Field of Invention:

The present invention relates to an improved process for the preparation of sucralose.

Background of the Invention :

Sucralose (4,1', 6'-trichloro-4,r,6'-trideoxy-galactosucrose ) is an artificial sweetener derived from sucrose. It is claimed to be about 600 times sweeter than cane sugar. It is considered safe because it is excreted in humans without undergoing any metabolism. It has high resistance to acid hydrolysis and is highly stable to heat. Because of these advantages, sucralose is one of the most widely used sweeteners in the market.

Sucralose is synthesized by replacing hydroxyl groups at 4, 1', and 6' of sucrose with chlorine atoms. This requires blocking of the reactive hydroxyl group at 6-position of sucrose. Because of this reason, sucrose-6-acetate is widely used as the starting material for the preparation of sucralose (US 5498709, US7838642, US7932380, US8147672, etc). Chlorination of sucrose-6-acetate is a typical SN2 substitution reaction resulting in the inversion of the configuration at 4-position. Due to this inversion glucose part of sucrose converts to galactose configuration. Thus trichlorination of sucrose-6-acetate gives 4,1',6'-trichloro-4,1',6'-trideoxy-galactosucrose-6-acetate (TGS-6-acetate). At the final step, the acetyl group in TGS-6-acetate is removed to give sucralose. The removal of the acetyl group is achieved by various methods.

According to US5498709, the aqueous solution of TGS-6-acetate is treated with an alkali metal hydroxide such as sodium hydroxide, to obtain pH 11. The acetyl group gets hydrolyzed to give sucralose and sodium acetate (Scheme-1).

Later, the reaction mixture is neutralized with hydrochloric acid. The aqueous reaction mixture after neutralization contains high amount of salts such as sodium acetate and sodium chloride. Sucralose is extracted from the aqueous solution using organic solvents such as ethyl acetate. Since sucralose is soluble in water to a significant extent, the extraction process has to be repeated several times or large volumes of solvent have to be used to recover most of the product. The US8147672 describes a deacetylation process where sucralose-6-acetate was dissolved in 5N sodium hydroxide and the solution was circulated through strong basic anion exchange resin column for about 3 hours maintaining the pH at 9 to 10. The alkaline solution was made neutral by passing through weak acid cation exchange resin column. The resulting solution was concentrated to obtain sucralose. The US7838642 describes the use of an organic base for the deacetylation. The methanolic solution of sucralose-6-acetate is treated with an organic base such as tert-butylamine till the pH is 12.The reaction requires about 5 hours at room temperature. When triethylamine is used as the base, it requires about 7 hours at reflux temperature. The excess base and the solvent are removed by evaporation to give sucralose. According to US 7884203, the deacetylation is carried out in methanol using KOH as the base at pH 11 for 4 hours at 45°C. If the pH was higher than 11, impurities were formed and at lower pH, the conversion rate was very slow (column-4, line-20). A similar process is described in US7932380 where a methanolic solution of sucralose-6-acetate is treated with sodium methoxide and stirred for about 4 hours at 30°C. The reaction mixture is neutralized to pH 7.0; the salts formed are filtered and concentrated to give sucralose.

Most of these methods require high alkaline pH for the deacetylation reaction and needs neutralization after the reaction is completed.

Summary of the Invention :

The prior art methods for the removal of the acetyl group in TGS-6-acetate through hydrolysis using a base results in extensive salt formation and requires laborious and expensive methods for the separation of pure sucralose from the salts. The present inventors argued that the removal of the acetyl group from TGS-6-acetate through transesterification will result in sucralose and acetate ester which can be easily removed because of the low boiling point. Such a process will not result in salt formation and the isolation of pure sucralose will be easier. This invention discloses such a transesterification process for the conversion of TGS-6-acetate to sucralose. The transesterification reactions are catalyzed by both acids and bases. The metal oxides such as calcium oxide, magnesium oxide etc is chemically unique because they are composed of cations which act as Lewis acid and anions which act as a Bronsted base. Based on these unique properties of the metal oxides, the present inventors have developed a novel process for the conversion of TGS-6-acetate to sucralose through transesterification. The process involves the reaction of TGS-6-acetate with an alcohol in the presence of metal oxide to give sucralose and alkyl acetate (Scheme-2).

TGS-6-acetate Sucralose alkyllacetate
Scheme-2

In this process, alcohol also acts as a solvent. The reaction is a pseudo-first order reaction with respect to the reactant alcohol as it is present in large excess. This helps in increasing the rate of the reaction.

Another interesting feature of the process is that the metal oxides used as catalyst are insoluble in alcohols and can be removed by simple filtration. When a soluble base such as potassium hydroxide, sodium methoxide or organic amine is used, the reaction medium will be highly alkaline and has to be neutralized using ion-exchange resin or acid after the reaction. In the present process there is no need for any neutralization, thus avoiding the salt formation.

Detailed Description of the Invention :

According to the present invention, there is provided a process for the conversion of sucralose-6-acetate to sucralose which comprises:

a) dissolving TGS-6-acetate in an alcohol

b) treating the solution with a metal oxide catalyst and stirring the reaction mixture until no further transesterification takes place

c) filtering the reaction mixture to remove the catalyst, and evaporating the filtrate containing solvent and the alkyl acetate formed

d) recovering sucralose from the reaction mixture

The required TGS-6-acetate can be prepared by the chlorination of sucrose-6-acetate (for example US 4617269 and 4980463). The alcohol to be used acts as both solvent to dissolve sucralose-6-acetate and reactant in transesterification. The alcohol can be methanol, ethanol, propanol, butanol, or their branched analogs. However, alcohol with a shorter alkyl chain reacts faster and gives good conversion. When methanol is used, the reaction completes in a few hours and quantitative conversion is observed at room temperature. The alcohol used must be free from moisture.

