DESC:Field of Invention
The present invention relates to an industrially viable, economical 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 or stereoisomers thereof. The present invention also relates to an amorphous form of empagliflozin, or amorphous solid dispersions/solutions thereof with pharmaceutically acceptable polymers, or amorphous complexes thereof with pharmaceutically acceptable carriers, obtainable from the process of the present invention. Also, the products obtained from the present invention may be used for the preparation of medicaments for the prevention and/or treatment of diseases and conditions in which Empagliflozin is indicated.
Background of the Invention
The present invention is directed to 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, a ß-C-arylglucoside.
Empagliflozin is a novel sodium glucose co-transporter 2 (SGLT 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 represented by the structural formula:

It was approved by the FDA in August, 2014 in the form of oral tablets for human use under the proprietary name, JARDIANCE® indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; and to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease.
U.S. Patent No. 7,579,449 B2 discloses Empagliflozin, also known as 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3--yloxy)-benzyl]-benzene, and preparation process thereof. However, it does not mention any details about the character of solid form of the product.
U.S. Patent No. 7,713,938 B2 discloses a stable crystalline form of empagliflozin and a pharmaceutical composition or medicament comprising the crystalline form. Other crystalline forms are disclosed in U.S. Patent No. 7,723,309 B2, particularly crystalline Form-I and Form-II of 1- chloro-4-(ß-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]- benzene and preparation process thereof.
IN 1985/MUM/2013 discloses an amorphous form of empagliflozin as such, and its amorphous solid dispersion with a polymer, wherein the polymer is selected from a non-ionic polymer or an ionic polymer.
International patent applications, WO/2006/120208, WO/2013/068850, and WO/2015/155739 also describe various methods for the synthesis of empagliflozin.
PCT publication no. WO/2016/131431 and WO2016/051368 describe crystalline or amorphous complexes of empagliflozin with proline and cyclodextrins respectively, and preparation processes thereof
In the view of prior art, there exists a continuous need to develop improved, cost-effective processes for the preparation of Empagliflozin, or stereoisomers thereof. Also, there remains a need to develop amorphous complexes or dispersions/solutions of empagliflozin that exhibit higher physical and chemically stability profile when stored at elevated temperature and relative humidity.
The present inventors provide an improved, cost-effective, industrially viable process for preparing stable amorphous empagliflozin as such, or by converting the crude compound to a stable amorphous form by various techniques. Also, the present invention is aimed at preparing stable amorphous solid dispersions thereof with pharmaceutically acceptable polymers, stable amorphous complexes thereof with pharmaceutically acceptable carriers, having a suitable polymorphic and chemical stability when stored at higher temperature and humidity conditions.
Object of the Invention
An object of the invention is to provide an industrially viable, improved process for the preparation of (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl] oxy] phenyl] methyl] phenyl]-D-glucitol, i.e. Empagliflozin in an amorphous form with higher yield and better enantiomeric purity.
Another object of the invention is to use the product obtainable from the process of the present invention to provide stable amorphous solid dispersions/solutions with pharmaceutically acceptable polymers, and process for preparing the same.
Summary of the Invention
The present disclosure relates to an industrially viable, cost-effective process for preparing Empagliflozin, also chemically known as 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene or stereoisomers thereof.
In one embodiment, the present invention provides a process for preparing empagliflozin, comprising reacting a compound (7) in an alcoholic solvent with a compound (8) in the presence of a base, represented as follows:

Wherein R1 is hydrogen, or a hydroxy protecting group preferably an acyl group and R2 is C1-6 alkyl group optionally substituted with one or more halogens, or an aryl group optionally substituted in the para position with a halogen or C1-4 alkyl.
In a second embodiment, the process of the present invention comprises preparing a compound (7), wherein a compound (6) is subjected to O-demethylation in the presence of thiourea-aluminium chloride reagent pair and a suitable solvent,

Wherein PG is a hydroxy protecting group, preferably an acyl group, and R1 is defined as hereinbefore.
In a third embodiment, the present invention provides a single pot process for preparing a compound (6), wherein the process comprises the following steps:
(a) Coupling a compound (2) with a protected gluconolactone compound (3) in the presence of an alkyl lithium and suitable solvent to obtain an adduct, which is further treated with an alcohol in the presence of an acid to obtain a solution containing a compound (4);

Wherein in a compound (3), PG is a hydroxy protecting group preferably trimethylsilyl,
(b.1) the compound obtained from step (a) is treated with a suitable acylating agent in the presence of a base to yield a solution containing compound (5),

Wherein PG denotes an acyl group;
(Or)
(b.2) the compound obtained from step (a) is subjected to reduction to yield a solution containing a compound 5a;

(c.1) the solution of step (b.1) is further reacted with a reducing agent in the presence of a Lewis acid and a suitable solvent to isolate a compound (6);

(Or)
(c.2) the solution containing compound 5a obtained from step (b.2) is reacted with an acylating agent in the presence of a base to isolate a compound (6).

