WO2017071813A1

WO2017071813A1 - Process for the preparation of a pharmaceutical agent

Info

Publication number: WO2017071813A1
Application number: PCT/EP2016/001795
Authority: WO
Inventors: Dominika PODWYSOCKA; Robert RYNKIEWICK; Monika Oracz
Original assignee: Zaklady Farmaceutyczne Polpharma SA
Current assignee: Zaklady Farmaceutyczne Polpharma SA
Priority date: 2015-10-30
Filing date: 2016-10-28
Publication date: 2017-05-04
Anticipated expiration: 2018-04-30

Abstract

This invention provides a process for preparing canagliflozin, comprising: (a) reacting a tricyclic aromatic derivative and a substituted cyclic ester, quenching and deprotecting the resulting intermediate to provide a compound comprising a substituted tetrahydropyran-tricyciic aromatic derivative, and (b) reducing the tetrahydropyran-tricyclic aromatic derivative to provide canagliflozin. The invention also provides a process for preparing canagliflozin hemihydrate.

Description

Process for the preparation of a pharmaceutical agent

The present invention relates to a process for the preparation of a pharmaceutical agent, and particularly to a process for preparing a compound of formula I (canagliflozin).

Canagliflozin is an anti-diabetic used for the treatment of diabetes mellitus type II (also referred to as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes) to improve glycaemic control. Canagliflozin is also used in conjunction with add-on therapies, which include other glucose- lowering agents, for example insulin and metformin.

Type II diabetes is a milder, heterogeneous form of diabetes and often presents more frequently in older age. The disease results from relative insulin deficiency and insulin resistance. These problems frequently arise from, and are exacerbated by, obesity which causes impaired insulin action. Depending upon the severity of the disease the symptoms can be managed through weight loss and diet management, however pharmaceutical intervention is also prevalent.

Canagliflozin acts upon and inhibits subtype 2 of the sodium-glucose linked transport proteins (SGLT2). The SGLT proteins are found in both the intestinal mucosa of the small intestine and in the duct system of the nephron in the kidneys, and they are responsible for renal glucose reabsorption (over 90% of glucose reabsorption occurring in the kidney). In instances where the plasma glucose concentration is too high (hyperglycemic conditions), glucose is excreted in urine. As such, any inhibition of SGLT2 leads to a reduction in blood glucose levels, directly affecting the protein's ability to reabsorb glucose. Consequently, canagliflozin is often prescribed to adult patients presenting with hyperglycemia. The present invention relates to a process for the preparation of canagliflozin named (2S,3R,4R,5S,6R)- 2-{3-[5-[4-fluorophenyl)-thiophen-2-ylmethyl]-4-methylphenyl}-6-(hydroxymethyl) tetrahydro-2/-/-pyran- 3,4,5-triol. Canagliflozin is represented structurally by the formulae below (structural formula and Haworth projection, respectively).

Canagliflozin is commercially marketed by Janssen-Cilag Limited under the trade name Invokana® in the EU and in the US. Canagliflozin is formulated as a hemihydrate, oral film-coated tablet, and is administered in a 100 mg or 300 mg tablet once daily. WO2009035969 discloses a process for the synthesis of canagliflozin amongst various structurally related compounds.

The process involves a metal-mediated addition reaction between a phenyllithium adduct (formed in situ) and a protected sugar lactone. The reaction proceeds through phenyllithium addition to the sugar lactone, followed by an aqueous quench to provide a corresponding lactol intermediate.

Various other syntheses of canagliflozin are known in the art, however they often lack efficiency, utilise expensive or overly toxic reagents and lead to the generation of unwanted side products.

The synthetic methodology employed to produce multi-kilogram quantities of a market-approved pharmaceutically active ingredient, for example canagliflozin, differ greatly from the methodologies employed at the discovery stage. Early stage drug discovery campaigns typically require the production of 5-10 mg of material (per molecule of interest). Such an amount allows for thorough characterisation of physical and chemical parameters, and moreover represents a workable quantity for use in biological assessment. Synthetic chemists operating at the discovery level generally do not assess whether a synthetic route taken to access a molecule of interest, is indeed scalable. In fact, it would be prima facie difficult to predict accurately whether a step conducted at small-scale would in fact be amenable to being implemented upon a large scale.

