FORM 2
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 of high purity."

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 preparing Sucralose having

purity of at least 99.6%. Sucralose is represented by the structural formula (I) as

shown below.

OH

Background of the invention:

Sucralose is a potent sweetener having sweetness several hundred times that of sucrose. It is chemically known as 1 ,6-dichloro-l ,6-dideoxy-(3-D-fructofuranosyl-4-chloro-4-deoxy-a-galactopyranoside and having formula is C12H19Cl3O8 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 trade name Splenda@.

Sucralose is derived from sucrose by replacing the hydroxyl groups in the 4, 1', and 6' positions with chlorine. Synthesis of Sucralose is technically challenging because of the need to selectively replace specific hydroxyl groups with chlorine atoms, while preserving other hydroxyl groups including a highly reactive primary hydroxyl group.Numerous approaches to this synthesis have been developed and disclosed in US. Patent Nos. 4,362,869; 4,826,962; 4,980,463; 5,141,860; 4,807,100 and 4,920,209.

However, such approaches typically yield Sucralose containing varying levels of other chlorinated sugar compounds in addition to Sucralose.

U.S. Patent No.5,270,460 and W02005090374 disclose the process for purification of Sucralose by silicagel chromatography or other chromatographic methods. However, purification of Sucralose by chromatographic method is commercially not suitable and cumbersome at an industrial scale.

U.S. Patent Nos. 4,801,700; 4,783,526; 5,141,860; 4,977,254 and GB2224504
disclose the process for purification of Sucralose by recrystallization from
ethylacetate. This process provides Sucralose having some impurities which are
difficult to remove even after repeated crystallization. This process provides
Sucralose having purity of less than 99.6%. However, repeated crystallization would

result in a loss of yield of the final product.

Another problem associated with purity and yield of Sucralose relates to the
formation of a wide range of related chlorinated carbohydrates during Sucralose
synthesis, which are only partially removed during purification. These related
compounds, or impurities, have varying degrees of sweetness, and can interact with
the flavor systems of food and beverage products in adverse ways. Various
compendial sources, such as the Food and Drug Codex, the United States
Pharmacopoeia, and Joint Expert Committee on Food Additives have established
specifications for Sucralose. All of these authorities allow impurities in Sucralose of
up to 2%. Individuals can detect sweetness differences arising from impurities when
the impurity level is as low as about 1 %, and even lower impurity levels can affect
the perceived taste of complex flavor systems. Hence, chlorinated carbohydrates
generated during Sucralose synthesis may have a profound effect on taste, affecting
the quality of an end product. Conversely, the removal of impurities may beneficially
affect taste, sweetness, and palatability.

U.S. Patent No. 6,809,198 discloses a process for purification of Sucralose by
cystallization from aqueous solution in controlled pH condition at pH 5.5 to 8.5 using
buffer solution. This process requires regular monitoring of pH. It also requires
special kind of industrial apparatus for the purification process. These drawbacks
make the process cumbersome at an industrial scale.

U.S. Patent Nos. 5,034,551 and 4,980,463, incorporated herein relates to a process in
which the aqueous solution remaining after ester hydrolysis of Sucralose precursors is
extracted three times with ethyl acetate to remove methyl benzoate, unreacted
Sucralose-6-benzoate and other non-polar impurities. The aqueous layer was
charcoalized and Sucralose was crystallized from the aqueous layer. The recovered
crystals have a reported purity of 99.6%. Purification to this level is achieved
primarily through crystallization, rather than by solvent extraction processes.

However, this technique is less capable of removing polar impuirities from impure
Sucralose.

U.S. Patent No. 5,498,709 also relates to a process in which the aqueous solution
remaining after ester hydrolysis of Sucralose precursors is concentrated and then
Sucralose is isolated by three sequential extractions with ethyl acetate or other
suitable solvent. The extracts may then be combined, and optionally washed with
water to remove any dimethyl formamide remaining prior to recovering the Sucralose
by concentration and crystallization. Sucralose is crystallized from the same solvent
until the required purity is achieved. Aletematively, the Sucralose may be crystallized
from a solvent mixture or water. The purity obtained by this method may also be less
.
An additional approach discussed within U.S. Pat. No. 5,498,709, which is expressly
incorporated by reference herein, involves the toluene extraction of the alkaline
solution remaining after deesterification. Specifically, the solution is extracted twice

4

with toluene to remove non-polar impurities. The aqueous solution is then extracted
repeatedly with 2-butanone. The 2-butanone extracts are combined, and the solvent is
evaporated to yield a reddish syrup containing Sucralose. Non-polar impurities are
removed but still there is no effective manner disclosed to remove polar impurities.
Hence, Sucralose prepared according to this process may have purity lower than
99.6%.
U.S. Patent No.7,049,435 discloses the process for purification of Sucralose by
extractive method which involves repeated extraction from first solvent (i.e. water),
second solvent (i.e. ethyl acetate) and third solvent (i.e. ethylacetate). This process
provides purification selecting two different solvents with polarity based on
Hildebrand parameter.

