DESC:PROCESS FOR THE PREPARATION AND PURIFICATION
OF EMPAGLIFLOZIN INTERMEDIATES
FIELD OF THE INVENTION
The present invention relates to a process 5 for the preparation of 1-chloro-4-
(1-methoxy-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)
benzene of Formula II and its use for the preparation of empagliflozin. The present
invention also relates to a process for the purification of (3R,4R,5S,6R)-2-[4-
chloro-3-(4-hydroxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-
10 3,4,5-triol of Formula V and its use for the preparation of pure empagliflozin.
BACKGROUND OF THE INVENTION
Empagliflozin is a sodium glucose co-transporter-2 (SGLT-2) inhibitor,
chemically designated as (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-
15 3furanyl]
oxy]-phenyl]-methyl]phenyl]-D-glucitol and is being marketed for the
treatment of type 2 diabetes mellitus. Its chemical structure is represented by the
following Formula I.
O O
Cl O
OH
OH
HO OH
Formula I
20 U.S. Patent Nos. 7,579,449, and 7,713,938 disclose a process for the
preparation of empagliflozin, which comprises protection of 4-(5-bromo-2-
chlorobenzyl) phenol with tert-butyldimethylsilylchloride and triethylamine
followed by reaction of [4-(5-bromo-2-chlorobenzyl) phenoxy]-tert-butyl
dimethylsilane with 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in the
25 presence of tert-butyllithium and then reaction with methanesulfonic acid in
methanol. The obtained product is then reduced with triethyl silane and boron
trifluoride etherate to obtain 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-
hydroxybenzyl) benzene which is further reacted with (R)-3-(4-
3
methylphenylsulfonyloxy) tetrahydrofuran to obtain empagliflozin. The above
reduction step involves a tedious work-up like multiple extractions with ethyl
acetate and chromatographic purification, which is not desirable for commercial
scale production.
5
U.S. Patent No. 7,772,191 discloses a process for the preparation of 1-Chloro-
4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)
benzene of Formula II
O O
Cl O
OH
OH
HO OH
MeO
10 Formula II
which comprises a reaction of (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxybenzyl)
benzene and 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone with tertbutyllithium,
which involves the use of solvent like diethyl ether which has low
flash point, and therefore its use in the manufacture of drug substance is not
15 desirable.
U.S. Patent No. 9,024,010 discloses a process for the preparation of 1-Chloro-
4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)
benzene of Formula II
O O
Cl O
OH
OH
HO OH
MeO
20
Formula II
which comprises a reaction of (S)-4-iodo-1-chloro-2-(4-tetrahydrofuran-3-yloxybenzyl)
benzene and 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in the
presence of a turbogrignard reagent i.e., isopropyl magnesium chloride and lithium
25 chloride followed by reaction with hydrochloric acid in methanol. The
4
turbogrignard reagent preparation involves the use of isopropyl chloride and lithium
chloride which is highly volatile and hygroscopic respectively. Thus, their use for
the manufacture of drug substance is not advisable.
Process for the purification 5 of (3R,4R,5S,6R)-2-[4-chloro-3-(4-
hydroxybenzyl) phenyl]-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol of
Formula V in a mixture of two or more solvents are described in the PCT
Publication Nos. WO 2006/108842, WO 2007/000445, and WO 2009/026537.
10 There is a need in the art to develop a process for the preparation and
purification of empagliflozin intermediate of Formula II and Formula V
respectively, which obviates from the drawbacks associated with prior art
processes.
15 SUMMARY OF THE INVENTION
A first aspect of the present invention provides a process for the preparation
of empagliflozin of Formula I,
O O
Cl O
OH
OH
HO OH
Formula I
20 comprising the steps of:
a) reacting 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl) benzene
of Formula III;
O
Cl OH
OH
OH
HO OH
MeO
Formula III
25 with a compound of formula IV, wherein X is a leaving group;
5
O
X
Formula IV
to obtain a compound of Formula II;
O O
Cl O
OH
OH
HO OH
MeO
5 Formula II
b) optionally purifying the compound of Formula II; and
c) converting the compound of Formula II to empagliflozin.
