Method of water deacylation buffer stabilized

FIELD: chemistry.

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

EFFECT: improved method of water deacylation procedure stabilization.

22 cl, 1 tbl, 1 ex

 

The SCOPE of the INVENTION

The present invention relates to new methods of stabilizing water diallylamine through the use of buffers when receiving Sucralose. In the present invention, a method of obtaining Sucralose from the connection acyl-Sucralose, and the connection acyl-Sucralose decelerat in the presence of a buffering agent, which stabilizes the pH is supplied to the mixture and reduces the accumulation of unwanted angelasweeney. In addition, the present invention relates to a method in which the connection acyl-Sucralose decelerat directly, or before, or after removal of the reaction medium tertiary amide, neutralized chlorinated supplied (original) mixture. Receive an aqueous solution of Sucralose containing salts and other compounds from which Sucralose emit extraction and purified by crystallization.

Background of invention

Selective modification of Sucralose is a major synthetic challenge due to the presence of multiple reactive-Oh groups and acid lability glycosidic bonds. When the target product is Sucralose (4,1',6'-trichloro-4,1',6'-trimethoxybenzoate: in the process of obtaining compounds of the stereochemical configuration at position 4 is changed to the opposite, therefore, Sucralose is predstavljaet galactosidase), the difficulty lies in the need to gloriavale less reactive 4 - and 1-positions, without affecting the more reactive position 6.

Developed a number of different strategic approaches to obtain Sucralose for preliminary protection provisions 6, usually through education Sucralose-6-acylate, such as Sucralose-6-acetate, and removal of the blocking fragment by hydrolysis after chlorination to obtain Sucralose. For this strategy include the U.S. patents 4950746; 5023329; 5034551; 5470969; 4362869; 4826962; 5470868; 5530106 and 4980473 included in this description by reference.

Before isolation of pure Sucralose to Sucralose-6-Atzilut deesterification hydrolysis. One approach clonapine group again turn into the free hydroxyl group by alkaline hydrolysis. After hydrolysis of the feed mixture is adjusted to approximately neutral pH values and Sucralose subsequently isolated from the mixture supplied by one of several suitable methods. See, for example, application for U.S. patent entitled "Extraction cleaning methods Sucralose" and "the Way to improve purity and yield Sucralose", filed on 8 March 2002 and specifically are included in this description by reference. The reaction deesterification can be carried out in an organic system with the use of substances such as sodium methoxide, the cat is PoE leads to a reaction of transesterification. In this case, acid fragment, forming ester Sucralose, turns into a methyl ester of the acid, with methyl ether can be removed by distillation, shifting the direction of reaction to its completion. Alternatively, the reaction deesterification can be carried out in water under alkaline conditions, leading to an indirect basis of the conversion of ester in Sucralose and the salt of the acid, which was used for the formation of ester. Desirable is the use of the latter water hydrolysis, since it eliminates the use of expensive solvents that must be removed during subsequent purification.

However, one of the problems in the last cleanup strategy Sucralose is that Sucralose in deesterification form is unstable in alkaline conditions and can turn into unwanted connections. For example, angelasweeney are undesirable because they reduce the overall yield of the reaction and have an adverse effect on the sweetness of Sucralose. Therefore, these unwanted connections can also have a negative impact on the duration of the extraction process. In addition, high levels of such substances greatly increase the difficulty stages of refinement.

The present invention relates to a method in which the connection acyl-su is relasi decelerat directly to obtain aqueous solution of Sucralose, containing salt and other compounds from which Sucralose isolated and then preferably cleaned by flowing solvent extraction, crystallization, or a combination of such methods.

Accordingly, the present invention relates to a method of purification of Sucralose, which leads to Sucralose compositions of high purity and also minimizes the overall loss of Sucralose during cleaning method before any particular extraction, along with the fact that reduces the formation of undesirable compounds, such as anhydrosugars.

SUMMARY of the INVENTION

The present invention relates to a method for producing Sucralose from a supplied to the mixture containing the compound of the acyl-Sucralose in aqueous solution, the method comprises (a) bringing the pH of the supplied mixture to a value in the range from 8.0 to 12.0; (b) maintaining the specified supplied to the mixture at a suitable temperature and for a time to effect the conversion of compounds of acyl-Sucralose free to Sucralose; (C) adding a buffer to the supplied to the mixture from stage (b) to stabilize the pH; (d) reducing the pH supplied to the mixture from stage (b) to a value of from 4 to 8; and (e) the allocation of free Sucralose.

