FORM2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - AN IMPROVED PROCESS FOR THE PREPARATION
OF SUCRALOSE
2. Applicant(s)
(a) NAME: ALEMBIC LIMITED
(b) NATIONALITY: An Indian Company
(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 deacetylation of 4,1,6'-trichloro-4,1,6'-trideoxy galactosucrose penta-acetate (TOPSA) of formula (VI).
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-β-D-tructofuranosyl-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®.
It is also chemically known as 4, l'6,-trichloro-β-D'-trideoxygalactosucrose, (hereinafter referred to as "Sucralose") involves the substitution of chlorine atoms in the sucrose molecule in one of the five secondary hydroxyl positions and in two of the three primary hydroxyl positions. This particular selection of positions usually means that any synthetic route must involve the preparation of an intermediate sucrose derivative having the required positions available for chlorination while the other positions are blocked. In particular, the reactive 6-position must not be chlorinated, while the 4-position must be rendered available for chlorination.

A process for preparing Sucralose is. set forth in U.S. Pat. No.4,362,869. This process converts sucrose through a number of steps into Sucralose. This process describes the sequential steps of (1) tritylatibn of sucrose to block the three primary alcohol groups; (2) acetylation of the five secondary alcohol groups as acetates; (3) detritylation of the three . primary alcohol groups to deblock them; (4) acetyl migration from the 4-position to the 6-position; (5) chlorinating the desired alcohol groups at positions 4, 1', 6'; and (6) deblocking the remaining five alcohol groups by deacetylation using sodium methoxide in methanol thereby yielding Sucralose.
The schematic representation is as given below (Scheme I)

U.S. Patent No.4801700, U.S. Patent No.4783526 and U.S. Patent No.4920207 also discloses the process of preparation of Sucralose from 4,i\6,-trichloro-4,r,6,-trideoxy galactosucrose penta-acetate (TOPSA) via deacetylation using sodium methoxide in methanol.
In this process sodium methoxide is used for deacetylation step. The main disadvantage associated in using sodium methoxide is the formation of unknown impurities which are

very difficult to remove from the final product i.e. Sucralose even by. crystallization process. Moreover, sodium methoxide is a very moisture sensitive reagent and easily degrades in the presence of moisture. Hence, it becomes difficult to handle on a industrial scale.
It is therefore, a need to develop a process in which not only overcomes the aforementioned problems but also provide a process which is simple, easy to handle and feasible at commercial production.
The present inventors have observed that during deacetylation several impurities are formed. These impurities are difficult to remove from the final product even by crystallization process. The present inventors have directed their research work towards developing a new process which minimizes the formation of impurities. Unexpectedly, the present inventors have found that deacetylation can be effected by using reagent such as base excluding alkoxide or hydroxide of alkali or alkaline earth metal which not only minimize the formation of impurities but also easy to handle.
Object of the invention:
A primary object of the present invention is to provide an improved process for the preparation of Sucralose of formula (I) comprising a step of deacetylation of 4,1',6'-trichloro-4,1 ',6'-trideoxy galactosucrose penta-acetate (TOPS A) of formula (VI).
Another object of the present invention is to provide an improved process for the preparation of Sucralose which avoids the use of moisture sensitive base such as sodium methoxide or sodium hydroxide which create handling problem on industrial scale.
Another object of the present invention is to provide an improved process for the preparation of Sucralose which provide Sucralose with improved purity.

A further object of the present invention is an improved process for the preparation of Sucralose which avoid the use of base containing group such as alkoxide and hydroxide of alkali and alkaline earth metal for example sodium methoxide or sodium hydroxide which is responsible for the generation of impurities in the deacetylation process.
Yet another object of the present invention is to provide an improved process for the preparation of Sucralose, which is simple, easy to handle and feasible at commercial scale.
Summary of the invention:
Accordingly, present invention provides an improved process for the preparation of Sucralose of formula (I) comprising a step of deacetylating 4,^,6,-trichloro-4,^,6,-trideoxy galactosucrose penta-acetate (TOPSA) of formula (VI) in the presence of a base and a alcoholic solvent, wherein the base is selected from a group which does not include alkoxide or hydroxide group.
Detailed description of the invention:
According to the present invention, Sucrose is converted to 4,l,6'-trichloro-4,1,6T-trideoxy galactosucrose penta-acetate by methods known perse or by any method known to person skilled in art. 4,1,6'-trichloro-4,l\6,-trideoxy galactosucrose penta-acetate (TOPSA) is further deacetylated with a base excluding alkoxide or hydroxide of alkali or alkaline earth metal.
The deacetylation of TOPSA is carried out in the presence of a base and a suitable solvent to give Sucralose wherein the base is selected from a group which does not include alkoxide or hydroxide group.

