Title of Invention

"AN IMPROVED PROCESS FOR PRODUCTION OF 2-DEOXY-D-GLUCOSE"

Abstract

I ABSTRACT I A process for production of 2-deoxy-D-glucose (2-DG) A process for production of 2-deoxy-D-glucose (2-DG) comprising of following j steps of converting D-glucose to glucose pentaacetate is carried out by reacting D-glucose with acetic anhydride and acetic acid using suphuric acid as a catalyst at 80-85 0°C, reducing said aceto-bromoglucose to glucal triacetate by passing into it, hydrogen bromide gas generated in separate vessel by reaction of tetraline and bromine, reducing said aceto-bromoglucose to glucal triacetate is carried out by a reducing mixture comprising of zinc, sodium acetate, acetic acied and copper sulphate, deesterifying said glucal triacetate to D-glucal; and purifying said D-glucal in any known manner. i

Full Text

FIELD ON INVENTION The present invention relates to an improved process for the production of 2- deoxy-D- glucose (2 - DG), a potential rediomodifier. BACKGROUND INFORMATION 2-DG is a glucose analogue and has been extensively used as a tool to study the glucose transport and regulation of glucose metabolism in a variety of cellular systems and intact organisms including primates and humans. 2-DG has been extensively used in patients of different tumors and in patients of gastric ulcer diseases to test for completeness of vagotomy and also for differential diagnosis of hypoglycemia in children without any untoward side effects. The main goal of a successful cancer therapy is to completely remove the neoplastic cells without causing any appreciable damage to the normal tissues of the host. Many of the compounds such as S-2-3 propylamino ethyl phosphorothioic acid (WR 2721), 2- mercapto propionyl glycine (MPG ) have been widely used as radio protector for normal cells. However, clinical trials have shown that repeated dose of this can result in severe unpleasant side effects. 5- bromouracil (BU) and 5- bromodeoxyuridine (BudR) as radio- sensitizer have also been incorporated in the clinical trials with a view that their configurational similarity is matched with thymine. Hypoxic cells are glucose dependent for their survival. Two glucose analogues namely, 2-deoxy-D-glucose and 5- thio-D- glucose have thus been tested for their cytotixic and radio - sensitizing activity. It has been reported that 2-DG can preferentially inhibit repair processes in cells with high glycolytic activity and is able to inhibit post irradiation DNA repair and cell recruitment processes differentially in systems, which depends largely on glycolysis for their energy supply. The prognosis of patients suffering from malignant cerebral gliomas (heterogenous tumours) has remained dismal despite application of multimodal therapy and many advances in medical radiation technology. The failure of radiotherapy in cerebral gliomas is primarily due to the presence of hyposic, intrinsically radio- resistant, and repair proficient sub-populations of cells in the tumor. In living organisms, damage to DNA is the major cause of cell death and cell loss induced by ionizing radiations. It has been demonstrated that the cellular processes induced by ionizing radiations leading to the repair and fixation of radiation damage require continuous flow of metabolic energy supplied by the respiratory and/ or glycolytic pathways. Because glucose usage in transformed cells and tumors is increased and tumor cells derive a large part of their metabolic energy (ATP) from the glycolytic pathway, it was predicted that inhibitors of glucose transport and glycolysis could differentially inhibit repair processes in these cells, leading to an enhancement of the radiation damage. Several studies have demonstrated that presence of 2-DG, an inhibitor of glucose transport and glycolysis, during the first few hours following irradiation could indeed inhibit the repair of DNA lesions and potentially lethal damage, thereby enhancing the radiation damage in various cellular systems with high rates of glycolysis like the cancer cells under euoxic as well as hypoxic conditions. Thus, combination of ionizing radiations with 2-DG provides a unique opportunity to selectively destroy tumors by differentially enhancing the radiating damage in cancer cells and at the same time preventing radiation injuries to normal tissue. PRIOR ART Billiger et al have prepared 2-DG by the reaction of 2- ethylthiotetra benzoly-D-glucose diethyl mercaptal with cadmium and mercuric chloride. This process has got so many disadvantages. The first disagvantages is that this process consists of nine-steps. Another disadvantage of the above process is the batch time for processing is higher and it is a time consuming process. Another disadvantages of the above process is that the yield is very low -in the order of 2 to 5 % and the product is also impure. Stanek et al have also prepared 2-DG by the reaction of triacetyl D-glucal and silver salt of benzoly iodide [(BzCh)] Ag] followed by reduction of 1-benzoyl 3,4,6- triacetyl 2- deoxy-2- iodo-a-D- glucopyranose. The process has also the disadvantages that it is a seven-step process with very low yield. Crammer F.B. [A procedure for preparation of 2-Deoxy-D- glucose, journal of the Franklin Institute, Vol. 253, 277-80, 1952] has prepared 2-DG using D- Glucose as starting material. The D- glucose is converted to glucose pentacetate using acetic anhydride in the presence of sulphuric acid as catalyst. The reaction mixture is cooled and hydrogen bromide (HBr) gas from HBr gas cylinder is passed into the reaction mixture. The acetobromo glucose obtained is thereby reduced by a reducing mixture. After processing, the glucal triacetate so formed is deesterified to D- glucal using sodium metal followed by the addition of dry ice (solid -3-Carbondioxide). Finally D- glucal is hydrated to 2- deoxy D- glucose (2-DG) using sulphuric acid in aqueous medium. The major disadvantages of the process are that the product obtained is highly impure. The yield is also low. Further disadvantage of the above process is that during reduction of acetobromoglucose to glucal triacetate, the temperature has to be strictly and constantly maintained at zero degrees centigrade, which is difficult to maintain during the entire period of the reaction. Still further disadvantages of the above process of the known art is that sodium metal requires about two days of time for deesterification of glucal triacetate, which leads to an impure product. Still further disadvantage of the above process is that the process uses dry ice i.e., solid carbon dioxide, which is expensive. Pandey K S et al [An improved process for preparation of 2- Deoxy -D- glucose, Indian patent No 187908, dated 11-2-98] has improved the above process suggested by Crammer. They proposed an improved process for preparation of 1-D Deoxy -D- glucose through a six-step process, viz., conversion of D-glucose to glucose pentaacetate, bromination of glucose penta- acetate, reduction of aceto -bromoglucose to gucal triacetate, deesterificationof glucal triacetate to D-glucal, hydradation of glucal to 2- deoxy-D- glucose and finally, purification of crude 2-DG. According to this process conversion of D-glucose to glucose pentaacetate, which is an exothermic reaction, an additional chemical, viz., acetic acid is used. The process prepares hydrogen bromide gas instead of using hydrogen bromide gas cylinders, which are not easily available. The carbon-di-oxide required during deesterification is prepared by reaction of relatively cheap chemicals namely, sodium carbonate and hydrochloric acid as compared to the Crammer process which uses dry ice, i.e., solid carbon dioxide. During hydration of D- glucal, an optimum quantity of the sulphuric acid is used which leads to completion of reaction and eliminates impurities. The process is a multi-step one and purification of the crude 2DG is carried out after dissolving in water and then passing through membrane filter followed by passing though cation and anion exchange resins successively. One of the major disadvantages of the above process is that the yield is low (only 11%) in order to get 99.5% pure product. Further disadvantages of the above process is that the reaction of D-glucose with acetic anhydride being exothermic, temperature goes up which results in boiling of the mixture leading to reaction run over and to splashing out of the un- reacted acetic anhydride and acetic acid which is formed as a by product. This may cause serious health hazard and also create environment problems as well. Still further disadvantages of the above process is that due to intense heat generated as a result of uncontrolled exothermic reaction of D-glucose with acetic andydride, the D- glucose gets partially decomposed which leads to impurities and low yield. Still another disadvantages of the above process is that the conversion of D- glucose and acetic anhydride to glucose pentacaetate remains incomplete, since it is very difficult to maintain the temperature between 70-80°C using cooling water. Further disadvantages of the process is that for the conversion of the d- glucose to glucose pentacaetate due to exothermic reaction, a large quantity of cooling water is required and the variation of the rate of cooling water flow rate is exorbitantly high which a normal control system cannot take care of Even further disadvantage of the above process is that the reaction of hydrogen bromide with glucose penta-acetate is very slow at ambient temperature and major volume of hydrogen bromide passes out unrelated from the reaction vessel, which cause serious hazards to the users as it is toxic and it penetrates into the human skin and damages the muscle tissues. Further, disadvantage of the process is that in the reduction of acetobromoglucose to glucal triacetate, the reduction mixture is added in portions and therefore, processing time is higher and