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Title:
PROCESS FOR THE PREPARATION OF DAPAGLIFLOZIN AND ITS SOLVATE THEREOF
Document Type and Number:
WIPO Patent Application WO/2017/221211
Kind Code:
A1
Abstract:
The present invention provides for crystalline Dapagliflozin butane –1,2– diol solvate (VIII), crystalline Dapagliflozin (S) butane –1,2– diol solvate (VIIIa) and Dapagliflozin (R) butane –1,2– diol solvate (VIIIb). The present invention also provides industrial methods for production of crystalline Dapagliflozin butane –1,2– diol solvate (VIII), crystalline 5 Dapagliflozin (S) butane –1,2– diol solvate (VIIIa) and Dapagliflozin (R) butane –1,2– diol solvate (VIIIb). The present invention further provides an industrial method production of amorphous Dapagliflozin.

Inventors:
ASWATHANARAYANAPPA CHANDRASHEKAR (IN)
CHANDRA KUMAR SATEESH ROTTE (IN)
SHIVALINGAPPA MANJUNATHA (IN)
CHARYULU PALLE VENKATA RAGHAVENDRA (IN)
SHEKHARAPPA BHEEMA RAO BEGUR (IN)
VENKAT NOOKAAPPA RAO GORLI (IN)
Application Number:
PCT/IB2017/053768
Publication Date:
December 28, 2017
Filing Date:
June 23, 2017
Export Citation:
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Assignee:
BIOCON LTD (IN)
International Classes:
C07H7/04; A61K31/70; A61P3/10; C07C31/20; C07D309/10
Domestic Patent References:
WO2015132803A22015-09-11
WO2004063209A22004-07-29
WO2016178148A12016-11-10
Foreign References:
US20130303467A12013-11-14
US20060009400A12006-01-12
US6414126B12002-07-02
US20170166547A12017-06-15
Attorney, Agent or Firm:
MAJUMDAR, Subhatosh et al. (IN)
Download PDF:
Claims:
C L AIMS

A process for the preparation of crystalline Dapagliflozin 1,2-butanediol solvate, comprising:

a) Hydrolysing a compound of formula V I to a compound of formula V II i n presence of a base using a bi phasic solvent medium b) Separating the layers

c) Adding 1,2-butanediol and water to the compound V II

d) Isolating crystal line Dapagliflozin 1,2-butanediol solvate.

3a 2. Dapagliflozin 1,2-butanediol solvate.

3. A crystalline Dapagliflozin 1,2-butanediol solvate.

4. A crystalline Dapagliflozin 1,2-butanediol solvate of claim 3, characterized by an X - ray powder diffraction (X R PD) spectrum having peak reflections at about 3.9, 15.2, 15.7, 17.1, 19.0, 20.0, 20.3 and 21.6 e0.2 degrees 2 theta.

¾ 5. Dapagliflozin 1,2-butanediol solvate of any of the precedi ng claims in the form of monohydrate.

6. Dapagliflozin (S) - 1,2-butanediol solvate.

7. A crystalline Dapagliflozin (S) - 1,2-butanediol solvate.

8. A crystalline Dapagliflozin (S)- 1,2-butanediol solvate of claim 7, characterized by an iti X -ray powder diffraction (X R PD) spectrum having peak reflections at about 3.7, 15.1,

17.0, 18.9, 19.7 and 21.3 e0.2 degrees 2 theta.

9. A process for the preparation of crystalline Dapagliflozin (S)- 1,2-butanediol solvate, the process comprisi ng:

a) Hydrolysing a compound of formula V I to a compound of formula V II i n presence ¾ of a base usi ng a bi phasi c solvent medi um

b) Separating the layers

c) Adding (S)-1,2-butanediol and water to the compound V II

d) Isolating crystal line Dapagliflozin (S)- 1,2-butanediol solvate.

¾ 10. Dapagliflozin (S) - 1,2-butanediol solvate of any of the preceding claims 6 to 9 in the form of monohydrate.

11. Dapagliflozin (R) - 1,2-butanediol solvate.

12. A process for the preparation of Dapagliflozin (R)- 1,2-butanediol solvate, the process comprising:

3a a) Hydrolysing a compound of formula V I to a compound of formula V II in presence of a base using a bi phasic solvent medium b) Separating the layers

c) Adding (R)-1,2-butanediol and water to the compound V II

d) Isolating Dapagliflozi n (R)- 1,2-butanediol solvate.

13. A process for the preparation of Dapagliflozin amorphous forrn the process comprising:

a) Hydrolysing a compound of formula V I to a compound of formula V II i n presence of a base and using a bi phasic solvent medium

tin

b) Separating the layers

c) Isolating the amorphous Dapagliflozin.

14. Biphasic solvent medium according to any of the preceding claims comprising n- butanol -water, methyl ethyl ketone- water, methyl isobutyl ketone "water, methyl tert- butyl ether "water toluene-water and the like.

15. Biphasic solvent medium according claim 14 comprising n-butanol -water.

¾ 16. A compound 2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl)-4H-pyran-4- one of formula X III.

17. A compound (2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl) phenyl) (4-ethoxyphenyl) methanone of formula X IV .

18. A process for the preparation of Dapagl iflozin- 1,2-butanediol solvate from crude Dapagliflozin without subjecting to acetylation step.

19. A process for the preparation of Dapagliflozin (S)- 1,2-butanediol solvate from crude Dapagliflozin without subjecting to acetylation step.

20. A process for the preparation of Dapagliflozin (R)- 1,2-butanediol solvate from crude Dapagliflozin without subjecting to acetylation step.

21. A process for preparation of amorphous Dapagliflozin compound from Dapagliflozin - 1,2-butanediol solvate.

22. A process for preparation of amorphous Dapagliflozin compound from Dapagliflozin (S)- 1,2-butanediol solvate.

23. A process for preparation of amorphous Dapagliflozin compound from Dapagliflozin (R)- 1,2-butanediol solvate.

24. Highly pure C rystal I i ne Dapagliflozin- 1,2-butanediol solvate wherein impurity 2-(4- chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl)-4H-pyran-4-one of formula X III is less than 0.15 %.

