WO2005020930A2

WO2005020930A2 - Improved syntheses of alitame

Info

Publication number: WO2005020930A2
Application number: PCT/US2004/028424
Authority: WO
Inventors: Ken Knoblock; Pankaj Shah
Original assignee: Danisco A/S
Priority date: 2003-09-02
Filing date: 2004-09-01
Publication date: 2005-03-10
Also published as: WO2005020930A3

Abstract

The present invention relates to an improved synthesis of alitame (3-L-alpha-aspartyl-D-alanylamido-2,2,4,4-tetramethylthietanylamine) in which residual iodine species formed during the deodorization step are eliminated, resulting in an improved yield and a purer, more consistent product.

Description

IMPROVED SYNTHESIS OF ALITAME DESCRIPTION Field of the Invention

The present invention relates to the synthesis of a sweetener compound and more particularly to the improved synthesis of alitame (3-L-alpha-aspartyl-D-alanylamido- 2,2,4,4-tetramethylthietanylamine).

Background of the Invention

Alitame is an intense sweetener with approximately 2000 times the sweetening power of sugar. U.S. Patent No. 4,411,925 to Brennan, et al. and related patents describe a process for preparing alitame. In particular, the prior art processes use methods that are suitable for coupling of different amino acids together.

In one method disclosed in the '925 patent, a diprotected L-aspartic acid is condensed with an appropriate D-amino acid or a carboxyl-protected derivative to provide a diprotected dipeptide in the presence of a condensation agent. The diprotected dipeptide is then reacted with an equimolar amount of a primary amine to provide a corresponding diprotected dipeptide amide intermediate. Following this reaction, the protecting groups are removed providing alitame.

In another method disclosed in the '925 patent, alitame may be prepared by reacting an amino protected D-amino acid or its carboxylic acid derivative with an equimolar amount of a primary amine to obtain an amino protected D-amino acid amide. The protecting group is then removed by hydrogenolysis or hydrolysis resulting in a free amide amine. The free amide amine is then condensed with a diblocked L-aspartic acid derivative or carboxyl activated derivative thereof to provide a diblocked dipeptide which is then deprotected.

In yet another method disclosed in the '925 patent, alitame is formed by the direct reaction of D-amino acid amide with L-aspartic acid N-thiocarboxyanhydride.

In the above processes of manufacture of alitame, an undesirable odor is typically found in the crude product due to small amounts of impurities formed in the reaction by undesired side reactions or degradation of species in the reaction mixture, which impart an unpleasant odor to the alitame. Such odorous impurities are not removed in conventional procedures for recovery and purification, such as recrystallization, and are thus still present in the otherwise purified crystalline product.

U.S. Patent No. 4,238,392 to Vinick discloses a process for deodorizing an L- aspartyl-L-phenylalanine alkyl ester having odorous impurities formed by the reaction of L-aspartic acid N-thiocarboxyanhydride and a L-phenylalanine alkyl ester by treatment with an alkali metal periodate, such as sodium periodate, in aqueous solution. After this treatment, the L-aspartyl-L-phenylalanine alkyl ester can be isolated by crystallization, and is free of undesirable odor.

The process disclosed in U.S. Patent No. 4,238,392 to Vinick can be applied to the manufacture of alitame and, upon crystallization, odorless alitame is produced. As in any typical industrial process, the mother liquor is recycled to the next crystallization. However, after relatively little crystallization, the level of iodine species in the mother liquor increases to the point where it is not possible to crystallize alitame without incorporating small amounts of these iodine species, causing the alitame to gradually turn yellowish in color during storage due to the presence of iodine. To avoid this problem, the crystallization mother liquor must be purged periodically, causing loss of yield. In view of the above drawbacks with the prior art processes of making alitame, there is a need for providing an improved process for synthesizing alitame that is odorless and is substantially free of iodine species. Summary of the Invention

The present invention provides a simple and effective process for removing iodine species from alitame resulting in a higher overall recovery and a higher quality product than prior art processes.

