FIELD OF THE INVENTION:
The present invention relates to improved, safe and industrially feasible process for preparing 2-Deoxy-D-Glucose.
BACKGROUND OF THE INVENTION:
2-|DG, also known as 2-Deoxy-D-glucose of formula-1 is a natural anti-metabolite antibiotic with a variety of physiological and pharmacological effects and widely used in the fields of medicine.food and agriculture. It is used as anti-virus, anti-bacterial, anti-cancer, anti-epileptic and anti-aging.
Bolliger et al have prepared 2-DG by the reaction of 2-ethylthiotetra benzoyl-D-glucose
diethyl mercaptal with cadmium carbonate and mercuric chloride.
Stanek et al have also prepared 2-DG by the reaction of triacetyl D-glucai and silver salt of
benzoyl iodide ((Bz02)IAg) followed by reduction of 1-benzoyl 3,4.6- triacetyl 2-deoxy-2-
iodo-a-D-glucopyranose.
Cramer F.B has prepared 2-DG using D-glucose as starting material. The D-glucose is
converted to glucose pentaacetate using acetic anhydride in the presence of sulphuric acid as
catalyst. The reaction mixture is cooled and Hydrogen bromide (HBr) gas from a HBr gas
cylinder, is passed into the reaction mixture. The acetobromoglucose obtained thereby- is
reduced by a reducing mixture. After processing, the glucal triacetate so formed is
deesterified to D-glucal using sodium metal followed by addition of dry ice (solid carbon
dioxide). Finally Dglucal is hydrated to 2-deoxy-D-glucose (2-DG) using sulphuric acid in
aqueous medium.
The main disadvantage of prior art process is that the processes having long reaction steps
which is time consuming. Another disadvantage is lower total reaction yield. Moreover
another drawback of the prior art process is difficulty in purification which results lower
purity of the product. Hence prior art process is difficult to commercialize.
Hence, it is necessary to develop simple process to avoid prior an complex processes with higher yield and higher purity.

The present invention provides process for preparation of 2-Deoxy-D-glucose with mild method conditions with higher yield. Moreover, the present invention provides simple purification method and easy large scale preparation.
SUMMARY OF THE INVENTION:
The present invention relates to robust, eco-friendly and effective process for the preparation of 2-Deoxy-D-glucose of formula-1
One embodiment of the present invention provides process for preparing of (2R.3S.4R)-2-(acetoxymethyl)-3;4-dihydro-2H-pyran-3:4-diy! diacetate of formula-5 comprises;
(a) acetylating D-glucose anhydrous in presence of acetic anhydride and per chloric acid
(b) brominating in presence of brominating agent and solvent
(c) reducing in presence of reducing agent and solvent
(d) isolating (2R;3S:4R)-2-(acetoxymethyl)-3)4-dihydro-2H-pyran-3,4-diyl diacetate
One another embodiment of the present invention provides process for preparing of 2-Deoxy-D-glucose of formula-1 comprises;
(a) deesterificating (2R,3Sr4R)-2-(acetoxymethyl)-3?4-dihydro-2H-pyran-3:4-diyl diacetate
in presence of base, solvent and resin
(b) hydrating in presence of resin and water
(c) isolating 2-deoxy-D-glucose in presence of solvents
One another embodiment of the present invention provides process for preparing of 2-Deoxy-D-glucose of formula-1 comprises:
(a) deesterificating i2R.3S.4R)-2-(acetoxymeihyn-3.4-dihydro-2H-pyran-3.4-diyl diacetate in presence of water, solvent and resin

(b) acidifying in presence of acid and water
(c) neutralizing in presence of alkaline earth metal carbonate
(d) isolating 2-deoxy-D-glucose in presence of solvents
One another embodiment of the present invention provides process for preparing of2-Deoxy-D-giucose of formula-1 comprises;
(a) deesterificating (2R,3S,4R)-2-(acetoxymethyl)-3.4-dihydro-2H-pyran-3,4-diyl diacetate
in presence of water and solvent
(b) acidifying in presence of acid and heating
(c) basifying in presence of resin
(d) isolating 2-deoxy-D-glucose
One another embodiment of the present invention provides process for preparing of 2-Deoxy-D-glucose of formula-1 comprises;
(a) acidifying in presence of resin, solvent and water
(b) neutralizing in presence of resin
(c) deesterificating (2R.3S.4R)-2-(acetoxymethyl)-3:4-dihydro-2H-pyran-3,4-diyl diacetate in presence of base, solvent and resin
(d) isolating 2-deoxy-D-glucose in presence of solvents
One another embodiment of the present invention provides process for preparing of2-Deoxy-D-glucose of formula-1 comprises;
(a) acidifying in presence of acid and water
(b) neutralizing in presence of alkaline earth metal carbonate
(c) deesterificating (2R.3S.4R)-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-3.4-diyl diacetate in presence of water, solvent and resin
fd) isolating 2-deoxy-D-glucose in presence of solvents

