PROCESS FOR THE PREPARATION OF DAPAGLIFLOZIN.
Field of the Invention
The present invention provides an improved process for the preparation of dapagliflozin.
Background of the Invention
Dapagliflozin propanediol monohydrate is chemically designated as (1 5')- 1,5-anhydro- 1 -
C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol, (5')-propylene glycol, monohydrate
and is marketed for the treatinent of type 2 Diabetes mellitus. Its chemical structure is
represented by the following Formula I.
Formula I
U.S. Patent Nos. 6,5 15,117, 7,375,213, 7,932,379, and 7,919,598 disclose processes for
the preparation of dapagliflozin comprising the step of hydrolyzing an acetylated dapagliflozin,
represented by Formula 111, in the presence of an alkali metal hydroxide such as lithium
hydroxide or sodium hydroxide. Dapagliflozin obtained from these processes has a significant
level of an impurity detected at a relative retention time (RRT) of 1.61 when measured by high
performance liquid chromatography (HPLC).
The present invention provides an improved process to minimize or remove this processrelated
impurity during the manufacture of dapagliflozin.
Summary of the Invention
1
! A first aspect of the present invention provides an improved process for the preparation
i
I \ of dapagliflozin of Formula.11,
OC~H,
Formula I1
wherein the process comprises the step of hydrolyzing the compound of Formula I11
Formula I11
in the presence of an amine base.
A second aspect of the present invention provides dapagliflozin substantially free of an
impurity detected at a RRT of 1.61 when measured by HPLC.
Brief Description of the Figures
Figure 1 depicts the X-Ray Powder Diffraction (XRPD) pattern of dapagliflozin
I produced by the process of the present invention.
,I Figure 2 depicts the Differential Scanning Calorimetry (DSC) pattern of dapagliflozin
i produced by the process of the present invention.
Detailed Description of the Invention
The term "about", as used herein, refers to any value which lies within the range defined
I
I by a number up to *lo% of the value.
I The term "substantially free of the impurity detected at a RRT of 1.61", as used herein,
I refers to dapagliflozin or its solvates having less than about 0.8%, preferably less than about
ra- - - P 1- ------bgG&2&&2W=i2---~ -
0.5%, and most preferably, less than about 0.1% of the impurity detected at a RRT of 1.61, when
I measured by HPLC. The term "substantially frse of the impurity detected at a RRT of 1.61"
I -. also includes dapagliflozin or its solvates having no detectable amount of the impurity.
-. In the context of the present invention, "solvates" refers to complexes of dapagliflozin
with water, methanol, ethanol, n-propanol, propanediol, and butynediol.
The compound of Formula I11 is hydrolyzed.in the.presence of an amine base. Examples
of amine bases include ammonia, methylamine, dimethylamine, triethylamine, tertbutyldimethylamine,
phenylethylamine, and diisopropylarnine.
I In an embodiment of the present invention, the hydrolysis .can be carried out in the
1 presence or absence of a solvent. Examples of solvents include water, alcohols, chlorinated
!
I hydrocarbons, aromatic hydrocarbons, nitriles, and mixtures thereof.
In another embodiment of the present invention, the hydrolysis of the compound, of
Formula 111 is carried out in the presence of methylamine and methanol to obtain the compound
of Formula 11.
In another embodiment of the present invention, the dapagliflozin prepared by the
process of the present invention is characterized by an XRPD pattern as depicted in Figure 1 or a
DSC as depicted in Figure 2.
The compound of Formula 111 may be prepared by the process described in U.S. Patent
No. 6,5 15,117.
Methods
XRPD of the samples were determined by using a ~ ~ ~ a l y i t iXc'Paelrt~ P ro X-Ray
Powder Diffractometer in the range 3-40 degree 2 theta and under a tube voltage and current of
45 Kv and 40 mA, respectively. Copper radiation of wavelength 1.54 angstroms and an
x'celeratorB detector were used.
The HPLC purity .of dapagliflozin was determined using a ~urospherS~T AR RP-18e
(150 x 4.6 mm), 3pm column with a flow rate of 1.0 mL/minute to 1.5 mL/minute (flow gradient
and organic gradient); column oven temperature: 25°C; sample tray temperature: 25"C;.detector:
UV at 225 nm; injection volume: '10 pL; run time: 60 minutes.
