Field of Invention
The present invention relates to process of preparation of canagliflozin. Background of the invention
Canagliflozin which is chemically known as l(S)-l,5-anhydro-l-[3[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol, is represented by a compound of formula I,

Canagliflozin, is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to
diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Brief Description Of The Accompanying Figures
Fig.l: PXRD pattern of crystalline canagliflozin monohydrate, as obtained in example 8.
Fig.2: DSC of crystalline canagliflozin monohydrate, as obtained in example 8.
Fig. 3: TGA of crystalline canagliflozin monohydrate, as obtained in example 8.
Fig. 4: PXRD of amorphous canagliflozin, as obtained in example 15.
Fig. 5: DSC of amorphous canagliflozin, as obtained in example 15.
Fig. 6: TGA of amorphous canagliflozin, as obtained in example 15.
Summary Of The Invention
In one embodiment, the present invention provides a process for the preparation of canagliflozin, a
compound of formula I comprising:

a) reacting a compound of formula II with a reducing agent;

to obtain a compound of formula III;
b) coupling the compound of formula III with a compound of formula IV to obtain a compound of formula V;

c) converting the compound of formula V to a compound of formula VI; and

d) converting compound of formula VI to the compound of formula I a salt or hydrate thereof. In one embodiment, the present invention provides a compound selected from the following:

In one embodiment, the present invention provides a process for the preparation of canagliflozin by using a compound selected from the group consisting of


DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of canagliflozin, a
compound of formula I comprising:

a) reacting a compound of formula II with a reducing agent to obtain a compound of formula III;

b) coupling the compound of formula III with a compound of formula IV to obtain a compound of formula V;

c) converting the compound of formula V to a compound of formula VI; and


d) converting the compound of formula VI to the compound of formula I.
In one embodiment, in step a) of the above process, compound of formula II is reduced to a compound of formula III in the presence of a reducing agent. The reducing agent may be selected from the group consisting of diborane, diazene, metal hydrides such as sodium borohydride, potassium borohydride, lithium aluminium hydride, diisobutyl aluminium hydride, aluminum hydride and the like. Preferably the reducing agent is sodium borohydride. The reduction of the compound of formula II may be carried out in presence or absence of a solvent. The solvent may be selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like; chlorinated solvents such as methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride and the like; esters such as ethyl acetate, butyl acetate and the like;ketones such as acetone, methyl ethyl ketone, isobutyl ketone;nitriles such as acetonitrile, propionitrile;water; amides such as dimethyl formamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxides and the like; hydrocarbons such as hexane, toluene, xylene, cyclohexane, n-heptane and the like; ethers such as diethyl ether, methyl-tertiary butyl ether, diisopropyl ether, tetrahydrofuran and.the like or mixtures thereof. Preferably, the solvent is a mixture of methylene dichloride and methanol.
In one embodiment, the compound of formula II is reduced to the compound of formula III in the absence of a Lewis acid. The compound of formula II is reacted with sodium borohydride in the presence of methylene dichloride and methanol. The compound of formula II is reacted with sodium borohydride in the presence of methylene dichloride and methanol in the absence of a lewis acid. The compound of formula III is isolated from the reaction mixture by methods such as filtration, distillation and the like. The compound of formula III may also be purified by treating the compound of formula III with a solvent. The solvent may be selected from the group consisting of hydrocarbons such as cyclohexane, hexane, toluene, xylene, n-heptane and the like; alcohols such as methanol,ethanol, isopropanol, propanol, butanol, and like. The term "treating" refers to contacting, slurrying, dissolving or suspending.

In one embodiment, the compound of formula III is slurried in n-heptane and isolated by filtration
or centrifugation. Preferably, the compound of formula III is isolated by filtration.
In one embodiment, the present invention provides compound of formula III characterized by
1HNMR having peaks at 2.18, 5.97, 6.29, 6.79, 6.94, 7.16-7.26, 7.52, 7.58-7.62, 7.85.
In one embodiment, in step b) of the above, process, the compound of formula III is coupled with a
compound of formula IV to obtain a compound of formula V. The coupling reaction may be carried
out by reacting the compound of formula III with proton abstracting agent followed by reaction
with the compound of formula IV. Proton abstracting agents are generally strong bases such as n-
butyl lithium, sec-butyllithium, sodiumhydride, potassium hydride, isopropylmagnesium
chloride.lithium chloride complex in THF. Preferably, the base is n-butyl lithium.
In one embodiment, the coupling reaction may be carried out by reacting the compound of formula
III with a Grignard reagent followed by reaction with the compound of formula IV.
In one embodiment, the compound of formula III is reacted with a base followed by adding the
compound of formula IV or the mixture of the compound of formula III with a base is added to the
compound of formula IV or the base may be added in one lot to a mixture of compound III and IV.
In one embodiment, in step b) the coupling reaction is carried out by the addition of a strong base to
a mixture of the compound of formula III and the compound of formula IV in a solvent. The
coupling reaction is carried out by adding n-butyl lithium to a mixture of compound of formula III
and compound IV in a solvent. The solvent may be selected from water, alcohols such as methanol,
ethanol, propanol, isopropanol, n-butanol and the like; amides such as dimethyl acetatmide, N, N-
dimethyl formamide and the like; hydrocarbons such as cyclohexane, hexane, toluene, xylene, n-
heptane and the like; chlorinated solvents such as methylene dichloride, ethylene dichloride,
chloroform, carbon tetrachloride and the like; ethers such as diethyl ether, diisopropyl ether,
methyl-tertiary butyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, isopropyl
acetate and the like or mixtures thereof. The reaction may be carried out at about -100 to 5°C.The
compound of formula V may be isolated by methods such as filtration, distillation and the like.
In one embodiment, in step c), the compound V is converted to the compound VI. The compound V
is converted to the compound VI in presence of an acid. The compound ,V may not be isolated in
step b) and in-situ converted to the compound VI.
In one embodiment, in step c) the conversion of compound V to compound VI may be carried out
by treating the compound V with a suitable acid in methanol. The suitable may be selected from the

