RU2379314C1 - Method for making allobetulin - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method for making allobetulin exhibits an evident antiviral activity and is of the upmost interest for chemical-pharmaceutical industry. Allobetulin is made of upper birch bark by combining the stages of betulinole extraction from birch bark with aromatic hydrocarbon, and betulinole isomerisation in allobetulin with 30-70% sulphuric acid added.

EFFECT: simplified technology ensured by reduced stages of allobetulin process.

1 cl, 2 tbl, 10 ex

Description

The invention relates to the chemical industry and for obtaining from the outer layer of the birch bark (birch bark) allobetulin.

Allobetulin, a pentacyclic triterpenoid of C ₃₀ H ₅₀ O ₂ oleanan series, is of interest for the pharmaceutical, pharmaceutical and medical industries as a biologically active compound with pronounced antiviral activity.

Allobetulin (19β, 28-epoxyoleanan-3-ol) is formed during the isomerization of betulinol (lup-20 (29) -en-3β, 28-diol) in the presence of acid catalysts.

A known method of isomerization of betulinol to allobetulin by boiling betulin in 88% formic acid, followed by saponification of the resulting allobetulin formate with potassium hydroxide [Chem. Ber., 1922, B55, S.2322].

Similarly, according to the same two-stage scheme, allobetulin is formed through the acyl derivative by heating betulinol in acetic acid containing a catalytic amount of sulfuric acid [Barton D.H.R., Holness N.I. Triterpenoids. Part V. Some Relative Configuration in Rings C.D. and E. The Amirin and the Lupeol Group of Triterpenoids. / J. Chem. Soc., 1952, p. 78-92.].

The disadvantages of the methods are the complexity and multi-stage process of isomerization and, as a consequence, the low yield of allobetulin.

A known method of isomerization of betulinol to allobetulin in hydrochloric or hydrobromic acid [Errington S.G., Chisalberti E.L., Jefferies P.R. The Chemistry of the Euphorbiaceae. Xxiv. Lup-20 (29) -ene-3p, 16β, 28-triol from Beyeria brevifolia var. brevifolia. / Austr. J. Chem., 1976, 29, N8, 1809-1814.].

The disadvantage of this method is that when using hydrohalic acids, special acid-resistant equipment is required, as well as the fact that isomerization in hydrochloric acid along with allobetulinol, with a yield of up to 20%, produces a by-product of isomerization - 20,28-epoxy-19βН-lupan- 3β-ol, which significantly reduces the yield of the target product.

A known method of isomerization of betulinol to allobetulin by boiling betulinol in dichloromethane with iron nitrate adsorbed on silica gel, or ferric chloride adsorbed on silica gel or alumina [Synthesis of betulin derivatives with solid supported reagents. Lavoie Serge, Pichette Andre, Garneau Francois-Xavier, Girard Michel, Gaudet Daniel (Laseve, Univ. Du Quebec a Chicoutimi, 555 boul. Univ., Chicoutimi, Quebec, Canada, G7H 2B1). Synth. Commun. 2001.31, No. 10, p. 1565-1571.].

The disadvantages of the method are the use of environmentally harmful dichloromethane and the difficulty of allocating allobetulin from the reaction medium.

A known method of producing allobetulin directly from birch bark by processing raw materials in a solution of dichloromethane in the presence of FeCl ₃ deposited on silica gel at room temperature. The yield of allobetulin is 11.9% [US 6280778, publ. November 2, 1999].

The disadvantages of this method are the low yield of allobetulin, the difficulty of isolating it in the presence of a heterogeneous catalyst in the reaction mixture, and the use of an environmentally hazardous chlorine-containing solvent.

The closest in technological essence and the achieved result is a method for producing allobetulin [RU 2174126 from 09/27/2001]. It involves the process of betulinol isomerization in the presence of phosphoric acid when heated in a solution of oxygen-containing organic solvents (homogeneous catalysis) or in a hydrocarbon solution coated with an inert carrier orthophosphoric acid (heterogeneous catalysis).

The known method has the following disadvantages: firstly, the need for preliminary isolation of betulinol from the birch bark, which is quite a long and costly process (additional stage); secondly, when phosphoric acid supported on an inert carrier is used in the process of betulinol isomerization, the process of isolating the resulting allobetulin from the reaction medium is complicated.

The technical result of the invention is to simplify the technology by reducing the stages of the process of obtaining allobetulin.

The technical result is achieved by the fact that in the method for producing allobetulin, which includes the isomerization of betulinol to allobetulin in an organic solvent in the presence of an inorganic acid catalyst, the isolation of betulinol from birch bark and its acid isomerization to allobetulin are carried out simultaneously by boiling birch bark in an aromatic hydrocarbon in the presence of 30-70% sulfuric acid.

