Field of the Invention:
The present invention is related to an improved process for the preparation of amorphous form of Canagliflozin with high purity and high yield.
Background of the Invention:
Canagliflozin is sodium glucose co transported (SGLT) inhibitor, chemically known as (2S, 3R, 4R, 5S, 6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methyl-phenyl]-6-(hydroxymethyl) tetrahydropyran-3, 4, 5-triol and structurally represented as below

Compound I Canagliflozin
Canagliflozin is first disclosed in US 7943788 and marketed as canagliflozin hemi hydrate under the brand name INVOKANA®.
U.S. Patent No. 7,943,582 discloses crystalline hemihydrate form of canangliflozin and its preparation, wherein dissolving canagliflozin in a polar solvent (e.g. ketones or esters) crude or amorphous compound prepared in accordance with the procedures described in WO 2005/012326, and adding water and non-polar solvent (e.g. alkanes or ethers) to the resulting solution, followed by filtration.
U.S. Patent No. 8,999,941 discloses amorphous dapagliflozin and amorphous canagliflozin and also discloses 1:1 crystalline complex of canagliflozin with L-proline (Form CS1), ethanol solvate of a 1:1 crystalline complex of canagliflozin with D-proline (Form CS2), 1:1 crystalline complex of canagliflozin with L-phenylalanine (Form CS3), 1:1 crystalline complex of canagliflozin with D-proline (Form CS4). It also discloses preparation of amorphous canagliflozin by adding its heated toluene solution into n-heptane. After drying in vacuum the product was obtained as off-white solid with melting point of 54.7°C to 72.0°C.

PCT publication No. WO2014195966 discloses the stable amorphous form of canagliflozin and process for preparing it, wherein the process involves spray drying, anti-solvent techniques and use L-Proline crystalline complex for the preparation of canagliflozin.
As per WO'966 applicant has repeated the US8999941 patent process the observations are: the obtained amorphous canagliflozin was having higher amount of residual solvents. Therefore, the amorphous canagliflozin obtained by process as disclosed in US '941 is not suitable for pharmaceutical preparations. In the US '941 further discloses that amorphous canagliflozin obtained by the above process is hygroscopic in nature which was confirmed by Dynamic vaporsorption (DVS) analysis. Further, it was observed that the amorphous form underwent a physical change between the sorption/desorption cycle, making the sorption/desorption behavior different between the two cycles. The physical change that occurred was determined to be a conversion or partial conversion from the amorphous state to a crystalline state. This change was supported by a change in the overall appearance of the sample as the humidity increased from 70% to 90% RH.
The inventors of the present of invention have developed an alternate improved process for the preparation of amorphous form of canagliflozin with high yield and purity. The present process is cost effective and feasible in large scale production also.
Summary of the Invention:
One aspect of the present invention is to provide an improved process for the preparation of amorphous form of Canagliflozin of formula (1)
QH HOv J>*. .^N.
^y ^y OH
HO1"'V0
CH3
(1) comprising the steps of:
i. reacting Gluconolactone of formula (2) with trimethyl silyl chloride in presence of N-
methyl morpholine in tetrahydrofuran and isolating from cyclohexane to get 2, 3, 4, 6-
tetra-o-Trimethyl silyl-B-D-Gluconolactone of formula (3)

11.

(3)
condensing compound of formula (3) with 2-[(5-bromo-2-methyl-phenyl) methyl] -5-(4-fluorophenyl) thiophene of formula (4) in THF-toluene mixture in the ratio of 10-13 volumes in presence of n-BuLi under inert atmosphere and isolated from toluene-heptane solvent mixture to afford (3R,4S,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-(hydroxymethyl)-2-methyl-tetrahydropyran-
3,4,5-triol of formula (5)

OH

HO
111.

