DESC:FIELD OF THE INVENTION
The present invention relates to a process for preparation of amorphous dapagliflozin.

BACKGROUND OF THE INVENTION
Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU). It is a medication used to treat type 2 diabetes, adults with heart failure and chronic kidney disease. It reversibly inhibits sodium-glucose co-transporter 2 (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion. The brand product contains dapagliflozin propanediol monohydrate having following chemical structure.

It is described chemically as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1). Dapagliflozin chemically is (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol and has following structure.
(Formula 1)

US 7,375,213 describe preparation of dapagliflozin as a glassy off white solid. Example 20 of US 7,375,213 describe tetraacetylated ß-C-glucoside (Formula 2) was treated with LiOH monohydrate in THF/MeOH/H2O (2:3:1) to get dapagliflozin. The reaction scheme is shown below.
(Formula 2) (Formula 1)

US 9,845,303 disclose stable amorphous dapagliflozin and its preparation.

US 10,556,877, WO 2021245253 and IN 3707/CHE/2015 disclose preparation of highly pure amorphous dapagliflozin.

US 10,738,038 disclose preparation of amorphous dapagliflozin from dapagliflozin co-crystals.

WO2015104658A2 and WO2017042683A1 disclose preparation of amorphous dapagliflozin.

However, there is still need for the preparation of amorphous dapagliflozin which is simple, economical, environment friendly and commercially useful.

SUMMARY OF THE INVENTION
The present invention provides an efficient process for preparation of an amorphous dapagliflozin that provides dapagliflozin with higher purity and lower levels of residual solvent(s) in accordance with the ICH guidelines which is suitable for pharmaceutical preparations.

The present invention relates to a process for preparation of amorphous dapagliflozin comprising steps of
i. reacting Compound of formula 2 with alkali hydroxide in aqueous alcohol

(Formula 2)
ii. adjusting the pH to about 7 with organic acid,
iii. extracting with the water immiscible organic solvent,
iv. evaporating the solvent in a tray drier under vacuum not less than 700 mm/Hg at 25-35 °C and
v. isolating amorphous dapagliflozin under nitrogen atmosphere.

BRIEF DESCRIPTION OF DRAWINGS
Figure 1: Powder X-ray diffractogram (PXRD) pattern of amorphous dapagliflozin obtained in example 1.

DETAILED DESCRIPTION OF THE INVENTION
According to the present invention “Pure” means having purity of at least 99.5%, when measured by area percentage of HPLC.

The present invention relates to an efficient process for preparation of an amorphous dapagliflozin that provides pure dapagliflozin with lower levels of residual solvent(s) in accordance with the ICH guidelines. Amorphous dapagliflozin prepared according to the present invention is suitable for pharmaceutical preparations.

The process for preparation of amorphous dapagliflozin according to the present invention is presented in scheme 1.
Scheme 1
(Formula 2) (Formula 1)

In one embodiment, the present invention relates to a process for preparation of amorphous dapagliflozin comprising steps of
i. reacting Compound of formula 2 with alkali hydroxide in aqueous alcohol

(Formula 2)
ii. adjusting the pH to about 7 with organic acid,
iii. extracting with a water immiscible organic solvent,
iv. evaporating the solvent in a tray drier under vacuum not less than 700 mm/Hg at 25-35 °C and
v. isolating amorphous dapagliflozin under nitrogen atmosphere.

Alcohol used in the present invention is selected from methanol, ethanol, propanol or isopropanol, preferably methanol.

Alkali hydroxide used in the present invention is selected from potassium hydroxide (KOH), lithium hydroxide (LiOH) or sodium hydroxide (NaOH), preferably potassium hydroxide.
Organic acid used in the present invention is selected from citric acid, oxalic acid or tartaric acid, preferably citric acid.
Water immiscible organic solvent used in the present invention is selected from ethyl acetate, chloroform or dichloromethane, preferably ethyl acetate.

An amorphous dapagliflozin obtained according to the present invention is stable for at least one month, at least two months, at least three months, at least six months or at least for twelve months at a storage condition of 5±3 °C.

The process for preparation of amorphous dapagliflozin according to the present invention wherein amorphous dapagliflozin obtained exhibit Powder X-ray diffractogram (PXRD) depicted in Figure 1.

An amorphous dapagliflozin obtained according to the present invention is pharmaceutically acceptable and can be used in the preparation of pharmaceutical compositions of dapagliflozin.

An amorphous dapagliflozin obtained according to the present invention is at least 99.5%, preferably at least 99.6%, more preferably at least 99.7% w/w pure, when measured by area percentage of HPLC.

