Extraction processes of obtaining sucralose

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

 

The scope of the invention

The present invention relates to new extraction methods of cleaning Sucralose. The present invention also relates to compositions containing preparations Sucralose received in accordance with the method of the present invention.

Background of the invention

Sucralose, 4,1',6'-trichloro-4,1',6'-trimethoxybenzoate, sweetener intensity of sweetness, several hundred times the intensity of the sweetness of sucrose, obtained from sucrose by replacing chlorine hydroxyl groups in the 4, 1' and 6' positions. Synthesis Sucralose is a technical problem because of the need for selective replacement of specific hydroxyl groups by chlorine atoms while maintaining the other hydroxyl groups, including highly reactive primary hydroxyl group. Developed numerous approaches to this synthesis. See, for example, U.S. patent No. 4362869; 4826962; 4980463; and 5141860 that are specifically included in this description as a reference. However, such approaches generally provide a product that contains various levels of other chlorinated compounds sugars, in addition to Sucralose. Although the synthesis Sucralose was directed many attempts, allocation Sucralose in high-purity form of this complex mixture of impurities so far paid very little attention to the project. Known to the present time, as a rule, are of crystallization Sucralose directly from the synthetic mixture, introducing a way that gives the material with high levels of impurities. Sometimes Sucralose extracted from synthetic mixtures by chromatography on silica gel. See, for example, U.S. patent No. 5128248, which is specifically included in this description by reference. This procedure due to the fact that it uses silica gel, may be unsuitable for large volumes of production of high-purity Sucralose on an industrial scale. In addition, relatively little attention has been paid to other approaches to remove impurities halogenated sugars from Sucralose. Effective removal of these impurities is important due to the fact that even at very low concentrations they can have a negative effect on the sweetness, the taste and properties of Sucralose associated with a modification of smell.

Proposed various methods of synthesis Sucralose and related compounds. U.S. patent No. 4405654, which is specifically included in this description as a reference, for example, relates to a method of synthesis of related compounds, 1',4',6'-trichloro-1',4',6'-trimethoxysilane. After deacetylation pentaacetate predecessor, the reaction mixture was purified using column chromatog is the her on silica gel. Product elute from the silica gel using ethyl acetate.

U.S. patent No. 4980463, which is specifically included in this description by reference, relates to a method in which Sucralose obtained by processing KOH methanol solution Sucralose-6-benzoate. The methanol is removed by evaporation and the residue is dissolved in water. The aqueous solution is extracted with three times the individual quarters of the total volume of ethyl acetate. The combined organic extracts are concentrated and then subjected to back extraction with water to extract Sucralose present in the ethyl acetate. The joint portions of aqueous solutions are concentrated and treated with decolorizing reagent. Additional concentration makes possible the crystallization Sucralose. The extracted crystals, as reported, have a purity of 99.6 percent. Cleaning up this level is achieved, first of all, rather, by crystallization, than by using the methods of solvent extraction. Obviously, this approach only includes the extraction with ethyl acetate of the original aqueous solution, and Sucralose never re-extracted from aqueous solution into the organic phase, in order thereby to achieve further purification.

U.S. patent No. 5034551, which is specifically included in this description by reference, relates to a similar method, in which the e is used for hydrolysis of a solution of Sucralose-6-benzoate in methanol. The methanol is removed by evaporation and containing Sucralose the residue is dissolved in water. This solution is extracted with three times the individual quarters of the total volume of ethyl acetate. The remaining aqueous layer discolor with activated charcoal, concentrated and Sucralose allow to crystallize.

U.S. patent No. 5498709, which is specifically included in this description by reference, refers to solvents that can be used for extracting Sucralose from aqueous saturated salt solution obtained by the alkaline hydrolysis of compounds of the predecessor on the basis of complex 6-etilovogo ether. Possible solvents include methyl acetate, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, methylisobutylketone, methylene chloride, chloroform, diethyl ether and methyl tert-butyl ether. The ethyl acetate is a suitable for use with solvent for reasons of selectivity of the extraction, ease of recycling and Toxicological safety.

U.S. patent No. 5498709, which is specifically included in this description by reference, also applies to the way in which the aqueous solution remaining after ester hydrolysis predecessors, Sucralose, concentrated, and then Sucralose distinguish three consecutive ekstragirovanie those who acetate or another suitable for use with solvent. Then the extracts can be combined and optionally washed with water to remove any remaining DMF (dimethylformamide), before removing Sucralose by concentration and crystallization. This patent also refers to the ways in which Sucralose contained in an aqueous saturated salt solution obtained after alkaline deesterification, is extracted in a solvent immiscible with saturated salt solution, such as dichloromethane, chloroform, 2-butanone, cyclohexanone or ethyl acetate. Organic extracts can then be reverse extraction of water for transfer Sucralose back in the aqueous phase. This aqueous solution can then discolour, concentrated and the resulting purified Sucralose extracted using crystallization. This approach results in a material with a relatively low purity.

An additional approach is discussed in U.S. patent No. 5498709, which is specifically included in this description by reference, involves extraction with toluene alkaline solution remaining after deesterification. Specifically, the solution is extracted twice with toluene to remove non-polar impurities. Then the aqueous solution is repeatedly extracted with 2-butanone. 2-Butanone extracts are combined and the solvent is evaporated to obtain a reddish syrup, containing Sucralose./p>

U.S. patent No. 5530106, which is specifically included in this description by reference, relates to an extraction method for the solution of the original Sucralose obtained after alkaline hydrolysis of Sucralose-6-acetate and subsequent neutralization. An aqueous solution of Sucralose extracted with water saturated with ethyl acetate. Some impurities are selectively distributed in the organic phase by the extraction. Then an ethyl acetate phase is subjected to the backwash water to extract the part of Sucralose, which is also distributed in the organic phase. Aqueous solution and the solution after the reverse water washing unite, concentrate, discolor and Sucralose extract using crystallization from the aqueous phase.

Currently existing methods, consisting in the crystallization without using at least two of extraction, carefully controlled solvents, can not effectively remove impurities more polar and less polar than Sucralose. Therefore, a less expensive and more effective way of industrial production Sucralose. The present invention attempts to solve these problems and provides methodologies that are both industrial feasible and effective at removing impurities.

