Getting sucralose without intermediate the selection of crystalline sucralose-6-ester
(57) Abstract:Describes how to obtain Sucralose, including diallylamine 6-ether Sucralose, characterized in that the mixture of raw materials (a) 6-O-acyl-4,1',6'-trichloro-4,1', 6'-tridyakisicosahedron, (C) salts, including chloride alkali or alkaline earth metal, (C) water and (d) other by-products of the chlorination of sucrose is treated in a reaction medium containing a tertiary amide, and this processing includes: (i) diallylamine 6-O-acyl-4,1', 6'-trichloro-4, 1',6'-tridyakisicosahedron by raising the pH of an aqueous solution (a), (b), (C) and (d) up to about 11 (1) at a temperature and for a period of time sufficient to perform a specified diallylamine with obtaining an aqueous solution containing Sucralose, salt, comprising a chloride of an alkaline or alkaline-earth metal, and other by-products of the chlorination of sucrose in the reaction medium containing tertiary amide, (ii) deletes the specified tertiary amide and (iii) the allocation of Sucralose from the product of stage (ii). The technical result is simplification. 2 C. and 13 C.p. f-crystals. This application is a partial continuation of concurrently pending application ser. N 08/323954, filed October 17, 1994D. the ASS="ptx2">Synthetic sweetening agent 4,1',6'-trichloro-4,1',6'-tridyakisicosahedron ("Sucralose") is produced from sucrose by the substitution of hydroxyl in the 4, 1', and 6' positions of the chlorine. In the process of obtaining compounds is the conversion of stereoconfiguration in the 4 position. Therefore, Sucralose is a galacto-sucrose having the following molecular structure:
< / BR>The main problem of the synthesis is the direction of the chlorine atoms only in the correct position, because the hydroxyl, which are replaced, have different reactivity, are two primary and one secondary. In addition, the synthesis is complicated by the fact that the primary hydroxyl in the 6-position is not substituted in the final product.There are a number of different ways to obtain Sucralose, in which reactive hydroxyl in the 6 position first, before chlorination of the hydroxyl at the 4, 1', and 6' positions, blocking, for example, in the form of ester groups, and then gidrolizuut to remove the ether Deputy, receiving Sucralose. Some of these ways of synthesis include mediasound the synthesis of sucrose-6-esters. Examples of such mediasound tin syntheses syntheses are disclosed Navia (U.S. patent N 4950746), Neiditch et.al. (pate. N 08/237947, filed may 2, 1994, and related to the decision of the same issue as this application.Sucrose-6-esters obtained by the method presented in the application, usually glorious according to the method of U.S. patent N 4980463 (Walkup et al. -II). This method of chlorination gives in the form of product Sucralose-6-ester, such as 4,1', 6'-trichloro-4,1',6'-trimethoxybenzoate-6-acetate ("TGS-6-Ac" ("TGS-6-AC"), including when Sucralose-6-ester is an acetate ester, or, more generally, "TCC-6-ester") "TGS-6-ester in the solution of the tertiary amide is usually N,N-dimethylformamide (DMF), plus salt (obtained by neutralization glorieuses agent after completion of the reaction of chlorination), and impurities. One aspect of this invention is the method of allocation of TGS-6-ester from a solution of the tertiary amide, which is a by-product of chlorination by Walkup et al. II.In previously known methods, such as methods disclosed Walkup et al. - II, and the way opened Navia et al., "RECOVERY OF SUCRALOSE INTERMEDIATES", patent application U.S. ser. N 08/198744, filed February 18, 1994 - (and re-filed February 1, 1995, as the patent application U.S. ser. N 08/368466), and related to the same issue as this application, Sucralose receive from the reaction mixture the ranks amide for the chlorination reaction is removed, for example, by steam distillation (disclosed Navia et al.), the resulting aqueous mixture containing salt, TGS-6-ester and impurities,
b) then TGS-6-ester is recovered from the aqueous mixture by extraction using a suitable organic solvent, such as ethyl acetate,
c) then the crude TGS-6-ester decelerat with the formation of Sucralose, and
d) Sucralose allocate by countercurrent extraction and purified by crystallization.The present invention provides a method in which TGS-6-ester decelerat right, getting an aqueous solution of Sucralose plus salt and impurities, from which allocate Sucralose, for example, by extraction with an organic solvent and, preferably, Sucralose then purified using countercurrent extraction, crystallization, or by a combination of both techniques.The method of this invention has several potential economic advantages compared to methods of making Sucralose, previously described, for example, by the method disclosed Navia et al., ser. N 08/368466. These benefits include the following:
1. The reduction stage of handling solids throughout the process, in which TGS-6-AC does not separately allocate. This erdich substances from liquids).2. The likely reduction in the need to re-collect uterine fluids (i.e., less stage precrystallization). This is probably because the crystallization of Sucralose is easier than the crystallization of Sucralose-6-acetate, and
3. Total outputs seem to be slightly increased. This may be due to conversion of diacetato that have the correct replacement by chlorination, Sucralose. These diacetate would be lost in the way Navia et al. because of the tough cleaning TGS-6-AC by Navia et al.This invention provides a method for production of Sucralose from a mixture of raw materials (a) 6-O-acyl-4,1',6'-trichloro-4,1',6'-tridyakisicosahedron ("TGS-6-ester"), (b) salts, including chloride of alkali metal or alkaline earth metal, (c) water and (d) other by-products of chlorinated sucrose, in a reaction medium comprising a tertiary amide, and the method includes:
(i) diallylamine 6-O-acyl-4,1'6'-trichloro-4,1',6'-tridyakisicosahedron with obtaining an aqueous solution containing Sucralose, (b) a salt comprising an alkali metal chloride or alkaline earth metal, and (d) other by-products of chlorinated sucrose, and
(ii) the designation of Sucralose from the product of stage (i) by ekstrak is gaining
