This invention relates to a process for producing chlorinated sucrose, mainly l',6'- Dichloro-rjό'-Dideoxy-β-D-Fructo-FuranosyW-Chloro^-Deoxy Galactopyranoside by using an agitated thin film dryer during the intermediate step of solvent stripping and deacetylation. And there after obtaining a pure dried form of high purity molecule.

BACKGROUND OF THE INVENTION:

Chloro derivatives derived from sugars, exhibit the organoleptic properties with a very high degree of sweetness compared to the parent sugar. One such chloro sugar prepared from sucrose is 1', β'-Dichloro-l', 6'-Dideoxy-β-D-Fructo-Furanosyl-4-Chloro-4-Deoxy- α-D-Galactopyranoside. It is a well-known sweetener used widely, including in food and food preparations. Various synthetic routes for the production of 1', 6'-Dichloro-F, 6'- Dideoxy-β-D-Fructo-Furanosyl^-Chloro^-Deoxy-α-Galactopyran oside are reported in literature, for e.g. Fair Clough et a!, carbohydrate research 40(1975) 285-298 Mufti et.,al., US PatentNo. 4,380,476 and British PatentNo. 1543167.

Following major challenges are faced during the preparation:

1. Introduction of chlorine atoms in positions 4, 1 ' and 6' of sucrose molecule.

2. Isolation of the pure 1', 6'-Dichloro-l', 6'-Dideoxy-β-D-Fructo-Furanosyl-4- Chloro-4-Deoxy-α-D-Galactopyranoside from quenched reaction mixture.

3. Isolation of solids from reaction mixture.

4. Extraction of the product from solids and crystallization of the product.

5. Isolation of pure product from the solid extracts.

Sucrose -6 acetate is chlorinated using Vilsmeyer Haack reaction. The bottleneck was the isolation of pure 1', 6'-Dichloro-l', 6'-Dideoxy-β-D-Fructo-Furanosyl-4-Chloro-4- Deoxy-α-D-Galactopyranoside from the quenched chlorinated mass. Procedures for this also have been reported in patent literature. The major concern here was the complete removal of the solvent from the reaction mixture before deacetylation of the V, 6'- Dichloro-r,6'-Dideoxy-β-D-Fructo-Furanosyl-4-chloro-4-Deoxy -6-acetoxy-α-D- Galactopyranoside that is the main intermediate in almost all the reported process. The solvents used in this process may be dimethyl sulphoxide, dimethyl formamide, pyridine, hexane, or cyclohexane.

The desired product is produced from Sucrose 6 Acetate. During the process, a major problem is removal of solvents and isolation of the solids from the reaction mixture at low temperature without causing appreciable degradation. Earlier the solvents removal was done by steam distillation. The suggested steam distillation operation, in the prior art, is highly energy consuming and the volume of the mass increases to 4 - 5 times of the original, volume. Isolation of the product from this reaction mass is again a time consuming and tedious process.

BRIEF SUMMARY OF THE INVENTION:

The chlorination of sucrose-6-acetate was carried out by using Vilsmeier- Haack reagent, which was generated by adding phosphorus oxy chloride or phosphorous penta chloride to a highly polar solvent like dimethyl formamide. The reaction mass was quenched by sodium hydroxide solution in ice and the deacetylation of 1 ', 6'-Dichloro-P, 6'-Dideoxy- β-D-Fructo-Furanosyl-4-Chloro-4-Deoxy-6-acetoxy-α-D-Galact opyranoside-6-acetate was carried out by adjusting the pH of the quenched mass with agitation.

The quenched mass was fed into the agitated thin film dryer of appropriate cross section area having a flanged scrapper type rotor. The description of the agitated thin film dryer is discussed in details in this document. The solids obtained from the dryer contain essentially the product as well as the inorganic salts such as chlorides and phosphates. Three different approaches are attempted to isolate the pure product from the solids obtained from the dryer. a) Extracting the solids with an appropriate solvent e.g. an alcohol and purification of the crude mass by column chromatography followed by crystallization using ATFD or spray dryer.

b) Direct column chromatography of the solids over a packed column using for example silica or alumina.

c) Dissolving the solids in water and then extracting the aqueous solution with Organic solvents which are not miscible with water like dichloromethane, ethyl acetate or toluene. Stripping of the solvent to get a mass which is finally crystallized to afford pure V, 6'-Dichloro-l',6' Dideoxy-β-D-Fructo-Furanosyl-4-Chloro-4-Deoxy-α-D-alactopy ranoside.

Removal of solvent from the quenched mass of the reaction mixture by ATFD is being reported for the first time in this type obtaining a dry or semidry powder on removal of the solvent is being reported of for the first time reaction. The design of the agitated thin film dryer is such that the whole operation is done at a lower temperature & pressure. This in turn affords better quality product and yield compared to the earlier methods as mentioned in the experimental section of this document.