In an alternate embodiment, the compounds (4), (5) and (5a) may be isolated at each step and proceeded further to the next reaction.
In a fourth embodiment, the present invention provides a process for preparing a compound (2), comprising reducing a compound (1) in the presence of a reducing agent and Lewis acid;

The compound (1) may be prepared according to synthetic procedures well known in the art.
In a fifth embodiment, present invention provides amorphous empagliflozin substantially free of any other crystalline form, when stored at accelerated and long term storage conditions for a period of at least six months or more, characterized by HPLC purity of 95% or more.
In a sixth embodiment, the present invention provides amorphous solid dispersions/solutions of empagliflozin with pharmaceutically acceptable polymers, and preparation processes thereof, when stored at accelerated and long term storage conditions for a period of 3 months or more.
In a seventh embodiment, the present invention provides amorphous solid dispersion of empagliflozin with hydroxypropyl cellulose, characterized by HPLC purity of more than 99.5%, substantially free of any other crystalline form when stored at accelerated and long term storage conditions for a period of 3 months or more.
Brief description of drawings:
Figure 1 represents an overlay of powder X-ray diffraction pattern of amorphous empagliflozin at 1st, 3rd, 6th and 12th months.
Figure 2 represents powder X-ray diffraction pattern of an amorphous solid dispersion comprising empagliflozin and hydroxypropyl cellulose.
Detailed description of the invention
The present inventors have surprisingly found an industrially viable, cost-effective process for the preparation of (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl] oxy] phenyl] methyl] phenyl]-D-glucitol, i.e. Empagliflozin, useful as an SGLT 2 inhibitor.
According to the present invention, the industrially viable process yields a stable amorphous empagliflozin as such or by converting the crude compound obtainable from the said process to a stable amorphous form by techniques known in the art.
The present invention also provides stable amorphous solid dispersions/solutions of empagliflozin with pharmaceutically acceptable polymers, stable amorphous complexes of empagliflozin with pharmaceutically acceptable carriers, having a suitable polymorphic and chemical stability profile when stored at higher temperature and relative humidity conditions.
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, preferably being empagliflozin or solid forms thereof.
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)].
The term “solid forms” as used herein refer to amorphous solid dispersions/solutions with pharmaceutically acceptable polymers, amorphous solid complexes with pharmaceutically acceptable carriers, of empagliflozin obtainable from the present invention.
As used herein, the term “solid dispersion” or “solid solution” means any solid composition having at least two components, wherein one component is dispersed homogeneously throughout the other component or components. For the purpose of the present invention, the terms “solid dispersion” and “solid solution” are herein used interchangeably. In certain embodiments, a solid dispersion as disclosed herein includes empagliflozin dispersed among at least one other component, such as a polymer.
The term "amorphous solid dispersion" as used herein, refers to stable solid dispersions comprising drug substance and a polymer matrix, preferably an amorphous drug substance.
The term “amorphous complex” as used herein refers to a composition comprising a drug substance and a pharmaceutically acceptable carrier, preferably an amorphous drug substance.
In general, the term “substantially free of residual solvents” herein means residual solvents are within the permissible ICH (International Council for Harmonization) limits suitable for pharmaceutical preparations. For example but not limited to less than 0.5%, particularly less than 0.3% or more particularly less than 0.2%, or most particularly not in detectable amount.
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 HPLC purity of about 95 %, preferably a purity of 99% or more.
The term “stable” as used herein refers to amorphous empagliflozin, amorphous solid dispersions thereof, amorphous complexes thereof, that does not convert to any other solid form when stored at accelerated and long term storage conditions for a period of at least six months or more, having HPLC purity of about 99% or more.
In one embodiment, the process of the present invention may be described in scheme A.

According to Scheme A, the commercially scalable, cost-effective process for the preparation of Empagliflozin comprises reacting a diphenylketone compound (1) with a reducing agent in the presence of a Lewis acid and a solvent to obtain a diphenylmethane compound (2).
The reduction may be conducted with a reducing agent in the presence of, or without a Lewis acid depending on the reducing agent used. Suitable reducing agents include for example silanes such as triethylsilane, tripropylsilane, triisopropylsilane, or diphenylsilane; borohydrides such as sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes; aluminum hydride such as lithium aluminum hydride, diisobutylaluminum hydride. Suitable Lewis acids include without limitation boron trifluoride etherate, trifluoroacetic acid, aluminum chloride, tin (II) chloride, indium (III) chloride, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper (II) triflate, or zinc iodide and the like. Suitable Bronsted acids such as e.g. hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid, or acetic acid may also be used. The reaction may be carried out in a solvent such as for example dichloromethane, chloroform, acetonitrile, diethyl ether, tetrahydrofuran, dioxane or mixtures thereof. The solvent is preferably selected in view of the reducing agent and the optional Lewis acid.
In preferred embodiments of the invention, the conversion of a diphenylketone to a diphenylmethane compound is performed using sodium borohydride in the presence of aluminum chloride and tetrahydrofuran.
In the present disclosure, the compound (1) may be prepared according to the process disclosed in scheme A or by methods known in the art.
In another embodiment, the process of the present invention comprises coupling a diphenylmethane compound (2) with a protected gluconolactone (3) in the presence of an alkyl lithium and suitable solvent to obtain an adduct, which is further in-situ treated with methanol in the presence of an acid to obtain a solution containing a compound (4), wherein in a compound (3), PG is a hydroxy protecting group preferably trimethylsilyl.
In the present context, the alkyl lithium may be selected from n-, sec-, and tert-butyl lithium, preferably n-butyl lithium is used. Suitable solvents include diethyl ether, tetrahydrofuran, toluene, hexane or dichloromethane, preferably tetrahydrofuran is used. Examples for acid include without limitation, methanesulphonic acid, hydrochloric acid, sulphuric acid, acetic acid and the like.
In a preferred embodiment, the adduct formed after coupling compound (2) with protected gluconolactone (3) is treated in-situ with methanol in the presence of methanesulphonic acid to obtain solution containing compound (4).
The compound (3) may be used from commercially available sources or prepared according to procedures known in the literature.
In another embodiment, the solution containing the compound (4) is further treated with a suitable acylating agent in the presence of dimethylaminopyridine to yield a solution containing compound (5), wherein PG denotes an acyl group preferably being an acetyl, propionyl group. Other protecting groups such as benzoic anhydride, benzoyl chloride, 4-nitrobenzoyl chloride may also be used.
The solution containing compound (5) is further reacted with a reducing agent described as hereinbefore, in the presence of a Lewis acid and a suitable solvent to isolate a compound (6).
In preferred embodiment, reduction is carried out using triethylsilane in the presence of boron trifluoride etherate and dichloromethane.
In another embodiment, a compound (6) is subjected to O-demethylation using a suitable reagent selected from hydrogen bromide, boron tribromide, aluminum chloride, dodecanthiol and thiourea, in the presence of a suitable solvent to yield a compound (7), wherein R1 is an acyl group. The choice of solvent depends on the type of reagent used. In preferred embodiment, O-demethylation is carried out using dodecanethiol in the presence of thiourea-aluminium chloride reagent pair.
Thiourea and aluminium chloride (AlCl3) form together a reagent pair. In thiourea/AlCl3 reagent pair, the sulphur atom acts as a weak nucleophile and is capable of easily cleaving a methyl group from a methoxy, similar to the AlCl3/Triethylsilane reagent.
Surprisingly the present inventors have found that O-demethylation using dodecanethiol and thiourea-aluminium chloride reagent pair in dichloromethane resulted in the desired compound with higher purity and better yields compared to dodecanethiol or other thiol reagent or any other reagent which when used alone.
In an alternative embodiment, the compound (6) is subjected to hydrolysis to first cleave the hydroxy protecting groups, followed by cleaving the phenolic methyl ether to yield a compound (7), wherein R1 is hydrogen.
In the present disclosure, an acyl protecting group is 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.
In another preferred embodiment, the process of the present invention may also be described in Scheme B, represented as follows:




