WO2007096726A2

WO2007096726A2 - Process for the preparation of a glucose derivative

Info

Publication number: WO2007096726A2
Application number: PCT/IB2007/000332
Authority: WO
Inventors: Milind Moreshwar Gharpure; Baburao Manikrao Bhawal; Umesh Rewaji Zope; Sanjay Shankar Deshmukh; Swapnil Panditrao Sonawane; Satish Ramnalal Mehta
Original assignee: Emcure Pharmaceuticals Limited
Priority date: 2006-02-20
Filing date: 2007-02-13
Publication date: 2007-08-30
Also published as: WO2007096726A3

Abstract

The present invention relates to an improved, safe, commercially viable, cost effective and eco friendly process for the preparation of 4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose (Sucralose). The invention is directed towards the convenient synthesis of 2,3,4,3',4'-penta-O-acetyl sucrose (4-PAS) from 6,1',6'-tri-O-trityl-penta-O-acetyl sucrose ('TRISPA').

Description

PROCESS FOR THE PREPARATION OF A GLUCOSE DERIVATIVE

FIELD OF THE INVENTION

This invention relates to an improved, safe, commercially viable, cost effective and eco friendly process for the preparation of 4,r,6'-trichloro-4,r,6'-trideoxygalactosucrose (Sucralose). The invention is directed towards the convenient synthesis of 2,3,4,3 ',4'- penta-O-acetyl sucrose (4-PAS) from 6,l',6'-tri-O-trityl-penta-O-acetyl sucrose CTRISPA").

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 and 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/~e wood/food additives . htm 1) .

4,r,6'-Tπchloro-4,r,6'-trideoxygalactosucrose i.e. "Sucralose" (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.co.in/search?hl=^:en&lr=&oi^:=defmore&defl=en&q=define:sucralose 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.

The preparation of sucralose involves the substitution of chlorine atoms in 4, 1' and 6' positions of the sucrose moiety. This means that any synthetic route must involve the preparation of an intermediate sucrose derivative with the blocked sites other than the sites required for chlorination (US 4,801,700).

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

4,1',6' Trichloro,4,1',6'trideoxy

Galacto sucrose Penta acetate 4,1',6'-trichloro-4,1',6,-deoxygalactosucrose

(TC-PAS) Sucralose

(ID _(l)

Scheme (I): Method as disclosed in US 4,362,869.

According to US 4,362,869, TC-PAS as disclosed in Scheme (I), Sucralose 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 Sucralose was further recrystallised from water. There was a loss in yield as recrystallization is carried out by making use of water. The low yields and stringent reaction conditions makes the process industrially unfavouorable and costly. US 4,362,869 disclosed that the detritylation process can be obtained with high yields of 2,3,4,3 ',4'-penta-O-acetyl sucrose ("4-PAS") (upto 95%) by treating 6,l ',6'-tri-O-trityl- sucrose-penta-acetate ("TRISPA") with hydrochloric acid in an inert solvent such as dichloromethane and acetic acid. However, this process has several disadvantages. The excess of the acid in the reaction mixture lead to degradation of 4-PAS and the formation of by products, and this problem becomes more troublesome when the process is scaled up. The excess of acid needed to be neutralized using high quantity of resins. Further, the highly reactive trityl chloride gets trapped in the reaction mixture, which was not suitable to combine the detritylation step with other stages of the process for the preparation of sucralose. The product purity also may not be upto the pharmaceutically acceptable limits. Therefore it was necessary to isolate and purify the intermediate, which increased the cost and the time of the reaction.

US 4,783,526 discloses the tritylation process by making use of dimethyl formamide and N-methyl morpholine as base. Use of sodium hydrogen carbonate is required as per the process. This process has the following disadvantages: (a) N-methyl morpholine is a flammable liquid. It causes-severe skin burns and eye burns, (b) Use of sodium hydrogen carbonate on manufacturing scale for such high volume products requires even higher volumes of sodium hydrogen carbonate, which increases cost, additional unit operation and increased batch time and more man power, utilities apart from the frothing problems.

US 4,362,869 discloses the tritylation reaction by making use of pyridine as a solvent. Further, as per this process, the pyridine required is more i.e. 6 times of sucrose. Pyridine is flammable, skin and eye irritant, causes burns and is toxic to health. Hence, there is a need to develop a process, which does not make use of pyridine in such high volumes. The use of pyridine needs to be curtled to its minimum quantities such as in catalytic amount.

US 4,801,700 disclosed the detritylation process by making use of toluene and bubbling of hydrogen chloride gas on TRISPA. This patent also disclosed the alternative detritylation of TRISPA in dichloromethane and methanolic HCl. Detritylation is also disclosed by making use of methylene chloride and formic acid. Detritylation is also carried out using methylene chloride and aluminium trichloride. However, this process had following disadvantages.

a) Formic acid is corrosive and causes severe burns. b) It is a severe eye irritant and lacrimetric. c) The base used for neutralization of formic acid is solid sodium carbonate, which causes trouble during the work up at plant level. It generates higher quantities of sludge, which creates load on effluent treatment plant. Thus, it is not eco friendly. d) The workup is carried out in the aqueous phase, which might result in the formation of small quantities of the deacylated product, thus decreasing the yield. e) The product obtained is also not upto the pharmaceutically acceptable purity limits, due to the impurities formed during the process. f) The hydrogen chloride gas used along with toluene creates stringent reaction conditions. g) Aluminium trichloride used is moisture sensitive and handling of the same is hazardous. h) During workup of the reaction, the undesirable compound aluminium hydroxide is formed, which is generated as a semi solid, is difficult to remove.

Hence, there is a need to develop the process using the safe solvent devoid of the above mentioned disadvantages.

Sucralose crystallizes out from water as needle shaped crystals, which had been described in US 4,343,934, US 5,136,031, US 4,980,463, US 4,977,254, US 5,530,106, US 5,498,709 and US 4,950,746. The crystallization of Sucralose has also been disclosed in US 5,141,860, US 4,783,526, US 4,380,476 US 5,298,611 US 4,362,869 and US 4,801,700. Typically, if any such needles are broken produces undesirable dust. Such crystalline sucralose has poor handling characteristics, poor flow, which makes it difficult to incorporate into formulations with other ingredients.

US 6,943,248 discloses a method to produce a crystalline form of sucralose 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 sucralose 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 Sucralose needed to be used in the composition should be thermally stable, without dispensing the undesirable color. However, such stable Sucralose 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 sucralose 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 Sucralose.

a) The yield of detritylation reaction is low. b) The purification of the final detritylatyed product is required, which results in increased labor, time cycle, cost of utilities, reactor occupancy and decrease in yield, while increasing the solvent cost and time cycle. c) The solvents used in the prior art are corrosive, lacrymetric and cause severe burns. d) The neutralization using bases like solid sodium bicarbonate is industrially unfeasible. e) The aqueous work up of the detritylation reaction, which might result in the deacylation product thus decreasing the yield. f) The product obtained may not be of pharmaceutically acceptable purity. g) Amount of resin required for the neutralization of acid in the detritylation step is more, h) The process for the preparation of particle size of crystalline sucralose is costly, tedious and time consuming. i) The process for detritylation makes use of higher quantities of pyridine or in some processes sodium hydrogen carbonate is also used during work up. In view of the above shortcomings, it was necessary to develop an alternate synthetic route for the detritylation step, which would give Sucralose i.e. compound of formula (I), by a process, which is industrially feasible and viable.

SUMMARY OF THE INVENTION

The present inventors have developed a synthetic route for the preparation of Sucralose

(I), in good yields.

The present inventors have also developed a process for the preparation of Sucralose, which is eco friendly. The present inventors have developed a process for the preparation of sucralose which makes use of catalytic amount of resins for neutralization in the detritylation step.

The present inventors have developed a process for the preparation of Sucralose by making use of simpler acid neutralization reagents.

The present inventors have also developed a better work up condition for the detritylation step by avoiding the use of aqueous phase thus preventing the deacylation product, which might result in decrease in the yields.

The present inventors have developed a process of tritylation by making use of pyridine, not as solvent and avoiding use of sodium hydrogen carbonate.

The present inventors have developed an approach to obtain the final product in pharmaceutically acceptable purity.

The present inventors have also developed a method for production of sucralose of desired particle size, which is easy, requires less equipments and manpower. The process is also cost effective and economically feasible.

OBJECT OF THE INVENTION First object of the present invention is to provide an improved process for the preparation of Sucralose of formula (I) by a synthetic route, which is simple, industrially feasible, economical and safe.

Second object of the invention is to provide Sucralose in pharmaceutically acceptable yields. Third object of the invention is to provide Sucralose by making use of cost effective acid neutralizing reagents. Fourth object of the invention is to provide Sucralose in pharmaceutically acceptable purity.

Fifth object of the invention is to provide particles of crystalline sucralose by a process which is simple, economical, cost effective and requires less man power.

