DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

SUBSTANTIALLY PURE CANAGLIFLOZIN

FIELD OF THE INVENTION
The present application relates to a process for the preparation of substantially pure canagliflozin.
BACKGROUND
Canagliflozin is chemically described as 1-([ß-D-glucopyranosyl)-4-methyl-3-[5-(4-fluoro phenyl)-2-thienylmethyl]benzene. It has the chemical structure:

The US patent 7943788 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 7943582 discloses crystalline form of Canagliflozin hemihydrate and process for its preparation.
Various processes for the preparation of Canagliflozin, its polymorphs and intermediates, have been reported in the patent publications US20090233874, US20100099883, US20110087017, US8772512, US20130052266, WO2012140120, WO2012154812, WO2013068850, WO2013064909, CN103896930A and WO2014195966A2.
Up on qualitative analysis of Innovator’s tablet of Canagliflozin (Invokana) by liquid chromatography method illustrated as below, it is found that Innovator's Canagliflozin has an impurity eluting at an RT of about 11 minutes and an RRT of about 0.53. After LC-MS and NMR analysis the impurity eluting at an RT of about 11 minutes and an RRT of about 0.53 is determined to be having the following structure of formula I:

LC method:
Chromatographic conditions:
Column : ACE C18-AR 250x4.6 mm, 5 µm
Flow : 0.8 mL/min
Detection : UV @290nm
Load : 10 µL
Diluent : Acetonitrile : Water (8 :2)
Sample Conc : 1.5mg/mL
Elution : Gradient
Runtime : 55min
Column Temp : 35°C
Buffer : 0.005M Ammonium formate
Mobile phase A : 550:60:390 (Buffer: Methanol: Acetonitrile)
Mobile phase-B : 950:50 (Acetonitrile: water)
Gradient:
Time (min) Mobile phase-A Mobile phase-B
0 100 0
25 100 0
40 0 100
50 0 100
50.1 100 0
55.0 100 0

Sample preparation: Taken 15mg of canagliflozin sample in to 10ml volumetric flask dissolved and diluted up to the mark with diluent.
SUMMARY OF THE INVENTION
In an embodiment the present application provides canagliflozin substantially free of compound of formula I.
In an embodiment the present application provides amorphous form of canagliflozin substantially free of compound of formula I.
In an embodiment the present application provides crystalline form of canagliflozin substantially free of compound of formula I.
In an embodiment the present application provides storage stable amorphous form of canagliflozin substantially free of compound of formula I.
In an embodiment the present application provides amorphous form of canagliflozin having a particle size D[0.9] of less than about 100 or less than about 80 or less than about 50 or less than about 40 or less than about 30 or less than about 20 or less than about 10 microns which is substantially free of compound of formula I.
In an embodiment the present application provides a process for the preparation of canagliflozin substantially free of compound of formula I, comprising:
a) conversion of a compound 5 to Compound 18a’ using compound 13:

wherein Z is H or suitably selected oxygen protecting group; X is suitably selected halogen;
b) isolating compound 18a’ in a solid form;
c) converting compound 18a’ in a solid form to a compound 6;
d) conversion of compound 6 to canagliflozin substantially free of compound of formula I, comprising slow addition of BF3.Etherate to compound 6 under anhydrous conditions:

Wherein R1 is an alkyl group.
In an embodiment, the present application provides a process for the preparation of canagliflozin substantially free of compound of formula I, comprising:
a) conversion of a compound 5 to Compound 18a’ using compound 13:

wherein Z is H or suitably selected oxygen protecting group; X is suitably selected halogen;
b) isolating compound 18a’ in a crystalline form;
c) converting compound 18a’ in a crystalline form to compound 6;
d) conversion of compound 6 to Canagliflozin substantially free of compound of formula I:

In an embodiment the present application provides a process for the preparation of amorphous canagliflozin substantially free of compound of formula I, comprising:
a) conversion of a compound 5 to Compound 18a’ using compound 13:

wherein Z is H or suitably selected oxygen protecting group; X is suitably selected halogen;
b) isolating compound 18a’ in a solid form;
c) converting compound 18a’ in a solid form to compound 6;
d) conversion of compound 6 to amorphous Canagliflozin substantially free of compound of formula I:

wherein R1 is as defined above.
In an embodiment the present application provides a process for the preparation of substantially pure Canagliflozin substantially free of compound of formula I, comprising isolating canagliflozin in the presence of an anti-oxidant.
In an embodiment, the present application provides a substantially pure compound 18a’, which is substantially free of impurity of formula A.