(S)
CH,
reducing compound of formula (5) with triethyl silane in presence of boron trifluoride dietherate under inert atmosphere to afford crude Canagliflozin of formula (1)

OH

HOv
HO

IV.

purifying crude Canagliflozin of formula (1) by converting it to piperidine-4-carboxylic acid complex in aqueous organic solvent mixture to afford piperidine-4-carboxylic acid complex of Canagliflozin of formula (6)

OH



HO
H O

COOH

C H3

(«>

v. regenerating pure Canagliflozin of formula (1) by treating piperidine-4-carboxylic acid complex of Canagliflozin of formula (6) in water-organic solvent mixture to afford pharmaceutical grade Canagliflozin of formula (1)

Another aspect of the present invention is related to the preparation of amorphous form of canagliflozin, comprising the steps of:
a) reacting (3R, 4S, 5S, 6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-(hydroxymethyl)-2-methyl-tetrahydropyran-3,4,5triol of formula-5 with triethylsilane in dichloromethane,
b) cooling the reaction mixture to -5 to 5°C,
c) adding the boron trifluoride ethyl ether at -50 to -30°C,
d) adding base at-5 to 5°C, and
e) isolating amorphous form of canagliflozin.
Yet another aspect of the present invention is related to purification of amorphous form canagliflozin, comprising the steps of:
a) dissolving amorphous form of canagliflozin in a solvent,
b) adding piperidine-4-carboxylic acid to step a) mixture to get piperidine-4-carboxylic acid complex of canagliflozin, and
c) converting the piperidine-4-carboxylic acid complex of canagliflozin to amorphous form of canagliflozin.
Yet another aspect of the present invention is to provide a crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1) having the XRPD pattern as 3.48, 10.38, 11.36, 11.96, 13.86,16.27, 16.61,17.24,17.60, 18.00, 19.01, 19.93, 20.47,21.05, 21.77,21.99,22.25,22.8, 23.4,24.05,24.61,24.86,25.58,26.02,26.23,26.71,28.34,29.10, 31.33, 32.21,33.61(±0.2°9).

Yet another aspect of the present invention to provide a crystalline piperidine-4-carboxylic acid complex ofcanagliflozin(CP2) having the XRPD pattern as 10.35, 12.72,12.99, 14.15, 15.70, 17.29, 17.66, 18.46, 18.81, 19.34, 20.80, 21.23, 22.63, 22.99, 23.63, 24.31, 26.03, 26.51 , 28.31(±O.2°0).
Yet another aspect of the present invention is to provide a process for the preparation of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1) comprising reacting canagliflozin of formula (1) with piperidine-4-carboxylic acid in ketone-water solvent mixture and isolating the crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1).
Yet another aspect of the present invention is to provide a process for the preparation of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2) comprising reacting canagliflozin of formula (1) with piperidine-4-carboxylic acid in alcohol-water solvent mixture and isolating the crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2).
The present invention is shown in below scheme-1

1. N-Methylmorpholine, A-Tcinelhytsilylchloride, S* ^Q 0> C to 40° C ,0. .,0 and then to RT, 24h HO' ^< ^<^
13 (1)

Scheme-1
Detailed description of the Invention:
The present invention relates to an improved process for the preparation of amorphous form of canagliflozin, wherein one step is related to the direct isolation of amorphous form of

canagliflozin from reaction mixture and other step is related to purification of amorphous form of canagliflozin through piperidine-4-carboxylic acid complex of canagliflozin.
One embodiment of the present invention is to provide an improved process for the preparation of amorphous form of Canagliflozin of formula (!■)■

CH,
(1)
comprising the steps of: i. reacting Gluconolactone of formula (2) with trimethyl silyl chloride in presence of N-methyl morpholine in tetrahydrofuran and isolating from cyclohexane to get 2, 3, 4, 6-tetra-o-Trimethyl silyl-P-D-Gluconolactone of formula (3)

r
ii. condensing compound of formula (3) with 2-[(5-bromo-2-methyl-phenyl) methyl] -5-(4-fluorophenyl) thiophene of formula (4) in THF-toluene mixture in the ratio of 10-13 volumes in presence of n-BuLi under inert atmosphere and isolated from toluene-heptane solvent mixture to afford (3R,4S,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thieny 1] methyl] -4-methy 1 -phenyl] -6- (hy droxymethy l)-2 -methyl -tetrahy dropy ran-3,4,5-triol of formula (5)

iii. reducing compound of formula (5) with triethyl silane in presence of boron trifluoride dietherate under inert atmosphere to afford crude Canagliflozin of formula (1)

