PROCESS FOR THE PURIFICATION OF DAPAGLIFLOZIN
Field of the ~nvention
The present invention provides a process for the preparation of (1C)-2,3,4,6-tetra-0-
acetyl- 1 ,5-anhydro- 1 -[4-chloro-3-(4-ethoxybenzyl)phenyl]-~-glucito of Formula 111. The
invention also provides a process for the purification of dapagliflozin using (1C)-2,3,4,6-tetra-0-
acetyl- 1,Sanhydro- 1 -[4-chloro-3-(4-ethoxybenzyl)phenyl]-D-gucito of Formula 111.
Background of the Invention
Dapagliflozin propanediol monohydrate is chemically designated as (19-1,Sanhydro-1-
C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol,( 9-propylene glycol, monohydrate
and is marketed for the treatment of type 2 Diabetes mellitus. Its chemical structure is
represented by Formula I.
O C ~ H ~
Formula I
U.S. Patent Nos. 6,5 15,1.17, 7,375,2 13, 7,932,379, and 7,9 19,598 disclose processes for
the purification of dapagliflozin, comprising the step of acetylating -crude dapagliflozin to (1C)-
2,3,4,6-tetra-0-acetyl- 1,Sanhydro- 1 -[4-chloro-3-(4ethoxybenzyl)phenyl]-D-glucitol of
Formula I11 in pyridine. Pyridine is toxic and therefore its use as a solvent should be avoided for
industrial production of a pharmaceutical ingredient. Thus, there is a need in the art to develop a
process for the preparation of dapagliflozin that avoids the use of pyridine as a solvent.
The present invention provides an improved process for the preparation of the compound
of Formula I11 which circumvents the use of pyridine.
Summarv of the Invention
A first aspect of the present invention provides a process for the preparation of a
compound of Formula I11
OC~H,
Formula I11
comprising acetylating dapagliflozin of Formula I1 in a solvent,
Formula I1
wherein the acetylation is carried out in the absence of pyridine.
A second aspect of the present inv-ention provides a process for the purification of
dapagliflozin of Formula 11, or solvates thereof, wherein the process comprises the steps of:
a) acetylating dapagliflozin of Formula I1 in a solvent to obtain a compound of Formula
111, wherein the acetylation is carried out in the absence of pyridine; and
Formula, I11
b) deacetylating the compound of Formula 111.
I Detailed Description of the Invention
The term "about", as used herein, refers to any value which lies within the range defined
by a number up to * 10% of the value.
In the context of the present invention, "solvates" refers to complexes of dapagliflozin
with water, methanol, ethanol, n-propanol, propanediol, and butynediol.
The term "acetylation", as used herein, refers to the addition of acetyl group(s) to a given
compound. This can be performed by a reaction of the compound with acetylating agents
selected from a group comprising of acetic anhydride, acetyl chloride, and the like. /
The term "deacetylation", as used herein, refers to the removal of acetyl group(s) from a
given compound.
The acetylation of dapagliflozin is performed in a solvent selected from a ketone or a .
chlorinated solvent. Examples of ketone solvents include acetone, methyl ethyl ketone, methyl
isobutyl ketone, diisoproyl ketone, methylisopropyl ketone, methylphenyl ketone, and mixtures
thereof. Examples of chlorinated solvents include dichloromethane, chloroform, carbon
tetrachloride, dichloroethane, and mixtures thereof.
I In an embodiment of the present invention, the acetylation of dapagliflozin of Formula I1
i is performed in the presence of a catalyst. Examples of catalysts include
dimethylaminopyridine, N-methylpiperazine, copper triflate Cu(OTf)z, copper(I1)
tetrafluroborate, phosphomolybdic acid (PMA), and the like.
In another embodiment of the present invention, the deacetylation is performed in the
presence of a base. Examples of bases include lithium hydroxide, sodium hydroxide, and the
like.
In general, acetylation of dapagliflozin is performed using acelic anhydride in the .
I presence of a catalytic amount of dimethylaminopyridine in acetone or dichloromethane to
I obtain the compound of Formula 111, which upon deacetylation with a base gives dapagliflozin.
The preparation of dapagliflozin, which is used as the starting material to prepare the
compound of FormulaIII, is carried out by following the processes described iri U.S. Patent
Nos. 6,5 15,117, 7,375,2 13, 7,932,379, and 7,919,598, which are' incorporated herein by.
reference.
Methods
The HPLC purity of dapagliflozin was determined using a purospherB STAR RP-18e
(150 x 4.6 mm), 3pm column with a flow rate 1.0 mllminute to 1.5 mL1minute (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.
The examples below are set forth to aid the understanding of the invention but are not
intended to and should not be construed to limit its scope in any way.
EXAMPLES
Example 1A: Preparation of (1C)-2.3.4.6-tetra-0-acetyl- 15-anhydro- 1-r4-chloro-344-
ethoxvbenzyl)vhenyll-D-nlucitol (Formula 111)
Acetic anhydride (1 1.6 mL) was added to dapagliflozin (10'g) in acetone (50 mL) at
about 25°C. The reaction mixture was cooled to about 20°C and dimethylaminopyridine (0.15
g) was added to it at 20°C to 25OC. The reaction mixture was stirred for about 3 hours at 25°C
to 30'32. After completion of the reaction, the reaction mixture was concentrated under vacuum
at 40°C to 45°C to obtain a residue. The residue was dissolved in dichloromethane (50 mL) and
!
washed with water (50 mL). The organic layer was separated and concentrated under vacuum to
! obtain a residue. The .residue was dissolved in ethanol (20 mL).and again concentrated at 50°C
/ .
to 55°C to obtain a residue. ,The residue was dissolved in ethanol (100 mL) and heated to 70°C
to 75PC to obtain a clear solution. The solution was slowly cooled to about 20°C and stirred for
one hour at 15°C to 20°C to obtain a solid. The solid was filtered, washed with ethanol (10 mL),
and dried under vacuum at 40°C to 45°C -for about 16 hours to obtain (1C)-2,3,4,6-tetra-0-
acetyl- 1,Sanhydro- 1 -[4-chloro-3-(4-ethoxybenzy1)phenyll-D-glucitol.