OBJECT OF THE INVENTION:
(1) one object of the present invention is to provide simple purification method which results in higher purity.
(2) Another object of the present invention is to provide two stage in-situ process to prepare 2-Deoxy-D-glucose with six chemical conversations.
(3) Another object of the present invention is to provide higher yield.
(4) Another object of the present invention is that the de-acetylation process done at mild condition.
(5) Another object of the present invention is that cation resin used to control reaction mass pH to avoid other elemental impurities.
(6) Another object of the present invention is that use of cation resin results in less pollution and environment friendly process.
DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to improved, effective, economical and industrially applicable process for the preparation of 2-Deoxy-D-glucose of formula-1
One aspect of the present invention provides process for preparing of (2R.3S.4R)-2-(acetoxymethyl)-3.4-dihydro-2H-pyran-3.4-diyl diacetate of formula-5 comprises;
(a) acetylating D-glucose anhydrous in presence of acetic anhydride and perchloric acid
(b) brominating in presence of brominaiing agent and solvent f c) reducing in presence of reducing agent and solvent

(d) isolating (2R,3S,4R)-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate
The brominating agent used for step (b) is phosphorus bromide.
The solvent used for step (b) is selecting from the group consisting of dichloromethane, ethylene dichloride, dibromomethane, carbon tetrachloride or mixture thereof.
The reducing agent used for step (c) is sodium dihydrogen phosphate, zinc powder.
The solvent used for step (c) is selecting from the group consisting of toluene, ethyl acetate, isopropyl acetate, 2-methyl THF or mixture thereof.
The isolation solvent used for step (d) is selecting from the group consisting of water, methanol, n-Hexane.
The process for preparation of (2R,3S,4R)-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-3,4-
diyl diacetate of formula-5 given in the below reaction scheme-1
One another aspect of the present invention provides process for preparing of 2-Deoxy-D-gkicose of formula-1 comprises:

(a) deesterificating (2R.,3S,4R)-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate in presence of base, solvent and resin
(b) hydrating in presence of resin and water
(c) isolating 2-deoxy-D-glucose in presence of solvents
The base used for step (a) is selecting from the group consisting of sodium methoxide. sodium ethoxide, sodium hydroxide.
The solvent used for step (a) is selecting from the group consisting of methanol, ethanol. isopropyl alcohol or the mixture thereof.
The resin used for step (a) is Anion resin Indion 300 OH.
The resin used for step (b) is cation resin Indion 225H and Anion resin Indion 300 OH.
The solvent used for step (c) is selected from the group consisting of methanol, acetone, ethyl acetate or mixture thereof.
The process for preparation of 2-Deoxy-D-glucose of formula-l given in the below reaction scheme-2

One another aspect of the present invention provides process for preparing of 2-Deoxy-D-glucose of formula-1 comprises;
(a) deesterificating (2R,3S,4R)-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate in presence of water, solvent and resin
(b) acidifying in presence of acid and water
(c) neutralizing in presence of alkaline earth metal carbonate
(d) isolating 2-deoxy-D-glucose in presence of solvents
The solvent used for step (a) is selecting from the group consisting of methanol, ethanol. isopropyl alcohol or the mixture thereof.
The resin used for step (a) is Anion resin Indion 300 OH.
The acid used for step (b) is sulphuric acid.
The alkaline earth metal carbonate used for step (c) barium carbonate, beryllium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, radium carbonate.
The solvent for step (d) is selected from the group consisting of methanol, acetone, ethyl acetate or mixture thereof.
The process for preparation of 2-Deoxy-D-glucose of formula-1 given in the below reaction scheme-3