25. Highly pure Crystalline Dapagliflozin- 1,2-butanediol solvate wherein impurity (2- chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H- pyran-2-yl) phenyl) (4-ethoxy phenyl) methanone of formula X IV is less than 0.15 %.

26. Highly pure C rystalline Dapagliflozin- 1,2-butanediol solvate wherein impurity ((2R,3S,4R,5R,6S)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4,5- trihydroxytetrahydro-2H-pyran-2-yl)methyl acetate of formula X V is less than 0.15 %.

27. Highly pure C rystall ine Dapagliflozin (S)- 1,2-butanediol solvate wherein impurity 2- (4-chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl)-4H-pyran-4-one of formula X III is less than 0.15 %.

28. Highly pure Crystalline Dapagliflozin (S)- 1,2-butanediol solvate wherei n impurity (2- chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H- pyran-2-yl) phenyl) (4-ethoxy phenyl) methanone of formula X IV is less than 0.15 %. > ^Highly pure Crystalline Dapagliflozin (S)- 1,2-butanediol solvate wherein impurity ((2R,3S,4R,5R,6S)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4,5- trihydroxytetrahydro-2H-pyran-2-yl) methyl acetate of formula X V is less than 0.15 %.

Description:
PROCESS FOR THE PREPARATION OF DAPAGLIFLOZIN AND ITS

SOLVATE THEREOF

Related Application:

¾ This application claims the benefit of priority of our Indian patent application number IN 201621021835 filed on J une 24, 2016 which is incorporated herein by reference.

TECHNICAL FIELD

The present inventi on relates to a novel process for the preparation of (2S, 3R, 4R, 5S, 6R)- 3a 2-(4-chloro-3-(4-ethoxybenzyl) phenyl )-6-(hydroxymethy I) tetrahydro-2H-pyran-3, 4, 5- triol [Dapagliflozin] represented by the structural Formula-VII, and its butane-1,2-diol solvate.

BACKGROUND AND PRIOR ART OF THE DISCLOSURE

¾ Dapagliflozin (FARXIGA) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor

1 ndi cated as an adjunct to diet and exercise to improve glycemic control in adults with type

2 diabetes mellitus.

Dapagliflozin approved as D-glucitol, 1, 5-anhydro-1-C-[4-chloro-3-[(4ethoxyphenyl) methyl] phenyl]-, (1S)-, compounded with (2S)-1, 2- propanediol, hydrate (1:1:1) in United iti States on January 08, 2014 and in Europe on November 12, 2012. Dapagliflozin and its process for the preparati on were f i rst disci osed i n U S 6515117.

The purification step involves conversion of crude Dapagliflozin into tetra acetylated Dapagliflozin, which readily crystallizes. This compound upon treatment with LiOH.H 2 0 provides Dapaglilfozin as an amorphous glassy off-white solid with purity 94%. Hence, ¾ there is a need in the art to develop a process which not only overcomes the disadvantages of prior art but also is economical, operationally simple and industrially applicable to yield Dapagliflozin with high purity. V arious crystalline forms of Dapagliflozi n, its solvates, complexes, co-crystals solid dispersions are reported earlier.

PCT Publication No. WO 2008002824 (A 1 ) discloses various solvates of dapagliflozin and its pharmaceutically acceptable salts. The solvates disclosed are crystalline dapagliflozin ¾ (S)-propylene glycol ((S)-PG) structure la designated as form SC-3, dapagliflozin ( R)- propylene glycol ((R)-PG) structure lb designated as form SD-3, dapagliflozin mono- ethanol dihydrate structure Ic designated as form SA-1, dapagliflozin ethylene glycol structure Id designated as form SB-1, dapagliflozin ethylene glycol structure Ie designated as form SB-2, dapagliflozin 1 :2 crystalline complex with L-proline structure I h designated 3a as form 3, dapagliflozin 1:1 crystalline complex with L-proline structure li designated as form 6, dapagliflozin hemi hydrate of the 1 : 1 crystalline complex with L-proline structure Ij designated as form H.5-2 and dapagliflozin 1:1 crystal l ine complex with L phenylalanine structure Ik designated as form 2.

¾ PC T Publ i cati on N o. WO 2012163546 ( A 1 ) disci oses i ncl usi on complexes of dapagl i f I ozi n and cyclodextrin, and processes for their preparation.

PCT Publication No. WO 2013079501 (A1 ) discloses the crystalli ne dapagliflozin hydrate and a process of obtaining the same.

da

PCT Publication No. WO2014178040 (A 1 ) discloses the dapagliflozin lactose cocrystal and a dapagl iflozin asparagine co-crystal.

PCT Publication No. WO2015011113 (A 1 ) discloses the dapagliflozin amorphous solid ¾ dispersion of at least one suitable polymer, polymer is selected from the group consisting of polyvinyl pyrrolidone (PV P), polyvinyl alcohol (PVA), polyacrylic acid (PAA), poly( ethylene glycol) (PEG), poly( ethylene oxide) (PEO), hydroxypropyl cellulose (H PC), hydroxypropyl methyl cel lulose 5 (H PMC), copovidone, hypromel lose acetate succinate (AQOAT), polyacrylates and mixtures thereof.

PCT Publication No. WO2015104658 (A 1 ) discloses the dapagliflozin amorphous solid dispersion with pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, hydroxy propyl methyl celluloses, hydroxypropyl celluloses or hydroxypropyl methyl eel I ulose acetate succinate.

C hinese patent application C N104829573 A discloses a crystalline form of dapagliflozin ¾ characterized by an X -ray powder diffraction (X R PD) spectrum having peak reflections at about 4.4, 4.8, 5.4, 7.7, 10.6, 15.3, 15.4 and 20.2 degrees 2 theta and processes for its preparation.

PCT Publication No. WO2015117538 (A1 ) discloses a crystalline form of dapagliflozina characterized by an X -ray powder diffraction (X R PD) spectrum having peak reflection at about 4.318 degrees 2 theta and processes for its preparation.

US patent publication US2015307540 (A1 ) discloses an amorphous form of dapagliflozin 1,2- propanediol or hydrates thereof and their process for preparation.

R

PCT Publication No. WO2016155578 (A 1) discloses crystal form I of Dapagliflozin characterized by an X -ray powder diffraction (X R PD) spectrum having peak reflections at about 15.8¾ 19.8e and 28.7ee0.2 degrees 2 theta and processes for its preparation.

