Method of obtaining and purification gemcitabine hydrochloride

FIELD: chemistry.

SUBSTANCE: claimed invention relates to method of gemcitabine hydrochloride purification, which includes enriching gemcitabine hydrochloride with its p-anomer, according to which solution of gemcitabine hydrochloride in water is taken with ratio of water to gemcitabine hydrochloride from 3:1 to 12:1 (wt/vol); solution is processed with activated coal, activated coal being taken in amount from 0.1 to 10 wt % of gemcitabine hydrochloride amount in solution; activated coal is removed from solution with formation of filtered solution; concentration of gemcitabine hydrochloride in filtered solution is increased until ratio of filtered solution to gemcitabine hydrochloride equals from 1:1 to 1:5 (wt/vol), efficient for gemcitabine hydrochloride sedimentation; deposited gemcitabine hydrochloride is isolated; and in case admixture content in deposited gemcitabine hydrochloride is not reduced to required level, stages (a)-(e) are repeated. Claimed invention also relates to method of obtaining gemcitabine hydrochloride using claimed purification method.

EFFECT: creation of efficient method of gemcitabine hydrochloride purification.

5 cl, 1 tbl, 5 dwg, 8 ex

 

Cross references to related applications

This patent application claims the priority of patent applications in India No. 183/DREAMS/2006 and 874/DREAMS/2006, registered on 6 February 2006 and may 18, 2006, respectively, which are entirely included here as a reference, and provisional patent application U.S. No. 60/804836 registered on 15 June 2006, which is entirely incorporated here by reference.

The level of technology

The present invention relates to a process for the preparation of gemcitabine hydrochloride. More specifically, the invention relates to a method for you to receive gemcitabine hydrochloride, not containing impurities related to the manufacturing process.

Gemcitabine hydrochloride is known under the chemical name 2'-deoxy-2',2'-diversityin monohydrochloride (β-anomer) (hereafter denoted as the adopted name of gemcitabine hydrochloride and has the structural formula I

Gemcitabine hydrochloride is a nucleoside analogue exhibiting antitumor activity, and available on the market under the trade name GEMZAR®in the form of a preparation for injection. Bottle Gemzar contains the amount of gemcitabine hydrochloride equivalent to 200 mg or 1 g of free base.

Ways to increase the number β-anomer known in the art. For example, U.S. patent No. 5945547 RA the create method of purification of gemcitabine hydrochloride in respect of its anomeric purity. The method includes dissolving a 1:1 α/β anomeric mixture in hot water, followed by addition of acetone by heating to boiling under reflux, cooling the solution to a temperature of about -10 to 50°C. the Precipitate gemcitabine hydrochloride is collected and subjected to further purification by repeating the above process until receiving gemcitabine hydrochloride with a purity of about 99%.

Methods of obtaining gemcitabine is also well known in the art. For example, U.S. patent No. 4808614 reveals gemcitabine hydrochloride composition comprising gemcitabine hydrochloride, and their use for the treatment of infections of the herpes virus. It also describes how to receive gemcitabine hydrochloride, is depicted in scheme I.

Scheme I:

The aforementioned method discloses the use of hydrolytic reagents, such as weakly acidic ion-exchange resin, for the conversion of compounds of Formula III to the compound of Formula IV.

U.S. patent No. 5223608 discloses a method of obtaining gemcitabine hydrochloride by using a hydrolytic reagent, such as a strong acid to obtain 2-deoxy-2,2-debtor-D-erythropoietins-1-ulose-3,5-dibenzoate Formula VA.

This method is represented by scheme II.

Scheme II:

Publication of the proposal is ARTICLE No. 2005/095430 A1 discloses a method of obtaining gemcitabine hydrochloride. This application describes the use of hydrolytic reagents such as strong acids, to obtain 2-deoxy-2,2-debtor-D-erythropoietins-1-ulose-3,5-dibenzoate Formula VA and also describes the purification of the compounds of Formula VA. This application also describes a method of purification of gemcitabine hydrochloride by dissolving 95% enriched β-anomer of gemcitabine hydrochloride in water allocation by use of solvents, such as isopropyl alcohol or acetonitrile or acetone.

The method is represented by scheme III.

Scheme III:

These are the main methods of receiving gemcitabine hydrochloride. The above approaches use a weakly acidic ion-exchange resin and a strong acid as agents of hydrolysis in the formation, unprotected or protected lactone. Both types gidroliznaya agents have the disadvantage that is associated with the formation of lactoovo rings. Can form undesirable reaction products in the form of impurities and the lactone often returns to its precursor with an open circuit due to the sensitivity to strong acids and resins.

The present invention relates to a method for producing intermediate products and to improve the methods of purification with the aim of obtaining the required β-anomer of gemcitabine hydrochloride, essentially not containing α-EN is a measure.

In accordance with the present invention offers a convenient way to receive gemcitabine hydrochloride and its intermediates with the desired purity and yield by using the best methods of synthesis that are simple, environmentally safe, cost effective, reliable and suitable for use on an industrial scale.

The invention

The present invention provides a method of purification of gemcitabine hydrochloride with the purpose of receiving gemcitabine hydrochloride, enriched it β-anomer.

According to a variant implementation of the method of purification of gemcitabine hydrochloride, enriched it β-anomer, involves the following stages:

a) a solution of gemcitabine hydrochloride in water at a ratio of water and gemcitabine hydrochloride from about 3:1 to about 12:1 (wt./vol.);

b) treating the solution with activated carbon in an amount of from about 0.1 to 10 wt.% the number of gemcitabine hydrochloride in solution;

c) removing the activated carbon from the solution to form a filtrate;

d) increasing concentrations of gemcitabine hydrochloride in the filtrate to the filtrate and gemcitabine hydrochloride from about 1:1 to about 1:5 (wt./vol.), effective for deposition of gemcitabine hydrochloride, and

e) allocation besieged gemcitabine hydrochloride.

<> In another aspect, the present invention relates to a process for the preparation of gemcitabine hydrochloride and its intermediates.

