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
< / BR>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 otherSelective 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.
< / BR>where
if OR3is set tothen
R1, R2and R3independently from each other represent a hydrogen atom, acyl groupin which R4represents an organic residue with a number of carbon atoms up to 11, or a residue -/CH2/nCOOH carboxylic acid, with n=1-4, and, in addition, R1denotes benzyl, C1-C8-alkilany or C3-C5-cycloalkenyl balance, and
if OR3is in "beta", then
R1, R2and R3independently from each other represent a hydrogen atom, acyl group with 1-12 C-atoms, and R1additionally represents C1-C8is an alkyl residue, and in both cases A-B denote ateno or ethano-bridge,
the method of production thereof, pharmaceutical preparations that contain these compounds and to the use for the preparation of Lech
< / BR>Known methods of obtaining betulin, namely, that the bark is then ground in aqueous alkali and extracted with isopropyl alcohol
exhibiting anti-AIDS activity
FIELD: organic chemistry, steroids, pharmacy.
SUBSTANCE: invention describes unsaturated 14,15-cyclopropanoandrostanes of the general formula (I):
wherein R1 means hydrogen atom (H), hydroxy-group (OH); R2 means hydroxy-group (OH), hydrogen atom (H); R3 means hydrogen atom (H), (C1-C10)-alkyl at α- or β-position; R4 means halogen atom (F, Cl, Br) or pseudohalogen group (azide, rhodanide), hydroxy-group (OH), perfluoroalkyl; R5 means (C1-C4)-alkyl; if double bond is at 1,2-position then R4 can mean hydrogen atom (H). Also, invention relates to a method for preparing these compounds and pharmaceutical compositions containing these compounds. Compounds of the formula (I) are compounds eliciting gestagenic and/or androgenic effect.
EFFECT: improved preparing method, valuable medicinal properties of compounds.
11 cl, 1 tbl, 9 ex
FIELD: chemical technology, natural materials, medicine, pharmacy.
SUBSTANCE: invention relates to the improved method for preparing betulin from betulinic acid that can be used in preparing anti-tumor and anti-HIV medicinal preparations. Method for preparing betulinic acid involves oxidation of betulin with chrome (VI) oxide in acetic acid to betulonic acid and reduction with sodium boron hydride to betulinic acid. Betulonic acid sodium salt is reduced to betulinic acid and reduction reaction is carried out at room temperature at the concentration of sodium boron hydride 1.0-6.0 wt.-%. Invention provides simplifying method for preparing betulinic acid, reducing its cost and enhancing ecological safety of the process of it producing.
EFFECT: improved preparing method.
1 cl, 4 ex
FIELD: organic chemistry, steroids, medicine, pharmacy.
SUBSTANCE: invention relates to steroid compounds of the formula (1)
wherein --- means optional double bonds; R6 means hydrogen atom (H), =CH, -CH3 or -CH2-CH3; R7 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C5)-alkenyl, or (C2-C5)-alkynyl; R11 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl, (C1-C4)-alkylidene; E means 5-7-memberd ring formed with 16 and 17 carbon atoms at α,cis-position relatively to steroid structure and comprising possibly up to two double bonds. Compounds can be used in therapy and in methods for selective modification of activity of estrogen receptors.
EFFECT: improved method for modifying, valuable medicinal properties of compounds.
10 cl, 1 sch, 1 tbl, 1 ex
FIELD: chemical technology.
SUBSTANCE: invention relates to methods for preparing oleanolic acid used as a standard sample (comparison samples) in carrying out standardization of medicinal vegetable raw and phytopreparations comprising triterpene saponins - derivatives of oleanolic acid. For preparing oleanolic acid method involves sum of saponins extracted by alkaline extraction from sugar or table beet root crops followed by reprecipitation in acid medium and extraction of precipitate with ethanol, chloroform. Method provides preparing oleanolic acid of high purity degree from inexpensive and available raw.
EFFECT: improved preparing method.
2 cl, 3 ex
FIELD: organic chemistry, steroids, chemical technology.
SUBSTANCE: invention describes a method for preparing 3-keto-7α-alkoxycarbonyl-substituted ▵4,5-steroid of the formula (I): wherein is taken among or R3 means hydrogen atom (H), lower alkyl, lower alkoxy-group or cyano-group (CN); R21 means hydrogen atom (H) or alkyl; R26 means (C1-C4)-alkyl; R8 and R9 form in common heterocyclic ring system. Method involves interaction of an alkylating agent with 4,5-dihydro-5,7-lactone steroid of the formula (II): wherein R18 means (C1-C4)-alkyl or R18O-group taken in common form O,O-oxyalkylene bridge or keto-group and R3, R8 and R9 have above given values in the presence of a base. Compounds of the formula (I) are used as intermediate compounds in improved methods for synthesis of epoxymexerone.
EFFECT: improved preparing method.
56 cl, 42 tbl, 30 sch, 5 dwg, 89 ex
FIELD: medicine; pharmaceutical industry; perfumery-cosmetic industry; methods production of betulin.
SUBSTANCE: the invention is pertaining to the method of extraction of betulin from the wastes products of wood-processing, in particular, a birch bark processing and may be used in medicine, pharmaceutical and perfumery-cosmetic industries. The method provides for activation of a birch bark by the shock-acoustic impulses, an alkaline hydrolysis and an extraction of betulin by an alcohol. The operations are conducted simultaneously. The technical result of the invention is simplification of the method of the process, reduction of its duration and power input.
EFFECT: the invention ensures simplification of the method of the process, reduction of its duration and power input.
1 cl, 2 ex
FIELD: natural compounds, chemical technology.
SUBSTANCE: invention relates to the improved method for preparing biologically active substances from products of chemical processing vegetable biomass, in particular, to a method for preparing betulinic acid from betuline. Method is carried out by oxidation of betuline with chrome anhydride in acetic acid to betulonic acid, and reduction of betulonic acid with sodium boron hydride is carried out in diethyl ether solution being without its preliminary isolation. Invention provides enhanced yield, simplifying technology, decrease of the process time and decreasing set of solvents used.
EFFECT: improved preparing method.
1 cl, 1 ex
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
FIELD: fine organic synthesis, in particular production of triterpene compounds, betulin, useful in pharmaceutical and cosmetic industry.
SUBSTANCE: betulin is isolated from birch bark by extraction with neutral organic solvents, namely dioxan aqueous solution containing 0-20 mass % of water.
EFFECT: accelerated extraction process, increased yield of target product, decreased concentration of ester contaminants, and simplified betulin purification.
1 cl, 7 ex, 1 tbl
FIELD: natural substances technology.
SUBSTANCE: method of preparing extractive substances from ground birch bark comprises extraction and filtration of precipitated extract. Extraction is effected with extractant condensate sprinkling ground birch bark bed in presence of ascending vapors of the same extractant. Extractant is two-component mixture of water and low-boiling solvent having boiling point below 100°C. Product is isolated by bringing extractant condensate containing dissolved extract with contents of receiver. Once extraction is completed, solvent is removed with live steam.
EFFECT: reduced consumption of extractant, increased degree of extractant regeneration, simplified isolation of product, and reduced fire and explosion risk.
1 tbl, 2 ex