FIELD OF THE APPLICATION

Present application relates to the process for the preparation of SGLT2 inhibitors. A process for the preparation of Canagliflozin, preparation of amorphous form of Canagliflozin and solid dispersion of Canagliflozin.

BACKGROUND

Inhibitors of sodium glucose co-transporter 2 (SGLT2) have recently been developed as a novel potential therapeutic option for the treatment of type 2 diabetes. SGLT2 inhibitors (gliflozins) lower the plasma glucose concentration by inhibition of glucose re-uptake in the kidney, without weight gain. As the mechanism of action of SGLT2 inhibitors is independent of insulin secretion and insulin action, they lower the plasma glucose concentration with lower risk of hypoglycemia.

The present applications related to an improved process for the preparation of SGLT2 inhibitors (gliflozins) such as canagliflozin, dapagliflozin, sergliflozin, ipragliflozin, empagliflozin, and luseogliflozin.

SGLT2 inhibitors (gliflozins) n be represented by general structural formula 1 :

Compound 1

Y = C, N, O, S

Canagliflozin is chemically described as (1 S)-1 ,5-anhydro-1 -[3-[[5-(4- fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol. It has the chemical structure of formula (1 a).

Compound 1a Dapagliflozin is chemically described as (1 S)-1 ,5-Anhydro-1 -[4-chloro-3-(4- ethoxy benzyl)phenyl]-D-glucitol. It has the chemical structure of formula (1 b).

Sergliflozin is chemically described as 2-(4-Methoxybenzyl)phenyl-p-D- glucopyranoside. It has the chemical structure of formula (1 c).

Ipragliflozin is chemically described as (1 S)-1 ,5-Anhydro-1 -[3-(1 -benzothiophen- 2-ylmethyl)-4-fluorophenyl]-D-glucitol. It has the chemical structure of formula (1 d).

Empagliflozin is chemically described as (1 S)-1 ,5-Anhydro-1 -(4-chloro-3-{4-[(3S)- tetrahydro-3-furanyloxy]benzyl}phenyl)-D-glucitol. It has the chemical structure of formula (1 e).

Luseogliflozin is chemically described as (1 S)-1 ,5-Anhydro-1 -[5-(4- ethoxybenzyl)-2-methoxy-4-methylphenyl]-1 -thio-D-glucitol. It has the chemical structure of formula (1 f).

The US patent document 7,943,788 discloses Canagliflozin in example 84, which is prepared in accordance with examples 1 through 4. The examples disclose the isolation of the crude desired compound in the form of a residue, which is then purified by column chromatography.

The US patent document 7,943,582 discloses crystalline hemihydrate form of canagliflozin and process for its preparation.

Various processes for the preparation of Canagliflozin compound 1 a, its polymorphs and intermediates, have been reported in the patent publications US8772512, US9024009B2, US9056850B2, US8999941 B2, US20130052266, WO2012140120, WO2012154812, WO2013068850, WO2013064909 and WO2014195966A2 each of which is incorporated herein by reference in their entireties.

The US patent application document US8999941 B2 discloses that amorphous form of Canagliflozin is hygroscopic as per Dynamic vapor sorption (DVS) analysis. Amorphous form undergoes physical changes. Further discloses, the preparation of amorphous Canagliflozin by adding a solution of Canagliflozin in toluene to n-heptane.

In this application, there are provided simple, economical, cost effective, scalable and robust processes for the preparation of SGLT2 inhibitors (gliflozins), and intermediates thereof. Also provided preparation of Canagliflozin which results in the control of unwanted a-anomer to a greater extent. Another objective of the present application is to provide a process for the preparation of amorphous form of Canagliflozin and a solid dispersion comprising amorphous form of Canagliflozin.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline compound 18a' obtained according to example 19.

Figure 2 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline compound 18a' obtained according to example 20.

Figure 3 is an illustration of modulated DSC thermogram of amorphous form of

Canagliflozin obtained before micronization according to example 35.

Figure 4 is an illustration of modulated DSC thermogram of amorphous form of

Canagliflozin obtained after 1 st micronization according to example 35.

Figure 5 is an illustration of modulated DSC thermogram of amorphous form of

Canagliflozin obtained after 2nd micronization according to example 35.

Figure 6 is an illustration modulated DSC thermogram of amorphous form of

Canagliflozin obtained after 3rd micronization according to example 35.

Figure 7 is an illustration of a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion comprising Canagliflozin and copovidone.

Figure 8 is an illustration of a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion comprising Canagliflozin and PVP-K30.

Figure 9 is an illustration of a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion comprising Canagliflozin and HPMC-AS.

Figure 10 is an illustration of a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion comprising Canagliflozin and Eudragit. Figure 1 1 is an illustration of differential scanning thermogram (DSC) of crystalline form of Canagliflozin obtained according to example 36.

Figure 1 2 is an illustration of XRD of crystalline form of Canagliflozin obtained according to example 36.

Figure 13 is an illustration of XRD of amorphous form of Canagliflozin obtained according to example 50.

Figure 14 is an illustrative HPLC method for measuring purity of compound 18a'.

Figure 15 is an illustrative HPLC method for measuring purity of canagliflozin (compound 1 a).

SUMMARY OF THE APPLICATION

The present application provides novel synthetic processes for obtaining Canagliflozin and its related intermediates.

In first embodiment, the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 4 to a compound 6 using a compound 5:

Compound 4 Compound 6

Wherein Z is H or suitably selected oxygen protecting group; X is suitably selected halogen; and Ri is suitably selected from H or lower alkyl group.

In second embodiment, the present application provides a process for preparing Dapagliflozin (Compound 1 b) comprising the conversion of a compound 4 to a compound 8 using a compound 7: Compound 4

Wherein Z is H or suitably selected oxygen protecting group; X is suitably selected halogen; and Ri is suitably selected from H or lower alkyl group.

In third embodiment, the present application provides a process for preparing Canagliflozin (compound 1 a), comprising the conversion of a compound 1 1 to compound 12:

Compound 11 Compound 12

Wherein X is suitably selected halogen; and Ri is suitably selected from H or lower alkyl group.

In fourth embodiment, the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 12 to a compound 14 using a compound 13:

Compound 13 wherein Z is H or suitably selected oxygen protecting group; X is suitably selected halogen; and Ri is suitably selected from H or lower alkyl group.

In fifth embodiment, the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 14 to a compound 15: Compound 15 wherein Ri is suitably selected from H or lower alkyl group.

In sixth embodiment, the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 15 to Canagliflozin (Compound 1 a):

Compound 15 Compound 1a wherein Ri is suitably selected from H or lower alkyl group.

In seventh embodiment, the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 14 to a compound 16:

Compound 1 ₄ Compound 1 wherein Ri is suitably selected from H or lower alkyl group.

In eighth embodiment, the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 16 to a compound 17:

Compound 16 Compound 17

In ninth embodiment, the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 17 to Canagliflozin (Compound 1 a):

Compound 17

In tenth embodiment, the present application provides a process for preparing SGLT2 inhibitors (Compound 1 ) comprising the conversion of a compound 18 to Compound 19:

wherein Z is H or suitably selected oxygen protecting group; Y is suitably selected C, N, O or S; Ri is suitably selected from H or lower alkyl group; and

In eleventh embodiment, the present application provides a process for preparing SGLT2 inhibitors (Compound 1 ) comprising the conversion of a compound 19 to Compound 1 :

Compound 19

wherein symbols are as defined above.

In twelfth embodiment, the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 14 to Compound 19a:

Compound 14 Compound 19a wherein symbols are as defined above.

In thirteenth embodiment, the present application provides a one pot process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 5 to Compound 19a using compound 13:

Compound 3 wherein symbols are as defined above. In fourteenth embodiment, the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 19a to Compound 1 a:

wherein symbols are as defined above.

In fifteenth embodiment, the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 5 to Compound 18a' using compound 13:

Compound 13 wherein symbols are as defined above.

In sixteenth embodiment, the present application provides a process preparing solid form of Compound 18a' comprising:

a) conversion of a compound 5 to Compound 18a' using compound 13:

Compound 13 wherein symbols are as defined above,

b) isolating compound 18a' in a solid form. In seventeenth embodiment, the present application provides a process for preparing crystalline form of Compound 18a' comprising:

c) conversion of a compound 5 to Compound 18a' using compound 13:

Compound 13 wherein symbols are as defined above.

d) isolating compound 18a' in crystalline form.

In the eighteenth embodiment, the present application provides solid form of compound 18a'.

Compound 18a'

In nineteenth embodiment, the present application provides a crystalline form of compound 18a'.

Compound 18a'

In the twentieth embodiment, the present application provides solid form of compound 18a' having a purity of at least 98% as measured by HPLC method.

In the twenty first embodiment, the present application provides crystalline form of compound 18a' having a purity of at least 98% as measured by HPLC method.

In the twenty second embodiment, the present application provides a crystalline form of compound 18a' characterized by one or more of:

1 ) DSC thermogram with an onset peak at about of 144°C, 2) X-ray diffraction pattern with peaks at about 10.81 , 13.50, 18.96, 20.99, 23.73 and 30.68 ± 0.2 degrees two-theta,

3) thermogravimetric analysis shows a mass loss of 0.052%.

In the twenty third embodiment, the present application provides a crystalline form of compound 18a' characterized by X-ray diffraction pattern with peaks at about 10.81 , 13.50, 18.96, 20.99, 23.73 and 30.68 ± 0.2 degrees two-theta.

In the twenty fourth embodiment, the present application provides a process for preparation of Canagliflozin comprising, conversion of solid form of compound 18a' in to Canagliflozin.

In the twenty fifth embodiment, the present application provides a process for preparation of Canagliflozin comprising conversion of solid form of compound 18a' with a purity of at least 98% as measured by HPLC in to Canagliflozin with high purity.

In the twenty sixth embodiment, the present application provides a process for preparation of Canagliflozin comprising, conversion of crystalline form of compound 18a' in to Canagliflozin.

In the twenty seventh embodiment, the present application provides a process for preparation of Canagliflozin comprising, conversion of crystalline form of compound 18a' with a purity of at least 98% as measured by HPLC in to Canagliflozin with high purity.

In twenty eighth embodiment, the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 18a' to Compound 1 a.

Compound 18a' Compound 1a In the twenty ninth embodiment, the present application provides a process for preparing pure Canagliflozin comprising conversion of a compound 6 to Canagliflozin by slow addition of BF3.Etherate to compound 6:

Compound 6 Canagliflozin wherein Ri is a lower alkyl group.

In the thirtieth embodiment the present application provides an amorphous form of Canagliflozin with a mean particle size D[4,3] of about 30 microns to about 200 microns.

In the thirty first embodiment the present application provides an amorphous form of Canagliflozin with a d(0.1 ) particle size of about 0.1 to about 30 microns, a d(0.5) particle size of about 30 microns to about 200 microns and/or a d(0.9) particle size of about 50 microns to about 400 microns.

In the thirty second embodiment, the present application provides a process for the preparation of amorphous form of Canagliflozin, comprising: a) providing a solution of Canagliflozin in a solvent;

b) mixing an anti-solvent and the solution obtained in step a) in a micro mixing reactor;

c) isolating the amorphous form of Canagliflozin

In the thirty embodiment, the present application provides a process for the preparation of amorphous form of Canagliflozin, comprising: a) heating, mixing and/or kneading Canagliflozin through an extruder to result in a homogenous melt; b) forcing the resultant melt obtained in step a) through one or more orifices, nozzles, or moulds; c) cooling the extrudate of step b) to yield amorphous form of Canagliflozin; In the thirty fourth embodiment, the present application provides a process for the preparation of solid dispersion comprising amorphous Canagliflozin and one or pharmaceutically acceptable excipients, comprising:

a) preparing a homogenous blend of Canagliflozin and a polymer;

b) heating, mixing and/or kneading the resultant blend of step a) through an extruder to result in a homogenous melt;

c) forcing the resultant melt obtained in step b) through one or more orifices, nozzles, or moulds;

d) cooling the extrudate of step c) to yield solid dispersion;

In the thirty fifth embodiment, the present application provides a process for the preparation of amorphous form of Canagliflozin, comprising:

a) providing a solution of Canagliflozin in a solvent

b) feeding the solution of Canagliflozin into a thin film dryer

c) drying the solution by thin film drying, and

d) collecting the amorphous form of Canagliflozin from thin film dryer.

In the thirty sixth embodiment, the present application provides an amorphous form of Canagliflozin showing a glass transition in modulated DSC thermogram with an onset temperature of at least about 45 °C.

In the thirty seventh embodiment, the present application provides a pharmaceutical composition comprising an amorphous form of Canagliflozin showing a glass transition in modulated DSC thermogram with an onset temperature of at least about 45 °C and one or more pharmaceutically acceptable carriers.

In the thirty eighth embodiment, the present application provides a process for preparing crystalline form of Canagliflozin by isolating from a solution of Canagliflozin in a solvent comprising isopropyl acetate, isopropyl alcohol or mixtures thereof.