According to a variant implementation of the method of receiving gemcitabine hydrochloride of Formula I includes:

i) the conversion of compounds of Formula III to the compound of Formula IV using reagents of decyclization in the presence of a suitable organic solvent, followed by azeotropic distillation;

ii) protection of the hydroxyl groups of the compounds of Formula IV using suitable reagents protection of hydroxyl groups in the presence of a suitable organic solvent at the desired temperature with the formation of the compounds of Formula VB;

iii) recovering the compounds of Formula VB by using a suitable reducing agent in the presence of a suitable organic solvent to form the compounds of Formula VIB;

iv) protection of the compounds of Formula VIB with alkyl - or arylsulfonate, in the presence of a suitable base and a suitable organic solvent to form the compounds of Formula VIIB;

v) the condensation of the compounds of Formula VIIB with the compound of the Formula VIII in the presence of a suitable organic solvent and suitable bases with the formation of the compounds of Formula IX and

vi) removing the protective groups of the compounds of Formula IX using a suitable reagent, followed about what the introduction of the reaction with hydrochloric acid in the presence of a suitable organic solvent with the formation of gemcitabine hydrochloride of Formula I.

Another aspect of the present invention provides crystalline gemcitabine hydrochloride, characterized by its restenosis powder diffraction pattern (RPD), the curve of differential scanning calorimetry (DSC) and/or infrared absorption spectrum (IR).

In another aspect the invention provides gemcitabine hydrochloride, essentially not containing residual solvents.

Brief description of drawings

Figure 1 is an x-ray powder diffraction pattern of gemcitabine hydrochloride, obtained as described in example 8.

Figure 2 represents the results of differential scanning calorimetry sample gemcitabine hydrochloride, obtained in accordance with example 8.

Figure 3 is an IR spectrum of the sample gemcitabine hydrochloride, obtained in accordance with Example 8.

Figure 4 is a thermogravimetric curve of the sample gemcitabine hydrochloride, obtained in accordance with Example 8.

Figure 5 is a HPLC-chromatogram (a chromatogram obtained by HPLC) sample gemcitabine hydrochloride, obtained in accordance with Example 8.

Detailed description of the invention

U.S. patent No. 5945547 describes the method of using the acetone/water. The authors of this of the Britania suddenly discovered, the use of water without acetone leads to the improvement of the anomeric purity.

Thus, the present invention provides a method of purification of gemcitabine hydrochloride with the formation of gemcitabine hydrochloride, enriched it β-anomer.

According to a variant implementation of the method of purification of gemcitabine hydrochloride, enriched it β-anomer:

a) take the solution of gemcitabine hydrochloride in water at a ratio of water and gemcitabine hydrochloride from about 3:1 to about 12:1 (wt./vol.);

b) is treated with a solution of activated carbon in an amount of from about 0.1 to 10 wt.% the number of gemcitabine hydrochloride in solution;

c) removing the activated carbon from the solution to form a filtrate;

d) increase the concentration of gemcitabine hydrochloride in the filtrate to the filtrate and gemcitabine hydrochloride from about 1:1 to about 1:5 (wt./vol.), effective for deposition of gemcitabine hydrochloride, and

e) allocate besieged gemcitabine hydrochloride.

Stage (a) comprises providing a solution of gemcitabine hydrochloride in a solvent consisting essentially of water.

A solution of gemcitabine hydrochloride may be obtained by dissolving in water. To obtain the solution suitable any form of gemcitabine hydrochloride, such as any crystalline or amorphous Faure is and gemcitabine hydrochloride.

Gemcitabine hydrochloride, intended for dissolution may be obtained by methods known in the art, or in the ways described.

The concentration of the anomeric mixture of salts in water is not critical, provided that the used amount of water sufficient to ensure complete dissolution. In order to avoid excessive loss of product in the crystallization process and the allocation is supported by a small amount of water used. The amount of water used to allocate beta-anomer is from about 3 to about 12-fold (wt./about.) compared to gemcitabine hydrochloride.

The solution can be prepared at a temperature in the range of from about 25 to 100°C. depending on the amount of solvent dissolution can be carried out in the temperature range 25-100°or dissolution may require the use of elevated temperatures in the range of from about 50 to 100°C.

The solution can be optionally treated with activated carbon to improve the color of the connection followed by filtration through a medium, such as through a layer of soda in the presence of sintering agent diatomaceous earth (Hyflow) to remove carbon.

The preferable number of carbon of the coal used for the selection of beta-anomer with improved color, extending t is from about 0.1 to about 10 wt./wt. carbon coal per gram of the mixture α/β anomers.

Processing of coal can be carried out at a temperature of dissolution or after cooling the solution to a lower temperature.

The solution can be optionally filtered by passing through paper, glass fiber or other membrane material, or a brightening agent such as celite. Depending on the equipment used, concentration and solution temperature filtering device may need to be pre-heated in order to prevent premature crystallization.

The concentration of the solution may range from about 1 g/ml to about 20 g/ml of solvent or in the range from 1 g/ml to 5 g/ml.

Stage (b) comprises increasing the concentration of gemcitabine hydrochloride in the specified solution to cause precipitation of the specified β-anomer.

Concentration may be carried out by evaporation, distillation at atmospheric pressure or distillation under vacuum.

Distillation of the solvent may be conducted under vacuum from about 100 mm Hg to about 600 mm Hg at a temperature of from about 40°With up to about 70°C. Can be used in any temperature and values of the vacuum, provided that the concentration occurs without increasing levels of impurities.

The concentration of the slurry is about Voditsa to the state, in which precipitation occurs gemcitabine hydrochloride from a solution by transformation of the solution into the suspension. In General, the concentration cease when the ratio of solvent to gemcitabine hydrochloride is from about 1:1 to about 1:5.

The reaction mass may then be maintained at a temperature below the temperature of the concentrate, for example, the following temperature from about 40°up to about 45°Since, during the period of time necessary for a more complete selection of product. The exact temperature of the cooling and the time required for complete crystallization, can be easily determined by a person skilled in the technical field and will also depend on parameters such as concentration and temperature of the solution or suspension.

Stage (C) includes the allocation of the specified β-anomer.

The allocation of solids can be carried out by conventional methods, such as filtering, decanting, centrifuging and the like, or by filtration in an inert atmosphere using gases such as, for example, nitrogen, etc.

Moist filter residue obtained in stage (C), does not need to be additionally dried. Drying can be conveniently carried out in a tray dryer, vacuum oven, drying oven, fluidized bed dryer, rotary spray is whilke, the spray dryer and the like, the Drying may be conducted at a temperature of from about 35°With up to about 70°C. Drying can be carried out for any desired period of time from about 1 to 20 hours.

In a specific embodiment of the invention described above, the method according to the invention can be adapted for use as the basis of a continuous crystallization process. The purity of the product obtained in stage (C), check to determine the percentage of impurities in alpha-anomer. If the impurity content is not decreased to the desired level below 0.1% by results of the analysis by HPLC, stage (a)-(C) repeat for wet material obtained in stage (C). If at the stage (C) reaches the desired purity, the loop stops.

