The method of obtaining diacetate betulinol

 

(57) Abstract:

The invention relates to organic synthesis. The method of synthesis of diacetate Betulinol the acetylation of Betulinol in the presence of a catalyst when heated is that acetylation are a mixture of acetic acid and acetates of alcohols WITH1-C4with simultaneous removal of water from the reaction mixture by known methods. The invention eliminates the use of expensive and toxic reagents (acetic anhydride, pyridine, benzene), simplifies the technology reduces costs and reduces the disutility of production. 3 C.p. f-crystals, 2 tab.

The invention relates to pulp and paper and timber industries and the receipt diacetate Betulinol from Betulinol - product obtained or from by-products selfaccelerating production (sulfate soap, tall oil pitch) or bark (outer layer of birch bark).

Betulinol (C30H50O2) is representative of the triterpenoids number of Lupan, in the molecule of which two hydroxyl groups differing in reactivity due to spatial difficulties of access to the secondary alcohol group. The diacetate is aktivnosti, in particular, antitumor, and is due to the availability of raw materials for Betulinol great potential interest for the chemical and pharmaceutical industry

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Organic chemistry is well known that acetyl derivatives of alcohols receive

or direct esterification of alcohols with acetic acid in the presence of catalysts;

or penetrabilities by treating alcohols acetates also in the presence of catalysts;

or, finally, acetylation of alcohols with acid chloride or acetic anhydride.

When the esterification of acetic acid should be expected that, in accordance with various reactive alcohol groups, the process will proceed in two stages: the formation of monoacetate and its subsequent esterification of the secondary alcohol group with obtaining diacetate Betulinol. The second stage of the process is relatively slow due to the availability of alcohol groups. The disadvantage of this method of obtaining diacetate Betulinol is the low selectivity of the process. We found that the selectivity of the process of esterification of Betulinol acetic acid to diacetate is about 66% (table. 1, example 1).

Although the diacetate formed a very large number (20,1%) of unidentified side product of the transformation of Betulinol. Betulinol in these conditions is not spent for its intended purpose, etherification one acetic acid is ineffective.

When using the interesterification (PL. 1, example 2), there remains a large number of Betulinol, diacetate is formed is small, the process is stopped mostly at the stage of formation of monoacetate. This process of obtaining diacetate is clearly unacceptable.

Acetylation with acetic anhydride is used for analytical purposes to determine hydroxyl groups or preparative syntheses, when the alcohol heat - or chemically labile. Literature data show that the diacetate Betulinol work out precisely this way - acetylation or in benzene [Lewandowski C. A., yeskin A. P., Polezhaev N.And. The allocation of betulin and suberin from birch bark, activated in conditions of "explosive autohydrolysis". - Chemistry of plant materials. Barnaul, Ed. Altai state University, 1998, No. 1, S. 5-9], or in pyridine [Lawrie W., McLean), Taylor G. R. Triterpenoids in the Bark of Mountain Ash (Sorbus ancuparia L.] Chem. Soc. 1960, p. 4303-4308] , which we have taken as a prototype, since only these known methods is obtained diacetate Betulinol. When the acetylation take, typically, a large excess of acetic anhydride ( and kept at this temperature for up to four hours. Products acetylation allocate or by cooling the reaction mixture, separating precipitated in the sediment acetate raw and subsequent recrystallization or by treatment with 10-fold volume of water, Department of acetate raw and recrystallization. The main disadvantages of the method acetylation include the following:

- the use of expensive and toxic chemicals (acetic anhydride, pyridine, benzene);

- the formation of two moles of a byproduct of acetic acid to one mole of the product - diacetate in accordance with the stoichiometry of a chemical reaction.

The aim of the invention is to simplify the technology, cost reduction, harm reduction of production due to failure from the use of acetic anhydride, pyridine, benzene and replace them with more technologically advanced and less toxic acetic acid and acetates of alcohols.

In the proposed method the process of acetylation is carried out in the presence of a catalyst by heating a mixture of acetic acid and acetates of alcohols C1-C4with simultaneous selective removal of water from the reaction mixture by known methods.

As catalyst, use one of acidic catalysts, for example, PA is in use acetate, the ethyl acetate, propyl, isopropylacetate, butyl acetate, isobutyl acetate and secondary butyl acetate. The choice of specific acetate alcohol depends on several factors, such as cost, availability, efficiency (from the point of view of removal of water from the reaction zone) and other

Selective withdrawal of water from the reaction zone carry out, or using the adsorbent is silica gel, or by using heterotetramer rectification, bringing the water in the aqueous layer heterogeneous distillate.

Use as acetylides agent mixture of acetic acid and acetate alcohol allows you to fully carry out the reaction of esterification of Betulinol: proportion of unreacted Betulinol is only one per cent, and the target product - 90,0-93,0%.