DETAILED DESCRIPTION OF THE INVENTION:

Sucralose (I) is prepared as per Scheme (II) disclosed below:

(Vl)

6,1', δ'-Tri-O-trityl sucrose pentaacetate

(TRISPA)

(Vl) (III)

sucrose

6,1',6'-Trι-O-tπtyl sucrose pentaacetate 2,3,4,3',4'-Penta-O-acetyl sucrose (IV)

(TRISPA) (III)

6,1',6'-Trι-O-trιtyl sucrose pentaacetate (TRISPA) (III) 2,3,4, 3',4'-Penta-O-acetyl sucrose (|V)

6,1',6'-Tπ-O-trιtyl sucrose pentaacetate 2,3,4,3',4'-Penta-O-acetyl sucrose (TRISPA) (III) (IV) Pd/c

2,3,4,3',4'-Penta-O-acetyl sucrose 2, 3,4, 3',4'-Penta-O-acetyl sucrose

(TRISPA) (III) (4-PAS) (IV)

2, ,3,4,3',4'-Penta-O-acetyl sucrose

2,3,6,3',4'-Penta-O-acetyl sucrose

(4-PAS) (IV) (6-PAS) (VII)

2,3,6,3',4'-Penta-O-acetyl sucrose

2,3, 6,3',4'-Penta-O-acetyl-4,1',6'-trichloi

(6-PAS) (VII) 4,1' .β'-trideoxy-galacto-sucrose

(TC-PAS) (H)

2,3,6,3',4'-Penta-O-acetyl-4,1',6'-trichloro 4, 1 ',6'-

trichloro-4, 1 ',6,-deoxygalactosucrose 4, 1 '.θ'-trideoxy-galacto-sucrose i.e. Sucralose (I)

(TC-PAS) (II)

2,3,6,3',4'-Penta-O-acetyl-4, 1 ',6'-trichloro ⁴' ¹ ',6'-trichloro-4, 1 ',6,-deoxygalactosucrose

4,1',6'-trideoxy-galacto-sucrose i.e. Sucralose (I) (TC-PAS)

sodium hydroxide

Acetic acid

(Reaction 6b)

2,3,6,3',4'-Penta-0-acetyl-4,1',6'-trichloro 4, 1 '.θ'-trideoxy-galacto-sucrose 4, 1 ',6'-trichloro-4, 1 ',6,-deoxygalactosucrose

(TC-PAS) (II) Le; Sucralose (I)

Sodium methoxide Methanol, Acetic Acid

MIBK and ethyl acetate

, ^• (Reaction 6c)

2,3,6,3',4'-Penta-O-acetyl-4,1',6'-trichloro 4, 1 ',6'-trichloro-4,1 ',6,-deoxygalactosucrose 4,1 ',6'-trideoxy-galacto-sucrose i.e. Sucralose (I)

(TC-PAS) (II)

SCHEME (II) The present embodiment describes the preparation of Sucralose as per the reaction sequence disclosed in Scheme (II).

As per the reaction 1 of Scheme (II), the conversion of Sucrose (V) to 6,1 ',6' tri-O-trityl Sucrose (VI) is carried out in the presence of solvent and a base. The solvent used for the tritylation reaction is selected from the group comprising of nitriles, amides, esters, ethers, hydrocarbons etc. The preferable solvent is amide. The more preferable solvent is dimethyl formamide. The amount of solvent used is in the range of 0.5 kg to 5 kg per kg of Sucrose. The amount of solvent used is preferably in the range of 1 kg to 3 kg per kg of Sucrose.

The base used for the tritylation reaction is selected from the group comprising of organic or inorganic bases. The organic base selected is such as pyridine.

The base used is in the range of 1: 1 to 1:6 mole ratio. The preferable range being 1:3 to 1 :5.

Trityl chloride used is in the range of 1:1 to 1:6 mole ratio. The preferable range being 1 :3 to 1 :5.

The reaction is carried at a temperature ranging from 30 to 70⁰C. The preferable range being 40 to 6O⁰C.

The time for the completion of the reaction is around 4 to 10 hours.

The sequence of addition of the reactants, solvents or reagents can be in any suitable way.

The trityl product obtained from this step can be isolated as solid or it can be taken further to the next step, without isolation per se.

As per the reaction 2 of Scheme (II), the conversion of 6,1 ',6' tri-O-trityl Sucrose (VI) to 6,l ',6'-tri-o-trityl sucrose penta acetate (TRISPA) (III) is carried out by making use an acylating agent and a base, optionally in a solvent, other than acetic anhydride.

The solvent used for the acylation reaction is inert solvent selected from the group comprising of nitriles, amides, esters, ethers, hydrocarbon including halogenated hydrocarbons etc. The solvent used can be in the range of 2 to 5 times of TRISPA volume

/wt.

The work up of the said reaction can be carried out as the standard procedure such as quenching the reaction mixture in alcoholic solvent or water to obtain the solid. The work up alcoholic solvent such as methanol used is in the range of 5 -20 kg per kg of the trityl sucrose.

The acylating agent used is selected from the group comprising of acetic acid, acetyl chloride, acetic anhydride etc. The preferable acylating agent is acetic anhydride. The amount of acetic anhydride used is in the range of 2-10 mole ratio. The preferred range being 5-8 mole ratio.

The base used is selected from the group comprising of inorganic or organic bases. The inorganic base used is selected from the group comprising of hydroxides, carbonates or acetates of alkali or alkaline earth metals. The preferred base used is the acetates of alkali or alkaline earth metals. The most preferred base used is potassium acetate. The amount of potassium acetate used is in the range of 0.5 to 3 mole ratio. The preferred range being 1 to 2 moles.

The time for the completion of the reaction is around 0.5 to 5 hours.

The reaction is carried at a temperature ranging from 100 to 150⁰C. The preferable range being 110 to 13O⁰C.

As per the reaction 3 of Scheme (II), the acid (reagent) used for the detritylation reaction can be selected from the group comprising of inorganic and organic acids. The inorganic acid is selected from the group comprising of HCl, H₂SO_4, HBr, Phosphoric acid etc. The preferable acid is HCl. The organic acid is selected from the group comprising of acetic acid, glacial acetic acid, para toluyl sulphonic acid, benzene sulphonic acid, trifluoro acetic acid, trifluoro methane sulphonic acid (triflic acid) etc. The preferred acid is trifluloro methane sulphonic acid and para-toluene-sulphonic-acid.

The paratoluene sulphonic acid is used in the range of 0.1 to 2.0 equivalents. The preferred range used is 0.2 to 1.0 equivalents.

The neutralizing agent, which is a proton acceptor, used for the detritylation reaction can be selected from the group comprising of organic or inorganic base. The organic base can be such as triethyl amine. The inorganic base can be such as ammonia, either in aqueous form or in the gaseous form. The neutralization can also be carried out in the presence of resins. Triflic acid is required in lesser quantities for the detritylation reaction. Hence, the amount of resin required for the neutralization is also less, thus making the process cost effective by recovering and reusing the resin.

The solvent used for the detritylation reaction is selected from the group comprising of nitriles, amides, esters, ethers, hydrocarbons, chlorinated solvents, water, alcohol etc or mixtures thereof. The niriles are selected from the group comprising of acetonitrile, propionitriles, etc. The nitrile solvent for the detritylation is acetonitrile. The chlorinated solvents are selected from, the group comprising of dichloromethane, dichloroethane, chloroform etc. The most preferred solvent is dichloroethane.

TRISPA (III) is detritylated using HCl/acetonitrile or para-toluene-sulphonic- acid/acetonitrile to give 4-PAS (IV). TRISPA (III) is also detritylated using trifluoro methane sulphonic acid (triflic acid) / in ethylene dichloride. Using the process known in prior art 2,3,4,3 ',4'-penta-O-acetyl sucrose (IV) can be converted into 2,3,6,3 ',4'-penta-O- acetyl-4,l ',6'-trichloro 4,l ',6'-trideoxy-galacto-sucrose (II).

The current invention makes use of acetonitrile/HCl or acetonitrile/para-toluene- sulphonic-acid and toluene as a solvent for the detritylation step. This helps significantly in making use of safe solvents.

According to reaction (3a) of Scheme (II), the HCl for the detritylation process is used in the range of 1 :3 to 1 :8 mole ratio. The preferred range being 1 :4 to 1 :7 mole ratio.

The acetonitrile used is in the range of 5 to 30 kg per kg of TRISPA. The preferable range being 10 to 20 kg per kg of TRISPA.

Further, the reaction time required is 0.5 to 10 hours. The preferable range being 1 to 5 hours.

The reaction is carried at a temperature of 0-5⁰C.

The sequence of addition of the reactants, solvents or reagents can be in any suitable way. The current invention also makes use of triflic acid / ethylene dichloride for the detritylation step, which reduces the solvent risk.

