FIELD OF THE INVENTION
The present invention relates to an industrially feasible and cost effective process for the
preparation of Empagliflozin having Formula X.
Formula X
O ^ v
^ O
BACKGROUND OF THE INVENTION
Empagliflozin is an inhibitor of the Na+-glucose cotransporter 2 (SGLT2) and is
marketed under the proprietary name JARDIANCE® by Boehringer. It is indicated for
prevention and/or treatment of metabolic disorders, particularly type-2 diabetes.
Empagliflozin belongs to a class of pyranosyl-oxysubstituted benzene derivatives and has
an enhanced inhibitory effect on SGLT2 in vitro and in vivo, while having improved
pharmacological or pharmacokinetic properties when compared with other type-2
diabetic medications. It is avaijable in 10 mg and 25 mg strengths as tablet dosage forms.
Empagliflozin is chemically named as (lS)-l,5-anhydro-l-C-[4-chloro-3-[[4-[[(3S)-
tetrahydro-3-furanyl] oxy] phenyl]methyl] phenyl]-D-glucitol and has the following
chemical structure of Formula X:
Formula X
-2 .of 30
U.S. Pat. No. 7,579,449, which is hereby incorporated by reference, discloses
Empagliflozin, stereoisomers of Empagliflozin, mixtures and salts thereof, and a
pharmaceutical composition containing Empagliflozin. It discloses a process for the
preparation of Empagliflozin comprising reaction of 4-bromo-l-chloro-2-(4-
methoxybenzyl)-benzene with tribromoborane in dichloromethane to produce 4-(5-
bromo-2-chloro-benzyl)-phenol which is reacted with t-butyl dimethyl silyl chloride in
dichloromethane in presence of triethylamine and dimethylaminopyridine to get [4-(5-
bromo-2-chloro-benzyl)-phenoxy]-tertbutyldimethyl-silane which is further reacted with
n-BuLi in tetrahydrofuran followed by coupling with 2,3,4,6-tetrakis-0-(trimethyIsilyl)-
D-glucopyranone. The resulting reaction mixture is treated with methanesulfonic acid
(MsOH) in methanol followed by reduction with triethylsilylhydride and boron trifluoride
etherate and acylated with acetic anhydride/pyridine in dichloromethane followed by
treating with KOH in methanol to produce (25, 37?, 47?, 5S, 6i?)-2-(4-chloro-3-(4-
hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (pentahydroxy
intermediate). This pentahydroxy intermediate is reacted with tetrahydrofuran-3-
yl (5)-toluene-4-sulphonate in presence of cesium carbonate in dimethylformamide
(DMF) to produce Empagliflozin.
The above prior art process also produces low yield of Empagliflozin on reaction of
pentahydroxy intermediate with tetrahydrofuran-3-yl (S)-toluene-4-sulphonate. Further, it
also involves the use of hazardous BBn, which reacts violently and decomposes to toxic
compounds when it comes in contact with moisture.
The above prior art discloses the purification of Empagliflozin via of O-acetyl
Empagliflozin or O-allyl Empagliflozin, which reduces the atom economy of the
molecule as protection and de-protection is used for the purification of Empagliflozin. On
completion of glycosylation, tedious work up, which involved pH adjustment using aq.
acids such as citric acid, distillation and layer separation. Over all yield of the process is
low due to purification of regio-isomer and anomers via column chromatography.
Further, the use of costly cesium carbonate as a base and use of column chromatography
to obtain the pure product increases the overall production cost.
3 of 30
The major disadvantage of the above process is the difficulty in controlling the formation
/separation of (i?)-isomer of Empagliflozin, which is formed on reaction of
tetrahydrofuran-3-yl (S)-toluene-4-sulphonate intermediate compound with pentahydroxy
intermediate. This is formed due to the presence of tetrahydrofuran-3-yl (S)-toluene-4-
sulphonate intermediate, which exists as a contamination in the R-isomer. Hence, this
process requires multiple purification steps to remove the undesired R-isomer of
Empagliflozin, which in-turn led to increasing the cost of the product. Therefore, the
above process is not viable for industrial scale preparation.
U.S. P^t. No. 7,772,191, which is hereby incorporated by reference, discloses reduction
of anomeric C-0 bond using heavy metals such as Raney Ni, Pd/C. Glycosylation was
introduced via trans-metalation using epoxide formation. During de-acetylation of acetyl-
Empagliflozin, sodium or potassium salt of Empagliflozin is formed as an intermediate
from which free Empagliflozin is isolated. Thus, increases the number of operational
steps on commercial scale. Further, over all yield from this process is also very low
(-20%).
U.S. Pat. No. 9,127,034, which is hereby incorporated by reference, discloses
deoxygenation process, which is carried out in multiple steps such as reduction followed
by de-hydroxylation.