The oxides of metals such as magnesium, calcium, zinc, barium, strontium, tin, or alkyl tin, etc can be used as the heterogeneous catalyst. With calcium oxide the reaction is completed within 4 hours at room temperature. With magnesium oxide about 24 hours is required for the completion. During the reaction the catalyst remain insoluble and no significant increase in the pH of the reaction medium is observed. The reaction can be conducted at room temperature (28° C ± 2). At higher temperature increase in the rate of the reaction is observed. The completion of the reaction can be monitored conveniently by thin layer chromatography.

After the reaction, the reaction mixture is filtered to remove the catalyst. The filtrate contains the excess alcohol solvent and the acetyl ester formed during the reaction. Generally the acetyl esters of lower alcohols have low boiling points. For example, the methyl acetate boils at 57°C and ethyl acetate at 77°C at normal pressure. Thus the acetyl ester formed during the reaction and the alcohol solvent is removed easily under reduced pressure.

From the residue obtained, pure crystalline sucralose can be obtained by dissolving the residue in minimum amount of water and saturating the solution with sodium chloride followed by extraction with an organic solvent such as ethyl acetate. The organic layer is dried and concentrated to about quarter of its volume, and stirred for 6 to 8 hours at room temperature. Sucralose precipitates out as colorless crystalline material. The sucralose thus obtained shows high purity (>99% HPLC) and is free from calcium and chloride ions.

The embodiments of the present invention are further described in the following examples, which are not intended in any way to limit the scope of the invention.

Examples: Example-1:
TGS-6-acetate (3 g, 6.8 mmol, 99.1 % HPLC purity) was dissolved in anhydrous methanol (30 mL). To the solution was added finely powdered calcium oxide (0.054 g, 0.93 mmol). The resulting suspension was stirred for 4 hours at 28°C (±2). The reaction mixture was filtered to collect calcium oxide. The filtrate was concentrated under reduced pressure to remove the methyl acetate formed and the solvent. The resulting residue was dissolved in minimum amount of water (5 mL) and the solution was saturated with sodium chloride and extracted with ethyl acetate (30 mL x2). The organic layer was dried over anhydrous sodium sulphate. The solution was concentrated under vacuum to about 15 ml, and stirred for 6-8 hours at room temperature. The precipitate was filtered and dried at 50°C under vacuum to give colorless crystalline sucralose, 2.46 g (91 % yield), 99.4 % HPLC.

Example-2:
TGS-6-acetate (1 g, 2.27 mmol, 94.79 % HPLC purity) was dissolved in anhydrous methanol (10 mL). To the solution was added powdered magnesium oxide (0.060 g, 1.49 mmol). The suspension was stirred for 24 hours at 28°C (±2). The reaction mixture was filtered to collect magnesium oxide. The filtrate was concentrated under reduced pressure to remove the solvent and the methyl acetate formed. The residue was dissolved in 2 mL water and was saturated with sodium chloride and extracted with ethyl acetate (10 mL x2). Workup of the organic phase as given in Example-1 resulted in sucralose, 0.70 g (78 % yield), 98.8 % HPLC,

Example-3:
TGS-6-acetate (1 g, 2.27 mmol, 94.79 % HPLC purity) was dissolved in anhydrous ethanol (10 mL). To the solution was added finely powdered calcium oxide (0.018 g, 0.31 mmol). The resulting suspension was stirred for 24 hours at 28°C (±2). The reaction mixture was filtered to collect calcium oxide. The filtrate was concentrated under reduced pressure to remove the methyl acetate formed and all the solvent. The resulting residue was dissolved in minimum amount of water (2 mL) and the solution was saturated with sodium chloride and extracted with ethyl acetate (10 mL x2). Workup of the organic phase as given in Example-1 resulted in sucralose, 0.60 g (66.7 % yield), 98.1% HPLC,

We Claim:

1. A process for the preparation of sucralose which comprises the steps of:

a) dissolving 4,1',6'-trichloro-4,1',6'-trideoxy-galactosucrose-6-acetate (TGS-6-acetate) in an alcohol,

b) treating the solution with a metal oxide,

c) stirring the reaction mixture until no further transesterification takes place,

d) filtering the reaction mixture to remove the metal oxide, and evaporating the filtrate containing solvent and the alkyl acetate formed,

e) recovering sucralose from the reaction mixture obtained in step (d).

2. Process as in claim-1, step (a), wherein the alcohol used is selected from the group consisting of methanol, ethanol, propanol, and butanol or their branched analogs, preferably methanol,

3. Process as in claim-1, step (b), wherein the metal oxide used is selected from the group consisting of magnesium oxide, calcium oxide, zinc oxide, barium oxide, strontium oxide, tin oxide or alkyl tin oxide or combinations thereof

4. Process as in claim-4, wherein the metal oxide is calcium oxide

5. Process as in claim-4, wherein the metal oxide is magnesium oxide