A second aspect of the present invention provides a process for the
10 preparation of a compound of Formula II,
O O
Cl O
OH
OH
HO OH
MeO
Formula II
comprising
a) reacting 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl) benzene
15 of Formula III;
O
Cl OH
OH
OH
HO OH
MeO
Formula III
with a compound of the formula IV, wherein X is a leaving group;
O
X
20 Formula IV
6
to obtain the compound of Formula II; and
b) optionally purifying the compound of Formula II.
A third aspect of the present invention provides a process for the purification
5 of a compound of Formula V:
O
Cl OH
OH
OH
HO OH
Formula V
comprising the steps of;
a) contacting a compound of Formula V with single solvent, and;
10 b) isolating pure compound of Formula V.
A fourth aspect of the present invention provides a process for the preparation
of pure empagliflozin, comprising the steps of:
a) contacting a compound of Formula V
O
Cl OH
OH
OH
HO OH
15
Formula V
with single solvent;
b) isolating pure compound of Formula V; and
c) converting the pure compound of Formula V to pure empagliflozin.
20
A fifth aspect of the present invention provides a pharmaceutical composition
comprising pure empagliflozin and one or more pharmaceutically acceptable
carriers and/or excipients.
25
7
DETAILED DESCRIPTION OF THE INVENTION
Various embodiments and variants of the present invention are described
hereinafter.
The term "about", as used herein, refers 5 to any value which lies within the
range defined by a number up to ±10% of the value.
The term “leaving group” as used herein, refers to a leaving group selected
from the group comprising halogen, mesyloxy, tosyloxy, 4-nitrophenylsulfonyloxy,
10 4-chlorophenylsulfonyloxy, benzenesulfonyloxy, or any other good leaving group.
The term “solvent” or “organic solvent” or “single solvent”, as used herein,
refers to a solvent which may include but not limited to alcohols such as methanol,
ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec15
butyl alcohol or t-butyl alcohol; ketones such as acetone, methyl ethyl ketone,
methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate,
ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate;
ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl
ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such
20 as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic
hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon
tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar
aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or Nmethylpyrrolidone;
water; or mixture(s) thereof.
25
The term “base”, as used herein, refers to an inorganic base or organic base
which may include but not limited to the group comprising of inorganic base like
hydroxides of alkali metal or alkaline earth metal such as sodium hydroxide,
potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide and
30 the like; carbonates of alkali metal or alkaline earth metal such as sodium carbonate,
potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium
8
hydrogen carbonate and the like; and phosphates such as disodium
monohydrogenphosphate, dipotassium monohydrogen phosphate, trisodium
phosphate, tripotassium phosphate and the like; or organic base like tertiary amines
such as triethylamine, diisopropylethylamine, tri(n-propyl)amine, tri(nbulyl)
amine, cyclohexyldimethylamine, 5 N-methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine and the like; and aromatic amines such as pyridine, lutidine,
N,N-dimethylaniline and the like.
The term “treating” as used herein, refers to dissolving, slurrying, stirring, or
10 a combination thereof.
The reaction of a compound of Formula III with a compound of Formula IV
is carried out in the presence of a base. Preferably, the base is cesium carbonate.
15 The reaction of a compound of Formula III with a compound of Formula IV
is carried out in the presence of a solvent. Preferably, the solvent is N,Ndimethylformamide.
The reaction of a compound of Formula III with a compound of Formula IV
20 is carried out at the temperature of about 20°C to about 80°C. Preferably, the
reaction is carried out at a temperature of about 50°C to about 60°C.
The reaction of a compound of Formula III with a compound of Formula IV
is carried out for about 5 hours to about 15 hours. Preferably, the reaction is carried
25 out for about 10 hours to about 14 hours.
The compound of Formula II can be isolated by common isolation techniques
such as extraction, crystallization, precipitation, filtration, decantation,
centrifugation, or a combination thereof.