In one aspect the invention provides a method for production of Sucralose from a mixture of raw materials (a) 6-O-acyl-4,1',6'-trichloro-4,1',6'-tridyakisicosahedron, (b) salts, including chloride of alkali metal or alkaline earth metal, (c) water, and (d) other by-products of the chlorination of sucrose in the reaction medium comprising a tertiary amide, and the method includes:
(i) diallylamine 6-O-acyl-4,1', 6'-trichloro-4,1',6'-tridyakisicosahedron by raising the pH of the aqueous solution (a), (b), (c) and (d) up to about 11 (1) at a temperature and for a period of time sufficient to perform a specified diallylamine to obtain an aqueous solution containing Sucralose, salt, comprising a chloride of alkali metal or alkaline earth metal, and other by-products of the chlorination of sucrose in the reaction medium containing tertiary amide,< / BR>(ii) delete the specified tertiary amide, for example, by steam distillation or extraction, and
(iii) the allocation of Sucralose from the product of stage (ii), for example, by extraction followed by crystallization or by using only methods of extraction.In another aspect the process of the invention carried out by the removal of the tertiary amide before diallylammonium, for example, using sleduj solution (a), (b) and (d), from which the main part of the tertiary amide in the above-mentioned mixture of raw materials is removed,
(ii) diallylamine 6-O-acyl-4,1',6'-trichloro-4,1',6'-tridyakisicosahedron, for example, by increasing the pH of an aqueous solution of the product of stage (i) to a pH of about 11 (1) at a temperature and for a period of time sufficient to perform a specified diallylamine to obtain an aqueous solution containing Sucralose, salt, comprising a chloride of alkali metal or alkaline earth metal, and other by-products of chlorinated sucrose, and
(iii) the allocation of Sucralose from the product of stage (ii), for example, by extraction followed by crystallization, or by using only methods of extraction.In the method of the present invention is used as the raw mix composition comprising 6-O-acyl-4,1',6'-trichloro-4,1',6'-tridyakisicosahedron in the reaction medium tertiary amide (preferably DMF), such as neutralized (repaid) the reaction product of chlorination described by Walkup et al. II mentioned above. Preferred esters of 6-O-acyl-4,1',6'-trichloro-4,1', 6'-tridyakisicosahedron are 6-O-acetyl-4,1',6'-trichloro-4,1',6'-tridyakisicosahedron and 6-O-benzoyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate.In a preferred method of carrying out such a method of damping a cold aqueous solution of alkali added under vigorous stirring as fast as possible, in sufficient quantity to raise the pH to 8-10. After stirring for several minutes at this moderately high pH, the cooled solution is neutralized to pH 5-7 by adding acid, such as, for example, concentrated aqueous hydrochloric acid or glacial acetic to the e, namely, that all the hydroxyl groups of the sucrose-6-ester, which were not replaced by chlorine atoms return to its original shape in the form of hydroxyl groups.Alternatively, you can add a sufficient amount of aqueous alkali to achieve a pH of 11 (1), and support for a time sufficient to remove the 6-acyl function and obtain directly Sucralose, in the presence of all salts, residual tertiary amide (DMF) and so It is with the loss of a certain amount of DMF lost during alkaline hydrolysis to dimethylamine and sodium formate. For this reason, and this is explained in more detail below, diallylamine to remove DMF less preferred because it is desirable to select the entire DMF for recycling and reuse.Periodic way of clearing the crude mixture of the chlorinated product has the disadvantage associated with limiting the amount due to the inefficiency of heat transfer and mass. Improved method, known as "dual-stream" ("dual-stream") method or method 'concurrent addition of" ("simultaneous addition") includes mixing water flows alkali and cooled (to about room temperature) raw kontrolowane pH and temperature. The main advantages of dual-stream method of damping is that it provides full control of pH, temperature and speed of mixing during rapid cooling. Therefore, side reactions leading to loss of product, minimum. Another advantage of "dual-stream" ("dual-stream") method of damping is that it can be done continuously by use of the vessel for damping equipped with either the outlet at the bottom, or pump. Implementing "dual-stream" ("dual-stream") method of damping in a continuous mode of operation, a relatively large amount of the crude chlorinated product can be subjected to processing using the vessel to absorb the small size. This continuous process is a rough approximation of the in-Jine the blending method, which can be used for damping in the commercial process.Using 1500 ml vessel with a jacket for cooling, it was found that a mixture of the crude Sucralose-6-ester product can effectively suppress using a constant feed rate of the chlorinated mixture of about 10 ml per minute, the temperature of the mixture hardening approximately 15oC (the temperature of the cooling agent 5oC) four-bladed propeller-type stirrer 24 ptrole pH to pH 8.5 to pH controlled pump. These results were obtained with 3N or 4N NaOH as the alkaline agent and start downloading about 100 ml of a mixture of from 3:1 to 1:3 DMF-H2O vessel for damping (in order to have a sufficient volume of a solution for the accurate measurement of pH in the initial stages of clearing).Remove DMF)
When using sodium hydroxide at the stage of clearing and DMF as a tertiary amide, salts, which are formed at the stage of extinction include sodium chloride, dimethylamine hydrochloride and a small amount of sodium formiate. If the damping must be accompanied by diallylammonium by increasing pH, sufficient for effective diallylamine, extrace Sucralose from suppressed and thus diallylamine mixture of the product must be complicated by the presence of DMF (or other tertiary amide) and a tendency Sucralose distributed between the organic and aqueous phases in the extraction step, which would logically be the next stage in the chain of successive stages of the method to obtain Sucralose. Tertiary amide can dissolve Sucralose in both phases and may also have a tendency to dissolve other substances that are present in both phases, making the allocation of Sucralose in good yield Ejoy for effective purification of Sucralose by crystallization from solvent extraction. Another possible complication may be caused by decomposition of the