In the thirty ninth embodiment, the present application provides a process for preparing pure 2-(4-fluorophenyl) thiophene comprising:

a) dissolving 2-(4-fluorophenyl) thiophene in an organic solvent, and b) isolating pure 2-(4-fluorophenyl) thiophene by mixing an anti-solvent.

In the fortieth embodiment the present application provides a process for preparing pure 2-(4-fluorophenyl) thiophene comprising:

a) dissolving 2-(4-fluorophenyl) thiophene in a solvent selected from polar protic or polar aprotic solvents or mixture of both and

b) isolating pure 2-(4-fluorophenyl) thiophene by mixing an anti-solvent.

In the forty first embodiment the present application provides a process for preparing pure 2-(4-fluorophenyl) thiophene comprising: a) dissolving 2-(4-fluorophenyl) thiophene in a solvent selected from acetone, methanol, ethanol, isopropyl alcohol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, tetrahydrofuran, ethylacetate; and b) isolating pure 2-(4-fluorophenyl) thiophene by mixing an anti-solvent selected from water, n-hexane, diethylether, 1 ,4-dioxane or mixture of water miscible organic solvents.

In the forty second embodiment present application provides a process for preparing pure 2-(4-fluorophenyl) thiophene comprising: a) dissolving 2-(4-fluorophenyl) thiophene in isopropyl alcohol, and

b) isolating pure 2-(4-fluorophenyl) thiophene by mixing water.

In the forty third embodiment, the present application provides a process for preparing canagliflozin from pure 2-(4-fluorophenyl) thiophene comprising:

c) dissolving 2-(4-fluorophenyl) thiophene in an organic solvent, and

d) isolating pure 2-(4-fluorophenyl) thiophene by mixing an anti-solvent.

In the forty fourth embodiment the present application provides a process for preparing canagliflozin from pure 2-(4-fluorophenyl) thiophene comprising:

c) dissolving 2-(4-fluorophenyl) thiophene in a solvent selected from polar protic or polar aprotic solvents or mixture of both and

d) isolating pure 2-(4-fluorophenyl) thiophene by mixing an anti-solvent. In the forty fifth embodiment the present application provides a process for preparing canagliflozin from pure 2-(4-fluorophenyl) thiophene comprising:

c) dissolving 2-(4-fluorophenyl) thiophene in a solvent selected from acetone, methanol, ethanol, isopropyl alcohol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, tetrahydrofuran, ethylacetate; and d) isolating pure 2-(4-fluorophenyl) thiophene by mixing an anti-solvent selected from water, n-hexane, diethylether, 1 ,4-dioxane or mixture of water miscible organic solvents.

In the forty sixth embodiment the present application provides a process for preparing canagliflozin from pure 2-(4-fluorophenyl) thiophene comprising:

c) dissolving 2-(4-fluorophenyl) thiophene in isopropyl alcohol, and

d) isolating pure 2-(4-fluorophenyl) thiophene by mixing water.

DETAILED DESCRIPTION

The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 1 1 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

The term "amorphous form" as used herein refers to any amorphous solid state which is known to a person skilled in the art. For example amorphous solids lack the three-dimensional long-range order found in crystalline solids, although short-range order may be present over several molecular dimensions. Due to the lack of three- dimensional long-range order, amorphous solids do not constructively diffract X-rays, as do crystalline solids. Therefore, in X-ray powder diffraction experiments, broad, diffuse haloes are observed instead of well-defined peaks [Journal Of Pharmaceutical Sciences, Vol. 93, no. 1 , January 2004, Page-3]. A glass is defined as an amorphous solid that exhibits a glass transition. The "glass transition" is a phenomenon in which the solid amorphous phase exhibits an abrupt change in derivative thermodynamic properties (e.g., heat capacity or thermal expansivity) with a change in temperature [Journal Of Pharmaceutical Sciences, Vol. 93, NO. 1 , January 2004, Page-3].

As used herein, the term "solid dispersion" means any solid composition having at least two components. In certain embodiments, a solid dispersion as disclosed herein includes an active ingredient Canagliflozin dispersed among at least one other component, for example a polymer.

Optionally, in carrying out the processes according to the present application, the reaction product of a given step can be carried forward to the next step without the isolation of the product i.e., one or more reactions in a given process can be carried out in-situ as one pot process optionally in the presence of the same reagent/s used in a previous step wherever appropriate to do so, to make the process of the present application economical and commercially more viable.

Optionally, in carrying out the processes according to the present application, the reaction product of a given step can be isolated and purified by the methods described herein or the methods known to a person skilled in the art before using in a subsequent step of the process.

In the present application, the isolation of products after completion of the reactions can be effected by removing the solvent. Suitable techniques which can be used for the removal of the solvent include evaporation techniques such as evaporation using a Buchi® Rotavapor®, spray drying, thin film drying, nauta drying, tray drying, freeze drying (lyophilization) or any other suitable technique.

Isolated product can be optionally further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, Buchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, cone dryer, agitated nutsche filter cum dryer, nauta dryer or the like or any other suitable dryer. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

The dried product can be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller, hammer mills and jet mills.

The reaction time should be sufficient to complete the reaction which depends on scale and mixing procedures, as is commonly known to one skilled in the art. Typically, the reaction time can vary from about few minutes to several hours. For example the reaction time can be from about 10 minutes to about 24 hours, or any other suitable time period.

Room temperature as used herein refers to 'the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located'. Typically, room temperature can be from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the person skilled in art.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about normal pressure, unless the context requires otherwise. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" (open-ended) means the element or elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open-ended. As used herein, "consisting essentially of" means that the application may include elements in addition to those recited in the claim, but only if the additional elements do not materially alter the basic and novel characteristics. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

"Halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

During any of the processes for preparation of the compounds of the present application, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 . The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The term "pure" or "high purity" when used in the present application with reference to canagliflozin or compound 18a' refers to a purity of at least about 98% or about 98.5% or about 99% or about 99.5% or about 99.8% or about 99.9% or 100%. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. In the case of stereoisomers, "pure" as used herein also means that the material contains 99% of one enantiomer or diastereomer, as appropriate. "Substantially pure" as used herein means at least about 98% pure and, likewise, "essentially pure" as used herein means at least about 95% pure.

"Substantially free of one or more of its corresponding impurities" as used herein, unless otherwise defined refers to the compound that contains less than about 2%, or less than about 1 %, or less than about 0.5%, or less than about 0.3%, or less than about 0.2%, or less than about 0.1 %, or less than about 0.05%, or less than about 0.03%, or less than about 0.01 %, by weight, of individual impurity.

In the first embodiment, compound 4 can be reacted with compound 5 in presence of alkyl lithium to obtain compound 6. Alkyl lithium includes, methyl lithium, n-propyl lithium, isopropyl lithium, cyclopropyllithium, n-butyl lithium, s-butyl lithium, t-butyl lithium, sec-amyl lithium, tert- amyl lithium, n-hexyllithium, 4-heptyllithium, cyclohexyllithium, triethylmethyllithium, 1 - methylcyclo-pentyllithium, phenyl lithium, mesityl lithium (i.e. 2,4,6-trimethylphenyl lithium), trimethylsilylmethyl lithium, triethylsilylmethyl lithium, adamantyllithium and the like.

The alkyl lithium is preferably present in an amount in the range of from about 1 .0 to about 3.0 molar equivalents, or any range therein, more preferably in an amount in the range of from about 2.0 to about 2.5 molar equivalents, or any range therein, most preferably about 2.0 molar equivalents.

The compound 4 can preferably be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein. Optionally, the reaction can be carried out in presence of organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether and the like; at a temperature in the range of from about 0° C. to about -78° C, or any range therein; to yield the corresponding compound 6.

In an aspect of the first embodiment, the reaction of the compound 4 with the compound 5 can be carried out by lithiating the compound 4, followed by reacting the resultant with the compound 5. In another aspect of the first embodiment, the alkyl lithium can be added to a mixture of the compound 4 and the compound 5.

Compound 6 can be converted to compound 1 a by the methods know in the art. Methods known in US7943788, US 20090233874, US 20100099883, US 201 10087017, US8772512, US 20130052266, WO 2012140120, WO 2012154812, WO 2013068850, and WO 2013064909, are incorporated herein by reference in their entirety.

In the second embodiment, compound 4 can be reacted with compound 7 in presence of alkyl lithium to obtain compound 8. Alkyl lithium can be as described in the first embodiment herein above. The alkyl lithium is preferably present in an amount as described in first embodiment herein above. The compound 4 can preferably be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein. Optionally, the reaction can be carried out in presence of organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether and the like; at a temperature in the range of from about 0° C. to about -78° C, or any range therein; to yield the corresponding compound 8.

In an aspect of second embodiment, the reaction of the compound 4 with the compound 7 can be carried out by lithiating the compound 4, followed by reacting the resultant with the compound 7. In another aspect of the second embodiment, the alkyl lithium can be added to a mixture of the compound 4 and the compound 7.

Compound 7 can be converted to compound 1 b by the methods known in the art. Methods known in US6414126, US7919598, US7375213, and US7932379 are incorporated herein by reference in their entirety.

In the third embodiment, the conversion of the compound 1 1 to the compound 12 can be carried out using alcohol optionally in presence of acid catalyst. Optionally, the said conversion can be carried out in presence of solvent. A suitable acid catalyst includes, but not limited to, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, boron trifluoride ammonium chloride, and sulfonic acid ion exchange resins. Alcohol corresponding to lower alkyl group can be used for the conversion. The solvent used include, but not limited to, alcohol solvent, aromatic hydrocarbon solvent, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents, or any mixture thereof. Optionally, dehydrating agent or other means of water removal can be performed during reaction that will drive the equilibrium to the right. Dehydrating agent includes, but not limited to ortho ester such as triethyl orthoformate, trimethyl orthoformate and the like.

In the fourth embodiment, compound 12 can be reacted with compound 13 in presence of alkyl lithium to obtain compound 14. Alkyl lithium can be as described in the first embodiment herein above. The alkyl lithium is preferably present in an amount as described in the first embodiment herein above. The compound 13 can preferably be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein. Optionally, the reaction can be carried out in presence of organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether and the like; at a temperature in the range of from about 0° C. to about -78° C, or any range therein; to yield the corresponding compound 14.

In an aspect of the fourth embodiment, the reaction of the compound 12 with the compound 13 can be carried out by lithiating the compound 13, followed by reacting the resultant with the compound 12. In another aspect of the fourth embodiment, the alkyl lithium can be added to a mixture of the compound 12 and the compound 13.

Optionally, the reaction of the compound 12 with the compound 13 can be carried out, wherein compound 12 is converted to compound 12a before reacting with compound 13.

Compound 12 Compound 12a

Compound 12 can be converted to compound 12a by reacting with a complex of di(Ci- ₄ alkyl) magnesium with lithium chloride such as di(sec-butyl)magnesium with lithium chloride, and the like; or a complex Ci- ₄ alkyl magnesium chloride with lithium chloride or a complex of Ci- ₄ alkyl magnesium bromide with lithium chloride; wherein the Ci- ₄ alkyl is preferably isopropyl or sec-butyl; wherein complex is present in an amount in the range of from about 1 .0 to 1 .5 molar equivalents (relative to the moles of the compound 12); in an organic solvent or mixture thereof, such as toluene, THF, hexane, pentane, MTBE, 1 ,4-dioxane, and the like; at a temperature in the range of from about ambient temperature to about -78° C, or any range therein; to yield the corresponding compound 12a.

The compound 12a is reacted with the compound 13; wherein the compound 13 can be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein; in an organic solvent or mixture thereof, such as toluene, THF, hexane, pentane, MTBE, 1 ,4-dioxane, and the like; at a temperature in the range of from about ambient temperature to about -78° C, or any range therein; to yield the corresponding compound 14. Preferably, the compound of formula 12a can be added to a mixture of the compound 13 in an organic solvent, to yield the compound 14.

In the fifth embodiment, conversion of the compound 14 to the compound 15 can be carried out using reducing agent. The reducing agent used includes, but not limited to, borohydrides such as sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, lithium cyanoborohydride, sodium triacetoxyborohydride, potassium triacetoxyborohydride, also in the presence of suitable additives such as sulfuric acid, methanesulfonic acid, acetic acid, titanium chloride, zinc chloride, cobalt (II) chloride, aluminium chloride, tin chloride, nickel chloride, phosphorus oxychloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, pyridine, iodine, trifluoroethanol or 1 ,2-ethanedithiol.

The molar ratio of the reducing agent that can be used with respect to the compound 14 can be easily derived by a person skilled in the art. For example, the said mole ratio can be about 0.01 , about 0.02, about 0.05, about 0.1 , about 0.2, about 0.5, about 1 .0, about 1 .5, about 2 or any other suitable mole per mole of the compound 14. The conversion can take place in the presence of solvent or in the absence of a solvent. The suitable solvent includes, but not limited to, alcohol solvents, ketone solvents, aromatic hydrocarbon solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents, ether solvents, polar aprotic solvents, nitrile solvents, or any mixtures thereof.

In the sixth embodiment, compound 15 can be converted to compound 1 a (Canagliflozin).