As per the reaction (3c), the triflic acid used is in the range of 0.01 to 0.5 wt/wt equivalent of TRJSPA. The preferred range being 0.05 to 0.3 equivalents. The triflic acid addition can be carried drop wise by maintaining the temperature in the range of 10 to 50⁰C.

The ethylene dichloride is used in the range of 2 kg to 50 kg per kg of TRISPA. The preferred range being 7 kg to 20 kg per kg of TRISPA.

The amount of resin used in the reaction is in the range of 0.10 to 0.60 kg per kg of

TRISPA. The preferred range is 0.20 to 0.50 kg.

The reaction is carried in a temperature range of 10 to 50⁰C.

The reaction is completed preferably in the range of 1 to 10 hours. The reaction is carried out at an ambient temperature.

The current invention also makes use of paratoluene sulphonic acid / acetonitrile for the detritylation step

As per reaction (3 c) of Scheme (II), the paratoluene sulphonic acid can be used in the range of 2 to 15 gm per 100 gm of TRISPA. The preferable range being 5 to 10 gm.

The acetonitrile used is in the range of 0.5 liters to 8 liters per 100 gm of TRISPA. The reaction can be carried out at a temperature range of -10 to 10⁰C.

The neutralization can be carried out by making use of organic or inorganic base, preferably aqueous ammonia or tri ethyl amine.

The reaction is completed in about 0.5 to 7 hours.

The sequence of addition of the reactants, solvents or reagents can be in any suitable way. As per reaction 3(d) of Scheme (II), the detritylatlon reaction can also be carried out in the presence of methanol / HCl and chlorinated solvents.

The chlorinated solvent used is dichloromethane or dichloroethane. The preferable solvent being dichloroethane.

The ethylene dichloride can be added in the range of 2 to 20 kg per kg of TRISPA.

The % of HCl in methanol can be used in the percentage range of 5% to 40%.

The methanolic HCl can be used in the range of 0.1 to 5 equivalent wt/wt of TRISPA.

Preferably methanolic HCl used is 0.5 to 3 equivalents.

The reaction is carried out at a temperature of 5 to 20⁰C. The preferred range being 8 to 15⁰C.

The reaction is carried out in 1 to 10 hours.

As per reaction (3e) of Scheme (II), TRISPA can also be detriylated by making use of catalytic agent in suitable solvent.

The solvents used can be selected from the group comprising acids, nitriles, amides, esters, ethers, hydrocarbons, chlorinated solvents, alcohol etc or mixtures thereof. The chlorinated solvents are selected from the group comprising of dichloromethane, dichloroethane, chloroform etc. The most preferred chlorinated solvent is chloroform. The alcoholic solvents can be selected from the group comprising of methanol, ethanol, propranol n-butanol etc. The most preferred alcoholic solvent is methanol. The preferred acid being acetic acid.

The reaction can be catalyzed by making use tetra-halogenated compounds like carbon tetrabromide etc.

The acetic acid used is in the range of 10 to 50 % vol / wt of TRISPA. The preferred range is 15 to 30 %. The chloroform used is in the range of 2 to 15 vol / wt of TRISPA. The preferred range being 3 to 10 volumes.

Methanol used is in the range of 2 to 20 vol / wt of TRISPA. The preferred range being 5 to 15 volumes.

Carbon tetrabromide used is in the range from 0.01 to upto 1.0 gm per gm of TRISPA. The most preferred range being 0.05 to 0.20 gm per gm of TRISPA.

During the work up, the aromatic solvents like toluene can also be added to the reaction mixture in the range of 2 to 15 volumes. The preferred range being 3 to 10 volumes.

The reaction time required is in the range of 0.5 to 5 hours.

The reaction is carried out at a temperature of 20 to 100⁰C. Preferably the reaction is carried out at a temperature from 40-70°C.

The reaction can also be performed devoid of acetic acid.

As per the reaction (3f) of Scheme (II), the detritylation can also be carried out by making use of hydrogenation. The hydrogenation of TRISPA can be carried out in the presence of catalyst selected from the group comprising of palladium or platinum.

The reaction can be carried out in the presence of aralkyl chloride. The solvent used for hydrogenation is selected from the group comprising of esters, ethers, hydrocarbons, chlorinated solvents, alcohol etc or mixtures thereof. The alcoholic solvents can be selected from the group comprising of ethanol, methanol, propranol. The chlorinated solvents are selected from the group comprising of dichloromethane, dichloroethane, chloroform etc. The more preferred solvent is dichloroethane.

The dichloroethane used is in the ratio of 2 volumes to 30 volumes. The preferable range being 5 volumes to 15 volumes. The catalyst used is in the ratio of 0.01 % to 5% weight by weight. The preferred range being 0.5 % to 3% weight by weight.

The neutralization is carried with the help of triethyl amine. The amount of triethyl amine used is 10 ml to 80 ml per kg of TC-PAS. The preferred range being 20 ml to 70 ml per kg ofTC-PAS.

The aralkyl chloride used is in the range of 0.2 to 5 equivalents mole / mole w.r.t. TC- PAS. The preferred range being 0.5 to 3 equivalents.

The reaction is completed within a period of 0.5 to 10 hours. The more preferable range is 1.5 to 5 hours.

The detritylated product obtained from this step can be isolated as solid or it can be taken further to the next step, without isolation per se.

The byproducts formed like trityl carbinol can be easily removed and it does not remain trapped in the 4-PAS. The HCl is easily neutralized by making use of aqueous ammonia. The triflic acid used can be easily neutralized by making use of resins. The amount of resin required for neutralization of triflic acid is less as it is used in small quantity. Hence, the process does not make use of high amounts of resin or reagents like sodium carbonate, which is difficult to remove at plant level.

The 4-PAS formed after the detritylation step is obtained in pharmaceutically acceptable yield and better purity, as the product formed after the reaction does not require purification step.

According to reaction 4 of Scheme (II), the isomerization of 2,3,4,3 ',4' penta-O-acetyl sucrose (IV) to 2,3,6,3',4'-penta-O-acetyl-sucrose (VII) is carried in the presence of acetic acid and methyl isobutyl ketone (MIBK). MIBK used is in the ratio of 1 : 1 w/v to 1 : 15 w/v w.r.t. 4-PAS. The preferable ratio is 1 : 3 w/v to 1 : 8 w/v. The acetic acid used in the reaction is in the ratio of 0.1 w/v to 2 w/v w.r.t. 4-PAS. The preferable ratio being 0.3 w/v to 0.7 w/v. During workup of the said reaction, hydrocarbon solvent can be used. The said hydrocarbon solvent can be selected from the group comprising of aliphatic or aromatic hydrocarbon. The preferable aliphatic hydrocarbon is pet ether. The preferable aromatic hydrocarbon is toluene.

The reaction is carried at a temperature ranging from 100 to 130⁰C. The time taken for the completion of the reaction is in the range of 1 to 10 hours.

The isomerization of 2,3,4,3',4' penta-O-acetyl sucrose (IV) to 2,3,6,3',4'-penta-O-acetyl- sucrose (VII) is carried in the presence of toluene and acetic acid. Toluene is used in the ratio of 1 : 2 to 1: 10 liters v/w w.r.t. 4-PAS. The preferable ratio being 1 : 3 to 1 : 8 liters.

The acetic acid used is in the ratio of 0.001 to 0.5 liters per gm of 4-PAS. The preferred ratio is 0.05 to 0.30 liters per gm of 4-PAS. The reaction is carried at a temperature ranging from 80 to 150⁰C. The time taken fort he completion of the reaction is in the range of 1 to 10 hours.

As per reaction-5 of Scheme (II), the chlorination of 6-PAS (VII) to TC-PAS (II) is carried out in the presence of tri phenyl phosphine oxide and thionyl chloride.

The triphenyl phosphine oxide used is in the range of 0.25 to 1.2 kg per kg of TC-PAS. The preferable range being 0.1 to 0.9 kg.

The thionyl chloride used is in the range of 0.25 to 1 kg per kg of TC-PAS. The preferable range being 0.1 to 0.8 kg. Thionyl chloride is added at a temperature ranging from -10 to 10⁰C. The reaction is carried out in the range of 70 ⁰C to reflux temperature.

The reaction is carried out in the presence of organic solvents selected from the group comprising of amides, nitriles, ketones, esters or hydrocarbon solvents. The preferable solvent used is toluene. Toluene is used in the range of 1 kg to 10 kg per kg of 6-PAS. The time taken for the reaction is in the range of 2 to 10 hours.

The sequence of addition of the reactants, solvents or reagents can be in any suitable way. The base for the deacylation step can be selected from the group comprising of hydroxides or carbonates, alkoxides of alkali or alkaline earth metals, but preferably the hydroxide of an alkali metal.

The deacylation is carried out in the presence of alkali metal hydroxide such as sodium hydroxide and the neutralization is carried out with the help of acid such as acetic acid.

