DESC:Form-2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

CANAGLIFLOZIN SUBSTANTIALLY FREE OF HYDROPEROXIDE IMPURITY

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
KONDAPUR, HITECH CITY,
HYDERABAD, 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed:
FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Canagliflozin of formula I which is substantially free of hydroperoxide impurity.

Formula I

BACKGROUND OF THE INVENTION

Canagliflozin is chemically known as (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]-methyl]-4-methylphenyl]-D-glucitol, which is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of the type-2 diabetes mellitus. Canagliflozin is marketed in USA and Europe under the trade name INVOKANA® in the form of tablets having strengths 100 mg and 300 mg.

Type-2 diabetes mellitus (non-insulin-dependent diabetes mellitus or NIDDM) is a metabolic disorder involving deregulation of glucose metabolism and insulin resistance, and long-term complications involving the eyes, kidneys, nerves, and blood vessels. Type 2 diabetes mellitus usually develops in adulthood (middle life or later) and is described as the body's inability to make either sufficient insulin (abnormal insulin secretion) or its inability to effectively use insulin (resistance to insulin action in target organs and tissues). More particularly, patients suffering from Type 2 diabetes mellitus have a relative insulin deficiency. That is, in these patients, plasma insulin levels are normal to high in absolute terms, although they are lower than predicted for the level of plasma glucose that is present.
Canagliflozin and its pharmaceutically acceptable salts first time disclosed in US 7,943,788 (IN 232231). US ‘788 also disclosed a process for the preparation of Canagliflozin, which is as shown below:

US 7,943,582 (IN 3871/CHENP/2009) discloses crystalline Canagliflozin hemihydrate. This patent also discloses the preparation of Canagliflozin hemihydrate, by crystallizing Canagliflozin from a good solvent and water, optionally containing a poor solvent; wherein the good solvent is selected from ketones, esters, alcohols and a mixture of these solvents; poor solvent is selected from alkanes, aromatic hydrocarbons, ethers and a mixture of these solvents.

Canagliflozin obtained by the processes described in the prior art are often associated with various impurities especially hydroperoxide impurity of formula (II). Unacceptable amounts of impurities are generally formed along with Canagliflozin.

Formula II

Like any Active pharmaceutical ingredient, Canagliflozin can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in Canagliflozin or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.

It is also known in the art that impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage. Regulatory authorities worldwide require that drug manufacturers isolate, identify and characterize the impurities in their products. Furthermore, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that any impurities are present in the lowest possible levels, even if structural determination is not possible.

As is known by those skilled in the art, controlled of process related impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.

The present invention offers a process for the preparation of Canagliflozin which is substantially free from hydroperoxide impurity.
OBJECTIVE

The primary objective of the present invention relates to a process for the preparation of Canagliflozin which is substantially free from hydroperoxide impurity.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Canagliflozin which is substantially free from hydroperoxide impurity, which comprises:
a) providing a solution of Canagliflozin or co-crystals or solvate thereof in a solvent treated with an antioxidant;
b) optionally treating the solution of step (a) with a base.
c) adding an anti-solvent to step (a) mass or vice-versa; and
d) isolating Canagliflozin.

The present invention also relates to a process for the preparation of Canagliflozin which is substantially free from hydroperoxide impurity, which comprises:
a) providing a solution of Canagliflozin in a solvent;
b) treating resulting solution with an antioxidant;
c) adding an anti-solvent to step (b) mass or vice-versa; and
d) isolating Canagliflozin.

The present invention further relates to a process for the preparation of Canagliflozin DL-proline co-crystal which is substantially free from hydroperoxide impurity, which comprises:
a) providing a solution or a suspension comprising antioxidant and a organic solvent;
b) adding Cangaliflozin into a solution or a suspension of step (a);
c) treating the solution of step (b) with DL-proline in a solvent; and
d) crystallizing Canagliflozin DL-proline co-crystals.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Canagliflozin which is substantially free from hydroperoxide impurity, which comprises:
a) providing a solution of Canagliflozin or co-crystals or solvate thereof in a solvent treated with an antioxidant;
b) optionally treating the solution of step (a) with a base.
c) adding an anti-solvent to step (a) mass or vice-versa; and
d) isolating Canagliflozin.

