Field of the invention:
The present invention provides a process for the preparation of amorphous (IS)-1,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol which is represented by the following structural formula-1:
Background of the invention:
(lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol, commonly known as Dapagliflozin. Dapagliflozin is an inhibitor of sodium dependent glucose transporters, used to treat type 2 diabetes. It is developed by Bristol-Myers Squibb in partnership with AstraZeneca. Dapagliflozin was approved as Dapagliflozin (2S)-1,2-propane-diol monohydrate in United States on January 8, 2014 and in Europe On November 12,2012.
Dapagliflozin and its process for the preparation were first disclosed in US6515117 (hereinafter referred as '117). One major step that is involved in the synthesis of Dapagliflozin is the purification of Dapagliflozin. The purification is done by converting the Dapagliflozin into tetra acetylated Dapagliflozin, which readily crystallizes. This compound upon treatment with LiOH.tbO provides Dapaglilfozin as an amorphous glassy off-white solid with purity 94%.
Hence, there is a need in the art to develop Dapagliflozin with high pure and enhanced yield.
Brief description of the invention:
The first aspect of the present invention is to provide a process for the preparation of amorphous (1S)-1,5 -anhydro-1 -C- [4-chloro-3 - [(4-ethoxyphenyl)methy ljphenyl] -D-glucitol

compound of formula-1.
The second aspect of the present invention is to provide a process for the purification of amorphous (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol compound of formula-1.
Detailed description of the invention:
The term "suitable solvent" used in the present invention is selected from, but not limited to "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; "ether solvents" such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents" such as toluene, hexane, N-heptane, pet ether, xylene, cyclohexane and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone and the like; "ketone solvents" such as acetone, methylethyl ketone, methylisobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like; "chloro solvents" such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like; "nitrile solvents" such as acetonitrile, butyronitrile, isobutyronitrile and the like; "polar solvent" such as water or mixtures thereof.
The term "solvate" used herein the present invention refers to a crystalline compound in which molecules of solvents are incorporated into the crystal lattice of Dapagliflozin. The term "glycerol solvate" refers to a crystalline dapagliflozin containing glycerol molecules in its crystal lattice.
The first aspect of the present invention provides a process for the preparation of amorphous (1S)-1,5 -anhydro-1 -C- [4-chloro-3 - [(4-ethoxyphenyl)methyl]phenyl] -D-glucitol compound of formula-1, comprising of:
a) Treating (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)
phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate with a mild base selected from alkali metal carbonates and bicarbonates in a suitable solvent to provide (1S)-1,5-anhydro-1 -C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol compound of
formula-1,
b) converting the compound of formula-1 into its glycerol solvate by treating it with glycerol in a suitable solvent,
c) dissolving the glycerol solvate in a suitable solvent, washed with water and then distilling off the solvent to provide pure compound of formula-1,
d) optionally, isolating the obtained compound of formula-1 from a suitable solvent provides amorphous compound of formula-1.
Wherein,
in step-b), c) & d) the suitable solvent used is selected from ether solvents, ester solvents, nitrile solvents, alcoholic solvents, polar aprotic solvents, polar solvents, ketone solvents, chloro solvents, hydrocarbon solvents or mixtures thereof.
The preferred embodiment of the present invention provides a process for the preparation of amorphous (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxylmethyl)tetrahydro-2H-pyran-3,4,5-triol compound of formula-1, comprising of:
a) Treating (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl) phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate with sodium carbonate in aqueous methanol to provide (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl) methyl] phenyl] -D-glucitol compound of formula-1,
b) converting the compound of formula-1 into its glycerol solvate by treating it with glycerol in water,
c) dissolving the glycerol solvate in methyltertiarybutyl ether, washed with methanol and then distilling off the solvent to provide pure compound of formula-1,
d) isolating the obtained compound using N-heptane provides amorphous compound of formula-1.
The second aspect of the present invention is to provide a process for the purification of amorphous (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol compound of formula-1, comprising of:
a) Adding a suitable solvent to the compound of formula-1,
b) treating the reaction mixture with charcoal,
c) distilling of the solvent completely from the reaction mixture,
d) adding a suitable solvent to the compound obtained in step-c),
e) stirring the reaction mixture,
f) filtering the solid and drying to get the pure amorphous compound of formula-1. Wherein,
in step-a) the solvent used is selected from alcohol solvents; and
in step-d) the solvent used is selected from hydrocarbon solvents and ether solvents.
The preferred embodiment of the present invention provides a process for the purification of amorphous (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl]-D-glucitol compound of formula-1, comprising of:
a) Adding methanol to the compound of formula-1,
b) treating the reaction mixture with charcoal,
c) distilling of the solvent completely from the reaction mixture,
d) adding N-heptane to the compound obtained in step-c),
e) stirring the reaction mixture,
f), filtering the solid and washed with N-heptane and drying to get the pure amorphous compound of formula-1.
The above obtained highly pure (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl) methyl]phenyl]-D-glucitol compound of formula-1 of the present invention can be utilized for the preparation of (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl]-D-glucitol (S)-l,2-propane-diol monohydrate and also in the preparation of pharmaceutical composition.
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation of the scope of the invention

