FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10, rule 13)
"PROCESS FOR THE ISOLATION OF A GLUCOSE
DERIVATIVE"
EMCURE PHARMACEUTICALS LIMITED of Emcure House, T-184, MIDC, Bhosari, Pune -411 026, Maharashtra, India.
The following specification describes the invention.

FIELD OF THE INVENTION
This invention relates to an improved, safe, commercially viable, quick and cost effective process for the preparation of 4,l',6'-trichloro-4,l',6'-trideoxygalactosucrosea. The invention is directed towards the convenient synthesis of chlorinated sucrose from 6-acetyl sucrose.
BACKGROUND OF THE INVENTION
Sucrose is still the most widely used sweetening agent. Efforts have also been made to find sweeter alternatives, which could be used for combination of high degree of sweetness, while having a low calorie content. Saccharin suffers a disadvantage of an unpleasantly bitter aftertaste. Cyclamate has recently been restricted or banned because of doubts about their safety (http://users.netconnect.com.au/~ewood/food additives.htmlaaa).
4,l',6'-Trichloro-4,l',6'-trideoxygalactosucrose i.e. "chlorinated sucrose" (I) is a sweetner made from sugar. It has no calories and no nutritional value. This compound is a potent non-caloric sweetener, which is known under the trade name "Splenda" ref:
http:// www.google.coin/search?hl=en&lr=&oi=defmaore&defl=en&q=define:chl orainated sucrose
It is 500-700 times sweeter than sucrose, making it twice as sweet as saccharin. It has a clean, quickly perceptible, sweet taste that does not leave an unpleasant aftertaste.

Chlorinated sucrose can be prepared from 4, 1’, 6'trichloro 4, 1', 6'-trideoxy-galacto-sucrose penta acetate (TC-PAS) (II) as per the Scheme (I).

CI 0H

AcO
(a) Methanolic NaOMe Methanol
__. (b) Aqueous workup
AcO / "* N CI
4,1,,6'Trichloro,4,1',6'trideoxy H0
galacto sucrose penta acetate 4,1',6'-Trichloro-4,1',6,-deoxygalactosucrose
(TC-PAS) (I)
(II)
Scheme (I): Method as disclosed in US 4,362,869.
According to US 4,362,869, TC-PAS as disclosed in Scheme (I), chlorinated sucrose was obtained from TC-PAS (II) by making use of sodium methoxide and methanol. According to this reference the deacylation step was carried out in the presence of sodium methoxide and methanol. However, this process suffers from disadvantages. The use of sodium methoxide makes the reaction condition less safe. The sodium methoxide use has following disadvantages:
a) Sodium methoxide is highly flammable,
b) It is explosive in traces of water,
c) Its inhalation may turn out to be fatal and
d) It causes burns.
e) Requires dry solvents for reaction.
f) Use of sodium methoxide leads to impurities of undesirable compounds. The chlorinated sucrose was further recrystallised from water, giving poor yield of chlorinated sucrose. The low yields and stringent reaction conditions makes the process industrially unfavouorable and costly.
Early reported work typically involved crystallizing chlorinated sucrose directly from the reaction mixture by silica gel chromatography. US 5,128,248 described a procedure by making use of silica gel chromatography. This procedure due to its use of silica gel may be ill-suited to large volume commercial production of highly pure chlorinated sucrose. In addition, relatively little attention has been focused on other approaches for removing halogenated sugar impurities from chlorinated
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sucrose. Efficient removal of impurities is important because, even at quite low concentration, they can have an adverse impact on the sweetness, taste, and flavour-modifying properties of chlorinated sucrose.
Chlorinated sucrose can be obtained by a generalized scheme as shown in Scheme II, m which chlorinated sucrose is obtained by an aqueous workup and is further extracted in organic solvents till required purity and yield is obtained.