tertiary amide catalyzed by base. For all these reasons, tertiary amide, such as DMF, should be removed prior to the extraction and purification of Sucralose. In addition, it is preferable to remove DMF) to the stage of diallylamine.The operation of distillation with water vapor carried out in such a way as to remove the major part of DMF (or other tertiary amide) of the quenched mixture of raw materials (preferred method) or suppressed, and deaccelerating the reaction mixture. It is desirable to remove at least 95%, and preferably from about 98 to 99.9% DMF, to prevent undesirable consequences described in the previous paragraph.When you remove DMF (or other tertiary amide) by distillation with water vapor, DMF effectively replaced by water flow method, and DMF can then be isolated from the water of the upper straps by distillation and then recycled.An example of a laboratory device for distillation vapor type Packed column from the drop-down film intended for distillation with water vapor DMF) from quenched chlorination products Sucralose-6-ester can serve as distillatively nozzle. Alternative you can use Oldershaw column with 15 plates, provided with a casing. The quenched product, generally preheated, is introduced into the upper part of the column with a speed of 5.0-5.5 g per minute. Pairs served in the column through the side branch, located at the bottom of the column. Because you want couples, free from condensation, the vapor passes through reboiler", which picks up any condensate from the top. In the laboratory this reboiler is usually a small flask with a large number of tubes, equipped with a heating jacket. The feed rate of water vapor is in the range 39-47 g per minute (calculated by summing the weights of the products selected at the top and bottom of the column, and then subtracting the weight of the chlorinated raw materials), which corresponds to the ratio of water vapor:the raw material is in the range from 4: 1 to 12:1, and the relationship between a 7.5:1 and 9:1 are typical to set the column head. In a preferred variant embodiment of the invention use a greater number of plates with a lower ratio of steam:raw materials, for example, 15 plates with relation to par: the raw material is about 4: 1.Pre-heating repaid chlorinated raw materials to its introduction at the top cha is e heating is usually carried out in the laboratory by passing the raw material through enclosed in the shroud glass tube the heated secondary source of steam. The raw material is usually heated to about 90-95oC. removal Efficiency DMF can also be enhanced by the use of "reboiler" (i.e., heating the residue from the pickup of the product to return them back to column distillation with water vapor).The temperature is mostly measured in two places set, using a thermocouple. In addition to the above-described temperature repaid chlorinated raw materials also determine the temperature of the vapors passing through the upper part of the distillation column. The temperature of the upper part of the column is typically in the range from about 99oC to about 104oC.Usually repaid product of the chlorination of sucrose-6-acetate contains about 1.5-5 wt.% Sucralose-6-ester, about 35-45 wt.% DMF, about 35-45 wt.% water and about 12 to 18 wt.% salts. After passing a product through the apparatus distillation with water vapor laboratory type products taken from the lower part of the column, usually consist of about 1-3 wt.% Sucralose-6-ester, about 0.1-0.5 weight. % DMF, about 80-90 wt.% water and about 8-12 wt.% salts (defined as NaCl, on the basis of the analysis of sodium and chloride).In normal laboratory conditions, at which time nagode is consistent raw material is neutral or slightly acidic (pH 5.0 - 7,0).Similar conditions can be used to distillation with water vapor DMF) from quenched and deaccelerating reaction mixture.Diallylamine Sucralose-6-ester
In a preferred variant of the method of the invention after removal of the tertiary amide Sucralose-6-ester decelerat by raising the pH of the reaction mixture to about 11 (1) at a temperature and for a period of time sufficient to effect diallylamine. This stage is usually carried out by adding sufficient alkali metal hydroxide such as sodium hydroxide, with stirring, to raise the pH to the desired level. It is established that the reaction time in the range of from about 30 minutes to 2 hours and the temperature is in the range of 15-35oC are useful. At the end of diallylamine present basis should normally be neutralized, for example, by adding hydrochloric acid to a pH of about 5-7. After neutralization of the aqueous reaction mixture contains Sucralose, salts (such as the aforementioned, plus salt, the resulting describes only what stage neutralization) and other by-products of chlorinated sucrose.Extraction of Sucralose
After deally is rastvoritelei. Such solvents include methyl acetate, ethyl acetate, methyl ethyl ketone, methyl isobutylketone, methyl-isoamylene, methylene chloride, chloroform, diethyl ether, methyl tertiary butyl ether, etc. due to the selectivity of the extraction, ease of recycling and Toxicological safety, the preferred solvent is ethyl acetate.In the laboratory the allocation of Sucralose is usually carried out first by partial evaporation of the crude neutralized reaction product of diallylamine. About half of the water present can optionally be removed, obtaining a solution containing about 2-5 wt.% carbon and about 15-25 wt.