According to Scheme B, the diphenylmethane compound (2) is coupled with a trimethylsilyl protected gluconolactone (3) in the presence of n-butyl lithium and tetrahydrofuran to obtain an adduct, which is further in-situ treated with methanol in the presence of concentrated hydrochloric acid to obtain a solution containing a compound (4). Alternatively, methanesulphonic acid in methanol may also be used.
Further the solution containing compound (4) is treated with triethylsilane in the presence of boron trifluoride etherate to yield a solution containing compound (5a), which is then subjected to acylation using acetic anhydride or propionic anhydride in the presence of a base such as dimethylaminopyridine and dichloromethane to isolate a compound (6), wherein PG denotes acyl group.
Further, compound (6) is subjected to O-demethylation in the presence of dodecanethiol and a Lewis acid such as aluminium chloride together with thiourea in dichloromethane to yield a compound (7).
In alternative embodiments, the compounds (4), (5) and (5a) may be optionally isolated and proceeded to further reactions.
In yet another embodiment, the process of the present invention comprises reacting a compound (7) obtained from Scheme A or Scheme B, wherein R1 is hydrogen or a hydroxy protecting group (preferably an acyl group) with a compound (8) in the presence of a base, to yield crude empagliflozin, wherein in a compound (8) R2 is C1-6 alkyl optionally substituted with one or more halogens, or an aryl group optionally substituted in the para position with a halogen or C1-4 alkyl. R2 is preferably methyl, phenyl, benzyl and the like.

The present inventors have surprisingly found a novel process for preparing the compound (8) in desired configuration, useful 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. The novel process of the present invention for preparing compound (8) may be represented in Scheme C.
According to Scheme-C, a 3-hydroxytetrahydrofuran compound (i) is treated with an alkyl or aryl sulfonyl chloride compound (ii), wherein R2 is C1-6 alkyl optionally substituted with one or more halogens, or an aryl group optionally substituted in the para position with a halogen or C1-4 alkyl, in the presence of a base to give a compound (iii), which is reacted with phase transfer catalyst to obtain a compound (iv). Suitable phase transfer catalysts include crown ethers preferably 18-crown-6, or quaternary ammonium salt such as tetra-n-butylammonium bromide, and the like.

In one preferred embodiments, (S)-3-hydroxytetrahydrofuran (i) is treated with an alkyl sulfonyl chloride compound (ii) in the presence of a base to give a compound (iii), which is reacted with an alkali metal acetate optionally in the presence of a phase transfer catalyst to obtain a compound (iv).
In another preferred embodiment, (S)-3-hydroxytetrahydrofuran (i) is treated with an aryl sulfonyl chloride compound (ii) in the presence of a base to give a compound (iii), which is reacted with an alkali metal acetate optionally in the presence of a phase transfer catalyst to obtain a compound (iv).
Examples of alkali metal acetate include without limitation, lithium acetate, sodium acetate, potassium acetate or cesium acetate. Suitable phase transfer catalysts (PTC) include crown ethers such as 12-crown-4, 15-crown-5 or 18-crown-6 or quaternary ammonium salt such as tetra-n-butyl ammonium bromide, and the like.
Further, the compound (iv) is subjected to hydrolysis in the presence of a base to yield a compound (v), which is further treated with compound (ii) wherein R2 is described as hereinbefore, to obtain the compound (8) in desired configuration. The compound (8) is further reacted according to any of the schemes A and B with compound (7) to yield empagliflozin in high yields and purity.
In more preferred embodiments, the novel process of the present invention for preparing compound 8 is represented as follows according to Scheme D:

Suitable bases used for preparation of compound 8 include without limitation triethylamine, methylamine, ethylamine, and the like. Examples of suitable solvents include without limitation, hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, pentane, o-, m- or p-xylenes and the like; ether solvents such as tetrahydrofuran, 1, 4-dioxane, diethyl ether, and the like; chlorinated solvents such as dichloromethane, chloroform and the like; and alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and the like.
In another embodiment, the crude empagliflozin or stereoisomers thereof obtained from the process of the present invention may be further purified by subjecting the crude to column chromatography, followed by evaporation of the solvent by various techniques known to a person of ordinary skill in the art, to yield an amorphous compound.
In one embodiment, the crude compound obtained from the improved process of the present invention may also be purified by dissolution in one or more solvents, followed by addition of an anti-solvent to form a precipitate, evaporating the solvent to yield an amorphous compound.
In another embodiment, the process of the present invention provides a stable amorphous empagliflozin having a purity of about 95% or more as determined by HPLC, and substantially free of any other solid form. In preferred embodiments, the process of the present invention provides a stable amorphous empagliflozin having a purity of about 99% or more. In more preferred embodiments, the process of the present invention provides a stable amorphous empagliflozin having a purity of about 99.5% or more.
The amorphous form comprises less than 5%, 3%, 1% of any other crystalline form. More preferably, the amorphous form comprises less than 0.5% of any other crystalline form. In most preferred embodiments, the process of the present invention provides amorphous empagliflozin, substantially free of any other crystalline form when stored at accelerated and long term storage conditions for a period of at least six months or more.
In another embodiment, the novel process of the present invention provides stable amorphous solid dispersions/solutions of empagliflozin with pharmaceutically acceptable polymers, such as water soluble and water insoluble polymers. Examples of water soluble polymers include polyvinyl pyrrolidone (povidone), copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, polyethylene glycol, polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol copolymers (Soluplus™), and the like. Examples of water insoluble polymers include methylcellulose, ethylcellulose, polymethacrylates, hypromellose phthalate, hypromellose succinate, hypromellose acetate succinate (HPMC AS), cellulose acetate phthalate, carboxymethyl ethyl cellulose, and the like. In preferred embodiments of the invention, a water soluble polymer is used for preparing amorphous solid dispersions of empagliflozin. More preferably, hydroxypropyl cellulose (HPC) is used.
The amorphous solid dispersions according to the present invention are prepared by dissolving crude or amorphous empagliflozin in water or suitable organic solvents selected from alcohols, esters, ethers, ketones, nitriles, halogenated hydrocarbons, aromatic hydrocarbons, aliphatic hydrocarbons, amides, nitroalkanes and the like to form a solution or suspension. The solvent may be removed by techniques known in the art such as evaporation, distillation, spray drying, filtration, lyophilization, or by using an agitated thin film drier (ATFD) to yield an amorphous substance.
The ratio of empagliflozin prepared by the process of the present invention to the amount of polymer within the amorphous solid dispersion may be from about 1:1 to about 1:10 (w/w).
In a preferred embodiment, the amorphous solid dispersion is prepared by dissolving empagliflozin and hydroxypropyl cellulose in methanol, followed by stirring to form a solution, optionally heating if a suspension is formed to obtain a clear solution. Removing the solvent by distillation under reduced pressure to give a residue, which may be further dried to yield amorphous empagliflozin.
In another embodiment, the amorphous solid dispersions prepared according to the present invention are characterized by a purity of about 99% or more, remain stable when stored at accelerated and long term storage conditions for a period of at least six months or more.
In yet another embodiment, the novel process of the present invention provides stable amorphous complexes of empagliflozin with pharmaceutically acceptable carriers when stored at accelerated and long term storage conditions for a period of at least six months or more, and preparation processes thereof.
Suitable pharmaceutically acceptable carriers may include cyclodextrins, saccharides, oligosaccharides, polysaccharides, amino acids, fats, waxes, urea etc. Examples of cyclodextrins include without limitation a-cyclodextrin, a ß-cyclodextrin, or a ?-cyclodextrin. In preferred embodiments of the invention, the cyclodextrin is a sulfobutyl ether ß-cyclodextrin.
Sulfobutyl ether ß-cyclodextrin (SBE7--CD) is a chemically modified cyclodextrin (-CD) that is a cyclic hydrophilic oligosaccharide which is negatively charged in aqueous media, available commercially as Captisol®. Captisol® is a sulfobutyl ether derivative of ß-cyclodextrin with a range of six to seven sulfobutyl ether groups per cyclodextrin molecule. The solubility in water for SBE7--CD (excess 70 g/100 ml at 25°C) (Lockwood et al., 2003) is significantly higher than the parent -CD (1.85 g/100 ml at 25°C) (Loftsson et al., 2004). Additionally, it does not exhibit the nephrotoxicity associated with -CD (Rajewski et al., 1995; Frank et al., 1976). Totterman et al. (1997) demonstrated no cytotoxic effects of SBE7--CD on the integrity of intestinal epithelial Caco-2 cells, while dimethyl--CD clearly showed cytotoxic effects. SBECD, a rationally designed ß-cyclodextrin derivative, has a more favorable toxicological profile compared to the parent cyclodextrins. In addition, these derivatives impart exceptional solubility and parenteral safety to the molecule.
Further according to an embodiment of the invention, the amorphous complex of empagliflozin with Captisol® may be prepared by dissolving empagliflozin and the cyclodextrin in a suitable solvent and isolating the amorphous complex. Alternatively, empagliflozin and cyclodextrin may be individually dissolved in suitable solvents or water, combining the two solutions, followed by removal of the solvent to isolate the amorphous complex. Solvent may be removed by techniques disclosed as herein before or by any other methods known in the art.
In the same context, the cyclodextrin and empagliflozin used for preparing the amorphous complex may be used in 1:1 molar ratio or in a weight ratio from about 1:1 (w/w) to about 1:20 (w/w).
In another embodiment, the amorphous solid dispersions, amorphous complexes of empagliflozin prepared by the processes of the present invention may be formulated into pharmaceutical compositions useful for the prevention and/or treatment of diseases or conditions in which empagliflozin is indicated.
Methods:
1. High Performance Liquid Chromatography (HPLC):
(a) (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl] methyl]phenyl]-D-glucitol, i.e., empagliflozin (amorphous)
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-Detector and Integrator.
Column: Promosil C18, 250 ? 4.6 mm, 100 A°, 5 µm or equivalent
Column Temperature: 40 °C
Wavelength: 225 nm
Flow rate: 1.2 mL/min
Injection volume: 5 µL
Run Time: 60 min
Elution: Gradient
Diluent: Acetonitrile: Water (50: 50 v/v)
Mobile phase A: Buffer solution
Mobile phase B: Acetonitrile: Water (95: 5 v/v)
Buffer solution: Transfer accurately about 1 mL of ortho phosphoric acid into 1000 mL of milli-Q water, filter through 0.45 µm nylon membrane and sonicate to degas.
(b) Amorphous solid dispersion of empagliflozin and hydroxypropyl cellulose (HPC)
Chromatographic conditions are same as given under (a), except for:
Wavelength: 220 nm
Column temperature: 35 °C
Mobile Phase B: Acetonitrile: Water (90: 10 v/v)
2. Powder X-ray Diffraction (PXRD):
The diffraction patterns were measured using Bruker D2 PHASER diffractometer equipped with LYNXEYETM detector, used radiation Cu K? (?=1.54060 Å), excitation voltage: 30 kV, anode current: 10 mA, measured range: 3 - 40° 2?, increment: 0.01° 2?.
Table No. 1
Chemical Purity of Empagliflozin
Stability Period
(Temp = 5 ± 3 °C) Chemical Purity (HPLC) PXRD Stability Period
(Temp = -20 ± 5 °C) Chemical Purity (HPLC) PXRD
Initial 99.88 Amorphous Initial 99.73 Amorphous
1 month 99.90 Amorphous 1 month 99.76 Amorphous
3 months 99.88 Amorphous 3 months 99.77 Amorphous
6 months 99.89 Amorphous 6 months 99.75 Amorphous
12 months 99.88 Amorphous 12 months 99.76 Amorphous