30
9
In one embodiment, the present invention provides a process for the
purification of a compound of formula II, comprising:
a) providing a compound of Formula II in an organic solvent to obtain a
solution;
b) washing 5 the solution of step a) with an aqueous base; and
c) isolating the pure compound of Formula II from organic layer,
wherein the aqueous base is selected from the group consisting of
aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous
lithium hydroxide, aqueous calcium hydroxide, or aqueous barium
10 hydroxide.
Preferably, the organic solvent is dichloromethane.
The concentration of aqueous base used in step b) is about 2%
(weight/volume) to about 15% (weight/volume). Preferably, the concentration of
15 aqueous base is about 5% (weight/volume) to about 10% (weight/volume).
The pure compound of Formula II can be isolated by common isolation
techniques such as extraction, crystallization, precipitation, filtration, decantation,
centrifugation, or a combination thereof.
20
The compound of Formula III used as a starting material may be prepared by
processes known in the art, such as by the processes described in the U.S. Patent
No. 7,662,790.
25 The conversion of a compound of Formula II to empagliflozin can be carried
out by processes known in the art, such as by the processes described in the U.S.
Patent No. 7,772,191, wherein the compound of Formula II is reduced with
triethylsilane and boron trifluoride etherate, followed by protection with acetic
anhydride and deprotection with aqueous potassium hydroxide to obtain
30 empagliflozin.
10
The term “contacting”, as used herein, refers to dissolving, slurrying, stirring,
or combinations thereof.
The purification of a compound of Formula V is carried out by dissolving or
slurrying a compound of Formula V in a single solvent 5 and then cooling the mixture
to obtain pure compound of Formula V.
Preferably, the single solvent is selected from the group comprising ethyl
acetate, acetone, isopropyl acetate, or methyl isobutyl ketone.
10
The dissolving or slurrying a compound of Formula V is carried out at a
temperature of about 0°C to about reflux temperature of the solvent. Preferably,
the dissolving or slurrying is carried out at a temperature of about 30°C to about
40°C.
15
The reaction mixture is cooled to a temperature of about 20°C to about 40°C
after dissolving or slurrying the compound of Formula V to obtain pure compound
of Formula V.
20 The reaction mixture is stirred for 1 hour to 6 hours after cooling the reaction
mixture. Preferably, the reaction mixture is stirred for 1 hour and 3 hours after
cooling.
The pure compound of Formula V can be isolated by methods including but
25 not limited to concentration, distillation, decantation, filtration, evaporation,
centrifugation, or a combination thereof.
The conversion of pure compound of Formula V to pure empagliflozin can
be carried out by methods known in the art, such as by the method described in the
30 U.S. Patent No. 7,713,938.
11
In a preferred embodiment of the fifth aspect, the process provides
empagliflozin having purity more than 99.5% when determined by HPLC.
Preferably, the process provides empagliflozin having purity more than 99.8%
when determined by HPLC.
5
Pure empagliflozin obtained from the present invention can be formulated
into pharmaceutical compositions with excipients and/or carriers.
The compound of Formula V as used herein may be prepared by methods
10 known in the art, such as by the method described in the U.S. Patent No. 7,579,449.
While the present invention has been described in terms of its specific aspects
and embodiments, certain modifications and equivalents will be apparent to those
skilled in the art and are intended to be included within the scope of the present
15 invention.
EXAMPLES:
Example-1: Preparation of 1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-
(S)-tetrahydrofuran-3-yloxy-benzyl) benzene
20 1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl] benzene
(23 g) was dissolved in N,N-dimethylformamide (100 mL) and added cesium
carbonate (36.4 g) to obtain a mixture. To this mixture, a solution of (3R)-
Tetrahydrofuran-3-yl-4-methylbenzenesulfonate (16.29 g) in N,Ndimethylformamide
(15 mL) was added, heated to 50°C to 60°C and stirred for 2
25 hours. Cesium carbonate (9.11 g) was added to the reaction mixture and stirred for
8 hours at 50°C to 60°C. To this mixture, cesium carbonate (9.11 g) was added and
stirred for 30 minutes at 50°C to 60°C. After completion of the reaction, the mixture
was cooled to 25°C to 35°C and water (920 mL) was added. The aqueous layer
was washed with toluene (325 mL x 2) and the organic layer was discarded. The
30 aqueous layer was extracted with dichloromethane (300 mL x 2) and the combined
organic layer was stirred with 10% aqueous potassium hydroxide solution (300 mL)
12
for 15 to 20 minutes and layers were separated. The organic layer was evaporated
under vacuum at 30 to 40°C to obtain a residue. The obtained residue was dissolved
in ethyl acetate (300 mL) and washed with 30% aqueous sodium chloride solution
(300 mL x 5), 5% aqueous lithium chloride solution (200 mL) and water (300 mL).