group consisting of acids such as hydrochloric acid, sulfuric acid, methane sulphonic acid, camphor
sulfonic acid, p-toluene sulfonic acid and the like. The compound of formula VI may be isolated by
methods such as distillation, concentration and the like.
In one embodiment, the compound of formula VI is purified in a solvent.
In one embodiment, the compound of formula VI is purified by a process comprising:
i) treating the compound of formula VI with a solvent;
ii) optionally, mixing with an anti-solvent; and
iii) isolating the compound of formula VI.
In one embodiment, in step i) the compound VI is treated with a solvent. The solvent may be
selected from the group consisting of nitriles such as acetonitrile, propionitrile and the like alcohols
such as methanol, ethanol, propanol, isopropanol, n-butanol and the like; halogenated solvents such
as methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride and the like; amides
such as dimethyl formamide, dimethyl acetamides and the like; ketones such as acetone, methyl
ethyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, butyl acetate,
isopropyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; ethers such as
diethyl ether, diisopropyl ether, tetrahydrofuran and the like; hydrocarbons such as hexane, toluene,
xylene, cyclohexane, heptane and the like or mixtures thereof.
In one embodiment, in step ii) the anti-solvent may be selected from the group consisting of water,
hexane, ethyl acetate and the like; Preferably, the anti-solvent is hexane. Preferably, the compound
VI in methylene dichloride is mixed with hexane.
In one embodiment, the reaction mixture containing the compound VI in methylene dichloride and
hexane is stirred for a period of about 30 min to about 3 hrs. The purified compound VI is isolated
by filtration, centrifugation and the like.
In one embodiment, the compound of formula VI is characterized by 1HNMR having peaks at 2.24,
2.9, 3.55, 3.75, 4.53, 4.66-4.70, 4.96, 5.68, 6.82, 6.91, 7.14-7.24, 7.35, 7.60-7.65.
In one embodiment, in step d), the compound VI is converted to the compound of formula I by
treating with a reducing agent. The reducing agent may be a silane reagent such as triethyl silane.
In one embodiment, in step d) of the above process, the compound of formula VI is not isolated in
step 'c' and converted in-situ to the compound of formula I. The reduction is carried out in the
presence of a Lewis acid such as boron trifluoride.diethyl ether complex, boron trifluoride.
tetrahydrofuran complex, aluminium chloride, zinc chloride and the like.

In one embodiment, in step d) of the above process, the compound of formula VI is converted to the compound of formula I by treating with triethyl silane in the presence of boron trifluoride.diethyl ether complex. The conversion may be carried out in a solvent. The solvent may be selected from the group as discussed supra. The addition is carried out at a temperature of about -100 to 50°C. The .reaction transpires at a temperature of about -5 to 25°C over a period of about 1 to 5 hrs. On completion of conversion to the compound of formula I, the reaction mixture is basified. The base may be selected from the group consisting of organic or an inorganic base. The inorganic base may be selected from but is not limited to hydroxides such as sodium hydroxide, potassium hydroxide; carbonates such as sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate, alkoxides such as sodium methoxide, potassium tertiary butoxide, hydrides such as sodium hydride; organic base such as triethyl amine, trimethyl amine, pyridine, dimethyl amino pyridine. Preferably, the base is sodium bicarbonate. The compound I may be isolated from the reaction mixture by concentrating or distilling the organic layer.
The compound of formula I is treated with a solvent selected from the group consisting of esters such as ethyl acetate, isopropyl acetate and the like; amides such as dimethyl acetamide, dimethyl formamide and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; chlorinated solvents such as methylene dichloride, ethylene dichloride, chloroform and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, methyl tertiary butyl ether and the like, water or mixtures thereof. Preferably, the compound of formula I is treated with ethyl acetate.
In one embodiment, the compound of formula I in ethyl acetate is subjected to charcoal treatment, filtered and then isolated by distillation, centrifugation or filtration.
In one embodiment, the present invention provides a process for the preparation of crystalline canagliflozin (1-S) comprising:
a) treating canagliflozin with an organic solvent to obtain a mixture;
b) optionally, heating the mixture of step'a';
c) adding water to the mixture of step 'b' wherein the amount of water is more than 2 molar equivalent with respect to canagliflozin,
d) adding an anti-solvent; and
e) cooling and isolating crystalline canagliflozin (1-S).

In one embodiment, in step 'a' of the above process the solvent may be selected from the group consisting of halogenated solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like, hydrocarbons such as n-hexane, n-heptane, cyclohexane, benzene, toluene, xylene and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether and the like; and mixtures thereof. Preferably, the solvent is ethyl acetate.
In one embodiment, in step 'b' of the above process the mixture of canagliflozin in a solvent is heated to 0°C to reflux temperature of the solvent. The mixture may be heated to a temperature of about 35-50°C to obtain a solution.
In one embodiment, in step 'c' of the above process more than two equivalents of water is added to the solution of canagliflozin. The addition of water is carried out at a temperature of about 30 °C to about reflux temperature of the solvent. Surprisingly, it was observed that the addition of more than two equivalents of water provides better yield.
In one embodiment, in step 'd' of the above process an anti-solvent is added to the mixture of step 'c'. The anti-solvent may be selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; -ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; amides such as dimethyl formamide, dimethyl acetamide; water; or mixtures thereof. Preferably, the solvent is methyl tertiary butyl ether.
In one embodiment, the present invention provides a process for the preparation of canagliflozin, a compound of formula I comprising:


a) reacting a compound of formula II with a reducing agent

to obtain a compound of formula III;
b) coupling the compound of formula III with a compound of formula IV

to obtain a compound of formula V;
c) converting the compound of formula V to a compound of formula Via, wherein R is an alkyl
group selected from the group consisting of methyl, ethyl, propyl, butyl, tert-butyl and the like; and

d) converting the compound of formula Via to the compound of formula I.
In one embodiment, the present invention provides process for the preparation of compound IV

comprising reacting D-glucono-l,5-lactone with trimethyl silyl halide such trimethyl silyl chloride. The reaction is carried out in presence of a solvent. The solvent may be selected from hydrocarbons, ether, chlorinated solvents, sulfoxide.


comprising the step of reducing a compound of formula II to obtain a compound of formula III.