Thus, the cycle of operations that can be repeated infinitely, making it possible to adapt the method according to the invention for continuous process with obvious attendant advantages when used on a commercial scale.

Purified gemcitabine hydrochloride obtained above, contains less than 0.1%, or less than 0.01% of any impurities cytosine and α-anomer.

Gemcitabine hydrochloride, obtained as described above were analyzed by HPLC according to the method described in the US Pharmacopoeia (UP) 29; NF 24; 2006; page No.990-991, as indicated in the table.

Method HPLC
Column and packingBond Rx C8 H 4.6 mm, 5 μ
The buffer13.8 g NaH2PO4·H2O and 2.5 ml of phosphoric acid diluted in 1000 ml of purified water (milli Q) and filter the solution through a porous membrane filter of 0.45 μm. The solution has a pH in the range of 2.4 to 2.6
The mobile phase AndAs the mobile phase used buffer
The mobile phaseUse a filtered and degassed methanol
GradientTime (in minutes)Solution A (% vol./about.)The solution In (% vol./about.)Elution
0-8973Isocratic
8-1397-503-50A linear gradient
13-205050Isocratic
20-2550-9750-3Re-balancing
25-30973Trim
Consumption 1.2 ml/min
Wavelength detectionUV 275 nm
Temperature25±2°
The volume of injected sample20 ál
ThinnerWater Milli Q
The analysis time30 minutes
Name impuritiesThe relative retention time (RRT)
The admixture α-anomer0,67
A mixture of cytosine0,37

In one aspect the present invention provides a method of receiving gemcitabine hydrochloride and its intermediates.

According to a variant implementation of the method of receiving gemcitabine hydrochloride and its intermediates involves the following stages:

i) the conversion of compounds of Formula III to the compound of Formula IV using reagents of decyclization in the presence of a suitable organic solvent, followed by azeotropic distillation;

ii) protecting the hydroxyl groups of the compounds of Formula IV using suitable reagents protection of hydroxyl groups in the presence of a suitable organic solvent at the desired temperature with the formation of compounds the Formula ia VB;

iii) recovery of the compounds of Formula VB by using a suitable reducing agent in the presence of a suitable organic solvent to form the compounds of Formula VIB;

iv) protecting the compound of Formula VIB with the use of alkyl - or arylsulfonate in the presence of a suitable base and a suitable organic solvent to form the compounds of Formula VIIB;

(v) condensing the compounds of Formula VIIB with the compound of the Formula VIII in the presence of a suitable organic solvent and suitable bases with the formation of the compounds of Formula IX and

vi) removing the protective groups of the compounds of Formula IX using a suitable reagent followed by reaction with hydrochloric acid in the presence of a suitable organic solvent with the formation of gemcitabine hydrochloride of Formula I.

Stage i includes the conversion of the compounds of Formula III to the compound of Formula IV using reagents of decyclization in the presence of a suitable organic solvent, followed by azeotropic distillation.

Suitable temperature range for the reaction is from about 20°With up to about 70°C.

Additionally, the reaction mass is subjected to azeotropic distillation after addition of the iodine in the alcohol solvent. The distillation can be conducted at a temperature of from about 50°With approximately 150°C.

Suitable solvents that can be used for the reaction include, without limitation, alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol and the like; hydrocarbons such as n-hexane, cyclohexane, n-heptane, toluene, chlorobenzene, 1,2-dichlorobenzene, xylenes, etc.

Stage ii includes the protection of hydroxyl groups of the compounds of Formula IV using suitable reagents protection of hydroxyl groups in the presence of a suitable organic solvent at the desired temperature with the formation of the compounds of Formula VB.

According to a variant implementation of the protective group used to protect the hydroxyl group of the compounds of Formula IV is tert-butyldiphenylsilyl, with the formation of the compounds of Formula VB.

Suitable protective groups of hydroxyl, which can be used in the above reactions include, without limitation, silyl hydroxyamine group, such as tert-butyldiphenylsilyl, trimethylsilane, isopropylimidazole, methyldiisopropanolamine, triisopropylsilyl etc., formyl, 2-chloroacetyl, benzyl, diphenylmethyl, triphenylmethyl, 4-nitrobenzyl, phenoxycarbonyl, t-butyl, methoxymethyl, phenoxyacetyl, isobutyl is l, etoxycarbonyl, benzyloxycarbonyl etc.

Suitable bases that may be used include, without limitation, organic bases such as pyridine, triethylamine, imidazole, 2,6-lutidine, 2,3-lutidine, 3,5-lutidine, etc.

Suitable solvents that can be used in the above reactions include, without limitation, ethers, such as tetrahydrofuran, 1,4-dioxane, diethyl ether and 1,2-dimethoxyethane and the like; hydrocarbons such as n-hexane, cyclohexane, n-heptane, toluene, chlorobenzene, 1,2-dichlorobenzene, xylenes and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide, dimethylacetamide, acetonitrile and the like; ketones, such as acetone, methyl isobutyl ketone, methyl tert-butylketone and the like, or mixtures thereof.

Suitable temperatures for conducting the reaction can be in the range from about 5 to 50°C.

Stage iii) includes the recovery of the compounds of Formula VB by using a suitable reducing agent in the presence of a suitable organic solvent to form the compounds of Formula VIB.

Suitable reducing agents which can be used include, without limitation, sodium bis(2-methoxyethoxy)aluminiumhydride (Vitride), borohydride sodium (NaBH4), lithium hydride-aluminum (LiAIH4), diisobutylaluminum getrid (DIBAL-H).

Suitable solvents that can be used for the above reactions include, without limitation, alcohols, such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and the like; ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether and 1,2-dimethoxyethane and the like; hydrocarbons such as n-hexane, cyclohexane, n-heptane, toluene, chlorobenzene, 1,2-dichlorobenzene, xylenes and the like, or mixtures thereof.

Suitable for the reaction temperature can be in the range from about -50 to 100°C.

Stage iv) provides for the protection of compounds of Formula VI using alkyl - or arylsulfonate in the presence of a suitable base and a suitable organic solvent to form the compounds of Formula VIIB.

According to a variant implementation of the present invention, the protective group used to protect the hydroxyl group of the compounds of Formula VIB is methansulfonate, with the formation of the compounds of Formula VIIB.

Suitable protective groups which can be used to protect hydroxyl groups include, without limitation, alkyl and arylsulfonate, such as methanesulfonate, benzosulphochloride etc.