The organic layer was distilled under 5 vacuum at 30°C to 40°C to obtain a residue.
To the residue, dichloromethane (100 mL) and acetonitrile (100 mL) were charged
and distilled under vacuum at 30°C to 40°C to obtain 1-chloro-4-(1-methoxy-Dglucopyranos-
1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl) benzene.
Yield: 17.0 g
10
Example-2: Preparation of 1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-
(S)-tetrahydrofuran-3-yloxy-benzyl) benzene
1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-hydroxy-benzyl]
benzene (10 g) was dissolved in N,N-dimethylformamide (30 mL) and added
15 cesium carbonate (15.8 g) to obtain a mixture. To this mixture, a solution of (3R)-
Tetrahydrofuran-3-yl-4-methylbenzenesulfonate (7.08 g) in N,Ndimethylformamide
(20 mL) was added and heated to 50°C to 60°C and stirred for
1 hour 30 minutes. Cesium carbonate (3.95 g) was added to the reaction mixture
and stirred for 4 hours at 50°C to 60°C. To this mixture, cesium carbonate (3.95 g)
20 was added and stirred for 4 hours at 50 to 60 °C. Another lot of cesium carbonate
(1.58 g) was added and stirred 3 hours at 50°C to 60°C. After completion of the
reaction, the mixture was cooled to 25°C to 35°C and water (400 mL) was added.
The aqueous layer was washed with toluene (150 mL x 2) and the organic layer was
discarded. The aqueous layer was extracted with dichloromethane (200 mL x 2)
25 and the combined organic layer was stirred with 5% aqueous potassium hydroxide
solution (200 mL) for 15 minutes to 20 minutes and layers were separated. The
organic layer was evaporated under vacuum at 30°C to 40°C to obtain a residue.
The obtained residue was dissolved in ethyl acetate (200 mL) and washed with 30%
aqueous sodium chloride solution (200 mL x 5), 5% aqueous lithium chloride
30 solution (150 mL) and water (300 mL). The organic layer was distilled under
vacuum at 30°C to 40°C to obtain a residue. To the residue, dichloromethane (100
13
mL) and acetonitrile (100 mL) were added and distilled under vacuum at 30°C to
40°C to obtain 1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-(S)-
tetrahydrofuran-3-yloxy-benzyl) benzene.
Yield: 8.5 g
5
Example-3: Preparation of 1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-
(S)-tetrahydrofuran-3-yloxy-benzyl) benzene
1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-hydroxy-benzyl]-
benzene (2 g) was added to N,N-dimethylformamide (20 mL) followed by the
10 addition of cesium carbonate (3.95 g) to obtain a mixture. To this mixture, (3R)-
Tetrahydrofuran-3-yl-4-methylbenzenesulfonate (1.4 g) was added, heated to 50°C
to 60°C and stirred for 10 hours. Cesium carbonate (1.58 g) was added to the
reaction mixture and stirred for 2 hours at 50°C to 60°C. After completion of the
reaction, the mixture was cooled to 25°C to 35°C and water (200 mL) was added.
15 The reaction mixture was extracted with ethyl acetate (50 mL x 3) and the combined
organic layer was washed with brine (50 mL x 2). The organic layer was distilled
under reduced pressure at 40°C to 50°C to obtain crude 1-Chloro-4-(1-methoxy-Dglucopyranos-
1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl) benzene which was
purified by column chromatography to obtain pure 1-Chloro-4-(1-methoxy-D20
glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl) benzene.