PCT Publication No. WO2015132803 (A 1 ) discloses dapagliflozin glycerol solvate in parti cular crystal I ine form-M of dapagliflozin glycerol solvate.

PCT Publication No. WO2015198227 (A 1 ) discloses dapagliflozin- citric acid cocrystal and processes for its preparation.

PCT Publication No. WO2016178148 (A 1 ) discloses a crystalline 2,3-butanediol solvate of dapagliflozin characterized by an X -ray powder diffraction (X R PD) spectrum having peak reflections at about 3.7, 9.6, 14.7, 16.7 and 18.4 e0.2 degrees 2 theta and processes for its preparation.

PCT Publication No. WO2017046730 (A 1 ) discloses a crystalline 2,3-butanediol solvate of dapagliflozin characterized by an X -ray powder diffraction (X R PD) spectrum having peak reflections at about characterized by X -Ray powder diffraction (X R D) pattern having one or more peaks at about 3.69, 8.62, 9.52, 10.70, 14.63, 15.74, 16.09, 16.60, 18.33, 18.55, 19.82, 20.15, 20.56, 21.20, 21.79, 22.75, 23.39, 24.23, 24.68, 25.15, 25.76, 26.50, 27.03, 27.36, 29.48, 29.94, 30.60, 31.66, 32.56, 34.21 and 36.95e0.2e2 theta and processes for its ¾ preparation. This PCT publication also discloses Co-crystals of Dapagliflozin and DL- pipecolic acid, characterized by an X -Ray powder diffraction (X R D) pattern having one or more peaks at about 3.91, 7.83, 8.41, 9.38, 11.76, 15.38, 15.65, 16.26, 16.99, 17.62, 17.95, 18.36, 19.96, 20.28, 21.29, 21.97, 23.02, 23.65, 24.68, 26.72, 30.43 and 31.34 e0.2e and processes for its preparation, This PCT publication also discloses co-crystals of 3a Dapagliflozin and D-pipecolic acid and co-crystals of Dapagliflozin and L-pipecolic acid.

Advantages of present invention:

C rystalline forms when compared to the amorphous form often show desired different physical and/or biological characteristics which usually contributes in the manufacture or ¾ formulation of the active compound, to the purity levels and uniformity required for regulatory approval. Hence, it is desirable to provide the pharmaceutically active ingredient in a substantially pure, crystall ine and stable form of A PI.

Furthermore, the provision of further crystal line forms of a pharmaceutically useful compound offers an opportunity to improve the performance profile of a pharmaceutical iti product. In particular, not all solid forms of a pharmaceutically useful compound are equally suited for development of a pharmaceutical dosage form It is therefore desirable to widen the reservoir of materials a formulation scientist can select from, such that he can design a new dosage form of a drug having improved characteristics.

The technical problem underlying the present invention is the provision of a crystalline ¾ form comprisi ng dapagl i f I ozi n and the provi si on of a process for obtai ni ng the same i n high yield and high purity.

It is therefore an object of the present invention to provide a highly reproducible and economical process of providing dapagliflozin in a substantially pure crystalline solvate form Furthermore, it would be desirable to provide a sol id form of dapagliflozin solvate til showi ng improved physical and/or biological characteristics which may assist i n the manufacture or formulation of the active compound, to the purity levels and/or uniformity required for regulatory approval. The technical problem is solved by crystalline dapagliflozin 1,2 butane diol solvate monohydrate.

Dapagliflozin was subjected to solvation studies using different 1,2 butanediols with respect to crystallinity trials. The 1, 2-butanediol, (S)-1, 2-butanediol and (R)-1, 2-

¾ butanediol were tested for the solvate formation with amorphous dapagliflozin. Solvates with 1, 2-butanediol and (S)-1, 2-butanediol with dapagliflozin resulted in excellent crystalline forms which were highly pure, filterable, reproducible and stable crystalline solids. Whereas, solvation of amorphous dapagliflozin with (R)-1, 2-butanediol solvate did not result in formation of a filterable solid. It appears like the dapagliflozi n ( R)-1,2-

3a butanediol solvate has a very low melting nature.

A morphous dapagliflozin process using bi phasic solvent medium:

Another object of the present invention is to prepare amorphous (2S, 3R, 4R, 5S, 6R) " 2-

(4-chloro-3- (4-ethoxy benzyl) phenyl )-6-( hydroxy methyl) tetrahydro-2H-pyran-3, 4, 5-

¾ triol (V II). (2R, 3R, 4R, 5S, 6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4- ethoxybenzyl) phenyl) tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (V I) is converted to (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4-ethoxy benzyl) phenyl )-6-( hydroxy methyl) tetrahydro-2H-pyran-3, 4, 5-triol (V II) (deprotection of acetyl group) using action of an alkali i nvolving a reaction with bi phasic solvent medium

iti Major challenge in this deprotection reaction is to avoid monoacetyl impurity i.e compound of formula X V and drive the reaction for completion. Reaction with bi phasic solvent medium facilitate the removal of aqueous sodium hydroxide layer and charge fresh lot of sodium hydroxide solution, even if reaction does not goes for completion in the stipulated time.

¾ Biphasic solvent medium reaction provides advantage of easy layer separations in the plant scale operations and n-butanol can be recovered significantly.

M onoacetyl impurity: ((2R,3S,4R,5R,6S)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4, 5- trihydroxytetrahydro-2H-pyran-2-yl) methyl acetate compound of formula X V

This reaction with biphasic solvent medium is aided by the usage of water immiscible organic solvents such as n-butanol, methyl ethyl ketone, methyl isobutyl ketone, methyl tert- butyl ether toluene and the like in combination with water could be used as bi phasic solvent mixture. n-Butanol - water combination was used as a preferred biphasic solvent of choice owing to its ease of operation, better reaction purity and significant recovery of n- butanol after reaction in the plant scale. The advantage of this process being that achieving highly pure amorphous dapagliflozin with greater than 99.5 % purity without need of any purification steps.

