F0RM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - PROCESS FOR PREPARING SWEETENING
AGENT

2. Applicant(s)
(a) NAME :
(b) NATIONALITY :
(c) ADDRESS:

ALEMBIC LIMITED
An Indian Company.
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 one pot process for the preparation of 4,1',6'-trichloro-.2,3,6,3’,4’-penta-O-acetyl sucrose from 6,1,6’-tri-O-tritylsucrose penta-acetate and an improved process for the preparation of Sucralose. 4,1',6'-trichloro-2,3,6,3’,4’-penta-O-acetyl sucrose is an important intermediate of Sucralose. Sucralose is a well known sweetening agent.

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(VI)

Background of the invention and Prior art:
Sucralose is a potent sweetener having sweetness several hundred times that of Sucrose. It is chemically known as 1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-a-galactopyranoside and represented by Formula (I). It is also chemically known as 4,1,l6,-trichloro-4,1,,6,-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.
One route proposed in the literature (Fairclough et al, Carbohydrate Research 40 (1975) 285-298) involves the formation of the 6,1’,6’-tritrityl derivative of sucrose, peracetylation of the molecule and then detritylation with migration of the 4-acetyl radical to the 6-position, to give 2,3,6,3',4'-penta-0-acetylsucrose which has the correct hydroxy groups unprotected. Subsequent reaction with a chlorinating agent provides the 4,1',6'-trichlorogalactosucrose penta-acetate which in turn yields sucralose on removal of the acetyl groups. The chlorination proceeds with inversion of configuration at the 4-position. The 1' and 6'-positions freely rotate,
but the 4-position cannot and the glucose ring is thus inverted at the 4-position yielding a galactose derivative so that the product is galactosucrose.
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A further 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) tritylation 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 thereby yielding sucralose. However this process is low yielding and requires isolation of intermediates at all stages. Hence it is not feasible at commercial production.
US Patent No. 4,920,207 discloses the process for preparation of 2,3,4,3,,4'-penta-O-acetyl sucrose from e.l.S'-tri-O-tritylsucrose penta-acetate by hydrogenation in presence of aralkyl chloride and palladium or platinum catalyst in inert organic solvent. However the 2,3,4,3',4'-penta-0-acetyl sucrose prepared by this process requires purification which is cumbersome and time consuming.
Therefore there is a need to develop a process for preparation of 4,1',6'-trichloro-2,3,613',4'-penta-0-acetyl sucrose and subsequent conversion to Sucralose which is simple, easy to handle and feasible at commercial production.
Object of the invention:
The primary object of the present invention is to provide one pot process for the preparation of 4,1',6'-trichloro-2,3,6,3,,4'-penta-0-acetyl sucrose from 6,1,6'-tri-0-tritylsucrose penta-acetate.
Another object of the present invention is to provide process for preparation of Sucralose, which is simple, easy to handle, high yielding and feasible at commercial production.
Summary of the invention:
According to the primary object of the present invention, there is provided a one pot process for the preparation of the preparation of 4l1,,6,-trichloro-2,3,6,3,,4'-penta-O-acetyl sucrose comprising the steps of
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(a) detritylating 6,1,6'-tri-0-tritylsucrose penta-acetate with sulphonyl chloride selected from para-toluene sulphonyl chloride, methane sulphonyl chloride or ammonium chloride, under hydrogen pressure in presence of noble metal catalyst and solvent
(b) optionally filtering the reaction mixture of step (a)
(c) isolating tritane by addition of alcohols to the detritylated reaction mixture
(d) concentrating the solvent to obtain residue of 2,3,4,3,,4,-penta-0-acetyl sucrose
(e) converting 2,3,4,3',4'-penta-0-acetyl sucrose to 2,3,6,3',4'-penta-0-acetyl sucrose
(f) chlorinating 2,3,6,3,,4'-penta-0-acetyl sucrose to obtain 4,1',6'-trichloro-2,3,6,3',4'-penta-0-acetyl sucrose
Yet another aspect of the present invention is to provide a process for the preparation of Sucralose comprising the steps of
(a) converting Sucrose to 6,1,6'-tri-0-tritylsucrose penta-acetate
(b) detritylating 6,1,6'-tri-0-tritylsucrose penta-acetate with sulphonyl chloride selected from para-toluene sulphonyl chloride, methane sulphonyl chloride or ammonium chloride, under hydrogen pressure in presence of noble metal catalyst and solvent
(c) optionally filtering the reaction mixture of step (b)
(d) isolating tritane by addition of alcohols to the detritylated reaction mixture
(e) concentrating the solvent to obtain residue of 2,3,4,3',4'-penta-0-acetyl sucrose
(f) converting 2,3,4,3,,4'-penta-0-acetyl sucrose to 2,3,6,3',4'-penta-0-acetyl sucrose
(g) chlorinating 2,3,6,3',4'-penta-0-acetyl sucrose to obtain 4,1',6'-trichloro-2,3,6,3',4'-penta-0-acetyl sucrose
(h) converting 4,1',6'-trichloro-2,3,6,3,,4,-penta-0-acetyl sucrose to Sucralose
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Detailed description of the invention:
Sucralose is a well known zero calorie sweetening agent and it is having sweetness several hundred times that of normal sweetening agents like Sucrose. Various synthetic approaches of Sucralose are reported in literature. One of the synthetic approaches of Sucraclose is shown below in Scheme (I):
Scheme (I)