Suitable solvents that can be used for the above reactions is, include, without limitation, ethers, such as tetrahydrofuran, 1,4-dioxane, diethyl ether and 1,2-dimethoxyethane and the like; hydrocarbons such as n-hexane, cyclohexane, n-heptane, toluene, chlorobenzene, 1,2-dichlorobenzene, xylenes and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide, dimethylacetamide, acetonitrile and the like; esters such as ethyl acetate, isopropylacetate and the like; ketones, such as acetone, methyl isobutyl ketone, methyl tert-butylketone etc. or mixtures thereof.

Suitable temperatures for conducting the reaction can be in the range from about 0 to 50°C.

Stage v) involves the condensation of the compounds of Formula VII with the compound of the Formula VIII in the presence of a suitable organic solvent and a suitable base to form compounds of Formula IX.

Suitable solvents that can be used in the above reactions include, without limitation, ethers, such as tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane and the like; hydrocarbons such as n-hexane, cyclohexane, n-heptane, toluene, chlorobenzene, 1,2-dichlorobenzene, xylenes and the like; esters such as ethyl acetate, isopropylacetate and the like; ketones, such as acetone, methyl isobutyl ketone, methyl tert-butylketone etc., or mixtures thereof.

Suitable bases that may be used include, without limitation, organic bases such as pyridine, triethylamine, hexamethyldisilazane, trimethylsilyltriflate etc.

Suitable temperatures for conducting the reaction can be in the range from about 20 to 100°C.

Stage vi) involves removal of the protective groups of the compounds of Formula IX using a suitable reagent followed by reaction with hydrochloric acid in the presence of a suitable organic solvent with the formation of gemcitabine hydrochloride of Formula I.

Suitable reagents for removal of the protective groups, which can be used can be selected from tert-butylamphetamine, ammonia, acetylchloride, diluted hydrochloric acid, etc.

The solvents used in the above reactions include, without limitation, herstorical, such as water; alcohols such as methanol, ethanol, ethanol hydrochloride, n-propanol, isopropanol, isopropyl alcohol, n-butanol and the like; halogenated solvents such as dichloromethane, dichloroethane, chloroform and the like; ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether and 1,2-dimethoxyethane and the like; hydrocarbons such as n-hexane, cyclohexane, n-heptane, toluene, chlorobenzene, 1,2-dichlorobenzene, xylenes, and so what.; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide, dimethylacetamide, acetonitrile and the like; esters such as ethyl acetate, isopropylacetate and the like; ketones, such as acetone, methyl isobutyl ketone, methyl tert-butylketone and the like, or mixtures thereof.

Optionally, one or more of the successive stages (i)-(iv) are carried out without isolating the compounds of intermediate products. In one embodiment of the invention stage (i) is carried out without isolating the intermediate product, followed by separation of the compounds of Formula VB.

Suitable temperatures for conducting the reaction can be in the range from about -10 to 70°C.

Optional, moist filter residue obtained at different stages of the process, can then be dried. Drying may conveniently be carried out in a tray dryer, vacuum oven, drying skupu, fluidized bed dryer, rotary spray dryer, spray dryer, etc. Drying can be carried out at a temperature of from about 35°With up to about 70°C. Drying can be carried out for any desired period of time from about 1 to 20 hours.

The overall process can be represented by scheme IV:

Another aspect of the present invention provide the supports crystalline gemcitabine hydrochloride, characterized by its x-ray powder diffraction pattern (RPD), the curve of differential scanning calorimetry (DSC) and/or infrared absorption spectrum (IR).

Crystal gemcitabine hydrochloride obtained according to the present invention, is characterized by its RPD-radiograph. All data RPD described here were obtained using Cu Kα radiation having a wavelength 1,541 Åand were obtained using x-ray diffractometer Bruker Axe D8 Advance Powder X-ray Diffractometer.

Crystal gemcitabine hydrochloride is characterized by the diffraction pattern RPD having characteristic peaks at values of 2θ approximately 9.57, 11.35, 13.74, 14.38, 15.29, 19.09, 20.36, 21.15, 22.755, 22.98, at 23.36, 24.02, at 26.58, 27.56, 28.29, 29.19, 30.74, 31.66, 34.45, 35.42, 37.1, at 37.96, 41.99, 44.023±0.2 degrees.

Analysis by the method of differential scanning calorimetry was carried out on the device model DSC Q1000 company TA Instruments at a heating rate of 5°C/minute with a modulation time equal to 60 seconds, and modulation of temperature ±1°C. the Initial temperature was 0°and the final temperature 200°C.

Crystal gemcitabine hydrochloride has a characteristic differential scanning calorimetry, essentially matching is shown in figure 2 and has an endothermic peak at 259-274°C.

Infrared (IR) spectra of gemcitabine g is drochloride were recorded using spectrophotometer model Perkin Elmer Spectrum System 1, in the range from 450 to 4000 cm-1with a resolution of 4 cm-1in the tablet of potassium bromide, at a concentration of tested compound 1 wt.%.

Crystal gemcitabine hydrochloride characterized by an IR spectrum having characteristic peaks at about 3392, 3259, 3117, 3078, 1679, 1535, 1283, 1199, 1065, 856, 814±1 cm-1.

In another aspect the invention provides gemcitabine hydrochloride, essentially not containing residual solvents.

Gemcitabine hydrochloride, obtained using the method according to the present invention, has a value of residual solvent, corresponding to the limits established by the regulations of the International conference on harmonization of technical requirements for registration of pharmaceuticals intended for human use (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, "ICH"). Normative levels of solvent depends on the type of solvent, but are not above about 5000 million-1or about 4000 million-1or about 3000 million-1.

Gemcitabine hydrochloride obtained according to this invention contains less than about 100 million-1or less than about 500 million-1acetone, less than about 100 million-1or less than about 500 million-1isopropanol, less than about 100 million-1 or less than about 500 million-1dichloromethane.

Some specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are illustrative only and should not be construed as in any way ogranichivaya scope of the invention.

EXAMPLES

Example 1

The way to obtain 3,5-bis(tert-butyldiphenylsilyl)-2-deoxy-2,2-debtor-1-uxoribus (Formula VB)

Download 100,3 g ethyl-2,2-debtor-3-hydroxy-3-(2,2-dimethylthiochroman-4-yl)propionate of the Formula III, 2000 ml of methanol and 10,02 g of iodine in a clean and dry round bottom flask and stirred over night. A solution of 22.5 g of sodium thiosulfate in 225 ml of water is added to the above reaction mass at a temperature of about 25-35°C for about 30 minutes, followed by distillation 1000 ml of methanol from the reaction mixture at about 80-95°C. at the same time 500 ml of toluene was added to the resulting reaction mass and 500 ml of solvent is distilled off under atmospheric pressure at 95°C. the above stage is repeated 5 times with 120°and apply vacuum from 650 to 750 mm for complete removal of toluene, obtaining the compound 2-deoxy-2,2-debtor-1-uxoribus Formula IV.