The compound 15 can be reacted with a suitably selected acid, such as, Lewis acid, which includes, but not limited to, BF ₃ .OEt ₂ , BF ₃ .THF, aluminum chloride, zinc chloride, iron chloride, and the like; or strong organic acid, which includes, but not limited to, trifluoroacetic acid, methanesulfonic acid and the like; wherein the acid is preferably present in an amount in the range of from about 0.5 to about 10.0 molar equivalents, or any range therein; in the presence of a suitably selected silane reagent such as triisopropylsilane, triethylsilane, tetramethyldisiloxane, and the like, preferably triethylsilane or tetramethyldisiloxane; wherein the silane reagent can be preferably present in an amount in the range of from about 1 .0 to about 10.0 molar equivalents, or any range therein; in an organic solvent or mixture thereof such as DCM, DCE, acetonitrile, toluene, and the like, or in a mixture of said organic solvents; preferably at a temperature in the range of from about -78°C. to about reflux, or any range therein; to yield the corresponding compound 1 a (Canagliflozin).

In the seventh embodiment, compound 14 can be converted to the compound 16. The reaction conditions such as acid, silane reagent and solvent can be such as described in sixth embodiment.

In the eighth embodiment, conversion of the compound 16 to the compound 17 can be carried out using reducing agent as described in fifth embodiment.

In the ninth embodiment, conversion of compound 17 can be converted to compound 1 a (Canagliflozin). The reaction conditions such as acid, silane reagent and solvent can be such as described in sixth embodiment.

In the tenth embodiment, conversion of a compound 18 to a compound 19 can be carried out in presence of an acid. The suitable acid includes, (+)-Camphor-10- sulfonic acid, (-)-Camphor-I O-suolfonic acid, (±)-Camphor-10-sulfonic acid, tnfluoromethanesulfonic acid, borontrifluoride and its various complexes, trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, acetic acid, hydrochloric acid, sulphuric acid, methane sulfonic acid, and thionylchoride. The amount of acid for intra molecular glycosidation can be easily derived by a person skilled in the art. For example, the said amount can vary from 0.5 mol% to 40 mol%. Typically, the reaction can be accomplished with amount from about 5.0 mol% to about 10.0 mol% of the reagent, relative to one molar equivalent of sugar derivative. The suitable solvent that can be used includes ethers such as tetrahydrofuran, dioxane, diisopropylether, diethylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; esters such as ethyl acetate, isopropyl acetate; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene or dichlorobenzene; aliphatic hydrocarbon solvents such as acetonitrile, methylcyclohexane, cyclohexane, heptane or hexane; aromatic hydrocarbon solvents such as toluene, benzene, chlorobenzene, 4-chlorotoluene, trifluorotoluene, o-xylene, m-xylene or p-xylene; or mixtures thereof. The conversion of a compound 18 to a compound 19 can take place at a temperature of about -50°C to about 150°C, about 0°C to about 100°C, about 0°C to about 50°C, about room temperature, about reflux temperature of the solvent used in the reaction, or any other suitable temperature, which facilitates the desired reaction to happen without substantially negatively affecting the quality of the substrates or the reaction product.

In the eleventh embodiment, compound 19 can be converted to the compound 1 by reacting with a suitably selected Lewis acid, which includes, but not limited to, BF ₃ .OEt ₂ , BF ₃ .THF, aluminum chloride, zinc chloride, iron chloride, and the like, also in the presence of a suitably selected silane reagent such as described in sixth embodiment; suitable borohydrides and suitable additives such as described in eighth embodiment.

The molar ratio of Lewis acid or borohydride that can be used with respect to the compound 19 can be easily derived by a person skilled in the art. For example, the said mole ratio can be about 0.01 , about 0.02, about 0.05, about 0.1 , about 0.2, about 0.5, about 1 .0, about 1 .5, about 2, about 3 or any other suitable mole per mole of the compound 19. The conversion can take place in the presence of solvent or in the absence of a solvent. The suitable solvent can be such as described in tenth embodiment.

In twelfth embodiment, conversion of a compound 14 to a compound 19a can be carried out in presence of an acid. The reaction conditions for the said conversion can be such as described in tenth embodiment.

In the thirteenth embodiment, the present application provides a one pot process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 5 to Compound 19a using compound 13, wherein intermediate compound 18b is formed by reacting compound 5 and compound 13, further compound 18b is converted to compound 19a without isolation or purification.

Compound 18b

Compound 5 can be reacted with compound 13 under conditions such as described in first embodiment to obtain compound 18b.

In an aspect of thirteenth embodiment, the reaction of the compound 5 with the compound 13 can be carried out, wherein compound 5 is converted to compound 5a before reacting with compound 13.

Compound 5 Compound 5a

Compound 5 can be converted to compound 5a under conditions such as described in fourth embodiment.

The compound 5a can be reacted with the compound 13 under conditions such as described in fourth embodiment to obtain compound 18b. Preferably, the compound of formula 5a can be added to a mixture of the compound 13 in an organic solvent, to yield the compound 18b.

Compound 18b is further converted to compound 19a without isolation or purification. The conversion of a compound 18b to a compound 19a can be carried out under the conditions such as described in tenth embodiment.

In the fourteenth embodiment, the compound 19a can be converted to the compound 1 a under conditions such as described in eleventh embodiment.

In the fifteenth embodiment, the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 5 to Compound 18a' using compound 13.

Compound 5 can be reacted with compound 13 in presence of alkyl lithium to obtain compound 18a'. Alkyl lithium includes, methyl lithium, n-propyl lithium, isopropyl lithium, cyclopropyllithium, n-butyl lithium, s-butyl lithium, t-butyl lithium, sec-amyl lithium, tert-amyl lithium, n-hexyllithium, 4-heptyllithium, cyclohexyllithium, triethylmethyllithium, 1 -methylcyclo-pentyllithium, phenyl lithium, mesityl lithium (i.e. 2,4,6-trimethylphenyl lithium), trimethylsilylmethyl lithium, triethylsilylmethyl lithium, adamantyllithium and the like. The alkyl lithium is preferably present in an amount in the range of from about 1 .0 to about 3.0 molar equivalents, or any range therein, more preferably in an amount in the range of from about 2.0 to about 2.5 molar equivalents, or any range therein, most preferably about 2.0 molar equivalents. The compound 13 can preferably be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein. Optionally, the reaction can be carried out in presence of organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether and the like; at a temperature in the range of from about 0° C. to about -78° C, or any range therein; to yield the corresponding compound 18a'.

In an aspect of the fifteenth embodiment, the reaction of the compound 5 with the compound 13 can be carried out by lithiating the compound 13, followed by reacting the resultant with the compound 5. In another embodiment, the alkyl lithium can be added to a mixture of the compound 5 and the compound 13.

Optionally, the reaction of the compound 5 with the compound 13 can be carried out, wherein compound 5 is converted to compound 5a before reacting with compound 13.

Compound 5 Compound 5a

Compound 5 can be converted to compound 5a by reacting with a complex of di(Ci- ₄ alkyl) magnesium with lithium chloride such as di(sec-butyl)magnesium with lithium chloride, and the like; or a complex Ci- ₄ alkyl magnesium chloride with lithium chloride or a complex of Ci- ₄ alkyl magnesium bromide with lithium chloride; wherein the Ci- ₄ alkyl is preferably isopropyl or sec-butyl; wherein complex is present in an amount in the range of from about 0.3 to 1 .5 molar equivalents (relative to the moles of the compound 12); in an organic solvent or mixture thereof, such as toluene, THF, hexane, pentane, MTBE, 1 ,4-dioxane, and the like; at a temperature in the range of from about ambient temperature to about -78° C, or any range therein; to yield the corresponding compound 5a.

The compound 5a can be reacted with the compound 13; wherein the compound 13 can be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein; in an organic solvent or mixture thereof, such as toluene, THF, hexane, pentane, MTBE, 1 ,4-dioxane, and the like; at a temperature in the range of from about ambient temperature to about -78° C, or any range therein; to yield the corresponding compound 18a'.

Based on the disclosure in the prior art US publication document US 2009/0233784 A1 , page-22, para [0243]; it is believed that the structure of the product obtained after the reaction of compound 5 with compound 13 is compound 18a as follows.

Compound 18a

However, the reaction product that is isolated as a solid in the process of the present application up on further structural studies is characterized by following spectral data.

¹ H NMR (400 MHz, DMSO-cfe): δ 7.87 (d, J - 1 .8 Hz, 1 H), 7.80 (dd, J = 7.9, 1 .9 Hz, 1 H), 7.60 (dd, J - 8.7, 5.4 Hz, 2H), 7.33 (d, J - 7.9 Hz, 1 H), 7.30 (d, J - 3.6 Hz, 1 H), 7.20 (t, J - 8.9 Hz, 2H), 6.85 (d, J - 3.6 Hz, 1 H), 5.17 (dd, J - 7.1 , 3.5 Hz, 1 H), 5.04 (d, J = 7.0 Hz, 1 H), 4.60 (d, J = 4.9 Hz, 1 H), 4.48 - 4.39 (m, 3H), 4.22 (s, 2H), 4.01 (dt, J = 6.9, 3.3 Hz, 1 H), 3.64 - 3.54 (m, 1 H), 3.55 - 3.46 (m, 2H), 3.40 - 3.35 (m, 1 H), 2.35 (s, 3H); ¹³ C NMR (101 MHz, DMSO) δ 199.82, 162.73, 160.30, 142.89, 142.26, 140.60, 138.94, 133.38, 130.60, 130.55, 130.52, 129.44, 127.39, 127.15, 127.07, 126.85, 123.64, 1 16.12, 1 15.90, 75.31 , 72.39, 71 .87, 71 .41 , 63.27, 33.32, 19.40. The said observed structural characterization data is in agreement with the structure of the obtained solid as compound 18a' as follows:

Compound 18a'

Therefore, it can be understood that the solid isolated from the reaction mixture obtained after the reaction of compound 5 with compound 13 in the process of the present application is compound 18a'.

In the sixteenth embodiment, compound 5 can be reacted with compound 13 in presence of alkyl lithium to obtain compound 18a' in solid form. In one variant the obtained solid form of compound 18a' is crystalline.

The said alkyl lithium includes, methyl lithium, n-propyl lithium, isopropyl lithium, cyclopropyllithium, n-butyl lithium, s-butyl lithium, t-butyl lithium, sec-amyl lithium, tert- amyl lithium, n-hexyllithium, 4-heptyllithium, cyclohexyllithium, triethylmethyllithium, 1 - methylcyclo-pentyllithium, phenyl lithium, mesityl lithium (i.e. 2,4,6-trimethylphenyl lithium), trimethylsilylmethyl lithium, triethylsilyl methyl lithium, adamantyllithium and the like. The alkyl lithium is preferably present in an amount in the range of from about 1 .0 to about 3.0 molar equivalents, or any range therein, more preferably in an amount in the range of from about 2.0 to about 2.5 molar equivalents, or any range therein, most preferably about 2.0 molar equivalents. The compound 13 can preferably be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein. Optionally, the reaction can be carried out in presence of organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether or mixture thereof at a temperature in the range of from about 0° C. to about -78° C, or any range therein.

In the present embodiment, compound 18a' can be obtained in a solid form by isolation. The said isolation may be effected by methods such as, removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, freeze drying, or any other suitable fast evaporation technique. The isolated solid form of compound 18a' may contain some amount of occluded mother liquor or higher than desired level of impurities. If desired, the obtained solid may be washed with a solvent or a mixture of solvents to wash out the impurities.

Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.

In one variant the obtained solid form of compound 18a' is crystalline.

In an aspect, the present application provides solid form of compound 18a' having a purity of at least about 98% as measured by HPLC (High performance liquid chromatography) method. Preferably at least about 99%, more preferably at least about 99.5%, still more preferably at least about 99.9% or most preferably at least about 99.99% as measured by a HPLC method.

In an aspect, the present application provides crystalline form of compound 18a' having a purity of at least about 98% as measured by HPLC method. Preferably at least about 99%, more preferably at least about 99.5%, still more preferably at least about 99.9% or most preferably at least about 99.99% as measured by a HPLC method.

The HPLC method that may be followed can be as herein described according to Figure 14.

In the twenty second embodiment, the crystalline form of compound 18a' can be characterized by one or more of: (i) a DSC thermogram with an onset peak at about of 144°C; (ii) an X-ray powder diffraction pattern having peaks expressed in degrees 2Θ at about 10.81 , 13.50, 18.96, 20.99, 23.73 and 30.68 ± 0.2°θ; (iii) a thermogravimetric analysis showing a mass loss of 0.052%. The crystalline form of compound 18a' may be further characterized by XRD peaks at about 5.40, 8.1 1 , 16.23 and 17.10 ± 0.2° 2Θ. Figure 1 shows typical X-ray powder diffraction pattern.

The compound 18a' can be further purified to reduce impurities using solvent; which includes; alcohol solvent, aromatic hydrocarbon solvent, ether solvent, ketone solvent, halogenated hydrocarbon solvent, hydrocarbon solvent, nitrile solvent, polar aprotic solvent, or mixtures thereof.