Brief description of the invention

One of the variants of embodiment of the present invention relates to a method of removing impurities from the composition, containing Sucralose and impurities in the first solvent, including the implementation phase extraction fluid composition using a second at least partially immiscible solvent to effect the removal of impurities in the second solvent and performing a second extraction of the composition with a third at least partially immiscible solvent to transfer Sucralose in the third solvent and the retention of impurities in the first solvent.

Another variant of the embodiment of the present invention relates to a method of removing impurities from a composition comprising an aqueous solution of Sucralose and impurities, including the implementation phase extraction fluid composition using at least partially immiscible non-aromatic organic solvent to effect the removal of impurities in the solvent and for the second extraction of the composition with an organic solvent to transfer Sucralose in the solvent and the retention of impurities in the aqueous phase.

The present invention also relates to a method of removing impurities from a composition comprising an aqueous solution of Sucralose and impurities, including the implementation phase extraction fluid composition using at least partially immiscible about the organic solvent to transfer impurities in the solvent, for the second extraction of the composition with an organic solvent to transfer Sucralose in the solvent and the retention of impurities in the aqueous phase, extraction of the organic solvent remaining from the first stage, aqueous solution to transfer Sucralose present in the organic phase in an aqueous solution, and combining the aqueous solution, thus obtained, in the third stage, with an aqueous solution, extracted in the first stage, before the implementation of the second stage.

Another variant of the embodiment of the present invention relates to methods of removal of compounds tetrachloroaurate from the solution Sucralose and halogenated derivatives of sucrose in the first solvent, including the extraction solution Sucralose and other derivatives halogenated Sucralose using, at least partially immiscible second non-aromatic solvent for the distribution of connections tetrachloroaurate in the second solvent and holding Sucralose in the first solvent.

An additional variant embodiment of the present invention relates to a method of removing impurities from a composition containing solution Sucralose and impurities in the first solvent, including the implementation phase extraction fluid composition through the Yu second solvent, which has a Hildebrand parameter lower than the first solvent, under conditions which selectively transfer impurities less polar than Sucralose, the second solvent, thereby providing a solution Sucralose in the first solvent, which has a high ratio Sucralose to impurities less polar than Sucralose, and the implementation of the extraction fluid composition with a third solvent, which has a Hildebrand parameter is higher than the first solvent, under conditions which selectively transfer the impurities more polar than Sucralose, the third solvent, thereby providing a solution Sucralose in the first solvent with a high ratio Sucralose the impurities more polar than Sucralose.

In the framework of the present invention also covers methods for removing impurities from a composition containing solution Sucralose and impurities in the first solvent, including the implementation phase extraction fluid composition with a second solvent which has a Hildebrand parameter is higher than the first solvent, under conditions which selectively transfer Sucralose in the second solvent, thereby providing a solution Sucralose second solvent which has a high ratio Sucralose to impurities IU the its polar than Sucralose, and the implementation of the extraction liquid solution Sucralose in the second solvent obtained at the previous stage, with the third solvent, which has a Hildebrand parameter is higher than the second solvent, under conditions which selectively transfer the impurities more polar than Sucralose, the third solvent, thereby providing a solution Sucralose second solvent which has a high ratio Sucralose to impurities more polar than Sucralose.

In the framework of the present invention also deals with the preparations Sucralose obtained by using one of the methodologies of the present invention and/or some combination thereof, and products containing drugs Sucralose obtained using any of the methodologies of the present invention and/or some combination thereof.

Other objectives, features and advantages of the present invention will become apparent from the following further detailed description. The detailed description and specific examples, though, and show the specific ways embodiment of the present invention, are given only as illustrations. Accordingly, the present invention also includes those various changes and modifications within the essence and scope of the present invention, which may be understandable specialist is in this field from this detailed description.

Brief description of drawings

Figure 1 provides a General block diagram of a variant of embodiment of the method according to the present invention.

Figure 2 provides a General block diagram of another variant embodiment of the method according to the present invention.

Detailed description of the invention

It is clear that the present invention is not limited to the particular methodologies, protocols, pH and reagents, and the like, described herein, as they may vary. It should also be understood that the terminology used in the description, is used only for the purposes of presenting the essence of particular variants of the embodiment and is not intended to limit the scope of the present invention. It should be noted that as in the description and in the accompanying claims, the singular number include reference to the plural, unless the context clearly dictates otherwise. So, for example, reference to "a solvent" is a reference to one or more solvents and includes cash equivalents, known to specialists in this field, and so on.

If not defined otherwise, all technical and scientific terms used in the description have the same meanings as those generally understood by experts in the field, belongs to the present invention. Describes predpochtitelnye ways devices and materials, although any methods and materials similar or equivalent to those described herein may be used in the implementation or study the present invention. All references cited in the description are incorporated as references in their entirety.

Definitions

Aroma: as used in the description, include solvents containing cyclic compounds with structures with resonant conjugated double bond, such as benzene, toluene or xylene.

Backwash: as used in the description, includes a stage of extraction, in which the phase of the second solvent remaining after its use for extracting the first solvent, re-extracted with a small portion of the first solvent. This provides a means for recovery of valuable materials, such as Sucralose, which are partially distributed in a second solvent that can be used for semi selective removal of impurities. The solution after backwashing can be combined with the first solvent, so that the extraction of valuable product, such as Sucralose, the first solvent can be maximized. The solution after backwashing optional can be concentrated before adding it to the first RA is the maker.

Drink: as used in this description includes any non-carbonated or carbonated drink, such as Cola, diet Cola, soda, diet soda, cocktail fruit juice, root beer, birch beer, any drink for sale in the machine, sparkling fruit juice, water, sparkling water, tonic, tonic and soda water for cocktails. The drink can also include any non-alcoholic or alcoholic beverage, such as any beer, including ale, Pilsner, lager or their derivative, a malt beverage, red wine, white wine, sparkling wine, fortified wine, soft drink based on wine, wine spritzer, any pre-mixed cocktail, including Margarita mix, mix for cocktails type or sour mix Daiquiri, any fermented fruit or tea drink, a strong alcoholic drink any flavored liquor such as brandy, schnapps, bitters or strong stimulating the drink. The beverage may include any dairy product, milk or cream product or any substitute dairy product, cream or milk, such as half substitute, cream of vegetable origin, dry cream, flavored dry cream, a product based on soy is th milk and dairy product, does not contain lactose. The drink can also include any fruit or vegetable juice, whole, concentrated or powdered form and any combination of fruit and vegetable juices or other beverages. The drink may also include coffee, any coffee drink, any flavored syrup for coffee, tea, iced tea and cocoa, as well as any combination of any of the products listed above.