OH

CH3
iv. purifying crude Canagliflozin of formula (1) by converting it to piperidine-4-carboxylic acid complex in aqueous organic solvent mixture to afford piperidine-4-carboxylic acid complex of Canagliflozin of formula (6)

CH3
(6)
v. regenerating pure Canagliflozin of formula (1) by treating piperidine-4-carboxylic acid complex of Canagliflozin of formula (6) in water-organic solvent mixture to afford pharmaceutical grade Canagliflozin of formula (1)

According to the present invention, in step (i) of the present invention, Gluconolactone of formula (2) is reacted with trimethyl silyl chloride in presence of N-methylmorpholine in tetrahydrofuran at about 40° C for 5-6h. After completion of reaction, the reaction mixture is cooled to ambient temperature and stirred for overnight. Later the reaction mixture is quenched in to chilled water and the product can be extracted with organic solvent. The organic solvent may be hexane or cyclohexane. Concentration under reduced pressure afforded quantitative yield of 2,3,4,6-tetra-o-Trimethylsilyl-p-D-Gluconolactone of formula (3) as yellow oil.
In step (ii) of the present invention, compound of 2-[(5-bromo-2-methyl-phenyl) methyl]-5-(4-fluorophenyl) thiophene of formula (4) is reacted with 2,3,4,6-tetra-O Trimethylsilyl-P-D-Gluconolactone of formula (3) in THF-toluene mixture at -90 to -100°C in the presence of n-BuLi under inert atmosphere for lh followed by quenching the reaction

mixture by adding methane sulfonic acid-methanol mixture in to the reaction mass. After quenching, the mixture is stirred for overnight and neutralized with saturated sodium bicarbonate solution. The organic layer is separated, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic layer is filtered and distilled out solvent completely under reduced pressure to afford thick oily syrup which is triturated using organic solvent mixture to afford 77% yield of (3R,4S,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-(hydroxymethyl)-2-methyl-tetrahydropyran-3,4,5-triol of formula (5) as off-white solid. The organic solvent can be toluene-heptane, toluene-cyclohexane mixture.
In step (iii) of the present invention, compound of (3R,4S,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-(hydroxymethyl)-2-methyl-tetrahydro pyran-3,4,5-triol of formula (5) is reduced using triethylsilane in the presence of boron trifluoride-dietherate in dichloromethane at 0-5° C for about 3h. After completion of reaction, the reaction mixture is quenched with saturated sodium bicarbonate solution and the layers are separated. The organic layer is washed with water followed by saturated sodium chloride solution. The excess solvent is distilled off completely under reduced pressure to yield >90% of crude Canagliflozin of formula (1) as foamy solid having purity > 90% by HPLC.
In step (iv) of the present invention, compound of (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methyl-phenyl]-6-(hydroxymethyl) tetrahydropyran-3,4,5-triol of formula (1) is complexed with acid reagent in an organic sol vent-water mixture at about 40° C for 6h. The organic solvent can be acetone, isopropyl alcohol or methanol. The acid reagent can be piperidine-4-carboxylic acid, piperidine-3-carboxylic acid, piperidine-2-carboxylic acid, nicotinic acid or isonicotinic acid preferably piperidine-4-carboxylic acid. The resulting precipitated complex is cooled to 0-5° C and stirred for about lh and filtered. The wet product is dried under reduced pressure to afford crystalline Canagliflozin complex of formula (6) as off-white solid with about 80% yield. The purity of crystalline Canagliflozin complex is >99.5% by HPLC.
In step (v) of the present invention, crystalline Canagliflozin complex of formula (6) is stirred in water-organic solvent mixture for about lh and resulting organic layer is separated. The organic solvent can be methyl tertiary butyl ether, diisopropyl ether preferably methyl tertiary butyl ether. The organic layer is clarified with activated charcoal and filtered. The excess solvent is distilled out partially under atmospheric pressure. The concentrated reaction mass is added into co-solvent and the product is filtered and dried under vacuum to afford about