B R IE F DE SC R IPTION OF T H E FIG U R E S

In order that the disclosure may be readily understood and put into practical effect, reference will now be made to exemplary embodiments as illustrated with reference to the accompanying figures. The figures together with a detailed description below, are incorporated in and form part of the specification, and serve to further ill ustrate the embodiments and explain various principles and advantages, in accordance with the present disclosure wherei n:

F igure 1 shows the X R D of crystal line form of Dapagliflozin-1,2- butanediol monohydrate (V III)

F igure 2 shows the DSC of crystal line form of Dapagliflozin-1,2- butanediol monohydrate (V III)

F igure 3 shows the IR of crystalline form of Dapagliflozin-1,2- butanediol monohydrate (V III)

F igure4 shows theTGA of crystal line form of Dapagliflozin-1,2- butanediol monohydrate (V III) F igure 5 shows the X R D of crystalline form of Dapagliflozin (S)-1,2- butanediol monohydrate

(V illa).

F igure 6 shows the DSC of crystalline form of Dapagliflozin (S)-1,2- butanediol monohydrate

(V illa).

F igure 7 shows the IR of crystalline form of Dapagliflozin (S)-1,2- butanediol monohydrate

(V illa).

F igure 8 shows the TGA of crystalline form of of Dapagliflozin (S)-1,2- butanediol monohydrate (V illa).

The method of analysis of the compounds represented in the figures as above are as below: PX R D analysis

About 300 mg of powder sample was taken onto the sample holder and was tightly packed on the sample holder uniformly by means of glass slide and Powder X -ray diffraction was recorded on Bruker D8 Advance diffractometer (Bruker-AX S, Karlsruhe, Germany) using ¾ C u-K X -radiation (≡ = 1.5406 j ) at 40 kV and 30 mA powder.X -ray diffraction patterns were col I ected over the 2 : :range 3 " 50e at a scan rate of 1 e mi n.

DSC Analysis

DSC was performed on a Mettler Toledo DSC 822e module. 4-6 mg of sample was placeda i n cri mped but vented al umi ni um sample pans. T he temperature range was from 30-250 eC @ 10 eC/min. Samples were purged by a stream of nitrogen flowing at 80 mL/min.

IR Anlaysis

IR was performed on a Fisher Scientific (NICOL ET-iS50-FTIR). About 5 mg of sample was spread over the region of diamond AT R sampling station and collected the sample spectrum between 4000 cm-1 to 400 cm-1 to obtain a spectrum of suitable intensity (above 60 % transmission at 2000 cm-1). DE TAIL E D DE SC R IPT ION O F T H E I NV E NT IO N

The term "suitable solvent" used in the present invention is selected frorn but not l imited to "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate ¾ and the like; "ether solvents" such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MT BE), 1 ,4-dioxane and the like; "hydrocarbon solvents" such as toluene, hexane, heptane, pet ether, xylene, cyclohexane and the li ke; "polar aprotic solvents" such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N- methyl -2- pyrrol i done and the like; "ketone solvents" such as 3a acetone, methylethyl ketone, methyl isobuty I ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like; "chlorinated solvents" such as dichloromethane, chloroforrn dichloroethane, carbon tetrachloride and the like; "nitrile solvents" such as acetonitrile, butyronitrile, isobutyronitrile and the like; "polar solvent" such as water or mixtures thereof.

¾ 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 " butane- 1,2-diol solvate" refers to a crystall ine dapagliflozin containing butane-1,2- diol molecules i n its crystal lattice.

The term ' hydrate , used herein the present invention refers to a crystalline compound in iti which molecules of water are incorporated into the crystal lattice of Dapagliflozin butane- 1 ,2-diol. T he term " hydrate" refers to a crystal I i ne Dapagl if I ozi n butane- 1 ,2-di ol contai ni ng water molecules in its crystal lattice.

The term "suitable base" used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides" such as lithium hydroxide, sodium ¾ hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassi um carbonate, lithium carbonate and the like; "alkal i metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium tert- tii butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia; and organic bases such as triethyl amine, methyl amine, ethyl amine, 1,8- Diazabicyclo[5.4.0] undec-7-ene (DBU), l,5-Diazabicyclo(4.3.0)non-5-ene (DBN), lithium dioisoporpylamide (L DA), n-butyl lithiurn tribenzylamine, isopropyl amine, diisopropylamine (DIPA), di isopropyl ethyl amine (DIPEA), N- methyl morpholine (NM P), ¾ N-ethyl morpholine, piperidine, di methylaminopyri di ne ( DMA P), Boron tri fluoride ethyl etherate (B F3.Et20), morphol ine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1- methyl imidazole, 1,2,4-triazole, 1,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.

The term ' reduci ng agent , used herein present i nvention until unless specified is selected 3a from reducing agents like triethyl silane, tri methyl silane, triisopropyl silane and the like.

The term ' acetyl ating agent , used herein present invention until unless specified is selected from acetyl chloride and acetic anhydride.

The present invention relates to a novel process for the preparation of (2S, 3R, 4R, 5S, 6R) "2- (4-chloro-3- (4-ethoxy benzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol [Dapagliflozin] represented by the structural Formula-VII, and its butane-1,2-diol solvate.

One aspect of the present invention is to provide a (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4- ethoxybenzyl) phenyl )-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol butane-1,2-

¾ diol (1 :1 ) hydrate (V III). The crystalline Dapagliflozin 1,2-butanediol hydrate is characterized by an X -ray powder diffraction (X R PD) spectrum having peak reflections at about 3.9, 15.2, 15.7, 17.1, 19.0, 20.0, 20.3 and 21.6 e0.2 degrees 2 theta. T he crystall ine Dapagliflozin 1,2-butanediol hydrate is characterized by an X -ray powder diffraction (X R PD) spectrum as represented in the figure 1. The crystalline Dapagliflozin 1,2- iti butanediol solvate is in the form of monohydrate. The crystalline Dapagliflozin 1,2- butanediol hydrate is further characterized by a differential scanning calorimetry thermogram having an endotherm at 57.8 °C as shown in figure 2.