Large-scale chemical synthesis (or process chemistry) concerns the development, optimisation and production of multi-kilogram and multi-tonne quantities of pharmaceutically active ingredients and speciality bulk chemicals. Consequently, and owing to economies of scale, any small improvement in a given reaction parameter is particularly economically significant. Therefore, optimisation of a large-scale synthesis that provides, for example, an increase in chemical yield/decrease in reaction time, decrease in reaction temperature, decrease in amount of catalyst or solvent used, reduction in side-product formation, a more environmentally benign synthesis or increase in chemical purity is of interest both to chemical manufacturers and suppliers. Moreover, step optimisation that reduces the need for multiple or hard-to-perform purifications are particularly beneficial. Conventional column chromatography and high-performance liquid chromatography (HPLC) are ubiquitous techniques, and resemble the cornerstone of the discovery chemist's purification arsenal. Unfortunately, these techniques are unsuitable for the production of multi-kilogram and multi-tonne quantities, yet begrudgingly, such purifications will have to be performed if the target is of high value and no feasible alternative exists. Consequently, any improvement in the ease of purification or isolation, through telescoping (wherein two or more, previously independent synthetic transformations converge into a "single" process and therefore require only one purification step) of synthetic procedures, or the identification of an intermediate for recrystallisation, or precipitation, or removal of impurities through conversion into a transient intermediate, or substitution for a cheaper, more environmentally friendly or less toxic reagent, provide an attractive and economically desirable goal. Practical achievement of this goal is however not straightforward, and even careful optimisation of each individual parameter of a synthetic step (on a small- or large-scale) will often fail to provide a workable advantage within a large-scale synthesis.

Owing to the potential economic and scientific gains there remains a constant need for the development and optimisation of large-scale chemical syntheses, and consequently, there remains a need in the art for improved synthetic approaches to canagliflozin.

Accordingly, an embodiment of the present invention provides a process for preparing a compound of formula I,

comprising the following steps:

(a) reacting a compound of formula II and a compound of formula III,

wherein the resulting intermediate, without isolation, is quenched and deprotected with hydrogen chloride in methanol to provide a compound of formula IV,

wherein R¹ is a silicon protecting group and X represents a halide, and

(b) reducing the compound of formula IV to provide a compound of formula I.

R¹ is a silicon protecting group, R¹ is for example a silyl ether, more specifically trimethylsilylether (TMS), triethylsilylether (TES), [2-(trimethylsilyl)ethoxy]methyl ether (SEM), ierf-butyldimethylsilylether (TBS/TBDMS), terf-butyldiphenylsilylether (TBDPS) and triisopropylsilyl ether (TIPS). It is most preferred when R¹ is trimethylsilylether.

The term "protecting group" refers to a chemical functionality used to mask (protect temporarily) the characteristic chemistry of a functional group because it interferes or is likely to affect the efficacy of a preceding reaction. Furthermore, "silicon protecting group" denotes a silicon-containing protecting group, wherein a silicon atom is contained within the group appended to the functionality being protected. Typical examples of silicon protecting groups are recited hereinabove.

Methods for addition and removal of silicon-containing protecting groups are known in the art, and furthermore can be found in Greene's Protective Groups in Organic Synthesis Ed.: Wuts and Greene, Wiley Interscience, 2006. The removal of protecting groups is also referred to as a deprotection step or more generally deprotecting.

The process of the present invention (step (a) and (b)) is performed without isolation. The term "without isolation" should be understood as referring to a single operational step, i.e. where reagents are added consecutively into one reaction vessel, and no intermediate is isolated, also known in the art as a "one pot" process.

In accordance with the present invention there is provided a process for the preparation of canagliflozin (a compound of formula I). The process comprises two distinct chemical transformations performed in a single operational step, wherein compounds of formula II and III are reacted together and the resulting intermediate is quenched, and furthermore deprotected by addition of hydrogen chloride in methanol - both transformations occurring without isolation. First, compounds of formula II and III react through a metal-mediated addition reaction, and secondly, the resulting intermediate is quenched to form a methyl acetal and furthermore deprotected to expose four hydroxyl groups upon the pyranose ring. These concomitant chemical transformations yield canagliflozin.

There is also provided a further process for increasing the purity of the canagliflozin obtained by the process of the present invention, there is also a process provided for the conversion of canagliflozin into canagliflozin hemihydrate.