In broad terms, the process of the present invention includes the steps of providing an aqueous solution which includes alitame and iodate ions; treating the aqueous solution with an acid to convert the iodate ions into iodide ions; and separating alitame from the aqueous solution containing iodide ions. The separated alitame obtained from the inventive process is odorless and is substantially free of iodine species. The term "substantially free" denotes that the separated alitame contains less than 500 ppm iodine (as I₂). More particularly, the alitame obtained from the inventive process contains less than 50 ppm iodine (as I₂). In the present invention, the aqueous solution that is obtained after the inventive process has been performed contains a high percentage of iodide therein. By 'high percentage', it is meant that the aqueous solution after alitame has been removed therefrom contains about 0.3 % or greater iodide. More particularly, the aqueous solution that is obtained after alitame removal contains from about 0.03 to about 0.15 % iodide. Thus, in instances in which the aqueous solution containing the higher percentage of iodide is reused, as in a continuous process, no iodine is present which will cause the odor problem mentioned above.

In one embodiment, the process of the present invention involves treating an aqueous alitame solution with an acid that converts the iodate, i.e., IO₃ ^", present in the aqueous solution first to iodine, i.e., , and then iodide, i.e., I^". Iodide is removed by selective precipitation of the alitame-tosylate, which leaves a high percentage of iodide in the mother liquor. Passing the alitame-tosylate slurry over a weak-base anion exchange resin removes both the tosylate and remaining traces of iodide. In an additional embodiment and prior to tosylate salt formation, the acidified aqueous alitame may be extracted with an organic solvent to reduce the iodine burden. The extraction process may be used in conjunction with tosylate salt formation or the tosylate formation step may be omitted. Detailed Description of the Invention

As indicated above, the present invention provides an improved method for synthesizing alitame which is odorless and which is substantially free of iodine. The inventive method begins with providing an aqueous solution that comprises at least alitame and iodate ions. The aqueous solution is formed by providing an admixture that contains alitame that has been treated with an alkali metal periodate and distilled water. Typically, from about 6 to about 10 gms of alkali metal periodate treated alitame is added to 100 ml of distilled water. The alkali metal periodate treated alitame is characterized as having a yellowish appearance due to the presence of loosely bound I?.

The aqueous alitame solution contains alitame in a concentration of from about 5 to about 14, more preferably from about 6 to about 10, %, w/v. The pH of this solution is typically from about 5 to about 7. The alitame may be hydrous or anhydrous, with preference given to anhydrous alitame.

The alitame used in the present invention is prepared using processes that are well known to those skilled in the art. For example, the alitame can be prepared using any of the methods disclosed in U.S. Patent No. 4,411,925 to Brennan, et al., the entire content of which is incorporated herein by reference. Thus, the alitame may be prepared by subjecting a diprotected L-aspartic acid, e.g., β-t-butyl-N-t-butoxycarbonyl-L-aspartate (1), and an appropriate D-amino acid, e.g., D-alanine to provide a diprotected dipeptide in the presence of a condensation agent. The diprotected dipeptide is then reacted with an equimolar amount of a primary amine such as 3-amino-2,2,4,4 tetramethylthietane to provide a corresponding diprotected dipeptide amide intermediate (2). Following this reaction, the protecting groups are removed providing alitame.

In another embodiment, alitame may be prepared by reacting an amino protected D-amino acid, e.g., N-t-butoxycarbonyl-D-alanine, with an equimolar amount of a primary amine such as 3-amino-2,2,4,4-tetramethylthietane to obtain an amino protected D-amino acid amide. The protecting group is then removed by hydrogenolysis or hydrolysis resulting in a free amide amine. The free amide amine is then condensed with a diblocked L-aspartic acid derivative such as, L-aspartic acid-N-thiocarboxyanhydride, to provide a diblocked dipeptide, which is then deprotected.

In yet another embodiment, alitame may be formed by the direct reaction of D- amino acid amide with L-aspartic acid N-thiocarboxyanhydride.

In the aqueous alitame solution, the source of iodate ions is the alkali metal periodate. Illustrative examples of alkali metal periodate that may be employed in the present invention include, but are not limited to: sodium periodate, lithium periodate, and potassium periodate. Mixtures of the aforementioned alkali metal periodates are also contemplated herein. Of the above-mentioned alkali metal periodates, sodium periodate is highly preferred in the present invention. The amount of alkali metal periodate added is typically from about 0.9 to about 1.1 equivalents based on 100 % alitame.