Another aspect of the present invention is to provide a (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3- ( 4-ethoxy benzyl) phenyl )-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (S)-butane- ¾ 1,2-diol (1 :1) hydrate (V illa). The crystalline Dapagliflozin (S)- 1,2-butanediol hydrate, characterized by an X -ray powder diffraction (X R PD) spectrum having peak reflections at about3.7, 15.1, 17.0, 18.9, 19.7 and 21.3 e0.2 degrees 2 theta. The crystall ine Dapagliflozin (S)-1,2-butanediol hydrate is characterized by an X -ray powder diffraction (X R PD) spectrum as represented in the figure 5. The crystall ine Dapagliflozin (S)-1,2-butanediol solvate is in the form of monohydrate. The crystalline Dapagliflozin (S)-1,2-butanediol hydrate is further characterized by a differential scanning calorimetry thermogram having an endotherm at 65.5 °C as shown in figure 6.

Another aspect of the present invention is to provide a (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3- (4-ethoxy benzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (R)-butane- 1, 2-diol (1 :1 ) (V HIb)

Another aspect of the present invention is to provide a process for the preparation of (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxy benzyl) phenyl )-6-( hydroxy methyl) tetrahydro- 2H-pyran-3,4,5-triol butane-1, 2-diol (1 :1 ) hydrate (V III) directly by hydrolyzing (2R, 3R, 4R, 5S, 6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4- ethoxybenzyl) phenyl) tetrahydro-2H- pyran-3, 4, 5-triyl triacetate (V I) using a base and a bi phasic solvent medium and without undergoing the isolation of (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4-ethoxybenzyl) phenyl )-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (V II).

Another aspect of the present invention is to provide a process for the preparation of (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxy benzyl) phenyl )-6-( hydroxy methyl) tetrahydro- 2H-pyran-3, 4, 5-triol (S)-butane-l, 2-diol (1 :1 ) hydrate (V III a) directly by hydrolyzing (2R, 3R, 4R, 5S, 6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4- ethoxybenzyl) phenyl) tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (VI) usi ng a base and a bi phasic solvent medium and without undergoing the isolation of (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4- ethoxybenzyl) phenyl )-6-(hydroxymethy I) tetrahydro-2H-pyran-3, 4, 5-triol (V II).

Another aspect of the present invention is to provide a process for the preparation of (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxy benzyl) phenyl )-6-( hydroxy methyl) tetrahydro- 2H-pyran-3,4,5-triol butane-1, 2-diol (1 :1 ) hydrate (V III) without undergoing the acetyl ati on step of crude (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4-ethoxybenzyl) phenyl)- 6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (V ). Another aspect of the present invention is to provide a process for the preparation of (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxy benzyl) phenyl )-6-( hydroxy methyl) tetrahydro- 2H-pyran-3, 4, 5-triol (S)-butane-1,2-diol (1 :1) hydrate (V III a) without undergoing the acetyl ati on step of crude (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4-ethoxy benzyl) phenyl)- 6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (V ).

Another aspect of the present invention is to provide a process for the preparation of (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxy benzyl) phenyl )-6-( hydroxy methyl) tetrahydro- 2H-pyran-3, 4, 5-triol (R)-butane-l, 2-diol ( 1:1 ) (VHIb) without undergoing the acetyl ati on step of crude (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4-ethoxy benzyl) phenyl)-6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (V ).

Another aspect of the present invention is to provide a process for the hydrolysis of (2R, 3R, 4R, 5S, 6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4- ethoxybenzyl) phenyl) tetrahydro- 2H-pyran-3, 4, 5-triyl triacetate (VI) using a bi phasic solvent medium resulting in amorphous (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4-ethoxybenzyl) phenyl)-6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (VII).

Another aspect of the present invention is to provide a process for the preparation of amorphous (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4-ethoxybenzyl) phenyl)-6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (V II) from (2S, 3R, 4R, 5S, 6R)-2-(4- chloro-3-(4-ethoxybenzyl) phenyl )-6-(hydroxymethy I) tetrahydro-2H-pyran-3, 4, 5-triol - butane-1,2-diol ( 1:1 ) hydrate (V III) .

Another aspect of the present invention is to provide a process for the preparation of amorphous (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4-ethoxybenzyl) phenyl)-6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (V II) from (2S, 3R, 4R, 5S, 6R)-2-(4- chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (S)-butane-1,2-diol (1 :1 ) hydrate (V illa). Another aspect of the present invention is to provide a process for the preparation of amorphous (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4-ethoxybenzyl) phenyl)-6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (V II) from (2S, 3R, 4R, 5S, 6R)-2-(4- chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (R)-butane-1,2-diol (1 :1 ) (VHIb).

E ffect of the Invention

The present invention describes the crystalline form of (2S, 3R, 4R, 5S, 6R)-2-(4-chloro- 3-(4-ethoxybenzyl) phenyl )-6-( hydroxy methyl) tetrahydro-2H-pyran-3,4,5-triol butane-

¾ 1,2-diol (1 :1 ) hydrate (V III), its process and a process for the preparation of amorphous form of (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4-ethoxybenzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (V II) with and without following the steps for the preparation of (2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl)-6-(4-chloro-3-(4-Ethoxy benzyl) phenyl) tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (VI) i.e acetylated dapagliflozin.

3a (2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl)-6-(4-chloro-3-(4-Ethoxy benzyl) phenyl) tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (V I) is converted to (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4-ethoxybenzyl) phenyl )-6-( hydroxy methyl) tetrahydro-2H-pyran-3, 4, 5- triol (VII) (deprotection of acetyl group) using action of an alkali involving a biphasic solvent medium This reaction with biphasic solvent medium is necessitated to avoid the

¾ monoacetyl dapagl iflozin impurity i.e ((2R,3S,4R,5R,6S)-6-(4-chloro-3-(4- ethoxy benzyl ) phenyl )-3, 4, 5-th hydroxytetrahydro-2H -py ran-2-yl ) methyl acetate compound of formula XV and other inorganic byproducts, as well as to avoid the formation of undesi red i mpuri ti es at thi s stage.

This reaction biphasic solvent medium is aided by the usage of water immiscible organic iti solvents such as n-butanol, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ether toluene and the l ike in combination with water could be used as biphasic solvent mixture. n-Butanol - water combi nation was used as a preferred biphasic solvent of choice owing to its ease of operation, better reaction purity and significant recovery of n-butanol after reaction in the plant scale. The advantage of this process being that achieving highly ¾ pure amorphous (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4-ethoxybenzyl) phenyl)-6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (VII), (2S, 3R, 4R, 5S, 6R)-2-(4-chloro- 3-(4-ethoxybenzyl) phenyl )-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol butane- 1,2-diol (1 :1) hydrate (V III), (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)- 6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (S)-butane-1,2-diol (1 :1 ) hydrate (V III a) and (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6-

¾ (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (R)-butane-l, 2-diol ( 1 :1 ) (V HIb) with greater than 99.5 % purity without need of any purification steps.