The process of the present invention is depicted as follows:

It should also be noted, that where practically possible and in accordance with the present invention, large-scale processes are ideally conducted at room temperature. Any heating (above room temperature (25°C)) or cooling (below room temperature (25°C)) leads to a substantial increase in operating costs. It is apparent that the greater the deviation away from room temperature (above or below) the greater the operating costs. Therefore the achievement of any reduction of a traditionally high-operating temperature, or increase in a traditionally low-operating temperature reaction is particularly preferred.

In accordance with the present invention, hydrogen chloride in methanol (equally termed methanolic hydrogen chloride) should be understood as methanol comprising hydrogen chloride. Hydrogen chloride in methanol can be purchased from commercial chemical suppliers, or alternatively it can be prepared using known laboratory procedures. Hydrogen chloride in methanol can be prepared by bubbling hydrogen chloride gas into dry methanol. Alternatively, concentrated aqueous hydrochloric acid in methanol can also be used. Preferably, and in accordance with the present invention, X represents a halide, more preferably a bromide or iodide, and most preferably bromide.

The processes of the present invention take place in a solvent (typically an organic solvent). Processes of the present invention, that are, for example, water- or air-sensitive transformations typically require the use of non-aqueous, non-protic solvents such as acetonitrile, tetrahydrofuran, methyltetrahydrofuran, dioxane, dimethylsulfoxide dichloromethane, chloroform or /V-methylpyrrolidine. Furthermore, water- or air-sensitive reactions may also require an atmosphere of inert gas (to prevent atmospheric water from compromising a transformation) typical inert gases include nitrogen and argon. Alternatively, reactions requiring the use of an aqueous reagent (e.g. aqueous hydrochloric acid or aqueous sodium hydroxide) may require the use of one or more organic co-solvents. In this context, an organic co-solvent is added to aid the dissolution, or partial dissolution of a less polar organic reagent. Typical organic co-solvents for use with such aqueous reagents include, toluene, alcohols (methanol, ethanol, propanol), tetrahydrofuran and dimethylsulfoxide. The only limitation in regard to reaction efficacy when using organic co-solvents with aqueous solvents is the requirement for some degree of miscibility of the organic co-solvent with water. To aid problems with miscibility and or reaction efficacy a phase transfer catalyst is employed (e.g. tetrabutylammonium bromide).

Step (a) is preferably facilitated by a metal-mediated addition reaction, wherein a compound of formula II is a pro-nucleophile and a compound of formula III is an electrophile. The metal mediated addition reaction is facilitated by the insertion of a metal into the Ar-X bond or by substitution of X for a metal, wherein Ar represents the structure of a compound of formula II and X a halide. Typical examples of metal-mediated addition reactions include Grignard reactions, Reformatsky reactions, organolithium additions and organocuprate additions. With reference to step (a) a lithium-mediated addition reaction is most preferred, wherein a compound of formula II is converted into its organolithium adduct prior to reaction with a compound of formula III. The lithium adduct can be prepared through treating a compound of formula II with an alkyl lithium reagent (e.g. n-butyllithium or n-butyllithium in hexanes). Typically, reactions involving alkyl and aryl lithium reagents are conducted at -78°C, owing to the reactivity and pyrophoric nature of the lithium-containing reagent. In accordance with the present invention, it is most preferred that the aryl lithium adduct is generated in the temperature range of from -30 to -40°C, and that the resulting aryl lithium adduct is added to a compound of formula III in the temperature range of from -30 to -40°C and that the addition reaction is conducted at a temperature of from -30 to -40°C, until complete. Furthermore, and in accordance with the present invention, it is preferred when the aryl lithium adduct used in step (a) is generated in 2-methyltetrahydrofuran (or in a mixture of solvents, for example, 2-methyltetrahydrofuran and toluene), and upon complete generation thereof, the adduct in 2-methyltetrahydrofuran (or in a mixture of solvents, for example, 2- methyltetrahydrofuran and toluene) is added to a solution of compound III in toluene. It is preferred when step (a) is conducted in a multi solvent system, wherein the solvents are 2-methyltetrahydrofuran and toluene. Methods for monitoring the consumption of a reagent are known in the art. Typical examples include thin layer chromatography (TLC), gas chromatography-mass spectrometry (GCMS) liquid chromatography-mass spectrometry (LCMS) and mass spectrometry (MS).

Upon reacting compounds of formula II and III the resulting intermediate is quenched and deprotected without isolation to provide a compound of formula IV.