The proposed method differs from the prototype in that, firstly, allobetulin is obtained directly from the outer layer of the birch bark - birch bark, which greatly simplifies the whole process, reduces the number of stages and duration; secondly, cheaper and more affordable sulfuric acid is used as a catalyst; thirdly, birch bark itself acts as a solid carrier for sulfuric acid.

Thanks to these distinguishing features, it was possible to significantly simplify the technology of the process of obtaining allobetulin by eliminating the stage of separation of betulinol from birch bark.

The method is as follows.

In a flask equipped with a reflux condenser, birch bark is crushed to a particle size of 1-3 mm, and such an amount of sulfuric acid is added that the entire bark is moistened, an aromatic hydrocarbon is added and boiled for 2-4 hours. A hot solution of allobetulin in an aromatic hydrocarbon is separated from the cortex by simple decantation or filtration and distilled off under vacuum. The precipitated light yellow powder is recrystallized from ethanol. White needle crystals with a melting point of 259-261 ° C precipitate.

The structure of the obtained allobetulin is confirmed by NMR spectroscopy. Data ¹ H-NMR (CDCl ₃ ): 3.75 (d, J = 8 Hz, 1H, 28-H), 3.49 (s, 1H, 19-H), 3.41 (d, J = 8 Hz, 1H, 28H), 3.22 (m, 1-H, 3-H), 1.00-1.77 (complex CH ₂ , CH), 0.95, 0.91, 0.83, 0 , 79, 0.76 (all singlets, 21 N, CH ₃ ).

The method is confirmed by specific examples.

Example 1. In a 500 ml flask equipped with a reflux condenser, 10 g of crushed birch bark were placed, 15 ml of 70% sulfuric acid and 200 ml of toluene were poured and boiled for 3.0 hours. The progress of the isomerization reaction is monitored by sampling from the reaction flask by TLC on Silufol plastics in the chloroform-methanol-formic acid system (100: 2: 0.5). A hot solution of allobetulin in toluene is separated from the remainder of the cortex by filtration, then toluene is completely distilled off on a rotary evaporator. The resulting allobetulin is recrystallized from ethanol. The yield of allobetulin in the form of white crystals was 1.8 g or 18 wt.% By weight of birch bark. The composition of allobetulin is confirmed by elemental analysis. Found,%: C 82.01; 81.73; H, 11.61; 10.45; C ₃₀ H ₅₀ O ₂ . Calculated,%: C 81.45; H, 11.31.

Examples 2-5. Carried out analogously to example 1, vary the concentration of sulfuric acid and the duration of the process. The yield of allobetulin is shown in table 1.

The effect of the concentration of H ₂ SO ₄ and the duration of the process on the yield of allobetulin by boiling birch bark in toluene.

Table 1 Example No. The concentration of H ₂ SO ₄ The duration of the reaction, h The output of allobetulin,% one 70 3.0 eighteen 2 60 3.0 19 3 fifty 3,5 22 four 40 4.0 21 5 thirty 4,5 twenty

Example 6. In a 500 ml flask equipped with a reflux condenser, 10 g of crushed birch bark are placed, 15 ml of 70% sulfuric acid are added, after the acid is absorbed into the bark, 150 ml of p-xylene are added and boiled for 2.0 hours. The progress of the isomerization reaction is monitored by sampling from the reaction flask by TLC on Silufol plastics in the chloroform-methanol-formic acid system (100: 2: 0.5). A hot solution of allobetulin in p-xylene is separated from the cortex by filtration, then p-xylene is completely distilled off on a rotary evaporator. The resulting allobetulin is recrystallized from ethanol. The yield of allobetulin in the form of white crystals was 1.7 g or 17 wt.% By weight of birch bark. The composition of allobetulin is confirmed by elemental analysis. Found,%: C 81.99; 81.54; H 11.74; 11.52; C ₃₀ H ₅₀ O ₃ . Calculated,%: C 81.45; H, 11.31.

Examples 7-10. Carried out analogously to example 6, vary the concentration of sulfuric acid and the duration of the process. The yield of allobetulin is shown in table 2.

The effect of the concentration of H ₂ SO ₄ and the duration of the process on the yield of allobetulin by boiling birch bark in p-xylene.

table 2 Example No. The concentration of H ₂ SO ₄ The duration of the reaction, h The output of allobetulin,% 6 70 2.0 17 7 60 2.0 eighteen 8 fifty 2.5 21 9 40 3.0 22 10 thirty 4.0 21

The present invention allows to significantly simplify the technology of obtaining allobetulin and reduce the duration of the process, eliminating the stage of separation of betulinol from birch bark.

Claims (1)

A method of producing allobetulin, comprising isomerization of betulinol to allobetulin in an organic solvent in the presence of an inorganic acid catalyst, characterized in that the separation of betulinol from birch bark and its acid isomerization to allobetulin are carried out simultaneously by boiling birch bark in an aromatic hydrocarbon in the presence of 30-70% sulfuric acids.