80% yield of off-white to white amorphous Canagliflozin. The co-solvent can be cyclohexane, hexane or heptane. The purity of the product is >99.8% by HPLC.
One embodiment of the present invention is related to preparation of amorphous form of canagliflozin, comprising the steps of:
a) reacting (3R, 4S, 5S, 6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-(hydroxymethyl)-2-methyl-tetrahydropyran-3,4J5triol of formula-5 with triethylsilane in dichloromethane,
b) cooling the reaction mixture to -5 to 5°C,
c) adding the boron trifluoride ethyl ether at -50 to -30°C,
d) adding base at-5 to 5°C, and
e) isolating amorphous form of canagliflozin.
According to the present invention, RB flask is charged (3R, 4S, 5S, 6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methyl-phenyl]-6-(hydroxymethyl)-2-methy 1-tetrahydropyran-3,4,5triol, of formula (5) is reacted with triethyl silane in the presence of BF3. 0(Et)2 in dichloromethane at -40° C to -30° C followed by quenching the reaction mixture with base at -5° to 0° C, extraction and distillation of methylene chloride to get amorphous form of Canagliflozin of formula (1) as foamy solid.
According to the present invention, base is selected form sodium bicarbonate and potassium bicarbonate preferably sodium bicarbonate.
Another embodiment of the present invention is related to purification of amorphous form canagliflozin, comprising the steps of:
a) dissolving amorphous form of canagliflozin in a solvent,
b) adding piperidine-4-carboxylic acid to step a) mixture to get piperidine-4-carboxylic acid complex of canagliflozin, and
c) converting the piperidine-4-carboxylic acid complex of canagliflozin to amorphous form of canagliflozin.
According to the present invention, to a solution of (2S, 3R, 4R, 5S, 6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methyl-phenyl]-6-(hydroxymethyl) tetrahydropyran-3, 4, 5-triol of formula (1) is complexed with piperdine-4- carboxylic acid in aq. organic solvent at

40-45° C to yield Canagliflozin complex forms (CP1 & CP2) of formula (6) as an off-white solid.
According to the present invention, organic solvent is selected from ketone /alcohol solvents.
According to the present invention, ketone solvent is selected from acetone, butanone, cyclopentanone, 2-pentanone, methyl ethyl ketone, methylisobutyl ketone and methylisopropyl ketone preferably acetone.
According to the present invention, alcohol solvent is selected from methanol, ethanol, propanol, isopropanol and butanol preferably isopropanol.
Pure amorphous form of Canagliflozin of formula (1) is regenerated from (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-(hydroxy methyl) tetrahydro pyran-3,4,5-triol complex of formula (6) in DM Water-ether solvent medium at RT and the resulting Canagliflozin of formula (1) is separated, followed by distillation and isolation from ether-alkane solvent mixture to get pure amorphous form of Canagliflozin of formula (1) as white solid.
According to the present invention, ether solvent is selected from diethyl ether, diisopropyl ether, and methyl tert-butyl ether preferably methyl tert-butyl ether.
According to the present invention, alkane solvent is selected from pentane, hexane, heptane, cyclohexane preferably cyclohexane.
Yet another embodiment of the present invention is to provide a crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1) having the XRPD pattern as 3.48,10.38,11.36, 11.96,13.86,16.27,16.61,17.24,17.60,18.00,19.01,19.93,20.47,21.05,21.77,21.99,22.25, 22.8, 23.4, 24.05, 24.61, 24.86, 25.58, 26.02, 26.23,26.71, 28.34, 29.10, 31.33, 32.21, 33.61(±O.2°0).
Yet another embodiment of the present invention is to provide a crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2) having the XRPD pattern as 10.35, 12.72,
11

12.99,14.15,15.70,17.29,17.66,18.46,18.81,19.34,20.80,21.23,22.63,22.99,23.63,24.31, 26.03,26.51 ,28.31(±O.2°0).
Yet another embodiment of the present invention is to provide a process for the preparation of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1) comprising reacting canagliflozin of formula (1) with piperidine-4-carboxylic acid in ketone-water solvent mixture and isolating the crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1).
According to the present invention, wherein to a solution of (2S, 3R, 4R, 5S, 6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methyl-phenyl]-6-(hydroxymethyl) tetrahydropyran-3, 4, 5-triol in ketone solvent, added the piperdine-4- carboxylic acid in DM water solution at 40° C, stirred for 6 hrs at 40 °C later on allowed to room temperature, then stirred for overnight at room temperature, solid precipitated, cooled to 0 ° C to 5 °C, maintained for 1 hr, filtered the solid and slurry washed with ketone solvent twice, dried under reduced pressure at 55 °C for 3hrs to yield crystalline complex (CP1) as an off white Solid.
According to the present invention, ketone solvent is selected from acetone, butanone, cyclopentanone, 2-pentanone, methylisobutyl ketone and methylisopropyl ketone preferably acetone.
Yet another embodiment of the present invention is to provide a process for the preparation of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2) comprising reacting canagliflozin of formula (1) with piperidine-4-carboxylic acid in alcohol-water solvent mixture and isolating the crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2).
CD
U)
(0
°- According to the present invention, wherein to a solution of (2S, 3R, 4R, 5S, 6R)-2-[3-[[5-(4-
j£ fluorophenyl)-2-thienyl] methyl]-4-methyl-phenyl]-6-(hydroxymethyl) tetrahydropyran-3, 4,
CN

