DESC:Field of Invention
The present invention relates to a new process for the preparation of a sodium glucose co-transporter-2 (SGLT-2) inhibitor. More particularly, the present invention relates to a new process for the preparation of empagliflozin, a ß-C-arylglucoside compound. Also disclosed are novel intermediates obtainable from the new process and process for preparing the same. The product obtained may be amorphous or crystalline, preferably stable amorphous form, substantially free of any crystalline form.
The present invention also relates to an amorphous solid dispersion of empagliflozin with pharmaceutically acceptable carriers, preparation process thereof.
Background of the Invention
The present invention is directed to a new process for the preparation of a SGLT-2 inhibitor compound i.e., Empagliflozin. The present invention also relates to novel intermediates useful for the synthesis of empagliflozin and preparation process thereof.
A significant number of SGLT-2 inhibitors, commonly known as gliflozins, are currently under clinical development, of which ß-C-arylglucosides constitute a major portion of drugs under development. So far, members of gliflozin class of drugs approved for human use are Dapagliflozin, Canagliflozin, Empagliflozin and Ipragliflozin.
Empagliflozin is a sodium glucose co-transporter 2 inhibitor chemically known as (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl ]phenyl]-D-glucitol and has the following structural formula:

Empagliflozin is approved by FDA for human use in the form of oral tablets under the proprietary name, JARDIANCE® marketed by Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly & Company. It is indicated for the prevention and/or treatment of metabolic disorders, particularly type 2 diabetes.
Several methods are known in the art for the synthesis of ß-C-arylglucosides, useful as SGLT-2 inhibitors.
While there are different approaches to the preparation of C-arylglycosides, highly efficient methods for their preparation have not yet been realized for certain functionalized ß-C-arylglucosides. Inefficiencies known in the art for preparing ß-C arylglucosides include (1) a lack of stereo selectivity during formation of the desired ß anomer of the C-arylglucoside, (2) relatively long synthetic routes (linear syntheses),
(3) the use of toxic metals such as palladium, and/or (4) uneconomic protection of hydroxyl groups.
In the view of the above facts and drawbacks, it is ideal to prepare safe, economic, cost effective synthetic route for the preparation of SGLT-2 inhibitors, particularly empagliflozin, preferably in mixture of crystalline and amorphous, more preferably amorphous form.
Hence it is an object of the present invention, to provide a new stereoselective, efficient and industrially scalable process for the preparation of empagliflozin, as well as to provide useful intermediates in the desired configuration at relatively low costs.
Object of invention
An object of the present invention is to provide a new cost-effective, efficient process for the preparation of a ß-C-arylglucoside compound, preferably empagliflozin.
Another object of the invention is to provide novel compounds useful as intermediates for the stereoselective synthesis of empagliflozin and process for preparing the same.
Further object of the invention is to provide novel intermediates and their use for the preparation of empagliflozin, via synthetic procedures which allow manufacture of the product on commercial scale with a low technical expenditure and high space/time yield.
It is also an object of the invention to provide a new process for the preparation of empagliflozin and novel intermediates thereof in amorphous or crystalline form, or a mixture thereof, preferably amorphous form.
Yet another object of the invention is to provide an amorphous empagliflozin from the new process in substantially pure form, characterised by a purity of about 99% or more by HPLC, free of any residual solvents.
Further an object of the invention is to provide amorphous empagliflozin in the form of solid dispersion comprising pharmaceutically acceptable carriers, and/or amorphous/crystalline complexes with amino acids, preparation process thereof.
Summary of Invention
In one aspect, the present invention provides a new process for preparing empagliflozin, comprising reducing a compound of formula VII in the presence of a reducing agent to obtain empagliflozin of formula VIII.

In a second aspect, the present invention provides a new process for preparing empagliflozin, comprising the step of in-situ hydrolysing a compound of formula VIIa, wherein R1 is a hydroxy protecting group, to obtain a compound of formula VII,

and further reacting the compound of formula VII with a reducing agent to obtain empagliflozin.
In a third aspect, the present invention provides a new process for preparing empagliflozin, alternatively by exhaustive reduction of the isolated compound of formula VIIa to obtain empagliflozin.

