WO2005090376A1 - An improved process for producing chlorinated sucrose - Google Patents

An improved process for producing chlorinated sucrose Download PDF

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Publication number
WO2005090376A1
WO2005090376A1 PCT/IN2004/000064 IN2004000064W WO2005090376A1 WO 2005090376 A1 WO2005090376 A1 WO 2005090376A1 IN 2004000064 W IN2004000064 W IN 2004000064W WO 2005090376 A1 WO2005090376 A1 WO 2005090376A1
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WIPO (PCT)
Prior art keywords
solvent
dryer
removal
mass
product
Prior art date
Application number
PCT/IN2004/000064
Other languages
French (fr)
Inventor
Ramesh Ratnam
Srikant Kulkarni
Suneet Aurora
Original Assignee
Pharmed Medicare Private Limited
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Publication date
Application filed by Pharmed Medicare Private Limited filed Critical Pharmed Medicare Private Limited
Priority to PCT/IN2004/000064 priority Critical patent/WO2005090376A1/en
Priority to PCT/IN2004/000142 priority patent/WO2005090374A1/en
Priority to AT04770659T priority patent/ATE508136T1/en
Priority to JP2007503498A priority patent/JP2007529505A/en
Priority to DE602004032578T priority patent/DE602004032578D1/en
Priority to KR1020067019138A priority patent/KR20080043194A/en
Priority to AU2004317336A priority patent/AU2004317336A1/en
Priority to CNA2004800424982A priority patent/CN1946731A/en
Priority to US10/593,158 priority patent/US20090324513A1/en
Priority to CA002560284A priority patent/CA2560284A1/en
Priority to MXPA06010665A priority patent/MXPA06010665A/en
Priority to EA200601742A priority patent/EA200601742A1/en
Priority to NZ550064A priority patent/NZ550064A/en
Priority to EP04770659A priority patent/EP1735327B1/en
Publication of WO2005090376A1 publication Critical patent/WO2005090376A1/en
Priority to IL178046A priority patent/IL178046A0/en
Priority to ZA200607891A priority patent/ZA200607891B/en
Priority to LVP-06-113A priority patent/LV13585B/en
Priority to NO20064775A priority patent/NO20064775L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/04—Disaccharides