a lot of energy is wasted because the temperature has to be maintained for longer time of 0°C i.e., the process is energy inefficient. Further disadvantage of the process is that in the extraction of GTA from the reactin mixture, benzene is used as solvent, which is carcinogenic and not environmentally friendly. Further disadvantage of the process is that in the conversion of acetobromoglucose to glucal triacetate after the reduction, the slurry containing high solid content is filtered, but the rate of filtration is very low and therefore it takes longer time and practically impossible to adopt filtration in the processing plant. Further disadvantage of the process is that in the conversion of acetobromo glucose to glucal triceatate. After filtration the residue is dried, the residual zinc is highly pyroforic and therefore, there is high danger of fire hazard. Still further disadvantage of the above process is that in the conversion of acetobromoglucose to glucal triacetate after extraction a chemical, anhydrous Na2SO4 is used for complete drying of the extract phase. It increases the process time and steps. Still further a disadvantage of the process is that in the conversion of glucal to 2-DG, barium barbonate is used for neutralization of the medium. Barium is highly toxic to human and comes as an impurity of the product. Still further disadvantages of the process is that to remove the barium, which comes as an impurity of the product, a purification method is adopted, where the yield is very low. Yet, another disadvantage of the process is that after the hydration during the conversion of glucal to 2-DG the neutralisation is carried out at 40°C, which requires heating temperature sensitive material. Still further disadvantage of the process is that the purification is carried out after crystallizing 2-DG and again re- dissolving the 2-DG in water. This increases the number of working steps as well as the batch time. Consequently the yield is low. NEED FOR THE INVENTION Once 2-DG is inducted as a drug, the demand will increase to a large extent. Moreover a large number of population in the world are affected by cancer and they can be treated with the radiation therapy in combination with 2-DG. Therefore, it should be produced at a reasonable price so that people can afford it. To the best of the applicants' knowledge no technology is available, which is suitable for industrial scale of production of 2-DG. The available process needs to be suitably improved to get a process technology for production of 2- deoxy-D- glucose (2- DG), which provides higher yield of 2-DG with higher purity and at the same time is effective. The process should be non- hazardous and need to be eco-friendly. The process should overcome the drawbacks/ disadvantages of the processes known in the art;, OBJECTS OF THE INVENTION It is an important object of the present invention to provide a process for the production of 2- deoxy-D- glucose) 2-Dg) Another object of the present invention is to provide an improved process for the production of 2-DG, which provides higher yield of 2-Dg. Still another object of the present invention is to provide an improved process for preparation of 2-DG which provides 2-DG of purity of the order of higher than 99.5 % Yet another object of the present invention is to provide an improved process for preparation of 2-DG, which is eco- friendly. Yet another object of the present invention is to provide a process for the production of 2-Dg where the reaction between D- glucose and acetic andydride is carried out in a semi-continuous manner so that the reaction temperature can be controlled easily and reaction runaway can be avoided. Yet further object of the present invention is to provide a process for the production of 2-DG in which reaction run-away and the flashing of the material are avoided in the exothermic reaction of D- glucose and acetic anhydride. Yet another object of the invention is to provide a process for the production of 2-DG in which benzene is totally avoided as solvent since it is highly carcinogenic and eco-friendly solvents are used in the extraction of GTA. Yet another object of the invention is to provide a combo- system where the reaction and separation by extraction is cared out in a single equipment (combo- system) so as to increase the yield and as well as to reduce the batch time, energy requirement and cost of production. Yet another object of the invention is to provide a process for the productin of 2-DG in which the reduction of acetobromo glucose to glucal triacetate is carried out in a time, energy and cost effective manner. Yet another object of the invention is to provide a cost effective process, which does not require drying using sodium sulphate so as to avoid lot process steps and to reduce the overall yield and batch time. Yet another object of the invention is to provide an improved process for production of 2-DG in which optimum proportion of