In a fourth aspect, the present invention provides a new process for preparing empagliflozin, said process comprising, coupling a compound of formula VI, wherein X is a leaving group (selected from halogen, mesylate, tosylate, brosylate, besylate, nosylate and triflate) and R1 is a hydroxy protecting group, with tetrahydrofuran-3-ol of desired configuration in the presence of a base and suitable solvent, followed by insitu hydrolysis of the resulting compound of formula VIIa to isolate a compound of formula VII, represented as follows:


Reacting the compound of formula VII with a reducing agent to obtain empagliflozin.
In a fifth aspect, the present invention provides a new process for preparing empagliflozin, alternatively comprising coupling a compound of formula VI, wherein X is a leaving group (selected from halogen, mesylate, tosylate, brosylate, besylate, nosylate and triflate) and R1 is a hydroxy protecting group, with tetrahydrofuran-3-ol of desired configuration in the presence of a base and suitable solvent, to isolate a compound of formula VIIa, which is exhaustively reduced to obtain a compound of formula VIII (empagliflozin) represented as follows:


In a sixth aspect, the present invention provides a new process for preparing empagliflozin, characterized in that the process comprises preparing a compound of formula VI, by reacting a compound of formula V, wherein R1 is defined as hereinbefore with a compound B, wherein X is defined as hereinbefore, represented as follows:

In a seventh aspect, the present invention provides a new, stereoselective, economic process for preparing empagliflozin of formula VIII, said process comprising the following steps: (a) treating a compound of formula V with a compound B in the presence of a lewis acid and solvent to obtain a compound of formula VI; (b) coupling the compound of formula VI with tetrahydrofuran-3-ol in a base and suitable solvent to obtain a compound of formula VIIa, which is in-situ hydrolyzed to isolate a compound of formula VII; (c) reducing the compound of formula VII with a reducing agent to yield empagliflozin.
In an eighth aspect, the present invention provides a new, stereoselective, economic process for preparing empagliflozin of formula VIII, said process comprising the following steps: (a) treating a compound of formula V with a compound B in the presence of a lewis acid and solvent to obtain a compound of formula VI; (b) coupling the compound of formula VI with tetrahydrofuran-3-ol in a base and suitable solvent to isolate a compound of formula VIIa, (c) exhaustively reducing the compound of formula VIIa to yield empagliflozin.
In a ninth aspect, the new process of the present invention involves the use of a compound of formula V, which may be prepared according to a method reported in the literature (for example, see J. Org. Chem., 2007, 72 (25), pp 9746-9749) or by methods known to persons skilled in the art.
In a tenth aspect, the present invention provides a novel intermediate obtainable from the new process, for the preparation of empagliflozin, represented as follows:

Wherein R1 is a hydroxy protecting group selected from acyl (acetyl, propionyl, pivaloyl, benzoyl) groups; X is a leaving group selected from halogen (fluorine, chlorine, bromine, iodine), mesylate, tosylate, brosylate, besylate, nosylate and triflate.
In an eleventh aspect, the present invention provides a novel intermediate obtainable from the new process for the preparation of empagliflozin, represented as follows:

Wherein R1 is hydrogen or a hydroxy protecting group selected from acyl (acetyl, propionyl, pivaloyl, benzoyl) groups.
In a twelfth aspect, the new process of the present invention provides substantially amorphous empagliflozin characterized by a purity of about 99.5 % or more as determined by HPLC, with no detectable amount of any crystalline form, free of any residual solvents, stable for 12 months on storage at 5 ± 3 °C.
In a thirteenth aspect, the present invention provides a process for preparing amorphous empagliflozin, comprising subjecting crude empagliflozin of formula VIII to silica gel chromatography to obtain the eluent which is evaporated by the techniques such as rotary evaporation, lyophilization, spray drying.
In a fourteenth aspect, the present invention provides a process for the preparation of amorphous empagliflozin comprising: a) dissolving crude empagliflozin of formula VIII in a suitable solvent or mixtures thereof; b) optionally filtering the undissolved particles; c) removing the solvent by a suitable technique as described herein; and/or d) drying the solid at suitable temperature.
In a fifteenth aspect, the new process of the present invention provides amorphous solid dispersions of empagliflozin with pharmaceutically acceptable polymers, characterized by a purity of about 99.5% or more as determined by HPLC, with no detectable amount of any crystalline form, free of any residual solvents, stable for 6 months on storage at 25 ± 2 °C and a relative humidity of 60 ± 5%.
In a sixteenth aspect, the process for preparing amorphous empagliflozin solid dispersions comprises milling a solid-solid mixture of empagliflozin and a polymer.
In a seventeenth aspect, the new process of present invention provides a process for preparing amorphous solid dispersion of empagliflozin with one or more pharmaceutically acceptable polymer or mixtures thereof, comprising: (a) dissolving empagliflozin and a pharmaceutically acceptable polymer in suitable solvent or mixtures thereof; (b) optionally filtering the un-dissolved particles; (c) isolating amorphous solid dispersion of empagliflozin with a pharmaceutically acceptable carrier; (d) optionally drying the amorphous solid dispersion of empagliflozin.
Detailed description of the invention
The present disclosure relates to a new process for the preparation of empagliflozin. Also disclosed are novel intermediates obtainable from the new process of the present invention. Together, the novel intermediates and new process provide an economic, efficient process for the preparation of empagliflozin.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
As used herein, the term "SGLT-2" refers to sodium glucose co-transporter 2, which is a sodium-dependent glucose transport protein. SGLT-2 is the primary co transporter involved in renal glucose reabsorption. As used herein, "SGLT-2 inhibitor" refers to any molecule that can modulate SGLT-2 activity in vitro or in vivo.
As used herein, the term “protecting group” refers to a compound that is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or “deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as “protecting groups”. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry [See e.g. Protective Groups in Organic Synthesis by T. W. Greene and P. G. M. Wuts, 2nd Edition; John Wiley & Sons, New York (1991)].
As used herein, the term “leaving group” refers to an atom or group of atoms which breaks away from the rest of the molecule, taking with it the electron pair which used to be the bond between the leaving group and the rest of the molecule. According to the present invention, the leaving groups include without limitation, halides such as fluoride, chloride, bromide and iodide, and sulfonate esters such as mesylate (OMs), tosylate (OTs), brosylate (OBs), besylate (OBS), nosylate (ONs) and triflate (OTf).
The term “exhaustive reduction” as used herein refers to the reduction of all carbonyl C-O bonds including keto and ester groups in the molecule.
As used herein, the term “solid dispersion” means any solid composition having at least two components. In certain embodiments, a solid dispersion as disclosed herein includes empagliflozin dispersed among at least one other component, such as a carrier.
The term “substantially pure” or “substantially pure amorphous” as used herein refers to polymorphic purity of amorphous empagliflozin or amorphous solid complexes or amorphous solid dispersion having a purity of about 95 % or more, more preferably 97 % or more, most preferably 99.5 % or more. The amorphous forms may comprise less than 5%, 3%, 1% of any other crystalline form. More preferably, the amorphous forms may comprise less than 0.5% of any other crystalline form. Most preferably, the amorphous form/ amorphous complex/amorphous solid dispersion of empagliflozin may not show any detectable amount of any other crystalline form.
In one embodiment, the present invention relates to a new process for the preparation of empagliflozin, wherein the process comprises the following steps:
(a) Treating a compound of formula V with a compound B to obtain a compound of formula VI;

Wherein in a compound of formula V, R1 is a hydroxy protecting group, and in a compound B, X is a leaving group;
(b) 1. Coupling the compound of formula VI with tetrahydrofuran-3-ol (C) to obtain a compound of formula VIIa, without being isolated;

(or)
(b) 2. Coupling the compound of formula VI with tetrahydrofuran-3-ol (C) to isolate a compound of formula VIIa;

(c) In-situ hydrolyzing the compound of formula VIIa from step (b) 1 to obtain a compound of formula VII;

(d) 1. Reducing the compound of formula VII with a reducing agent to yield empagliflozin.

(or)
(d) 2. Subjecting the compound obtained from step (b) 2 to exhaustive reduction to obtain empagliflozin.