In an embodiment, the present application provides a process for the preparation of a substantially pure compound 18a’, which is substantially free of impurity of formula A, comprising: purification of compound 18a’ by precipitation from a solvent.
In an embodiment, the present application provides substantially pure canagliflozin, which is substantially free of impurity of formula A.
In an embodiment, the present application provides a process for the preparation of a substantially pure canagliflozin, which is substantially free of impurity of formula A, comprising:
1) purification of compound 18a’ by precipitation from a solvent,
2) converting compound 18a’ to substantially pure canagliflozin which is substantially free of impurity of formula A.
In an embodiment the present application provides a process for the preparation of Canagliflozin, comprising reducing a compound of formula 6 in the presence of AlCl3.

Wherein R1 is as defined above.
In an embodiment, the present application provides an isolated compound of formula A:

DETAILED DESCRIPTION
“Substantially pure” as used herein refers to the purity of the material which is at least about 98.0 %, at least about 98.5 %, at least about 99.0 %, at least about 99.1 %, at least about 99.2 %, at least about 99.3 %, at least about 99.4 %, at least about 99.5 %, at least about 99.6 %, at least about 99.7 %, at least about 99.8 %, at least about 99.9 % or 100 % as measured by a liquid chromatography method.
“Substantially free of” as used herein refers to the level of impurity present in the material which is less than about 0.020 % or less than about 0.010 % or less than about 0.009 % or less than about 0.008 % or less than about 0.007% or less than about 0.006 % or less than about 0.005 % or less than about 0.004 % or less than about 0.003 % or less than about 0.002 % or less than about 0.001 %.
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 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.
“Slow addition or adding slowly” of BF3.etherate as used herein means the reagent may be added at a rate of for example at least 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 or any other suitable rate.
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.
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 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 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.
Up on qualitative analysis of Innovator’s tablet of Canagliflozin (Invokana) by liquid chromatography method as illustrated above, it is found that Innovator's Canagliflozin has an impurity eluting at an RT of about 11 minutes and an RRT of about 0.53 and having structure of formula I. Suitable column for carrying out said chromatography method may be selected from the group comprising Betasil C8, ACE C18-AR, Bonus RP 18, Inertsil C18, sunfire C18 or any other suitable column. Preferably the column can be ACE C18-AR. The length of the column may vary from about 150 mm to about 250 mm. preferably the column length is about 250 mm. The diameter of the column may vary from about 4 mm to about 4.6 mm. preferably the column diameter is about 4.6 mm. The particle size of the packing material within the column may vary from about 3 µm to about 5 µm. Preferable particle size of the packing material can be 5 µm.
In an embodiment, the present application provides substantially pure compound 18a’, which is substantially free of impurity of formula A.
In an embodiment, the present application provides a process for the preparation of a substantially pure compound 18a’, which is substantially free of impurity of formula A, comprising: purification of compound 18a’ by precipitation from a solvent.
The solvent used in the preparation of substantially pure compound 18a’, can be an organic solvent or water or mixtures thereof. The organic solvent can be selected from but not limited to isopropylacetate, dihloromethane, methyltertiarybutyl ether or mixtures thereof.
In an embodiment, the present application provides substantially pure canagliflozin, which is substantially free of impurity of formula A.
In an embodiment, the present application provides a process for the preparation of a substantially pure canagliflozin, which is substantially free of impurity of formula A, comprising:
1) purification of compound 18a’ by precipitation from a solvent,
2) converting compound 18a’ to substantially pure canagliflozin which is substantially free of impurity of formula A.
In the second step the substantially pure compound 18a’ is converted to canagliflozin by any of the methods known in the art.
In yet another embodiment, the compound 6 can be converted to canagliflozin by reducing compound 6 with TES (triethyl silane) in presence of AlCl3. The reaction can be carried out in any suitable solvent such as dichloromethane.
The said reaction can be carried out at a temperature of about -20 to about 20oC. More preferably, at a temperature of about -15 to about 15oC; most preferably at a temperature of about -5 to about 5oC.
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.
In an embodiment, the present application provides a process for the preparation of substantially pure Canagliflozin substantially free of compound of formula I, comprising isolating canagliflozin in the presence of an anti-oxidant.
The substantially pure canagliflozin substantially free of compound of formula I as used herein can be crystalline or amorphous.