(a) Aqueous work up
(b) Multiple extractions CI
^. HO

R=Acetyl or R=Benzoyl
Scheme II

US 4,980,463 relates to a process in which chlorinated sucrose is produced by KOH treatment of a methanol solution of chlorinated sucrose-6-benzoate. The methanol is removed by evaporation and residue is dissolved in water. The aqueous solution is extracted three times with ethyl acetate. The combined organic extracts are back extracted with water to recover chlorinated sucrose present in the ethyl acetate. The combined aqueous portions are concentrated and treated with a decolorizing agent. Additional concentration permits crystallization of chlorinated sucrose. However, this method suffers some disadvantages. Due to multiple extractions there is a loss in yields, thus making the process costly. The time required for multiple extractions is also more thus making the process economically unfeasible.

US 5,498,709 and US 5,530,106 relates to a process in which the aqueous solution remaining after the ester hydrolysis of chlorinated sucrose precursors is concentrated and then chlorinated sucrose is isolated by three sequential extractions with ethyl acetate or other suitable solvent. The patent also relates to process in which chlorinated sucrose contained in the aqueous brine obtained
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after alkaline de-esterification is extracted into a solvent not miscible in brine. The organic extracts may then be back extracted with water to transfer the chlorinated sucrose back into the aqueous phase. This approach yields a relatively impure material.
Further, this method has certain disadvantages. The volume of solvent used is high which makes the process costly and industrially unfeasible.
Considering the stiff challenges related to the impurities formed during the Known synthetic methods, various efforts have gone in to resolve the problem.
According to US 5,977,349, the purified chlorinated sucrose is obtained by making use of fixed bed adsorption chromatography. The adsorbant used is silanized silica gel. This technique is very costly for the production on commercial scale.
US 7,049,435 describes extractive methods for purifying chlorinated sucrose. The patent mentions that extractive methods involving crystallization without the use of at least two carefully controlled solvent extractions fail to effectively remove impurities, both more polar and less polar than chlorinated sucrose. The said invention relates to methods for removing impurities from a composition comprising chlorinated sucrose and impurities in the first solvent, comprising the steps of performing the liquid extraction of the composition with a second at least partially immiscible solvent to effect removal of the impurities into the second solvent and performing a second extraction of the composition with the third solvent, which is at least partially immiscible to effect removal of the impurities into the second solvent and performing a second extraction of the composition with a third at least partially immiscible solvent to effect the transfer of the chlorinated sucrose into the solvent and the retention of the impurities in the aqueous phase. The first extraction removes the substantial portion of impurities those are less polar than chlorinated sucrose. The second extraction transfers the bulk of chlorinated sucrose into the third solvent and the impurities that are more polar than chlorinated sucrose remain in the first solvent. However, this process requires a large volume of solvents with varied polarities. This process is also
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time consuming and hence industrially unfeasible. Further, the selective removal of impurities becomes very critical along with the loss of yields.
WO 2006061855 describes the process of extraction of chlorinated sucrose from aqueous solution into an organic solvent by addition of salts to the aqueous solution prior to the extraction. This application also mentions that when the aqueous solution of reaction mixture containing chlorinated sucrose is extracted with organic solvents to ensure satisfactory extent of extraction of the product chlorinated sucrose, the product recovered from such extract invariably contained a polar impurity, which traveled very close to TGS in TLC assay. Thus, WO '855 addresses that current issue of removing of impurities, formed during the production.
WO 2007017899 describes a process for isolation and purification of chlorinated sucrose from a composition containing chlorinated sucrose and impurities by adding a mixture of organic solvents to the composition and if required water such that the more hydrophobic impurities are extracted in organic layer and chlorinated sucrose retains in the aqueous layer. The aqueous layer is then extracted with a single organic solvent such that the ester derivatives are selectively extracted in the organic solvent. The aqueous layer was then saturated with salt and extracted in an organic solvent so that chlorinated sucrose passes in organic phase and can be recovered by crystallization or column chromatography.
The solubility of TGS is very high in aqueous solutions, with the result that while extracting from aqueous solutions into solvents of low miscibility in water, large volumes of solvents and repetitive extractions of TGS are required. This process is therefore less efficient and time consuming.
Further, it is also found that when the aqueous solution of reaction mixture containing TGS is extracted with organic solvents to ensure satisfactory extractions of the product TGS, the product TGS recovered from such extract invariably contained a polar impurity.
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US 6,943,248 discloses a method to produce a crystalline form of chlorinated sucrose by making use of heat exchanger and a pump configured for recirculation. However, this assembly been expensive makes the process costly and industrially unfeasible.
US 4,918,182 discloses that the crystalline chlorinated sucrose is said to have a mean particle size of at most 10 microns (with 5 microns preferred), the maximum particle size being no more than twice the mean (preferably atmost 10 microns). The said particle size obtained was found to be thermally stable. The chlorinated sucrose needed to be used in the composition should be thermally stable, without dispensing the undesirable color. However, such stable chlorinated sucrose is obtained by the process of jet milling. This process is tedious, time consuming and requires more man power, thus making it industrially unfeasible.
Hence, there remains a need to obtain chlorinated sucrose in a crystalline form with a simple, economical and cost effective process with a particle size that is stable and useful in composition.
Thus, there are a number of problems with literature processes for preparing chlorinated sucrose.
a) The purification of the final deacylated product is required, which results in increased labor, time cycle, cost of utilities and reactor occupancy.
b) Multiple extractions are involved for isolation of chlorinated sucrose which makes the process costly, cumbersome and time consuming.
c) A large volume of solvents are used in the prior art, which necessitates the higher reactor size.