The resulting residue is dissolved in 1325 ml of N,N-dimethylformamide (DMF) under a nitrogen atmosphere at about 25-35°C. Upload 8.5 g of imidazole and 303 ml of tert-butyldiphenylsilyl (TBDPSi-CI) is obtained, as indicated above, the reaction mixture at 25-35°C, and then stirred at a temperature of about 25-35°With during the night. Check the completeness of the reaction by thin layer chromatography and cooled to about 10-15°C. Add 2600 ml of water at 10°With simultaneous stirring, followed by extraction 2×500 ml dichloromethane. Organic and aqueous layers are separated, then the organic layer was washed with 500 ml of water, and then the organic layer is completely distilled under 50°under vacuum. The resulting crude product was then purified by chromatography on a column using the solvent system petroleum ether and ethyl acetate, obtaining 100 g of pure named in the connection header.

MS: 662,4 (M+NH4) atomic mass (AMI.).1H NMR: values δ 80.8 million-1(N), 1.1 million-1(N), 4.5 million-1(2H), 3.4 million-1(1H), 3.7 million-1(N).

Example 2

The way to obtain 3,5-bis(tert-butyldiphenylsilyl)-2-deoxy-2,2-diflorasone (formula VIB)

Loaded into a round bottom flask, 100 g of 3,5-bis(tert-butyldiphenylsilyl)-2-deoxy-2,2-debtor-1-uxoribus Formula VB, and 1000 ml of tetrahydrofuran (THF) under a nitrogen atmosphere at about 25-35°With simultaneous stirring. The reaction mixture is cooled to a temperature of from -45 to -50°With, then add 75,4 ml of sodium bis(2-methoxyethoxy is)aluminiumhydride (Vitride) for about 5-10 minutes, followed by stirring under pressure for about 10-15 minutes. Check the completeness of the reaction by thin layer chromatography. After completion of the reaction it received, as indicated above, the reaction mass was added 200 ml of saturated solution of ammonium chloride at about -45°With subsequent separation of the two layers. The resulting aqueous layer is extracted with 3×500 ml of ethyl acetate, after which the separated organic and aqueous layers. The organic layer is completely distilled under vacuum, getting to 103.5 g specified in the connection header.

MS: 664,4 (M+NH4) u (a.m.u.).1H NMR: values δ 0.9 million-1(N), 1,1 (N), 5.1 million-1(1H).

Example 3

The way to obtain 3,5-bis(tert-butyldiphenylsilyl)-1-methanesulfonate-2-deoxy-2,2-diflorasone (formula VIIB)

Loaded into a round bottom flask 103 g of 3,5-bis(tert-butyldiphenylsilyl)-2-deoxy-2,2-diflorasone Formula VIB, 1030 ml of dichloromethane and of 55.5 ml of triethylamine under a nitrogen atmosphere with simultaneous stirring. The reaction mass is cooled to 0-5°C, after which the above reaction mass was added 18.6 ml methanesulfonanilide at 0°C for 10 minutes. The reaction mass is allowed to warm to a temperature of 25-35°C and stirred under pressure for about 3-4 hours until no starting material. Completeness of the reaction is checked by thin layer chromatography. To receive the Noi, as indicated above, the reaction mass was added 300 ml of water and the two layers separated, then the aqueous layer was again extracted with 300 ml dichloromethane. The resulting organic layers are completely distilled under vacuum, obtaining 111,0 g specified in the connection header.

MS: 742,2 (M+NH4) u (a.m.u.).1H NMR: values δ 5.9 million-1(1H), 0,8 (N), 1.1 million-1(N), 3.1 million-1(3H).

Example 4

The way to obtain 1-[2'-deoxy-2',2'-debtor-3',5'-ribofuranose-3,5-bis(tert-butyldiphenylsilyl)-N-acetylcytosine (formula IX)

Loaded into a round bottom flask 92,98 g n-acetylcytosine and 1925 ml of toluene under nitrogen atmosphere. Add the specified flask also 204,6 ml hexamethyldisilazane (HMDS) for about 5 minutes at 25-35°With subsequent distillation of 20% of the solvent under vacuum at about 65°and allow the reaction mass to cool to about 50°C. To the above reaction mixture was added 41 ml trimethylsilylpropyne, after which the reaction mass is heated to boiling under reflux and maintain the reaction mass at the boiling point under reflux for about 2-3 hours under pressure. Distilled from the reaction mixture 585 ml of toluene, then added 1375 ml of toluene and the reaction mass is then cooled to 25-35°C. To the above reaction mass is added to 102.3 ml trimethylsilyl is iflat (TMS-triflate) over a period of 5-10 minutes and the reaction mass is stirred for about 20-30 minutes. The solution metilirovannah the compounds of Formula VIIB in 550 ml of toluene was added to the obtained above Siciliano reaction mass at 25-35°C, after which the reaction mass is heated to boiling under reflux and maintained the reaction mass for about 15 hours under pressure. The reaction mass is then cooled to about 25-35°With simultaneous stirring, then add 40 ml of methanol for about 10 minutes. From the resulting reaction mass is distilled off 50% of the total solvent volume at about 50°under vacuum, then cooled the reaction mass to 0-5°C for about 15-20 minutes. The obtained resinous reaction mass is decanted and the organic layer was washed with 700 ml of a saturated solution of NaHCO3and separated into two layers. The organic layer is distilled under vacuum, getting 134 g specified in the connection header.