(a) deeste'rificating (2R33S.4R)-2-(acetoNymethyl)-3;4-dihydro-2H-pyran-3,4-diyl diacetate in
presence of water and solvent
i
(b) acidifying in presence of acid and heating
(c) basifying in presence of resin
(d) isolating 2-deoxy-D-glucose
The solvent used for step (a) is selecting from the group consisting of acetone, ethyl acetate, tetrahydrofuran. dimethylformamide. dimethylsulfoxide. acetonirile or the mixture thereof.
The acid used for step (b) is sulphuric acid with I to I ON.
The resin used for step (c) is Anion resin Indion 300 OH.
The temperature for the above said process is 30. to 50"C.
The pH for the above said process ranges between 0.5 to 9.

The process for preparation of 2-Deoxy-D-glucose of formula-1 given in the below reaction scheme-4
Scheme-4
One another aspect of the present invention provides process for preparing of 2-Deoxy-D-glucose of formula-1 comprises;
(a) acidifying in presence of resin, solvent and water
(b) neutralizing in presence of resin
(c) deesterificating (2R,3S,4R)-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate in presence of base, solvent and resin
(d) isolating 2-deoxy-D-glucose in presence of solvents
The resin used for step (a) is cation resin Indion 225H.
The resin for step (b) is Anion resin Indion 300 OH.
The solvent used for step (a) is selecting from the group consisting of acetone, ethyl acetate, tetrahydrofuran. dimethylformamide. dimethylsulfoxide. acetonirile or the mixture thereof.
The base used for step (c) is selecting from the group consisting of sodium methoxide, sodium ethoxide, sodium hydroxide.
The solvent used for step (c) is selecting from the group consisting of methanol, ethanol. isopropyl alcohol or the mixture thereof
The resin used for step (c) is cation resin indion 225H.
The solvent used for step (d) is selected from the group consisting of methanol, acetone, ethyl acetate or mix-lire thereof.

The pH for above said process ranges between 2.0-4.0.
The process for preparation of 2-Deoxy-D-gIucose of formula-1 given in the below reaction scheme-5
One another aspect of the present invention provides process for preparing of 2-Deoxy-D-glucose of formula-1 comprises;
Formula-1
(a) acidifying in presence of acid and water
(b) neutralizing in presence of alkaline earth metal carbonate
(c) deesierificating (2R.3S.4R)-2-(acetoxyniethyl)-3.4-dihydro-2M-pyran-3.4-diyl diacetate in presence of water, solvent and resin
(d) isolating 2-deoxy-D-g!ucose in presence of solvents The acid used for step (a) is sulphuric acid.

The alkaline earth metal carbonate used for step (b) barium carbonate, beryllium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, radium carbonate.
The base used for step (a) is selecting from the group consisting of sodium methoxide, sodium ethoxide, sodium hydroxide.
The solvent used for step (c) is selecting from the group consisting of methanol, ethanol, isopropyl alcohol or the mixture thereof.
The resin used for step (c) is Anion resin Indion 300 OH and cation resin Indion 225H .
The solvent for step (d) is selected from the group consisting of methanol, acetone, ethyl acetate or mixture thereof.
The process for preparation of 2-Deoxy-D-gIucose of formula-1 given in the below reaction scheme-6

The following examples explain various other embodiments without limiting the scope of the present invention.
Example-1: Preparation of (2R,3S,4R)-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate
To a solution of Acetic anhydride and per chloric acid, D-glucose was added lot-wise at 15 -50°C. The reaction mixture was stirred for 2 h at 25 - 50°C. Conversion of D-giucose to penta acetate-D-glucose was confirmed by TLC. The reaction mixture was used in next step without further process. Phosphorus bromide was added to the solution at 0 - 10°C, followed by addition of water. The reaction mixture was stirred at 20 - 40°C for 2h. The progress of reaction was checked by TLC. Dichloromethane was added into reaction mixture and reaction mixture was slowly quenched into Ice water. The dichloromethane layer was washed with saturated sodium bicarbonate solution and brine solution. The resultant organic layer was distilled out under vacuum and used in next step without further purification. Saturated sodium dihydrogen phosphate was added to the solution in acetone and followed by Zinc powder. The reaction mixture was stirred at 25 - 35°C for 3 h. After complete conversion Toluene was added and stirred at 25 - 35°C for 1 h and decantation of toluene layer from reaction mass. The organic layer was washed with sodium bicarbonate solution and brine solution. The resultant organic layer was distilled out under vacuum and isolate with Methanol/water to give said product as white solid.
HPLC Purity: 99.65%
Assay by HPLC: 97.5%
Example-2: Preparation of (2R,3S,4R)-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate
To a solution of Acetic anhydride and per chloric acid. D-glucose was added lot-wise at 15 -50°C. The reaction mixture was stirred for 2 h at 25 - 50°C. Conversion of D-glucose to penta acetate-D-glucose was confirmed by TLC. The reaction mixture was used in next step without further process. Phosphorus bromide was added to the solution at 0 - I0°C. followed by addition of water. The reaction mixture was stirred at 20 - 40"C for 2h. The progress of reaction was checked by TLC. Dichloromethane was added into reaction mixture and reaction mixture was slowh quenched into Ice water. The dichloromethane layer was washed with saturated sodium bicarbonate solution and brine solution. The resultant organic Saver