sulphuric acid is used during hydratinof glucal into 2-DG. Yet another object of the invention is to provide an improved process for production of 2-DG, in which optimum amount of water is used during hydration of glucal into 2-Dg. Yet another object of the invention is to provide an improved process for production of 2-DG in which optimum proportion of sodium methoxide is used during conversion of glucal triacetate to glucal. Yet further object of the present invention is to provide an improved process for the preparation of 2-DG, which provides higher yield of 2-DG. Still further object of the present invention is to provide an improved process for preparation of 2-DG, which uses multi-step purification process, which leads to 2-Dg of very high purity. Yet another object of the invention is to provide a technology for the large scale production of 2-DG with higher yield. Yet another object of the present invention is to use a neutralization method, which is carried out at room temperature during conversion of glucal to 2-Dg. Yet another object of the invention is to provide a technology for the large scale production of 2-DG with higher purity. Yet another object of the invention is to provide a technology for the large scale production of 2-DG which utilize less number of steps for production. Yet another object of the invention is to provide a technology for the large scale production of 2-DG to reduce the work up steps and the batch time. SUMMARY OF INVENTION To achieve the above objects, the present invention provides a process for pilot plant production of 2-DG. According to the present invention the process technology provides an improved cost effective and time efficient process for the production of 2 deoxy-D-glucose. The process provides a final product 2-DG of very high purity of order higher than 99.5% and at the same time provides higher yield of product as compared to known processes. During the first step of conversion of D- glucose pentaacete, the reaction is carried out in a semi- continuous manner compared to batch process earlier. By making the process semi-continuous, the reaction temperature of the exothermic reaction is controlled very easily. The process is so innovative that no cooling water is required though it is an exothermic reaction. Complete conversion of d- glucose is obtained by doing the reaction this manner. The time required for completion of reaction is reduced drastically. In another embodiment of the present invention the process uses optimum amount of bromine and tetralin for generation of hydrogen bromide gas during the bromination of glucose pentaacetate. Yet in another embodiment of the present invention, the conversion of acetobromoglucose to glucal triacetate is carried out in a combo-system, where, after the reduction is over, solvent is added for extraction and extraction phase is taken out by siphoning out. This innovative method reduces the work-up steps and the extraction efficiency. In another embodiment of the present invention, the reduction of acetobromoglucose is carried out in different way where the reducing mixtures were added in one portion instead of two portions. In the new process the laboratory grade zinc is used and it is used in a single portion. The process prepares hydrogen bromide gas instead of using highly expensive hydrogen bromide gas cylinders, which are not easily available. In the new process, toluene is used as a solvent for the extraction of glucal triacetate from the reaction mixture. Therefore, the process is more eco-friendly and involves less health hazard. Yet another embodiment of the present invention is the use of a method neutralization, which is carried out at room temperature. In yet another embodiment, the use of sodium sulphate is avoided for the drying of the extract phase. In yet another embodiment, the present invention uses 0.5 N sodium methoxide to enable completion of reaction during conversion of glucal triacetate to glucal. During hydration of D- glucal, an optimum quantity of the sulphuric acid is used which leads to completion of reaction and eliminates impurities. Yet another embodiment of the present invention uses sodium carbonate or sodium bicarbonate or any other neutralizing agent for neutralizing excess sulphuric acid. According to further embodiment of invention, the final purification of the product is done in alternative method, where the work-up steps as well as the batch time is reduced and consequently, the yield is increased. After the hydration of glucal to 2-DG, the water is neutralized and evaporated to one third of the total volume and then treated with resin (successively through cation and anion exchange resins). Detailed Description 1. Conversion of D- glucose to glucose pentaacetate In the present process the glucose pentaacetate is produced through a semi continuous process. Acetic anhydride and acetic acid are charged into the reaction vessel and then one potion of D- glucose is added and mixed in the reaction vessel. To this mixture, about 0.1 to 0.2.ml of H2 SO4 serves as catalyst is added. The reaction is exothermic and the reaction temperature state increasing and reaches up to 70-80 °C when the temperature is stable. Then the remaining 2-DG was added at the rate of 10-40 gm per minute. At this condition the reaction temperature remains maintained at 80-85°C. The reaction mixture is stirred under atmospheric pressure and allowed to cool down at room temperature. A transparent solution of glucose penta- acetate in acetic acid solution is obtained. 