Method for preparing betulinic acid from betulonic acid

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

 

The invention relates to methods of producing biologically active substances from the products of the chemical processing of the outer layer of birch bark (bark), and in particular to methods of obtaining Betulinol acid from betulone acid. Betulin acid (3β-hydroxy-20(29)-lupen-28-OIC)-natural biologically active substance suppressing the growth of cancer cells, as well as possessing anti-HIV activity.

A known method of obtaining Betulinol acid recovery betulone acid with sodium borohydride in tetrahydrofuran for 12 hours at 0° [Kim Darric S.H.L., Chem Zhidong, Nguen van Tayen, Pezzuto, John M. // Synth. Commun., 1997, V.27, N 9, P.1607-1612]. The allocation of Betulinol acid is carried out by distillation, 50% of tetrahydrofuran under vacuum, dilute the reaction mixture with ethyl acetate, washing the organic solution with water, drying and distillation of the organic solvent. Betulinol acid is obtained in the form of a mixture of biologically active 3β-hydroxyether and inactive 3α-isomer in a ratio of 19:1.

The disadvantage of this method is the use of highly explosive tetrahydrofuran as solvent, the increase in energy costs associated with the need to cool the reaction mass to 0°during the whole recovery process, as well as the duration of the process (12 the Asses).

Known methods of recovery betulone acid in Betulinol in propanol-2 or mixed solvents (ethanol-dioxane or methanol-chloroform) [Flechter O., Nigmatullin LR, Baltina L.A. and other Chemical and pharmaceutical journal T.36, No. 9, P.26-28, 2002]. In this way betulonovoi acid restores the sodium borohydride in isopropanol at a temperature of 0°or 20°C for two hours with the release of 92-95% (mixture of 3βand 3α-isomers) or dioxane for 1.5 hours at a temperature of 0°or 20°exit 90-92% or in mixtures (1:1, v/v) ethanol-dioxane or methanol-chloroform for 2 hours at a temperature of 0°or 20°exit 90-92% 85-88%, respectively.

The disadvantages of this method include the use of flammable and toxic solvent is isopropanol, dioxane, chloroform.

The closest in technical essence and the achieved result is the method of obtaining Betulinol acid, which betulonovoi acid restores the sodium borohydride at room temperature in alcohols C2-C4for three hours, followed by separation of the target product by recrystallization [EN 2190622, 10.10.2002]. In this way the output of Betulinol acid in a mixture of 3βand 3α-isomers is 98%.

The disadvantages of this method include the use of potaroo the ACLs and toxic solvents - alcohols With2-C4.

Object of the invention is the simplification of the process, its cheaper, creating a safe and environmentally friendly way of getting Betulinol acid.

The problem is solved in that in the method of obtaining Betulinol acid by restoring betulone acid with sodium borohydride at room temperature and then videleniem the target product by recrystallization, according to the invention, the recovery is carried out in water.

Comparative analysis with the prototype shows that the distinctive features of the prototype indicator is a restoration betulone acid in water but not in alcohol C2-C4that greatly simplifies and reduces the cost of the recovery process, making it more environmentally friendly and safe.

The process is as follows.

A portion of sodium borohydride dissolved in water at room temperature, followed by stirring in small portions to the solution is injected betulonovoi acid (ratio betulone acid and sodium borohydride remains constant and equal to 1:8). Stirring is continued for 4 hours. Upon completion of the reaction the excess sodium borohydride is decomposed with 10% hydrochloric acid solution. The precipitate is washed with water and dried. Betulin acid is a mixture of 3βand 3α-hydroxy isomers in a ratio of 19:1 records PMR-spectroscopy. The selection of biologically active 3β-hydroxy isomer perform double recrystallization from ethanol.

Data spectroscopic 3β-hydroxy-isomer: (CDCl3) (δ), (ppm) 4,79 (single. 1H, 29N); 4,65 (single. 1H, 29N); 3,22 (duplicates. the duplicates. 1H, 3H 3β-hydroxy-isomer); 3,02 (the trip. 1H, M); 1,66 (single. 3H, 3-Me); 0,79; 0,83; 0,88; 1,0; 1,01 (all single. 5 metal bands: 23-, 24-, 25-, 26-, 27 - Me); 1,05; 2,24 (multiplet C-H). The data of IR spectroscopy: (KBr) 3449, 2941, 2869, 1686, 1639, 1451, 1376,1235, 11186, 1043, 886 (cm-1).

Example. Sodium borohydride - 2,53 g (66,7 mmol) dissolved in 40 ml of water (initial concentration of sodium borohydride 6%), then small portions under stirring solution is injected of 3.78 g (8.3 mmole) betulone acid. Stirring is continued for 4 hours at room temperature. The excess sodium borohydride is decomposed 83 ml of 10% hydrochloric acid. Precipitate Betulinol acid is filtered off, washed with water and dried. The selection of biologically active 3β-hydroxy-isomer perform double recrystallization from ethanol. The output of Betulinol acid in the form of biologically active 3β-hydroxy-isomer is of 85.2%.

This example shows that the solvent can be water use when restoring betulone acid sodium borohydride as the recovery proceeds with quantitative yield(to 85.2).

Thus, this invention provides a simpler, more environmentally friendly way of getting Betulinol acid from betulone acid due to the use as solvent of water instead of organic solvents in the recovery of the sodium borohydride.

The method of obtaining Betulinol acid from betulone acid recovery by sodium borohydride at room temperature, followed by separation of the target product by recrystallization, characterized in that the recovery is carried out in water.



 

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