DESC:Field of the invention

The present invention relates to process for the preparation of amorphous form of Canagliflozin (I), chemically known as (2S, 3R, 4R, 5S, 6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxy methyl-tetrahydro-pyran-3, 4, 5-triol useful as sodium–glucose co-transporters (SGLTs) inhibitors. The present invention provides an improved and commercially viable process for preparation of amorphous Canagliflozin substantially free of impurities.

Background of the invention

Diabetes is one of the most important and prevalent chronic diseases today. Pathophysiology of diabetes remains multi-factorial and hence any drug acting on a particular receptor has limitation arising out due to resistance. Varying degree of insulin resistance and insulin deficiency exist in almost all diabetic patient.

The kidney has a key role in regulating glucose levels by mediating the reabsorption of glucose back into the plasma following filtration of the blood; this is a crucial evolutionary adaptation to maintaining glucose homeostasis and to retaining calories. This process contributes to the sustained elevated serum glucose levels observed in individuals with diabetes, as they have an increased capacity for renal glucose reabsorption. Inhibiting this glucose reabsorption, thereby allowing its excretion in the urine (glycosuria), is therefore emerging as a potential new approach to the treatment of diabetes.
Sodium–glucose co-transporters (SGLTs) are responsible for renal glucose reabsorption, with SGLT2 performing most of this task and the remainder by SGLT1. As SGLT2 inhibitors do not target the major pathophysiology defects in diabetes namely insulin resistance and impaired insulin secretion they represent a potentially promising new option in the treatment of diabetes. There are various SGLT inhibitors which are currently marketed for diabetes like Dapagliflozin, Canagliflozin, Empagliflozin and many are under development like Sergliflozin, Remogliflozin, DSP-3235, LX-4211, TS-07, etc.
Canagliflozin, chemically known as (2S, 3R, 4R, 5S, 6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3, 4, 5-triol is described in US7943788.
Synthetic route described in US7943788 patent is as follows:

Canagliflozin obtained by the process as described in the '788' patent is not satisfactory from purity point of view. The yield of Canagliflozin obtained according to the process described in the '788' patent is very poor and the process involves column chromatography purifications. Methods involving column chromatography purifications cannot be used for large-scale operations, thereby making the process commercially not viable.
The prior art process as described above for the preparation of Canagliflozin have major disadvantages with respect to the formation and removal of process related chemical and polymorphic impurities; poor commercial viability due to time consuming separation methods such as column chromatography and/ or low yields and purity of final and intermediate products. Therefore, there is a need to develop a process, which overcomes the above limitations of prior art process. Present inventors have developed a process which is commercially viable, economical and removes the drawback of prior art.

Object of the invention:

The object of present invention is to provide a process for preparation of amorphous form of Canagliflozin, comprising of following steps:
(i) reacting compound (V) using suitable lithiating reagent in presence of suitable solvent(s) at suitable temperature and further reacting it with compound (VI) to obtain compound (VII) and subsequently with suitable organic acid to obtain compound (VIII);
(ii) reacting compound (VIII) with suitable alkylating reagent in presence of suitable solvent(s) and further reacting it with suitable lewis base and silylating reagent in presence of suitable solvent(s) to provide compound X;
(iii) reacting compound X with suitable oxygen protecting group in presence of suitable base and solvent(s) to give compound of formula (XI) and further purifying the compound (XI) using suitable solvent(s) and
(iv) deprotecting compound (XI) using suitable base and solvent to provide Canagliflozin.
In another object, the present invention further provides a process for preparation of substantially pure amorphous form of Canagliflozin, comprising of following steps:
(i) treating Canagliflozin obtained in step (iv) with suitable solvent(s) and
(ii) isolating amorphous Canagliflozin using suitable techniques.

The present invention further relates to a process for preparation of highly pure amorphous form of Canagliflozin with improved yields making it reliable for large scale production.

Brief description of the Drawings

Figure 1 is an illustration of a PXRD pattern of an amorphous Canagliflozin.