The present application further provides a process for the preparation of Canagliflozin with high purity from solid form of compound 18a' with a purity of at least 98% as measured by HPLC. The Canagliflozin obtained can be in any of the forms such as amorphous, crystalline or mixtures thereof.

In an aspect, the present application provides crystalline form of canagliflozin having a purity of at least about 98% as measured by HPLC method. Preferably at least about 99%, more preferably at least about 99.5%, still more preferably at least about 99.9% or most preferably at least about 99.99% as measured by a HPLC method.

The HPLC method that may be followed can be as herein described according to Figure 15.

The present application further provides a process for the preparation of Canagliflozin with high purity from crystalline form of compound 18a'. The Canagliflozin obtained can be in any of the forms such as amorphous, crystalline or mixtures thereof.

The present application further provides a process for the preparation of Canagliflozin with high purity from crystalline form of compound 18a' with a purity of at least 98% as measured by HPLC. The Canagliflozin obtained can be in any of the forms such as amorphous, crystalline or mixtures thereof.

In twenty eighth embodiment, the compound 18a' can be converted to canagliflozin (compound 1 a) by reacting with a suitably selected Lewis acid, which includes, but not limited to, BF3.0Et2, BF3.THF, aluminum chloride, zinc chloride, iron chloride, and the like, also in the presence of a suitably selected silane reagent such as triisopropylsilane, triethylsilane, tetramethyldisiloxane, and the like; borohydrides such as sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, lithium cyanoborohydride, sodium triacetoxyborohydride, potassium triacetoxyborohydride, also in the presence of suitable additives such as sulfuric acid, methanesulfonic acid, acetic acid, titanium chloride, zinc chloride, cobalt (II) chloride, aluminium chloride, tin chloride, nickel chloride, phosphorus oxychloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, pyridine, iodine, trifluoroethanol or 1 ,2-ethanedithiol. The molar ratio of lewis acid or borohydride that can be used with respect to the compound 18a' can be easily derived by a person skilled in the art. For example, the said mole ratio can be about 0.01 , about 0.02, about 0.05, about 0.1 , about 0.2, about 0.5, about 1 .0, about 1 .5, about 2, about 3 or any other suitable mole per mole of the compound 19. The conversion can take place in the presence of solvent or in the absence of a solvent. The suitable solvent that can be used includes ethers such as tetrahydrofuran, dioxane, diisopropylether, diethylether, 2- methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; esters such as ethyl acetate, isopropyl acetate; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene or dichlorobenzene; aliphatic hydrocarbon solvents such as acetonitrile, methylcyclohexane, cyclohexane, heptane or hexane; aromatic hydrocarbon solvents such as toluene, benzene, chlorobenzene, 4-chlorotoluene, trifluorotoluene, o-xylene, m-xylene or p-xylene; or mixtures thereof.

In the twenty ninth embodiment, compound 6 can be converted to pure Canagliflozin by first protecting compound 6 with TES (triethyl silane) and then adding slowly BF3.Etherate. Lot wise or fast addition of BF3.Etherate results in more amount of unwanted anomer. Further, unwanted anomer formation is more when water is present in the reaction system. "Slow addition or Adding slowly" as used herein means the reagent may be added at a rate of for example about 1 ml/minute or about 1 .5 ml/minute or about 2 ml/minute or about 2.5 ml/minute or about 3ml/minute.

Approved product of Canagliflozin which is there on the market is a-anomer. Impurities formation is more when water is present in the reaction system. For example, the reaction must not contain water more than about 0.05%. Also impurities formation is less when BF3.Etherate is added slowly.

The said BF3.etherate reaction can be carried out at a temperature of about -40 to about -10°C. More preferably, at a temperature of about -35 to about -20°C; most preferably at a temperature of about -30 to about -25°C. BF3.Etherate addition can be carried out below about -25°C. Unwanted a-anomer formation may be more when addition takes place at a temperature of greater than about -25°C.

The obtained Canagliflozin can be isolated from a solution of Canagliflozin in a solvent comprising isopropyl acetate, isopropyl alcohol or mixtures thereof optionally to provide crystalline form of Canagliflozin.

The isolation may be effected by conventional crystallization methods such as concentration to a minimum volume, cooling, adding anti-solvent or any other suitable technique. Anti-solvent is a solvent other than isopropyl acetate, isopropyl alcohol or mixtures thereof in which canagliflozin is poorly soluble. The isolated crystalline form of Canagliflozin may contain some amount of occluded mother liquor or higher than desired level of impurities. If desired, the crystalline form may be washed with a solvent or a mixture of solvents to wash out the impurities.

Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.

The resulting crystalline Canagliflozin can be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller, hammer mills and jet mills.

The crystalline form of Canagliflozin obtained in the process of the present application can be characterized by X-ray powder diffraction pattern having peaks expressed in degrees 2Θ at about 3.90, 15.51 , 18.86, 17.37 and 10.97 ± 0.2°θ. The said crystalline form of Canagliflozin can be also characterized by x-ray diffraction pattern substantially as illustrated by Figure 12. The said crystalline Canagliflozin also can be characterized by differential scanning thermogram (DSC) with an onset temperature of at about 90°C as illustrated by Figure 1 1 . In the thirtieth embodiment, the present application provides an amorphous form of Canagliflozin with a mean particle size D[4,3] of about 30 microns to about 200 microns.

In the thirty first embodiment, the present application provides an amorphous form of Canagliflozin with a d(0.1 ) particle size of about 0.1 to about 30 microns, a d(0.5) particle size of about 30 microns to about 200 microns and/or a d(0.9) particle size of about 50 microns to about 400 microns.

In the thirty second embodiment, the step a) of the process comprises providing a solution of Canagliflozin in a solvent. Suitable solvents, which include, but are not limited to: water; alcohols, such as, for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, and the like; ketones, such as, for example, acetone, butanone, pentanone, methyl isobutyl ketone, and the like; esters, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers, such as, for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, and the like; aliphatic or alicyclic hydrocarbons, such as, for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, and the like; halogenated hydrocarbons, such as, for example, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2- dichloroethene, and the like; aromatic hydrocarbons, such as, for example, toluene, xylene, chlorobenzene, tetraline, and the like; nitriles, such as, for example, acetonitrile, propionitrile, and the like; polar aprotic solvents, such as, for example, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; nitromethane; and any mixtures thereof.

In step b), the solution obtained in step a) is mixed with an anti-solvent in a micro mixing reactor. Suitable anti solvents, which include, but are not limited to: water; alcohols, such as, for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, and the like; ketones, such as, for example, acetone, butanone, pentanone, methyl isobutyl ketone, and the like; esters, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers, such as, for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, and the like; aliphatic or alicyclic hydrocarbons, such as, for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, and the like; halogenated hydrocarbons, such as, for example, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2- dichloroethene, and the like; aromatic hydrocarbons, such as, for example, toluene, xylene, chlorobenzene, tetraline, and the like; nitriles, such as, for example, acetonitrile, propionitrile, and the like; polar aprotic solvents, such as, for example, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, and the like; nitromethane; and any mixtures thereof.

In step c), amorphous form of Canagliflozin is isolated.

The isolation may be effected by methods such as, removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, freeze drying, or any other suitable fast evaporation technique. The isolated amorphous form of Canagliflozin may contain some amount of occluded mother liquor or higher than desired level of impurities. If desired, the amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities.

Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.

In thirty third embodiment, canagliflozin used as a starting material in the step a) of the process can be any physical form of Canagliflozin, such as crystalline, amorphous or their mixtures. Heating, mixing and/or kneading Canagliflozin through an extruder to result in a homogenous melt in step a). In step b) the melt obtained in step a) can be forced through one or more orifices, nozzles, or moulds. In the step c) the extrudate can be collected by sudden cooling to room temperature or below room temperature.

Canagliflozin used in the step a) of thirty third embodiment includes, direct use of a reaction mixture containing Canagliflozin obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers. Optionally, Canagliflozin can be dissolved or dispersed in a suitable solvent or mixture of solvent, either alone followed by addition of one or more pharmaceutically acceptable carriers, or in combination with one or more pharmaceutically acceptable carriers. Optionally, auxiliaries such as diluents or disintegrant can be added during dissolution or dispersion.

Any physical form of Canagliflozin, such as crystalline, amorphous or their mixtures can be utilized in step a) of thirty third embodiment.

In the thirty fourth embodiment, the present application provides a process for preparation of solid dispersion comprising amorphous canagliflozin. Polymer used in step a) of the embodiment can be selected from alkylcellulose, hydroxyalkylcelluloses, hydroxyalkylalkyl cellulose, methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyethylmethylcellulose(HEMC), hydroxypropylmethylcellulose succinate, hydroxypropylmethyl cellulose acetate succinate (HPMC AS), carboxymethylethylcellulose, sodium carboxymethylcellulose, pottasium carboxymethyl cellulose, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyacrylic acid copolymer, poly(meth)acrylic acid polymers, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates), polyvinylpyrrolidone (PVP), homopolymers of vinylpyrrolidone, copolymers of vinylpyrrolidone, povidone, vinylpyrrolidone-vinylacetate copolymer (copovidone), copolymers of vinyl acetate, copolymers of vinyl propionate, copolymers of vinyl acetate and crotonic acid, polyethylene glycol, polyvinyl alcohol, partially hydrolyzed polyvinyl acetate, gelatin, sodium alginate, soluble starch, gum acacia, dextrin, hyaluronic acid, sodium chondroitin sulfate, propylene glycol alginate, agar, tragacanth, xanthan gum, aminoalkyl methacrylate copolymers, polyvinyl-acetal- diethylaminoacetate, methacrylate copolymer, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, macrogol, polyethylene oxide, polypropylene oxide, copolymers of ethylene oxide (EO) and propylene oxide (PO), carrageenans, galactomannans, Eudragit and mixtures thereof.

Heating, mixing and/or kneading the resultant blend of step a) through an extruder to result in a homogenous melt in step b). In step c) the melt obtained step b) can be forced through one or more orifices, nozzles, or moulds. In the step d) the extrudate is collected by sudden cooling to room temperature.

In thirty fifth embodiment, in step a), a solution of Canagliflozin is prepared by dissolving Canagliflozin with an organic solvent. The organic solvent can be selected from, for example, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile and the like. The solution is fed into a thin film dryer. The bath temperature, feed rate and speed of the thin film dryer rotor can be adjusted to optimize the output. In one variant the said thin film dryer can be agitated thin film dryer (ATFD).

The bath temperature is preferably maintained between about 46°C to about 55°C. The feed rate can be set between about 6 ml/1 minute to about 8 ml/1 minute. The set feed rate is preferably constant for the whole process. The speed of the rotor can be set between about 1300 to about 1400 revolutions per minute.

The drying process is accompanied by the application of vacuum. The drying process is performed at about 40°C to about 45°C and for sufficient time to effect maximum removal of the solvents and then cooled to room temperature and unloaded. Optionally the resulting amorphous form can be further dried by a process as described herein above. Optionally the resulting amorphous form can be converted into solid dispersion.

In the thirty sixth embodiment, the present application provides an amorphous form of Canagliflozin showing a glass transition in modulated DSC thermogram with an onset temperature of at least about 45 °C.

In the thirty seventh embodiment, the present application provides a pharmaceutical composition comprising an amorphous form of Canagliflozin showing a glass transition in modulated DSC thermogram with an onset temperature of at least about 45°C and one or more pharmaceutically acceptable carriers.

In the thirty eighth embodiment, the present application provides a process for preparing crystalline form of Canagliflozin by isolating from a solution of Canagliflozin in a solvent comprising isopropyl acetate, isopropyl alcohol or mixtures thereof with any other solvent. The isolation may be effected by methods such as, removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, freeze drying, or any other suitable fast evaporation technique. The isolated crystalline form of Canagliflozin may contain some amount of occluded mother liquor or higher than desired level of impurities. If desired, the crystalline form of canagliflozin may be washed with a solvent or a mixture of solvents to wash out the impurities.

Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.

The crystalline canagliflozin can be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller, hammer mills and jet mills.

Canagliflozin used as a starting material in thirty eighth embodiment of the present application can be any physical form of Canagliflozin, such as crystalline, amorphous or their mixtures.

The step a) of the purification of 2-(4-fluorophenyl) thiophene comprises dissolving 2-(4-fluorophenyl) thiophene in an organic solvent. The organic solvent is selected from polar protic or polar aprotic solvents or mixture of both. Suitable solvents which include, but are not limited to acetone, methanol, ethanol, isopropanol, DMSO, DMF, acetonitrile, tetrahydrofuran, ethylacetate and any mixtures thereof. In the step b) of the solution obtained in step a) of the purification of 2-(4- fluorophenyl) thiophene is mixed with an anti-solvent. Suitable anti solvents, which include, but are not limited to: a solvent selected from water, n-hexane, diethylether, 1 ,4-dioxane or mixture of water miscible organic solvents. The said mixing can be either way i.e. adding anti-solvent to the solution obtained step a) or adding the solution obtained in step a) to an anti-solvent.

Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.