Advantages of Present Invention:
1. Use of anisole in the preparation of compound (1), which is further used for preparing empagliflozin reduces cost and provides better yields and purities when compared with the use of fluorobenzene as observed in the prior art.
2. Use of Lewis acid such as TiCl4 in the conversion of compound (1) to compound (2) is known in the art. Titanium tetrachloride (TiCl4) is a strong Lewis acid, exothermically forming adducts with even weak bases such as THF and explosively with water and releasing HCl. However, the present invention uses aluminium chloride which is better, cheaper and safer Lewis acid when compared to titanium tetrachloride as used in the prior art.
3. O-demethylation using dodecanethiol and thiourea-aluminium chloride reagent pair provides the desired compound with higher purity and better yields compared to dodecanethiol or any other thiol reagent when used alone. The reagent pair method is advantageous when compared to boron tribromide as well as HBr.
4. Present inventors surprisingly provide a simplified, cheaper process for preparation of (R)-3-hydroxytetrahydrofuran, from a less expensive, commercially available (S)-3-hydroxy tetrahydrofuran, such process otherwise being expensive.
Further the process for preparing empagliflozin and intermediates thereof according to the present invention are illustrated in the following examples. The following specific and non-limiting examples are to be construed as merely illustrative, and do not limit the present disclosure in any way whatsoever.
Examples
Example 1: Preparation of (5-bromo-2-chlorophenyl)(4-methoxyphenyl) methanone (1): A solution of 5-bromo-2-chloro benzoic acid (150 g) in dichloromethane (750 ml) was stirred for 15-30 min. Dimethylformamide (0.6 ml) and thionyl chloride (138.7 ml) was charged to the above reaction mass (RM), stirred for 10-15 min. The RM was heated to 40-45°C and maintained for 2h. After completion of reaction, distilled the RM completely under vacuum at 45°C. Charged dichloromethane (1200 ml) in to the mass, cooled to 0-5°C. Charged aluminum chloride (101.9 g) into the RBF, slowly added anisole (74.2 g) into the mass at same temperature. After the reaction is complete, water (750 ml) was added to the RM, and slightly warmed to 20-30°C. The organic and aqueous layers were separated, the aqueous layer was extracted with dichloromethane (2 ? 750 ml). Then the organic layer was washed with 2N hydrochloric acid solution, dichloromethane (2 ? 750 ml), followed by washing with sodium bicarbonate (2 ? 750 ml). The organic layer was then washed with sodium chloride solution (750 ml) and dried over sodium sulfate. Then distilled the organic layer completely under vacuum at 40 °C to remove the solvent completely. The solid obtained was washed with methanol (300 ml), cooled to 0-5 °C and stirred for 60 min to obtain a precipitate. Filtered the mass and the compound was washed with 100 ml of chilled (about 10 °C) methanol. Then air dried the compound for 6h to obtain the title compound (168.5 g, 81.24 %). (Purity by HPLC: 99.22 %).
Example 2: Preparation of 2-(4-methoxybenzyl)-4-bromo-1-chlorobenzene (2): A solution of compound 1 (50 g) from Example 1 and tetrahydrofuran (100 ml) was stirred for 10 min. Cooled the RM to 0-5°C. Aluminum chloride (42.9 g) was charged to the RM at the same temperature, stirred for 30 min at 0-5°C. Sodium borohydride (18 g) was added to the RM, stirred for 60 min at 5-10 °C. RM was heated to 65-70°C and maintained for 15h. After completion of reaction, the RM was cooled to 20-30°C and then to 0-5 °C. Slowly added water (500.0 ml) in to the mass at 5-10°C. Charged ethyl acetate (500 ml) to the RM and stirred for 10 min at 20-30°C. The aqueous and organic layers were separated, aq. layer was extracted with ethyl acetate (250 ml). Organic layer was washed with saturated sodium bicarbonate solution (2 ? 250 ml). Combined organic layers were dried over sodium sulfate. The organic layer was distilled completely under vacuum at 40°C and residue was treated with methanol (100 ml). Stirred and, cooled the mass to -5 to 0°C and maintained for 60 min. Filtered the mass and compound was washed with 30 ml of chilled (about 10°C) methanol. The compound was air dried for 6h to obtain the title compound (36.2 g, 75.65 %). (Purity by HPLC: 99.63 %).
Example 3: Preparation of Compound (4): A mixture of toluene (300 ml) and 50 g of compound (2) from example 2 was heated to 110-115°C and stirred for 90 min. Charged 113g of protected lactone (3) (wherein PG = trimethylsilyl) and tetrahydrofuran (350 ml) in to the RM. Cooled the RM to -70 to -75°C and slowly added n-butyl lithium (216 ml) to the RM at same temperature. After completion of reaction, slowly added 85.5 g of methane sulfonic acid in methanol solution (see the note below). Then the mass was warmed to 20-30°C and stirred for 15h. The pH of the RM was adjusted to 8.0 by using saturated sodium bicarbonate solution. Aqueous and organic layers were separated. The organic layer was distilled completely under vacuum at 50°C. After removal of solvent, ethyl acetate was added and stirred for 10 min. Aq and organic layers were separated and combined organic layers were washed with sat. Sodium chloride solution (200 ml). Organic layer dried with sodium sulfate and distilled the organic layer under vacuum at 50°C to obtain a wet residue containing the title compound (4).
Note: Methane sulfonic acid solution was prepared by mixing 85.5gm of methane sulfonic acid in 250.0 ml of methanol.
Example 4: Preparation of Compound (5) (PG = Acetyl): To the residue obtained from Example 3, was added dichloromethane (400 ml), followed by addition of N,N-dimethylaminopyridine (3.5 g) and acetic anhydride (82.3 g).The RM was stirred for 12h at 20-30°C. After the completion of reaction, water (250 ml) was added to the RM and stirred for 10 min. Aqueous and organic layers were separated. The aqueous layer was extracted with dichloromethane (100 ml).Total organic layer were combined and 250 ml of 2N hydrochloric acid solution was added. Stirred the RM for 5 min. Layers were separated, followed by washing with water (250 ml) and stirred for 10 min. Combined organic layers were dried with 20 g of sodium sulfate. The organic layer was distilled completely under vacuum at 45°C. After distillation, methanol (100 ml) was charged and distilled completely under vacuum, to obtain a residue containing the compound (5).