According to the reaction 6 (a) of Scheme (II), the deacylation step is carried out in the presence of sodium methoxide and methanol.

The sodium methoxide added is in the ratio of 0.001 to 0.015 kg per kg of TC-PAS. The preferred range being 0.005 to 0.010 kg per kg of TC-PAS.

The pH is adjusted in the range of 7 to 11. The preferable range being 8-10.

The resin used is in the ratio of 0.05 to 0.50 kg per kg of the TC-PAS.

Methanol is used in the range of 2 kg to 15 kg per kg of TC-PAS.

The solvent used for workup is in the range of 2 kg to 15 kg per kg of TC-PAS.

The time taken for the reaction is in the range of 2 to 10 hours.

The reaction is carried at a temperature range of 10 to 60⁰C.

According to the reaction 6 (b) of Scheme (II), the deacylation is carried out in the presence of base and acid neutralizing agent.

The amount of the alkali hydroxide employed is in the mole ratio 0.05 to 2.0 moles of the alkali hydroxide per mole of the compound (II), but preferably between 0.1 to 1.5 moles of the alkali hydroxide per mole of the compound (II).

The alkali metal hydroxide is preferably sodium hydroxide or potassium hydroxide.

The pH is adjusted in the range of 7 to 11. The preferable range being 8-10. The neutralizing agent used is acetic acid. The acetic acid used is in the range of 0.2 to 5 gm per 100 gm of TC-PAS. The preferred range being 0.75 gm to 2.0 gm per 100 gm of TC-PAS.

The reaction is carried at a temperature of 10 to 60°C.

The reaction is completed in the time interval range of 5 minutes to two hours.

The sequence of addition of the reactants, solvents or reagents can be in any suitable way

The resin used for the deacylation step is selected from the group comprising of acidic resins. The acidic resins are selected from the group comprising of Amberlyst resins, Amberlite resins, Staybelite resins, Tulsion resins etc. The use of resin can be substituted by using acetic acid in the deacylation step. Carbon dioxide, either gaseous or solid form can also be used as a substitute for the resins.

The deacylation reaction is carried in the presence of suitable solvent. The solvents can be used from the group comprising of organic solvents.

The organic solvents can be selected from the group comprising of acids, nitriles, amides, esters, ketones, ethers, hydrocarbons, chlorinated solvents, water, alcohol etc or mixtures thereof. The niriles are selected from the group comprising of acetonitrile, propionitriles, etc. The chlorinated solvents are selected from the group comprising of dichloromethane, dichloroethane, chloroform etc. The alcoholic solvents can be selected from the group comprising of ethanol, methanol, propranol. The acids can be selected from the group comprising of acetic acid, methane sulphonic acid, formic acid etc. The esters can be selected from the group comprising of ethyl acetate, methyl acetate etc. The ketones are selected from the group comprising of methyl isobutyl ketone, acetone etc.

In one of the aspects of the embodiment, the compound (II) i.e. TC-PAS is then deacylated in the presence of sodium methoxide and methanol. The neutralization is further carried out with the help of resin. The product is crystallized from cold acetonitrile. According to reaction (6c) of Scheme (II), the deacylation of TC-PAS is carried out in the presence of sodium methoxide and methanol. The reaction is neutralized with the help of acetic acid and the product is further purified by making use of solvents like MIBK and ethyl acetate.

The sodium methoxide added is in the ratio of 0.05 eq to 0.5 eq.

The acetic acid used is in the range of 0.5 to 5 gm per 100 gm of TC-PAS.

The pH is adjusted in the range of 5 to 11. The preferable range being 6-10.

Methanol is used in the range of 2 kg to 15 kg per kg of TC-PAS.

The solvent used for workup is in the range of 2 kg to 30 kg per kg of TC-PAS.

The time taken for the reaction is in the range of 30 mins to 5 hours.

The reaction is carried at a temperature range of 10 to 60°C.

The reaction of detritylation, when carried out in various combination of solvents with para toluene sulphonic acid. Trityl acetyl sucrose was treated with para toluene sulphonic acid separately in the presence of a) toluene, b) ethyl acetate, c) dichloromethane, d) methanol. In all the solvents the reaction was continued for an hour and it was observed that the reaction did not proceed to give the desired product. The reaction was monitored with the help of TLC, which showed the presence of the starting material and the absence of the desired product. However, when the reaction was carried out in the presence of para toluene sulphonic acid and acetonitrile, the reaction proceeded quickly, thus proving the superiority of solvent selection with para toluene sulphonic Acid over the above mentioned solvents.

Further, the detritylation was also carried in the presence of aqueous hydrochloride and toluene. The reaction was monitored with the help of TLC, which showed the presence of starting material and absence of the desired product. Hence, there remains a need to develop a system to carry out the detritylation reaction which would give the desired (4- PAS) in good yields.

The detritylation reaction when carried out in the presence of aqueous hydrochloric acid and solvents such as dichloromethane, toluene, methanol failed to give complete detritylation even after extended reaction time (10-20 hours). In all the cases the TLC of the reaction mixture indicated presence of a mixture of 4 to 5 products consisting of small amount of desired 4-PAS along with large amount of starting material (around 40% to 50%).

The improved method of preparation of Sucralose according to the instant invention reduces the load on utilities, reactor occupancy, manpower, time cycle etc. A further result to this is the increased "cost efficiency" of said detritylated product and hence Sucralose (active pharmaceutical ingredient).

The purification of Sucralose is carried out using a solvent or a combination of solvents.

The sucralose obtained is washed with the same solvent. Further it is dissolved in the same and the solution is allowed to cool to give sucralose crystals. Thus, the Sucralose obtained after the neutralization of the deacetylation reaction, can be purified by extracting sucralose using the solvent such as ethyl acetate. In order to avoid the losses during the extraction, the repetitive extractions can be given and finally the combined organic layer can be concentrated, followed by crystallization in solvent such as ethyl acetate. This leads to purified sucralose, as well as it provides the desired particle size.

In one aspect of the invention, the crude Sucralose formed after deacylation step is dried completely and swapped with methyl isobutyl ketone. After dissolving the crude product in aqueous phase, the same is extracted in ethyl acetate and is concentrated. Again dissolved in ethyl acetate and cooled to give sucralose crystals.

The recrystallization solvent can be selected from the group comprising of esters, ketones, nitriles etc. The preferable recrystallisation solvents used are nitrites and esters. The solvents used more preferably are acetonitrile, propionitrile, ethyl acetate and methyl acetate. The present invention relates, for example, a multistep extractive process for removing impurities from crude sucralose.

The less polar impurities are transferred during the first extraction into the first solvent, selected from the group comprising of solvents in which sucralose is only partially soluble, where as less polar impurities are soluble. The first solvent is methyl isobutyl ketone (MIBK) wherein, less polar impurities are transferred in MIBK.

Carrying out second extraction of partly purified sucralose with water, wherein more than 50% sucralose and polar impurities are transferred in water.

Further, carrying out the third extraction, with a third solvent which is less polar than water and having high solubility of sucralose. The solvent used is ethyl acetate wherein the sucralose is extracted in ethyl acetate and retaining the polar impurities in water.

Isolating sucralose from third solvent.

Impurities consist of less polar impurities or more polar impurities either forward in the deacylation step or carried forward from earlier steps, either sucralose derivatives or the byproducts formed in one of the steps towards preparation of sucralose.

The crystals obtained by this process have a particle size between 10 microns to 400 microns. The preferred particle size is 20 microns to 200 microns. The most preferred particle size is between 70 microns to 90 microns. '

In the preferred embodiment the particle size is dso : 40 ± 5

In the preferred embodiment the particle size is d₉₀ : 88 ± 5

Thus, the current embodiment makes use of a process, which is advantageous in following ways: a) Use of (a) HCl / acetonitrile or (b) para-toluene-sulphonic-acid / acetonitrile : toluene or (c) trifluoromethane sulphonic acid / ethylenedichloride for detritylation step, thus obtaining the pharmaceutically acceptable yields and pharmaceutically acceptable purity. b) Adopting the safe reaction conditions, while avoiding the highly hazardous reaction conditions like hydrogenation for detritylation. c) Avoiding use of easily poisonable and costly catalyst like platinium and palladium for detritylation. d) Cost effective and industrially feasible process. e) Reduction in the time cycle of the process. f) Avoiding the use of aqueous phase in the workup of the detritylation reaction thus increasing the yields of the product. g) Use of easy reagents for acid neutralization. h) Preparation of particles of sucralose crystals in a simple, cost effective and industrially feasible process. i) Sucralose crystallization is not required after the deacylation. j) Avoiding the use of micronizing techniques like jet milling, heat exchanger and recirculating pump. k) Preparation of Sucralose composition by retaining its sweet properties and color.

1) Cost effective and industrially feasible process, m) Pharmaceutically acceptable yields, n) Pharmaceutically acceptable purity, o) Reduction in the time cycle of the process. p) No loss of yield as aqueous phase is not used in the workup of the detritylation step.