A positive effect on the esterification of Betulinol acetic acid in the presence of acetates of alcohols quite well illustrate the comparative experiment, the results of which are given in table. 1. In experiments in which the etherification is carried out either only with acetic acid, or alkyl acetate (butyl acetate), the selectivity is low and is on target product - diacetate, respectively 65,8 and 25.5%. At the same time Ispolkom. table. 1, example 3). One of the possible reasons for such a positive influence butyl acetate is a decrease in the concentration of butanol (due to the esterification of butanol, acetic acid), which impedes the process of interesterification of Betulinol-butyl acetate.

Thus,

the acetates are involved in the synthesis reaction diacetate Betulinol, providing an additional positive influence on the process of acetylation;

- acetates prevent unwanted side turn Betulinol in by-products under the action of p-TJC that take place in other solvents (heptane, toluene, dioxane);

- acetates highly soluble catalytic amount of p-TJC, thus ensuring that the reaction in homogeneous phase;

the acetates are effective separating agents for azeotropic the conclusion of the reaction water from the reaction zone.

The process of acetylation is carried out in a reactor equipped with a reflux condenser to selectively remove water from the reaction mixture. In the reactor load Betulinol, acetic acid and alkyl acetate (isopropylacetate, ethyl acetate, butyl acetate, and others ). The lower limits of the ratios of Betulinol : acetic acid and Betulinol : alkyl acetate due to the degree determined by technological considerations. A very large excess of acetic acid or butyl acetate (or together) will lead to a decrease in specific capacity acetylation and large reciclar reagents. The ratio of acetic acid and acetate alcohol can theoretically vary in a fairly wide range.

As the catalyst in the initial mixture was added p-TJC. The mixture is heated to boiling point. The resulting pair after condensing in the reflux condenser arrive in a device for the selective removal of water. Dehydrated distillate is returned back to the reactor. The process is carried out under boiling the reaction mixture for 4-6 hours After the acetylation reaction mixture is evaporated, then cooled to 5-10oC for crystallization diacetate Betulinol. The obtained semi-product has the following composition, wt.%:

Betulinol - 0,1-0,5

Monoacetate Betulinol - 0,8-2,5

The diacetate Betulinol - 90,0-93,0

Unidentifiable components - 4,0-7,0

To obtain a more pure product - diacetate Betulinol is isolated from the reaction mixture, the intermediate may be subjected to additional cleaning - recrystallization from isopropyl alcohol. After OBR what kristallizatsiei at 5-10oC diacetate Betulinol mass fraction of the basic substance is 98%.

In example 1 (table. 2) the process of acetylation of Betulinol acetic acid and butyl acetate is carried out in periodic mode for periodically operating facility, consisting of a cube-Tarifficator equipped with a heater, distillation column efficiency about 15 theoretical plates, reflux condenser with Florentino (the decanter) for selection in aqueous heterogeneous layer of the distillate. In the cube load 10 g Betulinol, at 88.1 g of butyl acetate, 26,0 g of acetic acid and 0.5 g PTS. The reaction mixture is in the cube, bring to a boil. After heating installation and the appearance of vapor reflux for 4 h hold acetylation of Betulinol with simultaneous sampling of water in the aqueous layer of Florentine as it accumulates. After completion of the reaction the mixture is evaporated, cooled to -10oC for crystallization diacetate Betulinol. Data on the composition of the obtained semi-product are given in table. 2. After recrystallization of the intermediate obtained in the conditions of example 1 (table. 2), isopropyl alcohol (mass ratio diacetate:alcohol of 1:10) at 20-25oC get 98% diacetate Betulinol.

In examples 2-Aime. The plant consists of a reactor with heating, fridge-dephlegmator and ciliegiolo desiccant from which the dehydrated distillate flows back into the reactor. In the reactor load Betulinol, acetate, alcohol, acetic acid and 150 mg PTSC. The original mixture is heated to boiling point and conduct the process under boiling for 4 hours Then the reaction mixture is evaporated, cooled to 5-10oC for crystallization diacetate Betulinol. Data on the composition of the obtained semi-product are given in table. 2.

Thus, the way to replace acetic anhydride and pyridine for more sophisticated and less toxic acetic acid and acetates, alcohols, simplify the production technology diacetate, will reduce waste and provide a less harmful working conditions.

The method developed in the laboratory, the implementation of it will not be difficult due to the simplicity of technological operations.

Production of diacetate Betulinol planned for OJSC "Mondi Syktyvkar LPK" and "Lesosibirsk KAS".

1. The method of obtaining diacetate Betulinol the acetylation of Betulinol in the presence of a catalyst when heated, characterized in that the process aznam removing water from the reaction mixture by known methods.

2. The method according to p. 1, characterized in that the catalyst used paratoluenesulfonyl.

3. The method according to PP.1 and 2, characterized in that as acetates of alcohols using methyl acetate, ethyl acetate, propyl, isopropylacetate, butyl acetate, isobutyl acetate and secondary butyl acetate.

4. The method according to PP.1 to 3, characterized in that the selective withdrawal of water from the reaction zone carry out, or using the adsorbent is silica gel, or by using heterotetramer rectification, bringing the water in the aqueous layer heterogeneous distillate.

 

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