In one embodiment, the present invention provides a process for the preparation of canagliflozin, a compound of formula I
In one embodiment, the present invention provides a process for the preparation of compound of formula II from 5-iodo-2-methylbenzoic acid by a process as depicted schematically:

In one embodiment, in the above scheme, the compound of formula II is prepared by condensing the activated derivative of 5-iodo-2-methylbenzoic acid which may be selected from an acid halide or a reactive ester with 2-(4-fluorophenyl)thiophene. The condensation reaction may be carried out in presence of a Lewis acid and a solvent. The lewis acid may be selected from the group consisting of AlCl3, FeCl3, SnCl2, boron trifluoride and the like. The solvent is selected from the group as discussed supra. Preferably the solvent is methylene dichloride.The condensation reaction is carried out at a temperature of about 5°C to about 30°C. Preferably, the condensation reaction transpires at a temperature of about 0-5°C. The compound of formula II is purified in a solvent. The solvent may selected from the group as discussed supra.
In one embodiment, 2-(4-fluorophenyl)thiophene is prepared by a process comprising lithiating 2-bromothiophene with n-butyl lithium followed by reaction with triethyl borate to obtain 2-thiophene boronic acid, the compound of formula IX. The compound of formula IX may be crystallized from a solvent selected from the group as discussed supra.


The compound of formula IX is reacted with 4-fluoro bromobenzene in the presence of a palladium catalyst to obtain 2-(4-fluorophenyl)thiophene. The 2-(4-fiuorophenyl) thiophene compound obtained may be crystallized from a solvent selected from group consisting of methylene dichloride, methanol, chloroform, isopropanol, propanol, n-butanol or mixtures thereof.The compound 2-(4-fluorophenyl)thiophene is prepared by a process comprising reacting (4-fluorophenyl) boronic acid with 2-bromothiophene.
In one embodiment, the present invention provides a process for the preparation of glucono-1, 5-lactone by a fermentation process of continuous type. The process comprises use of aerobic oxidative fermentation process in conversion of glucose syrup to produce glucono-delta lactone. In one embodiment, the present invention provides a process for the preparation of glucono-1, 5-lactone by a process of conversion of sodium gluconate to gluconic acid via ion exchange method followed by conversion to glucono-1, 5-lactone. In one embodiment, the present invention provides a compound selected from the following:

In one embodiment, the present invention provides a method of producing canagliflozin by using a compound selected from the group consisting of


In one embodiment, the present invention provides pharmaceutical compositions comprising
canagliflozin or salt thereof obtained by the processes herein described, having a D50 and D90
particle size of less than about 150 microns, preferably less than about 100 microns, more
preferably less than about 50 microns, still more preferably less than about 20 microns, still more
preferably less than about 15 microns and most preferably less than about 10 microns. The particle
size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other
particle size reduction method known in the art to bring the solid state canagliflozin into any of the
foregoing desired particle size range.
In one embodiment, the present invention provides canagliflozin having chemical purity of about
99.9% as measured by HPLC. The invention further present invention provides canagliflozin
having stereochemical purity of about 100% as measured by HPLC:
In one embodiment, canagliflozin obtained is substantially free of l-(alpha-D-glucopyranosyl)-4-
methyl-3-[5-(4-flurophenyl)-2-thienylmethyl] benzene, as measured by HPLC.
In one embodiment, canagliflozin obtained is substantially free of l-(beta-D-glucopyranosyl)-2-
methyl-3-[5-(4-flurophenyl)-2-thienylmethyl] benzene, as measured by HPLC.
In one embodiment, canagliflozin obtained is substantially free of l-(beta-D-glucopyranosyl)-3-[5-
(4-fluorophenyl)-2-thienylmethyl] benzene, as measured by HPLC.
In one embodiment, canagliflozin obtained is substantially free of l-(beta-D-glucopyranosyl)-4-
methyl-3-[5-(4-phenyl)-2-thienylmethyl] benzene, as measured by HPLC.
In the present application, the term "substantially free" means an amount which is less than 0.10%
w/w with respect to canagliflozin, as determined by high performance liquid chromatography.
In one embodiment, the present invention provides amorphous canagliflozin.
In one embodiment, the present invention provides amorphous canagliflozin which is stable and
wherein the moisture content does not increase more than 0.4% when exposed for a period of 48
hours to a temperature 25°C and 60%) relative humidity.
In one embodiment, the present invention provides amorphous canagliflozin which is stable and
wherein the moisture content does not increase more than 0.4% when exposed for a period of 48
hours to a temperature 25°C and 90% relative humidity.
In one embodiment, the present invention provides a process for the preparation of amorphous
canagliflozin comprising isolating amorphous canagliflozin from a slurry of canagliflozin in a
single solvent. The solvent may be selected from the group consisting of esters such as ethyl