2-(4-fluorophenyl) thiophene used as a starting material in the step a) of the purification of 2-(4-fluorophenyl) thiophene can be prepared by any of the methods known in the literature or by the methods described in the present application.

In the present application, the above obtained pure 2-(4-fluorophenyl) thiophene can be converted to canagliflozin.

Canagliflozin obtained in process of the present application may be further formulated as: solid oral dosage forms such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The formulation may be prepared using techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Formulation may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated. Amorphous form of Canagliflozin obtained in process of the present application or a solid dispersion comprising amorphous form of Canagliflozin and one or more pharmaceutically acceptable excipients obtained in the present application may be further formulated as: solid oral dosage forms such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The formulation may be prepared using techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Formulation may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.

PXRD data reported herein are obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer or a PANalytical X-ray Diffractometer, using copper Ka radiation wavelength 1 .5418A.

DSC analysis is conducted using a Modulated Differential Scanning Calorimeter (Model-TA Instruments (Q2000) (New Castle DE 19720, USA) equipped with refrigerated cooling accessory. The temperature and heat flow was calibrated using Indium. All measurements were performed by taking 3 to 7 mg of samples encapsulated into aluminum sample pans with pierced aluminum lid. The measurements were conducted under nitrogen with a purging rate of 50 mL/min.

PSD analysis is carried in Malvern mastersizer-2000 by a wet method.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner. Example 1 : Preparation of compound 3

Compound 2 Compound 3

Compound 2 (20 g, 0.1 12 moles) and morpholine (100 mL) were charged in round bottom flask under nitrogen atmosphere at room temperature. Reaction mass was heated to 90-95°C and stirred for 24 hours. After completion of the reaction, the reaction mass was cooled to room temperature and concentrated under reduced pressure at 50- 55°C. Crude compound was triturated with ethanol (50 mL) and diethyl ether (250 mL) twice to remove traces of morpholine and impurities. Organic layer was decanted and syrup was concentrated under reduced pressure at 50°- 55°C to obtain compound 3 (28g, 94%) as a red color syrup.

Example 2: Preparation of compound 4

Compound 3 Compound 4

Compound 3 (28 g, 0.10 moles) and THF (140 mL) were charged in round bottom flask at 25 - 30°C and stirred for 10 minutes to get brown color clear solution. Reaction mass was cooled to 5-10°C and triethylamine (109 mL, 0.8 moles) was added to the reaction mass. Trimethyl chlorosilane (64 mL, 0.633 moles) was added to the reaction mixture at 5-10°C over a period of 10-15 min. Temperature was raised to room temperature and stirred for 22h. After completion of the reaction, the reaction mass was diluted with ice cold water (1 12 mL) and stirred for 30 min. Layer were separated and organic layer was kept aside for further use. Aqueous layer was extracted with DCM (100 mL) and layers were separated. Organic layers were combined and washed with water (224 mL X 2) and brine solution (140 mL X 2). Organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to get compound 4 (35g, 53%) as wine red color syrup. Example 3: Preparation of compound 6

Compound Λ Compound

Compound 5 (1 g, 0.0027 moles), THF (16.6 mL) and Toluene (16.6 mL) were charged in round bottom flask under nitrogen atmosphere at room temperature. Reaction mass was cooled to -75 to -78°C. n-BuLi (2.6 mL, 0.004 moles) was added to the reaction mixture at -75 to -78°C over a period of 5-10 min. The resulting reaction mixture was stirred at -75 to -78 °C for 30 min. Compound 4 (1 .57g, 0.0025 moles) was diluted with Toluene (8.3 mL) and added to the reaction mass at -75 to -78°C over a period of 10-15 min. Reaction mass was further stirred for 1 hour at -75 to -78°C. Methanesulphonic acid (0.76 mL, 0.01 moles) , methanol (16.6 mL) were mixed and this solution was added to the reaction mass at -75 to -78°C over a period of 15-20 min. Temperature of the reaction mass was raised to room temperature and stirred for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 5- 10°C and aqueous NaHC0 ₃ solution was added to the reaction mass. Reaction mass was extracted with EtOAc (30 mL X 2). Organic layers were combined and washed with brine solution (50 mL X 2). The organic layer was dried over anhydrous sodium sulfate and filtered. Organic layer was dried under reduced pressure at 45 - 50°C to give crude compound 6 as a brown color residue. Crude compound was triturated twice with toluene (3 mL) and n-Hexane (10 mL), organic layer was decanted. Product was dried under reduced pressure to give compound 6 (500 mg, 38.4%) as a pale brown solid.

Example 4: Preparation of compound 1a.

Compound 6 Compound 1a

Compound 6 (400 mg, 0.86 Mmoles) and DCM (4 mL) were charged in round bottom flask under nitrogen atmosphere at 25 - 30°C and stirred for 10 minutes to get brown color clear solution. Reaction mass was cooled to -40 to -45°C and triethylsilane (0.4 mL, 2.58 Mmoles) was added slowly to the reaction mass. BF ₃ etherate (0.76 mL, 2.58 moles) was added to the reaction mixture at -40 to -45°C over a period of 5-10 min and stirred for 30 min at same temperature. Temperature of the reaction mass was raised to 0 to 5°C and stirred for 2 hours. After completion of the reaction, the reaction was quenched with Aq.NaHCO ₃ solution (4.6 mL) and stirred for 30 min at 0 to 5°C. Reaction mass was concentrated under vacuum and the residue was diluted with water (1 1 mL). Reaction mass was extracted with EtOAc (30 mL X2). Organic extracts were combined, washed with water (3.2 mL). Organic layer was dried over Na2SO ₄ and concentrated under reduced pressure to get compound 1 (282 mg, 75.2%) as an off-white colored solid.

Example 5: Preparation of compound 8

Compound 4 Compound 8

Compound 7 (1 g, 0.003 moles), THF (16.6 mL) and Toluene (16.6 mL) were charged in round bottom flask at room temperature under inert atmosphere. Reaction mass was cooled to -75 to -78 °C. n-BuLi (3.7 mL, 0.009 moles) was added to the reaction mixture at -75 to -78 °C over a period of 5 min and stirred for 30 min at same temperature. Compound 4 (1 .64g, 0.0026 moles) was diluted with Toluene (8.3 mL) and added to the reaction mass at-75 to -78°C over a period of 5-10 min. Reaction mass was stirred for 1 hour at -75 to -78°C. Methanesulphonic acid (0.8 mL, 0.012 moles), methanol (16.6 imL) were mixed and this solution was added to the reaction mass at -75 to -78°C over a period of 5-10 min. Temperature was raised to room temperature and stirred for 15-16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mass was cooled to 5 - 10 ⁰ C. pH of the reaction mass was around 2. The reaction mass was basified using aqueous NaHC0 ₃ solution till the pH of 8. Reaction mass was extracted with EtOAc (10 mL X 2). Organic layers were combined and washed with brine solution (10 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 45 - 50°C to give crude compound 8 as a pale yellow color residue. Crude compound was purified by column chromatography by using 60-120 mesh silica gel. Column was eluted with 10% MeOH: DCM. All pure fractions were collected and concentrated under reduced pressure. Compound 8 (280 mg, 21 %) as a off-white solid.

Example 6: Preparation of compound 1 b.

Compound 8 Compound 1 b

Compound 8 (150 mg, 0.342 Mmoles) and DCM (5 mL) were charged in round bottom flask under inert atmosphere at room temperature. Reaction mass was cooled to -40 to -45°C and triethylsilane (0.16 mL, 1 .026 Mmoles) was added slowly in to the reaction mass and stirred for 5 min. BF ₃ etherate (0.3 mL, 1 .026 Mmoles) was added in to the reaction mixture at -40 to -45°C over a period of 2-3 min. Temperature of the reaction mass was raised to 0-5°C and stirred for 2 hours. Aqueous NaHCO ₃ solution (2 mL) was added to the reaction mass at 0-5°C and stirred for 10-15 min. Reaction mass was concentrated under reduced pressure. Reaction mass was extracted with EtOAc (10 mL), layers were separated and organic layer was kept aside for further use. Aqueous layer was again extracted with EtOAc (10 mL) and layers were separated. Organic extracts were combined and washed with brine solution (10 mL). Organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Compound 1 b was isolated (100 mg, 71 .5%) as an off-white solid.

Example 7: Preparation of compound 11

Compound 9 (30g, 0.139moles) and DCM (405 mL) were charged in round bottom flask at room temperature under inert atmosphere and stirred for 10 minutes. DMF (0.5 mL, 0.0064 moles) and Oxalylchloride (13.17 mL) were charged to the reaction mass at room temperature and stirred for 6 hour Progress of the reaction was monitored by TLC. Reaction mixture was concentrated under reduced pressure at 50°C under inert atmosphere. Black colour syrup acid chloride derivative of compound 9 was obtained. Compound 10 (24.8g, 0.023 moles) and DCM (810 mL) were charged at room temperature. Reaction mass was cooled to 0-5°C and AICI ₃ (20.3g, 0.025 moles) was added in to the reaction mixture and stirred for 30 minutes. Temperature of the reaction mass was raised to room temperature and for 16 hours. Reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 0 - 5°C, ice cold water (810 mL) was added with stirring in to the reaction mixture over the period of 10- 20 min. Layers were separated and organic layer was kept aside to use it further. Aqueous layer was extracted with DCM (150 mL X 2) and layers were separated. Organic layers were combined and dried over anhydrous K ₂ CO ₃ and filtered. Organic layer was concentrated under reduced pressure at 45 - 50°C to give crude compound 1 1 (52g, HPLC purity -92%) as yellow color solid. Crude compound was triturated with hexane (90 mL) for 30 min at RT. Reaction mixture was filtered and wet cake was washed with hexane (60 mL). Wet cake was dried under vacuum at room temperature for 2 hours to give compound 1 1 (45g, 86%, HPLC purity 98.1 %) as pale yellow solid.

Example 8: Preparation of compound 5

Compound 11 Compound 5

Compound 1 1 (2g, 0.0053 moles), trifluoro acetic acid (20 mL) and 1 ,1 ,3,3,- tetramethyldisiloxane (2.82 mL, 0.0159 moles) were charged in round bottom flask at room temperature. Reaction mixture was heated at 75-80°C and stirred for 24h. Progress of the reaction was checked by TLC. After completion of the reaction, the reaction mass was cooled to room temperature. Aqueous NaHCO ₃ solution (10%, 30 mL) was charged in to the reaction mixture. DCM (25 mL x 2) was charged in to the reaction mixture at room temperature and stirred for 10-20 min. Layers were separated. Organic layers were combined and washed with brine solution (20 mL). Organic layer was dried over anhydrous Na ₂ SO ₄ and filtered. Organic layer was concentrated under reduced pressure at 45° - 50°C to give crude compound 12 (3g) as off-white color semi solid. Crude compound was triturated with hexane (15 mL) for 30 min at room temperature. Reaction mixture was filtered and wet cake was washed with hexane (5 mL). Wet cake was dried under vacuum at room temperature for 2 hours to give compound 12 (1 .6g, 83%) as off-white solid.

Example 9: Preparation of compound 12

Compound 11 Compound 12

Compound 1 1 (500 mg) and methanol (5 mL) were charged in round bottom flask under an inert atmosphere at 25-35 ^° C. Trimethyl orthoformate (2.5 mL) and toluene (6 mL) were charged in reaction mixture and stirred. P-Toluene sulfonic acid (1 12 mg) was charged in reaction mixture at 25-35°C. Reaction mixture was heated to 65-70°C and stirred for 40 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was cooled to room temperature and ethyl acetate (15 mL) was added. Aqueous sodium bicarbonate was added to the reaction mass at room temperature, layers were separated and organic layer was kept aside for further use. Aqueous layer was extracted with ethyl acetate (10 mL) and layers were separated. Combined organic layers were washed with brine solution (10 mL), dried over sodium sulphate, distilled under reduced pressure to obtain crude compound 12. Crude compound 12 was further purified using column chromatography.

Example 10: Preparation of compound 14

ompoun

Compound 12 (400 mg), THF (6.6 mL) and Toluene (16.6 mL) were charged in round bottom flask under nitrogen atmosphere at room temperature. Reaction mass was cooled to -75 to -78°C. n-BuLi (0.9 mL) was added to the reaction mixture at -75 to - 78°C over a period of 2-5 min. The resulting reaction mixture was stirred at -75 to -78°C for 30 min. Compound 13 (402 mg) was diluted with Toluene (3.3 mL) and added to the reaction mass at -75 to -78°C over a period of 5 min. Reaction mass was further stirred for 1 hour at -75 to -78°C. Methanesulphonic acid (0.26 mL) , methanol (6.6 mL) were mixed and this solution was added to the reaction mass at -75 to -78°C over a period of 5-10 min. Temperature of the reaction mass was raised to room temperature and stirred for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 0°C and aqueous NaHCO ₃ solution was added to the reaction mass. Reaction mass was extracted with EtOAc (5 mL X 2). Organic layers were combined and washed with brine solution (5 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. Organic layer was dried under reduced pressure at 45 - 50°C to give crude compound 14. Crude compound was triturated twice with mixture of toluene (2 mL) and n-Hexane (10 mL), organic layer was decanted. Product was dried under reduced pressure to give compound 13 (100 mg, 38.4%).