In another embodiment, the present invention provides a new, cost-effective process for the preparation of empagliflozin, represented in Scheme A.
According to Scheme A, the compound B, wherein X is a leaving group selected from halogen (fluorine, chlorine, bromine, iodine), mesylate, tosylate, brosylate, besylate, nosylate and triflate is reacted with thionyl chloride in the presence of a lewis acid and a suitable solvent to form the corresponding acid chloride, which upon further reaction with a compound of formula V, wherein R1 is a hydroxy protecting group, results in the formation of a compound of formula VI. The reaction may be carried out using a lewis acid selected from aluminum chloride, iron (III) chloride, zinc chloride and boron trifluoride etherate. Lewis acids may be used in stoichiometric or excess quantities. The reaction may be carried out in the presence of solvents such as dichloromethane, chloroform or mixtures thereof. The solvent may be selected in the view of the lewis acid used. The reaction may be carried out a temperature ranging from about 0°C to solvent reflux temperature.
In some embodiments, the acid may be converted into an acyl halide using thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, acetyl chloride.
Within the context of the present disclosure, the compound of formula VI, wherein R1 is a hydroxy protecting group, and X is a leaving group defined as hereinbefore, is coupled with (S)-tetrahydrofuran-3-ol in a solvent in the presence of a suitable base at a temperature of about 80 °C to 100 °C to obtain a compound of formula VIIa. The solvent may be selected from alcoholic solvents such as methanol, ethanol, or dimethylformamide, tetrahydrofuran, dioxane, or mixtures thereof. Examples of suitable bases include without limitation, sodium hydride, sodium hydroxide, sodium methoxide, sodium ethoxide, lithium hydroxide, potassium hydroxide, potassium tertiary-butoxide and the like.
In the present context, the compound of formula VIIa is not isolated and in-situ subjected to hydrolysis, to cleave the hydroxy protecting group resulting in the formation of a compound of formula VII. The compound of formula VII is then reacted with a reducing agent in a solvent to obtain empagliflozin of formula VIII.

In some alternate embodiments, the compound of formula VIIa may be optionally isolated and subjected to exhaustive reduction in the presence of a lewis acid and suitable reducing agent to yield empagliflozin.
According to the present disclosure, the hydroxy protecting group may be cleaved for example hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide potassium hydroxide or alkali metal carbonates such as lithium carbonate sodium carbonate, potassium carbonate, cesium carbonate or amine derivatives such as, ammonia, methylamine, dimethylamine or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120°C, preferably at temperatures between 10 and 100°C.
The reduction may be conducted with a reducing agent in the presence of or without a Lewis acid. Suitable reducing agents include for example silanes such as e.g. triethylsilane, tripropylsilane, triisopropylsilane, or diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride. Suitable Lewis acids are such as e.g. boron trifluoride etherate, tin (II) chloride, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, copper (II) triflate, or zinc iodide. The reaction may be carried out in a solvent such as for example methylene chloride, chloroform, acetonitrile, diethylether, tetrahydrofuran, dioxane or mixtures thereof. The solvent is preferably selected in view of the reducing agent and the optional Lewis acid. Preferred reaction temperatures are between -80°C and 120°C, more preferably between -30 and 80°C.
In another embodiment, present invention involves preparing a compound of formula V,

Wherein R1 is a hydroxy protecting group selected from acyl (acetyl, propionyl, pivaloyl, benzoyl) groups. Processes for preparing the compounds of formula V are reported in the literature (see J. Org. Chem., 2007, 72 (25), pp 9746-9749) or well known to skilled persons in the relevant art.
In the present context, the process for preparing the compound of formula V, comprises the following steps:
(a) Protecting the hydroxy groups of compound of formula I to obtain a compound of formula II;

(b) Reacting the compound obtained in step (a) with an aryl lithium reagent to obtain a compound of formula III;

(c) Protecting the hydroxyl groups of the compound obtained in step (b) to obtain a compound of formula IV;

(d) Reducing the compound of formula IV to obtain a compound of formula V.

According to an embodiment of the invention, the process for preparing the compound of formula V may be represented as given in Scheme B.


In another embodiment, the new process of the present invention provides novel compounds useful as intermediates for the preparation of empagliflozin, represented as follows:

In more preferred embodiments of the present invention, the new process for preparation of empagliflozin may be represented in Scheme C.
In another embodiment, the compound of formula VIII i.e., empagliflozin and novel intermediates obtained from the new processes of the present invention may be obtained in amorphous form or crystalline form or a mixture of both. Particularly, the new process of present invention provides empagliflozin, which may be amorphous, or crystalline, or semi-crystalline.
In an embodiment, the crystalline form or semi-crystalline form or a mixture of amorphous and crystalline forms of empagliflozin obtained from the new process of the present invention may be used as a starting material for the preparation of substantially amorphous empagliflozin.
In one embodiment, the present invention further provides a process for the preparation of amorphous empagliflozin comprising: a) dissolving crude empagliflozin of formula VIII in a suitable solvent or mixtures thereof; b) optionally filtering the undissolved particles; c) removing the solvent by a suitable technique as described herein; and/or d) drying the solid at suitable temperature.
In another embodiment, the present invention provides a process for the preparation of amorphous empagliflozin comprising: a) dissolving crystalline or semi crystalline empagliflozin in a suitable solvent or mixtures thereof; b) optionally filtering the undissolved particles; c) removing the solvent by a suitable technique as described herein; and/or d) drying the solid at suitable temperature.
In some embodiments, the present invention provides a process for preparing amorphous empagliflozin, comprising subjecting the compound of formula VIII, which may be crystalline or semi-crystalline obtained from the new process of the present invention to one or more spray drying techniques and optionally drying the solid at a suitable temperature.
Suitable solvents include without limitation, water; polar aprotic solvents such as N, N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone dimethyl sulphoxide; ketones such as acetone, ethyl methyl ketone, butanone, 2-pentanone, 3pentanone, methyl butyl ketone, methyl isobutyl ketone; esters such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate; alcohols such as methanol, ethanol, propanol, isopropanol, 2-propanol, 1-butanol, tbutyl alcohol; nitriles such as acetonitrile; halo solvents such as chloroform, dichloromethane; or any mixtures thereof.
Suitable techniques that may be used for the removal of solvent include but are not limited to rotational distillation using a device such as Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization) and the like, optionally under reduced pressure. One aspect of the present invention relates to a solution comprising empagliflozin is subjected to spray-drying or freeze-drying technique, to provide pure amorphous form of empagliflozin. Alternatively, an anti-solvent may be added to the solution of empagliflozin to precipitate amorphous form and the precipitated solid may be isolated by any methods known in the art, such as filtration.
The resulting solid may be collected by using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used. The isolated solid may be optionally further dried to afford pure amorphous form of empagliflozin.
Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer. The dried product may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
In one embodiment, the new process of the present invention provides amorphous empagliflozin characterised by a purity of about 95% or more, as determined by HPLC (High Performance Liquid Chromatography). In preferred embodiments, the new process of the present invention provides substantially amorphous empagliflozin characterised by a purity of about 97% or more, as determined by HPLC. In more preferred embodiments, the new process of the present invention provides substantially amorphous empagliflozin characterised by a purity of about 99% or more, as determined by HPLC.
In most preferred embodiments, the new process of the present invention provides substantially amorphous empagliflozin characterised by purity of about 99.5 % or more, as determined by HPLC, with no detectable amount of any crystalline form, free of any residual solvents, stable for 12 months on storage at 5 ± 3 °C.
Table No. 1
Chemical Purity of Empagliflozin
Stability Period
(Temp = 5 ± 3 °C) Chemical Purity (HPLC) PXRD
Initial 99.88 Amorphous
1 month 99.90 Amorphous
3 months 99.88 Amorphous
6 months 99.89 Amorphous
12 months 99.88 Amorphous

Table No. 2
Chemical Purity of Solid Dispersions of Empagliflozin with Ethyl Cellulose
Stability Period
Temp = 25 ± 2 °C,
RH = 60 ± 5%
Empagliflozin-Ethyl Cellulose Dispersion

Chemical Purity (HPLC) PXRD
Initial 99.89 Amorphous
1 month 99.89 Amorphous
3 months 99.88 Amorphous
6 months 99.86 Amorphous