In one embodiment of the present invention to Sucralose can be obtained from the supplied mixture containing the compound of the acyl-Sucralose is an aqueous solution, by bringing the pH of the mixture supplied to the values in the range of from about to 8.0 to about 12, 0mm; maintaining the indicated supplied to the mixture at a suitable temperature over a period of time sufficient for conversion of the specified connection acyl-Sucralose free to Sucralose; add buffer to the specified supplied to the mixture in sufficient quantity to stabilize the indicated pH in the specified range for a specified stage-keeping; reduction specified specified pH supplied to the mixture to a value from about 4 to about 8; and allocation of Sucralose. In a specific embodiment, the pH is supplied to the mixture can be increased to roughly 10.5.

In one embodiment of the present invention, the buffer may be an amine, amino acid, phenol, inorganic acid, saccharin, xanthine, hydrochinone or their mixture. In another embodiment, the amine may be represented as ammonia, alkylamines followed RNH2dialkylamide R1R2NH, trialkylamine R1R2R3N where R, R1, R2 and R3 represent methyl, ethyl, 1-propyl, 2-propyl, butyl, cyclohexyl, benzyl, pyrrolidin and 2 hydroxypyridine. In another embodiment of the present invention, the amino acid may be a glycine, alanine, arginine, dimethylglycine, cysteine, or mixtures thereof. In one embodiment, the infusion is his invention, the phenol may be a phenol or resorcinol. In another embodiment, the inorganic acid may be a carbonate. In a specific embodiment of the present invention, the buffer may be a dimethylamine or dimethylamine salt.

In another embodiment of the present invention, the connection acyl-Sucralose can be a 6-O-acyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate. In another embodiment, the compound 6-O-acyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate is a 6-O-acetyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate. In another embodiment, the compound 6-O-acyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate can be a 6-O-benzoyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate.

In the embodiment of the present invention the feed mixture essentially may not contain a tertiary amide. In another embodiment, the feed mixture essentially may not contain dimethylformamide.

In one embodiment, the present invention allocated Sucralose may contain 20 parts per million or less of an organic solvent. In this embodiment, the organic solvent may be methanol, ethanol, methyl acetate, toluene, pyridine, DMF, dichloromethane, chloroform or a mixture thereof. In one embodiment, about what westline selected Sucralose may contain about 7 parts per million or less of methanol. In another embodiment, the selected Sucralose may contain about 7 parts per million or less of ethanol. In another embodiment, the selected Sucralose may contain about 10 parts per million or less of acetate. In another embodiment, the selected Sucralose may contain about 10 parts per million or less of toluene. In one embodiment, the selected Sucralose may contain about 20 parts per million or less DMF. In another embodiment, the selected Sucralose may contain about 10 ppb or less dichloromethane. In another following embodiment, the selected Sucralose may contain about 10 ppb or less of chloroform.

One variant of implementation of the present invention may include a composition of matter containing Sucralose, while Sucralose contains 20 ppm or less of an organic solvent. In this embodiment, the organic solvent may be methanol, ethanol, methyl acetate, toluene, pyridine, DMF, dichloromethane, chloroform or a mixture thereof. In one embodiment, the selected Sucralose may contain about 7 parts per million or less of methanol. In another embodiment, the selected Sucralose may contain about Casta per million or less of ethanol. In another embodiment, the selected Sucralose may contain about 10 parts per million or less of acetate. In another embodiment, the selected Sucralose may contain about 10 parts per million or less of toluene. In one embodiment, the selected Sucralose may contain about 20 parts per million or less DMF. In another embodiment, the selected Sucralose may contain about 10 ppb or less dichloromethane. In another following embodiment, the selected Sucralose may contain about 10 ppb or less of chloroform. The present invention may also include a combined sweetener, beverage or consumer product, combined with Sucralose.

One variant of implementation of the present invention may include a composition Sucralose, where Sucralose was diallylamine, and may contain about 20 parts per million or less of an organic solvent. In this embodiment, the organic solvent may be methanol, ethanol, methyl acetate, toluene, pyridine, DMF, dichloromethane, chloroform or a mixture thereof. In one embodiment, the selected Sucralose may contain about 7 parts per million or less of methanol. In another embodiment, selected when celosa may contain about 7 parts per million or less of ethanol. In another embodiment, the selected Sucralose may contain about 10 parts per million or less of acetate. In another embodiment, the selected Sucralose may contain about 10 parts per million or less of toluene. In one embodiment, the selected Sucralose may contain about 20 parts per million or less DMF. In another embodiment, the selected Sucralose may contain about 10 ppb or less dichloromethane. In another following embodiment, the selected Sucralose may contain about 10 ppb or less of chloroform. The present invention may also include a combined sweetener, beverage or consumer product, combined with Sucralose.

Other objectives, features and advantages of the present invention will be apparent from the following detailed description. The detailed description and specific examples, while and show specific embodiments of the invention, given only as an illustration. Accordingly, the present invention also includes those possible changes and modifications within the scope and essence of the invention that may be obvious to experts in this field from this detailed description.