This process also requires special kind of industrial apparatus to perform the
purification. Moreover, this kind of process requires repeated extraction is tedious
and laborious to perform.

All above references as mentioned hereinabove are incorporated in its entirety. The
preceding discussion identifies an unmet need for a Sucralose purification process
that produces Sucralose compositions of enhanced purity and also minimizes the
overall loss of Sucralose during the purification process. Hence, a less expensive and
more effective method is needed for the commercial production of Sucralose. The
present inventions attempt to solve these problems and provide methodologies that
are both commercially practicable and effective at removing impurities.

The present inventors have directed their research work towards developing an

improved purification process which not only overcome the problems mentioned

hereinabove but also provides Sucralose having purity of at least 99.6%. Surprisingly

the present inventors found a process which provides Sucralose having purity of at

least 99.6%.

Object of the invention:

A primary object of the present invention is to provide highly pure Sucralose having
purity of at least 99.6%.

Another object of the present invention is to provide a process for the preparation of
highly pure Sucralose having purity of at least 99.6%.

Another object of the present invention is to provide Sucralose having Organic
Volatile Impurity (OVI) less than 100 parts per million (ppm).

Another object of the present invention is to provide Sucralose having chlorinated
impurities less than 0.2%.

Yet another object of the present invention is to provide an improved a process for
preparing Sucralose, which is simple, easy to handle and feasible at commercial scale.

Summary of the invention:

The present invention relates to a process for the preparation of highly pure Sucralose
having purity of at least 99.6% comprising steps of
(i) Dissolving substantially impure Sucralose in water
(ii) Treating the solution obtained in step (i) with a partially water immiscible solvent
(iii) Washing the said solvent phase obtained in step (ii) with an amount of water
sufficient to remove polar impurities
(iv) Crystallizing the product from partially water immiscible solvent
(v) recrystallizing the solid obtained in step (iv) from water.

Another embodiment of the present invention relates to optionally recycling of the
Sucralose remaining in mother liquor obtained in step (v) i.e. after the
recrystallization from water is extracted with a solvent and subsequently mixed with
the solvent phase obtained in step (iii).

Brief description of the drawings

Fig. 1 depicts a flow diagram of the operations performed as per process of the
present invention.
Fig. 2 depicts Chromatogram of Sucralose obtained by Gas Chromatography
representing the purity of 99.88% of Sucralose obtained as per process of the present
invention.
Detailed description of the invention:

Accordingly, present invention provides a process for the preparation of highly pure
Sucralose having purity of at least 99.6% comprising steps of

(i) Dissolving substantially impure Sucralose in water
(ii) Treating the solution obtained in step (i) with a partially water immiscible
solvent
(iii) Washing the said solvent phase obtained in step (ii) with an amount of water
sufficient to remove polar impurities
(iv) Crystallizing the product from partially water immiscible solvent
(v) Recrystallizing the solid obtained in step (iv) from water.

In a preferred embodiment of the present invention, substantially impure Sucralose is
dissolved in water to form an aqueous solution of Sucralose. This solution is treated
with an excess amount of an organic solvent which is partially immiscible in water.
The solvent phase is washed with an amount of water sufficient to remove polar
impurities. The product obtained is crystallized from partially water immiscible
solvent. The isolated product is recrystallized from water.

In another embodiment of the present invention, after obtaining Sucralose having
purity of at least 99.6%, optionally the remaining residue in mother liquor in step (v)
is extracted with a partially water immiscible solvent and subsequently mixed with
the solvent phase obtained in step (iii).

"Crystallization" as used herein includes processes in which a solution is rendered
saturated or supersatured with respect to a dissolved component and the formation of
crystals of this component is achieved. The initiation of crystal formation may be
spontaneous, or it may require the addition of seed crystals. As used herein,
crystallization or recrystallization also describes the situation in which a solid or
liquid material is dissolved in a solvent to yield a solution which is then rendered
saturated or supersatured so as to obtain crystals. Also, included in the term
crystallization are the ancillary processes of washing the crystals with one or more
solvents, drying the crystals, and harvesting the final product so obtained.

The term "Treating" as used herein includes processes in which, suspending,
extracting, dissolving, washing, mixing and refluxing of two components either solid,
liquid or in a solution form takes place.

"Substantially impure Sucralose" refers to Sucralose having purity of less than 99.6%
for the purpose of this specification.

"Highly pure Sucralose" refers to Sucralose having purity of at least 99.6% for the
purpose of this specification.

The example of organic solvent includes but not limited to ethyl acetate,
methylisobuty1 ketone and the like or mixture thereof.