Example 5: Preparation of compound (6): To the residue obtained from Example 4 was added dichloromethane (250 ml) and acetonitrile (250 ml) in to the RB flask. The reaction mass was cooled to -60 ± 5°C and slowly added triethylsilane (35.5 g) at the same temperature, stirred for 5 min. Borontrifluoride etherate (52 g) was slowly added to the reaction mass at -60 ± 5°C. Warmed the mass to 20-30°C. After completion of reaction, charged ethyl acetate (500 ml) in to the RM and stirred for 5 min. Aqueous and organic layers were separated and extracted with ethyl acetate (500 ml). Combined the total organic layers and dried over anhydrous sodium sulfate. Distilled the organic layer completely under vacuum at 55°C followed by washing with methanol and removing the solvent to yield the compound (6) (36 g). (Purity by HPLC: 99.16 %)
Example 6: Preparation of compound (5a)
The compound 5a was prepared from compound 4 using the conditions and reagents as described under Example 5.
Example 7: Preparation of compound (6) from compound 5a
Compound 6 was prepared from compound 5a using the conditions and reagents described under Example 4.
Example 8a: Preparation of compound (7): To compound 6 (2 g) obtained from example 5 or example 7, was added dichloromethane (15.0ml) and cooled the mass to -5 to -10°C. Slowly added 20.0 ml of Borontribromide to the reaction mass. After completion of reaction, water (50.0ml) and dichloromethane (20.0ml) was added at 0-5°C. Stirred, aqueous and organic layers were separated. The aqueous layer was extracted with dichloromethane. Combined organic layers were dried with sodium sulfate after washing with water. The organic layer was distilled completely under vacuum at 40°C and dried for 4hrs to yield the title compound (1.8g, 92.31 %) (Purity by HPLC: 94.36%)
Example 8b: Preparation of compound (7): To compound 6 (2 g) obtained from example 5 or example 7, was added dichloromethane (15 ml), and cooled the mass to -5 to -10°C. Slowly added 20 ml of dodecanethiol & thiourea-AlCl3 to the reaction mass. After completion of reaction, water (50 mL) and dichloromethane (20 mL) was added at 0-5°C. Stirred and aqueous and organic layers were separated. The aqueous layer was extracted with dichloromethane. Combined organic layers were dried with anhydrous sodium sulfate after washing with water. The organic layer was distilled completely under vacuum at 40 °C and dried for 4h to yield the title compound (1.8 g, 92.31 %) (Purity by HPLC: 98.65 %).
Example 9: Preparation of compound (8)
(a) Preparation of compound iii:
To a solution of (S)-3-hydroxytetrahydrofuran (30 g, 0.34 mol) and triethylamine (0.4 mol) in THF (150 ml) at 10°C, was added alkyl or aryl sulfonyl chloride (0.4 mol) in three portions. The RM was stirred for 3h at RT and diluted with hexane (75 ml). The precipitated triethylamine hydrochloride was filtered and the filtrate was evaporated under vacuum to obtain the corresponding sulfonate as a syrup which was taken to next step without further purification.
(b) Preparation of compound iv:
Toluene (200 ml) was added to the residue obtained from step (a) followed by potassium acetate (0.4 mol) and 18-crown-6 (0.04 mol) and the RM was refluxed for 20h. The RM was cooled to RT, water (100 ml) was added and stirred at RT for 30 min. The organic layer was separated, dried over anhydrous sodium sulfate and the solvent was distilled completely under vacuum to obtain (R)-3-acetoxytetrahydrofuran (iv) as an oil. This reaction can also be performed in the absence of 18-crown-6 without affecting yield and purity of the product.
(c) Preparation of compound v:
The oil obtained from step (b) was dissolved in methanol (150 ml) containing sodium hydroxide (0.4 mol) at RT. The RM was stirred at RT for 4h. The solvent was removed under vacuum and the residue was diluted with dichloromethane (150 ml). The organic layer was washed with water (2x100 ml) and the organic layer was dried over anhydrous sodium sulfate and the solvent was removed under vacuum to obtain (R)-3-hydroxy tetrahydrofuran as an oil which was purified by vacuum distillation (24 g, 80 % overall)
(c) Preparation of compound (8):
To a solution of (R)-3-hydroxytetrahydrofuran (20 g, 0.23 mol) from step (c) and triethylamine (0.27 mol) in THF (125 mL) at 10°C, was added alkyl or aryl sulfonyl chloride (0.27 mol) in three portions. The RM was stirred for 3h at RT and diluted with hexanes (65 mL). The precipitated triethylamine hydrochloride was filtered and the filtrate was evaporated under vacuum to obtain compound (8) as a syrup which was taken to next step without further purification.
Example 10: Preparation of compound (9) i.e., Empagliflozin: To Compound (7) (25 g), obtained from example 8a or example 8b, was charged acetonitrile (250 ml) in to the RB flask, followed by addition of potassium carbonate (25 g). The RM was stirred for 10 min at 20-30°C. Compound (8) (15 g), obtained from example 9, was charged to the RM, heated to 70-75°C and stirred for 36h. After completion of the reaction, the RM was cooled to 10-15°C. Slowly water (250 ml) was added followed by addition of ethyl acetate (250 ml), stirred for 10 min. The aqueous and organic layers were separated. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled under vacuum to obtain the crude product which was chromatographed on silica gel (60-120 mesh) beginning 5% methanol in dichloromethane and gradually increased the polarity to 50% methanol in dichloromethane. The product fractions were distilled off under vacuum at 45°C to obtain empagliflozin in amorphous form (15g). (Purity by HPLC: 99.88%) (PXRD pattern: Amorphous as observed in Figure 1)
Example 11: Preparation of amorphous solid dispersion of empagliflozin and Hydroxypropyl cellulose (HPC): To a solution of the product obtained from example 10 (2 g), in methanol (360 ml) was charged hydroxypropyl cellulose (4 g) at RT. The RM was stirred for 20 min at 45°C. Dichloromethane (360 ml) was charged to the RM and stirred for 10 min. The solvent was distilled completely under vacuum to give a wet residue, which upon drying for 30 min resulted in the title product as a solid. The product obtained was crushed using mortar-pestle. (Purity by HPLC: 99.78%)
(PXRD pattern: Amorphous as observed in Figure 2)
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 the preparation of (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy] phenyl]methyl]phenyl]-D-glucitol i.e., Empagliflozin represented by compound (9), comprising reacting compound (7) with compound (8);