In another embodiment of the present invention, organic solvent used in step (a) is selected from the group comprising of methylene chloride, ethylene chloride, ethyl ether, methyl tert-butyl ether, diethyl ether, propyl acetate, methyl acetate, butyl acetate, isopropyl acetate, ethyl acetate, methyl isobutyl ketone, toluene and/or mixtures thereof.

In yet embodiment of the present invention, co-crystals used in step (a) is selected from amino acid co-crystal such as alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan or methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid or glutamic acid. The amino acid used may be either optically active or racemic form. The optically active amino acid may have either L or D configuration.

In yet another embodiment of the present invention, base is selected from the group comprising of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and/or mixtures thereof.

In yet embodiment of the present invention, solvate may be defined as a compound formed by solvation, for example as a combination of solvent molecules with molecules or ions of a solute. Well known solvent molecules include water, alcohols and other polar organic solvents.

In yet another embodiment of the present invention, the organic solvent used in step (a) is treated with an antioxidant.

The antioxidant used for treating the solvent used in step (a) is selected from BHA (butylated hydroxyanisole), BHT (dibutylhydroxytoluene), PG (propyl gallate), TBHQ (tert-butyl hydroquinone), SMBS (sodium metabisulfite) & TPP (triphenyl phosphine).

In another embodiment of the present invention the organic solvent used in step (a) is treated with antioxidant which involves the dissolution of catalytic quantity of antioxidant in an organic solvent to obtain organic solvent which is treated with an antioxidant.

In yet another embodiment of the present invention, the organic solvent is optionally concentrated to remove water and striped of with same or different organic solvent before the addition of anti-solvent.

In yet another embodiment of the present invention, anti-solvent is selected from the group comprising of hydrocarbons such as hexane, heptane, cyclohexane and the like.

The present invention also relates to a process for the preparation of Canagliflozin which is substantially free from hydroperoxide impurity, which comprises:

a) providing a solution of Canagliflozin in a solvent;
b) treating resulting solution with an antioxidant;
c) adding an anti-solvent to step (c) mass or vice-versa; and
d) isolating Canagliflozin.

In another embodiment of the present invention, organic solvent used in step (a) is selected from the group comprising of methylene chloride, ethylene chloride, ethyl ether, methyl tert-butyl ether, diethyl ether, propyl acetate, methyl acetate, butyl acetate, isopropyl acetate, ethyl acetate, methyl isobutyl ketone, toluene and/or mixtures thereof.

The antioxidant used for treating the solvent used in step (b) is selected from BHA (butylated hydroxyanisole), BHT (dibutylhydroxytoluene), PG (propyl gallate), TBHQ (tert-butyl hydroquinone), SMBS (sodium metabisulfite) & TPP (triphenyl phosphine).

In yet another embodiment of the present invention, the organic solvent is optionally concentrated to remove water and striped of with same or different organic solvent before the addition of anti-solvent.

In yet another embodiment of the present invention, anti-solvent is selected from the group comprising of hydrocarbon such as hexane, heptane, cyclohexane and the like.

The present invention further relates to a process for the preparation of Canagliflozin DL-proline co-crystal which is substantially free from hydroperoxide impurity, which comprises:
a) providing a solution or a suspension comprising antioxidant and a organic solvent;
b) adding Cangaliflozin into a solution or a suspension of step (a)
c) treating the solution of step (b) with DL-proline in a solvent; and
d) crystallizing Canagliflozin DL-proline co-crystals.

In yet another embodiment of the present invention, the solvent used in step (a) & step (c) is selected from water or mixture of water and water miscible organic solvent; wherein water miscible organic solvent is selected from methanol, ethanol, 1-propanol, isopropanol and/or mixtures thereof.

The antioxidant used for treating the solvent used in step (a) is selected from BHA (butylated hydroxyanisole), BHT (dibutylhydroxytoluene), PG (propyl gallate), TBHQ (tert-butyl hydroquinone), SMBS (sodium metabisulfite) & TPP (triphenyl phosphine).

Canagliflozin which is used as a starting material in the present invention can be in any physical form such as crystalline, amorphous, mixture of crystalline and amorphous, solvates, hydrates etc., Canagliflozin that may be used as the input for the processes of the present invention may be obtained by any process including the processes described in the art and optionally can be purified using any method known in the art to enhance its chemical purity.