In another embodiment, the present invention provides amorphous solid dispersions of empagliflozin with pharmaceutically acceptable carriers, and preparation process thereof.
Pharmaceutically acceptable carriers include without limitation, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, polysaccharides, heteropolysaccha- rides (pectins), sodium lauryl sulfate, phosphatidylcholines (lecithins), mixtures of two or more thereof, copolymers thereof and derivatives thereof; amino acids such as tyrosine, histidine, lysine, arginine, glycine.
In one embodiment, the present invention provides a process for preparing an amorphous solid dispersion of empagliflozin, comprising milling a solid-solid mixture of empagliflozin and a polymer. In general, the step of milling a solid-solid mixture of empagliflozin and a polymer comprises triturating or grinding a solid-solid mixture of crystalline empagliflozin and a polymer. Such milling may be performed using machines such as ball mills, roller mills, gyratory mills, multi-mills, Jet-mills, and the like.
In another embodiment, the present invention provides a process for preparing amorphous solid dispersion of empagliflozin with one or more pharmaceutically acceptable polymer or mixtures thereof, comprising: (a) dissolving empagliflozin and a pharmaceutically acceptable polymer in suitable solvent or mixtures thereof; (b) optionally filtering the un-dissolved particles; (c) isolating amorphous solid dispersion of empagliflozin with a pharmaceutically acceptable carrier; (d) optionally drying the amorphous solid dispersion of empagliflozin.
Isolation of amorphous solid dispersion of empagliflozin may involve one or more methods including removal of solvent by techniques known in the art e.g. evaporation, distillation, filtration of precipitated solid and the like, cooling, concentrating the reaction mass, and the like. Stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolation.
In one embodiment, the new process of the present invention provides amorphous solid dispersion of empagliflozin with ethyl cellulose characterised by a purity of about 99.5 % or more as determined by HPLC, with no detectable amount of any crystalline form, free of any residual solvents, stable for 6 months on storage at 25 ± 2 °C and a relative humidity of 60 ± 5%.
Further the new process for preparing the empagliflozin and novel intermediates thereof, according to the present invention is illustrated in the following examples. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
Examples
The product (3R,4S,5S,6R)-2-(4-chlorophenyl)-6-(hydroxymethyl)-2-methoxy tetrahydro-2H-pyran-3,4,5-triol (III) was prepared according to the procedure which is given in the journal J. Org. Chem., 2007, Vol. 72 (25), pp: 9746-9749, from which, the compounds mentioned in the invention were prepared according to the general procedures mentioned below.
Example 1: General procedure to prepare (3R,4S,5R,6R)-6-(acyloxymethyl)-2-(4-chlorophenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacylate (IV)
To a solution of 40 mmol of (3R,4S,5S,6R)-2-(4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol in toluene (120ml), DMAP (0.4 mmol), Hunig’s base (165 mmol), and acyl anhydride or acyl halide (170 mmol) were added sequentially under nitrogen atmosphere at ambient temperature. After stirring for 6 h the reaction was complete by HPLC. A 1 N H3PO4 solution was added to the reaction mixture to neutralize to pH 6.5-7 and the aqueous layer was extracted further with EtOAc (100 mL). The organic extracts were combined and washed with brine (50 mL), dried (Na2SO4), and filtered. The filtrate was evaporated to obtain the product as a semi solid.
Example 2: General procedure to prepare (2R,3R,4R,5S,6S)-2-(acyloxymethyl)6-(4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacylate (V)
A solution of (3R,4S,5R,6R)-6-(acyloxymethyl)-2-(4-chlorophenyl)-2-methoxytetra- hydro-2H-pyran-3,4,5-triyl triacylate from example 1 (34 mmol) in CH3CN (170 mL) was prepared at room temperature under nitrogen atmosphere and 1 mol equiv of water was added. The solution was cooled in an ice bath and Et3SiH (109 mmol) was added. To this solution was added BF3.Et2O (82 mmol) over 30 min, and the mixture was allowed to warm to 15 °C over 20 min. Upon completion, the reaction was quenched with aqueous saturated NaHCO3 (100 mL); the pH of the aqueous layer was 7. The organic layer was washed with brine (170 mL) and the solution was dried (Na2SO4). The mixture was filtered and the solvent was evaporated to give the corresponding product as a white solid.
Example 3: General procedure to prepare (2R,3R,4R,5S,6S)-2-(acyloxymethyl)-6-(4-chloro-3-(4-halo / alkyl or aryl sulfonato / triflato-benzoyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacylate (VI)