£ 5-triol in alcohol solvent, added the piperdine-4- carboxylic acid in DM water solution at 40°
o
^ C, stirred for 6 hrs at 40 °C later on allowed to room temperature, then stirred for overnight
CO
8 at room temperature, solid precipitated, cooled to 0 ° C to 5 °C, maintained for 1 hr , filtered
the solid and slurry washed with alcohol solvent twice, dried under reduced pressure at 55 °C for 3hrs to yield crystalline complex (CP2) as an off white Solid.
CN
O
CD
O CN
CN
o
CO JN
5:FA TENT OFFICE CR'ENR 7H T^r^~&T~^TWlTE FTT^ITY
<* 12

According to the present invention, alcohol solvent is selected from methanol, ethanol, propanol, isopropanol and butanol preferably isopropanol.
Brief description of drawings:
Fig-1: XRPD pattern of amorphous form of canagliflozin.
Fig-2: XRPD pattern of crystalline piperidine-4-carboxylic acid complex of canagliflozin
(CPl).
Fig-3: IR spectrum of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CPl).
Fig-4: XRPD pattern of crystalline piperidine-4-carboxylic acid complex of canagliflozin
(CP2).
Fig-5: IR spectrum of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2).
Fig-6: XRPD pattern of amorphous form of canagliflozin prepared from crystalline piperidine-
4-carboxylic acid complex of canagliflozin.
The following examples are provided for illustrative purpose only and are not intended to limit the scope of invention in anyway.
Experimental section:
Example-I: Process for preparation of amorphous form of Canagliflozin from novel
crystalline complex
a) Preparation of 2,3,4,6-tetra-O-trimethylsiIyI-p-D-GIucolactone (3):
Into a 5L 4 necked RB flask were added with Gluconolactone (200g, 1.12 moles) and N-methyl morpholine (908g, 8.98 moles) followed by tetrahydrofuran (1.0L). Then the reaction mixture was cooled to -10°C, and added chlorotrimethylsilane (732 g, 6.74 moles) slowly drop wise for 90 min at below 10 °C under nitrogen atmosphere. Thereafter, the reaction mixture was warmed and maintained at 40°C for 5h. After maintenance, reaction mixture was cooled to ambient temperature and stirred for overnight. Later, the reaction mixture was quenched with water at -10° C and extracted with heptane. The organic layer was finally washed with satd. sodium chloride solution and separated. The solvent was recovered by distillation under vacuum to afford 529 g, (~ 100 %) of compound (3) as a light yellow liquid.
b) Preparation of (3R,4S,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyI] methyl]-4-methyl-
phenyl]-6-(hydroxymethyl)-2-methyI-tetrahydropyran-3,4,5-triol (5)
13