acetate, isopropyl acetate, butyl acetate and the like; hydrocarbons such as cyclohexane, n-heptane, toluene, xylene and the like; ethers such as diisoproyl ether, methyl tertiary butyl ether, tetrahydrofuran and the like; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propanol, isopropanol; chlorinated solvents such as methylene dichloride, ethylene dichloride, chloroform; nitriles such as acetonitrile, propionitrile and the like and mixtures thereof.
In one embodiment, the present invention provides a process for the preparation of amorphous canagliflozin comprising;
a) preparation of canagliflozin by a process as described above;
b) optionally treating the canagliflozin of step 'a' with an alcoholic solvent;
c) optionally removing the solvent of step 'b';
d) adding hydrocarbon solvent to step 'a' or step 'b' or step 'c'; and
e) isolating amorphous canagliflozin from step 'd'.
The alcoholic solvent in the above step 'b' may be selected from the group consisting of methanol,
ethanol, propanol, isopropanol, butanol and the like.
The removal of solvent in the above step 'c' may be accomplished by substantial or complete
evaporation of the solvent or concentrating the solution, cooling the solution if required and
filtering the obtained solid. The solution may also be completely evaporated, for example, using a
rotavapor, a vacuum paddle dryer or in conventional reactor under vacuum above about 720mm Hg.
The hydrocarbon solvent in the above step 'd' may be selected from the group consisting of an
aliphatic hydrocarbon or aromatic hydrocarbon. The aliphatic hydrocarbon solvent is selected from
the group consisting of n-hexane, cyclohexane and n-heptane and the aromatic hydrocarbon solvent
is selected from the group consisting of toluene, benzene, xylene.
The isolation of amorphous canagliflozin in step'd' may be achieved by spray drying,
lyophilisation, filtration, distillation or centrifugation.
In one embodiment, the present invention provides a process for the preparation of amorphous
canagliflozin comprising;
a) preparation of canagliflozin by a process as described above;
b) optionally treating the canagliflozin of step 'a' with methanol;
c) optionally removing the solvent of step 'b';
d) adding cyclohexane solvent to step 'a' or step 'b' or step 'c'; and

e) isolating amorphous canagliflozin from step 'd'.
In one embodiment, the present invention provides a process for the preparation of amorphous
canagliflozin comprising:
a) subjecting canagliflozin to treatment with a single hydrocarbon solvent; and
b) isolating the amorphous canagliflozin.
The hydrocarbon solvent in step 'a' may be selected from the group consisting of an aliphatic hydrocarbon solvent selected from the group consisting of n-hexane, cyclohexane and n-heptane and aromatic hydrocarbon solvent selected from the group consisting of toluene,benzene, xylene. In one embodiment, the present invention provides a process for the preparation of amorphous canagliflozin comprising:
a) subjecting canagliflozin to treatment with cyclohexane; and
b) islating the amorphous canagliflozin.
In one embodiment, the present invention provides a process for the preparation of amorphous
canagliflozin comprising converting crystalline canagliflozin (1-S) to amorphous canagliflozin.
In one embodiment, the present invention provides amorphous canagliflozin characterized by X-ray
diffraction (XRD) spectrum as depicted in fig.4.
In one embodiment, the present invention provides amoprhous canagliflozin characterized by
Differential Scanning Calorimetric (DSC) thermogram having an endothermic peak at about
59.9±2°C and l91.83±2°C
In one embodiment, the present invention provides amorphous canagliflozin characterized by
Differential Scanning Calorimetric thermogram which is substantially in accordance with fig. 5.
In one embodiment, the present invention provides amorphous canagliflozin characterized by
Thermogravimetric analysis (TGA) profile showing a weight loss of about about 2% to about 3%
weight loss from about 50°C to about 100°C;which is substantially in accordance with fig. 6.
In one embodiment, the present invention provides process for the preparation of crystalline
canagliflozin hemihydrate comprising converting crystalline canagliflozin to crystalline
canagliflozin hemihydrate or converting amorphous canagliflozin to crystalline canagliflozin
hemihydrate without seeding or converting crystalline canagliflozin to crystalline canagliflozin
hemihydrate without seeding.
In one embodiment, the present invention provides process for the preparation of crystalline
canagliflozin hemihydrate comprising:

a) treating canagliflozin with a solvent to obtain a solution or a suspension;
b) optionally adding an anti-solvent to step 'a'; and
c) isolating crystalline canagliflozin hemihydrate.
The solvent in step 'a' may be selected from the group consisting of halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform and carbon tetrachloride; alcohols such as methanol, ethanol, lpropanol, isopropanol, tert-butanol; ketones such as acetone, methyl isobutyl ketone; esters such as ethyl acetate, isopropyl acetate and butyl acetate; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetarnide; dimethyl sulfoxide; nitrile such as acetonitrile, propionitrile; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, 1,4-dioxane, tetrahydrofuran; hydrocarbons such as heptane, benzene, toluene, cyclohexane, methyl cyclohexane and toluene, water; or mixtures thereof. The anti-solvent in step 'b' may be selected from the group consisting of water, alcohols such as methanol, . ethanol, isopropanol, propanol; hydrocarbons such as heptane, benzene, toluene, cyclohexane, methyl cyclohexane and toluene; esters such as ethyl acetate, isopropyl acetate and butyl acetate; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether; and the like or mixtures thereof.
The canagliflozin used in the preparation of crystalline canagliflozin hemihydrate may be crystalline canagliflozin or amorphous canagliflozin. The present invention provides process for the preparation of crystalline canagliflozin hemihydrate comprising isolating crystalline canagliflozin hemihydrate canagliflozin from a mixture of acetone and water without seeding. In one embodiment, the present invention provides crystalline canagliflozin monohydrate. In one embodiment, the present invention provides crystalline canagliflozin monohydrate characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 13.0, 15.7, 17.6, 20.0 and 25.0 ±0.2 degrees 2 theta. The present invention further provides crystalline canagliflozin monohydrate characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 6.7, 13.0, 15.7, 17.6, 20.0, 25.0 and 33.5 ±0.2 degrees 2 theta. The crystalline canagliflozin monohydrate is characterized by X-ray diffraction spectrum as depicted in fig. 1. In one embodiment, the present invention provides crystalline canagliflozin monohydrate characterized by Differential Scanning Calorimetric (DSC) thermogram having an endothermic peak at about 62±2°C.The crystalline canagliflozin monohydrate is characterized by DSC thermogram, which is substantially in accordance with fig. 2.