Complex sweetener: as used in this description includes any combination or partial combination of sweeteners, including combinations of Sucralose, saccharin, aspartame, Acesulfame potassium, cyclamate, alitame, reveal, glucose, fructose, levulose, maltose, lactose, any sugar alcohol, sorbitol, xylitol and mannitol.

Consumer product: as used in the description, includes fruit products such as Apple sauce, jams, jellies, marmalades, fruit snacks, fruit oils and pastes. Consumer product may also include any dairy product, milk or cream product, such as cheese, ice cream and yogurt. Consumer product includes baked products such as bread, donuts, cakes, cheese cakes, sweet biscuits, pastries, pies, baguettes, rolls, tortillas, crackers, muffins and waffles. Consumer product includes the impact of the products of the cereals, such as cereal, oatmeal cereal and flour, cereal, cereal mixture, a mixture of oatmeal and bran. Consumer product includes condiments such as butter, peanut butter, whipped cream, sour cream, barbecue sauce, chili sauce, syrup, meat sauce, mayonnaise, olives, dressings, snacks, pickles, sauces, thick sauces, chips, ketchup, salsa, mustard, seasoning for salads and marinated peppers. Consumer product includes light snacks, such as pudding, candy sticks, lollipops, chocolate products, lollipops, fruit chewing marmalade, medlar, chewing gum, chewing gum bubble, molded chewing marmalade, caramel, filling for pies, syrups, jelly products, mints, popcorn, chips and pretzels. Consumer product includes meat products such as hot dogs, canned fish, sausages, meat products, canned meat, liofilizirovannoe meat and meat for Breakfast. Consumer product includes soups, consomme and broths. Consumer product includes the products for the care of oral hygiene, such as toothpaste, means for leveling the enamel of the teeth, rinse mouth, adhesive for removable dentures, bleach the tooth enamel, fluoride toothpastes and gels for the care of teeth. Consumer about the SPS includes beauty products, such as lipstick, lip balm, lip gloss and petroleum gel. Consumer product includes therapeutic products, such as replacement of snuff tobacco, tobacco substitutes, pharmaceutical compositions, chewing medicines, cough syrups, sprays expectoration, tortillas for the expectoration, cough drops, antibacterial products, coatings for tablets, gel caplet, preparations based soluble fiber, antacids, excipients for tablets, rapidly absorbed liquid compositions, compositions on the basis of stable foams, quick getintegervalue pharmaceutical dosage forms, beverage concentrates for medical purposes, the aqueous pharmaceutical suspension, the liquid composition of the concentrates and stable solutions of sorbic acid. Consumer product includes health food products, such as sticks, simulating food, cocktails, replacing food, dietary Supplement, protein mixtures, protein stick to control carbs, stick with a low carb diet, nutritional supplements, electrolyte solutions, products based on whey proteins, metabolic response modifiers, drinks for appetite control and sprays of Echinacea. Consumer product includes food for animals, such as the food for dogs and cats and food for birds. Consumer product includes food products, such as baby food. Consumer product includes tobacco products such as pipe tobacco, cigarette tobacco, and chewing tobacco.

Crystallization: as used in this description includes the ways in which the solution is saturated or supersaturated with respect to dissolved component and is achieved by the formation of crystals of this component. Initiation of crystal formation can be spontaneous, or it may involve adding seed crystals. As used in the description, the term "crystallization" also describes a situation in which solid or liquid material is dissolved in a solvent to obtain a solution, which then becomes saturated or supersaturated, so that the obtained crystals. Also, the term "crystallization" includes an auxiliary washing processes of crystals of one or more solvents, drying crystals and extraction of the final product thus obtained.

Original mix: as used in this description includes any mixture of compounds, which is formed by a process of synthesis Sucralose. Contains a mixture of Sucralose and any and all impurities.

Admixture: as used in the description, includes compounds other than cukrlo is a, and includes products of any number of processes of synthesis Sucralose who are not Sucralose. The admixture includes any monochloro-, dichloro-, tetrachloro - and pentachloropropane sucrose and any other disaccharide derived from sucrose, as well as any trichlorpropane other than itself Sucralose, because it is present in free form or in the form of esters of carboxylic acids. The admixture includes any halogenated derivatives of sugars, are shown in tables 1-4, such as dichloroacetate acetate, 6,1',6'-trichlorosucrose, 4,6,6'-trichlorosucrose, 4,1',4',6'-tetrachlorophthalate, 4,1',6'-trichlorogalactosucrose-6-acetate, 4,6,1',6'-tetrachloroethane, 4,1'-dichloroacetophenone, 3',6'-dichlorohydroquinone, 4,6'-dichloroacetophenone, 1',6'-dichloroacetone, 6,6'-dichloroacetone, 4,1',6'-trichlorosucrose, 4,6,6'-trichlorogalactosucrose, 4,1',5'-trichlorogalactosucrose-6-acetate and 4,6,6'-trichlorogalactosucrose. Includes any organic or inorganic salt, a carbohydrate or acylated to Sucralose.

Solvent: as used in the description, includes a liquid that can dissolve another substance.

Product sweetener: as used in this description includes any product containing any combination or combination Sucralose and/or any other sweeteners, VK is UCA saccharin, aspartame, Acesulfame potassium, cyclamate, alitum, stevioside, glucose, sucrose, fructose, levulose, maltose, lactose, any sugar alcohol, sorbitol, xylitol and mannitol.

The present invention relates to a new method of separation of derivatives of sucrose from impurities and includes methods of particle separation halogenated derivatives of sucrose. Such methods provide an opportunity for the Department, among other things, Sucralose from impurities and, in particular, other impurities halogenated sugars. The present invention also relates to new extraction methods of cleaning Sucralose.