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: Preparation of 6,1',6' tri-O-trityl Sucrose (VI) from Sucrose (V):

In clean and dry 4 neck round bottom flask, dimethyl formamide (1.94 kg) and Sucrose (1.0 kg) were charged with stirring, under nitrogen atmosphere. Pyridine (0.97 kg) was charged in the reaction mixture. The reaction mixture was heated to 50-55⁰C. Trityl chloride (2.85 kg) was added in four equal lots in 2.5 hrs at 50-55⁰C. The reaction mixture was stirred and maintained the temperature 50-55°C for 3-4 hrs. After the completion of the reaction the mixture was cooled to 25-30⁰C. Demineralised water (16.0 kg) was charged in a separate flask and was cooled to 0-5⁰C. The cooled reaction mixture was added to the cold demineralised water at 0-5⁰C. The reaction mixture was stirred and maintained for one hour. The product was filtered and washed with demineralised water (3x 2 kg).

Example 2: Preparation of 6,l',6'-tri-o-trityl sucrose penta acetate (TRISPA) (III) from 6,1',6' tri-O-trityl Sucrose (VI)

Tri-O-Trityl Sucrose (1.0 kg) was charged in toluene (13.05 kg). The mixture was heated to 60⁰C for 60 min. The layers were separated. The toluene was distilled out at 50 -55⁰C. Potassium acetate (0.300 kg.) was added under nitrogen atmosphere. To the said mixture, acetic anhydride (2.08 kg.) was added under nitrogen atmosphere. The reaction mixture was heated to 115-12O⁰C. The reaction temperature was maintained until the completion of the reaction. After the completion of the reaction, the mass was cooled to 25-3O⁰C. In another round bottom flask methanol (15.6 liters) was added and cooled to 0-5⁰C. To this cooled methanol, the reaction mixture was added. The reaction mass was stirred at 0-5⁰C for 1 hour. The product was filtered i.e. Trityl Acetyl Sucrose. Dry the product in oven at 4O⁰C to 45°C to give the product of 2.90 kg.

Example 3: Preparation of 6,l',6'-tri-o-trityl sucrose penta acetate (TRISPA) (III) from Sucrose (V)

DMF (1.94 Kg) was charged with sucrose (1.0 kg) at 25-30⁰C. Pyridine (0.97 kg) was charged to the mixture at 25-30⁰C under stirring. The reaction mixture was heated to 50- 55°C. Trityl chloride (2.85 kg) was added in four equal lots in 2.5 h at 50-55⁰C. The reaction mixture was maintained under stirring at 50-55⁰C for 3-4h. After completion, the reaction mixture was cooled to 25-30⁰C. Ethylene dichloride (7.0 L) was added and washed with water. The ethylene dichloride layers were combined and dried over sodium chloride (0.5 kg). Ethylene dichloride (5 lit) was distilled under vacuum at 50-55⁰C. Potassium acetate was added under nitrogen atmosphere at 25-30⁰C. Acetic anhydride (2.08 kg.) was added to the reaction mixture under nitrogen at 25-30⁰C. The reaction mixture was refluxed to 90-95⁰C for 1-2 hours. Ethylene dichloride (10 liters) was added. The mixture was washed with water (4 x 2.5 L). Ethylene dichloride was dried over sodium sulphate.

Example 4: Preparation of 2, 3,4, 3',4'-penta-O-acetyl sucrose (4-PAS) (IV) from TRISPA (III)

Concentrated (35.0%) hydrochloric acid (27 ml) was added to a mixture of tri-O-tirtyl- penta-O-acetyl sucrose (20Og) in acetonitrile (2000 ml), at 5°C. The reaction mixture was stirred for 1.5 to 2.0 hours at 5°C. The reaction mixture was neutralized by aqueous ammonia and stirred. Acetonitrile was distilled under vacuum at 40-45⁰C. To the reaction mass methanol (220 ml) was added and mixture was stirred for 1.5 hours at 0 to 5°C. The solid trityl carbinol was filtered. To the filtrate, activated carbon (10 g) was added and stirred for 30 min. Carbon was filtered and methanol layer was concentrated completely. To concentrated mass ethyl acetate (432 ml) was added and extraction was carried out with water. To the aqueous layer, sodium chloride (35 gm) was added and the said layer was extracted with ethyl acetate. The combined organic layer was concentrated to afford viscous 2, 3,4,3', 4'-penta-O-acetyl sucrose. Yield: 76 gm i.e. 88%.

Example 5: Preparation of 2, 3,4,3',4'-penta-O-acetyl sucrose (4-PAS) (IV) from TRISPA (III)

Water (8.4 ml) was added to a mixture of tri-O-tirtyl-penta-O-acetyl sucrose (10Og) in acetonitrile (1 lit), with stirring. Para toluene sulphonic acid (7.4 g) was charged under stirring. The reaction was stirred at room temperature till a clear solution was obtained. The reaction mixture was cooled to O⁰C. Triethyl amine was added till the reaction mixture was neutralized. The acetonitrile from the reaction mixture was concentrated. Methanol (220 ml) was added to the reaction mixture and the reaction mixture was stirred. The solid was obtained which was filtered. To the solid, was added ethyl acetate (240 ml). Small quantities of ethyl acetate was evaporated to remove traces of methanol. To the remaining ethyl acetate layer, water (10ml x 2) was added. The aqueous layer was separated and was washed with ethyl acetate (20ml x 2). The combined organic layer was concentrated to yield 37 gm of 2, 3,4,3',4'-penta-O-acetyl sucrose (4-PAS). Yield: 37 gm i.e. 86%. Example 6: Preparation of 2, 3,4,3',4'-penta-O-acetyl sucrose (4-PAS) (IV) from TRISPA (III)

Water (16.8 ml) was added to a mixture of tri-0-tirtyl-penta-O-acetyl sucrose (20Og) in acetonitrile (2 lit), with stirring. Para toluene sulphonic acid (14.8 g) was charged under stirring till a clear solution was obtained in 1.5 hr. The reaction mixture was cooled to O⁰C. The reaction mixture was neutralized using aqueous ammonia. The acetonitrile from the reaction mixture was concentrated. To the mixture methanol (440 ml) was added and the reaction mixture was stirred at 0 to 5⁰C for an hour. The reaction mixture was filtered. The obtained solid was washed with chilled methanol (200 ml). The filtrate obtained was concentrated. To the reaction mass ethyl acetate (480 ml) was added. The ethyl acetate was distilled. The reaction mixture was washed with water (40 ml). To the aqueous layer sodium chloride was added. The aqueous layer was filtered and was extracted with ethyl acetate (100 ml x 3). The combined organic layer was concentrated to yield 74.26 gm of 2, 3,4,3',4'-penta-O-acetyl sucrose (4-PAS). Yield: 74.26 gm i.e. 86%.

Example 7: Preparation of 2, 3,4,3',4'-penta-O-acetyl sucrose (4-PAS) (IV) from TRISPA (III) Dichloroethane (10 kg) was added to tri-O-tirtyl-penta-O-acetyl sucrose (1 kg) with stirring. To the mixture, methanol (0.20 kg ) was added at ambient temperature. Triflic acid solution (0.014 kg in 0.125 kg ethylene dichloride) was slowly charged by maintaining the ambient temperature. The reaction mixture was stirred for 3-4 hours and monitored by TLC. After the completion of the reaction, the pH was adjusted to 6.0 to 6.5 at 0⁰C to 2°C, with the help of Tulsion W.B. resin (0.35 kg). The reaction mixture was filtered and washed with ethylene dichloride (0.125 kg). The reaction mixture was dried over sodium chloride. Dichloroethane was distilled out under vacuum. To the mass methanol (1.7 kg) was added. Methanol was distilled out completely under vacuum. Methanol was added again and the reaction mixture was stirred at 0-5⁰C for an hour. The solid was filtered and washed with methanol to yield 0.2 (w/w) of TRISPA. Example 8: Preparation of 2, 3,4,3',4'-penta-O-acetyl sucrose (4-PAS) (IV) from TRISPA (III)

Dichloroethane (8.0 kg) is charged in round bottom flask. Trityl acetyl Sucrose was added under stirring (1.0 kg.). The reaction was cooled to 10^°C ± 2 ⁰C. 20% HCl in methanol solution (0.142 kg.) was added slowly by maintaining temperature 1O⁰C ± 2 °C over a period of 40-45min. The temperature was maintained at 10⁰C ± 2 ⁰C for 2-3h. After completion of reaction the pH was adjusted 6.0-6.5 at 0⁰C ± 2 ⁰C with Triethyl amine (~0.075 kg). The dichloroethane was completely distilled out under vacuum (650- 700mm Hg) at 40⁰C to45°C. Toluene (1.74 kg.) was charged at 25-3O⁰C. D. M. water (0.8 kg.) was charged at 25-30⁰C. The reaction was stirred for 30 min. at 50 -55 ⁰C. The lower aqueous layer was separated. The toluene layer was extracted with D. M. water (2 X 0.4 kg) at 50-55⁰C. All aqueous extracts (product layer) were combined and sodium chloride (1.0 kg) was added. The aqueous layer was extracted with ethyl acetate (1 X 0.9 kg, 3 X 0.675 kg). All ethyl acetate extracts were combined and charcolised with activated charcoal (0.03 kg) at 25-30⁰C for 30 min. The mixture was filtered and the bed was washed with ethyl acetate (0.675 kg). Ethyl acetate was distilled completely under vacuum (650-700mm Hg) at 40⁰C to 45°C.