% salts. The selection is usually carried out by performing three successive extraction with ethyl acetate or other suitable solvent. The extracts are combined and they may not necessarily be water-washed (to remove residual DMF and derivative dichlorodibenzofuran, which, to some extent, is distributed in the organic phase).In addition to the methods manual extraction described above in General terms, the extraction can also be performed continuously diluted (not concentrated by evaporation flow in the system extract stage evaporation-concentration. The technique of this countercurrent extraction known in the art.In the case where the untreated Sucralose separated from the aqueous salt solution in the form of a solution in an appropriate organic solvent, the solution concentrated and the product can be purified by crystallization and recrystallization from the same solvent to the desired purity. Alternatively, to achieve the desired level of purity, Sucralose can be recrystallized from a mixed solvent, such as metalon-ethyl acetate, or water. Consistent distribution of Sucralose in mixtures of solvent-water in countercurrent method also allows to achieve cleanup and also opens the possibility of direct liquid loading (i.e., no allocation of substance, and the final flow method having the required technical specifications, can be directly packaged for use).Another noteworthy aspect of the above method, the purification/isolation (i.e., extraction with subsequent crystallization) is that for the extraction and purification stages, you can use the same solvent. Normally (i.e. with other chemical substances is of Italia, used for its extraction. In this case, however, the combination of dilution and relatively low levels of impurities allow Sucralose to remain in solution during the extraction, and then the solution containing the extracted Sucralose, concentrate, and Sucralose product can be crystallized from the same solvent.Experiment
A solution of the crude sucrose-6-acetate in DMF (1,447 kg) containing 416,94 g (1,084 mole) of sucrose-6-acetate, diluted of 2.51 kg of fresh DMF. The solution is cooled to -2oC (bath with a mixture of dry ice/acetone/water) and vigorously stirred, while adding phosgene (1.125 kg, 99%, of 11.26 moles) at a rate of from 5.4 to 6.7 g/min. and the Temperature of the mixture support at 5-12oC during the greater part of the add.The reaction mixture is left under stirring at ambient temperature for 30 minutes, then heated to 115oC over a period of 2-3 hours, then incubated at 1151oC for about 1.75 hours, then cooled to 35oC for 30 minutes. The final mass, 4,34 kg, serves on stage alkaline damping in dual stream and further processing.Damping in dual l/min equipped with a casing 2 l plastic solution (without the top) with a stop-cock at the bottom, containing 200 ml of 1:1 mixture of DMF-water. Aqueous NaOH (3,12%). 5 kg, administered at the same time using pH-controlled pump with pH set point to 9.0, and the stroke of the pump set at 25%. Proportional band width was set at maximum deviation (1 pH unit) to minimize any deviation pH. The temperature of the casing of the cooled vessel was controlled by Forma Scintific circulating baths. The temperature of the casing supported at the 5oC. the Temperature of the mixture subjected to quenching, was originally a 6oC and then raised to 20oC within the first 10 minutes. After the temperature stabilized at around 17oC throughout the period of extinction. During blanking pH in the reactor was varied in the range of 8.0 to 8.5. The mixture is vigorously stirred with a laboratory stirrer designed for operation in harsh conditions. The hardened mixture is removed from the reactor parts, as the vessel for damping reaches its capacity. Each portion extinguish within approximately 6 hours at the above conditions. For most portions receive approximately 9 kg suppressed the mixture. 4,1', 6'-trichloro-4,1', 6'-tridyakisicosahedron-6-acetate ["TGS-6-Ac", "TGS-6-AC") prisutstvuet what about the time of clearing.All paid-out portion is filtered under vacuum to remove insoluble particulate material, using either vacuum filtration through a porous glass Buchner funnel, or centrifugation. The filtrate is taken for analysis, and conducting distillation with water vapor.Distillation with water vapor.1. Laboratory scale.Quenched mixture is distilled with water vapor portions. Two objectives in distillation with water vapor: 1) removal of DMF to light extraction, 2) removal of resinous, polymeric soluble substance found in quenched mixtures. The distillation with steam is carried out in a well-insulated glass column to a height of 4 ft (122 cm) with EXT. with a diameter of 4 inches (10.16 cm). Conditions optimize to obtain less than 1% DMF in Cuba. Column packing rings process size 1/4" inch (0,64 cm). The ratio of steam:the raw material is supported in the range of 6:8. After every three othonos with water vapor column purify 1N alkaline solution that removes the resinous substance from the nozzle and the surface of the column. Usually the passage of the distillation with steam is completed after 6 hours. On each portion of 9 kg of raw materials receive approximately 13 kg cube after distillation of vodev pumping repaid, the filtered mixture FMI Lab pump (RP-C20) through the pre-heater, a 4 "Graham-type condenser with water vapor in the casing, and then directly in the center of the top of the column. Water vapor passes through the reboiler (3-necked, 500 ml vessel with a magnetic sensor low pressure and heating the casing to remove the condensate before entering the column at the bottom of the nozzle. The pressure in the column support with 0-3 inches (0-76,2 mm) of water throughout the process. The feed rate determined initially by measuring the time rate of pumping from a calibrated reservoir. The acquisition speed cube is measured when the selection in a graduated vessel. The rate of distillation measure the condensing eluent from the top of the column, in ml/min Rate of water vapor is determined by the difference (PARA-TOP + CUBA - SUBMISSION)...2. Distillation with water vapor on a large scale.Chlorinated and discharged flows method, composition, similar to the previous examples of laboratory scale, served on top of the top plate of the column with a diameter of 10 inches (25.4 cm) containing 20 mesh plates, while steam is fed directly from the bottom of the column. Set zootoxin is, is based on a specific analysis of the amount of DMF in raw material loaded in the column). Preheating the flow of raw materials to 80-90oC has a beneficial effect on the efficiency of distillation with water vapor in the column. The flow of DMF/water is distilled off from the top of the column by the method of countercurrent flow. Cuba columns containing TGS-6-Ac (TGS-6-AC), salt and water, proceed to the next area of the technological line for cleaning. Taken from the top of the column shoulder straps sent to another column to highlight DMF (typical composition of 12% DMF, 88% water). Thus, the quenched feedstock containing 1.8% of TGS-6-Ac (TGS-6-AC), 8.5% of salts, 54.6% of water, and 30.4% DMF is distilled off with steam, getting cubes containing 1.6% of TGS-6-Ac (TGS-6-AC), or 9.8% of salts, 84,9% water and 0.1% residual DMF (removes 99.6% in DMF). The ratio of the weight of the raw material supplied to the distillation with water vapor to the mass of the cube was about 1,22.Diallylamine cubes after distillation with water steam