DETAILED description of the INVENTION

PON the IDT, that the present invention is not limited to the particular methodology, protocols, solvents and reagents, etc. given in the description, as they may change. It should also be understood that the terminology used used only for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. It should be noted that as used in this description and the claims, the indefinite and the definite singular includes reference to the plural, unless the context clearly indicated a different. Thus, 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 the like.

Unless otherwise stated, all technical and scientific terms have the same meaning as that usually understood by the person skilled in the art to which belongs the present invention. Here are numerous methods, devices and materials, although in practice or testing of the present invention can use any methods and materials similar or equivalent described. All cited in this description of the documents included in this description in its entirety.

The term "batch"as used in this description, describes the way in which in the process of introducing a fixed number of substances and produce products derived from this fixed amount of load before adding additional quantities of feed material.

The term "beverage"as used herein, includes any non-carbonated or carbonated drink, such as Cola, diet Cola, soda water, diet soda, cocktails based on juices, fizzy drink from the roots, seasoned with nutmeg oil, birch beer, any drinking water, sparkling fruit juice, water, spring water, tonic related to sports drink, fruit juices, isotonic drinks and sparkling water. The drink may also include any fermented or non-fermented beverage, such as any beer, including ale, pilzenskoe beer, lager or its derivatives, malt beverage, red wine, white wine, sparkling wine, fortified wine, soft drink based on wine, the drink of white wine and soda water, any pre-made cocktail mix, including margaritas, sour cocktail or cocktail "Daiquiri", any fermented fruit or tea drink, strong drink and any aromatizirovannam is the first alcoholic drink, such as brandy, schnapps, the bitter liqueur or liquor. The drink can include any liquid or dry milk product, milk or milk product, milk or any liquid or dry milk substitute product, cream or milk, such as in half-in-half, non-dairy milk powder, powdered milk, flavored milk, soy milk products, and dairy products with reduced content of lactose and the like. The drink may also include any fruit or vegetable juice in a solid, concentrated or powdered form and any combination of fruit and vegetable juices or other beverages. The drink may also include coffee, any coffee, any coffee flavouring syrup, tea, iced tea and cocoa, as well as any combination of any of the above in powder or liquid form. The drink may also include a powder mixture for drinks every taste, including mixtures requiring add sweetener before or after reconstitution to form a liquid form.

The term "blocked (protected) Sucralose", as used herein, refers to molecules Sucralose, in which some or all of the remaining hydroxyl group is blocked (protected) by esterification or by other means.

The term is a combination of the first sweetener", as it is used herein, includes any combination or a modified form of sweeteners, including the combination of Sucralose, saccharin, aspartame, Acesulfame potassium, cyclamate, alitame, reveal, glucose, fructose, levulose, maltose, lactose, any sugar alcohol, sorbitol, xylitol and mannitol. Combined sweeteners can be granular in form but may be in any suitable form, such as powder, liquid or syrup. Combined sweetener may consist essentially of Sucralose. Combined sweetener may consist essentially of Sucralose and media, such as dextrose, lactose, maltodextrin and water.