The present invention relates to improvements in efficiency of Department Sucralose from impurities. The present invention relates to new methods for isolation and purification of compounds such as Sucralose. The combination of extraction, which removes impurities more polar than Sucralose, with subsequent extraction, which, for example, remove less polar impurities, leads to a more efficient cleaning method that provides a purified preparation Sucralose.

The present invention includes, for example, multi-stage extraction method of removing impurities from a solution containing Sucralose and impurities. The first extraction stage involves the extraction of original solution Sucralose in water or neodnorodnostei using a second immiscible solvent. In a particular variant embodiment of the second solvent to the first solvent may be equal to 0.35:1 or from about 1:2 to about 1:5, or from about 1:3 to about 1:4, or, in another particular variant embodiment of the present invention, about 1:3,5. This extraction removes a significant portion of the impurities that are less polar than Sucralose. Optionally, the phase of the second solvent from the extraction may be washed with water, aqueous solution or a nonaqueous solvent, to extract the part of Sucralose, which is transferred to the phase of the second solvent. The original solution Sucralose remaining in the first solvent, optionally combined with liquid from the backwash of the second solvent may then be subjected to a second extraction of the third solvent, immiscible with the first solvent. This extraction can be carried out in order to transfer the amount of Sucralose in a third solvent; therefore, the impurities, which are more polar than Sucralose remain in the first solvent. The second and third solvents may be identical, or they may represent a chemically different solvents. Then partially purified Sucralose can be extracted from the third solvent by crystallization and the other separation procedures. Such procedures are readily available and known to experts in this field. Actually, you can, in particular, to use the methodology of crystallization, as described in the provisional application for U.S. patent entitled "Process for Improving Sucralose Purity and Yield, registered simultaneously with this, and specifically included in the description by reference.

This combination of extraction stages refers to new ways sufficient cleaning Sucralose without crystallization. The combination of extraction, which removes impurities less polar than Sucralose, followed by an additional extraction, which removes the more polar impurities, leads to the creation of effective cleaning method that provides a purified preparation Sucralose. In addition, the exact usage of the optimized relationship solvents, duration of extraction and the optimal extraction conditions allow the use of the same solvent for the implementation of multiple extraction stages. Using the same solvent on the number of stages reduces the list of solvents that must be maintained, and reduces the problems of security and environmental protection. As described in this application, the ethyl acetate is a suitable for use illustrative RA is the maker of these stages of extraction.

Many extraction methods of the present invention can be used as mixtures of starting materials of the composition containing Sucralose and impurities, in particular, impurities resulting from the synthesis of Sucralose, and, more specifically, related derivatives halogenated sucrose remaining from the synthesis process, the remnants of the intermediate compounds of esters and/or organic and inorganic salts remaining from the synthesis process. These mixtures of starting materials are formed as a result of many processes of synthesis Sucralose.

The solvents considered for use in the extraction stages, include those which are immiscible with water or other solvents, which are easily soluble halogenated derivatives of sucrose. Also included solvents, which are partially soluble in the first solvent such as water, aqueous solution or other solvent in which the halogenated derivatives of sucrose is easily soluble, but in which the second solvent still forms a separate phase when mixed with the first solvent in the relevant respects, and under appropriate conditions. Solvents suitable for use in variants of the embodiment of the present invention include, but are not limited to only what they n-pentane, n-hexane, Freon® TF, n-heptane, diethyl ether, 1,1,1-trichloroethane, n-dodecane, white spirit, turpentine, cyclohexane, amylacetate, carbon tetrachloride, xylene, ethyl acetate, toluene, tetrahydrofuran, benzene, chloroform, trichloroethylene, Cellosolve acetate®, methyl ethyl ketone, acetone, datetoday alcohol, ethylene dichloride, methylene chloride, butyl Cellosolve®, pyridine, Cellosolve®, morpholine, dimethyl formamide, n-propyl alcohol, ethyl alcohol, dimethylsulfoxide, n-butyl alcohol, methyl alcohol, propylene glycol, ethylene glycol, glycerin and water.

The choice of solvents can preferably be determined by the relative solubilities of Sucralose and the main impurities formed as a result of the synthesis process, in the first and second solvents. Additional factors related to the choice of specific solvents include Flammability, ease of recycling in the process, considerations related to the environment, toxicity and cost. The solvents can be selectively filled with water or other solvent before use in the stages of extraction. Wide range of both pure solvents and combinations of solvents can be used to achieve the separations described in this application, and for this reason, the scope of the present invention, as before alagaesia, not limited to a particular solvent or combination of solvents.

The position and degree of halogenation, particularly chlorination, derivatives of sucrose affect the polarity of the resulting connection. For example, various halogenated derivatives of sucrose can be more polar or less polar than Sucralose. More polar derivatives are more soluble than Sucralose, in more polar solvents. Similarly, less polar derivatives are soluble in solvents less polar than Sucralose. For this reason, the methods of the present invention use solvents, temperature and conditions of extraction and volumetric relationship of solvents that provide maximum separation Sucralose and more or less polar impurities between phases solvents. The person skilled in the art will easily discover that a variety of solvents, temperature, and extraction conditions and volume relations of solvents can be used in the stages of extraction solvent of the present invention to implement the desired branch of Sucralose, for example, from various impurities and, specifically, from those impurities which are more or less polar than Sucralose.

One aspect of the methods of the present invention relative is seeking to select the first solvent and the second solvent. The second solvent, for example, preferably is sufficiently polar so Sucralose is at least partially divided from the first by more polar solvent in the second less polar solvent, the second solvent, preferably, may be sufficiently non-polar, so it remains immiscible with the first solvent. Examples of pairs suitable for use in more polar or less polar solvents include water and ethyl acetate, water and methyl isobutyl ketone and water and methyl tert-butyl ether. Although the present invention is easily accomplished by using a binary solvent system (i.e. a system containing two solvent), the use of three or even more complex systems of solvents (i.e. systems containing three or more solvents) is included in the scope of the present invention.