Yield: 1.0 g
Example-4: Preparation of 1-Chloro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos
-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl) benzene
25 1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-
yloxy-benzyl) benzene (10 g) was dissolved in dichloromethane (57 mL) and
acetonitrile (114 mL) to obtain a solution. To this solution, triethyl silane (6.6 ml)
was added and cooled to -12°C to -8°C. Boron trifluoride diethyl etherate (4.4 mL)
was added dropwise to the reaction mixture at -12°C to -8°C and stirred for 1 hour
30 30 minutes at -12°C to -8°C. After completion of the reaction, ethyl acetate (30 mL)
and saturated sodium bicarbonate solution (100 mL) were added and stirred at 25°C
14
to 35 °C. The layers were separated and the aqueous layer was extracted with of
ethyl acetate (30 mL). The combined organic layer was washed with 30% aqueous
sodium chloride solution (100 mL) and distilled under vacuum at 35°C to 40 °C to
obtain a residue. The obtained residue was dissolved in dichloromethane (114 mL),
added triethylamine (9.44 g) and cooled to 5 5°C to 10 °C. To this solution, acetic
anhydride (9.54 g) and 4-dimethylaminopyridine (0.15 g) were added and stirred
for 1 hour 30 minutes at 10°C to 20°C. After completion of the reaction, 10%
aqueous hydrochloric acid solution (80 mL) was added and stirred for 10 minutes.
The layers were separated and the organic layer was washed with saturated sodium
10 bicarbonate solution (100 mL) followed by 30% aqueous sodium chloride solution
(100 mL). The organic layer was distilled under vacuum at 30°C to 40 °C to obtain
a residue. To the residue, ethanol (80 mL) was added and stirred for 3 hours at 25°C
to 35°C. The solid obtained was filtered, washed with ethanol (10 mL) and dried
under vacuum at 30°C to 40°C.
15 Yield: 5.0 g
Example-5: Preparation of empagliflozin crystalline Form-I
1-Chloro-(4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(4-(S)-
tetrahydrofuran-3-yloxy-benzyl) benzene (5.0 gm) was added to methanol (67.5
20 mL) and cooled to 10°C to 15°C. To the obtained mixture, 4M aqueous potassium
hydroxide solution (2.03 g potassium hydroxide in 9 mL water) was added at 10°C
and stirred for 1 hour 30 minutes at 10°C to 15°C. Water (125 ml) was added to the
reaction mixture, stirred for 5 minutes and then layers were separated. The aqueous
phase was extracted with ethyl acetate (90 mL x 3), then the combined organic layer
25 was washed with 30% aqueous sodium chloride solution (50 mL) and distilled
under vacuum at 30°C to 40°C. Acetonitrile (50 mL) was added and distilled under
vacuum 30°C to 40 °C to obtain a residue. Ethyl acetate (81 mL) and water (2.4
mL) were added to the residue, heated to 50°C to 60°C and stirred for 20 minutes
at 50°C to 60°C. The mixture was cooled to 25°C to 30°C and stirred for 2 hours.
30 The solid was filtered and washed with ethyl acetate (10 mL). To the wet solid,
ethyl acetate was added (31 mL) and heated to 55°C to 60°C. Subsequently, water
15
(0.9 mL) was added to the mixture and stirred for 20 minutes at 55°C to 60°C to
obtain a clear solution. The mixture was cooled to 25°C to 30°C and stirred for 2
hours at 25°C to 30°C. The solid was filtered and dried under vacuum at 45°C to
50°C for 2 hours.
5 Yield: 0.7 g
Example-6: Preparation of empagliflozin amorphous
Empagliflozin (0.7 g) was added to dichloromethane (3.5 mL) and methanol
(3.5 mL) and heated to 35°C to 40°C to obtain a clear solution. The obtained
10 solution was evaporated under vacuum 40°C to obtain a foamy solid. The obtained
foamy solid was degassed and unloaded to obtain empagliflozin amorphous.