In one embodiment, the present invention provides crystalline canagliflozin monohydrate
characterized by thermogravimetric analysis profile showing about 3% to about 5% weight loss
from about 50°C to about 150°C.The crystalline canagliflozin monohydrate is characterized by
having a water content ranging from 3% to about 5% as measured using karl Fischer(KF).
In one embodiment, the present invention provides crystalline canagliflozin monohydrate
characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 13.0, 15.7,
17.6, 20.0 and 25.0 ±0.2 degrees 2 theta and Differential Scanning Calorimetric (DSC)
thermogram having an endotherm peak at about 62±2°C.
The theoretical water content of the crystalline canagliflozin monohydrate of the present invention
is about 3.9%. The crystalline canagliflozin monohydrate is further characterized by
thermogravimetric analysis (TGA) thermogram, showing a weight loss of about 3 to about 5%
determined over the temperature range of 50°C to 100°C and heating rate 10°C/min, which is
substantially in accordanc with fig.3.
In one embodiment, the present invention provides crystalline canagliflozin monohydrate
characterized by at least one of the following:
a) X-ray Diffraction (XRD) spectrum having peak reflections at about 13.0, 15.7, 17.6, 20.0 and 25.0 ±0.2 degrees 2 theta.
b) differential Scanning Calorimetric thermogram having an endothermic peak at about 62±2°C.
c) TGA profile showing about 3% to about 5% weight loss from about 50 °C to about 100 °C.
In one embodiment, the present invention provides a process for the preparation of canagliflozin
monohydrate comprising isolating from a mixture of water and an organic solvent without seeding.
The organic solvent may be selected from the group as discussed supra.
In one embodiment, the present invention provides a process for the preparation of crystalline
canagliflozin monohydrate by solvent-anti solvent method. The solvent may be selected from the
group consisting of esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like;
ketones such as acetone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene,
heptane, hexane and the like; water or a mixture of thereof. The anti-solvent may be selected from
the group consisting of heptane and water.
In one embodiment, the present invention provides preparation of crystalline canagliflozin
monohydrate using acetone as solvent and water as an anti-solvent.

In one embodiment, the present invention provides a process for the preparation of crystalline-canagliflozin monohydrate comprising dissolving canagliflozin in acetone and adding water as an anti-solvent to precipitate crystalline canagliflozin monohydrate. The addition of water to a solution of canagliflozin in acetone is carried out at about 25 to 30°C. The crystalline canagliflozin monohydrate precipitated is isolated by methods such as filtration, centrifugation and like. The crystalline canagliflozin monohydrate may be prepared by a process comprising isolating crystalline canagliflozin monohydrate from mixture of acetone and water without seeding. The present invention provides a process for the isolation of crystalline canagliflozin monohydrate from a solvent system comprising of ethyl acetate and water and no additional solvent and no seeding. In one embodiment, the present invention provides a process for the preparation of crystalline canagliflozin monohydrate comprising:
a) treating canagliflozin with ethyl acetate;
b) heating the above reaction mixture of step "a"; . c) addition of water to above step "b";

d) cooling the above mixture of "c";
e) isolating the precipitated crystalline canagliflozin monohydrate.
In one embodiment, in step a) of the above process canagliflozin is treated with ethyl acetate.
In one embodiment, in step b) of the above process the slurry of canagliflozin in ethyl acetate is
heated to obtain a solution.
In one embodiment, in step c) of the above process water is added to a solution of canagliflozin.
The addition of water to a solution canagliflozin in ethyl acetate is carried at about 35-40°C.
In one embodiment, in step d) of the above process the reaction mixture comprising canagliflozin,
ethyl acetate and water is cooled to a temperature of about -5 to about 25 °C. Preferably, the
reaction mixture is cooled to a temperature of about 0-5°C.
In one embodiment, in step e) crystalline canagliflozin monohydrate is precipitated from a mixture
of ethylacetate and water and isolated by methods such as filtration, centrifugation like.
In one embodiment, the preparation of crystalline canagliflozin monohydrate comprises isolating
from an aqueous solution.
In one embodiment, the present invention provides a process for the preparation of crystalline
canagliflozin monohydrate, comprising:
a) treating canagliflozin with water;
b) cooling the reaction mixture of step b); and