The base is selected from the group comprising organic base and inorganic base. Organic base is selected from the group comprising non-alkoxy amines or non-hydroxy amines. Inorganic base is selected from alkali or alkaline earth metal carbonate or bicarbonate.
The example of organic base as mentioned hereinabove includes but not limited to 1,8 diazabicyclo [5,4,0] undec 7-ene (DBU), Tetramethyl guanidine (TMG), 1,4 diazabicyclo [2,2,2] octane (DABCO), 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), dicyclo hexyl amine (DCHA) and the like or mixture thereof. The preferred base is DBU.
The example of inorganic base as mentioned hereinabove includes but not limited to NaHC03, KHCO3, LiHC03, Na2C03, K2C03, Li2C03, CaC03, MgC03 and the like or mixture thereof.
The alcoholic solvent is selected from the group comprising methanol, ethanol, isopropanol, n-propanol, butanol and the like or mixture thereof. The preferred solvent is methanol.
The reaction is carried out at ambient temperature ranging from about 18°C to about 20°C for period of time sufficient to complete deacetylation. Generally it takes 1.5-2 hours to complete. The reaction mixture is neutralized by stirring with cation resin to pH from about 7 to about 7.5. The resin is removed by filtration and washed with the reaction solvent. The combined filtrate and wash is treated with activated charcoal and filtered through highflobed. The solvent is evaporated optionally under vacuum to give residue. The crude product is optionally crystallized from ethylacetate to give pure Sucralose.
According to another embodiment of the present invention, a process of preparation of
Sucralose comprises steps of;
(i) tritylation of compound of formula (II)


followed by acetylation to give compound of formula (III);

(ii) detritylation of compound of formula (III) obtained in step (i) to give compound of formula (IV);
(iii) acetyl migration of compound of formula (IV) obtained in step (ii) to give compound of formula (V);

(iv) chlorinating the compound of formula (V) obtained in step (iii) to give TOPSA of formula (VI);


(v) deacetylation of TOPSA of formula (VI) obtained in step (iv) to give Sucralose of formula (I).

characterized in that the deacetylation step utilizes a base in the presence of a alcoholic solvent, wherein the base is selected from a group which does not include alkoxide or hydroxide group.
The Sucralose obtained by the process of present invention is highly pure and having HPLC purity of 99.5 to 99.7%.
In another embodiment of the present invention, it provides pharmaceutical composition comprising Sucralose prepared according to the above process as sweetening agent.
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 Sucralose using DBU
DBU (0.3ml) was added to a stirred solution of 4,1,6'-trichloro^J'^'-trideoxy galactosucrose penta-acetate (TOPSA) (lOg) in methanol (100ml) at ambient temperature (25-30°C) and adjusted the pH of solution to 9.5 to 10.5 to give clear solution. The reaction mixture was stirred at ambient temperature (25-30°C) for 2 hours. The reaction mixture is then neutralized with sulphuric acid cation resin and adjusted pH 6.8 to 7.0 at ambient temperature. The resin is filtered off and filtrate is charcoalized using decolorizing charcoal and refluxed (65-70°C) for 30 min. The mass is filtered through

highflobed. The solvent is evaporated from the filtrate to give residue which is recrystallized from ethylacetate (20ml). The product is dried at 45°C for 6 hours to give Sucralose (5.2g).
Example 2
Preparation of Sucralose using Sodium carbonate
4,1,6'-Trich]oro-4,1 ',6'-trideoxygalactosucrose pentaacetate (TOPSA) (1 OOg) was stirred at ambient temperature with sodium carbonate (lgm) in methanol (1000ml). Reaction was stirred till reaction completion. Thereafter excess sodium carbonate was neutralized with Amberlite H+ resin and filtered. The solution was treated with decolorizing charcoal (5g) filtered and distilled to foam. Ethyl acetate (200ml) was added to precipitate Sucralose (55g). (Purity by HPLC: 99.78%)
Example 3
Preparation of Sucralose using Sodium bicarbonate
4,1,6'-Trichloro-4,r,6'-trideoxygalactosucrose pentaacetate (TOPSA) (100g) was stirred at ambient temperature with sodium bicarbonate (5g) in methanol (1000ml). Reaction was stirred till reaction completion. Thereafter excess sodium carbonate was neutralized with Amberlite H+ resin and filtered. The solution was treated with decolorizing charcoal (5g) filtered and distil Jed to foam. Ethyl acetate (200ml) was added to precipitate Sucralose (53g). (Purity by HPLC: 99.6%)
Example 4
Preparation of Sucralose
(a) Preparation of 6,1,6'-Tri-0-trityIsucrose pentaacetate
Sucrose (400g) in pyridine (390ml) and dimethylformamide (600ml) was treated with Trityl chloride (1053g) in toluene (1053ml) at 50°C in three equal portions in 2.5 hrs and heated for next 4 hrs. Thereafter the reaction was diluted with toluene (1400ml) and washed with brine (1500ml) at 60°C. Toluene was distilled completely. Added acetic anhydride (750ml) and pyridine (50ml) and heated at 90°C for 8-10 hrs. Then cooled to room temperature and added methanol (4200ml) to precipitate product. Solid was filtered