The alkali metal periodates, such as sodium periodate, are process aides typically used in the last stage of processing to reduce undesirable odors that develop during alitame's multi-step preparation. Alkali metal periodates also maintain low odor levels throughout alitame's shelf life. During processing, alkali metal iodate builds up in the mother liquor after several recrystallizations with a concomitant yellowing of alitame solutions and solids. Yellowing is postulated to result from I₂ loosely bound in the crystal structure or surface of solids. In aqueous solution, I₂ is in equilibrium with at least two other ionic forms (IO₃ ^" and I^"). The evidence for iodine's role in yellowing is 1) distinct yellow color and characteristic iodine odor upon acidification; 2) development of a characteristic pink to violet color in the organic layer upon extraction of acidified solutions with slightly polar or non-polar organic solvents; and 3) marked decrease in [IO₃ ^"] following organic extraction of aqueous solutions accompanied by loss of yellow color. The acidification of yellow alitame solutions containing IO₃ ^" results in the irreversible formation of I^" via I as the intermediate. Easily discernable amounts of I₂ may be present in acidified aqueous alitame solutions for 1 to 3 hours, depending upon solution acidity.

The inventive process of reducing the iodine content, which involves three embodiments that can be used individually or in combination, is described below.

Recrystallization with pTSA and ion exchange:

In the first embodiment of the present invention, conversion of iodine species in the aqueous solution of alitame to T is achieved by adjusting the pH of the aqueous solution to a pH value of from about 2.5 to about 4.0 with an aqueous mineral acid such as sulfuric or hydrochloric. Other types of mineral acids that may be employed in the present invention include, but are not limited to: phosphoric, polyphosphoric, sulfurous, selenic, or selenious acids. Mixtures of the aforementioned aqueous mineral acids are also contemplated in the present invention. The amount of aqueous mineral acid added is dependent on the concentration of iodate ions present in the aqueous alitame solution. Typically, the amount of the aqueous mineral acid added is from about 12 to about 20 ml, per 100 ml of aqueous alitame solution. The addition of the mineral acid to the aqueous alitame solution containing iodate ions occurs at room temperature or at a temperature slightly above room temperature. The addition of the mineral acid occurs under agitation.

After the conversion to I^" is complete, alitame is crystallized as the tosylate salt as follows. The pH of the solution is adjusted to between 4 and 5 by adding a base to the mineral acid treated solution. Illustrative examples of a base that may be employed at this point of the present invention include, but are not limited to: NaOH, KOH, Li OH, potassium carbonate, sodium carbonate, trisodium phosphate as well as mixtures thereof. At room temperature or slightly above room temperature, about 0.9 to about 1.1 equivalents, preferably one equivalent, of an aromatic sulfonic acid such as para- toluenesulfonic acid, i.e., pTSA, is added over the course of 1- 2 hours. Only enough agitation is provided to allow mixing of reagents. After all the aromatic sulfonic acid is added, the solution is chilled to a temperature of about 7°C or less for at least three hours to allow adequate crystal fonnation. The crystals are collected and washed with several volumes of cold deionized water. The wetcake may be stored under refrigeration or dried in vacua at 60°C for 4 hours to remove moisture.

The tosylate group (as described, for example, in U.S. Patent Nos. 4,375,430 and 4,465,626, both to Sklavounos) and remaining anionic iodine are removed by passage over a weak base anion exchange resin. An example of such a weak base anion exchange resin is a resin supplied by Rohm & Haas, known as Amberlite IRA®-93. Amberhte IRA®-93 is a macroreticular, weakly basic anion exchange resin containing tertiary amine functionality within a styrene-divinylbenzene matrix. Such resins are particularly suited to scavenge strong acids from solution. Purified alitame is then crystallized from chilled water. By 'chilled water', it is meant water having a temperature of about 7°C or less.

The aromatic sulfonic acids that may be employed in the present invention are aromatic compounds of the fonnula

wherein R , 1 ; is, hydrogen, chloro or methyl and R >2 i ^•s hydrogen or methyl. The resulting salt is generally, but not always, hydrated. When the anhydrous salt is desired, the water of hydration is removed by heating in vacuo over phosphorus pentoxide. Illustrative examples of aromatic sulfonic acids that may be used in the present invention, which fit the above formulas include, but are not limited to: benzenesulfonic acid, p- toluenesulfonic acid, p-chlorobenzenesulfonic acid, 3,4-xylenesulfonic acid, 2,5- xylenesulfonic acid, alpha-napthalenesulfonic acid and beta-naphthalenesulfonic acid. P-toluenesulfonic acid is a highly preferred aromatic sulfonic acid that is employed in the present invention.