By “substantially free of hydroperoxide impurity” is meant that Canagliflozin prepared in accordance with the present invention contains less than about 0.5%, more preferably less than about 0.1%, and even more preferably, less than about 0.05% of the corresponding peroxide impurity as characterized by HPLC and NMR.

Canagliflozin obtained by the process disclosed herein preferably contains hydroperoxide impurity in an amount of less than about 0.25%, more preferably less than 0.15%, still more preferably less than 0.05% and most preferably less than 0.02%.
The total purity of the Canagliflozin obtained by the process disclosed herein is of greater than about 99.9%, specifically greater than about 99.95%, and more specifically greater than about 99.99% as measured by HPLC.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention in any manner whatsoever.

EXAMPLES:

EXAMPLE – 1
PROCESS FOR PREPARING CANAGLIFLOZIN SUBSTANTIALLY FREE OF HYDROPEROXIDE IMPURITY
In a round bottom flask, Canagliflozin DL-proline co-crystal (5 g) in DM water (50 ml), sodium carbonate solution (10 ml, 10% w/w) was added at 20-30 °C. To the reaction mass, methylene chloride (40 ml) and methanol (5 ml) were added at 20-30 °C and stirred for 30 min. Organic layer contains product was separated and washed with mixture of DM water (22.5 ml) and methanol (2.5 ml) at 20-30 °C. The separated organic layer was distilled under vacuum at 20-30°C. The residue was dissolved in methyl-tert-butyl ether solution which is treated with BHT (10 ml) at 20-30°C. The solution was treated with carbon at 45-50 °C, filtered, washed with methyl-tert-butyl ether and cooled to 20-30 °C. The obtained solution was dropped to cyclohexane (100 ml) at 20-25 °C and stirred. Solid was filtered under nitrogen atmosphere and dried at 55-60°C.
Yield: 2.95 gm; Hydroperoxide content by HPLC; 0.27 ppm.

EXAMPLE – 2
PROCESS FOR PREPARING CANAGLIFLOZIN DL-PROLINE CO-CRYSTAL SUBSTANTIALLY FREE OF HYDROPEROXIDE IMPURITY
Suspend BHT (0.55g) in IPA (350 ml) at 20-30 °C. Heat the suspension to 45-50 °C and continue stirring at this temperature for 30 min. Took 200 ml of the IPA solution, under N2 atmosphere and Cangaliflozin (25gm) was added at 45-50 °C. The obtained solution was treated with DL-proline (9.66 gm) which is dissolved in mixture of IPA solution (100ml) and DM water (10 ml) at 70-80 °C and stirred for 4 hours. Lowering the temperate of solution to 60-65 °C and stir for 1 hour to precipitate out DL-proline co-crystal of Canagliflozin as slurry. Cool the obtained slurry slowly to 15-20 °C and continue the stirring for 2 hours. Filter the obtained product at 15-20 °C and washed with (50 ml, 20-30 °C) IPA. Dried the product at 50-60°C.
Yield: 30 gm: Hydroperoxide content by HPLC: Not detected.