The term quench or quenching can be understood as the addition of a substance to a reaction vessel, which acts to deactivate any unreacted reagents. In accordance with the present invention hydrogen chloride in methanol deactivates any unreacted reagents and quenchs an intermediate lactol cation to form a methyl acetal.

In accordance with the present invention, the reaction is preferably quenched with hydrogen chloride in methanol, more preferably with a 5-7% hydrogen chloride in methanol solution. Quenching is preferably conducted upon completion of the metal-mediated addition reaction, typically the addition reaction requires of from 10 to 30 minutes at a temperature of from -30 to -40°C to reach completion, more preferably the addition reaction requires 10 minutes at a temperature of from -30 to -40°C to reach completion. It is more preferred when step (a) is a metal-mediated addition reaction and the reaction is conducted at a temperature of from -30 to -40°C and wherein the reaction is quenched (after completion) with hydrogen chloride in methanol, X is a bromide or iodide and the solvent is a mixture of 2- methyltetrahydrofuran and toluene. It is even more preferred when step (a) is a lithium-mediated addition reaction, wherein n-butyllithium in hexanes is added to a compound of formula II to generate an organolithium adduct prior to its reaction with a compound of formula III, and when step (a) is conducted at a temperature of from -30 to -40°C and wherein the reaction is quenched (after completion) with a 5-7% hydrogen chloride in methanol solution, X is a bromide or iodide and the solvent is a mixture of 2-methyltetrahydrofuran and toluene.

In accordance with the present invention, the hydrogen chloride in methanol quenches and deprotects the reaction intermediate. Advantageously, all hydrogen chloride in methanol required for the quench and deprotection is added in a single operation.

Generally, methods for the deprotection or removal of silicon protecting groups are known in the art, and are dependent on the type of protecting group used, which vary in their relative stabilities. Silicon protecting groups of both low and high stability are removed upon exposure to aqueous and or methanolic acidic environments. Furthermore, removal of silicon protecting groups of higher stability can be achieved with fluoride ions. Examples of fluoride ion sources include tetrabutylammonium fluoride (TBAF), pyridine.(HF), triethylamine trihydrofluoride, hydrofluoric acid, tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) and ammonium fluoride, however often these reagents are expensive and furthermore particularly hazardous to handle on both small- and large-scale. Less stable silicon protecting groups, for example trimethylsilyl are particularly amenable to removal with acidic or basic media. Step (b) provides a compound of formula I, through the reduction of a compound of formula IV. Reduction is any chemical reaction that involves the gaining of electrons. More typically, and in accordance with the present invention, reduction is the gain of hydrogen into a molecule, wherein the hydrogen is provided in the form of a reactive hydride. Reduction reactions may be acid- or base- mediated (base-catalysed dehydration). Furthermore, reduction reactions may be mediated by a Lewis acid. Preferably step (b) is mediated by a Lewis acid and a reducing agent. Typical examples of Lewis acids include aluminium-, boron-, iron-, tin-, scandium-, titanium- and copper-containing derivatives. In accordance with the present invention preferably a boron-containing Lewis acid is used. Most preferably boron trifluoride diethyl etherate (BF3.0Et,2) is used. Preferably step (b) is mediated by a Lewis acid and a reducing agent. Preferably the reducing agent is a hydride-containing reducing agent. Typical examples of hydride-containing reducing agents include lithium aluminium hydride, Red-AI®, sodium hydride, sodium borohydride, diisobutylaluminium hydride, trialkylsilanes and triethylsilane. With reference to step (b), triethylsilane is most preferred. With further reference to step (b) it is most preferred when the reduction reaction is mediated by boron trifluoride diethyl etherate (BF3.0Et2) and triethylsilane.

Furthermore, in accordance with the present invention, it is preferred when step (a) is a lithium-mediated addition reaction, wherein n-butyllithium in hexanes is added to a compound of formula II to generate an organolithium adduct prior to its reaction with a compound of formula III, and when step (a) is conducted at a temperature of from -30 to -40°C, when the reaction is quenched (after completion) with a 5-7% hydrogen chloride in methanol solution, X is a bromide or iodide, the solvent is a mixture of 2-methyltetrahydrofuran and toluene, and step (b) the reduction step is mediated by a Lewis acid and a reducing agent.