Into a 3L 4 necked RB Flask, were added 2-[(5-bromo-2-methyl-phenyl) methyl]-5-(4-fluorophenyl) thiophene of formula (4) (100 g, 0.27 moles), THF (600 ml) and toluene (600ml). Resulting solution was cooled to -100 ° C, and was added 1.6M N-BuLi in hexane solution (208 ml, 0.33 moles) at -90 to -100°C followed by 2, 3, 4, 6-tetra-o-Trimethylsilyl-p-D-Gluconolactone of formula (3) (142.3 g, 0.30 mole) in toluene (142 ml) under nitrogen atmosphere. After addition, the reaction mixture was stirred for 60 min and was added methane sulfonic acid (72.7 g 0.75 moles) in methanol (600 ml) at -90 to -100°C. Later the reaction mixture was allowed to ambient temperature, stirred for overnight and was quenched with satd. NaHC03 solution (1.0L). Organic layer separated and washed with aqueous saturated sodium chloride solution and dried over Na2S04. Excess solvent was recovered under reduced pressure to afford thick oily liquid and product was isolated from toluene (300 ml) - n-heptane (1200 ml) mixture. Resulting solid was filtered off and dried under reduced pressure to afford compound of formula (5) (101 g, 77%) as off-white solid.
c) Preparation of (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-
methyl-phenyl]-6-(hydroxymethyl) tetrahydropyran-3,4,5-triol (1)
Into a 2L 4 necked RB flask were added (3R,4S,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-(hydroxymethyl)-2-methyl-tetrahydropyran-3,4,5-triol of formula (5) (lOOg, 0.21 moles), triethylsilane (77.0g, 0.63 moles) in dichloromethane (1300 ml). The resulting solution was cooled to 0°C, and was added BF3-0(Et)2 (91.8 0.63 moles) drop wise at -40° to -30° C. The reaction mixture was warmed to 0°C and stirred for 3 hrs. The reaction mixture was then quenched with satd.NaHCCh solution (1.5 L) at 0°C and the layers were separated. The organic layer was washed with DM water (650 ml) and aq. saturated sodium chloride solution (650 ml). The solvent distilled off completely under reduced pressure to yield (97. lg, > 90%) titled compound of formula (1) as a foamy solid.
d) Preparation of (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-
methyl-phenyl]-6-(hydroxymethyl) tetrahydropyran-3,4,5-triol with piperdine-4-
carboxylic acid complex (5) from acetone-water (CP-1)
Into a 250 mL RB flask, were added, (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methyl-phenyl]-6-(hydroxymethyl) tetrahydropyran-3,4,5-triol of formula (1) (25g, 0.05 moles), acetone (125 ml), piperdine-4- carboxylic acid (7.2 g, 0.05), and DM water (12.5 ml). The reaction mixture was heated to 40° C and stirred for 6h and then cooled to ambient _ „.temperature..The^resulting.precipitated-so.lidjwas„copled4aFQr^C,,5tiired fp.r^lh andXiltered-
14