DSC was recorded using a Mettler ole do@ DSC 82 1 e instrument.
The examples below are illustrated to aid the understanding of the invention but are not
intended to and should not be construed to limit its scope in any way.
- .
-- Reference Example: Preparation of dapagliflozin (Formula 11)
A solution of lithium hydroxide monohydrate (1 g dissolved in 10 mT. water) was added
to a mixture of (1 C)-2,3,4,6-tetra-0-acetyl- 1,5-anhydro- 1 -[4-chloro-3-(4-ethoxybenzy1)phenylJ-
. . D-glucitol (10 g), methanol (30 mL), and THF (20 mL) at'20°C to 25°C. The reaction mixture
was stirred for about 2 hours at 25°C to 30°C. After completion of the reaction,the-reacthpp
--
mixture was concentrated under vacuum at 40°C to 45°C. Ethyl acetate (100 mL) was added to
the concentrated mixture and the reaction mixture was washed twice with brine solution (20
mL). The organic layer was separated and concentrated under vacuum at 40°C to 45°C to obtain
a residue. The residue was dissolved in methyltertiarybutyl ether (30 mL) to obtain .a solution.
The solution was slowly added over hexanes (100 mL) at 5°C to 7OC. The mixture was stirred
for about 60 minutes at 5OC to 7°C and filtered under a nitrogen atmosphere to obtain a solid
residue. The solid residue was washed with hexanes (10 mL) and dried under vacuum at about
40°C to about 45°C to obtain dapagliflozin. .
HPLC Purity: 97.02%
Impurity at RRT 1.6 1 : 0.84%
Other impurity: 1.49%
Example: Preparation of davagliflozin (Formula 11) . .
Methylamine (40% in water; 0.75 mL) was added to a solution of (1C)-2,3,4,6-tetra-0-
I
acetyl-1,5-anhydro-l-[4-chloro-3-(4-ethoxybenl)phenyl]-D-glucitol(1 g) in methanol (20 mL)
at 25°C. The reaction mixture was stirred for about 5 hours at 20°C to 25°C. After completion
I of the reaction, the reaction mixture was concentrated under vacuum at 25°C to 30°C. The pH
of the reaction mixture was adjusted to 6-7 using hydrochloric acid (35% in water; -0.5 mL).
Ethyl acetate (20 mL) was added to the reaction mixture and the mixture was stirred for about 10
minutes. The organic layer was separated, washed with water (10 mL), and dried using sodium
sulphate (0.5 g). The organic layer was concentrated under vacuum at 40°C to 45°C to obtain a
residue. The residue was dissolved in methyltertiarybutyl ether (MTBE; 5 mL) to obtain a
solution. The solution was added to hexanes (10 mL) at 5°C to 7°C and stirred for 60 minutes to obtain a solid residue. The solid residue was filtered under nitrogen atmosphere and dried under
vacuum at 25°C to 30°C to obtain dapagliflozin.
HPLC Purity: 99.92%
Impurity at RRT 1.61: 0.08
Other impurity: Not detected
XRPD as depicted in Figure 1
DSC as depicted in Figure 2

WE CLAIM:
1. A process for the preparation of dapagliflozin of Formula 11,
Formula I1
wherein the process comprises the step of hydrolyzing the compound of Formula I11
Formula I11
in the presence of an amine base.
2. The process according to claim 1, wherein the amine base is selected from the .group
consisting of ammonia, methylamine, dimethylamine, triethylamine, tertbutyldimethylamine,
phenylethylamine, and diisopropylamine.
3. , The process according to claim 1, wherein the hydrolysis is carriedout in the presence of
an alcohol solvent.
4. The process according to claim 3, wherein the alcohol solvent is selected from the group
consisting of methanol, ethanol, n-propanol, isopropanol, butanol, and mixtures thereof.
5. The process according to claim 1, wherein the dapagliflozin produced is substantially
free of an impurity detected at a RRT of 1.6 1, when measured by HPLC.
6. Dapagliflozin substantially free of an impurity detected at a RRT of 1.61, when
measured by HPLC.
7. . The dapaglifloziil according lo claim 6 characterized by an XRPD pattern substantially
as depicted in Figure 1 or a DSC substantially as depicted in Figure 2.