Example 9: Preparation of 2, 3,4,3',4'-penta-O-acetyl sucrose (4-PAS) (IV) from TRISPA (III) :

In an autoclave, ethylene dichloride (2000 ml) was charged. TRISPA (200) gm was added to the solvent. 10% Palladium on carbon (2 gm) was added to the mixture. Benzyl chloride (19.74 gm) was added with stirring. The autoclave was closed and flushed with nitrogen. 10 kg hydrogen pressure was applied and the stirring was started. The reaction is completed within 2-3 hours. The mixture was cooled and filtered to remove the catalyst. The reaction mixture was neutralized with triethyl amine. The ethylene dichloride was removed under vacuum at 40-45⁰C. Toluene (500 ml) was added and this layer was extracted with water (100 x 2). The aqueous layer contained emulsion so filtered through hyflo bed and hyflo bed was washed with 100 ml water. The organic layer was extracted with water (50 ml). All the aqueous layers were collected and saturated with sodium chloride. The aqueous layers were extracted with ethyl acetate (100 x 5). Ethyl acetate was concentrated. Toluene (100 ml x 2) was added and stripped out. The reaction mixture was degassed for one hour at 50 ⁰C to give 4-PAS.

Example 10: Preparation of 2, 3, 6, 3', 4'-penta-O-acetyl sucrose (6-PAS) (VII) from TRISPA (III):

10% Pd/C (10.Og) was charged at 27 ± 2⁰C to a 1OL hydrogenator. TAS (1.0Kg) was dissolved in ethylene dichloride (8.0 liters). This solution was charged to hydrogenator under nitrogen at 27 ± 2⁰C. Benzyl chloride (98.90 g) was charged at 27 ± 2⁰C. The hydrogenator was flushed with nitrogen. The reaction was stirred at 10Kg pressure at 27 ± 2⁰C till completion of reaction. After completion of reaction hydrogen gas was solely released and the mixture was flushed with nitrogen. The reaction mixture was filtered. The bed was washed with methanol. The reaction mixture was cooled to 0-5⁰C. The pH was adjusted to 6-6.5 with triethyl amine (~ 40ml) at 0-5°C. Ethylene dichloride was distilled (7.5L) under vacuum (500-600mmHg) at 40-45⁰C. Methanol (4.0 liters) was charged. Methanol was distilled under vacuum (500-600mmHg) at 40-45⁰C. The reaction mixture was cooled to 0-5⁰C. The mixture was stirred for 1.0 h and filtered. The reaction mixture was washed with methanol (250ml). Methanol was distilled. MIBK (3.0L) was charged in the reaction mixture. MIBK (1.0L) was distilled under vacuum (500-600mmHg) at 70- 75⁰C. Acetic acid (0.21Kg) was charged at ambient temperature and the reaction mixture was refluxed at 100-110⁰C for three hours. MIBK (2.1L) was distilled under vacuum (650- 700mmHg) at 40-45⁰C. MIBK (l .OL) was again charged to the reaction mixture and MIBK was distilled (900 ml) under vacuum 650-700mmHg) at 40⁰C to45°C. Toluene was charged (3.0L) at ambient temperature. Toluene (l.OL) was distilled off under vacuum (650-700mmHg) at 4O⁰C to 45⁰C. The reaction mixture was gradually cooled to 22±2°C, and stirred for 4.0 hours. The solid was filtered and washed with toluene. The solid was dried under vacuum (650-700mmHg) at 40⁰C to 45°C for 8-10 hours to yield (6-PAS). Yield: 0.26 w/w

Example 11: The isomerization of 2,3,4,3',4' penta-O-acetyl sucrose (4-PAS) (IV) to 2,3,6,3',4'-penta-0-acetyI-sucrose (6-PAS) (VII)

0.16 gm MIBK was added to the slurry of concentrate mass of 2,3,4,3',4' penta-O-acetyl sucrose obtained from Example 4. MIBK was distilled completely under vacuum at 40 ⁰C and charge MIBK 1.71 Kg. Acetic acid 0.208 kg. was added at 50⁰C. The reaction mixture was refluxed for 3.0 hrs. at 110°C. The reaction mixture was cooled to 6O⁰C to 70⁰C. Pet ether (2.0 L). was added slowly by maintaining the temperature 6O⁰C to 70⁰C The mixture was seeded with the 6- PAS. The mixture was cooled to 25°C to 30⁰C. The reaction mixture was stirred for 2 hrs. at 25°to 3O⁰C. The solid was filtered and washed with pet ether. The product was dried in air at 25°C to 30°Cto get 6-PAS Yield = 0.200 Kg.

Example 12: The isomerization of 2,3,4,3',4' penta-O-acetyl sucrose (4-PAS) (IV) to 2,3,6, 3',4'-penta-0-acetyI-sucrose (6-PAS) (VII) 4-PAS (1 gm) was charged along with methyl isobutyl ketone in a round bottom flask. Acetic acid was added and the reaction mixture was heated to reflux. After the completion of the reaction, the reaction was cooled to room temperature. Pet ether (10 ml) was added and the solid was filtered and washed with pet ether.

Example 13: The isomerization of 2,3,4,3',4' penta-O-acetyl sucrose (4-PAS) (IV) to 2,3,6,3',4'-penta-O-acetyl-sucrose (6-PAS) (VII)

4-PAS (4 gm) was added toluene (200 ml) with stirring. 4 ml acetic acid was added to the reaction mixture. The reaction mixture was refluxed for 6 hours. The reaction mixture was cooled at room temperature gradually and was stirred overnight at room temperature. The mixture was filtered and washed with 80 ml toluene to yield (6-PAS).

Example 14: The chlorination of 2,3,6,3 ',4 '-Penta-O-acetyl sucrose (6-PAS) (VII) to 2,3,6,3',4'-Penta-0-acetyl-4,l',6'-trichIoro 4,l',6'-trideoxy-galacto-sucrose (TC-PAS) (II). 6-PAS (1 Kg) was charged to (2.61 kg) of toluene under inert atmosphere (under nitrogen) at 25⁰C to 3O⁰C under stirring. (0.5 ) kg of triphenylphosphine oxides at 25°C to 3O⁰C was added under stirring. The reaction was cooled to -5 to 0⁰C. Thionyl chloride 0.554 kg. was added under inert atmosphere at-5 to 0⁰C. in 2 to 3 hrs. The temperature was raised to 25⁰C to 30⁰C under stirring. The reaction mixture was heated to reflux (100⁰C) for 3 to 4 hours. The reaction mixture was cooled to 4O⁰C. Dimeneralised water (4.0 kg) was added. The reaction mixture was cooled to O⁰C to 5⁰C. The mixture was stirred for 2.0 hours at 0⁰C to 5⁰C. The solid obtained was filtered at 0⁰C to 5°C. The solid was dried In another clean RBF was charged 4.0 kg. D.M. Water. The solid obtained was added. The suspension was neutralized by using solid sodium carbonate at 25 to 30⁰C. The solid obtained was filtered and washed with 1.0 kg. demineralised water. The solid was suck dried well and the product was dried in vacuum oven at 45 to 50⁰C Yield = 0.80 kg.