Example 5

The method of receiving gemcitabine hydrochloride of formula I

Loaded into a round bottom flask 133 g of 1-[2'-deoxy-2',2'-debtor-3',5'-ribofuranose-3,5-bis(tert-butyldiphenylsilyl)-N-acetylcytosine Formula IX obtained in accordance with example 4, under nitrogen atmosphere. Add 7.5 l of methanol and the reaction solution is cooled to 0-5°C, then added to the reaction solution 1330 ml of ammonia. The resulting solution was concentrated at 50°LMS minimum volume and the reaction mass is extracted with 12 liters of ethyl acetate, after concentrating the organic layer under 50°C. is Added to the obtained, as described above, the reaction mass 1180 ml of tetrahydrofuran (THF) and 79.8 ml of TBAF (Tetra-n-butylammonium) at 25-30°C and stirred for about 1 hour. Completeness of reaction is controlled by thin-layer chromatography and then concentrate the reaction mass under vacuum at 50°C. is Added to this reaction mass of demineralized water and then the aqueous layer was washed with dichloromethane. The resulting aqueous layer is concentrated at 55°With, receiving 72% α-anomer and 24% β-anomer. To the above crude mass was added 190 ml of isopropyl alcohol and then the reaction mass is heated to 60°With, then add 25 ml of concentrated hydrochloric acid. The resulting reaction mass is then cooled to 10-15°C and stirred for approximately 3 hours at 10°C. the Obtained solid is filtered, getting to 69.9% α-anomer and 28,48% β-anomer, and the resulting filtrate concentrated at 45°C. To the obtained crude filtrate was added acetone and stirred for about one night. The obtained solid is filtered, receiving 2% α-anomer and 71% β-anomer. The obtained solid substance was dissolved in demineralised water (qty) and add material darco (coal), after h is th stirred for about 30-45 minutes. The resulting reaction mass is filtered and the resulting filtrate concentrated to a minimum amount, receiving 700 mg specified in the connection header. Purity according to the results of HPLC: 95% pure β-anomer.

Example 6

Purification of gemcitabine hydrochloride

Placed in a reactor 26,4 l (3 volume) of demineralized water and heated to a temperature of about 80-85°C. In the above reactor was added 6.6 kg raw gemcitabine hydrochloride with about 1:1 mix ratio α/β anomeric salts according to the results of HPLC with simultaneous stirring until a clear solution is formed. The reaction solution is cooled to about 20-25°then filter the separated solid under a nitrogen atmosphere and the solid is washed with 5 l of acetone. The obtained solid is dried under vacuum for about 1 hour under nitrogen pressure, gaining 2.7 kg gemcitabine hydrochloride. The selection of enriched β-anomer of the compound may be, for example, at a temperature of from 0 to 10°C. Purity according to HPLC: 98.1 per cent. % α-anomer: 1,7%.

Example 7

Purification of gemcitabine hydrochloride

Placed in a reactor 860 ml of purified water with 86 g of raw gemcitabine hydrochloride with value α/β anomeric mixture of about 1:1. The mixture is heated to a temperature which s about 35-40° With simultaneous stirring until a clear solution is formed. Added to the reaction mass of 0.1 volume of coal at 35-40°With stirring for about 30 minutes. The reaction mass is filtered through Hyflow, then washed with 3×30 ml of demineralized water at room temperature. The resulting filtrate is concentrated to 3 volumes of the reaction mass at 45-50°under a vacuum of 600 mm Hg and then cooled to 15-20°With simultaneous stirring for about 30 minutes at 15-20°C. the Reaction mass is filtered and then washed with 50 ml of acetone at 15-20°and dried under vacuum for 30 minutes. The obtained solid mass was dried at a temperature of about 35-40°C for about 4 hours under vacuum 600-620 mm Hg, receiving 31 g of gemcitabine hydrochloride. Purity according to HPLC: 95,6%, % α-anomer of 3.8%.

Example 8

Purification of gemcitabine hydrochloride

Placed in a reactor 342 ml (12 volumes) of water treated with 28.5 g of gemcitabine hydrochloride having a purity of 95.6% of and is heated to a temperature of about 35-40°With simultaneous stirring until a clear solution is formed. Added to the reaction mass of 0.1 volume of coal at 35-40°With stirring for about 30 minutes. The reaction mass is filtered through Hyflow and then washed 3×25 demineralized water is ri room temperature. The resulting filtrate concentrated to 2 volumes of the reaction mass at 45-50°under vacuum 600-620 mm Hg and then cooled to 25-30°C. the Reaction mass is filtered, and then washed with 31 ml of acetone at 25-30°C. the above process is repeated once and, finally, the obtained solid mass was dried at a temperature of 35-40°C for about 4 hours under vacuum 600-620 mm Hg, receiving 24 g of gemcitabine hydrochloride. Purity according to HPLC: 99,96%. % α-anomer of 0.01%. Optical rotation: [α]D20(10 mg/ml aqueous solution): +47,1°.

1. The method of purification of gemcitabine hydrochloride, suggesting enrichment of gemcitabine hydrochloride it β-anomer, according to which a) take the solution of gemcitabine hydrochloride in water at a ratio of water to gemcitabine hydrochloride from 3:1 to 12:1 (wt./vol.); b) treated solution with activated carbon, and activated carbon charge in the amount of from 0.1 to 10 wt.% the number of gemcitabine hydrochloride in solution; c) removing the activated carbon from the solution with the formation of the filtered solution; (d) increase the concentration of gemcitabine hydrochloride in the filtered solution until the ratio of the filtered solution to gemcitabine hydrochloride from 1:1 to 1:5 (wt./vol.), effective for deposition of gemcitabine hydrochloride; (e) allocate besieged gametab is on hydrochloride; and (f) if the content of impurities in the besieged the gemcitabine hydrochloride has not decreased to the desired level, stage (a)-(e) repeat.

2. The method according to claim 1, in which the specified stage of increasing concentrations involves removing part of the solvent.

3. The method according to claim 1, in which the allocation enriched β-anomer of the compound is carried out at a temperature of from 0 to 10°C.

4. The method of receiving gemcitabine hydrochloride, according to which

a) carry out the reaction of 2-deoxy-2,2-debtor-1-uxoribus Formula IV with t-butyldiphenylsilyl with the formation of 3,5-bis(t-butyldiphenylsilyl)-2-deoxy-2,2-diflorasone Formula VB;

b) restore 3,5-bis(t-butyldiphenylsilyl)-2-deoxy-2,2 - diflorasone Formula VB, using sodium bis(2-methoxyethoxy) aluminium hydride, to obtain 3,5-bis(t-butyldiphenylsilyl)-2-deoxy-2,2-diflorasone Formula VIB;

c) carry out the protection of hydroxyl groups in the 3,5-bis(t-butyldiphenylsilyl)-2-deoxy-2,2-diflorasone Formula VIB, using methansulfonate, with the formation of 3,5-bis(tert-butyldiphenylsilyl)-1-methanesulfonate-2-deoxy-2,2-diflorasone Formula VIIB;

d) carry out the condensation of 3,5-bis(tert-butyldiphenylsilyl)-1-methanesulfonate-2-deoxy-2,2-diflorasone Formula VIIB diselenium compound of Formula VIII with the formation of 1-[2'-deoxy-2',2,-ditto the -3',5'-ribofuranose-3,5-bis(tert-butyldiphenylsilyl)-N-acetylcytosine Formula IX;

e) remove the protection of 1-[2'-deoxy-2',2'-debtor-3',5'-ribofuranose-3,5-bis(tert-butyldiphenylsilyl)-N-acetylcytosine Formula IX using tert-butylammonium, followed by reaction with hydrochloric acid, to receive gemcitabine hydrochloride; and

f) carry out the purification of gemcitabine hydrochloride by the method according to claim 1.