The term "consumer product"as used in this description, includes fruit products such as Apple juice, jams, jellies, marmalades, fruit cakes, fruit butter and fruit pastes. Consumer product may also include any viscous or solid dairy products, milk or milk-based products cream, such as cheese, ice cream, dairy ice cream, frozen yogurt, yogurt and the like. Consumer product also includes bakery products such as bread, donuts, cakes, cheese cakes, danesi, pastry, pies, bagels, pies, barley cakes, crackers, grief is their muffins and waffles. Consumer products include grain products, such as ready for consumption cereals, oat flour coarse, hot cereal products, granular mixture, oat flour and mix for travel. Consumer product includes condiments such as butter, peanut butter, whipping cream, sweet slices, sour cream, BBQ sauce, chili sauce, syrup, sauces, mayonnaise, olives, spices, herbs, pickles, fruit puree, cakes in sweet sauce, ketchup, salsa, mustard, salad dressing and salt and pepper. Consumer product includes snacks and pastries, such as Apple bars, puddings, candies, hard candies, chocolate products, lollipops, fruit chewing candy, cranberry, sugar, chewing gum, bubble gum, gummy candy, generowanie candy, caramel, butterscotch, fillings for cakes, syrups, cakes, jelly, mint candy, popcorn, chips and pretzels with salt. Consumer product includes meat products such as hot dogs, canned fish, sausages, meat products, canned meat, dehydrated meat and meat snacks. Consumer product includes soups, consomme and bouillon. Consumer product includes the products for the oral cavity, such as toothpaste, floss for cleaning teeth, rinse the mouth, the adhesive on the I of the dental prosthesis, bleach the tooth enamel, fluoride preparations and gels to care for the oral cavity. Consumer product includes cosmetics and tools for makeup, such as lipstick, lip balm, lip gloss and vaseline. Consumer product includes therapeutic objects, such as not containing tobacco snuff powder, tobacco substitutes, pharmaceutical compositions, chewing medicines, cough syrups, throat sprays, lozenges for throat, cough drops, antibacterial products, coatings for pills, gel caplet, soluble fiber antacids tools, core tablets, rapidly absorbed liquid compositions, stable foamed composition, quickly dezintegriruetsja pharmaceutical dosage forms, beverage concentrates for medical purposes, the aqueous pharmaceutical suspension, concentrated liquid compositions and stable solutions of sorbic islote, phosphate buffers, saline solutions, emulsions, non-aqueous pharmaceutical solvents (propylene glycol, polyethylene glycol, vegetable oil), aqueous pharmaceutical carriers (water, alcohol) and a solid pharmaceutical carrier (lactose, cellulose), pharmaceutical preservatives/additives (anti-microbial agents, antioxidants, chelating Genty, inert gases, flavors, dyes). Consumer product includes food products such as bars - meal replacement, bean meal replacements, diet supplements, protein mixes, protein bars, bars for regulation of carbohydrates, the bars low carb, nutritional supplements, electrolytic solutions, products from whey, milk, modifiers metabolic response, controlling appetite drinks and sprays on the basis of Echinacea. Consumer product includes food for animals, such as feed for dogs and cats, food for rats, feed for cattle, fodder for pigs and food for birds. Consumer product includes foods such as baby food, products for children and other products for health and nutrition for children, such as drinks for rehydration in the mouth. Consumer product includes tobacco products such as pipe tobacco, cigarette tobacco, and chewing tobacco. Consumer product includes any substance intended for internal use, either alone or together with another substance. Consumer product includes any composition intended for oral, parenteral, intravenous, subcutaneous, intramuscular, intraocular, vnutrispinalnaya is about, vnutribruchinnogo or intraarterial administration to a human or animal, such as cattle or pet. Consumer product optionally may contain additional agents such as the media (for example, starch, lactose and sucrose), fillers (for example, maltodextrins), adjuvants (e.g., indocyanine green, vanilla and peppermint oil), dyes, regulating the viscosity agents, including soluble cellulose derivatives (e.g. carboxymethylcellulose), thickening of the gums (such as xanthan gum, Gellan, carrageenan) and synthetic food supporting materials (e.g., polyoxyethylene, carbomer).

The term "continuous operation"as used in this description, includes procedures in which the product can be removed from the process, while the added input of raw materials; product removal or addition of downloadable raw material can be increased, intermittent or constant speed. Professionals in this field can easily be understood that it may be many intermediate processes between the true periodic process and a true continuous process. Variants of the present invention can be easily implemented in practice in a full range of possible processes.

The term "crude Sucralose"as it is used in the data the m description includes Sucralose mixed with other chlorinated sugars and Sucralose and other chlorinated sugar, among which some or all of the hydroxyl groups remaining after chlorination, can be blocked (protected) by esterification or by other methods known to experts in this field.

The term "crystallization"as used in this description, includes the processes that receive the solution, a saturated or supersaturated in respect of the dissolved component, and is achieved by the formation of crystals of the component. The initiation of crystal formation may be spontaneous or may require adding embryonic crystals. As used in this description, crystallization also describes the situation in which solid or liquid substance is dissolved in the solvent, obtaining a solution which then make a saturated or supersaturated to obtain crystals. Also, the term "crystallization" is included auxiliary washing processes of crystals of one or more solvents, drying of the crystals, and collecting the final product.

The term "operation extraction"as used in this description, includes procedures that can be performed to the mother liquor in order to remove various compounds of the fallopian R is the target. The specific operation may be selected from any number of which may be appropriate for the removal of unwanted compounds. Such operations may include, but are not limited to specified, distillation, solvent extraction, chromatography and obtaining derivatives with subsequent removal of the resulting substance.

The term "recycling mother liquor"as used in this description, refers to the practice of adding the mother liquor to another solution of Sucralose before or during its crystallization. The mother liquor may be further concentrated or purified before recycling. The allocation of a significant portion of Sucralose, remaining in this mother solution may be essential to achieve economically acceptable process exit.

The term "solvent"as used herein, includes a liquid that can dissolve another substance.