The crude salt solution TGS-6-Ac (TGS-6-AC) (15,4 kg), obtained after removal of the DMF by using distillation with water vapor, by the method described above, is subjected to decelerating by raising the pH to 11.5. This is carried out by adding 50 wt%./weight. sodium hydroxide in a rapidly stirred solution II to raise the pH to 11.5 and maintain it at this level for about 2 hours at ambient temperature. After diacetylpyridine deems complete, the solution is neutralized with concentrated hydrochloric acid.The allocation of Sucralose from diallylamine mix
Untreated deaccelerating the mixture is extracted continuously with ethyl acetate, using ROBATEL countercurrent extractor. The aqueous phase (raw materials) and ethyl acetate (extracting solvent) leave ROBATEL with two MASTER-FLEX DIGISTAT pulsating pumps in the ratio of 4:1 (extrogen:raw).The ethyl acetate solution containing the desired product, evaporated to a thick syrup which is dissolved in water. This aqueous solution is treated with carbon to bleach, then evaporated to a thick syrup. The syrup is diluted with fresh ethyl acetate. The solution is injected in the form of seed crystals Sucralose, leave the solution to stand and crystallize at ambient temperature for several days. Sucralose receive in the form of a white crystalline solid (24 g, 92.7% of the weight./weight.). Additional quantities produced by the repeated evaporation of the solvent and re-dissolve the syrup in fresh ethyl acetate. In General, 33,5 g (40,6%) Sucralose is isolated in the form of a solid product with purity, analogen solution for several days. The additional material can be obtained in the subsequent fees or by recycling the mother liquor in a subsequent crystallization.The allocation of crystalline Sucralose out of the water.An ethyl acetate solution obtained as described previously, concentrated to a thick dark syrup (62 g, 95-99% Sucralose). The syrup is diluted with water in a quantity sufficient to obtain a 20% solution of Sucralose, the solution is treated with 5 g of carbon for decoloration and filtered, obtaining a solution of a pale straw color, the Solution is concentrated to about 65% of the content of Sucralose, cooled to ambient temperature, introducing him to the seed crystals Sucralose and give him the opportunity to crystallize with stirring for 5 days. The crystal suspension is slightly concentrated using vacuum distillation of water up to about 70-75% of the content of Sucralose and continue crystallization for 24 hours. Crystalline product are filtered and dried in the air, getting a 20.2 g of product.Chlorination using ARNOLD reagent/get Sucralose
Sucrose-6-acetate (18,93 g) and DMF (172 g) are loaded into a 500 ml 4-necked round bottom flask equipped with stirrer, thermometrically (54,8 g is lost). (Stage drying to remove residual moisture).The residue is cooled to 0-5oC, the distillation apparatus is replaced with a water condenser and a tube for drying, add the chloride of chlorotriethylsilane (ARNOLD Reagent and 46.8 g, 347,34 mmol), big portions, keeping the temperature of the reaction mixture below 30oC. the mixture is Then heated to 65oC for 20 minutes, kept at this temperature for 5 minutes, heated to 110-115oC for 25 minutes and maintained within that range for a period of 3.75 hours. Then the reaction mixture is cooled to 0-5oC and make it basic by adding 189 g of 3-molar aqueous sodium hydroxide solution, pre-cooled to 0oC. After 45 minutes the deacetylation of obtaining the crude Sucralose is completed (monitoring by TLC), the mixture is neutralized by adding 17.8 g of glacial acetic acid. Analysis of the crude mixture by HPLC indicated that the mixture contained 11,35 g (65% yield) Sucralose.The distillation with water vapor carried out in order to remove the DMF, according to the methods described previously. The results of the chlorination according to the method of Arnold and chlorination carried out by direct introduction of phosgene into solutions of Sakha is x2">The crude product Sucralose is separated from the cube, depleted DMF) by steam distillation, by extraction with a suitable organic solvent that is not miscible with the aqueous salt solution (examples of which are dichloromethane, chloroform, 2-butanone, cyclohexanone, ethyl acetate, and the last two are particularly effective and desirable for the method and Toxicological reasons). Water, organic extracts again extracted with water to bring Sucralose in the aqueous phase. An aqueous solution provide carbon, concentrated and Sucralose crystallized with a purity of > 91% of the weight. /weight. in anticipation of carbohydrate. Uterine solutions can be used for recycle to get additional quantity of substance. Alternatively, Sucralose can be cleaned by additional crystallization from an organic extraction medium (particularly ethyl acetate), which can facilitate the separation of the desired product from the less polar substances and coloring tel.The following example demonstrates the use of an analog of sucrose-6-benzoate to implement the same transformation, i.e. dibenzoylmethane directly after stage chlorination emitting neoisolationist cleaning. This aspect of the invention (i.e., extraction cleaning in comparison with distillation with water vapor DMF), during the process, is not preferred because of DMF reduces the output, preventing the allocation of the crude Sucralose, for example, residual DMF), which is carried away by means of extraction, hinders the crystallization of Sucralose.Chlorination of sucrose-6-benzoate
Direct conversion into crude Sucralose