The known processes suffer from problems, such as a cumbersome purification of the
product by column chromatography, low yields, use of costly, hazardous,
environmentally unsafe, carcinogenic or pyrophoric reagents, etc. on industrial scale. In
view of the preparation methods available for Empagliflozin, there is a need for simple,
industrially scalable, cost effective and environmentally-friendly process for the
preparation of Empagliflozin that is free from one'or more of the above mentioned
drawbacks and achieves high yield and purity.
I 2 - Z 0 I 1 & I S . : 2 V f 3°
The problem has been solved by the applicant by providing an improved process, which
allows a convenient and efficient synthesis of Empagliflozin.
OBJECT OF THE INVENTION
It is a principal object of the present invention to improve upon limitations in the prior
arts by providing an improved process for the preparation of Empagliflozin.
It is another object of the present invention to provide a simple, commercially viable,
economical and environment friendly process for preparing Empagliflozin, in high yield
and purity.
It is yet another object of the present invention to provide a process for the preparation of
compound of Formula VI having chiral purity not less than 99.7%.
It is still another object of the present invention to provide a process for the preparation of
Empagliflozin using compound of Formula VI.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of Empagliflozin
of Formula X comprising the steps of:
(a) coupling of 5-bromo-2-chlorobenzoyl chloride as obtained from 5-bromo-2-
chlorobenzoic acid of Formula I, with Anisole of Formula II in presence of Lewis acid;
3
II
CI O
OH OCI
Br ^^
Formula I Formul
L
5 of 30
with or without isolation of compound of Formula III;
CI O
Formula III
(b) converting compound of Formula III to the compound of Formula IV in presence of
acidic reagent;
CI O
Formula IV
(c) coupling of the compound of Formula IV with (R)-tetrahydrofuran-3-yl-4-
methylbenzenesulfonate of Formula B to obtain compound of Formula V in presence of
base;
TsCT^
Formula B
CI O
Formula V
(d) reducing the compound of Formula V to obtain compound of the Formula VI in
presence of reducing agent;
- I . 2 - - ~ 2 ® I 18 I26$f3°
o ^ ^
^o
Formula VI
(e) coupling of the compound of Formula VI with the compound of Formula D to obtain
compound of the Formula VII;
:0
TMSCT ^y ^f
TMSO^'Nf 'OTMS
OTMS
Formula D
TMSO
TMSO°' "Y ''0TMS
-*\ OTMS
v
Formula VII
^0
(f) converting the compound of Formula VII to compound of Formula VIII;
°*&^W
Formula Vm
(g) reducing the compound of Formula VIII to obtain crude Empagliflozin of Formula IX
in presence of acid; and
•J,of30
Formula IX
(h) optionally, purifying crude Empagliflozin to get pure Empagliflozin of Formula X.
HO
^ Formula X
DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of Empagliflozin
of Formula X comprising the steps of:
(a) coupling of 5-bromo-2-chlorobenzoyI chloride as obtained from 5-bromo-2-
chlorobenzoic acid of Formula I, with Anisole of Formula II in presence of Lewis acid;
CI O
OH OCHBr
Formula I Formula II
with or without isolation of compound of Formula III;
L 2 - 2 I 8. : 2
8 of 30
CI O
Formula III
(b) converting compound of Formula III to the compound of Formula IV in presence of
acidic reagent;
CI O
Formula IV
(c) coupling of the compound of Formula IV with (R)-tetrahydrofuran-3-yl-4-
methylbenzenesulfonate of Formula B to obtain compound of Formula V in presence of
base;
Br
O
TsO'W
Formula B
CI O
Formula V
(d) reducing the compound of Formula V to obtain compound of the Formula VI in
presence of reducing agent; - '
9 of 30
-1Z..-2M1
/
Formula VI
(e) coupling of the compound of Formula VI with the compound of Formula D to obtain
compound of the Formula VII;
TMSO
TMS'0° y^ ''OTMS
OTMS
Formula D
''OTMS
OTMS
Formula VII
°*s^(f) converting the compound of Formula VII to compound of Formula VHI;
Formula VIII
(g) reducing the compound of Formula VIII to obtain crude Empagliflozin of Formula IX
in presence of acid; and
HO ^ / O
HO V
OJS)
Formula IX
-1.2.-20:18. I -Jflof30
(h) optionally, purifying crude Empagliflozin to get pure Empagliflozin of Formula X.
HO° Y^'^OH
OH
Formula X
In step (a), coupling of 5-bromo-2-chlorobenzoyl chloride obtained from 5-bromo-2-
chlorobenzoic acid of Formula I, with Anisole of Formula II is carried out in presence of
Lewis acid such as Aluminum chloride, Zinc chloride, Ferric chloride, Titanium chloride,
Zirconium chloride, Boron trifluoride and the like; preferably aluminum chloride. 5-
Bromo-2-chlorobenzoic acid of Formula I is converted into 5-bromo-2-chlorobenzoyl
chloride using chlorinating agent such as Oxalyl chloride, Thionyl chloride, PC13, PC15
and the like. This reaction is carried out in presence of solvents selected from the group
comprising of dichloromethane, chlorobenzene, nitrometane, toluene and
dimethylformamaide and the like. This coupling reaction is carried out at temperatures
between 0°C and 50°C, preferably at 25°C to 35°C.