Example 11 : Preparation of compound 15 Compound 15

Compound 14 (50 mg) and THF (3 mL) were charged in round bottom flask under an inert atmosphere at 25-35°C. The reaction mixture was cooled to 0-5°C and sodium borohydrate (5.8 mg) was added portion wise. Temperature of the reaction mixture was raised to room temperature and stirred for 4 hour. Reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to 5-10°C and quenched with ice cold water (3 mL). The reaction mass was concentrated under reduced pressure below 45°C. The reaction mass was diluted with water (10 mL) and extracted with DCM (2 x 5 mL). Combined organic layers were washed with brine solution (5 mL), dried over Na2S04 (2 gm) and distilled under reduced pressure to obtain compound 15 (28 mg).

Example 12: Preparation of compound 1a

Compound 15 Compound 1a

Compound 15 (20 mg) and DCM (3 mL) were charged in round bottom flask under nitrogen atmosphere at 25 - 30°C and stirred for 10 minutes. Reaction mass was cooled to -35 to -45°C and triethylsilane (0.2 mL) was added slowly to the reaction mass and reaction mixture was stirred for 5-10 min. BF ₃ etherate (0.036 mL) was added to the reaction mixture at -35 to -45°C over a period of 2 min and stirred for 30 min at same temperature. Temperature of the reaction mass was raised to 25 to 35°C and stirred for 2-3 hours. After completion of the reaction, the reaction was quenched with Aq.NaHC0 ₃ solution (10%, 0.72 mL mL) and stirred for 30 min at 0 to 5°C. Reaction mass was concentrated under vacuum and the residue was diluted with water (10 mL). Reaction mass was extracted with DCM (10 mL X2). Organic extracts were combined, washed with brine (5 mL). Organic layer was dried over Na ₂ SO ₄ and concentrated reduced pressure to get compound 1 a (16 mg).

Example 13: Preparation of compound 16

Compound 14 Compound 1

Compound 14 (80 mg) and DCM (0.8 mL) were charged in round bottom flask under inert atmosphere at room temperature. Reaction mass was cooled to -35 to -45°C and triethylsilane (57 mg) was added slowly in to the reaction mass and stirred for 5-10 min. BF ₃ etherate (0.14 mL) was added dropwise in to the reaction mixture at -35 to -45°C over a period of 2-3 min. Temperature of the reaction mass was raised to 0-5°C and stirred for 2 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, aqueous NaHCO ₃ solution (5 mL) was added to the reaction mass at 0-5°C and stirred for 30 min. Reaction mass was concentrated under reduced pressure. Reaction mass was diluted with water (10 mL) and extracted with EtOAc (2 x 15 mL). Organic extracts were combined and washed with brine solution (15 mL). Organic layer was dried over Na2SO ₄ and concentrated under reduced pressure to obtain compound 16 (40 mg).

Example 14: Preparation of compound 17

Compound 16 Compound 17

Compound 16 (40 mg) and THF (1 mL) were charged in round bottom flask under an inert atmosphere at 25-35°C. The reaction mixture was cooled to 0-5°C and sodium borohydrate (5 mg) was added portion wise. Temperature of the reaction mixture was raised to room temperature and stirred for 3-4 hour. Reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to 5-10°C and quenched with ice cold water (5 mL). The reaction mass was concentrated under reduced pressure below 45°C. The reaction mass was diluted with water (5 mL) and extracted with ethyl acetate (10+5 mL). Combined organic layers were washed with brine solution (15 mL), dried over Na ₂ SO ₄ (1 gm) and distilled under reduced pressure to obtain compound 17 (40 mg).

Example 15: Preparation of compound 1a

Compound 17 Compound 1a

Compound 17 (20 mg) and DCM (0.2 mL) were charged in round bottom flask under nitrogen atmosphere at 25 - 30°C and stirred for 10 minutes. Reaction mass was cooled to -35 to -45°C and triethylsilane (15.14 mL) was added slowly to the reaction mass and reaction mixture was stirred for 5-10 min. BF ₃ etherate (0.039 mL) was added to the reaction mixture at -35 to -45°C over a period of 2 min and stirred for 30 min at same temperature. Temperature of the reaction mass was raised to 0 to 5°C and stirred for 2 hours. After completion of the reaction, the reaction was quenched with saturated Aq.NaHCO3 solution (5 mL) and stirred for 30 min at 0 to 5°C. Reaction mass was concentrated under vacuum and the residue was diluted with water (10 mL). Reaction mass was extracted with ethyl acetate (10 mL X2). Organic extracts were combined, washed with brine (10 mL). Organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to get crude compound 1 a. Crude compound was triturated with n-Hexane (3 x 3 mL), organic layer was decanted. Product was dried under reduced pressure to give compound 1 a (10 mg).

Example 16: Preparation of compound 1a.

Compound 6 Compound 1a

Compound 6 (5 g, 0.0105 moles) and DCM (50 mL) were charged in round bottom flask under inert atmosphere at room temperature. Reaction mass was cooled to -40 to - 45°C. 1 ,1 ,3,3 -tetramethyl disiloxane (5.6 mL, 0.0316 moles) was charged in to the reaction mass at -40 °C to -45°C and stirred. BF ₃ . Et ₂ 0 (9.5 mL, 0.0316 moles) was added to the reaction mixture at -40 to -45°C over a period of 10-15 min and stirred for 30 min at -40 to -45°C. Temperature of the reaction mixture was raise to 0°C to 5°C and stirred for 2 hours. Aq. NaHC0 ₃ solution (58 mL) was charged into in to the reaction mass and stirred for 30 min at RT. Reaction mass was concentrated under vacuum at 40 °C-45°C. Residue was diluted with water (1 18.5 mL). Ethyl acetate (79 mL) was added in to the reaction mass at room temperature and stirred for 10-15 min. Layers were separated. Organic layer was washed with water (40 mL) and dried over Na2SO ₄ . Organic layer was under reduced pressure to give crude compound 1 a as an off-white color solid. Crude compound 1 a (5.5g) was triturate with ethyl acetate (15 mL) and n- hexane (50 mL) for 10-15 min. Organic layer was decanted and product was dried under reduced pressure to give compound 1 a as an off-white solid.

Example 17: Preparation of compound 19a.

Compound 14 Compound 19a

To a solution of compound 14 (2.50 g, 5.40 mmol ) in THF ( 10 mL) and ACN (20 mL) under argon atmosphere was added camphor-10-sulfonic acid (0.063 g, 0.27 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 4-6 h. After the completion of the reaction as confirmed by TLC, the reaction mixture was quenched with saturated solution of sodium bicarbonate. EtOAc (50 mL) was added to the mixture and layers were separated. The organic layer was dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The obtained crude material was purified by column chromatography using silica gel (60-120 mesh) eluted with 70% EtOAc-hexane to the title compound 19a (1 .2 g, yield 51 .7%, HPLC purity of 97.3%) as a yellow color solid.

Example 18: Preparation of compound 18a'.

Compound 13

Compound 5a (10 g, 27 mmol) and THF (16.6 mL) were charged in round bottom flask under nitrogen atmosphere at room temperature. Reaction mass was cooled to -78°C. n-BuLi (2.66 g, 41 .5 mmol) was added to the reaction mixture slowly at -78°C. The resulting reaction mixture was stirred at -78 °C for 5 min. Compound 13 (12.92g, 27.7 mmol) was diluted with THF (50 mL) and added slowly to the reaction mass at to -78°C. Reaction mass was further stirred for around 3 hours at -78°C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with 10% ammonium chloride solution (200 mL). Layers were separated and organic layer was kept aside for further use. Aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulphate and concentrated under vacuum. The crude compound was dissolved in ethyl acetate (100 mL), 2% HCI solution (200 mL) was added and stirred overnight at 29°C. The layers were separated and organic layer was kept aside for further use. Aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were combined, washed with brine, dried over sodium sulphate, filtered, and concentrated under vacuum. The obtained crude material was purified by column chromatography using silica gel (60-120 mesh) eluted with 70% EtOAc-hexane to obtain compound 18a' (6.5 g, yield 51 .0%, HPLC purity of 90.03%). Example 19: Preparation of compound 18a'.

Compound 13

Compound 5b (20 g, 49 mmol), Compound 13 (25.2 g, 53.9 mmol), THF (200 mL) and Toluene (60 mL) were charged in round bottom flask under nitrogen atmosphere at room temperature and stirred. Reaction mass was cooled to -75 to -80°C. n-hexyl lithium (5.63 g, 61 .2 mmol) was added to the reaction mixture slowly at -75 to -80°C. Reaction mass was further stirred for around 2 hours at -75°C and trifluroacetic acid (22.34 gm, 196 mmol) was added slowly and stirred. The temperature was raised to 0- 5°C and stirred. After completion of the reaction, the reaction was quenched with 5% sodium bicarbonate (200 mL) and stirred at 25-30°C. Layers were separated. The organic layer was concentrated up to 3 volumes and solid separation was observed. The solid was filtered and washed with toluene (40 mL). The wet compound and methanol (100 mL) were charged in round bottom flask and stirred for 15 minutes at room temperature. The compound was filtered and dried under vacuum at 40°C for 1 hour to obtain compound 18a' (7 gm). PXRD Pattern is shown as Figure 1.

Example 20: Preparation of compound 18a'

Compound 5b (20 g, 49 mmol), Compound 13 (25.2 g, 53.9 mmol), THF (200 mL) and Toluene (60 mL) were charged in round bottom flask under nitrogen atmosphere at room temperature and stirred. Reaction mass was cooled to -65 to -75°C. n-butyl lithium (3.92 g, 61 .2 mmol) was added to the reaction mixture slowly at -65 to -75°C. Reaction mass was further stirred for around 1 .5 hours at -75°C. After completion of the reaction, the reaction was quenched with methanol (10 mL) and stirred at 25-30°C. The reaction mixture was concentrated under vacuum at 50°C to obtain crude compound (40 gm). The crude compound (18 gm, 24.03 mmol) was dissolved in dichloromethane (100 mL) and trifluroacetic acid (2.74) in water (5 mL) was added slowly and stirred for 1 hour. The precipitated solid was filtered and washed with dichloromethane (50 mL). The compound was dried under vacuum at 25-30°C to obtain compound 18a' (8 gm). PXRD Pattern is shown as Figure 2.

Example 21 : Preparation of compound 1a.

Compound 1a

Compound 18a' (2 g, 4.34 mmol) and DCM (20 mL) were charged in round bottom flask under inert atmosphere at room temperature and stirred. Triethylsilane (1 .515 gm, 13.03 mmol) was charged in to the reaction mixture. Reaction mixture was cooled to -30 to - 40°C and stirred. BF ₃ . Et ₂ 0 (2.56ml, 48% solution) was added to the reaction mixture at -30 to -40°C over a period of 10-15 min and stirred for 30 min. Temperature of the reaction mixture was raised to 0°C to 5°C and stirred for 30-45 minutes. Temperature is further raised to room temperature and stirred overnight. Aq. 5% NaHC0 ₃ solution (50 mL) was charged into in to the reaction mass and stirred for 15-30 min at RT. The layers were separated. The organic layer was washed with water (50 mL) and dried under vacuum to obtain compound 1 a (1 .5 gm).

Example 22: Preparation of compound 1a.

Compound 1a Compound 18a' (1 g, 2.171 mmol) and methanol (10 mL) were charged in round bottom flask under inert atmosphere at room temperature and stirred. The contents were cooled to 0 to -5°C, methane sulphonic acid (0.1746 gm, 1 .520 mmol) was added slowly and stirred for 30 minutes. . Temperature of the reaction mixture was raised to 25-30°C and stirred for 1 hour. Aq. 5% NaHC0 ₃ solution (1 mL) and ethyl acetate (50 mL) were charged into in to the reaction mass and stirred for 15-30 min at RT. The layers were separated. The organic layer was dried under vacuum to obtain crude compound (0.5 gm).

Charge crude compound (0.5 g, 4.34 mmol) and DCM (20 mL) were charged in round bottom flask under inert atmosphere at room temperature and stirred. Reaction mixture was cooled to -30 to -40°C, triethylsilane (0.368 gm, 3.16 mmol) was charged in to the reaction mixture and stirred for 15 minutes. BF ₃ . Et20 (0.449 gm, 3.16 mmol) was added to the reaction mixture at -30 to -40°C over a period of 10-15 min and stirred for 60 minutes. Temperature of the reaction mixture was raised to room temperature and stirred for 45-60 minutes. Triethylamine (3 mL) and water (20 mL) were charged to the reaction mixture, and stirred. The layers were separated and organic layer was dried under vacuum at 40°C to obtain compound 1 a (1 gm).

Example 23: Preparation of compound 19a.