It is most preferred when R¹ is a trimethylsilyl radical, step (a) is a lithium-mediated addition reaction, wherein n-butyllithium in hexanes is added to a compound of formula II to generate an organolithium adduct prior to its reaction with a compound of formula III, and when step (a) is conducted at a temperature of from -30 to -40°C for a duration of 10 minutes, and the reaction is quenched (after completion) with a 5-7% hydrogen chloride in methanol solution, X is a bromide or iodide, the solvent is a mixture of 2-methyltetrahydrofuran and toluene and step ^'(b) is mediated by a Lewis acid that is boron trifluoride diethyl etherate and a reducing agent that is triethylsilane. The present invention additionally comprises a process for preparing a compound of formula V,

V wherein R² is independently an optionally substituted C₁-C₁₀ acyl group. The compound of formula V is prepared from a compound of formula I, wherein the compound of formula I is reacted with an acylating agent. Acylating agents are known in the art and typically include acid chlorides, acid anhydrides and acyl imidazoles, such agents may be accompanied by further activating agents, for example dimethylaminopyridine. Acylation reactions are typically performed in the presence of a non-nucleophilic base for example, triethylamine, W./V-diisopropyethylamine, W-methylmorpholine or 2,6- ditertbutylpyridine. It is preferred when R² is an acyl radical, that is when R² is COCH3.

The present invention also provides a process for preparing canagliflozin, or a hydrate thereof, comprising preparing a compound of formula I, and subjecting the compound of formula I to steps (c) and (d), wherein the steps comprise,

(c) acetylating a compound of formula I to provide a compound of formula VI, and

(d) deacetylating a compound of formula VI to provide canagliflozin. Purification processes and chemical purity measurements of canagliflozin can be performed and measured by UPLC (ultra-performance liquid chromatography).

Preferred solvents for purifying and analysing canagliflozin by UPLC are combinations of ammonia in water, typically (0.1 % ammonia in water) and acetonitrile and methanol, typically (acetonitrile : methanol 20:80). UPLC purification and analysis can be performed, for example, using a 100 x 2.1 mm Waters Acquity C18 RP column, where detection is set at 200-400nm, and wherein elution is conducted using a combination of two mobile phases (0.1 % ammonia in water and acetonitrile : methanol 20:80) over a period of 30 minutes. The acetylation reaction according to step (c) is provided by methods known in the art (e.g. acetic anhydride, triethylamine and dimethylaminopyridine (DMAP)).

The deacetylation reaction according to step (d) is also provided by methods known in the art, preferably by base-mediated methods known in the art. More preferably by aqueous metal hydroxides, and most preferably by aqueous sodium hydroxide.

Steps (c) and (d) provide a method for preparing canagliflozin. According to the present invention, performing step (b) without purification yields a compound of formula I (canagliflozin in crude form). The rapid and clean acetylation/deacetylation procedure provides access to canagliflozin, circumventing the need for more onerous chromatographic techniques.

With reference to the hydrates thereof, it is particularly preferred when canagliflozin as provided by the process of the present invention, is converted into a hydrate of formula la,

wherein the hydrate is the hemihydrate. Processes for the preparation of canagliflozin hemihydrate are disclosed in US7943582 and US8513202. Details therein indicate that preparation of the crystalline form typically involves dissolving canagliflozin in a suitable solvent (i.e. one in which canagliflozin is soluble, e.g. ketones and or esters) and adding water and/or a solvent in which canagliflozin is less soluble thereto. The hemihydrate can be obtained through filtration of the resulting mixture.

It can be seen that the present invention provides a process for preparing canagliflozin, comprising: (a) reacting a tricyclic aromatic derivative and a substituted cyclic ester, quenching and deprotecting the resulting intermediate to provide a compound comprising a substituted tetrahydropyran-tricyclic aromatic derivative, and (b) reducing the tetrahydropyran-tricyclic aromatic derivative to provide canagliflozin. The invention also provides a process for preparing canagliflozin hemihydrate.

The present invention will now be described with reference to the examples, which are not intended to be limiting.