In step (b), the compound of Formula III is converted to the compound of Formula IV
under neutral, acidic and basic conditions. Suitable acidic reagents for this conversion are
selected from the group comprising of aluminum chloride, aluminum bromide, boron
trichloride, boron tribromide, boron triiodide, trimethylsilyl iodide, hydrobromic acid,
hydrochloric acid, cerium chloride, trifluoroacetic acid, and trifluoromethylsulfonic acid ;
preferably aluminum chloride. Conversion under neutral or basic conditions is done with
metal thiolates such as sodium sulfide, sodium ethane thiolate, sodium trimethylsilylthiolate,
potassium thiophenolate, sodium cyanide, and lithium iodide in solvents such as
dimethylformamide, dimethylacetamide, l,3-dimethyl-2-oxohexahydropyrimidine, Nmethylpyrrolidone,
and tetrahydrofuran. This conversion reaction is carried out with or
11 of 30
without solvents. Depending on the acid used in step (b), solvents are selected from the
group comprising of halogenated hydrocarbons such as dichloromethane, chloroform,
chlorobenzene or 1,2-dichloroethane; acetonitrile, toluene, hexane, acetic acid and
combinations thereof. This conversion reaction under acidic condition is generally carried
out at -20°C to 150°C temperature, preferably at 5°C to 50°C. This conversion reaction
under basic or neutral conditions is carried out at temperatures between 0°C and 200°C,
preferably at 50°C to 180°C.
In step (c), coupling of the compound of Formula IV with (R)-tetrahydrofuran-3-yl-4-
methylbenzenesulfonate of Formula B is carried out to obtain compound of Formula V.
This coupling is carried out under basic conditions as nucleophilic substitution reaction.
Suitable base for this coupling reaction is selected from the group comprising of alkali or
alkaline earth metal salts, in particular carbonates, hydroxides, alkoholates and metal
hydrides such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium
methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride and calcium
hydride; preferably potassium carbonate, sodium hydroxide, sodium methoxide,
potassium tert-butoxide and sodium hydride; and more preferably potassium carbonate.
This coupling reaction is carried out with or without solvents. The solvent is selected
from the group comprising of polar and non-polar solvents, such as acetonitrile, ethanol,
isopropanol, butanol, acetone, water, dimethylformamide, dimethylacetamide, Nmethylpyrollidone,
dimethylsulfoxide, tetrahydrofuran, dichloromethane, toluene,
acetonitrile and mixtures thereof. This coupling reaction is carried out at 20°C to 180°C
temperature, preferably at 40°C to 120°C.
In step (d), reduction of the compound of Formula V is carried out to obtain compound of
the Formula VI. Suitable reducing agent is selected from the group comprising of silane
such as triethyl silane and triisopropylsilane, tetramethyldisiloxane; borohydride such as
sodium borohydride; and aluminum hydride such as lithium aluminum hydride;
preferably tetramethyldisiloxane. Reductions with hydrogen in the presence of a
transition metal catalyst such as Pd on charcoal, Pt on charcoal, use of Raney Ni are
another possible method of synthesis. This reduction is preferably carried out in the
12 of 30
presence of a Lewis acid such as boron trifluoride etherate, tris(pentafluorophenyl)
borane, trifluoroacetic acid, hydrochloric acid, and aluminum chloride. This reduction
reaction is carried out with or without solvents. The reactions are preferably carried out in
solvents selected from the group comprising of halogenated hydrocarbons such as
dichloromethane and 1,2-dichloroethane, toluene, benzene, hexane, acetonitrile and
mixtures thereof. This reduction reaction is carried out at -30°C to 150°C temperature,
preferably at 20°C to 100°C.