In some embodiments, the implementation of the term "Sucralose" can include compounds that differ from Sucralose, and applies to products of any number of processes of synthesis of Sucralose that are not Sucralose. They include any monochloro-, dichloro-, tetrachloro - and pentachloropropane sucrose and other disaccharides derived from sucrose, as well as any trichlorpropane, otlichuy the SJ from the Sucralose, whether they are in free form or in the form of esters of carboxylic acids. These include any halogenated derivatives of sugars, such as acetate dichloroacetyl, 6,1',6'-trichlorosucrose, 4,6,6'-trichlorosucrose, 4,1,4',6'-tetrachlorophthalate, 4,4,1',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 other, as shown in U.S. patents№№ 4405654, 4435440, 4980463, 5034551, 5498709 and 5530106. They include any organic or inorganic salt, a carbohydrate or acylated to Sucralose.

The present invention relates to methods by which the compounds of the acyl-Sucralose decelerat directly with obtaining aqueous solution of Sucralose containing salt and other compounds, which emit Sucralose. Then Sucralose can be isolated by extraction, for example using an organic solvent. Then Sucralose can be cleaned using countercurrent extraction, crystallization or a combination of both. In one embodiment, the present invention relates to a method for producing Sucralose from a feed mixture which, contains the connection acyl-Sucralose in water solution.

In one embodiment, the method of the present invention comprises (a) bringing the pH of the mixture supplied to the values in the range of from about to 8.0 to about 12, 0mm; (b) maintaining the specified supplied to the mixture at a suitable temperature over a period of time for carrying out the conversion of compounds of acyl-Sucralose free to Sucralose; (c) adding a buffer to the specified supplied to the mixture in sufficient quantity to stabilize the pH; (d) reducing the pH of the mixture supplied to values from about 4 to about 8; and (e) the designation of Sucralose. Data stage can be performed in any suitable order.

In one embodiment, the method according to the invention it is possible to use the feed mixture, which may contain di-, tri - and tetrachloropropane connection Sucralose. U.S. patent No. 5977349, which is specifically incorporated in this description by reference, relates to such compounds, and methods. In one embodiment of the present invention, the connection acyl-Sucralose may include esters of 6-O-acyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate. In addition, the connection acyl-Sucralose may include 6-O-acetyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate or 6-O-benzoyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate. Types of halogenated what soedinenii, present in this mixture supplied may vary in accordance with the used synthetic means and the specific synthesis conditions. Halogen-free, suitable for use in the context of the present invention include bromine, chlorine, fluorine and iodine. The person skilled in the art can easily occupy different positions in the same halogen or any combination or permutation of the various Halogens using methods known to experts.

In addition to the connection acyl-Sucralose, in the present invention it is possible to use the feed mixture, which contains at least one additional component selected from the group consisting of at least one other chlorinated sucrose, other than the first chlorinated sucrose, salt and solvent. U.S. patent No. 4980463, which is specifically incorporated in this description by reference, is supplied to the mixtures, which can be a product of the neutralization acyl-Sucralose and which are also used for the purification of Sucralose. In this embodiment, the feed mixture contains acyl-Sucralose (such as Sucralose-6-acetate or Sucralose-6-benzoate), most likely at least one other chlorinated sucrose (including its esters); the solvent is a tertiary amide, for the reaction is loriane (preferably N,N-dimethylformamide); different salt by-products of the reaction of chlorination and neutralization (including chlorides of alkali metals, alkaline earth metals, ammonium and alkylammonium, such as sodium chloride and dimethylamine hydrochloride, and formate, alkali metal such as sodium formate); and water.

Alternatively, the chlorinated feed mixture can be subjected to a steam distillation or the like to remove solvent - tertiary amide. U.S. patent No. 5530106, which is specifically incorporated in this description by reference, relates to such methods. The removal of the tertiary amide can be followed by hydrolysis to remove the 6-acyl fragment to obtain another supplied to the mixture, which can be used in the cleaning method according to the invention. In this embodiment, feeding the mixture used in the method according to this invention may contain Sucralose; possibly other chlorinated sucrose; various salt the reaction by-products of chlorination and neutralization (including chlorides of alkali metals, alkaline earth metals, ammonium and alkylammonium, such as sodium chloride and dimethylamine hydrochloride, and formate, alkali metal such as sodium formate); water; less than about 1 to 2 % by weight of the applied mixture solvent - tertiary amide; and some remaining connection is in the sucrose-6-ether complex (in the variant implementation where hydrolysis to remove the 6-acyl fragment was not completed).

In laboratory scale, the crude product of the chlorination can be repaid in periodic by adding (at one time) one molar equivalent (based on phosgene) cooled with ice water solutions or suspensions of hydroxides of alkaline or alkaline-earth metal. In one embodiment, the alkaline agents may include the hydroxides of sodium, potassium and calcium. In a particular embodiment, can be used in more dilute aqueous alkaline solutions, such as about 3-4n sodium hydroxide. You can also use the wide ranges of concentrations, for example from about 2n to about 8h of sodium hydroxide. At lower concentrations reduces or eliminates the precipitation of salts, which significantly reduces the amount of solids that can accommodate the process stream. However, when the concentration becomes too low (e.g. below approximately 2n), the process stream may be diluted to such an extent that it may affect the efficiency of the method.