EXAMPLE – 3
PROCESS FOR PREPARING CANAGLIFLOZIN SUBSTANTIALLY FREE OF HYDROPEROXIDE IMPURITY
Canagliflozin (0.75g) was contaminated with Canagliflozin DL-proline (4.25gm) in a mixture of methanol (10ml) and water (5ml) at 30-35 °C to get clear solution (Hydroperoxide impurity in this solution is 481 ppm). To this clear solution, Sodium metabisulfite (0.05g) was added at 30-35 °C and stirred for 1h at 30-35 °C. Dilute the obtained reaction mass with water (45ml) and stirred for 10 mins. sodium carbonate solution (10ml, 10% w/w) was added at 25-30 °C and stirred the solution for 30mins. Organic layer contains product was separated and washed with mixture of DM water (22.5 ml) and methanol (2.5 ml) at 20-30 °C. The separated organic layer was distilled under vacuum at 20-30°C. The residue was dissolved in methyl-tert-butyl ether solution at 40-45°C. The solution was treated with carbon at 45-50 °C, filtered, washed with methyl-tert-butyl ether and cooled to 20-30 °C. The obtained solution was dropped to cyclohexane (100 ml) at 20-25 °C and stirred. Solid was filtered under nitrogen atmosphere and dried at 55-60°C.
Yield: 3.25g: Hydroperoxide content by HPLC: 74 ppm.
EXAMPLE – 4
PROCESS FOR PREPARING CANAGLIFLOZIN SUBSTANTIALLY FREE OF HYDROPEROXIDE IMPURITY
Suspend ‘Complex of Canagliflozin with DL-proline’ (100g) (Hydroperoxide impurity content is 271 ppm) in DM water (1000ml) at 20-30 °C. To the above suspension, add sodium carbonate solution (200 ml, 10% w/w) was added at 25-30 °C. To the reaction mass, methylene chloride (200 ml) and methanol (100 ml) were added at 20-30 °C and stirred for 30 min. Organic layer contains product was separated and washed with mixture of DM water (450) and methanol (50 ml) at 20-30 °C. Add triphenyl phosphine (TPP) (0.2g) at 20-30 °C to this organic layer and continue the stirring for 10 mins. The organic layer was distilled under vacuum at 35-45 °C until the water content of the concentrated mass is less than or equal to 0.5% w/w and no more methylene chloride distils out. The residue was dissolved in methyl-tert-butyl ether (400 ml) at 40-45°C. The solution was treated with carbon at 45-50 °C, filtered, washed with methyl-tert-butyl ether and cooled to 20-30 °C. The obtained solution was dropped to cyclohexane (2000 ml) at 20-25 °C and stirred. Solid was filtered under nitrogen atmosphere and dried at 55-60°C.
Yield: 70 gm; Hydroperoxide content by HPLC; Not detected. ,CLAIMS:We Claim
1. A process for the preparation of Canagliflozin which is substantially free from hydroperoxide impurity, comprising the steps of:
a) providing a solution of Canagliflozin or co-crystals or solvate thereof in a solvent treated with an antioxidant;
b) optionally treating the solution of step (a) with a base.
c) adding an anti-solvent to step (a) mass or vice-versa; and
d) isolating Canagliflozin.

2. The process according to claim 1, wherein the solvent used in step (a) is selected from the group comprising of methylene chloride, ethylene chloride, ethyl ether, methyl tert-butyl ether, diethyl ether, propyl acetate, methyl acetate, butyl acetate, isopropyl acetate, ethyl acetate, methyl isobutyl ketone, toluene and/or mixtures thereof.

3. The process according to claim 1, wherein the co-crystals used in step (a) is selected from amino acid co-crystal such as alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan or methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid or glutamic acid.

4. The process according to claim 1, wherein the antioxidant used for treating the solvent used in step (a) is selected from BHA (butylated hydroxyanisole), BHT (dibutylhydroxytoluene), PG (propyl gallate), TBHQ (tert-butyl hydroquinone), SMBS (sodium metabisulfite) & TPP (triphenyl phosphine).

5. The process according to claim 1, wherein the base used in step (b) is base is selected from the group comprising of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and/or mixtures thereof.

6. The process according to claim 1, wherein the anti-solvent used in step (c) is selected from the group comprising of hydrocarbons such as hexane, heptane, cyclohexane.

7. A process for the preparation of Canagliflozin which is substantially free from hydroperoxide impurity, comprising the steps of:
a) providing a solution of Canagliflozin in a solvent;
b) treating resulting solution with an antioxidant;
c) adding an anti-solvent to step (c) mass or vice-versa; and
d) isolating Canagliflozin.

8. The process according to claim 7, wherein the solvent used in step (a) is selected from the group comprising of methylene chloride, ethylene chloride, ethyl ether, methyl tert-butyl ether, diethyl ether, propyl acetate, methyl acetate, butyl acetate, isopropyl acetate, ethyl acetate, methyl isobutyl ketone, toluene and/or mixtures thereof.

9. The process according to claim 7, wherein the antioxidant used for treating the solvent used in step (b) is selected from BHA (butylated hydroxyanisole), BHT (dibutylhydroxytoluene), PG (propyl gallate), TBHQ (tert-butyl hydroquinone), SMBS (sodium metabisulfite) & TPP (triphenyl phosphine).

10. The process according to claim 7, wherein the anti-solvent used in step (c) is selected from the group comprising of hydrocarbons such as hexane, heptane, cyclohexane.