and dried at 50-55° C under reduced pressure to yield (26.1 g, 80% ) complex of formula (5)
as an off white solid.
Analytical data:
IR (cm-1) KBr: 3477, 3355, 2970, 2915, 2524, 2489, 1699, 1644, 1576, 1509, 1369, 1225,
1045, 1013.
1HNMR (400 MHz; CD30D+D20; ppm): 7.55 (dd, 2H); 7.31 (s, 1H), 7.25 (d, J=8.0 Hz; 3H)),
7.18 (d, J=7.6 Hz, 1H), 7.11 (d, J=3.6 Hz, 1H), 7.07 (t, J=8.8 Hz, 2H), 6.71 (d, J=3.6 Hz, 1H),
4.12-4.15 (m, 1H), 3.88 (d, J=12 Hz, 1H), 3.68-3.72 (m, 1H), 3.33-3.53 (m, 6H), 2.94-3.01 (m,
2H), 2.34-2.42 (m, 1H),2.30 (s, 3H), 2.03-2.08 (m, 2H), 1.79-1.89 (m, 2H).
13CNMR (400 MHz; CD30D+D20; ppm): 181.60; 164.56; 144.98, 142.38, 139.33, 137.71;
132.29, 131.35, 130.40, 128.10(d, JC-F=8.0Hz); 127.50, 127.18, 123.92, 116.75 (d, JC-
F-22.0Hz), 83.30, 81.97, 79.57, 76.19, 71.77, 62.95, 44.76, 42.74, 34.87, 27.19, 19.35.
Mass: 574.8 (M+l)
PXRD (°29 (±0.2°): 3.48, 10.38, 11.36, 11.96, 13.86, 16.27, 16.61, 17.24, 17.60,
18.00,19.01,19.93, 20.47, 21.05, 21.77, 21.99, 22.25, 22.8, 23.4, 24.05, 24.61, 24.86, 25.58,
26.02, 26.23,26.71,28.34, 29.10, 31.33, 32.21, 33.61.
e) Preparation of (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyI] methyl]-4-methyl-phenyl]-6-(hydroxymethyl) tetrahydropyran-3,4,5-triol with piperdine-4-carboxylic acid complex (6) from isopropanol-water (CP-2)
Into a 250 mL RB flask, were added, (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methyl-phenyl]-6-(hydroxymethyl) tetrahydropyran-3,4,5-triol of formula (1) (25g, 0.05 moles), isopropyl alcohol (125 ml), piperdine-4- carboxylic acid (7.2 g, 0.05), and DM water (12,5 ml). The reaction mixture was heated to 40° C and stirred for 6h and then cooled to ambient temperature. The resulting precipitated solid was cooled to 0-5 °C, stirred for lh and filtered and dried at 50-55° C under reduced pressure to yield (26.1 g, 80%) complex of formula (6) as an off white solid. Analytical data:
IR (cm-1) KBr: 3406, 3076, 3007, 2928, 2853, 1641, 1571, 1505, 1367, 1228, 1096, 1126, 1041.
1HNMR (400 MHz; CD30D-D20; ppm): 7.53 (dd, 2H), 7.31 (s, 1H), 7.25 (d, J=8.0 Hz, 3H)), 7.18 (d, J=7.6 Hz, 1H),7.11 (d, J=3.6 Hz, 1H), 7.07 (t, J=8.8 Hz, 2H), 6.71 (d, J=3.6 Hz, 1H), 4.12-4.15 (m, 1H), 3.88 (d, J=12 Hz, 1H), 3.68-3.72 (m, 1H), 3.33-3.53 (m, 6H), 2.95-3.02 (m, 2H), 2.35-2.42 (m, 1H), 2304sJBXX0^Z0H^r2^),JJ3^SHmy2U).^^
15

13CNMR(400MHz;CD3OD+D2O;ppm): 182.07, 164.29, 144.79, 142.11, 139.37, 137.71, 131.92, 131.47, 130.27, 127.85(d, JC-F=8.0Hz), 127.35, 127.12, 123.87, 116.6 (d,JC-F=22.0Hz), 83.00, 81.51, 79.10, 75.73, 71.34, 62.52,44.67, 42.64, 34.67, 26.96, 19.31. Mass: 574.8 (M+l)
PXRD (° 29 (±0.2°): 10.35, 12.72, 12.99, 14.15, 15.70, 17.29, 17.66, 18.46, 18.81, 19.34, 20.80, 21.23, 22.63, 22.99, 23.63, 24.31, 26.03, 26.51, and 28.31.
f) Preparation of (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-methyl-phenyl]-6-(hydroxymethyl) tetrahydropyran-3,4,5-triol (1)
Into a 3L 4 necked RB flask, were added (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-
thienyl] methyl]-4-methyl-phenyl]-6-(hydroxymethyl) tetrahydropyran-3, 4, 5-triol complex
compound of formula (6) (100 g ), DM Water (500 ml) and methyl tert-butyl ether (2000ml).
The resulting mixture was stirred for 60 min, separated the organic layer, clarified over
activated carbon and filtered. The filtrate was distilled off partially under reduced pressure and
to the remaining solution added drop wise into cyclohexane (2400 ml). The precipitated solid
was filtered and dried under vacuum to afford highly pure compound of formula (1) (64.3g,
80%) as a white solid.
Analytical data:
IRtcm-^KBr: 3404, 3072,2918, 1509, 1231, 1048, 1159.
JHNMR (400 MHz; DMSO-d6; 5 ppm):7.59 (dd J=8.8 Hz, J=2.4Hz, 2H), 7.27 (d, J=3.6Hz,
1H) 7.15-7.21(m, 3H) 7.14 (d, J=8.0Hz, 1H), 7.1 l(d, J=8.0Hz, 1H), 6.79 (d, J=3.6Hz, 1H),
4.93-4.94(m, 2 -O-H); 4.74 (d, J=5.6Hz, -O-H), 4.46 (t, J=5.6Hz, -O-H), 4.14(d, J=16.0Hz,
1H), 4.09 (d, J=16.0Hz, 1H), 3.96 (d, J=9.6Hz, 1H), 3.67-3.69 (m, 1H), 3.40-3.46 (m, 1H),
3.13-3.28 (m,4H), 2.25 (s,3H).
13CNMR (400 MHz; DMSO-d6; 5 ppm): 161.40(d, JC-F=243.0Hz), 143.66, 140.26, 138.24,
137.40, 134.98, 130.54, 129.70, 129.09, 126.98 (d, JC-F=8.0Hz), 126.38, 126.27, 123.40,
115.90 (d, JC-F=22.0Hz), 81.35, 81.21, 78.51, 74.71, 70.47, 61.47, 33.47, 18.83.
Mass: 462.19 [M+NH4]+.
HPLC: >99.5% (by area normalization)
16