was distilled out under vacuum and used in next step without further purification. Saturated sodium dihydrogen phosphate was added to the solution in acetone and followed by Zinc powder. The reaction mixture was stirred at 25 - 35°C for 3 h. After complete conversion Toluene was added and stirred at 25 - 35°C for 1 h and decantation of toluene layer from reaction mass. The organic layer was washed with sodium bicarbonate solution and brine solution. The resultant organic layer was distilled out under vacuum and isolate with Methanot/n-hexane to give said product as white solid.
HPLC Purity: 99.75%
Assay by HPLC: 98.3 %
Example-3: Preparation of 2-Deoxy-D-glucose
To a solution of (2R,3S,4R)-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate and Methanol, Sodium methoxide solution was added drop wise at 10-30°C. The reaction mixture was stirred for 3 h at 10-30°C. The progress of reaction was checked by TLC. The reaction mass pH was adjusted with cation resin, distilled the methanol under vacuum to get oily residue, which is used next step without further process. To a solution added water, cation resin was to adjust pH of 2- 4. The reaction mass was stir for 16 h at 10-35 °C. After complete conversion, anion resin was added to neutralize the reaction mass. Charcoal was added into resultant reaction mass and stirred for 30 minute at RT. The resultant filtrate mL was distilled out !under vacuum at below 50 °C to get oily residue, which is used for further step. To a solution added methanol and stirred at 40-50°C for 1 h. Upon cool to RT. reaction mass become hazy and Acetone was added. The resultant slurry was stirred 12 h at room temperature. The slurry was filtered and washed with Ethyl acetate to give 2-Deoxy-D-glucose.
HPLC purity: 99.72 %
Assay: 99.2% w/w
ExampIe-4: Preparation of 2-Deoxy-D-glucose
To a solution of (2R.3S.4R)-2-(acetoxymethyl)-3.4-dihydro-2H-pyran-3.4-diyl diacetate. water and Methanol. Anion resin were added at 20 -30X. The reaction mixture was stirred for 3 h at 20-3OX. The progress of reaction wis checked b> TLC. The reaction mass pi i uas

adjusted with cation resin, distilled the methanol/water under vacuum to get oily residue, which is used next step without further process. To a solution water, dilute sulphuric acid were added to adjust pH of 1.5 - 4.0. The reaction mass was stirred for 16 h at 20-30°C. After complete conversion. Barium carbonate was added for neutralize the reaction mass. Charcoal was added into resultant reaction mass and stirred for 30 minute at. RT, The resultant filtrate mL was distilled out under vacuum at below 50 °C to get oily residue, which is used for further step. To a solution added methanol and stirred at 40 - 50 °C for 1 h. Upon cool to RT, reaction mass become hazy and Acetone was added. The resultant slurry was stirred for 12 h at room temperature. The slurry was filtered and washed with Ethyl acetate to give 2-Deoxy-D-glucose.
HPLC purity: 99.90%
Assay: 99.4 % w/w
Example-5: Preparation of 2-Deoxy-D-glucose
To a clear solution of I50gm of (2R,3S,4R)-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate in acetone was added 25mL of water and cooled the reaction mixture to 0-5 °C. The reaction mixture was acidified to pH 0.5-1.5 using ION H2SO4 at 0-5 °C. It was slowly allowed to room temperature, stirred for lh. Then reaction mixture was slowly heated at 40-45 °C and stirred for 4-5 hr. After complete consumption of (2R.3S,4R)-2-(acetoxymethyl)-3.4-dihydro-2H-pyran-3.4-diyl diacetate as judged by TLC. the reaction mixture was cooled to RT. It was diluted with water, then acetone was distilled out. The aqueous layer was brought to pH 8-9 using anionic resin, stirred for 4-5 h at 25-30 °C. The progress of the reaction was monitored by HPLC. The reaction mixture was filtered to remove the resin, concentrated under reduced pressure at 40"C to give 2-Deoxy-D-glucose as crude.
HPLC purity: 99.6%
Assay: 99.8 % w/w
Example-6: Preparation of 2-Deoxy-D-glucose
To a solution of I50gm of (2R,3S.4R)-2-(acetoxymethyl)-3.4-dihydi*o-2H-pyran-3.4-diyl diacetate in acetone was added water and cooled the reaction mixture to 0-5 °C. The reaction mixture was acidified 10 pH 1-2 using ION H:SOa at 0-5 °C. It was slowly allowed to room temperature, stirred for 24h. After complete consumption ol:(2R.3S.4Rt-2-iaceio\>meth>h-