Wherein the process for preparing compound (7) comprises:
(a) reducing the compound (1) to obtain diphenylmethane compound (2);

(b) coupling diphenylmethane compound (2) with the protected gluconolactone (3), to obtain compound (4),

wherein in compound (3), PG is a hydroxyl protecting group;
(c.1) treating compound (4) with a suitable reagent, wherein the hydroxy groups are protected to form compound (5), wherein PG denotes a hydroxyl protecting group;

(or)
(c.2) compound (4) obtained from step (b) is subjected to reduction to obtain compound 5a;

(d.1) compound (5) from step (c.1) is further reacted with a reducing agent to form compound (6);

(or)
(d.2) compound (5a) obtained from step (c.2) is reacted with suitable reagent to protect the hydroxy groups to form compound (6).

(e) subjecting compound (6) to O-demethylation, wherein R1 is hydrogen or a hydroxyl protecting group (PG).

2. A process according to claim 1, wherein R1 is hydrogen or a hydroxyl protecting group; R2 is C1-6 alkyl optionally substituted with one or more halogens, or an aryl group optionally substituted in the para position with a halogen or C1-4 alkyl.
3. A process according to claim 1, wherein reduction is carried out using silanes such as triethylsilane, tripropylsilane, triisopropylsilane, or diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride, and the like; Lewis acid selected from aluminum chloride, boron trifluoride etherate (BF3.Et2O), copper (II) triflate, iron (III) chloride, tin (II) chloride, tin tetrachloride, zinc chloride and the like; or Bronsted acids such as hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid or acetic acid;
coupling is carried out using alkyllithium selected from n-, sec-, and tert-butyl lithium; the acid is selected from methanesulfonic acid, toluenesulfonic acid, hydrochloric acid, sulphuric acid, acetic acid, and the like;
the suitable reagent for introducing the hydroxyl protecting group is selected from acetic anhydride, acetyl chloride, propionic anhydride, propanoyl chloride, benzoic anhydride, benzoyl chloride, 4-nitrobenzoyl chloride;
demethylation is carried out using reagents selected from dodecanethiol, hydrogen bromide, boron tribromide, and aluminum chloride, and in the presence of thiourea/AlCl3 reagent pair.
4. A process for preparing (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-fur anyl]oxy]phenyl]methyl]phenyl]-D-glucitol i.e., Empagliflozin represented by compound (9) according to claim 1, comprising reacting compound (7) with compound (8).