Detailed description of the invention:

The present invention relates to a process for the preparation of Canagliflozin of formula I with high purity and substantially free of impurities. The present invention also relates to a process for purification of Canagliflozin to achieve high purity.
In one embodiment, the present invention process step includes first lithiating the compound (V) using suitable lithium reagent preferably alkyl lithium reagent in presence of suitable solvent(s) at suitable temperature under inert conditions to obtain intermediate compound and subsequently reacting it with the compound (VI) to obtain insitu compound (VII) and further treating it using suitable organic acid to provide compound (VIII) as shown below.

Wherein M is lithium, Z is a protecting group trimethylsilyl (TMS).
In another embodiment, the present invention process step includes alkylating compound (VIII) using suitable reagent agent preferably methane sulfonic acid in presence of suitable solvent(s) to obtain compound (IX) and further reducing it with suitable Lewis acid preferably boron trifluoro etherate and silylating reagent preferably triethylsilane in presence of suitable solvent(s) to obtain compound of (X) which is subsequently treated with suitable oxygen protecting group preferable selected from acid anhydrides more preferably propionyl anhydride in presence of suitable base and solvent(s) to obtain the compound (XI) as shown below.

In another embodiment, the present invention process step includes purification of compound (XI) using suitable solvent(s) to obtain compound (XI) in substantially pure form.
In another embodiment, the present invention process step further includes deprotection of substantially pure form of compound (XI) using suitable base preferable selected from suitable alkali metal hydroxides or alkali metal alkoxides in presence of suitable solvent(s) at suitable temperature using suitable techniques to provide amorphous form of Canagliflozin as shown below.

In another embodiment, the present invention process for preparation of amorphous form of Canagliflozin, comprising of following steps:
(i) reacting compound (V) using suitable lithiating reagent preferably selected from alkyl lithium reagent in presence of suitable solvent(s) at suitable temperature and further reacting it with compound (VI) to obtain compound (VII) and subsequently with suitable organic acid preferably trifluoroacetic acid to obtain compound (VIII);
(ii) reacting compound (VIII) with suitable alkylating reagent preferably methane sulfonic acid in presence of suitable solvent(s) and further reacting it with suitable lewis base preferably boron trifluoro etherate and silylating reagent preferably triethylsilane in presence of suitable solvent(s) to provide compound (X);
(iii) reacting compound (X) with suitable oxygen protecting group preferably acid anhydride more preferably propionyl anhydride in presence of suitable base and solvent(s) to give compound of formula (XI) and further purifying the compound (XI) using suitable solvent(s) and
(iv) deprotecting compound (XI) using suitable base and solvent to provide Canagliflozin.

In another embodiment, the present invention further provides a process for preparation of substantially pure amorphous form of Canagliflozin, comprising of following steps:
(i) treating Canagliflozin obtained in step (iv) with suitable solvent(s) and
(ii) isolating amorphous Canagliflozin by using suitable techniques.