In step (e), firstly compound of Formula VI undergoes either halogen-metal exchange
reaction or direct insertion of the metal into the carbon halogen bond and then finally get
coupled with glucolactone compound of formula D to give compound of the Formula
VII. The Grignard or Lithium derivative of compound of Formula VI are preferred. The
halogen-metal exchange to synthesize the corresponding lithium derivative of compound
VI may be carried out with an organo-lithium compound such as n- butyllithium, secbutyllithium
or tert-butyllithium. The analogous magnesium compound may also be
generated by a halogen-metal exchange with a suitable Grignard reagent such as C3-4-
alkylmagnesium chloride or bromide, for example isopropyl- or sec-butylmagnesium
bromide or chloride or diisopropyl- or di-sec-butylmagnesium without or in the presence
of an additional salt such as e.g. lithium chloride. The organo-magnesium compound may
also be generated in situ from suitable precursors. The halogen-metal exchange reactions
are carried out between -100°C and 40°C, preferably between -80°C and 10°C and more
preferably between -80°C and -15°C. The halogen-metal exchange reaction is carried out
in the solvent selected from the group comprising of diethylether, dioxane,
tetrahydrofuran, diethylene glycol dimethyl ether, toluene, hexane, dimethylsulfoxide,
dichloromethane or mixtures thereof and preferably tetrahydrofuran, diethylene glycol
dimethyl ether, hexane and mixtures thereof. Alternatively, the metal derivative of
compound VI is prepared by directly inserting a metal into the carbon-halogen bond of
the compound of Formula VI. Lithium or magnesium are suitable elemental metals for
this insertion. This insertion reaction is carried out in solvents selected from the group
comprising of diethylether, dioxane, tetrahydrofuran, toluene, hexane, dimethylsulfoxide
and mixtures thereof. This insertion reactions are carried out at temperatures ranging
I . 2 6 - - I 2 - 2 0 1 S 18 : Z'i000
(
from -80°C to 100°C, preferably at -70°C to 40°C. Finally, this metal derivative of
compound VI get coupled with glucolactone compound of formula D to give compound
of the Formula VII. This coupling reaction is carried out at temperature between -100°C
and 40°C, preferably at -80°C to -10°C. This coupling reaction is carried out in solvents
selected from the group comprising of diethylether, diisopropyl ether, methyl tert-butyl
ether, toluene, methylene chloride, hexane, tetrahydrofuran, dioxane, Nmethylpyrrolidone
and mixtures thereof.
In step (f), the compound of Formula VII is converted to compound of Formula VIII by
treating it with an alcohol or water. The alcohol is selected from the group comprising of
CM alkanol, such as methanol or ethanol. This conversion reaction is performed in
presence of an acid such as acetic acid, methanesulfonic acid, toluenesulfonic acid,
sulfuric acid, trifluoroacetic acid and hydrochloric acid preferably methanesulfonic acid.
This reaction is carried out at temperatures in the range from about 0°C to 80°C,
preferably from 20°C to 60°C. During this reaction trimethylsilyl groups of compound of
Formula VII are cleaved.
In step (g), the compound of Formula VIII is reduced to crude Empagliflozin of Formula
IX. The reducing agent is selected from the group comprising of silanes such as
triethylsilane, tri-n-propylsilane, triisopropylsilane, or diphenylsilane; hydrides such as
sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes,
lithium aluminum hydride, diisobutylaluminum hydride, Hydrogen with transition metal
catalyst etc. The transition metal catalyst is selected from the group comprising of
palladium carbon, palladium oxide, platinum oxide, or Raney nickel. This reduction
reaction is carried out with or without Lewis acid. The Lewis acid is selected from the
group comprising of boron trifluoride etherate, trimethylsilyl triflate, titanium
tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate, zinc iodide,
hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid and
acetic acid; preferably boron trifluoride etherate. The reaction may be carried out in a
solvent selected from the group comprising of methylene chloride, chloroform,
acetonitrile, toluene, hexane, diethylether, tetrahydrofuran, dioxane, ethanol, water, or
14 of 30
mixtures thereof. The solvent is preferably selected in view of the reducing agent and the
optional Lewis acid. This reduction reaction is carried out at temperature -80°C and
120°C, preferably between -30°C and 80°C. One particularly suitable combination of
reagents comprising of triethylsilane and boron trifluoride etherate; preferably
triethylsilane, which is conveniently used in acetonitrile at temperatures from -30°C to
20°C.
In step (h), crude Empagliflozin of Formula IX is optionally purified to give pure
Empagliflozin of Formula X. This purification is carried out'by techniques already
known in prior art such as crystallization. The solvent used for purification is selected
from the group comprising of C1-4 alkanols, water, ethyl acetate, acetonitrile, acetone,
diethyl ether and mixture thereof. Preferred solvents are selected from the group
comprising of methanol, ethanol, isopropanol, water, ethyl acetate, acetonitrile, acetone,
diethyl ether and mixture thereof.
Empagliflozin obtained by the process of the invention is in fact substantially pure, and in
particular substantially free from the impurities. The expression "substantially pure"
means having a purity equal to or higher than 99%.
The present invention also relates to an improved process for the preparation of
compound of Formula VI having chiral purity not less than 99.7%, comprising the steps
of:
(a) coupling of 5-bromo-2-chlorobenzoyl chloride as obtained from 5-bromo-2-
chlorobenzoic acid of Formula I, with Anisole of Formula II in presence of Lewis acid;
OCH3 ]
A.
Formula II
15 of 30
il 2 I & - I 2 - 2 0 I . 8 - - 18. : 2 8.