c) isolating the precipitated crystalline canagliflozin monohydrate In one embodiment, in step a) of the above process canagliflozin is treated with water. In one embodiment step b) the slurry of canagliflozin in water is cooled to about -5 to about 20 °C. In one embodiment step c), the precipitated crystalline canagliflozin monohydrate is filtered and isolated by methods such as filtration, centrifugation and the like. The preparation of crystalline canagliflozin monohydrate comprises isolating from an aqueous solution without seeding. In one embodiment, the present invention provides canagliflozin sesquihydrate. The canagliflozin sequihydrate is characterized by TGA thermogram, showing a weight loss of about 5.1% to about 6.1% determined over the temperature range of 50°C to 100°C and heating rate 10°C/min. The present invention relates to crystalline canagliflozin sesquihydrate characterized by having a water content ranging from 5.1% to about 6.1% as measured using K .F. Instrumental settings for HPLC: Reagents and Solvents: Potassium dihydrogen phosphate,o-phosphoric acid, Methanol, Acetonitrile, Water. Column: Hypersil BDS C8, 250 X 4.6mm, 5u. Instrumental settings for XRPD: The measurements were performed on Philips X-Ray Diffractometer model XPERT-PRO (PANalytical) Detector: X'celerator [1] using Cu lamp with type and wavelength of the X-ray radiation: K-Alphal [A] and 1.54060 the conditions are: Generator settings: 40mA/45kV, Time per step: 50, Step size: 0.0170, Peak width 2.00 and start angle (°2 theta) 2.0 and End angle: 50.0, Scan type: continuous; measurement performed at 25°C. The XRPD instrument is calibrated using NISTSRM 6-40C silicon standard and NISTSRM1976 Alumina.
Instrumental settings for DSC: The DSC thermogram was measured by a Differential Scanning Calorimeter (DSC 822, Mettler Toledo) at a scan rate of 10°C per minute in the temperature range of range is "30°C to 300°C". The DSC module was calibrated with Indium and zinc standard. Instrumental settings for TGA: Instrument Name: TGA Q 500; Method: 5-8 mg of sample was taken in platinum pan and heated at 10°C/minute from room temperature to 250°C. Method for measuring the water content : canagliflozin was exposed to 25°C and 60% relative humidity and 25°C and 90% relative humidity conditions. Sample were taken at intervals and water content was calculated by the following formula:
water content (%)= Burrette reading x K.F.factor x 100 weight of sample in mg The following examples are provided to enable one skilled in the art to practice the invention and
are merely illustrative of the invention. The examples should not be read as limiting the scope of the
invention.

Examples
Example 1: Preparation of compound of formula-II:A mixture of 5-iodo-3-methyl benzoic acid (lOOgm), methylene dichloride (500ml) and dimethyl formamide (1.2ml) were stirred and to this oxalyl chloride (42.4ml) was added at 25-30°C. The reaction mixture was stirred for a period of 4hr at a temperature of 25-30°C. The reaction mixture was distilled and to the residue methylene dichloride were added to obtain a clear solution. The reaction mixture was cooled to 0-5°C. To the reaction mixture, aluminium chloride (55.83gm) and 2-(4-fluorophenyl) thiophene (67.93gm) in methylene dichloride at 0-5°C was added. To" the reaction mixture water was added, layers separated and the organic layer was distilled under vacuum and to this methanol was added. The slurry obtained was stirred, filtered and washed with methanol. The product was dried to obtain 152gm of the product.
1H NMR (300Mhz, DMSO d6) having peaks at 2.4, 7.09, 7.17, 7.26 , 7.40 , 7.73-7.81, 7.83,8.01 . Example 2: Preparation of compound [5-(4-fluorophenyl)thiophen-2-yl] (5-iodo-2-methylphenyl) methanol (III): To a mixture of compound II (150gm) in methylene dichloride (750ml), sodium borohydride (20.26gm) and methanol (150ml) were added at 25-30°C over a period of 90-120 min. The reaction mixture was stirred for 2hrs. To the reaction mixture, water was added followed by addition of 1:1 aq. HC1 at 25-30°C. The reaction mixture was stirred and layers were separated. The organic layer was distilled under vacuum. To the residue n-heptane was added. The reaction mixture was stirred and filtered. The product was dried at 40-45°C to obtain 142.5gm of the title product. 1H NMR (300Mhz,DMSOd6) having peaks at 2.18, 5.97, 6.29, 6.79, 6.94, 7.16-7.26, 7.52, 7.58-7.62, 7.85.
Examples 3: The above ex 2 was repeated without treatment with aq hydrochloric acid. Example 4: Preparation of 2, 3, 4, 6-tetra-O-trimethylsilyl-β-D-gluconolactone (IV): A mixture of D-glucono-l,5-lactone (30 g), THF (tetrahydrofuran, 300ml) and N-methylmorpholine (130ml) was cooled to about 0 to -10°C. Trimethyl silylchloride (130 ml) was added. The reaction mass was stirred and maintained for a period of about 60 min. The temp of the reaction mass was increased to 25-30°C. The reaction mass was maintain for 4-5 hrs and cooled to 0- 10°C. To the reaction mass toluene and water were added and layers were separated. The toluene layer was dried over sodium sulphate, filtered and distilled under vacuum to obtain 70g of title product. GC purity: 95.14% Example 5: Preparation of l-(l-methoxyglucopyranosyl)-4-methyl-3-(5-(4-fluorophenyl)-2-thienylhydroxymethyl)benzene (VI): A mixture of [5-(4-fluorophenyl)thiophen-2-yl](5-iodo-2-