Compound 18a'

Compound 19a

Compound18a' (0.2 g, 0.4 mmol) was dissolved in THF (2 mL) and ACN (2 mL) under argon atmosphere and reaction mixture was cooled at 0°C. Trifluoromethanesulfonic acid (2.5 μί) in THF (2 mL) was added dropwise in to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred till completion of the reaction. The reaction mixture was quenched with saturated solution of sodium bicarbonate to pH 6-7. EtOAc (20 mL) was added to the mixture and layers were separated. The organic layer was washed with water (20 mL), brine (20 mL), dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The obtained crude material was purified by flash column chromatography using ethyl acetate-methanol mixture to obtain the title compound 19a as a light yellow color solid.

Example 24: Preparation of compound 19a.

Compound 13

Compound 5b (0.87 g, 0.002 mol), compound 13 (1 .0 g, 0.002 mol), THF (10 mL) and Toluene (10 mL) were charged in round bottom flask under argon atmosphere at room temperature. Reaction mass was cooled to -78°C. n-BuLi (1 .87 mL, 0.003 mol) was added to the reaction mixture slowly at -78°C. The resulting reaction mixture was stirred at -78 °C for 2 hours. After completion of the reaction, the reaction was quenched with methanol (0.5 mL). The reaction mixture was allowed to reach room temperature and saturated aqueous ammonium chloride was added. Layers were separated and organic layer was washed with brine (50 mL). The organic layers was dried over sodium sulphate and concentrated under vacuum. The crude oily product (compound 18b) was dried over high vacuum and used in next step without further purification.

To a solution of compound 18b (0.15 g) in ACN (4 mL) under argon atmosphere was added camphor-10-sulfonic acid (0.007 g) at 0°C and stirred for 30 minutes. The reaction mixture was warmed to room temperature and stirred for 4-6 h. After the completion of the reaction as confirmed by TLC, the reaction mixture was quenched with saturated solution of sodium bicarbonate till pH 7-8. EtOAc (20 mL) was added to the mixture and layers were separated. The organic layer was dried over Na2S0 ₄ and concentrated under reduced pressure. The obtained crude compound 19a was used further without purification.

Example 25: Preparation of compound 19a.

Compound 13

Compound 5b (0.87 g, 0.002 moles), compound 13 (1 .0 g, 0.002 moles), THF (10 mL) and Toluene (10 mL) were charged in round bottom flask under argon atmosphere at room temperature. Reaction mass was cooled to -78°C. n-BuLi (1 .87 mL, 0.003 moles) was added to the reaction mixture slowly at -78°C. The resulting reaction mixture was stirred at -78 °C for 2 hours. After completion of the reaction, the reaction was quenched with methanol (0.5 mL). The reaction mixture was allowed to reach room temperature and saturated aqueous ammonium chloride was added. Layers were separated and organic layer was washed with brine (50 mL). The organic layers was dried over sodium sulphate and concentrated under vacuum. The crude oily product (compound 18b) was dried over high vacuum and used in next step without further purification.

Compound 18b (0.2 g), ACN (2 mL) and MgS0 ₄ (0.2 g) were charged in round bottom flask under argon atmosphere and stirred. Trifluoromethanesulfonic acid (2 μί) in ACN (2 mL) was added slowly at 0°C and stirred for 30 minutes. The reaction mixture was warmed to room temperature and stirred for 2 h. After the completion of the reaction, the reaction mixture was quenched with saturated solution of sodium bicarbonate till pH 7-8. Layers were separated and organic layer was washed with brine (10 mL). The organic layer was dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The obtained crude compound 19a was used further without purification.

Example 26: Preparation of Canagliflozin (Compound 1a)

Compound 9a Compound 1a A solution (1 R^S^S^RJ-S-ia-iiS-i^fluoropheny thiophen^-ylJmethyl)-^ methylpheny -G^-dioxabicyclotS^.l loctane^^^-triol (0.07 g, 0.15 mmol ) in DCM (2 ml_) was cooled to -60 °C by acetone-dryice bath under argon atmosphere. To that triethylsilane (76 μΙ_, 0.47 mmol), followed by borontrifluoride diethylether complex (59 μΙ_, 0.47 mmol) were added. The reaction mixture was slowly warmed to -20 °C and stirred for 2 h. After the completion of the reaction as confirmed by TLC, the reaction mixture was quenched with saturated solution of sodium bicarbonate. The crude compound was extracted with EtOAc (50 ml_). The organic layer was separated, dried over Na ₂ S0 ₄ and concentrated under reduced pressure to obtain the desired product as light yellow solid.

Example 27: Preparation of Canagliflozin

In a round bottom flask under nitrogen atmosphere methanol (1000 ml) was charged and (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl) -4-methylphenyl)-6- (hydroxyl methyl) tetrahydro-2H-pyran-2,3,4,5-tetraol (100 gm, 0.217 moles) was added and reaction mass was cooled to 0-10°C. At this temperature methane sulfonic acid (10.42/7.0 gm/ml, 0.108 mol) was added slowly and maintained for 30 minutes. The temperature of the reaction mass increased to 25-35°C and maintained for 3-4 hours. Adjust the pH to 7.0 to 8.0 by adding triethylamine (25 ml) under stirring at 25-35°C. Distil the solvent under vacuum at below 50°C and cool to 25-35°C. Now add dichloromethane (1000 ml), stir for 30-45 minutes and charged DM water (1000 ml) and stir for 30-45 minutes. The layers were separated and the organic layer was taken into a round bottom flask and DM water (500 ml) added at 25-35°C 30-45 minutes. Again the organic layer was separated and taken in a round bottom flask and sodiumchloride solution (50 gm in 500 ml water) added and stirred at 25-35°C 30-45 minutes and layers separated. The organic layer was washed with dichloromethane twice (500 ml each) and the solvent was distilled. To this dichloromethane (1000 ml) was added the cooled to -25 to -50°C. To this triethyl silane added at -25 to -50°C and BF ₃ .Etherate solution was added continuously and stirred for 3-4 hours at -25 to -30°C. Now raise the temperature to 0 to -5°C and maintain for 45±15 minutes. pH of the reaction mass was adjusted to 7.0 to 8.0 with triethylamine (400 ml) and temperature raised to 25-35°C and maintained for 30 minutes. The layers were separated and organic layer was washed with water (1000 ml) and methanol (200 ml). Again the organic layer was separated and sodiumchloride solution (50 gm in 500 ml) was added at 25-35°C. To this methanol (600 ml) was added and stirred for 30-45 minutes. The organic layer was separated and concentrated under reduced pressure at 45-50°C. The reaction mass was cooled to 25-30°C and toluene (800 ml) was added and distilled at 50°C under vacuum. Stir the reaction mass for 30-60 minutes at 45-50°C. Take n-heptane (600 ml) in another round bottom flask and add above toluene solution at 25-35°C and stir for 15- 30 minutes. The solid was filtered under vacuum at 25-35°C and washed with n- heptane (200ml) under N ₂ atmosphere. The solid was separated and dried to give the titled compound.

Example 28: Preparation of amorphous Canagliflozin (micro mixer)

Canagliflozin (6 gm) is dissolved in toluene (68 ml) at 45 °C. The completely dissolved solution is mixed with n-heptane (chilled to 5°C, 680 ml) with toluene to n-heptane ratio of 1 :10 by volume using valve assisted mixer. The precipitated solution is filtered and then dried to give titled compound. It has shown a glass transition in modulated DSC thermogram with an onset temperature of 65.6 °C and an end point of 68.9 °C.

Example 29: Preparation of amorphous Canagliflozin (HME)

Hot melt extruder with 4 chambers of which temperature can be independently fixed is used for extrusion. Temperature of chambers B1 (inlet), B2, B3 and B4 (outlets) are fixed at 30°C, 50°C, 100 °C and 105 °C. Canagliflozin hemihydrate is charged at B1 and material started to collect from B4. Sample is grinded with mortar pestle or analytical testing.

Example 30: Preparation of amorphous Canagliflozin (HME)

Hot melt extruder with 4 chambers of which temperature can be independently fixed is used for extrusion. Temperature of chambers B1 (inlet), B2, B3 and B4 (outlets) are fixed at 30°C, 50°C, 105°C and 1 10°C. Canagliflozin hemihydrate is charged at B1 and material started to collect from B4. Sample is ground with mortar pestle or analytical testing. It has shown a glass transition in modulated DSC thermogram with an onset temperature of 54.6 °C and an end point of 61.5 °C.

Example 31 : Solid dispersion with copovidone (1 :0.5 weight ratio)

Hot melt extruder with 4 chambers of which temperature can be independently fixed is used for extrusion. Temperature of chambers B1 (inlet), B2, B3 and B4 (outlets) are fixed at 30°C, 50°C, 105°C and 1 10°C. Canagliflozin hemihydrate was blended with copovidone in 1 :0.5 ratio and charged at B1 and material started to collect from B4. Sample is grinded with mortar pestle or analytical testing. It has shown a glass transition in modulated DSC thermogram with an onset temperature of 64.6 °C and an end point of 76.6 °C.

Example 32: Solid dispersion with PVP K-30 (1 :0.5 weight ratio)

Hot melt extruder with 4 chambers of which temperature can be independently fixed is used for extrusion. Temperature of chambers B1 (inlet), B2, B3 and B4 (outlets) are fixed at 30°C, 50°C, 105°C and 1 10°C. Canagliflozin hemihydrate was blended with PVP K-30 in 1 :0.5 ratio and charged at B1 and material started to collect from B4. Sample is grinded with mortar pestle or analytical testing. It has shown a glass transition in modulated DSC thermogram with an onset temperature of 51 .8 °C and an end point of 59.8 °C.

Example 33: Solid dispersion with H PMC- AS (1 :0.5 weight ratio)

Hot melt extruder with 4 chambers of which temperature can be independently fixed is used for extrusion. Temperature of chambers B1 (inlet), B2, B3 and B4 (outlets) are fixed at 30°C, 50°C, 105°C and 1 10°C. Canagliflozin hemihydrate was blended with HPMC AS in 1 :0.5 ratio and charged at B1 and material started to collect from B4. Sample is grinded with mortar pestle or analytical testing. It has shown a glass transition in modulated DSC thermogram with an onset temperature of 58.4 °C and an end point of 68.1 °C.

Example 34: Solid dispersion with Eudragit (1 :0.5 weight ratio) Hot melt extruder with 4 chambers of which temperature can be independently fixed is used for extrusion. Temperature of chambers B1 (inlet), B2, B3 and B4 (outlets) are fixed at 30°C, 50°C, 105°C and 1 10°C. Canagliflozin hemihydrate was blended with Eudragit in 1 :0.5 ratio and charged at B1 and material started to collect from B4. Sample is grinded with mortar pestle or analytical testing. It has shown a glass transition in modulated DSC thermogram with an onset temperature of 53.7 °C and an end point of 61 .0 °C.

Example 35: Preparation of amorphous form of Canagliflozin

Canagliflozin (2 Kg) was dissolved in Methanol (1 1 .1 L) at 30°C under stirring. Charcoal (0.1 Kg) was added to the solution and stirred for 45 minutes. Reaction mass was filtered and washed with methanol (4 L). The filtrate was heated to 42°C and subjected to Agitated Thin Film Dryer (ATFD). The solid material was dried under vacuum at 43°C for 13 hours to provide amorphous form of Canagliflozin.

ATFD settings: bath temperature: 48-53°C; Feeding rate: 4.2L/hour; Vacuum: 745 mm Hg and RPM: 1400. After completion of feeding, the mass was kept under vacuum (740-750 mm Hg) at 48-52°C for 15-30 minutes and then cooled to room temperature and unloaded.

The resulting amorphous form of Canagliflozin is micronized using Jet Mill at a mill pressure of about 3.5 kg/cm ² and a feed pressure of about 3.0 kg/cm ² for three times.

The amorphous form before and after micronization is analysed and the results are tabulated below.

micronization

Amorphous form 17.3 1 .6 12.0 40.6 56.2 67.1 Fig.4 after 1 ^st

micronization

Amorphous form 15.4 1 .4 10.2 36.7 59.0 69.7 Fig.5 after 2 ^nd

micronization

Amorphous form 14.9 1 .5 1 1 .2 32.9 61 .8 70.1 Fig.6 after 3 ^rd

micronization

Example 36: Preparation of crystalline form of Canagliflozin

In a round bottom flask (3R _! 4S _! 5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2- yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrah ydro-2H-pyran-3,4,5-triol (50 gm, 0.105 moles) and dichloromethane (500 ml) were added and stirred. The reaction mass was cooled to -30 to -50°C. At this temperature triethyl silane added and BF ₃ .Etherate (44.9 gm, 0.316 moles) was added continuously and stirred for 2 to 3 hours. Now raise the temperature to 0 to -5°C and maintain for 55±15 minutes. pH of the reaction mass was adjusted to 7.0 to 8.0 with triethylamine (100 ml) and temperature raised to 25-35°C and maintained for 2 to 3 hours. The layers were separated and organic layer was washed with water (250 ml) and methanol (100 ml). Again the organic layer was separated washed with water (250 ml) and methanol (100 ml). The organic layer was separated and layers were combined (500 ml). The combined organic layer was divided into 5 parts.