The anti-oxidant that can be used in the said isolation can be selected from but not limited to, butylated hydroxyanisole (BHA), butylated hydroxytolune (BHT), sodium metabisulfite (SMB), propyl gallate (PG), cysteine (CYS) or any other suitable anti-oxidant. Preferably butylated hydroxyanisole (BHA) or butylated hydroxytolune (BHT) can be used.
The isolation of Canagliflozin may be effected by methods such as, filtration by gravity or by suction, centrifugation, decantation, removal of solvent, cooling, slow cooling, crash cooling, concentrating the mass, adding an anti-solvent, adding seed crystals to induce crystallization, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or the like or combinations thereof. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
If desired, isolated form of Canagliflozin may be washed with a solvent or a mixture of solvents.
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, or any other suitable temperatures.
The 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.
In yet another embodiment, the present application provides an isolated compound of formula A.
Canagliflozin obtained in the process of our co-pending WO2016098016A1; the disclosures of which is incorporated herein by reference; was analysed by the liquid chromatography method illustrated above and it was observed that the impurity eluting at an RT of about 11 minutes and an RRT of about 0.53, having a structure of formula I was ranging from about 0.001 % to about 0.006 % by % area normalisation 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.
Examples
Example 1: Preparation 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 (10 gm) and methanol (75 ml) were added and stirred at room temperature. The reaction mass was cooled to 2oC. At this temperature methanesulfonic acid (0.914 gm) was added and temperature is raised to 13oC and stirred for 2 hours. The reaction mixture was quenched with 1.6% sodiumbicarbonate (1.120 gm) and dichloromethane (100 ml). The layers were separated and to the dichloromethane layer DM water (50 ml) was added and stirred. Now concentrate the contents to 2-3 volumes under vacuum and stripped with dichloromethane (50 ml). Dichloromethane (100 ml) charged to the reaction mass, stirred for 10 minutes and cooled to -30 to -400C. Now triethyl silane (4.97 gm) added and BF3.Etherate (5.41 gm) were added and stirred for 2 to 3 hours. Now raise the temperature to 0 to -5oC and maintain for 55±15 minutes. pH of the reaction mass was adjusted to 7.0 to 8.0 with 9% NaHCO3 (12 gm) and temperature raised to 25-35OC and maintained for 10 minutes. Methanol (20 ml) was added and maintained for about 30 minutes and layers separated. Organic layer was washed twice with water (50 ml) and methanol (20 ml). The organic layer was separated and layers were combined, SC-40 charcoal was added and stirred. The reaction mass was filtered and through hyflow and washed with dichloromethane (10 ml) and filtered. The solution was divided into 2 parts.
Purification 1: In a round bottom flask part 1 (60 ml) and Butylated hydroxy anisol (0.25 gm) were charged and stirred at room temperature for 5 minutes. The reaction mass was distilled under vacuum at 40oC and chased with dichloromethane (20 ml) up-to 2-3 volumes. Now charge methyl tertiarybutyl ether (30 ml), water (0.1 ml) and seed Canagliflozin (0.088 gm) and maintained for about 5-6 hours at room temperature. Now add water (0.1 ml) and maintained for about 5-6 hours at room temperature. To the reaction mass MTBE (30 ml) was added and distilled under vacuum at 40oC. Chased with MTBE (30 ml) and cooled to room temperature. At this temperature water (0.5 ml) was added and maintained for about 6-7 hours. Filtered and washed with MTBE (10 ml) and dried to give crude canagliflozin. Now isopropylacetate (40 ml) and crude canagliflozin are charged back into the round bottom flask heated to 55oC and maintained for 1 hour and cooled to room temperature. At this temperature water (0.1 ml), dichloromethane (2.5 ml), seed Canagliflozin (0.088 gm) and Butylated hydroxy anisol (0.25 gm) were added and maintained for about 6-7 hours. Filtered and washed with isopropylacetate (10 ml) and dried under vacuum to give title compound (3.5 gm). HPLC purity: 99.49%.
Purification 2: In a round bottom flask part 2 (60 ml) and Butylated hydroxy toluene (0.25 gm) were charged and stirred at room temperature for 5 minutes. The reaction mass was distilled under vacuum at 40oC and chased with dichloromethane (20 ml) up-to 2-3 volumes. Now charge methyl tertiarybutyl ether (30 ml), water (0.1 ml) and seed Canagliflozin (0.088 gm) and maintained for about 5-6 hours at room temperature. Now add water (0.1 ml) and maintained for about 5-6 hours at room temperature. To the reaction mass MTBE (30 ml) was added and distilled under vacuum at 40oC. Chased with MTBE (30 ml) and cooled to room temperature. At this temperature water (0.5 ml) was added and maintained for about 6-7 hours. Filtered and washed with MTBE (10 ml) and dried to give crude canagliflozin. Now isopropylacetate (40 ml) and crude canagliflozin are charged back into the round bottom flask heated to 55oC and maintained for 1 hour and cooled to room temperature. At this temperature water (0.1 ml), dichloromethane (2.5 ml), seed Canagliflozin (0.088 gm) and Butylated hydroxy toulene (0.25 gm) were added and maintained for about 6-7 hours. Filtered and washed with isopropylacetate (10 ml) and dried under vacuum to give title compound (3.3 gm). HPLC purity: 99.53%.