In one practical implementation of this method of damping to the cold aqueous alkali may be added to the buffer with vigorous stirring as fast as possible, the number, sufficient to raise and maintain pH in the range from about 8 to about 10. The buffer of the present invention will provide protection against sudden changes in alkalinity or acidity. After adding the buffer solution may be resistant to changes in pH when the solution is subjected to the action of acids or alkalis that otherwise would have caused drastic changes in pH. In particular, the buffer of the present invention is to maintain the concentration of hydrogen ions, H+at a fixed value.

In one embodiment of the present invention, the buffer must have a good buffer capacity at pH about 10.5. In addition, the buffer must be capable of maintaining the pH of the solution in the range from 8 to 12.0. The addition of a buffer can prevent the deviation of the pH to a higher level that may cause a relative increase in formation of undesirable compounds. In the embodiment, other compounds may include the formation of angelasweeney, such as 3',6'-anhydrous-4,1'-dichloroacetophenone and 1',2,3',6'-dialdehyde-4-Charalabopoulos. In addition, maintaining stricter control of pH by adding buffer can standardize the profile of purity and lead to increased reproducibility of the method of the present invention.

In one embodiment, BU the career of the present invention may include, but are not limited to these amines, such as ammonia, alkylamines followed RNH2dialkylamide R1R2NH, trialkylamine R1R2R3N (where R, R1, R2 and R3 represent methyl, ethyl, 1-propyl, 2-propyl, butyl, cyclohexyl, benzyl, etc., heterocycles, such as pyrrolidin, 2-hydroxypyridine etc.); alienability, such as glycine, alanine, arginine, dimethylglycine, cysteine; phenols, such as phenol or resorcinol, etc.; inorganic acid such as carbonate and other buffers, such as saccharin, xanthine, hydroquinone or mixture thereof. In another embodiment, the present invention suitable buffering agent may be a dimethylamine salt or dimethylamine.

After stirring for several minutes at this mildly elevated pH repaid the solution may be neutralized to pH 5-7 by adding acid, such as, for example, concentrated aqueous hydrochloric acid or glacial acetic acid. Short-term treatment suppressed chlorinated supplied to the mixture at pH 8-10 may have a beneficial effect, giving assurance that the hydroxyl groups of the sucrose-6-ether complex that have not been replaced by chlorine atoms, returned to his original form hydroxyl groups.

In an alternative embodiment, a sufficient amount of aqueous alkali and buffer AgentLog to be added to achieve pH, equal to 11 (± 1), and the mixture was incubated for a sufficient time to remove the 6-acyl function and obtain Sucralose in the presence of all salts, residual amounts of the tertiary amide (DMF), etc. However, some amount of DMF may be lost when alkaline hydrolysis due to the transformation into dimethylamine and sodium formate. For this reason, diallylamine to remove DMF is less preferred because it may be desirable to select the entire DMF for recirculatory and re-use.

Removal of DMF

When sodium hydroxide is used at the stage of clearing and tertiary amide is a DMF, at the stage of damping can form salts such as sodium chloride, dimethylamine hydrochloride, and small amounts of sodium formiate. If the damping continue with diallylammonium by increasing the pH to be sufficient to allow diallylamine, extraction of Sucralose from suppressed, and thus contains describeany product of the reaction mixture, may be complicated due to the presence of DMF (or other tertiary amide) and the propensity of the tertiary amide to the distribution between the organic and aqueous phases in the extraction step, which can logically be the next stage in the production sequence to obtain Sucralose. Tertiary amide m which can dissolve Sucralose in both phases and may also have a tendency to dissolve other substances present in both phases, which can make difficult allocation of Sucralose with a good yield and/or to make the process expensive. The presence of DMF or other tertiary amides can be bad for the purification of Sucralose by crystallization from a solvent used in the extraction. A further potential difficulty can be the decomposition of the tertiary amide catalyzed by base. For all these reasons, tertiary amides, as well as DMF, preferably removed prior to the extraction and purification of Sucralose. Further, it is preferable to remove DMF) to the stage of diallylamine.

For example, for removing the bulk of the DMF (or other tertiary amide) can be performed by distillation with steam repaid supplied to the mixture (preferred method) or suppressed and deaccelerating supplied to the mixture. In one embodiment, it may be desirable to remove at least 95%, and in a particular embodiment, at least from about 98 to 99.9% DMF) to limit such undesirable consequences.

