FORM2THE PATENTS ACT, 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10; rule 13)
1. Title of the invention. - "An improved process for the preparationof Sucralose."
2. Applicant(s)(a) NAME : ALEMBIC LIMITED(b) NATIONALITY : An Indian.(c) ADDRESS : Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of invention:
The present invention relates to an improved process for the preparation of Sucralose comprising a step of acetyl migration followed by isolation without addition of an antisolvent. The structural formula of Sucralose is represented by formula (I) as given below.

Background of the invention:
Sucralose is a potent sweetener having sweetness several hundred times that of sucrose. It is chemically known as l,6-dichloro-l,6-dideoxy-p-D-fructofuranosyl-4-chloro-4-deoxy-a-galactopyranoside and having formula is C12H19CI3O8 and molecular weight 397.64. Sucralose is used as sweetner in beverage, as coating tablet, chewing gum and other food products. It is marketed by McNeil under tradename Splenda®.
There are several process reported for the preparation of Sucralose. Traditionally, it starts with conversion of Sucralose to 6,l',6'-Tri-0-tritylsucrose pentaacetate which is detritylated to give 2,3,4,3',4'-Penta-0-acetylsucrose. This compound is further converted into 2,3,6,3',4'-Penta-0-acetylsucrose by acetyl migration and isolated by addition of an antisolvent. This compound is chlorinated and deacetylated to get Sucralose. In this process, the step of acetyl migration is extremely important because the undesired isomerization may lead to unwanted impurities. The process is schematically represented by Scheme-I.


US Patent No. 4801700 discloses process of preparation of Sucralose. In the example VIII, acetyl migration was carried out in methyl isobutyl ketone (MIBK) using t-butylamine as base. The product was isolated by concentrating the reaction mixture and taken as such for chlorination step in situ, without isolation and without purification. The impurities generated in the migration step is carry forwarded to the chlorination step and finally to Sucralose. Thus, Sucralose prepared by this process need repeated purification which increase overall cost of the production.
Further, in the example X, acetyl migration was carried out in mixture of ethyl acetate and heptane and compound was isolated by addition of heptane as antisolvent. Heptane is flammable liquid and is a dangerous fire hazard. Its flashpoint is low and is very prone to catch fire and this makes it uncomfortable to use at industrial scale. It is harmful, toxic and cause headache, loss of consciousness and dizziness when inhaled.

US Patent No. 4362869 discloses a process for the preparation of Sucralose wherein acetyl migration was carried out in methyl isobutyl ketone (MIBK) using acetic acid. The compound was isolated by addition of petroleum ether as antisolvent. Petroleum ether is extremely flammable liquid and is a dangerous fire hazard. Its flashpoint is low and is very prone to catch fire and this makes it uncomfortable to use at industrial scale. It is harmful if swallowed or inhaled. It affects central nervous system, cause irritation to skin, eyes, and respiratory tract.
US Patent No. 4783526 discloses a process in which acetyl migration was carried out in water using pyridine or collidine as base. The product was isolated by addition of heptane to a solution in methylene chloride containing product.
US Patent No. 4920207 discloses a process in which acetyl migration was carried out in toluene using acetic acid. The product was isolated by cooling the reaction mass and filtering the product. However, the product obtained by this process is not free flowing and sticky in nature which makes it difficult to isolate by filtration. Due to the sticky nature, stirring is also not possible. Moreover, the color of the product is also dull and the yields which are obtained are relatively lower.
Unexpectedly, when present inventors have directed their research work towards optimizing the acetyl migration step, they found out an industrially friendly process wherein the step of acetyl migration were carried out without addition of any antisolvent such as petroleum ether, heptane, hexane and the like.
Further, the process of the present invention not only gives the compound with unexpected improved purity but also with substantial reduction in cost. Moreover, the problem of dealing with tedious reagents such as petroleum ether, heptane, and hexane can be avoided and solvent recovery issues which make it industrially suitable.
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Object of the invention
An object of the present invention is to provide an improved process for the preparation of Sucralose comprising a step of acetyl migration followed by isolation without addition of an antisolvent.
Another object of the present invention is to provide a process for preparation of 2,3,6,3',4'-Penta-0-acetylsucrose with improved purity.
Another object of the present invention is to provide a process for preparation of highly pure Sucralose
Another object of the present invention is to provide a process which avoids the use of antisolvent whose flash point is low and which are prone to catch fire.
Yet another object of the present invention is to provide a process which is feasible, safe and cost effective at an industrial scale
Summary of the invention:
Accordingly, present invention provides an improved process for the preparation of Sucralose comprising a step of acetyl migration followed by isolation without addition of an antisolvent.
The present invention provides 2,3,6,3',4'-Penta-0-acetylsucrose with improved purity.
Detailed description of the invention:
According to the present invention, an improved process for the preparation of Sucralose comprising a step of acetyl migration in which isolation is done without addition of an antisolvent is given.
2,3,4,3',4'-Penta-0-acetylsucrose is converted into 2,3,6,3',4'-Penta-0-acetylsucrose using base or acid catalyst in methyl isobutyl ketone (MIBK).
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The solvent is selected from the group comprising methyl isobutyl ketone, ethylacetate, and the like or mixture thereof.
The base is selected from t-butylamine, triethylamine, triisopropyl ethylamine, isopropylamine, pyridine and collidine and the like or mixture thereof. The preferred base is t-butylamine.
The acid is selected from acetic acid, dichloroacetic acid or any such acid having the same order of strength. The preferred acid is acetic acid.
2,3,4,3',4'-penta-o-acetyl sucrose was dissolved in a solvent such as methyl iso butylketone. Base t-butyl amine was added. The reaction mixture was heated at 35-40°C for a time sufficient to migration take place. Generally it takes about 10-12 hours. 6-PAS is observed to crystallize during the reaction but complete crystallization is obtained by cooling and stirring for 1 hour. The cooling temperature is in a range of about -20°C to 0°C. The product is isolated by methods known in the art such as filtration, decantation or centrifugation. The wet cake is optionally washed with solvent and dried in a vacuum oven at about 35° to about 40°C for 12 to 14 hours. The product is optionally charcoalized in organic solvent such as ethyl acetate and then recrystallized.
The compound obtained in above step is used in the chlorination reaction for the preparation of Sucralose.
Following is comparison of the results of purity of the product as obtained by the process of the present invention vis-a-vis the purity of the product as prepared by process by addition of an antisolvent.
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Process Result
2,3,6,3',4'-Penta-0-acetylsucrose Purity obtained about 70%
prepared by addition of antisolvent
2,3,6,3',4'-Penta-0-acetylsucrose Purity obtained about 90%
prepared without addition of antisolvent
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Example 1
Preparation of 2,3,6,3',4'-Penta-0-acetyIsucrose
2,3,4,3',4'-penta-o-acetyl sucrose (400g) was dissolved in methyl isobutylketone (1600ml) and t-butyl amine (42ml) was added. The reaction mixture was heated at 35-37°C for about 10-12 hours. 6-PAS is observed to crystallize during the reaction but complete crystallization is obtained by cooling and stirring for 1 hour. After Alteration and washing of the cake with a methyl isobutyl ketone (40ml) it is dried in a vacuum oven at 35-40°C for 12-14 hours. Yield 280g containing 88-90% 6-PAS
(Purity by HPLC: 88.2%)
Example 2
Preparation of 2,3,6,3',4'-Penta-0-acetylsucrose
2,3,4,3',4'-penta-o-acetyl sucrose (400g) was dissolved in methyl isobutylketone (1600ml) and Acetic acid (200ml) was added. The reaction mixture was heated at 35-37°C for about 10-12 hours. 6-PAS is observed to crystallize during the