CI O
OH
Br
Formula I
with or without isolation of compound of Formula III;
CI O
Formula III
(b) converting compound of Formula III to the compound of Formula IV in presence of
acidic reagent;
CI O
OH
Formula IV
(c) coupling of the compound of Formula IV with (R)-tetrahydrofuran-3-yl-4-
methylbenzenesulfonate of Formula B to obtain compound of Formula V in presence of
base;
Br
O
Ts
Formula B
Ck O
Formula V
(d) reducing the compound of Formula V to obtain compound of the Formula VI in
presence of reducing agent;
ii_i> 2 - 2 B 1 8 - 1 & - 2.
6 of 30
(
Formula VI
In step (a), coupling of 5-bromo-2-chlorobenzoyl chloride obtained from 5-bromo-2-
chlorobenzoic acid of Formula I, with Anisole of Formula II is carried out in presence of
Lewis acid such as Aluminum chloride, Zinc chloride, Ferric chloride, Titanium chloride,
Zirconium chloride, Boron trifluoride and the like; preferably aluminum chloride. 5-
Bromo-2-chlorobenzoic acid of Formula I is converted into 5-bromo-2-chlorobenzoyl
chloride using chlorinating agent such as Oxalyl chloride, Thionyl chloride, PCb, PCI5
and the like. This reaction is carried out in presence of solvents selected from the group
comprising of dichloromethane, chlorobenzene, nitrometane, toluene and
dimethylformamaide and the like. This coupling reaction is carried out at temperatures
between 0°C and 50°C, preferably at 25°C to 35°C.
In step (b), the compound of Formula III is converted to the compound of Formula IV
under neutral, acidic and basic conditions. Suitable acidic reagents for this conversion are
selected from the group comprising of aluminum chloride, aluminum bromide, boron
trichloride, boron tribromide, boron triiodide, trimethylsilyl iodide, hydrobromic acid,
hydrochloric acid, cerium chloride, trifluoroacetic acid, and trifluoromethylsulfonic acid ;
preferably aluminum chloride. Conversion under neutral or basic conditions is done with
metal thiolates such as sodium sulfide, sodium ethane thiolate, sodium trimethylsilylthiolate,
potassium thiophenolate, sodium cyanide, and lithium iodide in solvents such as
dimethylformamide, dimethylacetamide, l,3-dimethyI-2-oxohexahydropyrimidine, Nmethylpyrrolidone,
and tetrahydrofuran. This conversion reaction is carried out with or
without solvents. Depending on the acid used in step (b), solvents are selected from the
group comprising of halogenated hydrocarbons such as dichloromethane, chloroform,
chlorobenzene or 1,2-dichloroethane; acetonitrile, toluene, hexane, acetic acid and
combinations thereof. This conversion reaction under acidic condition is generally carried
17 of 30
LHI. 26 - 1.2 - 2 9 1 $ 1 8 : 2 3
out at -20°C to 150°C temperature, preferably at 5°C to 50°C. This conversion reaction
under basic or neutral conditions is carried out at temperatures between 0°C and 200°C,
preferably at 50°C to 180°C.
In step (c), coupling of the compound of Formula IV with (R)-tetrahydrofuran-3-yl-4-
methylbenzenesulfonate of Formula B is carried out to obtain compound of Formula V.
This coupling is carried out under basic conditions as nucleophilic substitution reaction.
Suitable base for this coupling reaction is selected from the group comprising of alkali or
alkaline earth metal salts, in particular carbonates, hydroxides, alkoholates and metal
hydrides such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium
methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride and calcium
hydride; preferably potassium carbonate, sodium hydroxide, sodium methoxide,
potassium tert-butoxide and sodium hydride; and more preferably potassium carbonate.
This coupling reaction is carried out with or without solvents. The solvent is selected
from the group comprising of polar and non-polar solvents, such as acetonitrile, ethanol,
isopropanol, butanol, acetone, water, dimethylformamide, dimethylacetamide, Nmethylpyrollidone,
dimethylsulfoxide, tetrahydrofuran, dichloromethane, toluene,
acetonitrile and mixtures thereof. This coupling reaction is carried out at 20°C to 180°C
temperature, preferably at 40°C to 120°C.
In step (d), reduction of the compound of Formula V is carried out to obtain compound of
the Formula VI. Suitable reducing agent is selected from the group comprising of silane
such as triethyl silane and triisopropylsilane, tetramethyldisiloxane; borohydride such as
sodium borohydride; and aluminum hydride such as lithium aluminum hydride;
preferably tetramethyldisiloxane. Reductions with hydrogen in the presence of a
transition metal catalyst such as Pd on charcoal, Pt on charcoal, use of Raney Ni are
another possible method of synthesis. This reduction is preferably carried out in the
presence of a Lewis acid such as boron trifluoride etherate, tris(pentafluorophenyl)
borane, trifluoroacetic acid, hydrochloric acid, and aluminum chloride. This reduction
reaction is carried out with or without solvents. The reactions are preferably carried out in
solvents selected from the group comprising of halogenated hydrocarbons such as
t u-r -. 18 Of 30
LHZ Z©-12-20-18 18:28
dichloromethane and 1,2-dichloroethane, toluene, benzene, hexane, acetonitrile and
mixtures thereof. This reduction reaction is carried out at -30°C to 150°C temperature,
preferably at 20°C to 100°C.