2. Bromintion of glucose pentaacetate to acetobromoglucose In a separate vessel, tetralin in 50-55% of the wt of glucose penta acetate is taken and bromine is added continuously from dropper at the rate of 4-10 ml per minute. Total bromine added is about 85-90 wt % glucose penta acetate. Hydrogen bromide gas in thus generated continuously and is passed into the reaction mixture of step-I. The tatralin and final bromine are in the ratio of 3.5. Passing of hydrogen bromide gas is discontinued when the weight of reaction mixture increases by about 35-40%. The cooled intermediate of acetobromoglucose is used as such in the next step. 3. Reduction of acetobromoglucose to glucal triceatate The acetobromoglucose obtained by the step-2 is reduced to glucal triacetate by reducing mixture comprising of four different constituents. The constituents of reducing mixture are zinc, sodium acetate, acid and copper sulphate in aqueous medium at - 3° C to 1° C. The quantities of these constituents as wt % of glucose penta-acetate are 25-30%, 50-55 %, 2-3 %, respectively. The different constituents of the reducing mixture are in the simple ratio of 1:2:2:0.1. After reduction is over, toluene is added into the reaction mixture and is stirred properly for five minutes. After settling the organic phase is siphoned out from the reactor. Toluene/ hezane is evaporated from the extract phase to a viscous material, which is diluted with 95 % ethyl alcohol. The quantity of ethyl alcohol taken is about half of the volume of the product obtained after extraction and vacuum evaporation. The yield of crystallized glucal triacetate thus obtained is in the order of higher than 80% of acrtobromoglucose. 4. Deesterification of glucal triacetate to D- glucal The glucal triacetate obtained is dissolved in dry methanol and to this is added 0.5 N sodium methoxide. The quantity of dry methanol taken is four times the wt of glucal triacetate and volume of 0.5 N sodium methoxide is about 30 % of the weight of glucal triacetate (volume to weight percentage). The mixture is refluxed for about 15 minutes. In a separate vessel, sodium carbonate is taken and concentrated hydrochloric acid is poured over it through a pressure equalizing funnel. The carbon dioxide thus generated is passed into the reaction mixture till the reaction mixture becomes neutral to slightly acidic. The methanol is removed under vacuum and the product obtained, namely, D- glucal is used as such for next step. The yield at this stage is about 60-70 % of the glucal tri- acetate. 5. Hydration of D- glucal to 2- deoxy- D-glucose The product obtained is diluted with distilled water and to this 1 N -H2 SO4 is added. The quantity of water taken is about 4-10 times the weight of the product and the quantity of 0.5 N sulphuric acid -(H2 SO4) taken is about 30-60% of the weight of the product. The mixture is kept for 16 -18 hours for completion of hydratin. Excess acid is neutralized by sodium carbonate. After filtration, 50 to 75 % water is evaporated under vacuum , to get solution rich in 2-DG . The yield of 2-DG is about 65-70% of the D-glucal . The water solution in then used as such for the next step. 2- Purification The water solution of 2-DG obtained in step 5 is decolourised by charcoal. After filtration through a membrane filter of 0.45 micron, this solution is passed through cation exchange resin like Dower 50 w. The quantity of resin taken is about 10 to 25 % of the weight of 2-DG it is then passed through anion exchange resin like amberlite IRA 400 OH. The quantity of this resin taken is about 10 to 25 % of the weight of 2-DG. After this, shiny fluffy compound pure 2-DG is obtained. The overall yield of pure 2-DG of purity above 99.5 % is 15-18 % compared 11 % in the previous process. The present invention will now be described with reference to the following examples, which are merely for illustrative purposes. It will be apparent to a person skilled in the art that various modifications and embodiments are possible without departing from the spirit and scope of the invention. Example 1 Producation of glucose Pentaacetate 5.2L acetic anhydride and 500 ml acetic acid are charged into an all glass reactor of capacity 20 litres fitted with mechanical stirrer and condenser. D-glucose (500-1000 gm) is charged into the glass reactor. The mixture is stirred for 30 minutes. Then 1.0 