Example 15: Preparation of sucralose (I) from (TC-PAS) (II)

Methanol 7.91 kg was charged to compound (II) (1 kg). Sodium methoxide (0.0086 kg) was charged at 25-3O⁰C over 30min. The reaction mixture was stirred. The reaction mixture was then neutralized using Tulsion (xo-9H resin (0.117 kg) and stirred. The resin was filtered. Activated carbon was added to the mixture and stirred. The filtrate obtained by filtering was filtered through celite bed. The celite was washed with methanol. The clear reaction mixture was filtered through filter paper. Methanol was distilled out. Acetonitrile (2.4Kg) was charged and distilled out completely. Acetonitrile (4Kg) was charged again and the reaction mixture was stirred. The reaction mixture was filtered and washed with cold acetonitrile. The product was dried under vacuum. The particle size details of the product obtained were as follows: dso : 40.47 microns d9o : 88.16 microns d₉₅ : 110.18 microns

Example 16: Preparation of sucralose (I) from (TC-PAS) (II)

To a solution of methanol (8 Kg) and water (2 Kg) was charged compound (II) (1 Kg). The reaction mixture was stirred. To the above solution was charged an aqueous solution of NaOH. (NaOH = 0.0131 Kg + 0.1 Kg water). The reaction mixture was stirred for 15 minutes. The pH of the reaction mixture was 8-9. The reaction was further stirred for 20- 25 mins. The neutralization was carried out with the help of acetic acid (0.0116 Kg). The reaction mixture was charcolised, filtered and washed with methanol. The filtrate was concentrated. Water (2.0 Kg ) was added and the reaction mixture was concentrated till 1.6 lit. To the aqueous layer was added dichloromethane (0.5 lit). The organic layer was separated. To the aqueous layer was added ethyl acetate (2.7 Kg) and stirred for 15-20 mins. The ethyl acetate layer was separated. The aqueous layer was again extracted with ethyl acetate (2.7 Kg) and stirred for 15-20 mins. The aqueous layer was once again extracted with ethyl acetate (1.35 Kg) and stirred for 15-20 minutes. The ethyl acetate layers were combined and filtered. The ethyl acetate layer was distilled off under vacuum. The reaction mixture was swipped with ethyl acetate (1.8 Kg x 2). To the reaction mixture ethyl acetate (1.8 Kg) was added and stirred at 18-20⁰C for 2 hours. The solid was filtered and washed with ethyl acetate. The solid was dried under vacuum for 8-10 hours. The particle size obtained herewith is acceptable according to the invention.

Eample 17: Preparation of sucralose (I) from (TC-PAS) (II)

To a mixture of methanol (1000 ml) and water (100 ml) was added compound (II) (100 gm). The reaction mixture was stirred. To the mixture aqueous sodium hydroxide solution was added. (1.32 gm NaOH + 10 ml water). The reaction was further stirred for fifteen minutes. After completion of the reaction, the mixture was neutralized with Tulsion (CXO-9H resin) (52 gm). The reaction mixture was filtered through filter paper. The mixture was charcolized with activated charcoal and concentrated to 160 ml. To the reaction mixture was added water (200 ml) and the mixture was concentrated under vacuum. To the concentrated mass, sodium chloride (44 gm) and ethyl acetate (600 ml) was added and the reaction mixture was stirred for 20 minutes. The aqueous layers were separated. The aqueous layer was again extracted with 300 ml ethyl acetate. All the ethyl acetate layers were combined and concentrated till dryness. The solid was swapped with (2 X 200 ml) ethyl acetate. Finally 200 ml of ethyl acetate was added and stirred for 1-2 hrs. The solid obtained was filtered and washed with ethyl acetate. The solid was dried under vacuum to yield 56 gm of Sucralose. Yield (85%).

Example 18: Preparation of sucralose (I) from TC-PAS (II)

To (TC-PAS (II) ) (5 gm), was added a mixture of water (10 ml) and methanol (50 ml). The reaction mixture was stirred. Sodium hydroxide (0.20gm) was added and stirred till the reaction mixture became clear. The reaction was monitored by TLC. The excess of the base was neutralized by the Tulsion resin. The reaction mixture was filtered, charcolised. Water was added to reaction mixture and washed with ethyl acetate. The aqueous layer was separated and further concentrated to 20 ml. Example 19: Preparation of sucralose (I) from (TC-PAS) (II)

To (TC-PAS (II) ) (50 gm), was added a mixture of water (50 ml) and methanol (500 ml). The reaction mixture was stirred. Sodium hydroxide (0.66gm in 5 ml water) was added and stirred till the reaction mixture became clear. The reaction was monitored by TLC. The neutralization was carried out by acetic acid. The reaction mixture was charcolised and stirred. The reaction mixture was filtered. The filtrate was concentrated to 80 ml. To the filtrate water (100 ml) was added and the reaction mixture was concentrated to 80 ml. The reaction mixture was washed with dichloromethane (25 ml). The aqueous layer was separated and to the aqueous layer sodium chloride (22 g) was added. The aqueous layer was extracted with ethyl acetate (1 x 300ml and 1 x 150 ml). The ethyl acetate layer was combined and was extracted with 200 ml water. The ethyl layer was concentrated. To the aqueous layer was added ethyl acetate cyclohexane mixture (40 ml ethyl acetate and 10 ml cyclohexane). The aqueous layer was separated and submitted for analysis.

Example 20 : Preparation of Sucralose (I) from TC-PAS (II)

In clean and dry four neck round bottom flask equipped with overhead stirrer thermometer pocket, thermometer, was charged 125 gm TC-PAS to a solution of 1250 ml methanol and 125 ml D.M. water. To above solution was charged NaOH solution (1.64gm NaOH + 125 ml water). The Reaction mass becomes clear. The reaction mixture was neutralized by acetic acid after TLC confirmation. The mixture was charcolized and filtered through filter paper and washed with 125 ml methanol. The mixture was concentrated to 200 ml. 200 ml DM water was added and concentrated to 200 ml under vacuum. To reaction mixture was added 55 gm NaCl. The aqueous layer was extracted with Ix 750 ml and 1 x 325 ml of ethyl acetate. The ethyl acetate extracts were combined and filter through filter paper and concentrated at 40-45⁰C. The mixture was swapped with 2 X 250 ml ethyl acetate. Finally 250 ml ethyl acetate was added and stirred for 2.0 hrs at 25°C. The solid was filtered under vaccum and washed with 62.5 ml ethylacetate. The solid was dried under vacuum at 50- 55°C.

Example 21 : Preparation of Sucralose (I) from TC-PAS (II)

To a clean reactor was charged methanol (10 L) at 22 ± 2°C. Water (1.0 L) was charged to the reaction mixture. TC-PAS (II) (1.0 Kg) was charged at 22 ± 2⁰C. Aqueous sodium hydroxide solution (0.0131 kg in 0.1 kg water at 10⁰C) was prepared and added to the reaction mixture over 15-25 min at 22 ± 2°C. The pH of reaction mixture should be 8-9 on pH paper. The reaction mixture was stirred at 22 ± 2°C for 20-25 min. After completion of reaction the pH was adjusted to 6.5-7 with acetic acid ( — 0.0116 Kg) at 22 + 2°C. Activated charcoal (0.1Kg) was charged at 22 + 2°C. The reaction mixture was stirred for 30 min and filtered through nutch filter and washed with Methanol (0.4 Kg). The filtrate was charged in clean reactor. The reaction mixture was distilled under vacuum (650- 700mmHg) at 55-60⁰C till 1.6 liter. Water (2.0 Kg) was charged to the reaction mixture. The reaction mixture was distilled under vacuum (650-700 mm Hg) at 55-60 ⁰C till 1.6 liter. Ethyl acetate (6.0L) was charged at 25-30⁰C and stirred for 15-20 min. The upper ethyl acetate layer was separated and kept in another clean reactor. The aqueous layer was again extracted with ethyl acetate (2 X 3.0L) at 25-30⁰C and stirred for 15-20 minutes. The ethyl acetate layer was combined and filtered through 0.2 μ. The ethyl acetate layer was distilled off under vacuum (650-700mmHg) at 50 to 55°C. The ethyl acetate (2.0 L) was charged and distilled off under vacuum (650-700mm Hg) at 50 to 55⁰C. Again ethyl acetate (2.0 L) was charged and distilled off under vacuum (650-700mm Hg) at 50 to 55⁰C. Again ethyl acetate (2.0L) was charged and stirred at 25-30⁰C for 2h. The ethyl acetate layer was filtered and the solid was washed with ethyl acetate (0.5 L).The product was dried under vacuum (650-700 mmHg) at 45-50⁰C for 8-1 Oh.

Example 22: Preparation of Sucralose (I) from TC-PAS (II)

To a clean reactor methanol (5.0 L) was charged at 10-15⁰C. TC-PAS (II) (1 Kg) was charged at 10-15⁰C. Sodium methoxide solution in methanol (0.006 kg in 0.6 L methanol) was prepared and charged to the reaction mixture over a period of 1 hour at 10-15⁰C. The pH of the reaction mixture was 11. The reaction mixture was stirred at 10-15⁰C for 2-3 h. After completion of the reaction the pH of the reaction mixture was neutralized using acetic acid. The reaction mixture was charcolized and stirred for 30 minutes. The reaction mixture was filtered and washed with methanol (0.2 L). The filtrate was charged to a clean reactor and methanol was distilled under vacuum. Ethyl acetate was charged to the mass and distilled out under vacuum at 40-42⁰C. Ethyl acetate (3.0 L ) was charged to the reaction mixture. Water (2.0 L) was added at 25-30⁰C and stirred for 15-20 minutes. The upper ethyl acetate layer was separated and kept in another clean reactor. The aqueous layer was again extracted with ethyl acetate (4 X 1.5 L) at 25-30⁰C and stirred for 15-20 minutes. The ethyl acetate layer was charcolized with charcoal (0.02 kg) at 25-3O⁰C for 15-20 minutes. The reaction mixture was filtered and washed with ethyl acetate (1.0 L). The ethyl acetate layer was. distilled off. To the mass again ethyl acetate (2 L) was added and distilled off. Again (2 L ) of ethyl acetate was added and distilled off under vacuum. Again (2 L ) of ethyl acetate was added and stirred for 2 hours. The solid was filtered and washed with ethyl acetate (0.5 L). The product was dried under vacuum at 45-5O⁰C for 8- 10 hours.