To a solution of 4-halo / alkyl or aryl sulfonato / triflato-benzoic acid (B) (36 mmol) in dichloromethane (80 ml) was added thionyl chloride (43 mmol) drop-wise at RT. The reaction mass was refluxed for 3h. The solvent was distilled off completely under vacuum. Toluene (30 ml) was added to the reaction mass and distilled off toluene completely under vacuum to obtain corresponding acid chloride as a residue. Dichloromethane (50 ml) was added to the residue and cooled to 5°C. Anhydrous aluminium chloride (40 mmol) was added to the reaction mass in four portions under nitrogen atmosphere. A solution of (2R,3R,4R,5S,6S)-2-(acyloxymethyl)-6-(4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacylate obtained from example 2 (30 mmol) in dichloromethane (35 ml) was added drop-wise to the reaction mass at 5°C. The reaction mass was warmed to RT and stirred at RT for 3h. The reaction mass was cooled to 5°C and conc. hydrochloric acid (50 ml) was added and stirred at RT for 10 min. The organic layer was separated and washed successively with water (1x30 ml), 10% aq. sodium bicarbonate solution (2x30 ml) and brine (1x30 ml). The organic layer was dried over anhydrous sodium sulfate and the solvents distilled off under vacuum below 50°C. Methanol (50 ml) was added to the residue and stirred for 1h at 50°C, cooled to 5°C and filtered. The filtered solid was dried for 4h at 40°C to obtain the product as a white solid.
Example 4: General procedure to prepare (2R,3R,4R,5S,6S)-2-(acyloxymethyl)6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzoyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacylate (VIIa)
To a solution of (2R,3R,4R,5S,6S)-2-(acyloxymethyl)-6-(4-chloro-3-(4-halo / alkyl or aryl sulfonato / triflato-benzoyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacylate obtained from example 3 (12 mmol) and (S)-3-hydroxytetrahydrofuran (C) (12 mmol) in tetrahydrofuran (25 ml) was added solid potassium tert-butoxide (15 mmol) in several portions under nitrogen atmosphere. The reaction mass was refluxed for 8h, pH adjusted to 7 using dilute hydrochloric acid. The reaction mass was filtered, the volatiles were distilled off. The residue was dissolved in dichloromethane (50 ml) and washed with water (2x25 ml) and brine (1x25 ml). The solution was dried over anhydrous sodium sulfate and evaporated to yield the product as a solid.
Example 5: General procedure to prepare (2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)(4-(((S)-tetrahydro furan-3-yl)oxy)phenyl) methanone (VII)
To a solution of (2R,3R,4R,5S,6S)-2-(acyloxymethyl)-6-(4-chloro-3-(4-halo / alkyl or aryl sulfonato / triflato-benzoyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacylate obtained from example 3 (12 mmol) and (S)-3-hydroxytetrahydrofuran (C) (12 mmol) in tetrahydrofuran (25 ml) was added solid potassium tert-butoxide (15 mmol) in several portions under nitrogen atmosphere. The reaction mass was refluxed for 8h, pH adjusted to 3 using dilute hydrochloric acid. The reaction mass was heated to 50°C for 3h. The reaction mass was cooled and filtered, the volatiles were distilled off. The residue was dissolved in dichloromethane (50 ml) and washed with water (2x25 ml) and brine (1x25 ml). The solution was dried over anhydrous sodium sulfate and evaporated to yield the title product as a white solid.
Example 6: General procedure A (exhaustive reduction) to prepare Empagliflozin (VIII)
To a suspension of aluminium chloride (80 mmol) in THF (60 ml) pre-cooled to 10oC, was added sodium borohydride (320 mmol) in 5 portions under a nitrogen atmosphere. The reaction mass was stirred at RT for 2h. A solution of (2R,3R,4R,5S,6S)-2(acyloxymethyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzoyl)phenyl)tetra hydro-2H-pyran-3,4,5-triyl triacylate obtained from example 4 (10 mmol) in THF (25 ml) was added to the reaction mass drop-wise and temperature rose up to 50oC. The reaction mass was refluxed for 36h. The reaction mass was cooled to 10oC and 10% hydrochloric acid (50 ml) was added drop-wise. The reaction mass was stirred at RT for 1h. Ethylacetate (50 ml) was added and stirred at RT for 15 min. Organic layer was separated and the aqueous layer was extracted with ethylacetate (2x 25 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the solvent distilled off completely under vacuum to obtain the crude product which was chromatographed on silica gel (60-120 mesh) beginning 5% methanol in dichloromethane to 50% methanol in dichloromethane to obtain empagliflozin in amorphous form.
Example 7: General procedure B (carbonyl reduction) to prepare Empagliflozin (VIII)
A solution of (2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetra hydro-2H-pyran-2-yl)phenyl)(4-(((S)-tetrahydrofuran-3-yl)oxy)phenyl) methanone from example 5 (10 mmol) in CH3CN (60 mL) was prepared at room temperature under nitrogen atmosphere and 1 mol equiv of water was added. The solution was cooled in an ice bath and Et3SiH (36 mmol) was added. To this solution was added BF3.Et2O (28 mmol) over 30 min, and the mixture was allowed to warm to 15 °C over 20 min. Upon completion, the reaction was quenched with aqueous saturated NaHCO3 (35 mL); the pH of the aqueous layer was 7. The organic layer was washed with brine (60 mL) and the solution was dried (Na2SO4). The mixture was filtered and the solvent was evaporated to obtain the crude product which was chromatographed on silica gel (60-120 mesh) beginning 5% acetonitrile in dichloromethane to 50% acetonitrile in dichloromethane to obtain empagliflozin in amorphous form.
Example 8: Preparation of an amorphous solid form of empagliflozin with ethyl cellulose
0.5 g of solid amorphous empagliflozin was mixed with 1.0 g of ethyl cellulose and the mixture was subjected to ball mill to obtain a uniform mixture of the amorphous empagliflozin solid dispersion.