Although the present invention is not related to specific theories of solubility parameters the solubility of Hildebrand in units of the international system of units provide useful tools to assess what systems of solvents can operate at the desired separations of the present invention. See, in General, John Burke,Solubility Parameters:Theory and Applicationin 3 of the AIC Book and Paper Group International 13 (1984), http://palimpsest.stanford.edu/byauth/burke/solpar. The parameters of the solution is on the Hildebrand expressed in the International system of units (SI), in mega-Pascals (one mega-Pascal is equal to 1,000,000 Pascals). The higher the solubility parameter associated with the solvent, the more polar the solvent. The solubility parameter for a mixture of miscible solvents is determined as the weighted average of the values for the solubility of the individual solvents in the mixture (volume-weighted average value for the individual solvents). For example, amylacetate (the solubility parameter 17,1) and methyl ethyl ketone (solubility parameter 19,3) can be mixed in equal parts with a mixture of solvents with the same solubility parameter as ethyl acetate (solubility parameter of 18.2). This mixture would have functional properties similar to that of ethyl acetate, with the divisions that are part of the methods of the present invention.

Solvents, which significantly differ in solubility parameters will not be mixed, but, instead, will be essentially immiscible. The difference in polarity of the solvent is also critical for fractionation of dissolved material between the phases of immiscible solvents (she generally is a binary system of two phases, but, of course, triple, quadruple, and so on, the system can primarily be used to split the complex mixtures).

The more polar impurities in the solvent will be distributed in phase solvent of similar polarity, and less polar impurities will be distributed in solvents with similar low polarity. As a rule, the substitution of a hydroxyl group, a chlorine group makes the compound less polar (for example, the solubility parameter for methyl alcohol equal 29,7, but the solubility parameter for methylene chloride equal to 20.2). For this reason, derived tetrachloroaurate are less polar than Sucralose, while di - and monochloropropane are relatively more polar.

For this reason, in the methods of the present invention, the person skilled in the art, using such well-known polarity and solubility of the solvents, can choose a variety of solvents and combinations of solvents to effect the separation of Sucralose from impurities. For example, the difference in solubility parameters of about 20 units, and in particular, about 30 units, between phases or between phases of the solvents considered in one aspect of the methods of the present invention to achieve the desired separations of Sucralose and impurities. The Hildebrand parameter is empirical in nature and based on the chemical theory, it can be divided into three components factor (dispersion forces, polar forces and forces the hydrogen bonds).

Using the Hildebrand parameters as pointers, you can try to apply the methodology of extraction using, for example, three solvents: (a) one solvent with a high value of the solubility parameter ("heavy solvent"), (b) one solvent with an intermediate value of the solubility parameter ("intermediate solvent"), and (c) one solvent with a low value of the solubility parameter ("poor solvent").

For example, the intermediate extraction solvent containing Sucralose and impurities, a weak solvent will migrate impurities less polar than Sucralose, in a weak solvent to provide an intermediate solvent with a higher ratio of Sucralose to impurities less polar than Sucralose. The second intermediate extraction solvent in a strong solvent will migrate impurities more polar than Sucralose, in a strong solvent to provide an intermediate solvent with a higher ratio of Sucralose to impurities more polar than Sucralose.

Similarly, the extraction of the weak solvent containing Sucralose and impurities, the intermediate solvent will carry out selective migration Sucralose in an intermediate solvent to provide intermediate RA is a solvent with a higher ratio of Sucralose to the less polar impurities, than Sucralose. The second intermediate extraction solvent in a strong solvent will migrate impurities more polar than Sucralose, the third solvent to provide an intermediate solvent with a high ratio Sucralose to impurities more polar than Sucralose.

The stage of extraction used in aspects of the present invention can use any of the many available technologies for extracting liquid fluid. They include ways of mixing in the standard vessel, followed by sedimentation and decantation, continuous column extractors and/or continuous mixing and decanting. Boot, continuous and continuous-flow equipment can be used in the context of the present invention. Examples of this equipment include, but are not limited to, any reciprocating Poppet column Carr (Koch Inc., Kansas City, MO), any column of Sibelia (Koch Inc., Kansas City, MO), any Packed column, any pulsation of the Packed column, any set of mixer-settlers, any set of mixers and centrifugal separators and any centrifugal countercurrent extractors (for example, extractors manufactured by Robotel Inc., Pittsfield MA).

Actually, in the present invention are mainly used in order to find a variety of extraction approaches and scope of the present invention, for this reason, assumed not to be limited to a specific hardware configuration. Moreover, the various stages of the method described here (the first extraction, reverse rinsing after the first extraction and the second extraction)can be undertaken in a variety of containers or parts of the equipment. Alternatively, all these stages can be carried out in the same vessel or, in certain aspects, in any order or simultaneously.

Drugs Sucralose obtained using the methodology of the present invention may be included in the composition of the various products. Such products include, but are not limited to, beverages, compound sweeteners, consumer products, food sweeteners, fillers for tablets (U.S. patent No. 6277409, which is specifically included in the description by reference), pharmaceutical compositions (U.S. patent No. 6258381; 5817340; 5593696 that are specifically included in the description as the link), quickly which people absorb guided liquid compositions (U.S. patent No. 6211246, which is specifically included in the description by reference), the composition of stable foams (U.S. patent No. 6090401, which is specifically included in the description as links), a tool for aligning the tooth enamel (U.S. patent No. 6080481, which is specially VK is udaetsya in the description by reference), quickly dezintegriruetsja pharmaceutical dosage forms (U.S. patent No. 5876759, which is specifically included in the description by reference), concentrated beverages for medical purposes (U.S. patent No. 5674522, which is specifically included in the description by reference), the aqueous pharmaceutical suspension (U.S. patent№ 5658919; 5621005; 5409907; 5374659; 5272137, specifically included in the description as the link), fruit paste (U.S. patent No. 5397588; 5270071 that are specifically included in the description as the link), composition of liquid concentrates (U.S. patent No. 5384311, which is specially included in the description by reference) and stable solutions of sorbic acid (U.S. patent No. 5354902, which is specifically included in the description by reference). The definition of eligible sweets products of the present invention can be carried out using standard protocols "taste test", known in this area, such as the protocols referred to in a publication of the international application WO 00/01253 and Shamil & Birch, 25 LEBENSM. Wiss. U. Technol. 192-96 (1992), which specifically included in the description as references.

The methods of the present invention can be advantageously included in broader ways of cleaning Sucralose where additional purification stages are used before or after extraction, described what's here. In addition, the evaluation stage materials stages of extraction using HPLC or other methods known in this field may be included between stages described here. In addition, additional stages of purification or concentration of solutions containing Sucralose may be included between stages of extraction described here.