The schematic representation of the present invention is as shown in Fig. 1. The flow
diagram of Fig. 1 discloses sequential step of the operations performed as per process
of the present invention. This flow diagram also represents optionally recycling of the
Sucralose remaining in mother liquor obtained in step (v) i.e. after the
recrystallization from water, is extracted with a partially water immiscible solvent
and subsequently mixed with the solvent phase obtained in step (iii).

Substantially impure Sucralose is prepared by methods known perse or by any
method known to person skilled in art. The proecess for deacetylation step is
disclosed in US Patent No. 4,801,700 in example XIII and in co-pending Indian
application No. 0009/MUM/2006.

Sucralose obtained by performing purification mentioned in this application is having
purity of at least 99.6%. Fig. 2 confirms the purity of 99.88% of Sucralose by Gas
Chromatography. Sucralose obtained by performing purification mentioned in this
application is having Organic Volatile Impurity (OVI) less than 100 parts per million
(ppm) and chlorinated impurities less than 0.2%.

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-l

4,1' ,6' - Trichloro-4, I' ,6' -trideoxygalactosucrose pentaacetate (TOPSA) (100g) was
stirred at ambient temperature with sodium carbonate (1gm) in methanol (1000ml).
Reaction was stirred for about 2 hours. The reaction mixture was neutralized. The
solution was distilled to get thick residue. The residue was dissolved in D.M.Water
(75ml) and extracted with ethyl acetate (500ml). The ethyl acetate layer was separated
and washed with D.M.Water (75ml) and evaporated to dryness. The residue was
dissolved in fresh ethyl acetate (300ml) and allowed to stir for 5-20 hours. The
precipitates obtained were filtered and dried. The solid was recrystallized form water
and dried in oven to give solid (30g) Sucralose.
The mother liquor obtained after recrystallization from water was extracted with
ethylacetate and mixed with ethylacetate of the earlier stage (i.e. before water wash)
of subsequent batch.
(Total yield: 70%; Purity by Gas Chromatography (GC) ~ 99.8%)

We Claim:
1. A process for the preparation of Sucralose having purity of at least 99.6%
comprising steps of

(i) Dissolving substantially impure Sucralose in water

(ii) Treating the solution obtained in step (i) with a partially water immiscible

solvent

(iii) Washing the said solvent phase obtained in step (ii) with an amount of water

sufficient to remove polar impurities

(iv) Crystallizing the product from partially water immiscible solvent

(v) Recrystallizing the solid obtained in step (iv) from water.

2. A process for the preparation of Sucralose having purity of at least 99.6%
comprising steps of

(i) Dissolving substantially impure Sucralose in water

(ii) Treating the solution obtained in step (i) with a partially water immiscible
solvent

(iii) Washing the said solvent phase obtained in step (ii) with an amount of water

sufficient to remove polar impurities

(iv) Crystallizing the product from partially water immiscible solvent

(v) Recrystallizing the solid obtained in step (iv) from water.

and optionally recycling of the Sucralose remaining in the residue in mother

liquor obtained in step (v) is extracted with a partially water immiscible

solvent and subsequently mixed with the solvent phase obtained in step (iii).

3. The process as claimed in claim 1 or 2, wherein partially water immiscible
solvent is selected from the group comprising ethyl acetate and methyl isobutylketone or mixture thereof.

4. Sucralose having purity of at least 99.8%

5. Sucralose having Organic Volatile Impurity (OVI) less than 100 parts per

million (ppm).

6. Sucralose having chlorinated impurities less than 0.2%

Dated this 6th day of July 2006.

Sonali Bhokarikar
Of S. Majumdar & Co.

Abstract

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

having purity of at least 99.6% comprising steps of

(i) Dissolving substantially impure Sucralose in water

(ii) Treating the solution obtained in step (i) with a partially water immiscible

solvent

(iii) Washing the said solvent phase obtained in step (ii) with an amount of water

sufficient to remove polar impurities

(iv) Crystallizing the product from partially water immiscible solvent

(v) Recrystallizing the solid obtained in step (iv) from water.

,.

Water _ substantially

E h I t t impure sucralo

t y ace a e---

Extraction

ethylacetate layer

sucralose in

Water - ethyl acetate

Sheet 1 of

Sheets 2

aq. layer

Extraction _ aq. layer

ethylacetate layer

distillation till

Sucralose

residue

Ethylacetate-

Water _ Recrystallization

from water

Solid (Pure Sucralose)

Ethyl acetate

Dated this 6th day of July 2006.

Figure 1

ethyl acetate

layer

.y

extraction

with ethyl

acetate

.. Aq. layer

s~

c,o(
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Sonali Bhokarikar

Of S. Majumdar & Co.

Applicant's Agent

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