After removal of DMF (or other tertiary amide) by distillation with steam DMF) can be effectively replaced by water in the process stream and DMF can be subsequently separated from the water chasing by distillation and can be recycled.

Diallylamine Sucralose-6-ether complex

the one embodiment of the present invention Sucralose-6-ester decelerat by increasing the pH of the mixture supplied to 11(± 1) at a temperature and for a period of time sufficient for diallylamine after removal of the tertiary amide. This stage can be accomplished by adding sufficient alkali metal hydroxide such as sodium hydroxide, with stirring, to increase the pH to the desired level. In addition, there may be added a buffer agent, which exhibits good buffer activity for about pH of 10.5. In one embodiment, it is possible to use the reaction time and temperature in the range from about 30 minutes to 2 hours at from about 15°With up to about 35°C. At the end of diallylamine present base can be neutralized, for example, by adding hydrochloric acid to a pH of approximately from 5 to 7. After neutralization of the aqueous feed mixture can contain Sucralose, salt (as above, plus salt, formed just above the stage neutralization) and other chlorinated by-products of sucrose.

Extraction of Sucralose

After diallylamine Sucralose can be isolated by extraction of saturated aqueous salt solution many organic solvents. These solvents include methyl acetate, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, methylisobutylketone, methylene chloride, chloroform, IER is silt ether, methyl tertiary butyl ether and the like. Application for U.S. patent entitled "Extraction cleaning methods Sucralose"refers to such methods. In a specific embodiment, it is possible to use ethyl acetate due to the extraction selectivity, ease of recirculatory and Toxicological safety.

The allocation of Sucralose in the laboratory can be realized, partially mpariwa crude neutralized describeany the reaction product. About half of the water present may not necessarily be removed, giving a solution containing about 2 to 5 wt.% carbohydrate and from about 15 to 35 wt.% percent salt. The selection may be performed by performing three successive extraction using ethyl acetate or other suitable solvent. Extracts may be combined and may not necessarily be water-washed (for partial removal of any residual DMF and derivatives dichlorodibenzofuran, which to a certain extent, is distributed in the organic phase).

In addition to the summarized above periodic technologies of extraction, the extraction can also be carried out continuously for diluted (not concentrated through evaporation) flow in a countercurrent extraction system with alternating steps of paramesh is up and defend. The advantage of this method of conducting the extraction is that it does not require pre-stage evaporation-concentration. Such countercurrent extraction technology known in the field.

After separation of the crude Sucralose from aqueous saturated salt solution in the form of a solution in a suitable organic solvent him concentrate and the product can be purified by crystallization and recrystallization from the same solvent until then, until you reach the required purity. Application for U.S. patent, "Method of improving purity and yield Sucralose" refers to such processes. Alternatively, Sucralose can be recrystallized from a solvent mixture such as a mixture of methanol-ethyl acetate, or water to achieve the desired level of purity. The subsequent distribution of Sucralose between mixtures of solvent-water countercurrent manner can also give the opportunity for treatment and, moreover, to give the opportunity to create undertaken directly and completely in the liquid process, i.e. without the need of substances, as the final process stream may conform to the technical requirements for the immediate packaging for use.

Another variant of the above-described method of purification/separation lies in the fact that the same solvent can be used for the extraction step, and for the cleanup phase. Normally, i.e. in the case of other chemicals, it is unlikely that designed for cleaning chemical product crystallized from the same solvent used for extraction. However, in this case, the combination of dilution and low levels of other compounds may allow Sucralose to remain in solution during the extraction, and then after concentrating the solution containing Sucralose, product Sucralose may crystallize from the same solvent.

Another aspect of the present invention relates to Sucralose obtained are given in the description of the methods and methods that include the disclosed methods diallylamine, crystallization and extraction, which contains low levels of organic solvent. Such solvents are, for example, may include methanol, ethanol, methyl acetate, toluene, pyridine, DMF, dichloromethane, chloroform, and combinations thereof. In a specific embodiment, levels of solvents in Sucralose can be less than 20 parts per million. In particular, the levels of methanol or ethanol may be less than 7 parts per million. In another embodiment, the levels of acetate, toluene or pyridine can be less than 10 parts per million or less. In the following embodiment, the level DMF present in Sucralose, may be 20 ppm or less. In another embodiment, the level dichloromethane or chloroform in Sucralose may be 10 parts per billion or less.

The content of such solvents in Sucralose can be measured by known methods such as gas chromatography, and as shown in table 1. Organic solvents that can be tested include methanol, ethanol, methyl acetate, toluene, pyridine, DMF, dichloromethane, chloroform or mixtures thereof.