5. A process for preparing compound (7) according to claim 1, comprising
(a) reacting compound (1) with sodium borohydride in the presence of aluminium chloride and tetrahydrofuran to obtain diphenylmethane compound (2);

(b) coupling diphenylmethane compound (2) with the protected gluconolactone (3) in the presence of n-butyllithium and tetrahydrofuran, followed by treatment with methanesulfonic acid in methanol to obtain compound (4);

(c.1) treating compound (4) with acetic anhydride in the presence of N,N-dimethylaminopyridine, wherein the hydroxy groups are protected to form compound (5);

(or)
(c.2) compound (4) obtained from step (b) is subjected to reduction using triethysilane and boron trifluoride etherate to obtain compound 5a;

(d.1) compound (5) from step (c.1) is further reacted with triethylsilane in the presence of borontrifluoride etherate and dichloromethane to form compound (6);

(or)
(d.2) compound (5a) obtained from step (c.2) is reacted with acetic anhydride to protect the hydroxy groups in the presence of N,N-dimethylaminopyridine to form compound (6);

(e) subjecting compound (6) to O-demethylation in the presence of a reagent pair and thiol reagent to form compound (7),

Wherein the thiol reagent is dodecanethiol and reagent pair is thiourea-aluminium chloride.
6. A process for preparing a compound (8), in desired R configuration, comprising:
(a) reacting (S)-3-hydroxytetrahydrofuran with compound ii to form compound iii;

Wherein R2 is C1-6 alkyl optionally substituted with one or more halogens, or an aryl group optionally substituted in the para position with a halogen or C1-4 alkyl,
(b) treating compound iii with an alkali metal acetate, optionally in the presence of a phase transfer catalyst to form compound iv;

Wherein R2 is defined as hereinbefore.
(c) subjecting compound iv to hydrolysis to form compound v i.e., (R)-3-hydroxy tetrahydrofuran;

(d) treating compound v i.e., (R)-3-hydroxytetrahydrofuran with compound ii to form compound (8);

Wherein R2 is defined as hereinbefore.
7. A process for preparing compound (8) in desired R configuration according to claim 6, comprises:
(a) reacting (S)-3-hydroxytetrahydrofuran with compound ii to form compound iii;

Wherein R2 is C1-6 alkyl optionally substituted with one or more halogens, or an aryl group optionally substituted in the para position with a halogen or C1-4 alkyl;
(b) treating compound iii with an alkali metal acetate to form compound iv;

Wherein R2 is defined as hereinbefore; alkali metal acetate is selected from lithium acetate, sodium acetate, potassium acetate, cesium acetate.
(c) subjecting compound iv to hydrolysis to form compound v i.e., (R)-3-hydroxy tetrahydrofuran;

(d) treating compound v i.e., (R)-3-hydroxytetrahydrofuran with compound ii to form compound (8);

Wherein R2 is defined as hereinbefore.
8. A process for preparing compound (8) in desired R configuration according to claim 6, comprises:
(a) reacting (S)-3-hydroxytetrahydrofuran with compound ii to form compound iii;

Wherein R2 is C1-6 alkyl optionally substituted with one or more halogens, or an aryl group optionally substituted in the para position with a halogen or C1-4 alkyl;
(b) treating compound iii with an alkali metal acetate in the presence of a phase transfer catalyst to form compound iv;

Wherein R2 is defined as hereinbefore; alkali metal acetate is selected from lithium acetate, sodium acetate, potassium acetate, cesium acetate; phase transfer catalyst is selected from crown ethers such as 12-crown-4, 15-crown-5, 18-crown-6.
(c) subjecting compound iv to hydrolysis to form compound v i.e., (R)-3-hydroxy tetrahydrofuran;

(d) treating compound v i.e., (R)-3-hydroxytetrahydrofuran with compound ii to form compound (8);

Wherein R2 is defined as hereinbefore.
9. A process for preparing empagliflozin according to preceding claims in an amorphous form, comprising:
(a) dissolving empagliflozin in one or more solvents;
(b) optionally filtering the undissolved particles;
(c) distilling the solvent completely; and
(d) drying to isolate an amorphous compound.
10. A process for preparing empagliflozin according to preceding claims as an amorphous solid dispersion with a pharmaceutically acceptable polymer comprising:
(a) dissolving empagliflozin and the pharmaceutically acceptable polymer in one or more solvents;
(b) optionally filtering the un-dissolved particles;
(c) distilling the solvent completely;
(d) drying to isolate amorphous solid dispersion of empagliflozin and the polymer, wherein the pharmaceutically acceptable polymer is selected from water soluble polymers such as polyvinyl pyrrolidone, copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl caprolactam - polyvinyl acetate – polyethylene glycol copolymers, and the like, and water insoluble polymers such as methylcellulose, ethylcellulose, polymethacrylates, hypromellose phthalate, hypromellose succinate, hypromellose acetate succinate (HPMC AS), cellulose acetate phthalate, carboxymethyl ethyl cellulose, and the like; solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar aprotic solvents, chlorinated solvents, nitrile solvents, alcoholic solvents, polar solvents such as water or mixtures thereof.