Yield: 6.4 g
Purity: 95.42% (HBLC)
Example 1B: Preparation of (1C)-2,3,4,6-tetra-0-acetvl- 15-anhydro- 1 -[4-chloro-3-(4-
ethoxvbenzy1)phenyll-D-glucitol (Formula 111)
Acetic anhydride (7 mL) was added to dapagliflozin (5 g) in acetone (50 mL) at about
25°C. he reaction mixture was cooled to about 20°C and dimethylaminopyridine (0.15 g) was
added to it at 20°C to 25°C. The reaction mixture was stirred for about 5 hours at 50°C to 35°C.
After completion of the reaction, the reaction mixture was concentrated under vacuum at 40°C
to 45OC to obtain a residue. The residue was dissolved in ethano1:water (1 : 1) ('50 mL) at 70°C to
75°C and gradually cooled'to '5°C to 10°C and stirred for 1 hour at the same temperature. The
solid was filtered, washed with ethano1:water (1: 1) (5 mL), and the solid was again dissolved in
ethanol (50 mL) at 70°C to 7'5"C, gradually cooled to 5°C to 10°C, and stirred for 1 'hour at the
same temperature. The solid was filtered, washed with ethanol (5 mL), and dried under vacuum
at 40°C to 45°C for about 12 hours to obtain (1C)-2,3,4,6-tetra-0-acetyl-1,5-anhydro-1-[4-
Yield: 1.5g
Example .l C: Preparation of ( 1 C)-2.3.4.6-tetra-0-acetyl- 1,Sanhvdro- 1 -14-chloro-3-(4-
ethoxvbenzyl)phenyll-D-glucitol (Formula 111)
Acetic anhydride (1 1.6 mL) was added to dapagliflozin (10 g) in dichloromethane ( 1 00
mL) at about 25°C. The reaction mixture was cooled to about 20°C and dimethylaminopyridine
(0.3 g) was .added to it at 20°C to 30°C. The reaction mixture was stirred for about 3 hours at
40°C to 50°C. After completion of the reaction, the reaction mixture was cooled to about 30°C.
Water (100 mL) was added to the reaction mixture at the same temperature. The layers were
separated. The organic layer was concentrated under vacuum at 40°C to 4'5°C to obtain a solid
residue. The residue was dissolved in ethanol (20 mL) and the reaction mixture was
concentrated under vacuum at 40°C to 45°C to obtain a residue. The residue was again
dissolved in ethanol (100 mL) at 7 0 " ~to 75°C. The reaction mixture was gradually cooled to
about 20°C and stirred at the same .temperature for an hour to obtain a solid. The solid was
filtered, washed with ethanol (10 mL), and dried under vacuum at 40°C to 45°C for about 12
hours to obtain (1 C)-2,3,4,6-tetra-0-acetyl- 1 &anhydro- 1 -[4-chloro-3-(4-ethoxybenzy1)phenyll-
D-glucitol.
HPLC purity: 98.63%
Example 2: Preparation of dapagliflozin (Formula 11)
Lithium hydroxide (0.25 g) was added to a solution of (1C)-2,3,4,6-tetra-0-acetyl-1,5-
anhydro-l-[4-chloro-3-(4-ethoxybenzyl)phenyl]-D-glucito(lF ormula 111; 2.5 g) in methanol (12
mL), tetrahydrofuran (8 mL), and water (4 mL) at 20°C to 25°C and stirred for about 4 hours.
After completion of the reaction, the reaction mixture was concentrated under vacuum at 40°C
to 45°C. The residue was dissolved in ethyl acetate (25 mL) and washed with an aqueous
solution of sodium chloride (10%; 2 x 25 mL). The layers were separated and the organic layer
was concentrated under vacuum at 40°C to 45°C to obtain an oily residue. Dichloromethane (10
mL) was added to the oily residue and concentrated under vacuum at 40°C to 45°C to obtain
dapagliflozin.

WE CLAIM:
1. A process for the preparation of a compound of Formula II1
Formula I11
comprising acetylating dapagliflozin of Formula 11 in a solvent,
Formula I1
wherein the. acetylation is carried out in the absence of pyridine.,
2. A process for the purification of dapagliflozin of Formula 11, or solvates thereof, wherein
the process comprises the steps oE
a) acetylating dapagliflozin of Formula I1 in a solvent to obtain a compound of Formula
111, wherein the acetylation is carried out in the absence of pyridine; and
b) deacetylating the compound of Formula 111.
The process according to claim .1 or claim 2, wherein the solvent is selected from a
ketone solvent or a chlorinated solvent.
4. The process according to claim 3, wherein the .ketone solvent is selected from the group
consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone,.diisoproyl ketone,
methylisopropyl ketone, methylphenyl ketone, and mixtures thereof.
5. The process according to claim 3, wherein the chlorinated solvent is selected from the
group consisting of dichloromethane, chloroform, carbon tetrachloride, dichloroethane,
I and mixtures thereof.
6. The process according to claim 4, wherein the ketone solvent is acetone.
7. The process according to claim 5, wherein the chlorinated solvent is dichloromethane.
8. The process according to claim 2, wherein step b) is carried out in the presence of a base.
9. The process according to claim 8, wherein the base is selected from the group consisting
of sodium hydroxide and lithium hydroxide.