5. The method according to claim 4, whereby 2-deoxy-2,2-debtor-1-uxoribus by the Formula IV are obtained by the reaction of ethyl-2,2-debtor-3-hydroxy-3-(2,2-dimethylthiochroman-4-yl)propionate with iodine in a lower alcohol with subsequent azeotropic distillation.



 

Same patents:

FIELD: medicine, pharmacology, bioorganic chemistry, pharmacy.

SUBSTANCE: invention relates to the effective using amount of β-L-2'-deoxynucleoside of the formula (I) or (II) used in manufacturing a medicinal agent used in treatment of hepatitis B, pharmaceutical compositions containing thereof, and methods for treatment of hepatitis B. Proposed agent shows the enhanced effectiveness in treatment of hepatitis B.

EFFECT: enhanced and valuable medicinal properties of agent.

83 cl, 6 tbl, 11 ex

FIELD: organic chemistry, biochemistry, medicine, virology.

SUBSTANCE: invention relates to derivatives of 2'=amino-2'-deoxynucleosides of the formula:

wherein R means hydrogen atom (H), alkyl, aminoalkyl; R1 means -(R2NR3) wherein R2 and/or R3 means H, -OH, -NH2, alkyl, benzyl under condition that R doesn't represent H or methyl when R2 and R3 mean H. Compounds elicit an antiviral activity with respect to measles and Marburg viruses exceeding that of ribavirin.

EFFECT: valuable properties of compounds.

4 tbl, 2 dwg, 18 ex

The invention relates to a derivative of gemcitabine formula (I), where R1, R2, R3independently selected from hydrogen and C18and C20saturated and monounsaturated acyl groups, provided that R1, R2, R3can't all be hydrogen

The invention relates to the chemistry of nucleosides, in particular to an improved method for the preparation of 3'-azido-2',3'-dideoxythymidine (azidothymidine, AZT), used in medicine as an antiviral drug for the treatment of patients suffering from acquired immunodeficiency syndrome (AIDS)

The invention relates to a method for obtaining enriched beta-anomer nucleoside of the formula I, where T is fluorine and R is the corresponding nucleoside described in paragraph 1 of the formula
The invention relates to the synthesis of nucleosides and relates to an improved method for the preparation of 3'-azido-2',3'-dideoxythymidine with the ability to suppress the reproduction of human immunodeficiency virus and finds application in medical practice for the treatment of AIDS

The invention relates to new compounds of formula I Nu-O-Fa, where O is oxygen, Nu is a nucleoside or nucleoside analogue, including such nitrogen base, as adenine, Esenin, cytosine, uracil, thymine; Fa - acyl monounsaturated C18YPD C20-9-fatty acids, which fatty acid etherification hydroxyl group in 5-position of the sugar portion of the nucleoside or nucleoside analog, or a hydroxyl group, an acyclic chain of an analogue of the nucleoside

The invention relates to the chemistry of nucleosides, in particular to the compounds used in medicine as anti-viral drugs for the treatment of diseases caused by, for example, human immunodeficiency virus (HIV), myeloblastosis birds (VMP)

The invention relates to the field of organic chemistry and Virology and applies to new nucleoside analogues containing the carbohydrate components of the 3-oximino-2-deoxyribofuranosyl, 3 Allexinno-2-deoxyribofuranosyl (acyl= acetyl, propionyl, isobutyryl, pivaloyl, benzoyl and other) or a 3-methoxyimino-2-deoxyribofuranosyl possessing antiviral activity of a broad spectrum of activity against the human immunodeficiency viruses (HIV), herpes simplex (HSV) and hepatitis B (VHB), which can find application in medicine

The invention relates to chemical technology for acyclic guanosine analogues with antiviral activity, in particular, to the drug Acyclovir [9-(2'-hydroxyethoxymethyl )guanine] , used in medicine as an effective means Antiherpes virus effect

FIELD: chemistry.

SUBSTANCE: invention pertains to modified polysaccharide in particular to modified polysaccharide Neisseria meningitidis of serogroup A, which preserves immunogenicity, but has improved stability. The modified polysaccharide is obtained from reaction of capsular polysaccharide, or its fragment - oligosaccharide, with CDI type bifunctional reagent, accompanied by reaction with an amino-compound, such as dimethylamine. Description is also given of modified polysaccharide conjugates and vaccines, which are obtained from such conjugates.

EFFECT: obtaining modified saccharide.

70 cl, 17 dwg

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to method for production of indolo-pyrrolo-carbazole derivative according to formula (I) , or its pharmaceutically acceptable salt, that have antitumour activity. Invention also relates to method for production of indole compound according to formula (XII) , or its pharmaceutically acceptable salt, where R1 is protective hydroxy-group, distinguished by conducting interreaction between compound with formula (XIII) , or its pharmaceutically acceptable salt, where R1 is definitely above, Ra and Rb are either separately C1-C7-alkyl, or together form C3-C6-alkylene group, and hydrogen gas at 1 to 5 atmospheres, in presence of hydrogenation catalyst (applied as novel catalyst as well), which consist of rhodium compound, metal compound, and optionally amine, in inert solvent at room temperature; the rhodium compound being 1 to 10% rhodium on carbon, aluminium oxide, calcium carbonate, or barium sulphate, and metal compound being nickel (II), iron (II), iron (III), cobalt (II), or cobalt (III). Method is also submitted for production of bis-indole compound by formula (VIII) , or its pharmaceutically acceptable salt, where R1 is protective hydroxy-group, Y is hydrogen, C1-C7-alkyl, phenyl, benzyloxymethyl, or C7-C12-aralkyl, consisting in reaction of indole compound by formula (XII), or its pharmaceutically acceptable salt, where R1 is protective hydroxy-group, with ethylmagnesium chloride, or butylmagnesium chloride, or magnesium compound by formula (X) RdMgRd, where Rd is butyl, in inert solvent, followed by conducting interreaction between product obtained and maleimide compound by formula (IX) , where X is halogen, and Y as above, in inert solvent.

EFFECT: improved method for indolo-pyrrolo-carbazole production.