The present invention for the preparation of amorphous (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro- 3- (4-ethoxy benzyl) phenyl )-6-( hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (V II), (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl )-6-( hydroxymethyl)

3a tetrahydro-2H-pyran-3, 4, 5-triol butane- 1, 2-diol (1:1 ) hydrate (VIII), (2S, 3R, 4R, 5S, 6R)- 2-(4-chloro-3-(4-ethoxybenzyl) phenyl )-6-( hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5- triol (S)-butane-l, 2-diol (1 :1 ) hydrate (V III a) and (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4- ethoxybenzyl) phenyl )-6-( hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (R)-butane-l, 2-diol (1 :1) (V HIb) also aides in limiting the impurity ((2R,3S,4R,5R,6S)-6-(4-chloro-3-

¾ (4-ethoxybenzyl)phenyl)-3,4,5-trihydroxytetrahydro-2H-pyran- 2-yl)methyl acetate of formula X V preferably less than 0.15 %, more preferably less than 0.1 %, impurity 2-(4- chloro-3-(4-ethoxybenzyl) phenyl )-6-( hydroxymethyl )-4Hpyran-4-one of formula X III preferably less than 0.15 %, more preferably less than 0.1 % and (2-chloro-5- ((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl) iti phenyl) (4-ethoxyphenyl)methanone of formula X IV preferably less than 0.15 %, more preferably less than 0.1 %.

Some of the key impurities identified in the present invention and steps taken to eliminate or reduce the same are as f ol I ows:

E none Impurity: 2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl)-4H pyran-4- t¾ one

The E none impurity forms in (2S,3R,4S,5S, 6R)-2-(4-chloro- 3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (IV ) stage. It is controlled in the present invention less than 0.15% level at (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4- chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-tr iyl triacetate (VI) stage. ¾ The cause for the formation of this impurity is identified as presence excess of MSA in stage IV .

K eto Impurity: (2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymet hyl) tetrahydro-2H-pyran-2-yl) phenyl) (4-ethoxyphenyl)methanone.

XIV

The Ketone impurity forms as a carried over impurity from starting material I.

Silyl Impurity: (4-chloro-3-(4-ethoxybenzyl)phenyl)trimethylsilane

CS

-Si— XII

I

¾ This silyl impurity forms during (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4- ethoxy benzyl ) phenyl )-6-( hydroxymethy I )tetrahydro-2H - pyran-2,3,4, 5-tetraol (III) preparation. It is controlled in the present invention less than 0.15% level at (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybe nzyl)phenyl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (V I) stage.

tin

E X AM PL E S

Scheme I:

Scheme-II Scheme III:

The Scheme-I of the present invention provi des a crystal line form of (2S, 3R, 4R, 5S, 6R)- 2-(4-chloro-3-(4-ethoxybenzyl) phenyl )-6-( hydroxymethyl) tetrahydro-2H pyran- 3,4,5- triol butane- 1,2-diol (1:1 ) monohydrate (V III) and processes for its preparation.

The Scheme II of the present invention provides (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4- ethoxybenzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H pyran- 3,4,5-triol (R) butane-1,2- diol (1 :1 ) (V HIb) and (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6- ( hydroxymethyl) tetrahydro-2H pyran- 3,4,5-triol (S) butane-1,2-diol (1 :1 ) monohydrate (V illa) and its process for preparation from (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4- ethoxybenzyl) phenyl)-6- (hydroxymethyl) tetrahydro-2H- pyran- 3,4,5-triol (V ) without undergoing the purification step of acetylation or (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4- ethoxybenzyl) phenyl)-6- (hydroxymethyl) tetrahydro-2H-pyran- 3,4,5-triol (V II) after undergoing the purification step of acetylation.

T he Scheme-Ill of the present i nventi on provides a process for the preparati on of crystal I i ne form of (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6- (hydroxymethyl) tetrahydro-2H- pyran- 3,4,5-triol butane- 1,2-diol ( 1:1 ) hydrate (V III) without involving the need to proceed through the step for the preparation of (2R, 3R, 4R, 5S, 6S)-2- (acetoxymethyl)-6-(4-chloro-3-(4- ethoxybenzyl) phenyl) tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (V I) thereby eliminating two steps of acetylation and deprotection. E xample 1 : Preparation of (3R , 4S, 5R , 6R )-3, 4, 5- tris ((trimethylsilyl) oxy)-6- (((tri methylsilyl) oxy) methyl) tetrahydro-2H -pyran-2-one (II)

(3R, 4S, 5S, 6R)-3, 4, 5-th hydroxy- 6-( hydroxy methyl) tetrahydro-2H-pyran-2-one (glucono -lactone) (0.56 mol) was taken in to a R BF and T H F (1000 ml) was added under nitrogen. N-Methyl Morpholine (4.04 mol) was added to the above glucono lactone solution and cooled the reaction mass to OeC and trimethylsilyl chloride (3.36 mol) was added dropwise at 0 eC over 2 h [Care taken to keep the internal temperature is maintained below 5eC during addition]. T he reaction mass for stirred for 18 h at room temperature. T he reacti on mass was quenched with water (500 ml ) at room temperature and ethyl acetate (500 ml) was added to it. Stirred the reaction mass for 30 min. and separated the layers. Organic layer was washed with water (500 ml) followed by 1.5N HC I (500 ml) followed by brine solution (500 ml) and dried over anhydrous sodium sulphate. Organic layer was concentrated under vacuum to yield the compound II (240 gm, 0.51 mol.).