methylphenyl)methanol (15g), tetrahydrofuran (75ml), 2, 3, 4, 6-tetra-0-trimethylsilyl-(3-D-gluconolactone (21.43g) and toluene (75ml) under nitrogen was cooled to -60 to about -70°C. To the reaction mixture n-butyl lithium (75ml) in hexane was added. The reaction mixture was maintained for 2hrs. To this reaction mass methanesulfonic acid (13.6 g) in methanol solution (75 ml) was added. The temp of the reaction mixture was raised to 25-30°C and maintained for 5-6 hrs. The reaction mass was quenched with saturated sodium bicarbonate solution. To the reaction mass ethyl acetate was added. The layers were separated. The ethyl acetate layer was dried on sodium sulphate, filtered and distilled under vacuum. To the residue toluene (150ml) was added and stirred to obtain a solution. To this n-Hexane (500ml) was added. The reaction mass was maintained for 1-2 hrs at 25-30°C. The product was isolated by filtration and dried at 25-30°C under vacuum to obtain 14 gms of the product. 1H-NMR (DMSO, d6, 300 MHz): 2.24, 2.9, 3.55, 3.75, 4.53, 4.66-4.70, 4.96, 5.68, 6.82-6.91, 7.14-7.24, 7.35 ,7.60-7.65.
Example 6: Preparation of canagliflozin (I): A mixture of l-(l-methoxyglucopyranosyl)-4-methyl-3-(5-(4-fluorophenyl)-2-thienylhydroxymethyl) benzene (10g) and methylene chloride (100ml) was cooled to a temperature of about -70 to about -75°C. To the reaction mass triethylsilane (8ml) was added slowly. The reaction mass was maintained for a period of about 15 to 30 min. To the reaction mass boron trifluoride diethyl etherate (10ml) was added. The temp of the reaction mass was raised to 0°C. The reaction mass was maintained for a period of about 2-3hrs. To the reaction mass saturated sodium bicarbonate solution was added. The reaction mass was maintained for a period of about 30 to 90 min. The reaction mass was distilled under vacuum. To the reaction mass ethyl acetate and water were added. The ethyl acetate layer was separated, washed with water and brine solution. Ethyl acetate layer was dried on sodium sulphate, treated with activated carbon and filtered. The filtrate was distilled under vacuum to obtain a foamy solid.
Example 7: Preparation of crystalline canagliflozin: canagliflozin (100g) was dissolved in ethyl acetate (300 ml) to get clear solution. To this solution methyl tertiary butyl ether (1200 ml) and water (10 ml) were added. The mixture was stirred at 25-30°C for 12 hrs. The solid was filtered to obtain 60 gm of title product.
Example 8: Preparation of crystalline canagliflozin monohydrate: The solid obtained in example 6 was dissolved in acetone (14 ml). To this solution water (105 ml) was added slowly at 25-30°C. The reaction mass was maintained for 4-5hrs at 25-30°C. The crystalline canagliflozin monohydrate

precipitated was isolated by filtration and dried at 25-30°C under vacuum to obtain7 gms of title
product. HPLC purity: 99.99%, chiral purity: 100%
XRD of crystalline canagliflozin monohydrate: 13.0, 17.8, 20.0 and 24.6 ±0.2 degrees 2 theta

Po.[°2Th] d-spacing[A°] Rel.Int[%] Po.[°2Th] d-spacing[A°] Rel.Int[%]
3.5 24.8 3.42 17.8 5.01 40.77
6.7 13.09 8.96 20 4.42 100
13 6.77 29.31 24.5 3.55 31.81
15.7 5.62 28.22 33.4 2.67 4
Example 9: Preparation of crystalline canagliflozin hemihydrate(I): The solid obtained in example 6 was dissolved in ethyl acetate (40 ml). To this solution diethyl ether (150 ml) and water (1.0 ml) was added at 25-30°C. The reaction mass was maintained for a period of about 6 to about 8 hrs. The product was filtered and dried to obtain 6 gm of title product.
Example 10: Preparation of crystalline canagliflozin monohydrate: A mixture of amorphous canagliflozin (10 g) in water (150 ml) was maintained for a period of about 2-3hrs at 25-30°C. The reaction mixture was cooled to 5-10°C and maintained for a period of about 2-3hrs. Crystalline canagliflozin monohydrate was isolated by filtration and dried at 25-30°C under vacuum to obtain 10 gm of title product.
Example 11: Preparation crystalline canagliflozin monohydrate: A mixture of amorphous canagliflozin (10 g) in ethyl acetate (20ml) was prepared at a temperature of about 25-30°C . The reaction mixture was heated to 35-40°C and maintained till a clear solution was obtained. To this water (600ml) was added at 35-40°C and the reaction mass was maintained for a period of about 30 min to about 90 min at 35-40°C. The reaction mixture was then cooled to 0-5°C and maintained for about 2-3hrs. Crystalline canagliflozin monohydrate was isolated by filtration and dried at 25-30°C under vacuum to obtain 9 gm of title product.
Example 12: Preparation crystalline canagliflozin monohydrate: A mixture of amorphous canagliflozin (7.0gms ) and acetone (14 ml) was stirred to obtain a clear solution at 25-30°C. To this water (105ml) was added slowly at 25-30°C. The reaction mass was maintained for 17hrs at 25-30°C. The solid was filtered and dried at 25-30°C to obtain 6gm of product.
Example 13: Preparation crystalline canagliflozin monohydrate: A mixture of amorphous canagliflozin (2.0gm) and acetone (20ml) was stirred to obtain a clear solution. To this water (60ml) was added slowly at 25-30°C. The reaction mass was maintained for 15-20min at 25-30°C. The oil from the mixture was separated and charged in a clean flask. To this water was added