Suitable solvents used in process of present invention includes but not limited to alcohols, ethers, esters, hydrocarbons, nitriles, chlorinated solvents, water or mixtures thereof.
Alcohols include but not limited to such as methanol, ethanol, propanol, butanol, octanol, ethanediol, 1, 2-propane diol and S (+)-1, 2-propane diol.
Ethers include but not limited to such as diethyl ether, di isopropyl ether, di butyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran and cyclo pentyl methyl ether.
Hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclo hexane and tetraline.
Halogenated solvents include but not limited to such as chloroform, carbon tetrachloride, methylene chloride and 1, 2-dichloro ethane.
Esters include but not limited to such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and n-propyl acetate.
Nitriles include but not limited to such as acetonitrile, propionitrile and benzonitrile.
Alkyl lithium use in present invention process includes but not limited to such as methyl lithium, n-butyl lithium and t-butyl lithium.
Organic acid used in present invention process includes but not limited to such as p-toluenesulfonic acid, methanesulfonic acid and trifluoroacetic acid.
Silylating reagents used in present invention process includes but not limited to such as tri-lower alkyl silanes such as triethylsilane, triisopropylsilane or polyalkyl silanes such as poly(methylhydrosiloxane).
Lewis acids used in present invention process includes but not limited to such as boron trifluoride diethyl ether complex, aluminum chloride, titanium tetrachloride.
Base used in present invention process includes but not limited to such as alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and alkali metal alkoxide such as sodium methoxide and sodium ethoxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate and calcium hydroxide.
In another embodiment, the suitable temperature in overall process steps ranges from -78oC + 5oC to 200oC + 5oC, more preferably ranges from -78oC + 5oC to 100oC + 5oC.
In yet another embodiment, the present invention provides a process step for the preparation of an amorphous form of Canagliflozin by heating Canagliflozin and then cooling to obtain amorphous form of Canagliflozin.
In another embodiment, Canagliflozin obtained according to the present invention process is in amorphous form and free from other impurities.
In another aspect, the amorphous product obtained may be dried, sieved and milled to obtain suitable particle size range.
In another embodiment, Canagliflozin obtained is in substantially pure form.
Suitable techniques used in present invention process includes but not limited to such as distillation, distillation under reduced pressure or vacuum, evaporation, solvent-antisolvent, acid-base, spray drying, freeze drying or lyophilization
One of the embodiments of the present invention is to provide process for the preparation of an amorphous form of Canagliflozin comprising the step of dissolving Canagliflozin in a suitable solvent and recrystallize by using suitable antisolvent to obtain amorphous form of Canagliflozin.
The following examples are provided to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it is not intended in any way to limit the scope of the present invention.

Example-1: Preparation of 1-(1-Hydroxyglucopyranosyl)-4-methyl-3-[5-(4-fluoro phenyl)-2-thienylmethyl] benzene (Hydroxy) (VII)
Charge Tetrahydrofuran (4 L) to RB flask and cool it to -68°C to -72°C under nitrogen atmosphere. To this solution was added dropwise 2.5 M n-butyl lithium (1.23 L) followed by addition of solution of (5-Bromo-2-methylphenyl) [5-(4-fluorophenyl) thiophen-2-yl]methanone (1.0 Kg) in tetrahydrofuran (3 L). The mixture was stirred for 45-60 minutes at same temperature. The reaction mixture was added to a solution of 2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono-1,5-lactone (VI) (1.55 Kg) in tetrahydrofuran (2.0 L) at -60°C to -80°C under nitrogen atmosphere and the mixture was further stirred at the same temperature for 2 hour to give a lactol compound (VII). Without isolating this compound, the reaction mixture was added slowly to an aqueous solution of Trifluoroacetic acid (0.947 Kg) in water at -7±2°C and the mixture was stirred at -4°C to 0°C for 2 hour. Toluene was added to the reaction mixture followed by sodium bicarbonate solution. The mixture were extracted with toluene, the solvent was evaporated under reduced pressure, the residue was stripped with Ethyl acetate to give 1-(1-Hydroxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene (Hydroxy) (0.80 Kg)

Example-2: Preparation of Tetrapropionyl Canagliflozin (XI)
A solution of the 1-(1-Hydroxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene (Hydroxy) (1.0 Kg) in Methanol (6 L) was cooled to 3°C to 7°C, under nitrogen atmosphere, and thereto were slowly added methanesulfonic acid (0.21 Kg), and the mixture was stirred for 4 hrs at same temperature. Dichloromethane (4L) was added to the reaction mixture followed by addition of sodium bicarbonate solution. The organic layer was separated and washed with water. The organic layer was evaporated under reduced pressure; the residue was stripped with Dichloromethane to give compound of formula (IX). A solution of compound (IX) in Dichloromethane (10 L) was cooled to -36°C to -40°C, under nitrogen atmosphere, and thereto were slowly added successively triethylsilane (0.76 Kg), and Borontrifluoride etherate (0.92 Kg). The mixture was stirred for 3-4 hours at -40±2°C. Water was added to reaction mixture. The organic layer was separated out, the solvent was evaporated under reduced pressure to yield compound (X). To a solution of compound (X) in Tetrahydrofuran (5.0 Lit), 4-Dimethylaminopyridine (0.132 Kg) was at 23°C to 27°C. The mixture was cooled, and thereto Propionyl anhydride (1.27 Kg) was added slowly at 0±2°C. The mixture was stirred for 10-15 min at 0±2°C and for 6 hrs at 7±3°C. To the mixture were added Water, extracted with Ethyl acetate and dil. HCl. The organic layer was separated and washed with sodium bicarbonate and evaporated under reduced pressure to yield solid, a solid was crystallize with aqueous methanol to yield compound of formula (X) (1.0 Kg).