and washed with methanol (400ml) and dried it under vacuum at 45°C upto constant weight obtained (856g).
(b) Preparation of 2,3,4,3',4'-Penta-0-acetylsucrose
6,1 ,6'-Tri-0-tritylsucrose pentaacetate (lOOg) was dissolved in dichloromethane (300ml) and added Pd/C (lg) and catalytic trityl chloride (1.3g). This mixture was stirred under 2 kg of hydrogen pressure. After the completion of reaction, triethylamine (0.5ml) is added to neutralise the HC1. The mass was filtered through hyflobed and the filtrate was evaporated to dryness. Solid was slurried in Methanol (300ml) and filtered. The filtrate was evaporated to give 2,3,4,3',4'-Penta-0-acetylsucrose as residue which was used as such in the next step.
(c) Preparation of 2,3>6,3\4'-Penta-0-acetyIsucrose
2,354,3',4'-Penta-0-acetylsucrose was dissolved in MIBK (400ml) and was refluxed at 125°C in the presence of acetic acid (20 ml) for 5 hrs. The reaction mixture was then cooled to 60°C and petroleum ether (400ml) was added to precipitate the product. The solid was filtered , washed with ether (40ml) and dried in vacuum to give 2,3,6,3',4'-Penta-O-acetylsucrose (31g).
(d) Preparation of 4,l\6'-Trichloro-4,l%6'-trideoxygalactosucrose pentaacetate
(TOPSA)
To a stirred solution of 2,3,6,3\4'-Penta-0-acetylsucrose (lOOg) in ethylenedichloride (300ml) and pyridine (300ml) was added a mixture of sulfuryl chloride (300ml) in ethylenedichloride (300ml) without external cooling. The reaction mixture was heated to reflux for 5-6 hrs. The reaction mass was cooled and diluted with ethylenedichloride (1000ml). The resulting solution was washed successively with 10% hydrochloric acid (2000ml), D.M. water (2000ml) and 10% sodium bicarbonate (2000ml). The organic layer was distilled to a syrupy product which was further crystallised from toluene (300ml) to give the crude product (70g). Crude product was recrystallised with methanol (280ml) to yield pure 4,1 ',6'-Trichloro-4,l '^'-trideoxygalactosucrose pentaacetate (50g).

(e) Preparation of Sucralose
4,1' ,6'-Trichloro-4,1' ,6 '-trideoxygalactosucrose pentaacetate (TOPS A) (1 OOg) was stirred at ambient temperature with sodium carbonate (lgm) in methanol (1000ml). Reaction was stirred till reaction completion. Thereafter excess sodium carbonate was neutralized with Amberlite H+ resin and filtered. The solution was treated with decolorizing charcoal (5g) filtered and distilled to foam. Ethyl acetate (200ml) was added to precipitate Sucralose (55g). (Purity by HPLC: 99.78%)

What is claimed is:
1. A process for the preparation of Sucralose of formula (I) comprising a step of

deacetylation of 4,r,6,-trichloro-4,r,6'-trideoxy galactosucrose penta-acetate (TOPSA) of formula (VI)

in the presence of a base and alcoholic solvent, wherein the base is selected from a group which does not include alkoxide or hydroxide group.
2. A process of preparation of Sucralose comprises steps of;
(i) tritylation of compound of formula (II)

followed by acetylation to give compound of formula (III);

(ii) detritylation of compound of formula (III) obtained in step (i) to give compound of formula (IV);


(iii) acetyl migration of compound of formula (IV) obtained in step (ii) to give compound of formula (V);

(iv) chlorinating the compound of formula (V) obtained in step (iii) to give TOPS A of formula (VI);

(v) deacetylation of TOPS A of formula (VI) obtained in step (iv) to give Sucralose of formula (I).
characterized in that the deacetylation step utilizes a base in the presence of alcoholic solvent, wherein the base is selected from a group which does not include alkoxide or hydroxide group.
3. The process as claimed in claim 1 or 2, wherein said base is selected from the group consisting of organic and inorganic base or mixture thereof.

4. The process as claimed in claim 3, wherein the organic base is selected from the
group comprising non-alkoxy amines or non-hydroxy amines.
5. The process as claimed in claim 4, wherein the non-alkoxy amines or non-
hydroxy amines is selected from the group comprising 1,8 diazabicyclo [5,4,0]
undec 7-ene (DBU), Tetramethyl guanidine (TMG), 1,4 diazabicyclo [2,2,2]
octane (DABCO), 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), dicyclo hexyl
amine (DCHA) or mixture thereof
6. The process as claimed in claim 3, wherein the inorganic base is selected from the
group comprising alkali or alkaline earth metal carbonate or bicarbonate.
7. The process as claimed in claim 6, wherein alkali or alkaline earth metal
carbonate or bicarbonate is selected from NaHCCh, KHCO3, UHCO3, Na2CO3,
K2CO3, Li2CO3, CaCO3, MgCO3) or mixture thereof.
8. The process as claimed in claim 3 or 5, wherein the base is 1,8 diazabicyclo
[5,4,0] undec 7-ene (DBU).
9. The process as claimed in claim 1 or 2, wherein the alcoholic solvent is selected
from methanol, ethanol, isopropanol. n-Dropanol, butanol or mixture thereof.
10. A pharmaceutical composition comprising Sucralose as prepared according to any
preceding claim as sweetening agent.
Dated this 12th day of April 2006.