ml catalyst prepared by adding 0.5 ml H2 SO4 in 4.5 ml acetic acid, is added into the reactor with constant stirring. Due to the exothermic reaction the temperature of the reactor contents starts increasing and reaches up to 70-80%. Then remaining d- glucose is added in to the reactor at the rate of 10-20 gm per minute. The reaction temperature is automatically maintained at 80-85°C because here the heat generated by the exothermic reaction is dissipated by heat loss to the atmosphere through the surface of the reactor. After completion of the addition of d-glucose (total 1800 gm) the reaction mixture was stirred for another 30 minutes. Example 2 Bromination of glucose pentaacetate to Acetobromo Glucose Tetralen (13.5 litres) was taken in a glass reactor of 10 litres capacity fitted with cooling jacket. The tetralin is heated to 60-65 % C and then bromine is added slowly into it at the rate of 4-10 ml per minute. The gas generated is purified by passing through a tetralin solution at 10-20°C. A total of 2.25 litters tetralin is added. The reaction was completed in about 8 hrs. Example 3 Reduction of acetobromo glucose i) Reaction and extraction 5.235 kg sodium acetate is dissolved in 7. 95 litres of water and is charged into an all glass reactor of capacity 50 litres fitted with cooling jacket and mechanical stirrer. A solution of copper sulphate is prepared by dissolving 0.47 kg copper sulphate in 1.425 litre water and is added into the reactor. Then 2.25 kg zinc powder is charged into the reactor with constant stirring. The content of the reactor is cooled to 0°C. Then 5175 litre glacial acetic acid is added into the reactor and again cooled to 0°C. Then the solution of the acetobromoglucose is added into the reactor with continuous stirring of the reaction mixture and maintaining the reaction temperature at 2.0 0.5 0 °C using salt -ice mixture at the jacket. When the addition of acetobromoglucse mixture is over the reaction mixture is stirred for further 30 minutes maintaining the temperature at -2 to 0.5 0 °C. Then about 15 litres of toluene is added into the reactor and stirred for 5-10 minutes. Then the mixtures is allowed to settle for 5-10 minutes by gravity settling and then the organic phase (toluene) is siphoned out through a tube from the reactor. The reactor here is being used as a combo-system in which chemical reaction and separation (extraction) is carried out. ii) Washing, Neutralization the Extract Phase The combined extract phase is then washed twice with 7 litres of water each time in the above a mixer - cum - separator unit. The extract phase may contain acetic acid and therefore is neutralized with saturated sodium bicarbonate solution (twice to thrice, 6.0 litres each time). •. iii) Evaporation and Crystallizaiton of Glucal Triacetate Toluene is evaporated from the extract phase in a rotary evaporator to give a thick viscous solution of 2.0 litres. The residue is taken in 1.50 litres cold ethyl alcolhol and seeded with pure glucal triacetate and kept for crystallization. iv) Filtration , Washing and Drying of Glucal Triacetate The slurry from the cry stalliser is filtered under vacuum. The residue is washed with 0.5 litre cold alcohol and then dried under atmospheric conditions. 1.645 kg glucal triacetate is obtained. The process 1 to 3 is repeated again to get another 1.65 kg of glucal triacetate. Example 4 Production of Glucal Absolute methanol (4.0 litres ) and 2.5 kg glucal triacetate are charged into an all glass reactor of capacity 10 litres fitted with jacked , mechanical stirrer and reflux condenser. The mixture is than heated to 60-64 0 °C. About 300 ml of 0.5 N sodium methoxide is added into the reactor and the solution is refluxed for 10 minutes with stirring. When the solution is alkaline, carbon dioxide gas is passed through the mixture to neutralize the solution. Carbon dioxide gas is generated taking sodium carbonate in a round bottom flask and adding concentrated hydrochloric acid slowly. 2.0 litre of water is added and passing of carbon dioxide is continued till it becomes neutral. Methanol is then evaporated in a rotary evaporator under vacuum and a thin syrupy liquid of 2.0 litre volume is obtained. Example 5 Hydration of Glucal to D- glucose i) Reaction 3.8 Litres of process water is charged into the thin syrup of glucal taken in a 10 litre beaker fitted with mechanical stirrer. 