slowly at 25-30°C. The reaction mass was maintained for 30-60min at 25-30°C. Crystalline canagliflozin monohydrate was isolated by filtration and dried at 25-30°C under vacuum to obtain 1.7gms of title product.
Example 14: Preparation of canagliflozin (I) :A mixture of 5-(4-fluorophenyl)thiophen-2-yl](5-iodo-2-methylphenyl) methanol (10gm), tetrahydrofuran (25ml), 2, 3, 4, 6-tetra-O-trimethylsilyl-P-D-gluconolactone (33gm) and toluene (25ml) was cooled to -60 to about -70°C. To the reaction mass n-butyl lithium (70ml) 1.6M solution in hexane was added. To this methansulfonic acid (65 gm) in methanol was added. The temp of the reaction mixture was raised to 20-30°C. The reaction mass was quenched with NaHC03. Layers were separated and aq layer was extracted with methylenedichloride. The organic layer was distilled, to the residue methylene dichloride was added followed by addition of triethylsilane (15ml). The reaction mass was cooled to about -60 to -70°C and borontrifluoride diethyl etherate (10ml) was added. The reaction mass was quenched with NaHC03 solution and methylene dichloride was distilled and ethyl acetate was added and layers were separated. The ethyl acetate layer was distilled to obtain oil. To this ethyl acetate (24rhl) was added to get clear solution. To this mixture methyl tert-butyl ether (120ml) and water was added (1 ml) and stirred for 12hrs at 20-30°C. The solid was filtered, washed with methyl tert-butyl ether and dried to get 5-6gm of product. A mixture of this product and ethyl acetate (25ml) was heated to 40-45°C to get clear solution. To this solution was added methyl tert-butyl ether (75ml) and water (0.5ml). The solution was cooled gradually to 25-30°C and stirred for 12 hrs. Filtered the product and washed with methyl tert-butyl ether to get 4-5gm the product. HPLC purity: 99.60% 1H NMR (300Mhz, DMSOd6) :2.25, 3.19 , 3.36 , 3.68, 3.95, 4.12, 4.45, -, 4.74 , 4.95 , 6.79 , 7.13-7.27 , 7.59. Water Content: 2.12%, M.P: 96.6°C - 98.3 °C, FT-IR (KBr): 3590, 3549, 3477, 3409, 3273 , 2902 ,1508 , 1232, DSC: 104.07°C.
Example 15: Preparation of canagliflozin amorphous: A mixture of amorphous canagliflozin (40g) and methanol (240ml) was stirred at 25-30°C to get clear solution. The solution was filtered and distilled under vacuum at 35-40°C to get foamy solid. To this cyclohexane (400ml) was added at 25-30°C and stirred for 2 hrs. This was filtered, washed with cyclohexane and dried at 40-45°C title product. HPLC purity: 99.95%, DSC: 60.25°C, Content of cyclohexane: 1379 ppm. Results of hygroscopic study for canagliflozin obtained as per example 16

Time Point Initial lhr 2 hrs 4 hrs 8 hrs 12 hrs 24 hrs 48 hrs
25 °c/60 % RH
Description Off white powder Off white powder Off white powder Off white powder Off white powder Off white powder Off white powder Off white powder
Moisture
content bv
KF (%)' • 2.19 2.22 2.29 2.33 2.35 2.39 2.42 2.49
25°C790 RH
Description Off white powder Off white powder Off white powder Off white powder Off white powder Off white powdeT Off white powder Off white powder
Moisture
content by
KF(%)' 219 2.36 2.48 2.52 2.69 2.87 3.17 3.48
Example 16 : Preparation of crystalline canagliflozin hemihydrate :
Method 1: To a solution of amorphous canagliflozin in acetone was added water dropwise. The reaction mass was stirred for 18 hrs at 25-30°C. The product was filtered and washed with acetone and water and dried under vacuum to obtain 2.5gm of titled product. Water content: 2.70%. Method 2: To a solution of amorphous canagliflozin in ethyl acetate was added diethyl ether and water. The reaction mixture stirred at 25-30°C for 18 hrs The product was filtered and washed with ethyl acetate and diethyl ether to obtain 2.7 gm of titled product. Water content: 2.66%, HPLC purity: 99.95% .
Example 17: Preparation of amorphous canagliflozin: A mixture of crystalline canagliflozin hemihydrate and methanol was stirred at 25-30°C to get clear solution. The solution was filtered and distilled under vacuum to obtain foamy solid. To this foamy solid cyclohexane was added at 25-30°C. The product was filtered and washed with cyclohexane to obtain title product, dried at 40-45°C; HPLC purity: 99.49%
Example 18: Preparation of crystalline canagliflozin;canagliflozin (lOOg) was dissolved in ethyl acetate (300 ml) to get clear solution. To this solution methyl tertiary butyl ether (1200 ml) and water (8 ml) were added. The mixture was stirred at 25-30°C for 12 hrs. The solid was filtered and washed with methyl tertiary butyl ether to obtain 52 gm of title product.

WE CLAIM:

a) reacting a compound of formula II with a reducing agent

1] A process for the preparation of canagliflozin, a compound of formula I comprising:
to obtain a compound of formula III;
b) coupling the compound of formula III with a compound of formula IV

to obtain a compound of formula V;
c) converting the compound of formula V to a compound of formula VI; and

d) converting the compound of formula VI to the compound of formula I.

2] The process as claimed in claim 1, wherein in step "a" the reducing agent is selected from
the group consisting of diborane, diazene, sodium borohydride, potassium borohydride, lithium
aluminium hydride and diisobutyl_aluminium hydride and aluminum hydride.
3] The process as claimed in claim 1, wherein in step "a" the compound of formula II is
reduced to the compound of formula III in absence of a Lewis acid.
4] The process as claimed in claim 1, wherein in step "b" the coupling reaction is carried out in
presence of a base selected from the group consisting of n-butyl lithium, sec-butyl lithium, sodium
hydride, potassium hydride and isopropylmagnesium chloride.lithium chloride complex.
5] The process as claimed in claim 1, wherein in step "c" the compound of formula V is
converted to compound of formula VI in presence of an acid and in step "b" the compound of
formula VI is converted to compound of formula I by treating with a reducing agent.
6] A process for the preparation of amorphous canagliflozin comprising;
a) preparation of canagliflozin by a process as claimed in claim 1;
b) optionally treating the canagliflozin of step 'a' with an alcoholic solvent;
c) optionally removing the solvent of step 'b';
d) adding hydrocarbon solvent to step 'a' or step 'b' or step V; and
e) isolating amorphous canagliflozin from step'd'.
7] The process as claimed in claim 9, wherein in step 'b' the alcoholic solvent is selected from
group consisting of methanol, ethanol, propanol, isopropanol and butanol and in step 'c' the
hydrocarbon solvent is selected from the group consisting of aliphatic hydrocarbon or aromatic
hydrocarbon.
8] A process for the preparation of amorphous canagliflozin comprising:
a) subjecting canagliflozin to treatment with a single hydrocarbon solvent; and
b) isolating the amorphous canagliflozin.
91 A compound selected from the following:



10] A method of producing canagliflozin by using a compound selected from the group consisting of