The process for the preparation of Empagliflozin described in the present invention is
demonstrated in the examples illustrated below. These examples are provided as
illustration only and therefore should not be construed as limitation of the scope of the
invention.
Examples:
Synthesis of compound of Formula III (step a)
2-Chloro-5-bromo benzoic acid (200g), dichloromethane (lOOOmL) " and N,Ndimethylformamide
(lOmL) was taken. Oxalyl chloride (161.72g) was added to a
reaction mixture within 30-45 min below 10°C and temperature of the reaction mass was
raised to 25-30°C. This reaction mixture is stirred for 3h at ambient temperature. The
reaction mixture was concentrated under vacuum to obtain oily mass, which was cooled
to room temperature. To the oily mass dichloromethane (lOOOmL) was added and
resulting solution was cooled to 0-15°C followed by addition of anhydrous aluminium
chloride (133.65g). Anisole (96.45g) was added to reaction mixture in 4-5h and
maintained at same temperature under stirring for 3h. Completion of reaction was
monitored on HPLC.
Synthesis of compound of Formula IV (step b)
To the above reaction mixture (step a), anhydrous aluminium chloride (113.26g) was
added slowly at 25-30°C and the reaction mixture was heated to 40-45°C for lOh.
Reaction mixture was cooled to ambient temperature and further anhydrous aluminium
chloride (113.26g) was added and heated to 40-45°C for 8-10h. Cooled reaction mass
was quenched in pre-cooled water (2000mL) below 10°C and stirred at 5-10°C for 3-4h.
The solid was filtered off and washed with DM water (800mL) and dichloromethane
(200mL) to obtain desired product with 98% HPLC purity. Yield: 90%.
LttI ' 2 6 - 1 2 - 2 0 I 8 - 18. :21lof30
•>
"1
Synthesis of compound of Formula V (step c)
Acetonitrile (1400mL), compound of Formula IV, (R)-tetrahydrofuran-3-yI-4-
methylbenzenesulfonate (261.3g) and potassium carbonate (164.35g) was taken.
Resulting mixture was heated to 80-85°C for 5-8h under stirring. The resulting mixture
was cooled to ambient temperature and filtered and solid was washed with acetonitrile
(400mL). Filtrate was distilled and residue was dissolved in toluene (1200 mL) followed
by water washing to obtain the solution of compound of Formula V in toluene. HPLC
purity: 80%
Synthesis of compound of Formula VI (step d)
Solution of compound of Formula V as obtained in step (c) was cooled to 0-5°C. To the
cooled solution aluminum chloride (129.12g) was added, followed by addition of 1,1,3,3-
tetramethyldisiloxane (118.66g) in 2-3h below 15°C. Reaction mixture was stirred for 1-
4h at 10-15°C temperature. Acetone (40.0 mL) was added to the reaction mixture, stirred
at 25-30°C for lh and aq. HC1 solution (800mL) was slowly added below 25°C.
Temperature of reaction mass was heated to 50-55°C for 30 min. Reaction mass was
cooled to 25-30°C. Organic phase was separated and aqueous layer was extracted with
toluene (200mL). Combined organic layer was washed with DM water (400mL) at 25-
30°C. This organic layer was concentrated to obtain desired residue, which was further
crystallized in 1% ethyl acetate in isopropyl alcohol (600mL) at 0-5°C. Resulting solid
was collected by filtration to produce compound of Formula VI (200.Og) having chiral
impurity less than 0.10%, HPLC purity -99.0%.
Synthesis of compound of Formula B
Dichloromethane (900mL), (R)-3-Hydroxytetrahydrofuran (150g), Trimethylamine
hydrochloride (16.27g) and para toluene sulfonyl chloride (421 -94g) was taken. To the
solution, added triethylamine in l-2h below 10°C and reaction mass was stirred for 2h at
0-10°C. On completion, methanol (lOmL) was added to it and stirred for lh. Reaction
mass was washed with 5% aqueous HC1 solution (375mL) followed by washing with 5%
aqueous sodium carbonate solution (375mL) and DM water (375mL). Organic layer was
D E L H I . 2 © - 1 2 - 2 B I S 18 • i%of3°
distilled under vacuum at 40-45°C to obtain oily residue. Oily mass was dissolved in
ethyl acetate (275 mL) at 25-30°C and cooled to 10-15°C. Seeded the reaction mass with
(R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate (0.15g) and cyclohexane (2250mL)
was added. Reaction mass stirred for l-2h at 10-15°C and white solid was collected by
filtration to obtain desired compound of Formula B (GC Purity 99.24%). Yield: 80%
Synthesis of compound of Formula D
A suspension of the D-(+)-gluconic acid-delta-lactone (50.0g)5 dichloromethane
(lOOO.OmL), trimethylamine hydrochloride (2.68g) and triethylamine (170.36g) was
treated with trimethylsilyl chloride (137.17g) at 0-5°C in 2-3h. After completion of
addition, stirring was continued for 3-4h at 0-5°C. DM water (250.0 mL) was added to
reaction mass at 0-5°C and stirred for 30 min. Organic layer was separated, washed with
DM water (250mL*2) and concentrated under vacuum at 40-45°C. Dissolved the oily
residue in cyclohexane (250mL) and filtered through silica bed, at ambient temperature.