Examples:
Example-1: Preparation of (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl]-D-glucitol compound of formula-l through glycerol solvate formation using sodium carbonate as a base for deacetylation
Step-a) (1 S)-l ,5-anhy dro-l-C- [4-chloro-3- [(4-ethoxyphenyl)methyl] phenyl] -D-glucitol glycerol solvate
A mixture of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl) phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (100 gms), methanol (900 ml) and water (100 ml) was stirred for 30 mins at 25-30°C. Sodium carbonate (165.3 gms) was added to the reaction mixture at 25-30°C, heated to 45-50°C and stirred for 8 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 15 mins at the same temperature. Filtered the reaction mixture, washed with methanol and then distilled off the solvent from the filtrate under reduced pressure. A mixture of water (500 ml) and methyl tert.butyl ether (500 ml) was added to the obtained compound and stirred for 10 mins at 25-30°C. Separated both the organic and aqueous layers, combined the organic layer and washed with water and distilled off the solvent from the filtrate under reduced pressure to get (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol compound of formula-l. Purity: 99.1% Step-b) Preparation of Glycerol Solvate of compound of formula-l:
Water (1000 ml) was added to the obtained compound at 25-30°C and stirred for 20 mins. Heated the reaction mixture to 80-85°C and stirred for 1 hr 30 mins. Cooled the reaction mixture to 25-30°C. Glycerol (19.15 gms) and water (50 ml) were added to the reaction mixture at 25-30°C and stirred for 30 mins at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 2 hrs at the same temperature. Further cooled the reaction mixture to 2-8°C and stirred for 9 hrs. Filtered the precipitated solid, washed with water to get (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol glycerol solvate.
Step-c) Preparation of (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl]-D-glucitol compound of formula-l
Methyl tert.butyl ether (1200 ml) was added to the solid obtained in step-(b) at 25-30°C. A solution of sodium chloride and water was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 35-45°C and stirred for 20 mins at 25-30°C. Separated both the organic and aqueous layers. Combined the organic layers and washed with sodium chloride solution at 35-45°C. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound as a residue.
Step-d) Preparation of amorphous (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl) methyl] phenyl]-D-glucitol compound of formula-1
Methanol (50 ml) was added to the residue obtained in step-(c) and stirred for 20 mins at 25-30°C. Distilled off the solvent completely from the reaction mixture under reduced pressure. Methanol (500 ml) and carbon (10 gm) was added to the obtained compound and stirred for 20 mins at 40-50°C. Filtered the compound through hyflow bed and washed with methanol followed by distilled off the solvent completely under reduced pressure. N-heptane (200 ml) was added to the obtained solid and stirred the reaction mixture for 15 mins at 25-30°C. Filtered the solid and washed with N-heptane and dried to get the amorphous compound of formula-1. Yield: 60 gms; Purity by HPLC: 99.6%.

We Claim:
1. A process for the preparation of amorphous (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxy
phenyl)methyl]phenyl]-D-glucitol compound of formula-1, comprising of:
a) Treating (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl) phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate with a mild base selected from alkali metal carbonates and bicarbonates in a suitable solvent to provide (IS)-1,5-anhydro-1 -C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol compound of formula-1,
b) converting the compound of formula-1 into its glycerol solvate by treating it with glycerol in a suitable solvent,
c) dissolving the glycerol solvate in a suitable solvent, washed with water and then distilling off the solvent to provide pure compound of formula-1,
d) optionally, isolating the obtained compound of formula-1 from a suitable solvent provides amorphous compound of formula-1.
2. The process according to claim-1, wherein, in step-b), c) & d) the solvent used is selected from ether solvents, ester solvents, nitrile solvents, alcoholic solvents, polar aprotic solvents, polar solvents, ketone solvents, chloro solvents, hydrocarbon solvents or mixtures thereof.
3. A process for the preparation of amorphous (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxy
benzyl)phenyl)-6-(hydroxylmethyl)tetrahydro-2H-pyran-3,4,5-triol compound of
formula-1, comprising of:
a) Treating (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl) phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate with sodium carbonate in aqueous methanol to provide (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl] -D-glucitol compound of formula-1,
b) converting the compound of formula-1 into its glycerol solvate by treating it with glycerol in water,
c) dissolving the glycerol solvate in methyltertiarybutyl ether, washed with methanol

and then distilling off the solvent to provide pure compound of formula-1, d) isolating the obtained compound using N-heptane provides amorphous compound of formula-1.
4. Aprocess for the purification of amorphous (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-ethoxy
phenyl)methyl]phenyl]-D-glucitol compound of formula-1, comprising of:
a) Adding a suitable solvent to the compound of formula-1,
b) treating the reaction mixture with charcoal,
c) distilling of the solvent completely from the reaction mixture,
d) adding a suitable solvent to the compound obtained in step-c),
e) stirring the reaction mixture,
f) filtering the solid and drying to get the pure amorphous compound of formula-1.
5. The process according to claim-4, wherein, in step-a) the solvent used is selected from alcohol solvents; and in step-d) the solvent used is selected from hydrocarbon solvents and ether solvents.
6. A process for the purification of amorphous (lS)-l,5-anhydro-l-C-[4-chloro-3-[(4-
ethoxyphenyl)methyl] phenyl]-D-glucitol compound of formula-1, comprising of:
a) Adding methanol to the compound of formula-1,
b) treating the reaction mixture with charcoal at 40-5 0°C,
c) distilling of the solvent completely from the reaction mixture,
d) adding N-heptane to the compound obtained in step-c) at 25-30°C,
e) stirring the reaction mixture,
f) filtering the solid and washed with N-heptane and drying to get the pure amorphous compound of formula-1.
7. The process according to any of the preceding claims, the solvent used for isolation of
compound of formula-1 is N-heptane.
8. The amorphous compound of formula-1 obtained from any of the preceding claims is useful in the pharmaceutical composition.