Table 1
Organic solventContent
Methanol7 parts per million
Ethanol7 parts per million
The acetate10 ppm
Toluene10 ppm
Pyridine10 ppm
DMF20 ppm
Dichloromethane10 parts per billion
Chloroform10 parts per billion

Sucralose obtained according to the present invention can be used in beverages, consumer products, combined sweeteners and others is one of the products.

EXAMPLES

Example 1. Limited receiving angelasweeney with the addition of a buffering agent.

Got a solution containing acetyl-6-O-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate (or 6-acetyl ester)as described in U.S. patent No. 5977349, which is specifically incorporated in this description by reference. The Stripping steam used for removal of dimethylformamide remaining from the synthetic reaction. The feed mixture contained, in addition to acetyl-6-ether, other chlorinated derivatives of sucrose, the residual amount of N,N-dimethylformamide, by-products of chlorination reactions and neutralization, including alkali, ammonia and chlorides of alkylamine. The sodium chloride formed a significant part of products, and also attended dimethylamine hydrochloride.

To increase the pH of the mixture to about to 10.5 was added a sufficient amount of an aqueous solution of sodium hydroxide. This pH value was sufficient to facilitate the alkaline hydrolysis of acetyl-6-ether. Simultaneously with caustic soda was added dimethylamine hydrochloride to create a buffer tank to prevent an excessive increase in pH that causes the formation of undesirable derived anhydrosugars. The above conditions were sufficient for substantial conversion of acetyl-6-ether in Sucralose. For carrying out this the reaction you can use a wide range of reaction conditions.

1. A method for production of Sucralose from an initial mixture containing the compound of the acyl-Sucralose in water solution, providing

(a) bringing the pH of the specified initial mixture to a value in the range from 8.0 to 12.0 by the addition of alkali metal hydroxide;

(b) adding a buffer to the specified initial mixture in an amount sufficient to stabilize the indicated pH in the specified range during the step of curing ();

(c) maintaining the specified initial mixture at a suitable temperature for a time sufficient for the effective conversion of the specified connection acyl-Sucralose free to Sucralose;

(d) reducing the specified pH of the specified initial mixture to a value from 4 to 8;

(e) the designation of Sucralose from the product of stage (d), obtaining thus selected Sucralose.

2. The method according to claim 1, where the specified pH is about 10,5.

3. The method according to claim 1, where the specified buffer selected from the group consisting of amines, amino acids, phenols, salts of inorganic acids, saccharin, xanthine, hydrochinone and mixtures thereof.

4. The method according to claim 3, where these amines are selected from the group consisting of ammonia, RNH2, R1R2NH, R1R2R3N where R, R1, R2 and R3 are selected from the group consisting of methyl, ethyl, 1-propyl, 2-propyl, butyl, cyclohexyl, benzyl, pyrrolidine and 2-hydroxypyridine.

p> 5. The method according to claim 3, where these amino acids are selected from the group consisting of glycine, alanine, arginine, dimethylglycine, cysteine, and mixtures thereof.

6. The method according to claim 3, where these phenols are selected from the group consisting of phenol and resorcinol.

7. The method according to claim 3 where the specified salt of inorganic acid is a carbonate.

8. The method according to claim 1, where the specified buffer is dimethylamine or dimethylamine salt.

9. The method according to claim 1, where the specified connection etilakrilata is a combination of 6-O-acyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate.

10. The method according to claim 9, where the specified connection 6-O-acyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate is a 6-O-acetyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate.

11. The method according to claim 9, where the specified connection 6-O-acyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate is a 6-O-benzoyl-4,1',6'-trichloro-4,1',6'-trimethoxybenzoate.

12. The method according to claim 1, where the specified source mixture essentially contains no tertiary amide.

13. The method according to claim 1, where the specified original mix essentially does not contain dimethylformamide.

14. The method according to claim 1, where the specified allocated Sucralose contains 20 ppm or less of an organic solvent.

15. The method according to 14, where the specified organic solvent selected from the group consisting of the of ethanol, ethanol, acetate, toluene, pyridine, DMF, dichloromethane, chloroform and mixtures thereof.

16. The method according to clause 15, where the specified allocated Sucralose contains about 7 parts per million or less of methanol.

17. The method according to clause 15, where the specified allocated Sucralose contains about 7 parts per million or less of ethanol.

18. The method according to clause 15, where the specified allocated Sucralose contains about 10 parts per million or less of acetate.

19. The method according to clause 15, where the specified allocated Sucralose contains about 10 parts per million or less of toluene.

20. The method according to clause 15, where the specified allocated Sucralose contains about 20 parts per million or less DMF).

21. The method according to clause 15, where the specified allocated Sucralose contains about 10 ppb or less dichloromethane.

22. The method according to clause 15, where the specified allocated Sucralose contains about 10 parts per billion or less of chloroform.



 

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