Given herein below are the short forms used in the specification along with the expansions: POCL3 stands for Phosphorous oxy-chloride ATFD stands for Agitated Thin Film Dryer MEK stands for Methyl Ethyl Ketone TLC stands for Thin Layer Chromatography HPLC stands for High Pressure Liquid Chromatography

In the accompanying drawings: Fig. 1 illustrates the reaction scheme for the preparation of V, 6'-Dichloro-l', 6'- Dideoxy -β-D-Fructo-Furanosyl-4-Chloro-4-Deoxy-α-D-Galactopyranosi de; Fig.2 illustrates the agitated thin film dryer used in the process of the present invention, Fig. 3 is the flow sheet of the agitated thin film dryer; Fig. 4 is the flow chart of the process of the present invention, Fig. 5 is the IR Report of the product of the present invention; and Fig. 6 is the HPLC Chromatogram of the product of the present invention.

DETAILED DESCRIPTION OF THE INVENTION:

The process is an useful improvement in the manufacture of 1', 6'-Dichloro-l', 6'~ Dideoxy-β-D-Fructo-Furanosyl-4-Chloro-4-Deoxy-α-D-Galactop yranoside. The reaction scheme involved in the manufacture of product from sucrose-6- acetate is given in fig. 1 of the accompanying drawings.

The sucrose-6-acetate is chlorinated to give r,6'-Dichloro-l',6'-Dideoxy-β-D-Fructo- Furanosyl-4-Chloro-4-Deoxy-α-D-Galactopyranoside.

The Vilsemeyer reagent is prepared from Phosphorus Oxy Chloride (POCI3) or phosphorus penta chloride (PCI5). The sucrose-6-acetate is added to Vilsmeyer Reagent at 5°-10°C. After completion of the reaction, the reaction mass is heated to 80° to 1000C and preferably between 90°-95°C and maintained for 1A -lhr and then the temperature is raised to 110° to 135°C and preferably to 120°-125°C and maintained for 3-5 hours. There after the reaction mass is cooled to room temperature and quenched into an inorganic basic solution like alkali hydroxide or carbonate solution, for example Sodium hydroxide solution, containing ice or chilled using brine or other cooling agent solution in the jacket of the reactor. The temperature during the quenching operation is maximum 3O0C - 35°C. The pH is adjusted to 7.5 to 14 and preferably 10-13 by 15-20% of alkali hydroxide solution in water. At this pH the mass is stirred to complete the deacetylation.

The quenched mass comprises of inorganic salts, chlorinated sucrose-6-acetate, solvent and water. This is fed into ATFD for the removal of solvent and water. Schematic Diagram of ATFD is shown in Fig. 2 of the drawings. Tbe detailed process of ATFD is illustrated as follows.

Feed of the quenched mass was cooled to 5 to 1O0C degree in the feed tank by circulating a brine solution. A pump was used to lift the feed from feed tank to the dryer. The ATFD is a vertical dryer with area of cross section 0.25 to 0.35m2. The feed enters tangentially and spreads along the inside surface of the shell in to a thin film. The rotor blades are hinged, the hinged rotor blades keep the film under intense agitation preventing any scale formation. The speed of the rotor was 1000 to 1500rpm.The film progressively passes through different phases like liquid, slurry, paste, wet powder and finely powder of desired dryness, it is collected in a powder receiver.

The vapor flows countercurrent to the solids and was removed from the top of the dryer. Distillate was collected from the condenser and solids are obtained from the dryer. The distillate contains solvent and water. The distillate was subjected to fractional distillation, about 70-80% of solvent was recovered based on the input of solvent.

EXPERIMENTAL DETAILS: CHLOREVATION OF SUCROSE-6- ACET ATE:

lOOgrm of sucrose 6-acetate is mixed with 200 ml of fresh solvent such as hexane, cyclohexane, pyridine, dimethyl formamide, and others, and particularly dimethyl formamide and Chlorination undertaken in a 3 liter 3 neck round bottom flask. 500 ml of the solvent is charged. Thereafter, the solvent is cooled with stirring to 0 to -50C, to this reaction mass 166 ml of phosphorous oxy chloride (273.9gm) is added below O0C. To this lOOgπn of sucrose 6-acetate in solvent is added below 1O0C. Thereafter, the reaction mass is stirred at 20-250C for Vi-lhr.The temperature is raised to 70-1000C and preferably 80- 9O0C and maintained for 1 to 2 hours. Afterwards the temperature is raised to 110 to 13O0C and preferably 120- 1220C and maintained for 3 to 5 hrs. The reaction mass is cooled to 40°-45°C, the reaction mass is added to a solution containing 220grm sodium hydroxide solution, 220grm water and lOOOgrm ice. The pH is adjusted to 7.5 to 14 and preferably 10-13 and stirred for 3-5 hour at room temperature. The mass is filtered. The residue was washed with 20 ml of the solvent and then the washings are combined with the main filtrate. The resultant mass is fed into ATFD for solvent removal.