Filtrate was concentrated under vacuum below 40°C to obtain compound of Formula D.
Yield: 80%; GC purity: 90%.
Synthesis of compound of Formula VIII (step e and step f)
To a solution of compound of Formula VI (lOO.Og) and compound of Formula D
(254.Og) in tetrahydrofuran (800mL), n-BuLi (1.6M solution in hexane) (391.0 g) was
added at below -75°C within 3-4h and stirred at same temperature for 4-5h. After
completion of reaction, methanolic solution of methanesulphonic acid (MSA 156.83 g
and methanol 500ml) was added to the reaction mixture at -70°C to -50°c in l-2h and
stirred reaction for 4h at 0-5°C, further stirred for 14-16h at 25-30°C. Reaction mass was
quenched with 10% aqueous sodium carbonate (500mL) followed by quenching with
sodium bi-carbonate (lOOmL) below 10°C. Aqueous layer was washed with n-heptane
(500mL) at 25-30°C. Aqueous layer is extracted with ethyl acetate (1200mL). Organic
layer was washed with 10% brine solution (300mL). Organic layer was distilled off under
vacuum below 45°C. Residue oil of compound of Formula VIII was cooled to ambient
temperature. HPLC purity: 85%.
21 of 30
Synthesis of compound of Formula IX (step g)
Dichloromethane (900.0 mL) was charged to the above oil of compound of formula VIII
at 25-30°C and azeotropically refluxed at 40-45°C for 4h. Cooled the reaction mixture to
25-30°C, added acetonitrile (150mL) and cooled the reaction mixture to below -10°C.
Triethylsilane (69.58g) was added slowly below -10°C in 30min, followed by addition of
borontrifluoride etherate (135.1 lmL) in l-2h. Reaction mass was stirred for Ih below -
10°C, gradually raised the temperature to 0-5°C in lh and stirred for 4-5h at 0-5°C.
Further temperature of reaction m a s s w a s raised to 25-30°C and maintained for lh under
stirring. On completion, reaction mass was quenched with saturated aqueous sodium
bicarbonate solution (lOOOmL) at 0-5°C. Solvent was removed from reaction mass and
product was extracted in ethyl acetate (800.0 mL). Aqueous layer was re-extracted with
ethyl acetate (400mL) and combined organic layer was washed with 10% aq. brine
solution (300.0ml). The solvent is partially distilled off to (~500mL) by atmospheric
distillation and maintained for lh at 80-85°C. The mixture is cooled to 0-5°C in l-2h and
stirred at 0-5°C for 3-4h. Solid was filtered off under vacuum at 0-5°C and washed with
pre'-chilled ethyl acetate (100ml) at 0-5°C. Charged solid, ethyl acetate (750mL), and DM
water (37.5mL) and heated to 80-85°C. Volume of reaction mixture reduced to (~375mL)
by atmospheric distillation below 85°C. Cooled the reaction mixture to 0-5°C in l-2h and
stirred reaction mass for 3-4h. Resulting white solid of Empagliflozin was collected by
filtration and washed with pre-chilled ethyl acetate (75mL) at 0-5°C. HPLC purity:
99.5%
Purification of Empagliflozin (step h)
Methanol (210mL) and DM water (70mL) was taken and white solid of Empagliflozin as
obtained in step (g) was added to it at ambient temperature. Temperature of reaction mass
raised to 50-60°C and stirred at same temperature till clear solution observed. Activated
carbon (lg) was added to it at 50-60°C and reaction mixture was cooled to 40-50°C.
Reaction mixture was filtered below 50°C through hyflobed followed by micron and
washed with aq. Methanol (70mL). To the filtrate, DM water (980mL) was added to it
and reaction mass was maintained for 3-4h at 50-60°C. Reaction mixture was cooled to
25-30°C in 2-3h and stirred at ambient temperature for 10-12h. Resulting white Solid was
r u-r •-»<- 22 of 30
LHI- 2 6 - 1 2 - 2 Q 1 8 1 8 : 28
collected by filtration under vacuum at 20-25°C, washed with aq. Methanol (70mL) at
20-25°Cand dried under vacuum at 55-60°C to obtain Empagliflozin as white crystalline
solid having chiral purity(~99.95) and HPLC purity 99.5%. Yield: 95%
While this complete patent application contains the description of the principal inventive
concepts. The complete patent application pursuant here to, will fully and particularly
describe the preferred embodiments of the present invention.