Examples Example 1

Methyl 1-G-(3-{[5r(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl)-a-D-glucopyranoside

2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (20.5 g) was dissolved in 2-methyl- tetrahydrofuran (308 mL) and the mixture was cooled to approx. -36°C under nitrogen atmosphere. To the mixture was added dropwise n-buthylljthium (2.5 M hexane solution, 25 mL). Then, the reaction mixture was added dropwise at a temperature of -30 to -40°C to the solution of (3R,4S,5R,6f?)-3,4,5- tris[(trimethylsilyl)oxy]-6-{[(trimethylsilyl)oxy]methyl}tetrahydro-2AV-pyran-2-one (26.5 g) in toluene (180 mL) and the mixture was stirred at the same temperature for 10 min. Next, a solution of hydrogen chloride (concentration approx. 6%) in methanol (313 mL) was added and the mixture was stirred at a temperature of -10 to -5°C for 2 hours. Under ice-cooling, the mixture was added into saturated 8% aqueous sodium hydrogen carbonate solution. After that the solution was warmed to 20°C and the layers were separated. The organic layer was washed twice with 20% solution brine, and the solvent was evaporated under reduced pressure to give the title compound (25 g, 93% yield).

Example 2

(2S,3R,4R,5S,6R)-2-{3-[5-[4-fluorophenyl)-thiophen-2-ylmethyl]-4-methylphenyl}-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

A solution of triethylsilane (33.02 g) and the material obtained in Example 1 in toluene (308 mL) was cooled to -10°C under a nitrogen atmosphere, and thereto was added dropwise boron trifluoride-diethyl ether complex (40.45 g). The mixture was stirred at -10°C for 30 min and then warmed to 20°C. Then methanol (100 mL) was added, and saturated (8%) aqueous sodium hydrogen carbonate solution was added dropwise. Following neutralization, the layers were separated and the organic solvent was concentrated under reduced pressure. The resulting residue (oil/foam) was dissolved in ethyl acetate (308 mL) and washed twice with brine 20% and water at 35-40°C. The organic solvent was again concentrated under reduced pressure to give canagliflozin as a residue. Example 3

(1 S)-2,3 ,4,6-tetra-O-acetyl-l ,5-anhydro-1 -(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4- methylphenyl)-D-glucitol

To a stirred solution of canagliflozin (technical, obtained in Example 2) in ethyl acetate (308 mL) was added 4-dimethylaminopyridine (0.346 g) and triethylamine (28.7 g) at room temperature. Acetic anhydride (29 g) was then added dropwise avoiding increasing temperature above 30°C. The reaction mixture was allowed to cool down to room temperature and stirred for 60 min. The mixture was then quenched with water and stirred for a further 60 min. After that time the phases were separated and organic phase was washed with 1 N hydrochloride aquatic solution, sodium carbonate 10% aqueous solution, 20% brine and water. The organic phase was concentrated under reduced pressure. The residue was crystallized from ethanol/ethyl acetate mixture (8:2 (v/v)) with activated charcoal. The product was obtained 17.5 g, with 98% purity (50% yield based on 2-(5-bromo-2-methylbenzyl)-5-(4- fluorophenyl)thiophene). The solid could also be recrystallized further in the same manner giving 14 g of acetylated canagliflozin, with 99% purity (80% yield).

Example 4

Acetylated canagliflozin (14 g) was suspended in tetrahydrofuran (90 mL; 1 g acetylated canagliflozin / 6.5 mL) and methanol (42 mL; 1 g acetylated canagliflozin / 3 mL) at room temperature. A solution of sodium hydroxide (3.43 g, 1 g acetylated canagliflozin / 0.245 g) in water (38 mL, 1g acetylated canagliflozin / 2.7 mL) was added dropwise to the mixture for 5-10 min at 20-25°C. After the mixture was stirred for 1 hour at room temperature and methyl tert-butyl ether (MTBE) (154 mL, 1g acetylated canagliflozin / 11 mL) was added. The reaction mixture was washed with 20% brine and water. The organic phase was concentrated under reduced pressure to give canagliflozin as a residue (10 g, 98%).

Example 5

Canagliflozin (obtained in Example 4) was dissolved in acetone (100 mL, 1 g canagliflozin / 10 mL) and water (200 mL, 1 g canagliflozin / 20 mL) was added dropwise. The reaction mixture was cooled down till 0-5°C and stirred for 16 h. The solid was filtered off and washed with 30 mL of a acetone/water (1 :2) mixture. The solid was dried under vacuum at 35°C giving 8 g of pure canagliflozin hemihydrate with purity in excess of 99%. Example 6

Canagliflozin (obtajned in Example 4) was dissolved in ethyl acetate with 2% (v/v) of water (15 mL, g canagliflozin / 1.5 mL) and MTBE (60 mL, 1 g canagliflozin / 6 mL) was added dropwise. Seeds of canagliflozin are added. The reaction mixture was cooled down till 18-25°C and stirred for 4-6 h. The solid was filtered off and washed with 10 mL of ethyl acetate/MTBE (1 :4) mixture. The solid was dried under vacuum at 35°C giving 8 g of pure canagliflozin hemihydrate (78% yield) with purity in excess of 99%.