ATFD REMOVAL OF SOLVENT:

The quenched mass approximate volume of 2-2.3 lit and pH is adjusted to 10-13 and fed to ATFD with the following parameters. Area OfATFD= 0.20 - 0.50 m2 Feedrate = 7-lOkg/hr Pressure = 2 - lOmmHg. Jacket temp = 70- 1000C

Feed of 3 to 5Kg was cooled down to 5-1O0C in the feed tank by circulating the brine solution. pH of the feed was maintained at 7.5 to 14 and preferably between 10-13; the pump was fitted to lift the feed from feed tank to the dryer. The dryer is a vertical dryer with area of cross section 0.25-0.35 Sq.m. The feed enters tangentially and spreads along the inside surface" of the shell in to a thin film. The rotor blades are hinged, the hinged rotor blades keep the film under intense agitation preventing any scale formation. The speed of the rotor was 1000-1500rpm. Temperature was maintained around 70- 1000C in the jacket by circulating hot water taking inlet from bottom, outlet through the top. The film progressively passes through different phases like liquid, slurry, paste, wet powder and finely powder of desired dryness. This is collected in a powder receiver.

The vapor flows countercurrent to the solids and was removed from the top of the dryer; these vapors are condensed in the condenser. Distillate was collected from the condenser, solids are obtained from the dryer. The distillate contains solvent and water. The distillate was subjected to fractional distillation, about 70-80% of solvent was recovered based on the input of solvent. PRODUCT ISOLATION:

The mass obtained from the ATFD is subjected to solvent extraction. The solvent used may be any organic solvent, including but not limited to, ethyl acetate, methanol, methyl ethyl ketone, and acetone. The preferred solvent may be ethyl acetate. The solvent extracted mass is distilled in the rotary evaporator at low temperature. The syrup obtained is mixed with an appropriate column chromatography adsorbent like silica or Alumina and run through column chromatography. The adsorbing agent could be any known column packing preferably Alumina or silica. The-preferable solvents for desorbption are ethyl acetate, mixture of toluene and methanol, mixture of methanol and ethyl acetate, mixture of methanol and dichloromethane. The eluted fractions are collected in different receivers based on TLC showings. The fractions showing single spot on the TLC are collected separately. The solvent from this fraction was evaporated to provide a thick syrup. The thick syrup is subjected to purification. Crude product obtained showed by TLC to have a high concentration of the desired product. This was subjected to crystallization.

PURIFICATION OF THE PRODUCT:

The syrup obtained from the isolation stage is mixed with 2-5 volumes of a polar solvent, example methanol, and the mass is mixed with charcoal at 50 to 6O0C. The resulting mixture is filtered through a hyflo adsorbent and the hyflo bed is washed with 1 volume of the same solvent. Then, the filtered mass is distilled at low temperature to remove 90% solvent and to this 3-5 volumes of mass of ethyl acetate is added and mixed well. The mass is distilled at low temperature to remove 2-4 volumes of ethyl acetate resulting in a liquid product concentrate. The desired dry product was obtained from the liquid concentrate by three methods, a. Conventional crystallization, as reported as in the earlier patents cited in this document. b. Feeding liquid product concentrate to ATFD to obtain the dry desired pure product. This is being reported for the first time. c. Spray drying the liquid product concentrate to obtain dry desired pure product. This is being reported for the first time.

In the conventional crystallization method the liquid concentrate was crystallized to obtain solid product. The product was filtered and dried under vaccum at 40 to 500C. The solids isolated after feeding the concentrate in the ATFD were also found to be identical with the product obtained from the conventional crystallization method. Also the solid obtained after spray drying the liquid concentrate are found to be identical with the desired pure product obtained from the crystallization and ATFD method. The analysis of the solids from all the three methods showed the product purity or content is over 99% (HPLC Fig. 6 and IR Fig. 5 attached). In a separate experiment, the charcolised reaction mass after passing through the hyflo bed but before concentration is taken for further recovery of the product. The product can be isolated directly by feeding the purified charcoalised methanol solution into the ATFD. This also resulted in a desired pure product of high purity.

The solid product could be also isolated by an alternative method. This method comprises of feeding the charcoalised methanol solution obtained after column chromatography directly into the spray dryer to afford the solid product.