E xample 2: Preparation of (2S, 3R , 4S, 5S, 6R )-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-2, 3, 4, 5-tetraol (III)

T o a sol uti on of compound I ( 0.3 mol ) i n T H F ( 1000 ml ) under ni trogen was added n- butyl lithium (0.38 mol.) solution over a period of 1 h at -78eC. The reaction mixture was stirred for 60-90 minutes at the same temperature under nitrogen. Add tetra trimethylsilyl glucono I actone II ( 0.40 mol ) i n T H F . T he reacti on mass was sti rred for 2.5 h at -78eC . T he reacti on mass was quenched wi th aqueous tri f I uoroaceti c aci d and extracted i n to ethyl acetate ( 1000 ml). The aqueous layer was re-extracted with ethyl acetate (2 X 500 ml). Combined organic layers wash with water (1 X 500 ml) followed by brine (1 X 500 ml) and dried over anhydrous sodium sulphate and concentrated under vacuum to get the Compound III as crude.

E xample 3: Preparation of (2S, 3R , 4S, 5S, 6R )-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3, 4, 5-triol (IV ) Compound III (100 gm, 0.23 mol.) solution in methanol (1000 ml) under nitrogen atmosphere at room temperature was added Methanesulfonic acid (0.11 mol.) at room temperature and continue stirring for 6 h. After 6 h, reaction mass was concentrated to get the syrup which was dissolved in dichloromethane (1000 ml) and 10% NaHC03 (500 ml) was added to it and stirred for 20 min and separated the layers. Organic layer was washed with brine solution (500 ml), dried over anhydrous sodium sulphate and concentrated under vacuum to get the crude C ompound IV .

E xample 4: Preparation of (2S, 3R , 4R, 5S, 6R ) " 2- (4-chloro-3- (4-ethoxybenzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (V )- amorphous Dapagliflozin

¾ To a solution of Compound IV (100 gm, 0.22 mol.) in dichloromethane, acetonitrile (1 : 1, 1000 ml) mixture at -5eC was added B F 3 .OEt 2 (0.35 mol.) and Tri ethyl si lane (0.47 mol) sequenti al ly at -5eC . T he reacti on mi xture was sti rred at the same temperature for 5 h. A f ter 5 h, reaction mixture was quenched with 10% NaHC0 3 solution. Reaction mass was concentrated to remove vol ati I es and added 1000ml of ethyl acetate. Layers were separated

3a and organic layer was washed with water (500 ml) followed by brine solution (500 ml).

Organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum to get the crude Compound V (90 g, 0.22 mol) as foamy solid.

E xample 5: Preparation of (2R , 3R, 4R, 5S, 6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4- ethoxybenzyl) phenyl) tetrahydro-2H -pyran-3, 4, 5-triyl triacetate (V I)- Acetylated ¾ dapagliflozin

To a solution of Compound V (100 gm, 0.24 mol.) in dichloromethane (750 ml) Pyridine (1.41 mol.) was added followed by acetyl chloride (1.2 mol.) and catalytic amount of 4- Di methyl ami nopyridi ne (0.011 mol.) at room temperature and sti rred for 5 to 6 h. After the iti completion of the reaction (by H PLC), reaction mass was quenched with water (500 ml), sti rred for 30 min. and the layers were separated. Organic layer was washed with 1.5N HCI solution (500 ml) followed by brine solution (500 ml) and dried over anhydrous sodium sulphate. Organic layer was concentrated undervacuum to get the crude compound V I. The crude Compound VI was then crystallized fromlsopropyl alcohol followed by ethyl acetate and heptane to get a pure Compound V I as a white solid (0.20mol.).

E xample 6: Preparation of (2S, 3R , 4R , 5S, 6R )-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol butane-1,2-diol (1 : 1 ) ¾ hydrate (V III) - Dapagliflozin-1,2 butanediol monohydate

To a solution of compound V I (60 g, 0.1039 mol) in n-butanol (300 mL) was added 10% NaOH aq. solution (120 mL) at room temperature, heated to 80eC and stirred for 6 h. After 6h, 10 % NaOH aq. Solution (120 mL) was added and stirred at 80eC for additional 6 h. After completion of the reaction (by H PLC), temperature brought to 25e5eC. Organic layer

3a was separated, added water (300 mL) and adjusted the pH to 6.0-7.0 using 1.5N HC I solution. Organic layer separated and washed with 0.15 % NH 4 CI solution. Organic layer was separated and filtered through celite bed followed by concentration to get syrupy mass (crude V II). To this syrupy mass gave toluene ( 120 mL X 3) followed by ethyl acetate (180 mL) chasings to get syrupy mass. Ethyl acetate (78 mL) was added to above mass and

¾ stirred for 10min to dissolve. To this solution 1,2-butanediol (9.84 g) followed by water (1.87 mL) were added and stirred for 30 min at 25e5eC. Reaction mass was cooled to 15e2eC, Cyclohexane(180 mL) was added to reaction mass and sti rred at same temperature for 30min. Another lot of cyclohexane (90 mL) was added to reaction mass and continued stirring for 3hrs at 15e2 eC. After 3 h, filtered the mass and washed with pre-cooled (10- iti 15eC) ethyl acetate and cyclohexane mixture. Dried the material f or 12 h to get C ompound V III as a off white solid. (46.8 g, 0.09 mol, Purity: 99.80%).

E xample 7: Preparation of (2S, 3R , 4R , 5S, 6R )-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (S)-butane-1,2-diol (1 : 1 ) hydrate (V III a) - Dapagliflozin-(S)-1,2 butanediol monohydrate.

To a solution of compound V I (600 g, 1.039 mol) in n-butanol (3000 mL) was added 10% NaOH aq. solution (1200 mL) at room temperature and heated to 80eC and stirred for 6 h. After 6h, 10% NaOH aq. solution (1200 mL) was added and stirred at 80eC for additional 6h. After completion of the reaction (by H PLC), temperature brought to 25e5eC. Organic layer was separated, added water (3000 mL ) and adj usted the pH to 6.0-7.0 usi ng 1.5N H C I solution. Organic layer separated and washed with 0.15% N H4C I solution. Organic layer separated and filtered through celite bed followed by concentration to get syrupy mass (crude V II). To this syrupy mass gave toluene (1200 mL X 3) followed by ethyl acetate

¾ (1800 mL) chasings to get syrupy mass. Ethyl acetate (780 mL) was added to above mass and stirred for 10 min to dissolve. To this solution (S)-1,2-butanediol (98.4 g) followed by water ( 18.7 ml ) were added and sti rred for 30 mi n at 25e 5eC . R eacti on mass was cool ed to 15e2eC, Cyclohexane (1800 mL) was added to reaction mass and stirred at same temperature for 30min. Another lot of cyclohexane (900 mL) was added to reaction mass

3a and conti nued sti rri ng for 3hrs at 15e2 eC . After 3 h, f i Itered the mass and washed with pre cooled (10-15eC) ethyl acetate and cyclohexane mixture. Dried the material for 12 hrs to yield Compound V illa as a crystal l ine white sol id (489.2 g, 0.946 mol, Purity: 99.68%).