Method of extraction-based containers

1 shows one embodiment of the method of extraction liquid fluid according to the present invention. First, an aqueous solution of Sucralose 100 may be injected into the container 150 extractor for the extraction of liquid fluid and can be extracted with a volume of ethyl acetate in the ratio of about 1:3.5 (ethyl acetate:water solution). Impurities and a small part of the residual Sucralose can be removed via stream 200 less polar ethyl acetate, while a large part of Sucralose remains in the aqueous solution in the vessel 150 extractor for the extraction of liquid fluid. Optionally, an ethyl acetate stream 200 may be subjected to the reverse washing water in the optional device 250 for washing with water to remove any residual Sucralose from an ethyl acetate stream 200. Then less polar impurities can be removed from your system using flow 400 solvent ethyl acetate. Then any left is the lasting after backwashing water fluid 300 may be combined with the first aqueous solution in the vessel 150 extractor for the extraction of liquid fluid. Sucralose can be extracted, for example, using ethyl acetate in the ratio of ethyl acetate to the water from about 3:1 to about 4:1. A large part of Sucralose will be moved in the flow 500 less polar ethyl acetate, and the more polar impurities will remain in the aqueous phase. Then, the flow 500 solvent of ethyl acetate can be added to the distiller 350 to remove residual water 600 present in the system. Purified Sucralose in an ethyl acetate stream 700 may be injected into the mold 450, from which can be extracted purified crystallized Sucralose, and any remaining impurities are removed together with the solvent ethyl acetate 800.

Method of extraction fluid on the basis of the column

Figure 2 shows another variant embodiment of the method of extraction fluid liquid. First, an aqueous solution of 1000 Sucralose with impurities may be injected into the first column Carr 1500, where it can be combined with water-saturated ethyl acetate 2000, when the ratio of about 0.35 to:1 (ethyl acetate to water). Two different phases can be obtained from the first column Carr 1500: aqueous phase containing Sucralose, and an ethyl acetate phase containing residual Sucralose and impurities. An ethyl acetate stream 3000 can be entered in the second column Carr 2500, where it can be combined with water 4000 ratio of approximately 0.7:1 (ethyl acetate to water) to extract the OS is enough Sucralose. Also, in the second column Carr 2500 formation of two separate phases: the aqueous phase containing the extracted residual Sucralose, and an ethyl acetate phase. Water flow 5000 from the second column Carr 2500 can be combined with the aqueous phase of the first column Carr 1500. Then less polar impurities can be removed from the system together with the flow 9000 solvent ethyl acetate. United water flow 6000 can be entered in the column of Sibelia 3500 and unite with ethyl acetate 7000, with a ratio of approximately 3:1 (ethyl acetate:water). Sucralose of water flow 6000 will be wrapped in the less polar ethyl acetate 7000. Purified Sucralose in an ethyl acetate stream 8000 may be injected into the mold 4500, from which can be extracted purified Sucralose.

EXAMPLES

Without further details it is assumed that the person skilled in the art using the preceding description can apply the present invention to the full extent. The following examples are only illustrative and not limiting in any way the remainder of the description.

Example 1

The solution Sucralose containing various impurities can be obtained with the help of a number of previously described methods of synthesis Sucralose. See, for example, U.S. patent No. 5498709. In one variation of the embodiment of the present invention 6-O-acyl derivative Sucralose DEA is jirout and subjected to adsorption of vapor to remove any dimethylformamide, remaining from the reaction of chlorination. The result is an aqueous solution containing Sucralose, residual acylated to Sucralose, other halogenated derivatives of sugars and organic and inorganic salts.

This aqueous solution is injected into the vessel suitable for the extraction of liquid liquid, specifically, in a reciprocating Poppet column Carr diameter of 1 inch and a height of 12 feet (Koch, inc., Kansas City, MO). Backwashing is carried out in a column Carr diameter of 2 inches and a height of 12 feet. There are two sections to highlight a height of 2 feet x diameter 6 inches, at the top and bottom of the columns.

The columns consist of glass tubes with plates of stainless steel, with holes 3/8 inch, supported by the Central shaft. For the extraction, starting from the bottom of the column, the plates are separated from each other as follows: 1 m, at a distance of 6 inches, 2 feet, 4 inches; 1 foot at a distance of 3 inches; 8 feet, at a distance of 2 inches. For backwashing, starting from the bottom of the column, the distance between the plates is as follows: 2 feet, 4 inches; 2 feet at a distance of 3 inches; 7 feet, at a distance of 2 inches; 1 foot at a distance of 1 inch.

Mixing is accomplished by raising and lowering the package of plates using soedinitel the aqueous core, driven by an eccentric.

Positive displacement pumps are used for power extraction columns and for emptying the lower parts of the columns. Water is supplied to the column for backwashing using a control valve and flow meter. For flows from the upper parts of the columns there is a possibility of overflow in the intermediate tanks. The control is carried out by changing the flow rates to maintain the boundary in the middle of the sections allocation in the lower part of the column. The upper boundary is not controlled, but holding from time to time checked.

The aqueous solution is extracted with a volume of ethyl acetate at a ratio of 1:3.5 (ethyl acetate:water solution). Although part of Sucralose transferred to an ethyl acetate phase during the extraction, a proportionately greater amount of less polar impurities are removed by ethyl acetate. Thus, a large part of Sucralose remains in aqueous solution. An ethyl acetate phase is extracted from the first extraction, exposed to the backwash water at a separate stage of extraction. This extraction removes a significant part of Sucralose, but not impurities from ethyl acetate in the aqueous phase. Aqueous solution, thus obtained, is then merged with primary source materials and is supplied to the first extragear is improving.

In the following next, table 1 shows the average number of various impurities present in an ethyl acetate phase remaining after this extraction is optimized. The conditions used are: a) extraction: the ratio of solvent to the source material = from 0.3 to 1, with respect to free soluble substance; (b) backwash: the ratio of water to the source material = from 0.9 to 1, with respect to free soluble substance; (c) temperature: equal to the ambient temperature in both extraction. Values are expressed as the ratio of the mass of the impurities present to mass Sucralose present in this phase. Impurities are marked as unknown, assumed to represent uncertain chlorinated sucrose, other than Sucralose.