In a 100 ml 3-necked round bottom flask, equipped with magnetic stirrer, thermometer, addition funnel, air-cooled refrigerator and an inlet for argon, download 18 ml of DMF. The flask was cooled to -5oC, it is added dropwise 6.8 ml (99% purity, of 71.7 mmol) of the acid chloride phosphoric acid at such a rate to maintain the temperature inside the flask is less than or equal to 10oC. After completion of the addition, the mixture is cooled to -10oC, and to it is added dropwise a solution containing 5.0 g sucrose-6-benzoate (91.2% in purity of 10.21 mmol) dissolved in 9 ml of dry DMF at such a rate that the temperature of the reaction mixture did not exceed 6oC. After completion of the addition, the clear reaction mixture is heated to 60oC for 20 minutes. C is, is at this temperature, the mixture was incubated for 1 hour. The resulting Golden yellow solution is then heated to 115oC and incubated for 3 hours. The obtained red-brown mixture was then cooled to about 50oC and it was added, in one portion, 145 ml of 4N aqueous sodium hydroxide solution (580 mmol), pre-cooled together with 35 g of ice. The alkaline mixture was stirred at ambient temperature for 45 minutes, after which the analysis of the mixture by TLC indicates that the conversion of Sucralose-6-benzoate in Sucralose completed fully. The mixture is extracted twice with toluene (150 ml each time) to remove non-polar impurities and then re-extracted with 100 ml aliquot of 2-butanol. The organic extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure, obtaining of 3.42 g of reddish syrup, which contained 36.9% of the weight./weight. Sucralose (31,1% yield for two steps). The aqueous phase contained the additional amount of Sucralose that can be identified with the help of repeated extraction with 2-butanol.Getting Sucralose
Syrup solution (20 g) sucrose-6-acetate (43,6 mmol) in DMF was diluted with 180 ml of DMF and dehydration distillation 51 ml of the sterile 20oC, then heated to 65oC for 15 minutes, incubated at 65oC for 20 minutes, heated to 115oC for 20 minutes, then incubated at 112-114oC within 3.5-4 hours. The mixture is cooled to 0oC and quenched with 130 ml of 4 M NaOH was added in portions to control ectothermy neutralization. To complete diallylamine, as determined by TLC, requires adding 13,15 g of NaOH (pellets). The excess alkali is neutralized by adding 24 ml of acetic acid. At this point, the mixture may be directed through the steam distillation.Alternative DMF) can be substantially removed by extraction and evaporation. The crude mixture was extracted with 5 portions 2 butanone. The combined organic phases provide 11 g of charcoal, and then evaporated to a syrup (21,9 g). The syrup was dissolved in 50 ml of ethyl acetate and the maximum is extracted with water. The aqueous phase is maximally extracted with ethyl acetate. The organic phase is evaporated to a syrup (14.5 g), which is diluted with water to receive 72.5 g of the crude aqueous solution containing Sucralose and other chlorinated impurities, as shown by HPLC.Data analysis Sucralose and other chlorinated impurities formed at the stage of chlorination.
Water (by difference) 80,38%
Conditions of high performance liquid chromatography (HPLC) for analysis of the crude reaction mixtures Sucralose.
< / BR>Time deregualtion 6-ether Sucralose, characterized in that the mixture of raw materials (a) 6-O-acyl-4,1',6'-trichloro-4,1', 6'-tridyakisicosahedron, (b) salts, including chloride alkali or alkaline earth metal, (c) water and (d) other by-products of the chlorination of sucrose, treated in a reaction medium containing a tertiary amide, and this processing includes (i) diallylamine 6-O-acyl-4,1',6'-trichloro-4,1', 6'-tridyakisicosahedron increase the pH of an aqueous solution (a), (b), (c) and (d) up to about 11 (1) at a temperature and for a period of time sufficient to perform a specified diallylamine with obtaining an aqueous solution containing Sucralose, salt, comprising a chloride of an alkaline or alkaline-earth metal, and other by-products of the chlorination of sucrose in the reaction medium containing tertiary amide, (ii) deletes the specified tertiary amide and (iii) the allocation of Sucralose from the product of stage (ii).2. The method according to p. 1, in which stage (ii) is carried out by distillation with water vapor.3. The method according to p. 2, in which the tertiary amidon is N,N-dimethylformamide.4. The method according to p. 3, which is 6-O-acyl-4,1',6'-trichloro-4,1',6'-tridyakisicosahedron is 6-O-acetyl-4,1', 6'-trichloro-4,1',6'-tridyakisicosahedron or 6-O-benzoyl-4,1', 6'-trichloro-4,1',adiya's (iii) is carried out by periodic, continuous, or continuous countercurrent extraction.6. The method according to p. 5, in which Sucralose optionally purified by crystallization.7. The method according to p. 6, in which the crystallization was carried out from the water or ethyl acetate.8. The way to obtain Sucralose, including diallylamine 6-ether Sucralose, characterized in that the mixture of raw materials (a) 6-O-acyl-4,1',6'-trichloro-4,1', 6'-tridyakisicosahedron, (b) salts, including chloride alkali or alkaline earth metal, (c) water and (d) other by-products of the chlorination of sucrose, treated in a reaction medium containing a tertiary amide, and this processing includes (i) delete the specified tertiary amide to obtain an aqueous solution (a), (b) and (d), which removed the main part of the tertiary amide in the specified raw mixture; (ii) diallylamine 6-O-acyl-4,1', 6'-trichloro-4,1',6'-tridyakisicosahedron by raising the pH of an aqueous solution of the product of stage (i) to a pH of at least about 11 (1) at a temperature and for a period of time sufficient to perform a specified diallylamine with obtaining an aqueous solution containing Sucralose, salt, comprising a chloride of an alkaline or alkaline-earth metal, and other side products Hlil-4,1',6'-trichloro-4,1',6'-tridyakisicosahedron is 6-O-acetyl-4,1', 6'-trichloro-4,1',6'-tridyakisicosahedron or 6-O-benzoyl-4,1', 6'-trichloro-4,1',6'-tridyakisicosahedron.10. The method according to p. 9, in which stage (iii) is carried out by extraction of Sucralose from the product of stage (ii) with an organic solvent followed by crystallization of Sucralose from the specified organic solvent.11. The method according to p. 10, in which the specified organic solvent is ethyl acetate.12. The method according to p. 9, in which stage (iii) is carried out using the extraction of Sucralose from the product of stage (ii) with an organic solvent followed by crystallization of Sucralose from the water.13. The method according to p. 9, in which the tertiary amidon is N,N-dimethylformamide.14. The method according to p. 13, in which the removal of the tertiary amide in stage (i) is carried out with the help of distillation with water vapor.15. The method according to p. 11, in which stage the extraction of Sucralose from the product of stage (ii) is carried out by periodic, continuous, or continuous countercurrent extraction.