Claims:
1. A process for" the preparation of Empagliflozin of Formula X comprising the steps of:
(a) coupling of 5-bromo-2-chlorobenzoyl chloride as obtained from 5-bromo-2
chlorobenzoic acid of Formula I, with Anisole of Formula II in presence of Lewis acid;
CI O
OH QCH3
Formula II
with or without isolation of compound of Formula III;
CI O
Formula III
(b) converting compound of Formula III to the compound of Formula IV in presence of
acidic reagent;
CI O
Formula IV
.2-2
-24of30
(c) coupling of the compound of Formula IV with (R)-tetrahydrofuran-3-yl-4-
methylbenzenesulfonate of Formula B to obtain compound of Formula V in presence of
base;
Br
O
Tscrw
Formula B
CI O
Formula V
(d) reducing the compound of Formula V to obtain compound of the Formula VI in
presence of reducing agent;
Formula VI
(e) coupling of the compound of Formula VI with the compound of Formula D to obtain
compound of the Formula VII;
TMSO
^^0^0
TMSO° "V^ ''OTMS
OTMS
Formula D
TMSO
TMSO0 Y^ ''OTMS
OTMS
Formula VII
(f) converting the compound of Formula VII to compound of Formula VIII;
25 of 30
1 8 : 2 »
r^VC1
Formula VIII
(g) reducing the compound of Formula VIII to obtain crude Empagliflozin of Formula IX
in presence of acid; and
' HO
Formula IX V
(h) optionally, purifying crude Empagliflozin to get pure Empagliflozin of Formula X.
Formula X
2. The process according to claim 1, wherein step (a) is carried out in presence of Lewis
acid selected from the group comprising of Aluminum chloride, Zinc chloride, Ferric
chloride, Titanium chloride, Zirconium chloride, Boron trifluoride.
3. The process according to claim 1, wherein step (b) is carried out in presence of acidic
reagents selected from the group comprising of aluminum chloride, aluminum bromide,
boron trichloride, boron tribromide, boron triiodide, trimethylsilyl iodide, hydrobromic
2 6 - 1 2 - ZO Id 18 I 2
26 of 30
acid, hydrochloric acid, cerium chloride, trifluoroacetic acid, trifluoromethylsulfonic
acid.
4. The process according to claim 1, wherein step (c) is carried out in presence of base
selected from the group comprising of alkali or alkaline earth metal carbonate,
bicarbonate, hydroxide alkoholates and metal hydrides.
5. The process according to claim 1, wherein step (d) is carried out in presence of reducing
agent selected from the group comprising of triethylsilane, triisopropylsilane,
tetramethyldisiloxane sodium borohydride, lithium aluminum hydride and hydrogen with
transition metal catalyst.
6. The process according to claim 1, wherein step (g) is carried out in presence of acid
selected from the group comprising of acetic acid, methanesulfonic acid, toluenesulfonic
acid, sulfuric acid, trifluoroacetic acid and hydrochloric acid.
7. The process according to claim 1, wherein step (g) is carried out in presence of reducing
agent selected from the group comprising of triethylsilane, tri-n-propylsilane,
triisopropylsilane, diphenylsilane, sodium borohydride, sodium cyanoborohydri.de, zinc
borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride
and hydrogen with transition metal catalyst.
«^
8. The process according to claim 1, wherein step (h) is carried out by crystallizing crude
Empagliflozin in solvent selected from the group comprising of methanol, ethanol,
isopropanol, water, ethyl acetate, acetonitrile, acetone, diethyl ether and mixture thereof.
9. A process for the preparation of compound of Formula VI having chiral purity not less
than 99.7%, comprising the steps of:
L H I, • 2:6, - i 2" - 2 0; I W 1 8 1 2 8
(a) coupling of 5-bromo-2-chlorobenzoyl chloride as obtained from 5-bromo-2-
chlorobenzoic acid of Formula I, with Anisole of Formula II in presence of aluminum
chloride;
CI O
OH OCH
Formula II
with or without isolation of compound of Formula III;
CI O
L
Formula III
(b) converting compound of Formula III to the compound of Formula IV in presence of
aluminium chloride;
j
CI O
Formula IV
L 2: - Z
28 of 30
I
(c) coupling of the. compound of Formula IV with (R)-tetrahydrofuran-3-yl-4-
methylbenzenesulfonate.ofFormula B to obtain compound of Formula V in presence of
potassium carbonate;
O
Ts(T«>
Formula B
CI * 0
Formula V
(d) reducing the compound of Formula V to obtain compound of the Formula VI in
presence of tetramethyldisiloxane;
Formula VI
10. A process for the preparation of Empagliflozin using compound of Formula VI,
prepared according to claim 9.