EXAMPLES
Powder X-ray Diffraction of amorphous dapagliflozin was obtained under following conditions:
Instrument: X-Ray Diffractometer
Scan Axis: Gonio
Start position (° 2?): 2.0109
End position (° 2?): 49.9929
Step size (° 2?): 0.0220
Scan Step Time (s): 60.3260
Scan Type: Continuous
PSD Mode: Scanning
PSD Length (° 2?): 3.02
Offset (° 2?): 0.0
Divergence slit Type: Fixed
Divergence slit Size (°): 0.1146
Specimen length (nm): 10.00
Measurement Temperature (°C): 25.0
Anode material: Cu
K-Alpha 1 (Å): 1.54060
K-Alpha 2 (Å): 1.54443
K-Beta (Å): 1.39225
Generator settings: 15mA, 40kv
Diffractometer Type: 207564
Diffractometer Number: 0
Goniometer Radius (mm): 145.00
Dist. Focus-Diverg. Slit (mm): 95.00
Incident Beam Monochromator: No
Spinning: Yes

The following examples illustrate specific embodiments; however, the full scope of the disclosure is not limited to the examples described below.

Example 1
Preparation of amorphous dapagliflozin (Formula 1)
(Formula 2) (Formula 1)
Compound of formula 2 (100 g) was dissolved in methanol (500 mL). To this solution 25% aqueous potassium hydroxide solution (175 mL) was added at 15° C. The reaction mixture was stirred at 25 °C for 3h followed by addition of aqueous citric acid to adjust the pH to about 7. The solvent was removed under vacuum and water (400 mL) was added to the residue. The mixture was extracted with ethyl acetate (3 X 400 mL). The combine organic layer was washed with sodium bicarbonate solution (200 ml) followed by water (200 mL). The ethyl acetate solution was treated with activated carbon (5 g) followed by recovery of ethyl acetate under vacuum. Fresh ethyl acetate (500 mL) was added to get clear solution and subjected to vacuum tray drying. The ethyl acetate solvent was evaporated under vacuum NLT 700 mm/Hg at 25-35 °C. The dried product was isolated under nitrogen atmosphere to get amorphous dapagliflozin (68 g). HPLC Purity: 99.88 %.
Powder X-ray diffractogram (PXRD) of amorphous dapagliflozin is depicted in Figure 1.

Example 2
Stability study:
Stability of the amorphous dapagliflozin obtained in example 1 was performed at a storage condition of 5±3 °C.
Table 1: Stability of the amorphous dapagliflozin obtained in example 1 at a storage condition of 5±3 °C
Initial 1 Month 2 Month 3 Month 6 Month
Purity (%) 99.88 99.85 99.78 99.76 99.78
Polymorph Amorphous Amorphous Amorphous Amorphous Amorphous
Hydroxy Dapagliflozin ND ND ND ND ND
Methoxy Dapagliflozin ND ND ND ND ND
Tetra acetyl Dapagliflozin ND ND ND ND ND
Other individual impurity 0.04 0.05 0.03 0.04 0.05
*ND: Not detected.
,CLAIMS:1. A process for preparation of amorphous dapagliflozin comprising steps of
i. reacting Compound of formula 2 with alkali hydroxide in aqueous alcohol

(Formula 2)
ii. adjusting the pH to about 7 with organic acid,
iii. extracting with the water immiscible organic solvent,
iv. evaporating the solvent in a tray drier under vacuum not less than 700 mm/Hg at 25-35 °C and
v. isolating amorphous dapagliflozin under nitrogen atmosphere.
2. The process as claimed in claim 1 wherein alcohol used in step i) is selected from methanol, ethanol, propanol or isopropanol.
3. The process as claimed in claim 2 wherein alcohol is methanol.
4. The process as claimed in claim 1 wherein alkali hydroxide used in step i) is selected from potassium hydroxide (KOH), lithium hydroxide (LiOH) or sodium hydroxide (NaOH).
5. The process as claimed in claim 4 wherein alkali hydroxide is potassium hydroxide (KOH).
6. The process as claimed in claim 1 wherein organic acid used in step ii) is selected from citric acid, oxalic acid or tartaric acid.
7. The process as claimed in claim 6 wherein organic acid is citric acid.
8. The process as claimed in claim 1 wherein water immiscible organic solvent used in step iii) is selected from ethyl acetate, chloroform or dichloromethane.
9. The process as claimed in claim 8 wherein water immiscible organic solvent is ethyl acetate.
10. The process as claimed in claim 1 wherein the amorphous dapagliflozin is at least 99.5% pure, when measured by area percentage of HPLC and stable for at least six months at a storage condition of 5±3 °C.