Definitions

  • This invention relates to a process for producing chlorinated sucrose, mainly l',6'- Dichloro- ,6'-Dideoxy- ⁇ -D-Fructo-Furanosyl-4-Chloro-4-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.
  • 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', 6'-Dichloro-l', 6'-Dideoxy- ⁇ -D-Fructo-Furanosyl-4-Chloro-4-Deoxy- ⁇ -D-Galactopyranoside. It is a well-known sweetener used widely, including in food and food preparations.
  • Sucrose -6 acetate is chlorinated using Nilsmeyer Haack reaction.
  • the bottleneck was the isolation of pure 1', 6'-Dichloro-l', 6'-Dideoxy- ⁇ -D-Fructo-Furanosyl-4-Chloro-4- Deoxy- ⁇ -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- ,6'-Dideoxy- ⁇ -D-Fructo-Furanosyl-4-chloro-4-Deoxy-6-acetoxy- ⁇ -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.
  • a major problem is removal of solvents and isolation of the solids from the reaction mixture at low temperature without causing appreciable degradation.
  • 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.
  • 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- ⁇ -D-Fructo-Furanosyl-4-Chloro-4-Deoxy-6-acetoxy- ⁇ -D-Galactopyranoside-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.
  • POCL 3 stands for Phosphorous oxy-chloride
  • MEK stands for Methyl Ethyl Ketone
  • Fig. 1 illustrates the reaction scheme for the preparation of V, 6'-Dichloro-l', 6'-
  • 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
  • Fig. 6 is the HPLC Chromatogram of the product of the present invention.
  • the process is an useful improvement in the manufacture of 1', 6'-Dichloro-l'- 6'- Dideoxy- ⁇ -D-Fructo-Furanosyl-4-Chloro-4-Deoxy- ⁇ -D-Galactopyranoside.
  • the reaction scheme involved in the manufacture of product from sucrose-6- acetate is given in fig. 1 of the accompanying drawings.
  • sucrose-6-acetate is chlorinated to give l',6'-Dichloro- ,6'-Dideoxy- ⁇ -D-Fructo- Furanosyl-4-Chloro-4-Deoxy- ⁇ -D-Galactopyranoside.
  • the Vilsemeyer reagent is prepared from Phosphorus Oxy Chloride (POCl ) or phosphorus penta chloride (PC1 5 ).
  • POCl Phosphorus Oxy Chloride
  • PC1 5 phosphorus penta chloride
  • the sucrose-6-acetate is added to Vilsmeyer Reagent at 5°-10°C.
  • the reaction mass is heated to 80° to 100°C and preferably between 90°-95°C and maintained for Vz -lhr and then the temperature is raised to 110° to 135°C and preferably to 120°-125°C and maintained for 3-5 hours.
  • 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.
  • 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 30°C - 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. The detailed process of ATFD is illustrated as follows.
  • Feed of the quenched mass was cooled to 5 to 10°C 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 0.35m 2 .
  • 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.
  • EXPERIMENTAL DETAILS CHLORINATION OF SUCROSE-6- ACETATE: 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 -5°C, to this reaction mass 166 ml of phosphorous oxy chloride (273.9gm) is added below 0°C. To this lOOgrm of sucrose 6-acetate in solvent is added below 10°C.
  • 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.
  • reaction mass is stirred at 20-25°C for Vi-lhr.
  • the temperature is raised to 70-100°C and preferably 80- 90°C and maintained for 1 to 2 hours. Afterwards the temperature is raised to 110 to 130°C and preferably 120- 122°C 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.
  • Feed of 3 to 5Kg was cooled down to 5-10°C 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- 100°C 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 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.
  • 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 60°C.
  • the resulting mixture is filtered through a hyflo adsorbent and the hyflo bed is washed with 1 volume of the same solvent.
  • 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.
  • the liquid concentrate was crystallized to obtain solid product.
  • the product was filtered and dried under vaccum at 40 to 50°C.
  • 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.
  • 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).
  • 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.

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Abstract

Disclosed herein is a process for producing chlorinated sucrose, mainly 1',6'-Dichloro-1',6'-Dideoxy-β-D-Fructo-Furanosyl-4-Chloro-4-Deoxy-α-D-Galactopyranoside by chlorination of 6-acetyl sucrose in the presence of a solvent such as dimethyl sulfoxide, dimethyl formamide, pyridine, hexane, cyclohexane, deacetylation, removal of solvents used, extraction, purification and crystallization, the improvement comprising the removal of the solvents using an Agitated Thin Film Dryer or Spray Dryer by maintaining the temperature around 70-100°C in the jacket of ATFD and the pH of the feed at 7.5 to 14 by the addition of Alkali solution and optional crystallization of the product by feeding purified charcolised methanol solution into the said dryers, before or after concentration of the solvent mass after the removal of charcoal.

Description

ANIMPROVEDPROCESSFORPRODUCINGCHLORINATEDSUCROSE
This invention relates to a process for producing chlorinated sucrose, mainly l',6'- Dichloro- ,6'-Dideoxy-β-D-Fructo-Furanosyl-4-Chloro-4-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', 6'-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-4-Chloro-4-Deoxy-α-Galactopyranoside are reported in literature, for e.g. Fair Clough et al, carbohydrate research 40(1975) 285-298 Mufti et.,al., US Patent No.4,380,476 and British Patent No. 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', δ'-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 Nilsmeyer 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- ,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.
BRBEF 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-Galactopyranoside-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-alactopyranoside.
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-Galactopyranoside; 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-Galactopyranoside. 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 l',6'-Dichloro- ,6'-Dideoxy-β-D-Fructo- Furanosyl-4-Chloro-4-Deoxy-α-D-Galactopyranoside.
The Vilsemeyer reagent is prepared from Phosphorus Oxy Chloride (POCl ) or phosphorus penta chloride (PC15). 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 100°C and preferably between 90°-95°C and maintained for Vz -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 30°C - 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. The detailed process of ATFD is illustrated as follows.
Feed of the quenched mass was cooled to 5 to 10°C 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: CHLORINATION OF SUCROSE-6- ACETATE: 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 -5°C, to this reaction mass 166 ml of phosphorous oxy chloride (273.9gm) is added below 0°C. To this lOOgrm of sucrose 6-acetate in solvent is added below 10°C. Thereafter, the reaction mass is stirred at 20-25°C for Vi-lhr.The temperature is raised to 70-100°C and preferably 80- 90°C and maintained for 1 to 2 hours. Afterwards the temperature is raised to 110 to 130°C and preferably 120- 122°C 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 of ATFD= 0.20 - 0.50 m2
Feed rate = 7-10kg hr Pressure = 2 - lOrnmHg. Jacket temp = 70- 100°C
Feed of 3 to 5Kg was cooled down to 5-10°C 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- 100°C 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.
PURD7ICATION 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 60°C. 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 50°C. 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.