The above examples are merely illustrative, and do not limit the scope of the invention in anyway.
The foregoing embodiments and advantages are merely exemplary and are not to be construed as limiting the scope of the present invention. The description of the exemplary embodiments of the present invention is intended to be illustrative and not to limit the scope of the invention.
Various modifications, alterations and variations, which are apparent to a person skilled in the art, are intended to fall within the scope of the invention.
,CLAIMS:We Claim,
1. A process for preparing (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl ]phenyl]-D-glucitol i.e., empagliflozin, comprising reducing a compound of formula VII.

2. A process for preparing a compound of formula VII, comprising:
(a) Reacting a compound of formula V with compound B to form compound of formula VI;

(b) Coupling the compound of formula VI with tetrahydrofuran-3-ol (C) to form a compound of formula VIIa;

(c) Hydrolyzing the compound of formula VIIa to form a compound of formula VII;

Wherein R1 is a hydroxyl protecting group and X is a leaving group.
3. A process for preparing (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl ]phenyl]-D-glucitol i.e., empagliflozin, comprising subjecting a compound of formula VIIa to exhaustive reduction,

Wherein R1 is a hydroxyl protecting group.
4. A process for preparing (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol i.e., empagliflozin, wherein the compound of formula VIIa is prepared according to claim 2.
5. A process according to preceding claims, wherein in step (a), the compound B is converted to corresponding acyl halide and reacted with compound V in the presence of an acid such as lewis acid selected from aluminum chloride, iron (III) chloride, zinc chloride and boron trifluoride etherate;
In step (b), the coupling is carried out in the presence of base such as sodium hydride, sodium hydroxide, sodium methoxide, sodium ethoxide, lithium hydroxide, potassium hydroxide, potassium tertiary-butoxide and the like;
reduction or exhaustive reduction is carried out with a reducing agent selected from silanes such as triethylsilane, tripropylsilane, triisopropylsilane, or diphenylsilane; sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride; optionally in the presence of lewis acid selected from boron trifluoride etherate, tin (II) chloride, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, copper (II) triflate, or zinc iodide;
Hydroxyl protecting group is selected from acetyl, propionyl, pivaloyl, benzoyl groups; and leaving group is selected from halogen, mesylate, tosylate, brosylate, besylate, nosylate and triflate.
6. A process for preparing (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol i.e., empagliflozin, according to the preceding claims comprises:
(a) Reacting a compound of formula V with compound B to form compound of formula VI;

(b) Coupling the compound of formula VI with tetrahydrofuran-3-ol (C) to form a compound of formula VIIa;

(c) Hydrolyzing the compound of formula VIIa to form a compound of formula VII;

(d) 1. Reducing the compound of formula VII to form empagliflozin;

(or)
(d) 2. Subjecting the compound of formula VIIa to exhaustive reduction to form empagliflozin.

7. A process for preparing empagliflozin according to preceding claims in amorphous form comprising:
(a) dissolving empagliflozin in one or more solvents;
(b) optionally filtering the undissolved particles;
(c) removing the solvent completely; and
(d) drying to isolate an amorphous compound.
8. A process for preparing empagliflozin according to preceding claims as an amorphous solid dispersion with a pharmaceutically acceptable carrier comprising:
(a) dissolving empagliflozin and the pharmaceutically acceptable carrier in one or more solvents;
(b) optionally filtering the un-dissolved particles;
(c) removing the solvent completely;
(d) drying to isolate amorphous solid dispersion of empagliflozin and the polymer.
9. A process according to claim 8, wherein the pharmaceutically acceptable carrier is
selected from ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, polysaccharides, heteropolysaccharides (pectins), sodium lauryl sulfate, phosphatidylcholines (lecithins), mixtures thereof, copolymers thereof and derivatives thereof; amino acids such as tyrosine, histidine, lysine, arginine, glycine.
10. Compounds of formula VI, VIIa and VII


Wherein R1 is a hydroxyl protecting group and X is a leaving group.