,OCPh3

Accordingly Sucrose is initially tritylated to block the three primary alcohol groups and subsequently acetylated to give 6,1,6'-tri-0-tritylsucrose penta-acetate of formula (III). Further it is detritylated to give compound of formula (IV) which undergoes acetyl migration from the 4-position to the 6-position to give compound of formula (V) which on further chlorination at 4, 1', 6' positions and subsequent deacetylation gives Sucralose.
According to the present invention, 4,1',6'-trichloro-2,3,6,3,,4'-penta-0-acetyl sucrose is prepared from 6,1,6'-tri-0-tritylsucrose penta-acetate in a single pot. Sucrose is converted to e.I.e'-tri-O-tritylsucrose penta-acetate by methods known perse or by any method known to person skilled in art. 6,1,6'-tri-0-tritylsucrose penta-acetate is further detritylated with sulphonyl chloride selected from para-
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toluene sulphonyl chloride, methane sulphonyl chloride or ammonium chloride, under hydrogen pressure in presence of noble metal catalyst and solvent.
The noble metal catalyst is selected from palladium, platinum or Ni, preferably palladium. The solvent used in this reaction is selected from chlorinated solvent like methylenedichloride, ethylenedichloride, 1,1-dichloroethane, chloroform, carbontetrachloride, esters like from ethyl acetate, methyl acetate, isopropyl acetate, hydrocarbon like toluene, xylene, or dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, dioxane and the like, preferably methylene dichloride. The reaction is preferably carried out under 1 kg to 6 kg per cm2 of hydrogen pressure. The reaction can be carried out at temperature of about 15°C to 50°C, more preferably at room temperature. After completion of the reaction, the reaction mixture is neutralized with base such as triethylamine and filtered. The filtrate is concentrated and alcohol selected from methanol, ethanol, isopropanol, n-propanol, preferably methanol is added. After the addition of alcohol tritane is precipitated out from the reaction mixture and isolated and subsequently the reaction mixture is concentrated. Further the residue of compound of formula (IV) is converted to compound of formula (V) by treatment with mild acid like acetic acid or mild base like tert-butyl amine in organic solvent selected from methylisobutyl ketone, toluene, xylene, preferably in methylisobutyl ketone. This conversion is carried out at ambient temperature to reflux temperature. After complete conversion the solvent is distilled off and the residue is treated with chlorinating agent such as sulphuryl chloride in presence of base like pyridine in solvent like methylenedichloride, ethylenedichloride, 1,1-dichloroethane, chloroform, carbontetrachloride, toluene, xylene and like, preferably ethylene dichloride. This reaction is carried out at ambient temperature to reflux temperature. After the completion of the reaction the compound of formula (VI) is isolated by conventional methods and subsequently purified from toluene.
Thus obtained compound of formula (VI) is converted to Sucralose by known methods like treating with sodium methoxide in methanol to give Sucralose.
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.
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Example: Preparation of 4,1',6,-trichloro-2,3,6,3',4'-penta-0-acetyl sucrose
6,1,6'-tri-0-tritylsucrose penta-acetate (10gm) is added to methylene dichloride (300ml). para toluene sulfonyl chloride (1.3gm) is added to the reaction mixture and hydrogenated by addition of palladium/charcoal (1g) under 2kg/cm2 of hydrogen pressure at 30°C. After the completion of reaction, triethyl amine (0.5ml) is added to it and filtered to through high flow. Solvent is evaporated under vacuum and 300ml methanol is added to the residue and stirred for 15 minutes. The precipitated tritane is filtered out and filtrate is evaporated to dryness. 400 ml methyl iso butyl ketone and 20 ml acetic acid is added to the residue and refluxed for 5 hrs. The solvent is distilled off completely and 120 ml ethylene dichloride, 120 ml pyridine is added to it. 120ml Sulfuryl chloride in ethylene dichloride (120ml) is added portion wise to the reaction mixture and refluxed for 5 hrs. Further, 400ml ethylene dichloride is added to reaction mixture and the organic layer is washed with 10% HCI, DM water and 10% Sodium bicarbonate and water. The organic layer is distilled off and the solid is crystallized off by addition of toluene (120ml) to give 4,r,6'-trichloro-2,3,6,3',4'-penta-O-acetyl sucrose (Yield: 25gm).
Preparation of Sucralose:
4,1',6'-trichloro-2,3,6,3,l4,-penta-0-acetyl sucrose (25gm) is added to Methanol (250ml). Sodium methoxide solution in methanol is added to the reaction mixture and stirred. After completion of the reaction, Amberlite strong cation exchange resin is added to it. It is further filtered and charcoal is added to the filterate and heated for 10 mins. It is filtered, washed with methanol. Methanol is distilled out. Residue is treated with Ethyl acetate and stirred for 3-5 hrs. The reaction mixture is cooled and stirred for 30 minutes. It is filtered, washed with Ethyl acetate and dried to give Sucralose.
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We Claim:
1. An one pot process for the preparation of 4,1',6'-trichloro-2,3,6,3\4'-penta-0-
acetyl sucrose comprising the steps of
(a) detritylating 6,1,6'-tri-0-tritylsucrose penta-acetate with sulphonyl chloride selected from para-toluene sulphonyl chloride, methane sulphonyl chloride or ammonium chloride, under hydrogen pressure in presence of noble metal catalyst and solvent
(b) optionally filtering the reaction mixture of step (a)
(c) isolating tritane by addition of alcohols to the detritylated reaction mixture
(d) concentrating the solvent to obtain residue of 2,3,4,3,,4'-penta-0-acetyl sucrose
(e) converting 2,3,4,3',4'-penta-0-acetyl sucrose to 2,3,6,3',4'-penta-0-acetyl sucrose;
(f) chlorinating 2,3,6,3',4'-penta-0-acetyl sucrose to obtain 4,1',6'-trichloro-2,3,6,3',4'-penta-0-acetyl sucrose
2. A process for the preparation of Sucralose comprising the steps of
(a) converting Sucrose to 6,1,6'-tri-0-tritylsucrose penta-acetate
(b) detritylating 6,1,6'-tri-0-tritylsucrose penta-acetate with sulphonyl chloride selected from para-toluene sulphonyl chloride, methane sulphonyl chloride or ammonium chloride, under hydrogen pressure in presence of noble metal catalyst and solvent
(c) optionally filtering the reaction mixture of step (b)
(d) isolating tritane by addition of alcohols to the detritylated reaction mixture
(e) concentrating the solvent to obtain residue of 2,3,4,3',4'-penta-0-acetyl sucrose
(f) converting 2,3,4,3',4'-penta-0-acetyl sucrose to 2,3,6,3',4'-penta-0-acetyl sucrose
(g) chlorinating 2,3,6,3',4'-penta-0-acetyl sucrose to obtain 4,1',6'-trichloro-2,3,6,3',4'-penta-0-acetyl sucrose
(h) converting 4,1',6'-trichloro-2,3,6,3',4,-penta-0-acetyl to Sucralose
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3. A process as claimed in claim 1 or 2, wherein noble metal catalyst is selected from palladium, platinum or Ni
4. A process as claimed in claim 1 or 2, wherein detritylating is carried out in solvent selected from chlorinated solvent like methylenedichloride, ethylenedichloride, 1,1-dichloroethane, chloroform, carbontetrachloride, esters like from ethyl acetate, methyl acetate, isopropyl acetate, hydrocarbon like toluene, xylene, or dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, dioxane and the like, preferably methylene dichloride.
5. A process as claimed claim 1 or 2, wherein alcohol is selected from methanol, ethanol, isopropanol, n-propanol, preferably methanol.
6. A process as claimed in claim 1 or 2, wherein conversion of 2,3,4,3',4'-penta-O-acetyl sucrose to 2,3,6,3',4'-penta-0-acetyl sucrose is carried out in organic solvent in presence of mild acid or base.
7. A process as claimed in claim 6, wherein organic solvent is selected from methylisobutyl ketone, toluene, xylene and like.
8. A process as claimed in claim 6, wherein mild acid is acetic acid.
9. A process as claimed in claim 6, wherein mild base is tert-butyl amine.

10. A process as claimed in claim 6, wherein the reaction mixture is concentrated after the conversion.
11. A process as claimed in 1 or 2, wherein chlorination is carried out by sulfury chloride in presence of pyridine in organic solvent selected from methylenedichloride, ethylenedichloride, 1,1-dichloroethane, chloroform, carbontetrachloride, toluene, xylene and like
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12. A process for the preparation of 4,1,>6'-trichloro-2,3,6,3',4'-penta-0-acetyl sucrose and Sucralose such as herein described and illustrated by the examples.
Dated this 16th day of September 2005

Ashwini Sandu
Of S. Majumdar & Co. Applicant's Agent
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ABSTRACT
Title: PROCESS FOR PREPARING SWEETENING AGENT
The present invention relates to the one pot process for the preparation of 4,1',6'-trichloro-2,3,6,3',4'-penta-0-acetyl sucrose by detritylating 6,1,6'-tri-0-tritylsucrose penta-acetate with sulphonyl chloride selected from para-toluene sulphonyl chloride, methane sulphonyl chloride or ammonium chloride, under hydrogen pressure in presence of noble metal catalyst and solvent and subsequently acetyl migration and chlorination. It also relates to the process for the preparation of Sucralose
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