Comparative Example

To a solution of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (1 ) (3.61 g) in tetrahydrofuran (60 mL) and toluene (60 mL) was added n-butyllithium (2.5 M hexanes solution, 4.0 mL) dropwise at -67 to -70°C under a nitrogen atmosphere, and the mixture was stirred for 20 minutes at the same temperature. Thereto was added a solution of 2 (4.25 g) in toluene (30 mL) dropwise at the same temperature, and the mixture was further stirred for 1 hour at the same temperature. Subsequently, thereto was added a solution of methanesulfonic acid (2.63 g) in methanol (60 mL) dropwise, and the resulting mixture was allowed to warm to room temperature and stirred for 19 hours. The mixture was cooled under ice - water cooling, and thereto was added a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the combined organic layers was washed with brine and dried over sodium sulfate. The insoluble material was filtered off and the solvent was evaporated under reduced pressure. The residue was triturated with toluene (12.5 mL) - hexane (50 mL) to give methyl 1-C-(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl)-a-D- glucopyranoside (3) (2.93 g; Yield: 67.8%). Purity (HPLC: 78.70%). A solution of 3 (2.1 g) and triethylsilane (1.55 g) in dichloromethane (22 mL) was cooled by dry ice - acetone bath under nitrogen atmosphere, and thereto was added dropwise boron trifluoride ethyl ether complex (1.66 mL), and the mixture was stirred at the same temperature. The mixture was allowed to warm to 0°C and stirred for 2 hours. At the same temperature, a saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was stirred for 30 minutes. The organic solvent was evaporated under reduced pressure, and the residue was poured into water and extracted with ethyl acetate twice. The organic layer was washed with water twice, dried over sodium sulfate and treated with activated carbon. The insoluble material was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL), and thereto were added diethyl ether (20 mL) and H2O (0.2 mL). The mixture was stirred at room temperature overnight, and the precipitate was collected, washed with ethyl acetate - diethyl ether (1 :4) and dried under reduced pressure at room temperature to give (2S,3R,4R,5S,6R)-2-{3-[5-[4-fluorophenyl)-thiophen-2-ylmethyl]- 4-methylphenyl}-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol hemihydrate as colourless crystals (0.89 g; Yield: 44.5%). Purity (HPLC: 97.78%).

Claims

1. A process for preparing a compound of formula I,

comprising the following steps:

(a) reacting a compound of formula II and a compound of formula III,

wherein R¹ is a silicon protecting group and X represents a halide, and

(b) reducing the compound of formula IV to provide a compound of formula I.

2. A process as claimed in claim 1 , wherein step (a) is a lithium-mediated addition reaction.

3. A process as claimed in any one of claims 1 to 2, wherein step (a) is conducted at a temperature range of from -30 to -40°C.

4. A process as claimed in claim 1 , wherein the reduction step (b) is mediated by a Lewis acid and a reducing agent.

5. A process as claimed in claim 1 , wherein R¹ the silicon protecting group is independently substituted with a C₁-C₁₀ alkyl or aryl group, X represents bromide or iodide, step (a) is a metal-mediated addition reaction and is conducted at a temperature range of from -30 to -40°C and the reduction step is mediated by a Lewis acid and a reducing agent.

6. A process as claimed in any one of claims 1 to 5, further comprising a step for converting a compound of formula I into a compound of formula V,

wherein R² is independently an optionally substituted C₁-C₁₀ acyl group.

7. A process for preparing canagliflozin, or a hydrate thereof, comprising preparing a compound of formula I as claimed in any one of claims 1 to 5, and subjecting a compound of formula I to steps (c) and (d), wherein the steps comprise,

(d) deacetylating a compound of formula VI to provide canagliflozin.

8. A process as claimed in claim 7, wherein the deacetylation reaction is base-mediated.

9. A process as claimed in claim 7, wherein canagliflozin is converted into a hemihydrate of formula la,