FIELD: biotechnology, biochemistry, enzymes.
SUBSTANCE: invention relates to a method for preparing 4-O-β-D-galactopyranosyl-D-xylose used for in vivo assay of lactase activity in human intestine. Method involves interaction of D-xylose with β-D-galactopyranoside for 2-48 h in a solution at pH 5-9, at temperature that changes from the mixture freezing point to 45°C, and the following addition of 10-1000 U of β-D-galactosidase per 1 g of β-D-galactopyranoside. Reaction is terminated by inactivation of enzyme followed by isolation and crystallization of fraction containing 4-O-β-D-galactopyranosyl-D-xylose in the crystallization mixture chosen from acetone/methanol = (5-1):(20-1) and acetone/water = (5-1):(20-1). Invention provides increasing content of 4-O-β-D-galactopyranosyl-D-xylose in the final mixture.
EFFECT: improved preparing method.
42 cl, 2 tbl, 9 ex
FIELD: cosmetics, pharmacy.
SUBSTANCE: invention relates to associates containing trehalose and calcium chloride as a crystalline monohydrate comprising above said components and water in the molar ratio = 1:1:1, or as anhydrous crystal containing above said components in the molar ratio = 1:2. Indicated crystals of two species of associates of trehalose and calcium chloride can be used in different branches in production of foodstuffs, cosmetic agents and others.
EFFECT: valuable properties of compounds.
3 cl, 20 tbl, 15 dwg, 30 ex
SUBSTANCE: use of two carbohydrate residues in the structure of a divalent neoglycoconjugate enables sixfold increase in binding efficiency compared to the monovalent derivative of monolactosyl-L-glutamate-succinate-dihexadecyl-L-glutamic acid, which can be used to produce high-efficiency directed systems for delivering medicinal agents. EFFECT: high affinity of carbohydrate residues to proteins by forming new divalent ligands based on L-glutamic acid diether, which are specific to corresponding receptors which contain residues of different carbohydrates, via a 1,3-dipolar cycloaddition reaction.
2 cl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to new compounds of general formula I [X]n-Y-ZR1R2, wherein the radicals are specified in the description, effective as heparan sulphate-binding protein inhibitors. The invention also refers to a pharmaceutical or veterinary composition having heparan sulphate-binding protein inhibitory activity for preventing or treating a disorder in a mammal, and to the use of these compounds and compositions for antiangiogenic, antimetastatic, anti-inflammatory, antimicrobial, anticoagulant and/or antithrombotic therapy in a mammal.
EFFECT: preparing the new compounds of general formula I [X]n-Y-ZR1R2, wherein the radicals are specified in the description, effective as the heparan sulphate binding protein inhibitors.
10 cl, 31 ex, 11 tbl, 40 dwg
SUBSTANCE: invention relates to an oligosaccharide ingredient for adding to nutritional compositions or food products, which contains glycosylated amino acids and peptides of general formula RnSacm, where R is an amino acid residue, Sac is a monosaccharide selected from a group comprising N-acetyl-neuraminic acid, N-acetyl-galactosamine and galactose, n has a value between 1 and 10 with the proviso that if n equals 1, R is a threonine residue or a serine residue and if n has a value between 2 and 10, the peptide contains at least one threonine or serine residue, m has a value between 2 and 4 and at least 20 mol % of the ingredient is N-acetyl-neuraminic acid, where the oligosaccharide ingredient contains 15-20 mol % N-acetyl-galactosamine, 15-25 mol % galactose, 20-50 mol % N-acetyl-neuraminic acid and 15-25 mol % threonine or serine or mixture thereof.
EFFECT: obtaining an oligosaccharide ingredient.
7 cl, 1 tbl, 2 ex
SUBSTANCE: oligosaccharide ingredient, which is intended to increase content of sialic acid in baby formula, contains glycosylated amino acids and peptides of general formula RnSacm, where R is an amino acid residue, Sac is a monosaccharide selected from a group comprising N-acetyl-neuraminic acid, N-acetyl galactosamine and galactose n has a value from 1 to 10, under the condition that if n=1, then R is a threonine residue or a serine residue and if n has a value between (2) and (10) the peptide contains at least one threonine or serine residue, m has a value from 2 to 4 and at least 20 mol % of the ingredient is N-acetyl-neuraminic acid, where the oligosaccharide component contains 10-25 mol % N-acetyl galactosamine, 10-25 mol % galactose, 20-50 mol % N-acetyl-neuraminic acid and 15-50 mol % threonine or serine or mixture thereof.
EFFECT: obtaining an oligosaccharide ingredient intended for increasing content of sialic acid in baby formula.
6 cl, 2 ex
FIELD: pharmaceutical technology.
SUBSTANCE: invention relates to the improved sucralose formulation and a method for its crystallization. Method involves controlling pH value of solution in the range from about 5.5 to about 8.5 in the process of formation of sucralose crystals. Invention provides the development of the improved composition comprising crystalline sucralose and possessing the enhanced stability.
EFFECT: improved preparing method, improved properties of composition.