2 parts (200 ml) of the organic layer taken and distillation started and isopropylacetate (20 ml) added and distilled. To this, isopropylacetate (20 ml) added and distilled. To this distillate isopropylacetate (100 ml) and SC-40 charcoal (1 gm) added and stirred for 30 minutes at 48°C. The solution was filtered on hyfolw and washed with isopropyleacetate (40 ml) and the total solution (140 ml) divided into 2 parts. Purification 1 : In a round bottom flask one part of the solution (70 ml) was charged and crystalline form of Canagliflozin hemihydrate seed (5 mg) was added and stirred overnight at room temperature. The reaction mixture was cooled to 5°C and stirred for 1 hour. The solid was filtered and washed with isopropyleacetate (10 ml). The solid was charged into a round bottom flask and isopropyleacetate (30 ml) was added and stirred for 30 minutes at 65°C. The solution was cooled to 30°C and stirred for 30 minutes. The contents of the reaction was cooled to 5°C and stirred for 30 minutes. The solid was filtered and washed with isopropyleacetate (10 ml). The solid was dried under vacuum at 50°C to yield 7.75 gm of title compound. HPLC purity: 99.93%

Purification 2: In a round bottom flask one part of the solution (70 ml) was charged and stirred for 1 hour. The solid obtained was filtered and washed with isopropyleacetate (10 ml). The solid was charged into a round bottom flask and isopropyleacetate (30 ml) was added and stirred for 30 minutes at 65°C. The solution was cooled to 30°C and stirred for 30 minutes. The contents of the reaction was cooled to 5°C and stirred for 30 minutes. The solid was filtered and washed with isopropyleacetate (10 ml). The solid was dried under vacuum at 50°C to yield 7.75 gm of title compound. HPLC purity: 99.93%

Example 37: Process for the preparation of compound 18a'

In a round bottom flask THF (350 ml), toluene (150 ml), 2-(4-fluorophenyl)-5-(5- iodo-2-methylbenzyl)thiophene (50 gm, 0.122 moles) and (3R,4S,5R,6R)-3,4,5- tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tet rahydro-2H-pyran-2-one (62.9 gm, 0.135 moles) are added at room temperature and stirred. The reaction mass was cooled to -75°C and n-BuLi (1 1 .76 gm, 0.184 moles, 2.5 M solution in hexanes) was added under Nitrogen atmosphere and stirred for 30 minutes.

In another round bottom flask trifluoroacetic acid (55.9 gm, 0.490 moles) and DM water (100 ml) were added and stirred. Cool the reaction mass to 3°C. This reaction mass was slowly dumped into the precooled solution and stirred for 5 to 10 minutes. Now the temperature of the reaction mass was increased to 29°C. pH of the reaction mass was adjusted to 7-8 with NaHC03 (54 gm in 600 ml of DM water) and the layers were separated. Aqueous layer was extracted with toluene (150 ml) and layers were separated. Both the organic layers were combined and washed with water twice (150 ml each). Layers were separated and organic layer was divided into 2 parts.

The first part is taken into a round bottom flask and kept under stirring and toluene (375 ml) was added at room temperature and stirring continued for 12-13 hours. The solid obtained was filtered under vacuum and washed with toluene (50 ml). The wet compound dried under vacuum to give 22.9 gm of compound 18a'. HPLC purity: 99.24%

The second part is taken into a round bottom flask and kept under stirring and toluene (375 ml) was added at room temperature and stirring continued for 12-13 hours. The solid obtained was filtered under vacuum and washed with toluene (50 ml). The wet compound dried under vacuum to give 22.5 gm of compound 18a'. HPLC purity:

99.29%.

Example 38: Preparation of 2-(4-fluorophenyl) thiophene

In a round bottom flask 1 ,2-dimethoxyethane (160 ml), water (132 ml) and 2- bromothiophene (20 gm) and stirred for 15 minutes at room temperature. Sodiumcarbonate (39.018 gm) charged into the reaction medium and degassed with nitrogen for 10-15 minutes. Pd(dppf)2CI2 (0.897 gm) and 4-fluorophenyl boronic acid (17.17 gm) were charged into the flask and again degassed with nitrogen for 15-20 minutes. The temperature of the reaction mass slowly increased to 80-85oC and maintained for 4 hours. Now cool the reaction mass to room temperature and maintain for 16-17 hours. After the maintenance dilute the reaction mass with water 132 (ml) and stirred for 20 minutes. The reaction mass was extracted with ethyl actate (100mlx2 times) and combined the organic layers, filtered on a cellite bed and washed with ethyl actate (50ml). Combined the organic layers and dried with sodiumsulphate and evaporated to get crude title compound.

HPLC purity: 79.51 %; Yield: 22.0 gm

Example 39: Purification of 2-(4-fluorophenyl) thiophene using acetone and water Crude 2-(4-fluorophenyl) thiophene (1 g) obtained in example 1 was dissolved in acetone (4 ml) and the solution was added to water (8 ml) at 0-5oC. The precipitate was filtered to give pure 2-(4-fluorophenyl) thiophene.

HPLC purity: 90.7%; Yield: 0.68 gm

Example 40: Purification of 2-(4-fluorophenyl) thiophene using methanol and water

Crude 2-(4-fluorophenyl) thiophene (1 g) obtained in example 1 was dissolved in methanol (4 ml) and the solution was added to water (8 ml) at room temperature. The precipitate was filtered to give pure 2-(4-fluorophenyl) thiophene.

HPLC purity: 90.05%; Yield: 0.82 gm

Example 41 : Purification of 2-(4-fluorophenyl) thiophene using IPA and water

Crude 2-(4-fluorophenyl) thiophene (1 g) obtained in example 1 was dissolved in IPA (4 ml) and the solution was added to water (8 ml) at room temperature. The precipitate was filtered to give pure 2-(4-fluorophenyl) thiophene.

HPLC purity: 90.4%; Yield: 0.53 gm

Example 42: Purification of 2-(4-fluorophenyl) thiophene using ethanol and water

Crude 2-(4-fluorophenyl) thiophene (1 g) obtained in example 1 was dissolved in ethanol (4 ml) and the solution was added to water (8 ml) at room temperature. The precipitate was filtered to give pure 2-(4-fluorophenyl) thiophene.

HPLC purity: 90.5%; Yield: 0.6 gm

Example 43: Purification of 2-(4-fluorophenyl) thiophene using dimethylsulfoxide (DMSO) and water

Crude 2-(4-fluorophenyl) thiophene (1 g) obtained in example 1 was dissolved in DMSO (4 ml) and the solution was added to water (8 ml) at room temperature. The precipitate was filtered to give pure 2-(4-fluorophenyl) thiophene. HPLC purity: 89.64%; Yield: 0.6 gm

Example 44: Purification of 2-(4-fluorophenyl) thiophene using methanol and water

2-(4-fluorophenyl) thiophene (0.82 g) obtained in example 3 was dissolved in methanol (4 ml) and the solution was added to water (8 ml) at room temperature. The precipitate was filtered to give pure 2-(4-fluorophenyl) thiophene.

HPLC purity: 91 .66%; Yield: 0.6 gm

Example 45: Purification of 2-(4-fluorophenyl) thiophene using isopropyl alcohol (IPA) and water

2-(4-fluorophenyl) thiophene (0.53 g) obtained in example 4 was dissolved in IPA (4 ml) and the solution was added to water (8 ml) at room temperature. The precipitate was filtered to give pure 2-(4-fluorophenyl) thiophene.

HPLC purity: 97.39%; Yield: 0.3 gm

Example 46: Preparation of 2-(4-fluorophenyl) thiophene

In a round bottom flask 2-(4-fluorophenyl)tetrahydrothiophene (8 gm), toluene (80 ml) and chloranil (32.3 gm) were charged and warmed to 75-80oC. The reaction mass was maintained at this temperature for 8-9 hours and increase the temperature to 105- 1 10oC. The reaction mass is maintained at this temperature for 1 1 -12 hours and reaction progress is checked with TLC. Now the reaction mass is cooled to room temperature and quenched with saturated sodiumbicarbonate (100ml) and ethylacetate (100 ml) was added, filtered and washed with ethylacetate (100 ml). The organic layer dried over sodiumsulphate and evaporated to get crude title compound with HPLC purity of 55.6%.

The crude compound was purified over silica gel column using 100% hexane to give title compound with 96.7% HPLC pure compound. Yield: 4 gm

Example 47: Purification of 2-(4-fluorophenyl) thiophene using IPA and water 2-(4-fluorophenyl) thiophene (0.5 g) obtained in example 9 was dissolved in IPA (4 ml) and the solution was added to water (1 ml) at room temperature. The precipitate was filtered to give pure 2-(4-fluorophenyl) thiophene.

HPLC purity: 99.78%; Yield: 0.25 gm

Example 48: Purification of 2-(4-fluorophenyl) thiophene using methanol and water

2-(4-fluorophenyl) thiophene (0.5 g) obtained in example 9 was dissolved in methanol (4 ml) and the solution was added to water (1 ml) at room temperature. The precipitate was filtered to give pure 2-(4-fluorophenyl) thiophene.

HPLC purity: 99.2%; Yield: 0.2 gm

Example 49: Preparation of crystalline form of Canagliflozin

In a round bottom flask (2R _! 3S,4R _! 5R)-1 -(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4- methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1 -one (compound 18a') (90 gm, 0.195 moles) and methanol (675 ml) were taken and stirred at room temperature for couple of minutes. The reaction mass was cooled to 10°C. At this temperature methanesulfonic acid (9.38 gm) was added, temperature was raised to 10°C to 15°C and stirred for about 3 hours at this temperature. The reaction mixture was quenched with triethylamine (1 1 .70 ml) and concentrated under reduced pressure at an elevated temperature of about 50°C up to 2 to 3 volumes with respect to compound 18a'. The resulting mixture was cooled to room temperature, dichloromethane (720 ml) and DM water (450 ml) were added and stirred for about 15 minutes. The layers were separated. To the organic layer, water (450 ml) was added and stirred. Again layers were separated. Organic layer was concentrated under vacuum at an elevated temperature of about 50°C. The resulting mixture was cooled to room temperature, dichloromethane (450 ml) was added and distilled under vacuum up to 2-3 volumes below 50°C temperature. The resulting mixture was cooled to room temperature, dichloromethane (900 ml) was added and stirred at room temperature for about 10 minutes and cooled the mixture to -30°C to -40 °C. Triethyl silane (51 gm) was added and BF ₃ .Etherate (55.5 gm, 0.391 moles) was added continuously and slowly in about 60 minutes. The reaction mixture was stirred for 2 to 3 hours at -30°C to -40 °C. Now raise the temperature to -5°C to 0 °C and maintain for 55±15 minutes. pH of the reaction mass was adjusted to 7.0 to 8.0 with triethylamine (180 ml) and water (180 ml) was added. Temperature of the reaction mixture was raised to room temperature and maintained for about 20 minutes. The layers were separated and organic layer was washed with a mixture of water (450 ml) and methanol (180 ml). Again the organic layer was separated washed with water (450 ml) and methanol (180 ml). Again the organic layer was separated washed with water (450 ml) and methanol (180 ml). The organic layer was separated and layers were combined SC-40 charcoal was added and stirred. The reaction mass was filtered and washed with dichloromethane (90 ml). The organic layer was concentrated up to 2 volumes with respect to compound 18a'. To the resulting mixture, methyl tertiarybutylether (540 ml) and water (7 ml) were added followed by crystalline Canagliflozin seed (0.903 gm) were added. The resulting mixture was stirred for 4-5 hours at room temperature. To this water (1 .75 ml) added and stirred. Methyl tertiarybutylether (540 ml) was added and distilled below 60°C to 5-6 volumes. To this methyl tertiarybutylether (540 ml) was added and distilled below 60°C to 5-6 volumes and water (7 ml) was added and stirred for 3 hours. The reaction mass was filtered and washed with methyl tertiarybutylether (90 ml) to give crude Canagliflozin (65.9 gm).

Purification: In a round bottom flask isopropyleacetate (360 ml) and crude Canagliflozin were charged and heated to 60-65°C. The reaction mass was stirred for 30 minutes and cooled to room temperature. To the resulting mixture dichloromethane (450 ml) and water (3.5 ml) were added and stirred. Crystalline Canagliflozin seed (0.903 gm) was added and the resulting mixture was stirred for 5-6 hours at room temperature. The precipitated solid was filtered and washed with isopropyleacetate (90 ml) and dried under vacuum at 50°C to yield 59.8 gm of title compound. HPLC purity: 99.82%.

Example 50: Preparation of amorphous form of Canagliflozin

Charge methanol (13.98 L) and Canagliflozin (2.33 kg) into a reactor at 30°C under nitrogen atmosphere and stirred for 15-20 minutes. Reaction mass was filtered and reactor was washed with methanol (4.64 L). The filtrate was heated to 40°C to 45°C and subjected to Agitated Thin Film Drying (ATFD). The solid material was milled using multi mill. The resulting milled material was dried under vacuum at 45-55°C to provide amorphous form of Canagliflozin (1 .83 Kg). HPLC purity: 99.92%.

ATFD parameters: Bath temperature: 50-60°C; Feeding rate: 2-4 L/hour; Vacuum: About 700 mm Hg.