Yield: 0.65 g
Example-7: Preparation of a compound of formula V
15 A stirred solution of 1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-
hydroxy-benzyl] benzene (85 g) in a mixture of acetonitrile (1224 mL) and
dichloromethane (408 mL) was cooled to -50±5°C and then slowly added
triethylsilane (94.0 g). To this mixture, boron trifluoride diethyletherate (106 g) was
added at -50±5°C, then warmed to -10°±3°C and stirred for 2 hours at -10±3°C.
20 After completion of the reaction, saturated sodium bicarbonate solution (850 mL)
was added and stirred for 30 minutes at 25°C to 35 °C. The layers were separated
and sodium chloride (85.0 g) was added to aqueous layer. The aqueous phase was
then extracted with ethyl acetate (680 mL ×2). The combined organic layer was
washed with 10% aqueous sodium chloride solution (1275 mL) and distilled under
25 vacuum at 37°C to 42 °C to obtain residue.
Yield: 81.0 g
HPLC Purity: 91.95%
Example-8: Purification of a compound of Formula V
30 A stirred mixture of a compound of Formula V (81.0 g, HPLC Purity:
91.95%) in ethyl acetate (1275 mL) was stirred for 2 hours at 30°C to 35°C. The
16
separated solid was filtered, washed with ethyl acetate (170 mL), and dried under
vacuum at 50°C for 12 hours.
Yield: 48.5 g
HPLC purity: 99.09%
5
Example-9: Purification of a compound of Formula V
A stirred mixture of a compound of Formula V (0.7 g, HPLC Purity: 90.90%)
in acetone (10 mL) was stirred for 1 hour at 20°C to 30°C. The separated solid was
filtered, washed with acetone (10 mL), and dried under vacuum.
10 Yield: 0.35 g
HPLC purity: 98.7%
Example-10: Purification of a compound of Formula V
A stirred mixture of a compound of Formula V (1.0 g, HPLC Purity: 91.95%)
15 in isopropyl acetate (15 mL) was stirred for 3 hours at 30°C to 35°C. The separated
solid was filtered, washed with isopropyl acetate (5 mL), and dried for 6 hours.
Yield: 0.74 g
HPLC purity: 98.49%
20 Example-11: Purification of a compound of Formula V
A stirred mixture of a compound of Formula V (1.0 g, HPLC Purity: 91.95%)
in methyl isobutyl ketone (20 mL) was stirred for 3 hours at 30°C to 35°C. The
separated solid was filtered, washed with methyl isobutyl ketone (5 mL), and dried
for 6 hours.
25 Yield: 0.73 g
HPLC purity: 98.20%
Example-12: Preparation of pure compound of Formula V
A stirred solution of 1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-
30 hydroxy-benzyl] benzene (70.0 g) in a mixture of acetonitrile (1008 mL) and
dichloromethane (336 mL) was cooled to -50±5°C and then slowly added
17
triethylsilane (77.43 g). To this mixture, boron trifluoride diethyletherate (87.27 g)
was added at -50±5°C, warmed to -8°±3°C and stirred for 2.5 hours at -8±3°C.
After completion of the reaction, saturated sodium bicarbonate solution (700 mL)
was added and stirred for 30 minutes at 25°C to 35°C. The layers were separated
and the aqueous layer was extracted 5 with of ethyl acetate (560 ×4 mL). The
combined organic layer was distilled under vacuum at 35°C to 40 °C to obtain
residue. To the obtained residue, ethyl acetate (700 mL) was added and stirred for
2 hours at 25±5°C. The separated solid was filtered, washed with ethyl acetate (140
mL) and dried under vacuum at 55°C for 5 hours.
10 Yield: 48.0 g
HPLC purity: 99.49%
Example-13: Preparation of pure empagliflozin
To a stirred mixture of a compound of Formula V (42 g) in N,N15
dimethylformamide (168 mL), a solution of (3R)-Tetrahydrofuran-3-yl-4-
methylbenzenesulfonate (29.35g) dissolved in N,N-dimethylformamide (42 mL)
was added at 25°C to 30°C. To the obtained mixture, cesium carbonate (71.68 g)
was added, heated to 50°C to 60°C and stirred 6 hours. To this mixture, a second
lot of cesium carbonate (17.92 g) was added and stirred for 8 hours at 50°C to 60°C.