24 cl, 4 tbl, 4 ex
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to an improved solid-phase method for synthesis of radioisotope indicators, in particular, for synthesis of compounds labeled with 18F that can be used as radioactive indicators for positron- emission tomography (PET). In particular, invention relates to a method for synthesis of indicator labeled with 18F that involves treatment of a precursor fixed on resin if the formula (I): SOLID CARRIER-LINKER-X-INDICATOR wherein X means a group promoting to nucleophilic substitution by a definite center of a fixed INDICATOR with 18F- ion for preparing a labeled indicator of the formula (II): 18F-INDICATOR; to compound of the formula (Ib):
and compound of the formula (Ih): ;
to radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in PET; to a cartridge for radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in positron-emission tomography.
EFFECT: improved method of synthesis.
13 cl, 1 sch, 3 ex
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
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
SUBSTANCE: in method of obtaining compound aminoalkyl glucosaminide 4-phosphate of formula , X represents , Y represents -O- or NH-; R1, R2 and R3, each is independently selected from hydrogen and saturated and unsaturated (C2-C24) aliphatic acyl groups; R8 represents -H or -PO3R11R11a, where R11a and R11a, each is independently -H or (C1-C4) aliphatic groups; R9 represents -H, -CH3 or -PO3R13aR14, where R13a and R14, each is independently selected from -H and (C1-C4) aliphatic groups, and where indices n, m, p, q each independently is a integer from 0 to 6 and r is independently integer from 2 to 10; R4 and R5 are independently selected from H and methyl; R6 and R7 are independently selected from H, OH, (C1-C4) oxyaliphatic groups -PO3H2, -OPO3H2, -SO3H, -OSO3H, -NR15R16, -SR15, -CN, -NO2, -CHO, -CO2R15, -CONR15R16, -PO3R15R16, -OPO3R15R16, -SO3R15 and -OSO3R15, where R15 and R16, each is independently selected from H and (C1-C4) aliphatic groups, where aliphatic groups are optionally substituted with aryl; and Z represents -O- or -S-; on condition that one of R8 and R9 represents phosphorus-containing group, but R8 and R9 cannot be simultaneously phosphorus-containing group, including: (a) selective 6-O- silylation of derivative of 2-amino-2-desoxy-β-D-glucopyranose of formula , where X represents O or S; and PG independently represent protecting group, which forms ester, ether or carbonate with oxygen atom of hydroxy group or which forms amide or carbamate with amino group nitrogen atom, respectively; by means of tri-substituted chlorosilane RaRbRcSi-Cl, where Ra, Rb and Rc are independently selected from group, consisting of C1-C6alkyl C3-C6cycloalkyl and optionally substituted phenyl, in presence of tertiary amin, which gives 6-silylated derivative; (b) selective acylation of 4-OH position of obtained 6-O-silylated derivative with 6-3-alkanoyloxyalcanoic acid or hydroxyl-protected (R)-3-hydroxyalkanoic acid presence of a carbodiimide reagent and catalytic 4-dimethylaminopyridine or 4-pyrrolidinopyridine to give a 4-O-acylated derivative; (c) selectively deprotecting the nitrogen protecting groups, sequentially or simultaneously and N,N-diacylating the resulting diamine with (R)-3-alkanoyloxyalkanoic acid or a hydroxy-protected (R)-3-hydroxyalkanoic acid in presence of peptide condensation reagent; (d) introducing a protecting phosphate group at 3-position with a chlorophosphate or phosphoramidite reagent to give a phosphotriester; and (e) simultaneous or sequential deprotecting phosphate, silyl, and remaining protecting groups.
EFFECT: method improvement.
11 cl, 3 ex
SUBSTANCE: invention claims derivatives of 1-α-halogen-2,2-difluoro-2-deoxy-D-ribofuranose of the general formula (I) in solid state, where R1 is benzoyl or ; R2 is hydrogen; and X is CI, Br or I; which can be applied as intermediates in stereoselective method of gemcitabine obtainment. In addition, invention claims stereoselective method of obtaining compounds of the general formula (I), including stages of: (i) recovery of 1-oxoribose of formula to obtain lactol of formula ; (ii) interaction of compound of formula (III) with halogen phosphate compound of formula in the presence of a base to obtain 1-phosphatefuranose derivative of formula ; and (iii) interaction of compound of formula (V) (also included in the claim) with halogen source, with further recrystallisation of obtained product; where R1, R2 and X are the same as indicated above while R3 is phenyl.
EFFECT: efficient method of obtaining derivatives of the abovementioned agent.
11 cl, 6 ex
SUBSTANCE: invention refers to synthesis of [18F]fluororganic compounds ensured by reaction of [18F]fluoride and relevant halogenide or sulphonate with alcoholic vehicle of formula 1 where R1, R2 and R3 represent hydrogen atom or C1-C18 alkyl.
EFFECT: possibility for mild process with low reaction time and high yield.
21 cl, 2 tbl, 27 ex
SUBSTANCE: invention relates to a method of producing a protected fluorinated glucose derivative, involving reaction of a tetraacetylmannose derivative with a fluoride, distinguished by that the reaction is carried out in a solvent which contains water in amount of more than 1000 parts per million and less than 50000 parts per million. Preferably, the protected fluorinated glucose derivative is 2-fluoro-1,3,4,6-tetra-O-acetyl-D-glucose (tetraacetylfluroglucose or pFDG), the tetraacetylmannose derivative is 1,3,4,6-tetra-0-acetyl-2-0-trifluoromethanesulphonyl-β-D- mannopyranose (tetraacetylmannose triflate), the solvent is acetonitrile, the fluoride is a fluoride ion with a potassium counter-ion, and a phase-transfer catalyst, such as 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo-[8,8,8]-hexacosa, is added to the fluoride.
EFFECT: improved method.
14 cl, 2 tbl, 3 dwg, 3 ex