We Claim:
1. A process for the preparation of amorphous form of Canagliflozin of formula (1)
OH

HO,

CH,

(1)

1.

comprising the steps of:
reacting gluconolactone of formula (2) with trimethyl silyl chloride in presence of N-methyl morpholine in tetrahydrofuran and isolating from cyclohexane to get 2, 3,4, 6-tetra-o-Trimethyl silyl-p-D-Gluconolactone of formula (3)

u.

condensing compound of formula (3) with 2-[(5-bromo-2-methyl-phenyl) methyl] -5-(4-fluorophenyl) thiophene of formula (4) in THF-toluene mixture in the ratio of 10-13 volumes in presence of n-BuLi under inert atmosphere and isolated from toluene-heptane solvent mixture to afford (3R,4S,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-(hydroxymethyl)-2-methyl-tetrahydropyran-
3,4,5-triol of formula (5)

OH

HOH
HO,

m.

reducing compound of formula (5) with triethyl silane in presence of boron trifluoride dietherate under inert atmosphere to afford crude Canagliflozin of formula (1) ■

OH

H-

~£hir~

t, x

"biz—brR-EFH^N- A¥

17

4. A process for the purification of amorphous form canagliflozin, comprising the steps
of:
a) dissolving amorphous form of canagliflozin in a solvent,
b) adding piperidine-4-carboxylic acid to step a) mixture to get piperidine-4-carboxylic acid complex of canagliflozin, and
c) converting the piperidine-4-carboxylic acid complex of canagliflozin to amorphous form of canagliflozin.

5. The process according to claim 4, wherein solvent is selected from acetone, butanone, cyclopentanone, 2-pentanone, methyl ethyl ketone, methylisobutyl ketone, methylisopropyl ketone, methanol, ethanol, propanol, isopropanol and butanol.
6. A crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1), having the XRPD pattern comprising the following 29 values as 3.48, 10.38, 11.36, 13.86, 16.27, 17.60, 18.00, 19.01, 19.93, 20.47, 21.05, 21.77, 22.8(±0.2°9).

7. A crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP2) having the XRPD.pattern as 12.99, 14.15,15.70,17.29, 18.46, 18.81,21.23,22.63,22.99 (±0.2°G).
8. A process for the preparation of crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1) comprising reacting canagliflozin of formula (1) with piperidine-4-carboxylic acid in ketone-water solvent mixture and isolating the crystalline piperidine-4-carboxylic acid complex of canagliflozin (CP1).
Q_
w 9. The process according to claim 8, wherein ketone solvent is selected from acetone,
butanone, cyclopentanone, 2-pentanone, methylisobutyl ketone and methylisopropyl
c* ketone preferably acetone.
o
co 10. A process for the preparation of crystalline piperidine-4-carboxylic acid complex of
canagliflozin (CP2) comprising reacting canagliflozin of formula (1) with piperidine-
£ 4-carboxylic acid in alcohol-water solvent mixture and isolating the crystalline
piperidine-4-carboxylic acid complex of canagliflozin (CP2).
CO
10
CN
o 5
o CN
CN
o
CO CN
CD
0 F?n"€Tan^er^^
^ 19
LL ©

11. The process according to claim 10, wherein alcohol solvent is selected from methanol, ethanol, propanol, isopropanol and butanol preferably isopropanol.
Dated mislay of Jun, 2016.

Dr. A.K.S. BHUJANGA RAO President (Technical) Natco Pharma Limited Hyderabad, India