d) The purification using column chromatography or even other modified chromatographic techniques used in the prior art are industrially not feasible.
e) The product obtained may not be of pharmaceutically acceptable purity, compelling the further purification.
f) The yield of isolated chlorinated sucrose is low.
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In view of the above shortcomings, it was necessary to develop an alternate process for the deacylation step and isolation, which would give chlorinated sucrose i.e. compound of formula (I), by a process, which is industrially feasible.
SUMMARY OF THE INVENTION
The present inventors have also developed a process for the preparation of chlorinated sucrose, which is cost effective.
OBJECT OF THE INVENTION
The object of the present invention is to provide an improved process for the preparation of chlorinated sucrose of formula (I) by a synthetic route, which is simple, industrially feasible, quick and safe.
DETAILED DESCRIPTION OF THE INVENTION:
Chlorinated sucrose (I) is prepared as per Scheme (III) disclosed below:


ci 0H
Ammoniacal solvent
HO
HO
6-Acetyl chlorinated sucrose 4,1',6'-Trichloro-4,1',6,-deoxygalactosucrose
(III)
(I)
SCHEME (III)
The present embodiment describes the preparation of chlorinated sucrose as per the reaction sequence disclosed in Scheme (III).
The 6-acetyl chlorinated sucrose (III) is treated with ammonia in organic solvent (ammoniacal organic solvent) to obtain chlorinated sucrose. The organic solvents such that ammonia can be dissolved in the said organic solvent. The organic solvents are such as alcohols, ether etc and mixtures thereof. The alcohols used are methanol, ethanol, isopropyl alcohol, n-propyl alcohol etc. The preferred alcohol
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is methanol. The content of ammonia is in such a way that it can effectively hydrolyze the acetate. The content can preferable range from 9 to 20%.
The hydrolysis of acetate is monitored and after the reaction completion the solvent is removed, preferably under reduced pressure. Further, solid is obtained by precipitating it with the solvents selected from the group comprising of esters, alcohols, ketones, nitriles etc. or the combination thereof. Preferably the solvents used are ethyl acetate, propyl acetate, methyl acetate, acetonitrile, propionitrile etc. The more preferred solvent is ethyl acetate.
The reaction is carried in a temperature range of 15-30°C. The preferable range being 20-25°C.
The volumes of ammoniacal solvent can vary based on the % of ammonia present in the dissolved state.
The workup of the reaction is carried out by evaporating methanol and crystallizing the solid out by ethyl acetate.
Thus, the current embodiment makes use of a process, which is advantageous in following ways:
a) Use of a single phase during the workup of the reaction.
b) Making use of lesser amounts of solvents.
c) Avoiding the laborious techniques like extraction.
d) Having cost effective and industrially feasible process.
e) Reducing in the time cycle of the process.
f) Avoiding the use of aqueous phase in the workup, thus increasing the yields of the product.
g) Preparation of particles of chlorinated sucrose crystals in a simple, cost effective and industrially feasible process.
h) Chlorinated sucrose crystallization for aqueous phase step is not required
after the deacylation step
i) Avoiding the use of micronizing techniques like jet milling, heat exchanger
and recirculating pump.
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j) Acceptable yields.
k) Acceptable purity. The invention is described in detail here below with respect to the following examples, which are provided merely for illustration and are not intended to restrict the scope of the invention in any manner. Any embodiments that may be apparent to a person skilled in the art are deemed to fall within the scope of the present invention.