E xample 8: Preparation of (2S, 3R , 4R , 5S, 6R )-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H -pyran-3, 4, 5-triol (R )-butane-l, 2-diol ¾ (V HIb) - Dapagliflozin-(R )-1,2 butanediol

To a solution of compound VII (2 g, 0.0048 mol) in isopropyl acetate (10ml) was added (R)-butane-l, 2-diol (0.005 mol) at room temperature. The reaction mixture was stirred at 60eC for 1 hr. Cyclohexane (24 ml) was added dropwise to the reaction mass at 60 eC. The reaction mixture was allowed to cool down to room temperature and stirred for additional iti 2 h and further cooled to 0-5eC and stirred for 1 h. The reaction mass was filtered off and the solid was washed with (1: 1) isopropyl alcohol and cyclohexane mixture (20 ml) and dried undervacuum toyield Compound Vlllb ( 1.0 g, 0.0019 mol). Compound V HIb is low melting in nature.

E xample 9: Preparation of (2S, 3R , 4R , 5S, 6R )-2-(4-chloro-3-(4-ethoxybenzyl) ¾ phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol butane-1, 2-diol (1 : 1 ) hydrate (V III) - Dapagliflozin-1,2 butanediol monohydrate

To a solution of compound V (2 g, 0.0048 mol) in ethyl acetate (2.6 ml) was added butane- 1, 2-diol (0.005 mol) at room temperature and stirred for 30min. Water (1.0 eq) was added to the reaction mass and continued sti rring at room temperature for 30min. Temperature slowly reduced to 15e2eC and then Cyclohexane (9 ml) was added drop wise to the reaction mass. The reaction mixture was allowed to stir for additional 3 h at 15e2eC. The reaction mass was fi Itered off and the sol id was washed with ( 1.5:3.5) ethyl acetate and cyclohexane mixture (4 ml) and dried under vacuum to yield Compound V III as an off-white solid (2.2 ¾ g, 0.0044 mol).

E xample 10: Preparation of amorphous (2S, 3R , 4R , 5S, 6R ) " 2- (4-chloro-3- (4- ethoxybenzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (VII) amorphous dapagliflozin

3a To a solution of compound V I (80 g, 0.138 mol) in n-butanol (400 mL) was added 10% NaOH aq. solution (160 mL) at room temperature and heated to 80eC and stirred for 6 h. After 6h, another lot of 10% NaOH aq. solution (160 mL) was added and stirred at 80eC for additional 6h. After completion of the reaction (by H PLC), temperature brought to 25e5eC. Organic layer was separated, added water (400 mL) and adjusted the pH to 6.0-

¾ 7.0 usi ng 1.5N HC I solution. Organic layer separated and washed with NH4CI solution.

Organic layer separated and fi ltered through celite bed followed by concentration to get syrupy mass. To this syrupy mass gave toluene (160 mL X 3) followed by ethyl acetate (240 mL) chasings to remove traces of butanol and dried under vacuum toyield Compound V II as an amorphous sol i d wi th 95 % y i el d ( 53 g, 0.129 mol ) tin E xample 11 : Preparation of (2S, 3R, 4R, 5S, 6R ) " 2- (4-chloro-3- (4-ethoxy benzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (V II) - amorphous dapagliflozin

(2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl )-6-(hydroxymethyl) ¾ tetrahydro-2H-pyran-3, 4, 5-triol butane-1,2-diol (1 :1 ) hydrate V III (10g, 0.019 mol) was di ssol ved i n ethyl acetate ( 100 mL ) at room temperature. T o thi s added aqueous ammoni um chloride solution (0.15%, 50 mL) and stirred for 10min. Separated the ethyl acetate layer and washed with 0.15% ammonium chloride aqueous solution (50mL) for 3 more times. Ethyl acetate layer was separated and filtered through celite. Concentrated the organic layer til under vacuum to get amorphous Dapagl iflozin i.e (2S, 3R, 4R, 5S, 6R) " 2- (4-chloro-3- (4- ethoxybenzyl) phenyl )-6-( hydroxy methyl) tetrahydro-2H-pyran-3, 4, 5-triol (V II) as an off white solid (7.58g, 0.018 mol).

E xample 12: Preparation of (2S, 3R, 4R, 5S, 6R ) " 2- (4-chloro-3- (4-ethoxy benzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (V II) - amorphous dapagliflozin

(2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl )-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (S)-butane-l, 2-diol (1 :1 ) hydrate (V III a) ( 100g, 0.19 mol ) was dissolved i n ethyl acetate ( 1000 mL ) at room temperature. T o this added aqueous ammonium chloride solution (0.15%, 500 mL) and stirred for 10 min. Separate the ethyl acetate layer and wash with 0.15% ammonium chloride aqueous solution (500mL) for 3 more times. Separated the ethyl acetate layer and filter through celite. Concentrated the organic layer under vacuum to get amorphous Dapagl if lozi n as an off white sol id (75.05 g, 0.18 mol).

E xample 13: Preparation of (2S, 3R, 4R, 5S, 6R ) " 2- (4-chloro-3- (4-ethoxy benzyl) phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (V II) - amorphous dapagliflozin

(2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl )-6-(hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (R)-butane-l, 2-diol (1 :1 ) (Vlllb) (1g, 0.0019 mol) was dissolved in ethyl acetate (10mL) at room temperature. To this added aqueous ammonium chloride solution (0.15%, 5mL) and sti rred f or 10mi n. Separated the ethyl acetate layer and washed with 0.15% ammonium chloride aqueous solution (5mL) for 3 more times. Separated the ethyl acetate layer and filtered through celite. Concentrated the organic layer under vacuum to get amorphous Dapagliflozin as an off white solid (0.75g, 0.0018 mol).