20 After completion of the reaction, the mixture was cooled to 25°C to 35°C and water
(1680 mL) was added. The reaction mixture was extracted with ethyl acetate (630
mL x 4) and the combined organic layer was washed with brine solution (1050 mL
x 4). The organic layer was distilled under reduced pressure at 40°C to 50°C to
obtain residue. To the obtained residue, ethyl acetate (1080 mL) was added and
25 heated to 55±2°C. To this mixture, water (54 mL) was added, heated to 60±2°C and
stirred for 10 minutes. The mixture was cooled to 25±5°C and stirred for 1 hour.
Subsequently, the mixture was further cooled to 7±2°C and stirred for 1 hour. The
separated solid was filtered, washed with ethyl acetate (200 mL) and dried under
vacuum at 55°C for 8 hours. The dried solid was once again purified in a mixture
30 of ethyl acetate and water to obtain pure empagliflozin.
Yield: 19.0 g; HPLC purity: 99.88% ,CLAIMS:We claim:
1. A process for the preparation of empagliflozin of Formula I,
O O
Cl O
OH
OH
HO OH
Formula I
5 comprising the steps of:
a) reacting 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-
benzene of Formula III;
O
Cl OH
OH
OH
HO OH
MeO
Formula III
10 with a compound of formula IV, wherein X is a leaving group;
O
X
Formula IV
to obtain a compound of Formula II;
O O
Cl O
OH
OH
HO OH
MeO
15 Formula II
b) optionally purifying the compound of Formula II; and
c) converting the compound of Formula II to empagliflozin.
2. A process for the preparation of a compound of Formula II,
19
O O
Cl O
OH
OH
HO OH
MeO
Formula II
comprising,
a) reacting 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-
5 benzene of Formula III;
O
Cl OH
OH
OH
HO OH
MeO
Formula III
with a compound of the formula IV, wherein X is a leaving group;
O
X
10 Formula IV
to obtain the compound of Formula II; and
b) optionally purifying the compound of Formula II.
3. The process according to claim 1 or 2, wherein the reaction of a compound of
Formula III with a compound of Formula IV is carried out in the presence of
15 a base.
4. The process according to claim 3, wherein the base is selected from the group
comprising sodium carbonate, potassium carbonate, cesium carbonate,
sodium hydrogen carbonate, potassium hydrogen carbonate.
5. The process according to claim 1 or 2, wherein the reaction of a compound of
20 Formula III with a compound of Formula IV is carried out in the presence of
a solvent.
6. The process according to claim 5, wherein the solvent is selected from the
group comprising alkyl alcohol, alkyl acetates, ethers, nitriles, halogenated
20
aliphatic hydrocarbon, hydrocarbons, polar aprotic solvent, water, or
mixture(s) thereof.
7. A process for the purification of a compound of Formula V,
O
Cl OH
OH
OH
HO OH
5 Formula V
comprising the steps of:
a) contacting a compound of Formula V with single solvent, and;
b) isolating pure compound of Formula V.
8. A process for the preparation of pure empagliflozin, comprising the steps of:
10 a) contacting a compound of Formula V
O
Cl OH
OH
OH
HO OH
Formula V
with single solvent;
b) isolating pure compound of Formula V; and
15 c) converting the pure compound of Formula V to pure empagliflozin.
9. The process according to claim 7 or 8, the single solvent is selected from the
group comprising ethyl acetate, acetone, isopropyl acetate, or methyl isobutyl
ketone.
10. The process according to claim 7 or 8, the contacting a compound of Formula
20 V with single solvent is carried out at a temperature of about 0°C to about
reflux temperature of the solvent.
21
Dated this 22nd day of June, 2017
Dr. Rajiv G. Shah
Torrent P 5 harmaceuticals Limited
Torrent Research Centre
P.O. BHAT – 382 428,
Dist. Gandhinagar.
Gujarat, India