Claims

CLAIMS:
1. In a process for producing chlorinated sucrose, mainly r,6'-Dichloro-l',6'- Dideoxy-β-D-Fructo-Furanosyl-4-Chloro-4-Deoxy-α-D-Galactopyranoside by chlorination of 6-acetyl sucrose in the presence of a solvent such as dimethyl sulfoxide, dimethyl formamide, pyridine, hexane, cyclohexane, deacetylation, removal of solvents used, extraction, purification and crystallization, the improvement comprising the removal of the solvents using an Agitated Thin Film Dryer or Spray Dryer by mamtaining the temperature around 70-100°C in the jacket of ATFD and the pH of the feed at 7.5 to 14 by the addition of Alkali solution and optional crystallization of the product by feeding purified charcolised methanol solution into the said dryers, before or after concentration of the solvent mass after the removal of charcoal.
2. A process for producing chlorinated sucrose as claimed in claim 1, wherein the temperature in the dryer being maintained at 70-100°C and preferably at 80°C by . v circulating hot water in the jacket having inlet from the bottom of the vessel and outlet at the top.
3. A process for producing chlorinated sucrose as claimed in claim 1, wherein agitated thin film dryer is a vertical dryer having a rotor to keep the film formed by the chlorinated mass under intense agitation to prevent scaling and localized heating. 4. A process for producing chlorinated sucrose as claimed in claim 1, wherein the vapor flows countercurrent to the solids and is removed from the top of the dryer.
' 5. In a process for producing 1 ', 6'-Dichloro-l ', 6'-Dideoxy -β-D-Fructo-Furanosyl-
4-Chloro-4-Deoxy-α-D-Galactopyranoside by chlorination of 6-acetyl sucrose in the presence of a solvent such as dimethyl sulfoxide, dimethyl formamide, pyridine, hexane, cyclohexane, deacetylation, removal of the solvent used, extraction, purification and crystallization, the improvement comprising the removal of the solvent using an agitated thin film dryer having a rotor to keep the film formed by the chlorinated mass under intense agitation to prevent scaling, maintaining the temperature around 70 to 100°C and preferably at about 80°C by circulating hot water in the jacket having inlet from the bottom of the vessel and outlet at the top, the pH of the feed being maintained at 7.
5 to 14 and preferably at 10 to 13 by the addition of and optional isolation of the product by feeding purified charcolised methanol solution into the said dryer.
6. A process as claimed in claim 5, wherein the mass obtained from the thin film dryer is subjected to solvent extraction.
A process as claimed in claim 6, wherein the solvent used is selected from any organic solvent and particularly from ethyl acetate, methanol, methyl ethyl ketone, dimethyl sulphoxide, dimethyl formamide, pyridine, hexane, or cyclohexane and acetone.
A process as claimed in claim 7, wherein the solvent extracted mass is concentrated distilled in a rotary evaporator at low temperature, the syrup obtained is mixed with any adsorbent like silica, alumina and run through column chromatography.
A process as claimed in claim 8, wherein the isolated syrup obtained is mixed with two volumes of solvents example methanol and the mass is then treated with charcoal at 50-60°C, filtering the mass followed by distillation at low temperature to remove 90% solvent, thoroughly mixing the product obtained with three volumes of appropriate solvents, followed by a further distillation at low temperature to remove the solvents and crystallizing the product by known methods or by the said new methods i.e. Agitated Thin Film Drying or Spray Drying.