Recrystallization from water following organic solvent extraction

This embodiment is intended for alitame in which IO₃ ^" is the predominant form of iodine. An aqueous alitame solution is prepared as described above. The conversion of IO₃ ^" to I₂ is achieved, as indicated above, by adjusting the pH to a value of from about 2.5 to about 4.0 with an aqueous mineral acid such as sulfuric or hydrochloric.

A yellow color and characteristic odor develop as I₂ is evolved. This is transient: forming after a little as ten minutes and may last for two hours. As I₂ is formed, the aqueous solution is extracted several times with a non-polar or a slightly polar solvent such as hexane, toluene, methylene chloride, benzene, xylene, heptane, chloroform, or carbon tetrachloride. Mixtures of these solvents are also contemplated herein. The term "slightly polar" denotes a solvent that has a dipole moment, μ, of about 1.0 or less. The solvent extraction process is performed at room temperature or a temperature slightly above room temperature. A characteristic pink-to- violet color develops in the organic phase as the I₂ is transferred. The extraction process is repeated until evolution of I in the aqueous phase ceases. In one case, aqueous alitame is crystallized as the tosylate salt and processed as described above or, in another case, the aqueous alitame may be crystallized from chilled water.

Notwithstanding which of the above embodiments is employed, the present invention provides purified alitame that is odorless and has substantially no iodine species. The method of the present invention is capable of providing alitame that has a purity of about 98% or greater, as determined by high performance liquid chromatography. The amount of alitame recovered by the inventive process is about 92% or greater (overall yield assuming recycle of the centrates). The alitame produced by the inventive process has a white appearance and a moisture content of 13% or less. The alitame produced by the inventive process is crystalline and in the form of the 2.5 hydrate.

The following examples are provided to illustrate the inventive process as well as some of the advantages that can be obtained from utilizing the same.

Example 1 : Conservation of iodine mass during conversion from IO ^" to I^".

Alitame feedstock was prepared as an aqueous solution to a final concentration of 8.8% w/v (as the alitame 2.5 hydrate) using about 36 gm yellowed alitame in 400 ml deionized water. About 55 ml of this solution was adjusted to pH 2.7 with 10% H₂SO₄. The pH was readjusted to 5.8 with 50% w/w NaOH after a few hours. This resulted in complete conversion of IO₃ ^" to I^" as measured by anion cliromatography with UV detection.

Example 2: Conservation of iodine mass, reduction of iodine load and removal of yellow color.

Alitame feedstock was prepared as an aqueous solution to a final concentration of 10.6% w/v (as the alitame 2.5 hydrate) using about 122 gm yellowed alitame in 1080 ml deionized water. To about 780 gm (700 ml) of this solution was added 45 ml of 10% H₂SO₄ until pH 3.6 and the appearance of deep yellow color. Seven 75 ml aliquots were each serially extracted with 25 ml of organic solvent in the sequence: hexane, hexane, hexane, toluene, hexane, methylene chloride, methylene chloride, until only a faint yellow color persisted. The pH of the extracted aqueous alitame was adjusted to 5.4 with 50% NaOH after about 12-18 hours. The pH of unextracted aqueous alitame was adjusted to 5.3 with 50% NaOH after about 12-18 hours.

Both extracted and unextracted aqueous alitame solutions were concentrated to about 30%) w/v by rotary evaporation accompanied by high vacuum and mild heat (~ 80° - 90°F). The resulting slurries were chilled for 2-18 hours, and filtered; the precipitates were washed with chilled deionized water and dried with mild heat (40°-60°C) and high vacuum. Solvent extraction lowered the iodine burden and removed the undesirable yellow color. Example 3: Alitame contaminated with moderate iodate content: reduction of iodine and removal of yellow color in by precipitation of alitame as tosylate salt and resin treatment. Preparation of tosylate salt Alitame feedstock was prepared as an aqueous solution to a final concentration of 11.0% w/v (as the alitame 2.5 hydrate) using about 46 gm yellowed alitame in 400 ml deionized water. To about 400 gm of this solution was added 12.9 gm of 6N HC1 to a final pH of 3.0. After 18 hours the pH was raised to 4.7 by adding 5.5 gm of 50% w/w NaOH. Para-toluenesulfonic acid (~40 ml of a 50% w/v aqueous solution) was added drop-wise over a period of 75 minutes with enough agitation to ensure thorough mixing. A thick slurry formed which was refrigerated for 4 hours, filtered on Whatman #40 paper and washed with -400 ml chilled water. The resulting wetcake was dried under high vacuum at 60°C for 4 hours to less than 0.5 % water.