Example 23: Preparation of Sucralose (I) from TC-PAS (II) Methanol (5L) was charged in a round bottom flask at 22+2⁰C. TC-PAS (1.0 kg) was charged at 22+2⁰C. Sodium methoxide (17.76g) was charged to the reaction mixture with stirring at 22±2°C. The pH was checked and found to be in the range of 8-9. The reaction mixture was further stirred for half an hour. After completion of the reaction, the reaction mixture was neutralized with acetic acid (~0.0116 Kg) at 22+2°C. Activated charcoal (0.1 kg) was charged at 22+2°C. The reaction mixture was stirred for 30 minutes and filtered and further washed with methanol. The filtrate was distilled under vacuum at 55-6O⁰C. MIBK (2.0 liters) was added and 90-95% filtrate was distilled out under vacuum (650- 700mmHg) at 55-60 ⁰C. Again MIBK (2.0 liters) was added and 90-95% of the solvent was distilled out under vacuum (650-700mmHg) at 55-60 ⁰C. Charge MIBK (2.0 liters), stir at 22 + 2⁰C for 1.Oh. The solid was filtered and dried under vacuum. Demineralised water was charged (1.32 lit) at 25-30⁰C and stirred for 15-20 min. Ethyl acetate (5.4 kg) was charged to aqueous layer at 25-30⁰C and stirred for 15-20min. Upper ethyl acetate layer was separated and kept in another clean reactor. Aqueous layer was again extracted with ethyl acetate (2.7Kg) at 25-30°C and stirred for 15-20min. The aqueous layer was again extracted with ethyl acetate (1.35Kg) at 25-30⁰C and stirred for 15-20min. The ethyl acetate layers were combined and filtered thro 0.2μ. The ethyl acetate layer was distilled off under vacuum (650-700 mm Hg) at 50 to 55°C. Ethyl acetate (1.8 kg) was charged and distilled off under vacuum (650-700mmHg) at 50 to 55⁰C. Ethyl acetate (1.8 kg) was charged and distilled off under vacuum (650-700 mm Hg) at 50 to 55°C. Ethyl acetate (1.8 kg) was charged and the mixture was stirred at 18-20⁰C for 2h. The solid was filtered and washed with ethyl acetate (0.45 kg). The solid was dried under vacuum (650-700 mm Hg) at 45-50⁰C for 8-10 h. Example 24: Preparation of 2, 3, 4, 3',4'-ρenta-O-acetyl sucrose (4-PAS) The detritylation reaction was carried out in the presence of para toluene sulphonic acid and dichloromethane. Trityl Acetyl Sucrose (10 gm) was charged in dichloromethane (150 ml) under stirring. Water (0.84 ml) was charged to the reaction mixture with stirring. The reaction was continued over a period of one hour. However, the TLC showed that the reaction did not proceed to give the desired product, even till the detectable limits of TLC and hence, the reaction mixture was discarded.

Example 25: Preparation of 2, 3,4, 3',4'-penta-O-acetyl sucrose (4-PAS) The detritylation reaction was carried out in the presence of para toluene sulphonic acid and ethylacetate. Trityl Acetyl Sucrose (10 gm) was charged in ethyl acetate (150 ml) under stirring. Water (0.84 ml) was charged to the reaction mixture. Para toluene sulphonic acid (0.7 gm) was charged to the reaction mixture with stirring. The reaction was continued over a period of one hour. However, the TLC showed that the reaction did not proceed to give the desired product, even till the detectable limits of TLC and hence, the reaction mixture was discarded.

Example 26: Preparation of 2, 3,4, 3',4'-penta-O-acetyl sucrose (4-PAS)

The detritylation reaction was carried out in the presence of para toluene sulphonic acid and methanol. Trityl Acetyl Sucrose (10 gm) was charged in ethyl acetate (150 ml) under stirring. Water (0.84 ml) was charged to the reaction mixture. Para toluene sulphonic acid

(0.7 gm) was charged to the reaction mixture with stirring. The reaction was continued over a period of one hour. However, the TLC showed that the reaction did not proceed to give the desired product, even till the detectable limits of TLC and hence, the reaction mixture was discarded.

Example 27: Preparation of 2, 3,4, 3',4'-penta-O-acetyl sucrose (4-PAS) The detritylation reaction was carried out in the presence of para toluene sulphonic acid and toluene. Trityl Acetyl Sucrose (10 gm) was charged in ethyl acetate (150 ml) under stirring. Water (0.84 ml) was charged to the reaction mixture. Para toluene sulphonic acid (0.7 gm) was charged to the reaction mixture with stirring. The reaction was continued over a period of one hour. However, the TLC showed that the reaction did not proceed to give the desired product, even till the detectable limits of TLC and hence, the reaction mixture was discarded.

Example 28: Preparation of 2, 3,4, 3',4'-penta-O-acetyl sucrose (4-PAS) The detritylation reaction was carried out in the presence of aqueous hydrochloric acid and toluene. Trityl Acetyl Sucrose (10 gm) was charged in toluene (50 ml) under stirring. Aqueous hydrochloric acid (5 ml) was charged to the reaction mixture with stirring'. The reaction was continued over a period of one hour. However, the TLC showed that the reaction did not proceed to give the desired product, even till the detectable limits of TLC and hence, the reaction mixture was discarded.

Claims

WE CLAIM:

1) A process for the preparation of Sucralose comprising the steps of tritylating Sucrose, acylating tritylated Sucrose, detritylating, isomerizing, chlorinating and deacylating to give Sucralose, the improvement which comprises detritylating TRISPA using the reagents selected from the group comprising of :

(a) aqueous HCl / acetonitrile

(b) paratoluene sulphonic acid / acetonitrile

(c) triflic acid / ethylenedichloride.

2) The process as per claim 1 (a), wherein the neutralization is carried out using aqueous ammonia.

3) The process as per claim 1 (b), wherein the neutralization is carried out using aqueous ammonia or triethyl amine.

4) The process as per claim 1 (c), wherein the neutralization is carried out using resin.

5) The process as per claim l(d), wherein neutralization is carried out using triethyl amine.

6) A process for preparation of Sucralose comprising the steps of :

(a) deacylating TCPAS and obtaining crude Sucralose in aqueous medium;

(b) extracting Sucralose in ethyl acetate to retain impurities in aqueous medium; (c) optionally repeating step (b);

(d) concentrating the combined ethyl acetate layer;

(e) swapping the mixture from step (d) with ethyl acetate at least once;

(f) isolating Sucralose.

7) A process for preparation of Sucralose comprising the steps of :

(a) deacylating TCPAS and obtaining crude Sucralose in aqueous medium;

(b) optionally swapping the concentrated mass of step (a) with MIBK;

(c) extracting Sucralose in ethyl acetate to retain impurities in aqueous medium;

(d) optionally repeating step (b); (e) concentrating the combined ethyl acetate layer;

(f) swapping the mixture from step (d) with ethyl acetate at least once;

(g) isolating Sucralose.

A process for the preparation of Sucralose comprising the steps of:

(a) tritylating sucrose (V) to 6,1 '6' tri-O-trityl Sucrose (VI) in the presence of a solvent and a base;

(b) acylating 6,1 '6' tri-O-trityl Sucrose (VI) to 6,r6'-tri-o-trityl sucrose penta acetate (TRISPA) (III) in the presence of an acylating agent and a base, optionally in a solvent, other than acetic anhydride;

(c) detritylating 6,l '6'-tri-o-trityl sucrose penta acetate (TRISPA) (III) to yield 2,3,4,3',4' penta-O-acetyl sucrose (IV) in the presence of ;

(d) isomerizing 2,3,4,3 ',4' penta-O-acetyl sucrose (IV) to yield 2,3,6,3 '^'-penta-O- acetyl sucrose (VII); (e) chlorinating 2,3,6,3 ',4 '-penta-O-acetyl sucrose (VII) by treating it with tri phenyl phosphine oxide and thionyl chloride to obtain 4,1',6'trichloro 4,l',6'-trideoxy- galacto-sucrose penta acetate (II);

(f) deacylating 4, 1 ',6'trichloro 4, 1 'jό'-trideoxy-galacto-sucrose penta acetate (II) to obtain sucralose

wherein the step of detritylating TRISPA is effected in the presence of reagents selected from the group comprising

(a) aqueous HCl / acetonitrile

(b) paratoluene sulphonic acid / acetonitrile (c) triflic acid / ethylenedichloride.