Examples:
Example 1:
To a four neck round bottom flask, 160 ml of methanol-ammonia was charged. 6-Acetyl chlorinated sucrose (32gm) was added to the flask. The reaction was monitored by TLC. After the completion of the reaction activated charcoal was added to the reaction mass and stirred at 22-25°C. The reaction mass was filtered through hyflo and washed with methanol. The reaction mass was concentrated under vacuum at 45-50°C Methanol was stripped out by ethyl acetate twice. Ethyl acetate was further added and the reaction mass was stirred for 2 hr at 25-30°C. The reaction mass was filtered and the solids were washed with ethyl acetate. The solids were dried . Yield: 22 gm
Example 2:
To a four neck round bottom flask, 250 ml of methanol-ammonia (16 %) was charged. 6-Acetyl chlorinated sucrose (50gm) was added to the flask. The reaction was monitored by TLC. After the completion of the reaction activated charcoal was added to the reaction mass and stirred at 22-25°C. The reaction mass was filtered through hyflo and washed with methanol. The reaction mass was concentrated under vacuum at 45-50°C. Methanol was stripped out by ethyl acetate twice. Ethyl acetate was further added and the reaction mass was stirred for 2 hr at 25-30°C. The reaction mass was filtered and the solids were washed with ethyl acetate. The solids were dried. Yield: 35 gm.
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Example 3:
To a four neck round bottom flask, 1.5 lit of methanol-ammonia (14%) was charged. 6-Acetyl chlorinated sucrose (200 gm) was added to the flask. The reaction was monitored by TLC. After the completion of the reaction activated charcoal was added to the reaction mass and stirred at 22-25°C. The reaction mass was filtered through hyflo and washed with methanol. The reaction mass was concentrated under vacuum at 45-50°C. Methanol was stripped out by ethyl acetate twice. Ethyl acetate was further added and the reaction mass was stirred for 2 hr at 25-30°C. The reaction mass was filtered and the solids were washed with ethyl acetate. The solids were dried. Yield: 135 gm.
Advantages:
1. The process of the invention prepares chlorinated sucrose makes use of lesser amount of solvents.
2. The process is industrially feasible.
3. The process avoids multiple extractions and thus provides better work up conditions
4. The final product produced is of pharmaceutically acceptable purity.
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We claim:
1) A process for the preparation of chlorinated sucrose (I) from 6-acetyl chlorinated sucrose in the presence of a deacylating agent,

Deacylating reagent \ ^r-~^ HO
6-Acetyl chlorinated sucrose 4,r,6'-Trichloro-4,r,6,-deoxygalactosucrose
(III)
(I)
wherein deacylating agent is ammonia.
2) A process according to claim 1, wherein the deacylating agent used is ammonia in the presence of organic solvent(s).
3) A process according to claim 2, wherein the organic solvent is selected from the group comprising of alcohols and ethers or mixtures thereof
4) A process according to claim 3, wherein the alcohol used is selected from the group comprising of methanol, ethanol, isopropyl alcohol and n-propyl alcohol or mixtures thereof.
5) A process according to claim 4, wherein the preferred alcohol is methanol.
6) A process for preparing chlorinated sucrose (I) substantially as described herein with reference to the foregoing examples.
Dated this 4th day of April, 2007

ABSTRACT
PROCESS FOR THE ISOLATION OF A GLUCOSE DERIVATIVE"
The present invention relates to an improved, safe, commercially viable, quick and cost effective process for the preparation of 4,l',6'-trichloro-4,l',6'-trideoxygalactosucrose. The invention is directed towards the convenient synthesis of chlorinated sucrose from 6-acetyl sucrose.
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