15 cl, 68 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to method of isolation of 1-O-2-(3,4-dimethoxybenzyl)-3-carboxy-4-(3-methoxy-4-oxyphenyl)-butyl-β-D-galactopiranose of general formula (1) , which lies in exhaustive constant extraction of air-dry seeds of Scotch cottonthistle Onopordum acanthium L. with chloroform during 2 days in Soxlet apparatus, isolation from extract by means of triple procession with n-hexane with further exposure at 10°C during 7 days and further filtration.

EFFECT: new efficient method of isolation of 1-O-2-(3,4-dimethoxybenzyl)-3-carboxy-4-(3-methoxy-4-oxyphenyl)-butyl-β-D-galactopiranose.

1 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bio-organic chemistry and relates to the novel erythropoietin conjugate, the method of production and its pharmaceutical composition. The hydroxyethylamylum and erythropoietin conjugate containing one or several hydroxyethylamylum molecules, is invented. Each hydroxyethylamylum molecule is conjugated with erythropoietin via hydrocarbon fragment. The said hydroxyethylamylum has the molecular mass from 1 to 300 kDa and shows the correlation of the C2:C6-substitution in the range of 2-20 by hydroxylethyl groups. The method for producing the hydroxyethylamylum and erythropoietin conjugate is invented; in accordance with the method, the sialic acid is not necessarily removed, partially or totally, with use of enzyme and/or chemical way, and the erythropoietin end saccharide link is oxidised not necessarily partially or totally to receive the erythropoietin which is able to react with the modified hydroxyethylamylum. Into hydroxyethylamylum, the free hydrazide, hydroxylamine, thyol or semicarbazide functional group is entered to receive the modified hydroxyethylamylum which is conjugated with erythropoietin which is able to react with the modified hydroxyethylamylum, and the hydroxyethylamylum and erythropoietin conjugate containing one or several hydroxyethylamylum molecules, is obtained. The pharmaceutical composition contains the hydroxyethylamylum and erythropoietin conjugate with the erythropoietin activity, and the pharmaceutically acceptable solvent, adjuvant and/or carrier.

EFFECT: hydroxyethylamylum and erythropoietin conjugate with erythropoietin activity.

19 cl, 4 tbl, 25 dwg, 20 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a variant of admixture extraction from composition containing extraneous matter and sucralose, which is used as a sweetener. One of the variants includes following stages: (a) first solvent extraction of the said composition containing sucralose and admixtures in the first solvent with the help of another solvent, at least partially immiscible, in order to remove admixtures to the said second solvent; (b) second solvent extraction of the said composition containing sucralose and admixtures in the first solvent with the help of the third solvent, at least partially immiscible, in order to transfer sucralose to the said third solvent; where stage (a) removes at least a part of admixtures to the second solvent; and stage (b) transports most of sucralose to the third solvent and detains most of admixtures in the first solvent.

EFFECT: efficient removal of admixtures from compositions.

34 cl, 4 tbl, 2 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: developed method of sucralose production using acyl-sucralose implies (a) adjustment of pH factor of specified supplied mixture to value ranged from 8.0 to 12.0 by alkali metal hydroxide addition; (b) buffer addition to specified base mixture in amount enough for specified pH factor stabilization within stated range over holding stage (c); (c) holding of specified base mixture at appropriate temperature over time period enough for effective transformation of specified acyl-sucralose compound into free sucralose; (d) reduction of specified pH factor of specified base mixture up to value from 4 to 8; (e) sucralose release from product of step (d) resulted thereby in released sucralose.

EFFECT: improved method of water deacylation procedure stabilization.

22 cl, 1 tbl, 1 ex

FIELD: foods.

SUBSTANCE: invention refers to the improved technique of sucralose purification using the basic non-crystal purification procedures with the following three or more consecutive steps of remained mother liquor crystallization and recirculation used with feed stock of another crystallization or purification step. This invention refers also to the composition of sucralose.

EFFECT: obtained composition can be rather purified and have excellent taste.

32 cl, 2 tbl, 13 dwg, 7 ex

FIELD: CHEMISTRY.

SUBSTANCE: agglomerated zeolite adsorbing materials are suggested. They contain inert bonding agent based on zeolite X with Si/Al ratio within 1.15 < Si/Al ≤ 1.5 range, with at least 90% of cation exchange centres are occupied by either barium ions only or barium and potassium ions. In the latter case, fraction of exchange centres occupied by potassium may be up to 1/3 of those occupied by barium and potassium. Remaining centres are occupied by alkali or earth metals other than barium. The Dubinin volume of these adsorbing materials measured using nitrogen adsorption at 77°К after vacuum degassing for 16 h at 300°С is 0.240 cm3/g or more.

EFFECT: resulting adsorbing materials are efficient for isolation of p-xylene from mixtures of isomers of aromatic hydrocarbons in liquid or gas phase.

13 cl, 4 ex

FIELD: bioengineering.

SUBSTANCE: method involves producing acids polysaccharide fucoidan from laminaria by crushing raw material by treating it with 0.5-1.0% food acid solution during 4-5 h and subjecting acid extract to ultrafiltration on membrane of 100-300 kDa with following end product drying by applying lipophilic or spraying or vacuum drying method.

EFFECT: high purity of end product.

FIELD: biologically active compounds technology.

SUBSTANCE: invention relates to improved method for isolating individual biologically active anthocyan pigments, employed as naturally occurring pigments or biologically active components of therapeutical and cosmetic agents, from water-alcohol extract of red grape cake. Anthocyanes are sorbed on talk and then eluted with water-alcohol solution and separated chromatographically into individual anthocyans by passing solution under vacuum through column or filter filled by silica gel particles 0.040-0,063 mm in size and using, as eluent, ethyl acetate/acetic acid/water ternary mixture in volume proportions (0.67-4.67):1:1.

EFFECT: improved purification of anthocyans showing highest biological activities.

2 cl, 1 tbl, 3 ex

FIELD: pharmaceutical and food industries.

SUBSTANCE: invention relates to preparing water-soluble or water-dispersible carbohydrate-based powders and tablets. Carbohydrate matrix is composed of at least 90% carbohydrate, e.g. starch or sugar. Closed-porosity powder or tablet is treated with gas so that gas contained in pores enhances dissolution or dispersing when in contact with water. Gas can be selected from nitrogen, carbon dioxide, air, oxygen, helium, hydrogen, argon, neon, methane, ethane, krypton, chlorine, chlorofluorocarbon, and mixture thereof. Gas is forced preferably under pressure at temperature above Tg of carbohydrate. Powder or tablet can further contain protein, hydrocolloid, or fat and forms no foam on dissolution or dispersing.

EFFECT: improved consumer's property of powders and tablets.

35 cl, 1 dwg, 2 tbl, 5 ex

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