Table 1
ImpurityRelation to Sucralose
Unknown S 11,70,6
Dichloroacetate acetate0,7
6,1',6'-Trichlorosucrose3,5
4,6,6'-Trichlorosucrose1,2
4,1',4',6'-Tetrachlorophthalate3,5
4,1',6'-Trichlorogalactosucrose-6-acetate0,4
4,6,1',6'-Tetrachloroethane10,6

The composition of the carbohydrate source solution Sucralose is approximately 50-60% Sucralose, while the remainder are impurities, such as those specified in the table above. Therefore, the ratio of Sucralose to any individual impurity in the solution is greater than 1. As can be seen from table 1, less polar impurities (i.e tetrachloropropane 4,1',4',6'-tetrachlorophthalate and 4,6,1',6'-tetrachloroethane) are distributed mainly in an ethyl acetate phase. Also, 6,1',6'-trichlorosucrose distributed in the less polar phase. Thus, the initial extraction is used to remove a significant part of the less polar impurities from the solution Sucralose.

The water flow of a product from extraction then extracted with fresh ethyl acetate in a suitable container for the extraction of liquid fluid, when the ratio of ethyl acetate to water in the range from 3:1 to 4:1. Suitable for the extraction capacity is a reciprocating extraction column Carr. This extraction is used to transfer the greater part of Sucralose in an ethyl acetate phase, and the more polar impurities, as well as inorganic salts, remain in the aqueous phase. Table 2 shows the average number of various impurities, ostau is already in aqueous solution after extraction. Values are expressed as the ratio of the mass of the impurities present to mass Sucralose present in this phase, and reflect the average data obtained in the course of many ekstragirovanie.

Table 2
ImpurityRelation to Sucralose
4,1'-Dichloroacetophenone4,4
3',6'-Dichlorohydroquinone5,2
4,6'-Dichloroacetophenone32,0
1',6'-Dichloroacetone9,3
Unknown G of 5.70,4
Unknown H 6,00,5
6,6'-Dichloroacetone0,9
Unknown L to 7.90,8
4,1',6'-Trichlorosucrose0,5
Unknown Q 10,50,8

The results in table 2 show that Sucralose selectively removed in an ethyl acetate phase, leaving the aqueous phase with a much higher proportion of the more polar impurities.

For example, various dichloropropane, in particular, 4,6'-dichloroacetophenone, make up the volume derivatives of halogenated Sucralose remaining in the aqueous phase.

Thus, at this stage is significant clear who and Sucralose from the more polar impurities.

An ethyl acetate solution Sucralose and the remaining impurities, thus obtained, then distil to remove residual water present in the solution, and then Sucralose crystallized from solution. Crystallization promotes the concentration of the solution in the evaporation part of ethyl acetate and cooling solution. Remove water before crystallization significantly improves the crystallization rate and the purity of the crystalline Sucralose thus obtained.

Example 2

An aqueous solution of Sucralose obtained by alkaline diallylamine 6-O-acetyl precursor and subsequent neutralization, enter in column Carr with an inner diameter of 42 inches and the height at which the mixing of 50 feet. Saturated with water, the ethyl acetate is introduced into the column at a ratio of 0.35:1 (0,35 parts of ethyl acetate to 1 part water solution Sucralose). From the column receive two phases. An ethyl acetate phase is introduced into the column Carr with an inner diameter of 42 inches and the height at which the mixing is equal to 58 feet. Water is also injected into the column, so that the ratio of water to an ethyl acetate phase is 0.7:1.0 in. The aqueous solution obtained from this backwashing, together with primary source materials, and introduce for the first extraction. The aqueous phase after the first extraction uh what racedata injected into the column of Sibelia (Koch, Inc., Kansas City, MO) with an inner diameter of 56 inches and the height at which the mixing is equal to 33 feet. The column contains two separation sections 24 steps. The ethyl acetate is also injected into the column at a ratio of 3:1 (ethyl acetate:water). An ethyl acetate phase is removed and Sucralose extracted from an ethyl acetate phase by crystallization. Table 3 provides data on impurities present in an ethyl acetate phase extracted from the first column Carr. Table 4 provides data on impurities remaining in the aqueous phase after extraction in the column of Sibelia.

Table 3
ImpurityRelation to Sucralose
Unknown S0,14
6,1',6'-Trichlorosucrose1,71
4,6,6'-Trichlorogalactosucrose0,55
4,1',4',6'-Tetrachlorophthalate2,09
4,1',5'-Trichlorogalactosucrose-6-acetate0,26
4,6,1'6'-Tetrachloroethaneof 5.84

Table 4
ImpurityAttitude sucrose
4,1'-Dichloroacetophenone1,79
3',6'-dichlorohydroquinone2,84
4.6 dichloroacetophenone13,90
1',6'-Dichloroacetone4,32
Unknown G0,00
Unknown H0,28
6,6'-dichloroacetone0,40
Unknown L0,47
4,1',6'-Trichlorosucrose0,12
Unknown Q0,04
4,6,6'-Trichlorogalactosucrose0,02

Various modifications and variations of the described methods and systems of the present invention without deviating from the scope and essence of the present invention will be clear to experts in this field. Although the present invention is described in connection with specific preferred variant embodiment, it is necessary to understand that the present invention as it is claimed, should not be limited to such specific variant embodiment. Indeed, various modifications of the described ways of implementing the present invention, which is understandable to experts in this field, as expected, are within the scope of the following next of the claims.

1. Method of removing impurities from a composition containing Sucralose and impurities, including study is:

(a) the first solvent extraction of the specified compositions containing Sucralose and impurities in the first solvent, the second at least partially immiscible solvent to effect the removal of impurities in the specified second solvent; and

(b) the implementation of the second solvent extraction of the specified compositions containing Sucralose and impurities in the first solvent, with a third at least partially immiscible solvent to transfer Sucralose specified in the third solvent and the retention of impurities in the specified first solvent

where specified stage (a) shall remove at least some of the impurities in the specified second solvent; and

where specified stage (b) transports the most part Sucralose specified in the third solvent and the retention of a significant part of the impurities in the specified first solvent.