3,4-dihydro-2H-pyran-3.4-diyl diacetate as judged by TLC, the reaction mixture was cooled to RT. Then acetone was distilled out. The aqueous layer was brought to pH 8-9 using anionic resin, stirred for 4-5 h at 25-30 °C. The progress of the reaction was monitored by HPLC. The reaction mixture was filtered to remove the resin, concentrated under reduced pressure at 40 °C to give 2-Deoxy-D-glucose as crude.
HPLC purity: 99.7%
Assay: 99.2 % w/w
Example-7: Preparation of 2-Deoxy-D-glucose
To a solution of (2R,3S:4R)-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate, Acetone and water, cation resin was added for adjust pH of 2.0 - 3.5. The reaction mass was stir for 16 h at 20 - 30 °C. After complete conversion of (2R,3S,4R)-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-3,4-diyl diacetate, anion resin was added for neutralize the reaction mass. Charcoal was added into resultant reaction mass and stirred for 30 minute at RT. The resultant filtrate mL was distilled out under vacuum at below 50°C to get oily residue, which is used for further step. To a solution of Methanol, Sodium methoxide solution was added drop wise at 20 - 25 °C. The reaction mixture was stirred for 3 h at 20 - 25 °C. The progress of reaction was checked by TLC. The reaction mass pH was adjusted with cation resin, distilled the methanol under vacuum to get oily residue, which is used next step without ■ further process. To a solution of methanol stirred at 40 -;50°C for 1 h. Upon cool to RT, reaction mass become hazy and Acetone was added. The resultant slurry was stirred 12 h at room temperature. The slurry was filtered and washed with Ethyl acetate to give 2-Deoxy-D-glucose.
HPLC purity: 99.82%
Assay: 99.28 % w/w
Example-8: Preparation of 2-Deoxy-D-glucose
To a solution of (2R.3S.4R)-2-(acetoxynuuhyl)-3.4-dihydro-2H-pyran-3.4-diyi diacetate. Acetone and water, diluted sulphuric acid was added for adjust pH of 2.0 - 3.0. The reaction mass was stirred for 16 h at 20 - 30 °C After complete conversion of (2R.3S.4R)-2-(aceioxymc,thyl)-3.4-dihydro-2H-py!'an-j.4-di>! diacetate. Barium carbonate was added for neutralize the reaction mass. Charcoal was added into resultant reaction mass ar.d stirred for

30 minute at RT, The resultant filtrate mL was distilled out under vacuum at below 50 °C to get oily residue, which is used for further step. To a solution of water and Methanol, Anion resin was added at 20 - 25°C. The reaction mixture was stirred for 3 h at 20 - 25 °C. The progress of reaction was checked by TLC. The reaction mass pH was adjusted with cation resin, distilled the methanol/water under vacuum to get oily residue, which is used next step without further process. To a solution of methanol stirred at 40 - 50 °C for 1 h. Upon cool to RT. reaction mass become hazy and Acetone was added. The resultant slurry was stirred 12 h at room temperature. The slurry was filtered and washed with Ethyl acetate to give 2-Deoxy-D-glucose.