Removal of tosylate A 58 mm ID chromatography column was charged with 96 ml of wet IRA®-93 anion exchange resin. The resin was washed with 600 ml 0.16M HC1 followed by 125 ml 1.0M NaOH. This was repeated twice and then the column was washed with 1000 ml deionized water. About 42 gm alitame-pTS A was slurried in 240 ml deionized water. The slurry was charged onto the column. Undissolved salt was allowed to sit on top of the resin. The column was eluted with the supernatant liquid at a rate of approximately 20 ml/min., and the effluent was recirculated through the column until all of the solids dissolved (about 3 hours). The column was then washed with two 100 ml portions of deionized water. The main effluent and column wash contained about 28 gm hydrated alitame. This was passed over an additional 3 ml IRA®-93 resin at a rate of 2 ml/min. A portion of this solution (335 ml @ 5.0%) alitame w/v) was concentrated to about 30%) by rotary evaporation accompanied by high vacuum and mild heat (85-95°F). Once removed from heat and vacuum, the slurry was refrigerated for 3 hours, filtered with the aid of Buchner funnel, washed with about 50 ml chilled deionized water and air dried on the filter under suction for an hour. The alitame was further dried under high vacuum at 36°C for 1 hour. This resulted in a white crystalline powder with 7.4% moisture content.

Example 4: Alitame contaminated with high iodide content: reduction of iodine and removal of yellow color in by precipitation of alitame as tosylate salt and resin treatment.

Alitame feedstock as an aqueous solution of about 14% alitame was obtained from warehouse storage. To about 409 gm of this solution was added 10% HC1 to a final pH of 3.4. The solution did not change color and the pH was subsequently readjusted to 5.3 by addition of 50% NaOH and 10% HC1. Para-toluenesulfonic acid (~ 54 ml of a 50% w/v aqueous solution) was added drop-wise over a period of 2 hours with enough agitation to ensure thorough mixing. A thick slurry formed which was refrigerated for several hours, filtered and washed with chilled water. The resulting wetcake was dried under high vacuum at 60°C for 4 hours to less than 0.5% water. A slurry was prepared, the material purified on IRA-93 resin and recrystallized under conditions similar to those described in Example 3.

While the present invention has been particularly shown and described with respect to preferred embodiments thereof, it will be understood by those skilled in the art that the foregoing and other changes in forms and details may be made without departing from the spirit and scope of the present invention. It is therefore intended that the present invention not be limited to the exact forms and details described and illustrated, but fall within the scope of the appended claims.

Claims

CLAIMS Having thus described our invention in detail, what we claim as new is:

1. A process of synthesis of alitame comprising the steps of:

providing an aqueous solution which comprises alitame and iodate ions;

treating the aqueous solution with an acid to convert said iodate ions into iodide ions; and

separating alitame from said aqueous solution containing iodide ions, wherein the separated alitame is odorless and is substantially free of iodine species.

2. The method of Claim 1 wherein the alitame is present in the aqueous solution in a concentration of from about 5 to about 14%), on a w/v alitame basis.

3. The method of Claim 1 wherein the aqueous solution has a pH value of from about 5 to about 7.

4. The method of Claim 1 wherein the acid is a mineral acid that is capable of adjusting the aqueous solution to a pH value of from about 2.5 to about 4.0.

5. The method of Claim 4 wherein the mineral acid is selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, sulfurous acid, selenic acid, selenious acid and mixtures thereof.

6. The method of Claim 1 wherein the treating comprises adding from about 12 to about 20 ml of the acid to 100 ml of the aqueous solution.

7. The method of Claim 1 wherein iodine ions are formed in the treating step prior to formation of iodide ions.

8. The method of Claim 1 wherein the separating comprising forming a tosylate salt of alitame, crystallizing the tosylate salt of alitame, and removing the tosylate group and iodine by using ion exchange chromatography to obtain purified alitame.

9. The method of Claim 8 wherein the tosylate salt of alitame is formed by adding an aromatic sulfonic acid to the acid treated aqueous solution.

10. The method of Claim 9 wherein the aromatic sulfonic acid is added in an amount of from about 0.9 to about 1.1 equivalents.