Example 2: Preparation of Canagliflozin
In a round bottom flask dichloromethane (25 ml) and aluminiumchloride (14.5 gm) were added and cooled to -5oC and then acetonitrile (61 ml) was added for about 20 minutes. Now triethylsilane (10.8 gm) was added for about 30 minutes at the same temperature. Now dichloromethane (37 ml) and 2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (25 mg) were added and maintained for about 1 hour. Now temperature raised to 22oC and maintained for about 1 hour and cooled to -5oC. Water (125 ml) was added for about 30 minutes and the temperature of the reaction raised to room temperature. Now the reaction mass was charged into a separating funnel and the organic layer was separated and distilled under vacuum at 40oC for about 20 minutes. Now chased with dichloromethane (125 ml) and cooled to room temperature. Methyltertiarybutylether (150 ml), water (2 ml) and canagliflozin hemihydrate (0.25 gm) seed were added and maintained for about 6 hours. Again water (0.5 ml) was added and maintained for about 6 hours. Now Methyltertiarybutylether (150 ml) was added and distilled under vacuum for about 40 minutes at 40oC. To this Methyltertiarybutylether (150 ml) was added and distilled under vacuum for about 30 minutes and cooled to room temperature. At this temperature water (2 ml) was added and maintained for about 6 hours and filtered and washed with methyltertiarybutylether (25 ml) to give canagliflozin crude (16 gm) compound.
The above wet compound was charged into a round bottom flask and isopropylacetate (100 ml) was added and heated to 55oC. Maintained for about 10 minutes and cooled to room temperature and dichloromethane (12.5 ml), canagliflozin hemihydrate (0.25 gm) seed, water (1 ml) were added and maintained for about 5 hours. Filtered and washed with isopropylacetate (25 ml) to give canagliflozin (15.2 gm). HPLC purity: 99.58%.
The above wet compound was charged into a round bottom flask and charged isopropylacetate (100 ml) and heated to 55oC. Maintained for about 15 minutes and cooled to room temperature and dichloromethane (12.5 ml), canagliflozin hemihydrate (0.25 gm) seed, water (1 ml) were added and maintained for about 18 hours. Filtered and washed with isopropylacetate (25 ml) and dried under vacuum for about 6 hours at 55oC to give canagliflozin hemihydrate (12.5 gm). HPLC purity: 99.77%.
,CLAIMS:CLAIMS
We Claim:
1) A process for the preparation of substantially pure Canagliflozin, comprising:
a) conversion of a compound 5 to Compound 18a’ using compound 13:

wherein Z is selected from H or oxygen protecting group; X is halogen;
b) isolating compound 18a’;
c) converting compound 18a’ to a compound 6;
d) conversion of compound 6 to canagliflozin of claim 1, comprising slow addition of BF3.Etherate to compound 6 under anhydrous conditions:

wherein R1 is an alkyl group.

2) The process of claim 1, wherein the isolated compound 18a’ is in a solid form.

3) The process of claims 1, wherein isolated compound 18a’ is in a crystalline form.
4) The process of claim 1, wherein canagliflozin is in crystalline or amorphous form.

5) A process for the preparation of substantially pure canagliflozin, comprising isolating canagliflozin in the presence of an anti-oxidant.

6) The process according to claim 5, wherein the anti-oxidant is selected from the group comprising butylated hydroxyanisole (BHA), butylated Hydroxytoluene (BHT), sodium metabisulfite (SMB), propyl gallate (PG) or cysteine (CYS).

7) A process for the preparation of substantially pure compound 18a’, comprising: purification of compound 18a’ by precipitation from a solvent.

8) A process of claim 7, wherein compound 18a’ is in a solid form.

9) A process of claim 7, wherein compound 18a’ is in a crystalline form.

10) A process of claim 7, wherein the solvent is an organic solvent or water or mixtures thereof.

11) A process of claim 10, wherein the organic solvent is selected from the group comprising isopropylacetate, dihloromethane, methyltertiarybutyl ether or mixtures thereof.

12) A process for the preparation of canagliflozin, which is substantially free of impurity of formula A, comprising:
a) purification of compound 18a’ by precipitation from a solvent.
b) converting compound 18a’ to canagliflozin which is substantially free of impurity of formula A.

13) A process of claim 12, wherein compound 18a’ is in a solid form.

14) A process of claim 12, wherein compound 18a’ is in a crystalline form.

15) A process of claim 12 wherein the solvent is an organic solvent or water or mixtures thereof.

16) The process according to claim 15, wherein the organic solvent is selected from the group comprising isopropylacetate, dihloromethane, methyltertiarybutyl ether or mixtures thereof.