10. In a process for producing 1', 6'-Dichloro-l', 6'-Dideoxy-β-D-Fructo-Furanosyl- 4-Chloro-4-Deoxy-α-D-Galactopyranoside by chlorination of 6-acetyl sucrose in the presence of a solvent such as dimethyl sulfoxide, dimethyl formamide, pyridine, hexane, cyclohexane, deacetylation, removal of the solvent used, extraction, purification and crystallization, the improvement comprising the removal of the solvent using an agitated thin film dryer having a rotor to keep the film formed by the chlorinated mass under intense agitation to prevent scaling and localized heating mamtaining the temperature around 70 to 100°C and preferably at 80°C by circulating hot water in a jacket having inlet from the bottom of the vessel and outlet at the top, the pH of the feed being maintained at 7.5 to 14 and preferably at 10 to 13 by the addition of alkali hydroxide solution and crystallization of the product by feeding purified charcoalised solvent into the dryer.
11. A process as claimed in claim 10, wherein the isolation of the pure crystalline ,6'-Dichloro-l',6'-Dideoxy-β-D-Fructo- Furanosyl-4-Chloro-4-Deoxy-α-D-Galactopyranoside is carried out by using spray drying technique.
PCT/IN2004/000064 2004-03-19 2004-03-19 An improved process for producing chlorinated sucrose WO2005090376A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
PCT/IN2004/000064 WO2005090376A1 (en) 2004-03-19 2004-03-19 An improved process for producing chlorinated sucrose
CA002560284A CA2560284A1 (en) 2004-03-19 2004-05-20 An improved process for producing chlorinated sucrose
MXPA06010665A MXPA06010665A (en) 2004-03-19 2004-05-20 An improved process for producing chlorinated sucrose.
JP2007503498A JP2007529505A (en) 2004-03-19 2004-05-20 Improved process for the production of chlorinated sucrose.
DE602004032578T DE602004032578D1 (en) 2004-03-19 2004-05-20 IMPROVED METHOD FOR THE PRODUCTION OF CHLORINE SACCHAROSE
KR1020067019138A KR20080043194A (en) 2004-03-19 2004-05-20 An improved process for producing chlorinated sucrose
AU2004317336A AU2004317336A1 (en) 2004-03-19 2004-05-20 An improved process for producing chlorinated sucrose
CNA2004800424982A CN1946731A (en) 2004-03-19 2004-05-20 An improved process for producing chlorinated sucrose
US10/593,158 US20090324513A1 (en) 2004-03-19 2004-05-20 Process for Producing Chlorinated Sucrose
PCT/IN2004/000142 WO2005090374A1 (en) 2004-03-19 2004-05-20 An improved process for producing chlorinated sucrose
AT04770659T ATE508136T1 (en) 2004-03-19 2004-05-20 IMPROVED METHOD FOR PRODUCING CHLORINATED SUCCAROSE
EA200601742A EA200601742A1 (en) 2004-03-19 2004-05-20 IMPROVED METHOD FOR THE PRODUCTION OF CHLORINATED SACCHAROSE
NZ550064A NZ550064A (en) 2004-03-19 2004-05-20 An improved process for producing chlorinated sucrose (sucralose)
EP04770659A EP1735327B1 (en) 2004-03-19 2004-05-20 An improved process for producing chlorinated sucrose
IL178046A IL178046A0 (en) 2004-03-19 2006-09-12 An improved process for producing chlorinated sucrose
ZA200607891A ZA200607891B (en) 2004-03-19 2006-09-15 An improved process for producing chlorinated sucrose
LVP-06-113A LV13585B (en) 2004-03-19 2006-10-04 An improved process for producing chlorinated sucrose
NO20064775A NO20064775L (en) 2004-03-19 2006-10-19 An improved process for the preparation of chlorinated sucrose

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