11. The method of Claim 9 wherein the aromatic sulfonic acid is a compound of the fonnula:

wherein R¹ is hydrogen, chloro or methyl and R² is hydrogen or methyl or a salt thereof.

12. The method of Claim 9 wherein the aromatic sulfonic acid is an aromatic sulfonic salt that is hydrated.

13. The method of Claim 9 wherein the aromatic sulfonic acid is selected from the group consisting of benzenesulfonic acid, p-toluenesulfonic acid, p- chlorobenzenesulfonic acid, 3,4-xylenesulfonic acid, 2,5-xylenesulfonic acid, alpha- napthalenesulfonic acid and beta-naphthalenesulfonic acid.

14. The method of Claim 9 wherein the aromatic sulfonic acid is p-toluenesulfonic acid.

15. The method of Claim 8 wherein the crystallizing is performed at a temperature of about 7°C or less for a time period of at least 3 hrs.

16. The method of Claim 8 wherein the ion exchange chromatography includes a weak base anion exchange resin.

17. The method of Claim 16 wherein the weak base anion exchange resin comprises a macroreticular, weakly basic anion exchange resin containing tertiary amine functionality within a styrene-divinylbenzene matrix.

18. The method of Claim 8 further comprising crystallizing the purified alitame.

19. The method of Claim 1 wherein the separating comprises an organic solvent extraction.

20. The method of Claim 19 wherein the organic solvent extraction comprises adding a polar or a non-polar solvent to the acid treated aqueous solution to reduce evolution of iodine.

21. The method of Claim 20 wherein said polar or non-polar solvent is selected from the group consisting of hexane, toluene, methylene chloride, benzene, xylene, heptane, chloroform and carbon tetrachloride.

22. The method of Claim 19 further comprising crystallizing alitame from the solvent extracted aqueous solution.

23. The method of Claim 19 further comprising forming a tosylate salt of alitame, crystallizing the tosylate salt of alitame, and removing the tosylate group and iodine by using ion exchange chromatography to obtain purified alitame.

24. The method of Claim 23 wherein the tosylate salt of alitame is formed by adding an aromatic sulfonic acid to the acid treated aqueous solution.

25. The method of Claim 24 wherein the aromatic sulfonic acid is added in an amount of from about 0.9 to about 1.1 equivalents.

26. The method of Claim 24 wherein the aromatic sulfonic acid is a compound of the formula:

27. The method of Claim 24 wherein the aromatic sulfonic acid is an aromatic sulfonic salt that is hydrated.

28. The method of Claim 24 wherein the aromatic sulfonic acid is selected from the group consisting of benzenesulfonic acid, p-toluenesulfonic acid, p- chlorobenzenesulfonic acid, 3,4-xylenesulfonic acid, 2,5-xylenesulfonic acid, alpha- napthalenesulfonic acid and beta-naphthalenesulfonic acid.

29. The method of Claim 24 wherein the aromatic sulfonic acid is p-toluenesulfonic acid.

30. The method of Claim 23 wherein the crystallizing is performed at a temperature of about 7°C or less for a time period of at least 3 hours.

31. The method of Claim 23 wherein the ion exchange chromatography includes a weak base anion exchange resin.

32. The method of Claim 31 wherein the weak base anion exchange resin comprises a macroreticular, weakly basic anion exchange resin containing tertiary amine functionality within a styrene-divinylbenzene matrix.

33. A method of synthesis of alitame comprising the steps of:

providing an aqueous solution which comprises alitame and iodate ions;

treating the aqueous solution with an acid to convert said iodate ions into iodide ions;

forming a tosylate salt of alitame; '

crystallizing the tosylate salt of alitame; and

removing the tosylate group and iodine by using ion exchange chromatography to obtain purified alitame that is odorless and is substantially free of iodine species.

34. A method of synthesis of alitame comprising the steps of:

providing an aqueous solution which comprises alitame and iodate ions;

treating the aqueous solution with an acid to convert said iodate ions into iodide ions; adding a polar or non-polar solvent to the acid treated aqueous solution to reduce evolution of iodine;

forming a tosylate salt of alitame;

crystallizing the tosylate salt of alitame; and

35. A method of synthesis of alitame comprising the steps of:

providing an aqueous solution which comprises alitame and iodate ions;

adding a polar or non-polar solvent to the acid treated aqueous solution to reduce evolution of iodine; and

crystallizing the alitame to obtain purified alitame that is odorless and is substantially free of iodine species.