2. The method according to claim 1, further comprising a stage of extracting the specified Sucralose.

3. The method according to claim 2, where the specified phase extraction involves the crystallization of the specified Sucralose.

4. The method according to claim 1, where said first solvent contains water.

5. The method according to claim 1, where the specified second solvent includes ethyl acetate.

6. The method according to claim 1, where the specified third process is ITIL contains ethyl acetate.

7. The method according to claim 1, where the specified second solvent to the specified first solvent is from 1:2 to 1:5.

8. The method according to claim 7, where the ratio is from 1:3 to 1:4.

9. The method according to claim 1, where specified under implementation include the extraction method selected from the group consisting of a bootable extraction, continuous extraction and continuous countercurrent extraction.

10. The method according to claim 1, further comprising a stage of extraction of the specified second solvent after extraction of the specified first solvent, backwash specified second solvent a new portion of the specified first solvent and combining at least part of this new portion with a composition containing Sucralose and impurities in the first solvent before extraction using the specified third solvent at the stage (b).

11. Method of removing impurities from a composition comprising an aqueous solution of Sucralose and impurities, comprising the stage of:

(a) the first solvent extraction of the specified composition containing an aqueous solution of Sucralose and impurities, using, at least partially immiscible non-aromatic organic solvent to effect the removal of impurities in the indicated solvent; and

(b) the implementation of the second liquid extracti the specified composition, containing an aqueous solution of Sucralose and impurities with an organic solvent to transfer Sucralose in the specified solvent and retention of impurities in the aqueous phase,

where specified stage (a) shall remove at least some of the impurities in the specified solvent phase (a);

where specified stage (b) transports the most part Sucralose in the specified solvent phase (b) and hold a significant portion of the impurities in the aqueous phase.

12. The method according to claim 11, further comprising a stage of extracting the specified Sucralose.

13. The method according to item 12, where this phase extraction involves the crystallization of the specified Sucralose.

14. The method according to claim 11, where the specified solvent used in stage (a), represents the ethyl acetate.

15. The method according to claim 11, where the specified solvent used in stage (b)is ethyl acetate.

16. The method according to claim 11, where the relationship of these solvents to the aqueous phase ranges from 1:2 to 1:5.

17. The method according to clause 16, where these relationships range from 1:3 to 1:4.

18. The method according to claim 11, where specified under implementation include the extraction method selected from the group consisting of a bootable extraction, continuous extraction and continuous countercurrent extraction.

19. Method of removing impurities from the composition, tereasa aqueous solution of Sucralose and impurities, incorporating the following stages:

(a) the first solvent extraction of the specified composition containing an aqueous solution of Sucralose and impurities, using, at least partially immiscible organic solvent to transfer impurities in the indicated solvent;

(b) the implementation of the second solvent extraction of the specified composition containing an aqueous solution of Sucralose and impurities with an organic solvent to transfer Sucralose in the specified solvent and retention of impurities in the aqueous phase;

(c) extraction of the organic solvent remaining from stage (a), an aqueous solution to transfer Sucralose present in the organic phase in an aqueous solution; and

(d) combining the aqueous solution thus obtained in stage (C)with an aqueous solution, extracted in stage (a), before repeating stage (b);

where specified stage (a) shall remove at least some of the impurities in the specified solvent phase (a);

where specified stage (b) transports the most part Sucralose in the specified solvent phase (b) and hold a significant portion of the impurities in the aqueous phase;

where specified stage (s) shall transfer a significant part of Sucralose, present is in the organic phase, in aqueous solution.

20. The method according to claim 19, further comprising a stage of extracting the specified Sucralose.

21. The method according to claim 20, where the specified phase extraction involves the crystallization of the specified Sucralose.

22. The method according to claim 19, where the specified solvent used in stage (a), represents the ethyl acetate.

23. The method according to claim 19, where the specified solvent used in stage (b)is ethyl acetate.

24. The method according to claim 19, where specified under implementation include the extraction method selected from the group consisting of a bootable extraction, continuous extraction and continuous countercurrent extraction.

25. The method according to claim 19, where the specified phase extraction involves the extraction method selected from the group consisting of a bootable extraction, continuous extraction and continuous countercurrent extraction.

26. The way to remove compounds tetrachloroaurate from the solution Sucralose and chlorinated derivatives of sucrose in the first solvent, including extraction solution Sucralose and other chlorinated derivatives Sucralose using, at least partially immiscible second non-aromatic solvent for the distribution of connections tetrachloroaurate specified in the second solvent and holding Sucralose specified in the first solvent;

27. The method according to p where these connections tetrachloroaurate selected from the group consisting of 4,1',4',6'-tetrachlorophthalate and 4,6,1',6'-tetragenococcus.

28. The method according to p where the specified phase extraction involves the extraction method selected from the group consisting of a bootable extraction, continuous extraction and continuous countercurrent extraction.

29. Method of removing impurities from a composition containing solution Sucralose and impurities in the first solvent, which includes stages:

(a) the first solvent extraction of the specified compositions containing solution Sucralose and impurities in the first solvent with the second solvent, which has a Hildebrand parameter, which is higher than said first solvent, under conditions which selectively transfer Sucralose specified in the second solvent, thereby providing a solution Sucralose in the specified second solvent which has a high ratio Sucralose to impurities less polar than Sucralose; and

(b) the implementation of the second solvent extraction of the specified solution Sucralose in the specified second solvent obtained at the previous stage, with the third solvent, which has a Hildebrand parameter, which is higher than the specified second solvent, under the conditions to which that selectively transfer impurities, the more polar than Sucralose, the third solvent, thereby providing a solution Sucralose in the specified second solvent which has a high ratio Sucralose to the impurities more polar than Sucralose.

30. The method according to clause 29, further comprising a stage of extracting the specified Sucralose.

31. The method according to item 30, where this phase extraction involves the crystallization of the specified Sucralose.

32. The method according to clause 29, where the specified second solvent to the specified first solvent is from 2:1 to 5:1.

33. The method according to p, where the ratio is from 3:1 to about 4:1.

34. The method according to clause 29, where specified under implementation include the extraction method selected from the group consisting of a bootable extraction, continuous extraction and continuous countercurrent extraction.



 

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