200 ml of 1N sulphuric acid is added into the mixture and is allowed to stand at room temperature for 16-18 hrs. ii) Neutralization, Filtration and Evaporation Sodium carbonate (10-15 gm) is added into the above solution with occasional stirring for one hour. Charcoal powder (about 50 gms) is added and the mixture is filtered. The filtrate is evaporated under vacuum at 40-50 °C in a rotary evaporator to 1.5 to 3.0 litres. This solution is used in the purification step as such. Example 5 Purification •. The solution containing 2-DG obtained after step 5 is passed through ion exchange resins. The solution is first passed through a bed packed with cation exchange resin (300 kg) like Dower 50 w. The quantity of resin taken is about 15 to 60 % of the weight of 2-DG . It is then passed through another bed packed with anion exchange resin (300 gm) like amberlite IRA 400 OH. The quantity of this resin taken is about 30-65 % of the weight of 2-DG. The solution is then filtered through a membrane filter 0.45 micron. After this, the water is evaporated to in rotary evaporator at a temperature of 40-50 0°C to thin syrup. The residue from the evaporator is then dissolved in 1.5 litres isopropyl alcohol and seeded with pure deoxyglucose. The solution was stirred slowly for 30 minutes in the crystallizer, fitted with cooling jacket. The mixture is then allowed to crystallize for 12.15 hrs at room temperature. The mixture is filtered and the residue is washed with 500 ml isopropyl alcohol. Finally, the solid is dried under atmospheric conditions. About 350 to 370 gm crude 2-DG is obtained after drying. WE CLAIM: 1. A process for production of 2-deoxy-D-glucose (2-DG) comprising of following steps: { (a) converting D-glucose to glucose pentaacetate is carried out by reacting Dglucose with acetic anhydride and acetic acid using suphuric acid as a catalyst at 80-85 0°C, \ (b) reducing said aceto-bromoglucose to glucal triacetate by passing into it, hydrogen bromide gas generated in separate vessel by reaction of tetraline and ] bromine, (c) reducing said aceto-bromoglucose to glucal triacetate is carried out by a reducing mixture comprising of zinc, sodium acetate, acetic acied and copper sulphate, (d) deesterifying said glucal triacetate to D-glucal; and (e) purifying said D-glucal in any known manner. 2. A process as claimed in claims 1 or 2 wherein the said conversion of D-glucose to glucose pentaacetate is carried in a semi-continuous method, preferably in the absence of cooling water. 3. A process as claimed in claim 1, wherein the said reduction of acetobromo glucose to glucal tracetate is carried out by adding said reducing mixture comprising of Zinc, sodium acetate, acetic acid and copper sulphate in the reaction vessel in one portion. 4. A process as claimed in claim 1, wherein the reaction and separation of glucal triacetate by extraction us carried out in the same equipment (Combo-system). 5. A process as claimed in any one of claim, wherein the extraction of glucal triacetate from the solution is carried out using toluene,xylene, cychoxane or any other solvent. 6. A process as claimed in any preceding claim wherein the said deestrification of glucal triacetate to D-glucal is carried out by deestrification with 0.5 N sodium methoxide in methanol followed by passing carbon dioxide which is freshly prepared in separate vessel by reaction of sodium carbonate with concentrated hydrochloric acid. 7. A process as claimed in any preceding claim wherein the said D-glucal is hydrated prior to purification by addition of distilled water and IN-H2S04 preferably, 6NH2 S04. 8. A process as claimed in any preceding claim wherein said purification of crude 2- DG, after filtration through membrane filter of 0.45 microns is carried out by passing through cation exchange resin like Dowex 50 w, followed by passed through anion exhchange resin like amberlite lRA-400 OH. 9. A process as claimed in claim 7 wherein said reducing mixture comprises activated zinc, sodium acetate, acetic acid and copper sulphate in the ratio of 1:2:20.1. 10. A process as claimed in claim 11 wherein 0.5 N-sodium methoxide is used during deesterification if glucal tracetate to D-glucal. 11. A process as claimed in claim 6 wherein said reduction of acetobromoglucose to glucal triacetate is carried out at a temperature between -2°C to 1°C. 12.A process as claimed in claim 12 wherein said hydration of D-glucal to 2-DG is carried out in the presence of sodium carbonate or sodium bicarbonate as a neutralizing agent. 13.A process as claimed in claim 12 wherein during the said hydration of S-glucal, dry isopropyl alcohol is used as crystallizing medium. Dated this 21" day of October 2004 (MONA SAINI) OfL.S.DAVAR&CO. APPLICANT'S AGENT

Documents:

2075-del-2004-Abstract-(16-08-2013).pdf

2075-del-2004-abstract.pdf

2075-del-2004-Claims-(16-08-2013).pdf

2075-del-2004-Claims-(21-07-2014).pdf

2075-del-2004-claims.pdf

2075-del-2004-Correspondence Others-(06-06-2011).pdf

2075-del-2004-Correspondence Others-(09-05-2011).pdf

2075-del-2004-Correspondence Others-(16-08-2013).pdf

2075-del-2004-Correspondence Others-(21-07-2014).pdf

2075-del-2004-Correspondence-Others-(06-06-2014).pdf

2075-del-2004-correspondence-others.pdf

2075-del-2004-description (complete).pdf

2075-del-2004-description (provisional).pdf

2075-del-2004-form-1.pdf

2075-del-2004-Form-18-(18-09-2008).pdf

2075-del-2004-form-2.pdf

2075-del-2004-form-3.pdf

2075-del-2004-form-5.pdf

2075-del-2004-GPA-(06-06-2011).pdf

2075-del-2004-GPA-(21-07-2014).pdf