove azeotropic mixture of benzene with water in a water-jet vacuum pump (300 mm RT.CT.) within 3 hours. The temperature was then raised to 80oWith and drove the rest of benzene. Received 1062 g of benzene with a moisture content of 0.3% and 27 g of water after separation of the mixture.

b) Synthesis of Penta-O-nicotinate glycyrrhizic acid.

In the remaining after distillation of the benzene mixture at 75 80oWith loaded with vigorous stirring 695 g (3.9 mol) of the hydrochloride of the acid chloride of nicotinic acid (V), obtained by the method of [7] portions 40 60 g for 1 h while cooling the flask in a bath of water.

Maintained the reaction mixture with stirring for 3.5 h at 80oC. Then switch off the stirrer and bogra by decantation (563 g), the remaining thick dark brown mass was added, and 765 g of acetone under stirring, heat the mixture to 50oC and stirred until a homogeneous solution.

The solution was filtered and poured 22.5 l of distilled water under stirring. Stirring was continued for 30 min, then the precipitate nigrizia was filtered. The filtrate was poured into a bottle 21,4 liters of the Crude product from the filter was dissolved in 3000 ml of a mixture of chloroform methanol (10:1, v/v), was stirred for 30 min, allowed to settle for 1 h, separated aqueous (upper) phase (1948 ml) and the organic part (3400 ml) was poured into the flask with 7 l of ether with stirring, stirred 30 min, filtered, the precipitate nigrizia, washed it on the filter with 5 l of ether, and dried in a stream of nitrogen. Received 545 g of dry Penta-O-nicotinate glycyrrhizic acid. Output 77.1% in terms of glitsiram with 100% content of the basic substance or 85,3% in terms of industrial glitsiram (VFS) with the content of the basic substance 90,4% Rfof 0.61 (chloroform-methanol-water 45: 10: 1), []2D0= +28o(from 0.03; dioxane); +33o(c 0,015; 0,1 NKOH). Found, C 64,79; H 6,22; N 4,47; C72H77N5O21. Calculated C 64,13; H 5,76; N 5,19. UVdiomaxXan(lg): 246 nm (4,35); UV,0,1maxoWith and kept the mixture at this temperature until the termination of the distillation of benzene. Separated separated benzene (1014 g) and water (44 g).

Into the reaction flask at a temperature of 78 to 80oWith intensive stirring downloaded portions (40 to 60 g) 685 g (of 3.85 mol) of the hydrochloride of the acid chloride of nicotinic acid for 1 h and stirred the mixture at a temperature of 78 to 80o4 h, cooled the mixture to room temperature and allowed to stand for 2 hours is Formed of two layers: the upper tributylamine and lower reaction mass is dark brown. The top transparent layer leaked by decantation (separated 738 g TBA). The remaining dense mass added 910 g of acetone was heated to 50oC, stirred for 20 min to dissolve, filtered, and poured into the reactor containing 24 l of distilled water, and stirred 30 minutes the precipitate was Filtered nigrizia, then the crude product is transferred from the filter to the mix 3000 ml of chloroform and methanol (10:1, v/v), was stirred for 30 min and allowed to settle for 1 h After separation of the layers merged aqueous layer containing the impurity of TBA and the organic phase was filtered and poured into 8 l of ether under stirring, the precipitation nigrizia was filtered, washed on the filter with ether, and dried in a current of literam or 84.2% in terms of glitsiram with the content of the basic substance 90,4% VFS). Rfof 0.60 (chloroform-methanol-water 45:10:1); []2D0+40o(from 0.02; of 0.1 N KOH), IR , cm-1: 1810 (C=O); 1740 (COOR); 1660 (C110); 1600 (pyridine). UVdiomaxXan-methanol(lg0,1maxNKOH(lg90 100 g) to pH 8 to 9, allowed to settle for 2 h and was poured top layer TBA (1592 g). Just regenerates 1592 + 738 2330 g TBA, loss 2330 2670 340 g (13%).

Example 3. Getting nigrizia of trikalinos salts of glycyrrhizic acid.

a) Azeotropic dehydration of raw materials and tributylamine.

A 5-liter flask equipped with a mechanical stirrer, a refrigerator and a separating vessel, put 2450 g tributylamine (0,12% H2O) and 1570 g of benzene (0.04% of H2O) and heated the mixture up to 70oC. Drove azeotropic mixture of benzene with water for 2 hours turned Off the heat and loaded into the flask 600 g (0.64 mol) trikalinos salts of glycyrrhizic acid (III) (% H2O 5,67) that is made from the glycyram by the method of [5] at a temperature of 70 - 75oWith vigorous stirring. Again include heating the flask and continued azeotropic drying before the termination of allocation of water (4 to 6 h at to75 80oC). Then removed the separating vessel, the azeotropic mixture of benzene and water after separation divided. The remainder by vacuum distillation, 104,

b) stage of synthesis nigrizia.

In the remaining after distillation of the benzene, the reaction mixture is at a temperature of 65 - 70oWith downloaded 840 g (4,71 mol) of the hydrochloride of the acid chloride of nicotinic acid (V) portions 40 60 g when the cooling water temperature of the reaction mixture should not rise above 70oC) for 2 hours

The mixture was heated at 75 80oC for 3 hours turned Off the heating and after settling the mixture for 2 h separated tributylamine by decantation (396 g). The reaction mass was diluted 956 g of 1,4-dioxane with stirring and poured the mixture into a reactor containing 7 liters of distilled water and stirred for 20 min. was pumped out sediment nigrizia, washed on the filter with 150 l of water in portions of 25 l under pressure and dried the product first under a stream of nitrogen, then in a vacuum oven (40 mm RT.CT.) at t 60oC. Received 705 g (81.7 per cent) substance nigrizia, homogeneous by TLC. Rfof 0.61 (chloroform-methanol-water 4: 10: 1); []2D0= +40o(0,1; 0,1 NKOH), IR , cm-1: 1815 (C=O), 1730 (OOR), 1660 (C11O), 1590 (pyridine); UV,0,1maxNKOH(lg): 245 nm (4,53). Found, C 64,12; H Of 5.89; N To 4.52. C72H77N5O21. Calculated C 64,13; H 5,76; N 5,19. The filtrate after the CTD is Lily, received 1780 TBA. The aqueous layer (8300 g) was evaporated to 2000, was still mixed with 30 g of KOH and defended within 2 hours After stratification has allocated a further 230 g TBA. The aqueous layer was neutralized with hydrochloric acid and threw it into the drain.

Just regenerates 395 + 1780 + 230 g 2405 g of TBA, which is used in the following synthesis nigrizia. Loss TBA: 2405 2450 45 g (1.8 per cent).

The method of receiving Penta-O-nicotinate glycyrrhizic acid from glycyrrhizic acid using acid chloride of nicotinic acid in the environment of a nitrogenous base, wherein the glycyrrhizinic acid transferred in glitsiram or TRACELEVEL salt and subjected to azeotropic drying in a mixture of tributylamine and benzene at 69-70oWith vacuum and chlorhydric nicotinic acid is used in the form of hydrochloride at a temperature of 75-80oC for 3-4 h at a molar ratio of reagents 1:7,4 7,6 respectively, followed by decantation of tributylamine and treating the reaction mixture with acetone at 50oC.

 

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