reaction but complete crystallization is obtained by cooling and stirring for 1 hour. After filteration and washing of the cake with a methyl isobutyl ketone (40ml) it is dried in a vacuum oven at 35-40°C for 12-14 hours. Yield 280g containing 88-90% 6-PAS
(Purity by HPLC: 85%)
Example 3
Preparation of Sucralose
(a) Preparation of 2,3,6,3',4'-Penta-0-acetylsucrose
2,3,4,3',4'-penta-o-acetyl sucrose (400g) was dissolved in methyl isobutylketone (1600ml) and t-butyl amine (42ml) was added. The reaction mixture was heated at 35-37°C for about 10-12 hours. 6-PAS is observed to crystallize during the reaction but complete crystallization is obtained by cooling and stirring for 1 hour. After filteration and washing of the cake with a methyl isobutyl ketone (40ml) it is dried in a vacuum oven at 35-40°C for 12-14 hours. Yield 280g containing 88-90% 6-PAS (Purity by HPLC: 88.1%)
(b) Preparation of 4,l',6'-Trichloro-4,l',6'-trideoxygalactosucrose
pentaacetate (TOPSA)
A stirred solution of 2,3,6,3',4'-Penta-0-acetylsucrose (100g) in ethylenedichloride (300ml), pyridine (150ml), sulfuryl chloride (150ml), ethylenedichloride (300ml) was heated to reflux till the reaction completed. The reaction mass was cooled and diluted with ethylenedichloride (1000ml). The resulting solution was washed successively with 5% hydrochloric acid (1000ml), D.M. water (2000ml). The organic layer was distilled to a syrupy product which was further crystallised from toluene (600ml) to give the crude product (70g) (Purity by HPLC: 95.18%). Crude product was recrystallised with methanol
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(280ml) to yield pure 4,r,6'-Trichloro-4,r,6'-trideoxygalactosucrose pentaacetate (50g). (Purity by HPLC: 98.01%)
(c) Preparation of Sucralose
Pure TOPSA (462g) obtained in above step (b) was dissolved in methanol and stirred for complete dissolution. A solution of sodium methoxide in methanol (44ml) was added dropwise till pH of solution 10.5 was obtained. The mass was neutralized by adding H* cation resin (30g) and then filtered. The filtrate was charcoalized and then on evaporation of solvent gave pure Sucralose (313.8g). This product can optionally be purified by crystallizing from ethylacetate.
(Purity by HPLC: 99.5%)
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We claim:
1. A process for the preparation of Sucralose comprising a step of acetyl migration using an acid or base in an organic solvent followed by isolation of 2,3,6,3',4'-Penta-0-acetylsucrose without addition of an antisolvent.
2. The process as claimed in any preceding claim, wherein said acid is selected from the group comprising acetic acid, dichloroacetic acid or mixture thereof.
3. The process as claimed in any preceding claim, wherein said base is selected from the group comprising t-butylamine, triethylamine, triisopropyl ethylamine, isopropylamine, pyridine and collidine or mixture thereof.
4. The process as claimed in any preceding claim, wherein said organic solvent is selected from the group comprising methyl isobutyl ketone, ethylacetate or mixture thereof.
5. A process for the preparation of 2,3,6,3',4'-Penta-0-acetylsucrose comprising reacting 2,3,4,3',4'-penta-o-acetyl sucrose with t-butylamine in methyl isobutyl ketone for a time sufficient for migration take place, wherein the product is isolated without addition of an antisolvent.
Dated this 23rd day of June 2006.
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Sonali Bhokarikar
Of S. Majumdar & Co.
Applicant's Agent
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Abstract
The present invention relates to an improved process for the preparation of Sucralose comprising a step of acetyl migration followed by isolation of 2,3,6,3',4'-Penta-0-acetylsucrose without addition of an antisolvent.
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