Example-3: Purification of Tetrapropionyl Canagliflozin (XI)
Tetrapropionyl Canagliflozin (1 Kg) was suspended in methanol (11 L) and ethyl acetate (0.5 L). The mixture was warmed till clear, than after cooled & stirred for 4 hours. The powder was collected by filtration and washed with mixture of Methanol & ethyl acetate and dried to give the desired Tetrapropionyl Canagliflozin (XI) (0.5 Kg).

Example-4: Preparation of Canagliflozin (I)
A solution of sodium hydroxide (0.3 Kg) in water (3.0 L) was added to a solution of Tetra Propionyl Canagliflozin (1.0 Kg) in methanol (4.0 L) and stirred at 50±2°C for 3 hours. The mixture was cooled to 30±2°C and diluted hydrochloric acid solution was added till the pH of solution maintained between 6.0 and 7.0. Ethyl acetate was added to the reaction mixture and stirred for 10-15 min at 25±3°C. The organic layer was separated and sodium bicarbonate solution was added to it and again stirred for 10-15 min at 25±3°C. The organic layer was separated and washed with water and then after treated with Activated carbon and filtered through hyflow bed. The solvent was evaporated under reduced pressure. Toluene (4.0 L) was added to residue, warmed solution till clear, thereto were added n-Heptane (10.0 L), the powder was collected by filtration and washed with n-Heptane and dried to give the amorphous form of Canagliflozin (I) (0.6 Kg).
,CLAIMS:Claims:

1. A process for preparation of amorphous form of Canagliflozin (I)

comprising of following steps:
(i) reacting compound (X) with suitable oxygen protecting group preferably acid anhydride more preferably propionyl anhydride in presence of suitable solvent(s) to give compound of formula (XI)
(ii) further purifying the compound (XI) using suitable solvent(s) and
(iii) deprotecting compound (XI) using suitable base and solvent(s) to provide Canagliflozin.
(iv) further treating Canagliflozin obtained in step (iii) with suitable solvent(s) to obtain
amorphous Canagliflozin.

2. The process of claim 1 further comprising of following steps:
(i) reacting compound (V) using n-butyl lithium in presence of suitable solvent(s) and further reacting it with compound (VI) to obtain compound (VII) and subsequently reacting with trifluoroacetic acid to obtain compound (VIII);
(ii) reacting compound (VIII) with methane sulfonic acid in presence of suitable solvent(s) and further reacting it with boron trifluoro etherate and triethylsilane in presence of suitable solvent(s) to provide compound (X).

3. The process according to claim 1 and 2, wherein solvent(s) comprises of one or more of alcohols selected from methanol, ethanol, propanol, butanol, octanol, ethanediol, 1, 2-propane diol and S (+)-1, 2-propane diol; ethers selected from diethyl ether, di isopropyl ether, di butyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran and cyclo pentyl methyl ether; esters selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and n-propyl acetate; hydrocarbons selected from benzene, toluene, xylene, pentane, hexane, heptane, cyclo hexane and tetraline; nitriles selected from acetonitrile, propionitrile and benzonitrile; chlorinated solvents selected from chloroform, carbon tetrachloride, methylene chloride and 1, 2-dichloro ethane; water or mixtures thereof.
4. The process according to claim 1, wherein base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium methoxide, sodium ethoxide and calcium hydroxide.
5. Amorphous Canagliflozin obtained according to process of claim 1 is in substantially pure form and free from other impurities.
6. A compound of formula (XI)

Dated this 07th day of October 2016.