TECHNICAL FIELD OF THE INVENTION The present invention relates to novel process for the preparation of compounds useful as intermediates for the production of ezetimibe.

BACKGROUND OF THE INVENTION Hydroxy-alkyl substituted azetidinones are useful in the treatment of atherosclerosis. Ezetimibe is an agent used for reducing plasma cholesterol level. Ezetimibe is also used in combination with Simvastatin, when statins alone do not control cholesterol levels.

Ezetimibe is chemically designated as (3R, 4S)-l-(4-fluorophenyl)-3-((5)-3-(4-fluorophenyl)-3- hydroxypropyl)-4-(4-hydroxyphenyl)azetidin-2-one and is presented by the chemical structure of

Formula I.

Ezetimibe was first disclosed in EP 0720599 and the laborious process for its preparation addresses three focal points of the synthesis using well-established and name-accredited procedures (Scheme 1). The configuration of the feta-lactam ring is ensured by Evans oxazolidinone enolate chemistry (step a), the 4-fluorobenzyl group of the side chain is introduced through Negishi coupling (step d) and the alcohol moiety is stereoselectively constructed under influence of the Corey-Bakshi-Shibata chiral oxazaborolidine complex (step e). The overall process employs expensive reagents but affords low yields, while extensive purification steps are needed in order to remove the process-related impurities.

Several routes of synthesis have been since disclosed, attempting to improve on these pivotal synthetic checkpoints. With respect to the feta-lactam ring construction, the pathways employing the Evans chemistry, along with the manageable cost of the relevant chiral reagents, enjoy a clear advantage in terms of yield and diastereoselectivity. Concerning the incorporation of the chiral benzylic alcohol, most published approaches rely on the stereoselective reduction of the respective ketone either early or later in the synthesis.

For the reduction of late ketone intermediates, as depicted in the scheme below, the expensive Corey-Bakshi-Shibata technology is commonly employed (as for example in EP 0720599 and EP 0906278). Alternative approaches using asymmetric transfer hydrogenation (ATH) have also been disclosed. In most cases (WO 2007/030721, WO 2007/120824, WO 2007/144780), experiments with readily accessible catalysts are either lacking in terms of yield and stereoselectivity or require high catalyst loadings. Although custom ligands have been reported to provide high diastereoselectivities (WO 2008/089984, EP 1953140), the CBS methodology still appears to be the most efficient at this transformation with respect to product yields and stereoselectivities.

BH ₃ DMS The early reduction approaches to ezetimibe involve installing the chiral alcohol moiety before the beta-lactam formation. Boron-based methodologies (EP 1137634, WO 2005/049592, EP 1988071, WO 2007/017705), biocatalytic systems (WO 2010/113175, WO 2010/025085) and hydrosilylations using chiral metal complexes as catalysts (WO 2005/1 13495) have been disclosed for these reductions.

Y: chiral auxiliary, OR, NR ₂ , morpholine

However, no asymmetric transfer hydrogenation has been reported for the ketone intermediates early in the synthesis of ezetimibe. The ATH of prochiral ketones has emerged as a powerful tool for the synthesis of chiral alcohols, especially at a benzylic position, combining the efficiency of the transition-metal catalyzed asymmetric hydrogenations with the safety and applicability of transfer hydrogenation without requiring the use of hydrogen gas at high pressures and the respective specialized equipment.

Consequently, a process that efficiently employed asymmetric transfer hydrogenation, using readily available chiral catalysts, for the synthesis of these early ezetimibe intermediates would hold a substantial relative advantage with respect to existing ones in terms of cost and industrial applicability.

SUMMARY OF THE INVENTION

The object of the present invention is to provide an improved process for the preparation of compounds of general Formula III to be used as key intermediates for the synthesis of ezetimibe.

wherein

X is selected from hydrogen and halogen; and

Y is selected from -OR' , -NR R or a chiral auxiliary group. Chiral auxiliary groups are repre nted by the formula

R ¹ , R ² and R ³ may be independently selected from Cj-C alkyl, Q-C6 alkoxy, aryl or benzyl groups or may together form a cyclic group, optionally containing a heteroatom such as O; and each Z is independently selected from O and S.

Chiral auxiliary groups include, but are not limited to, the following structures

In particular, the process according to the present invention comprises a previously undisclosed asymmetric transfer hydrogenation (ATH) protocol for the stereoselective reduction of a ketone of Formula II to form an alcohol of Formula III.

As mmetric

wherein X and Y are defined as above.

A further object of the present invention is to provide an improved process for the preparation of compounds of Formula III, wherein a ketone of Formula II is converted to the alcohol of Formula III by an improved asymmetric transfer hydrogenation protocol which comprises the use of aqueous media and an organic ion pair additive.

Yet another object of the present invention is to provide the intermediate compounds of Formula III adequately functionalized, in high yield and purity, therefore efficient when used in the process for the preparation of ezetimibe. In accordance with the above, a preferred object of the present invention is to provide an improved asymmetric transfer hydrogenation (ATH) protocol for the stereoselective reduction of a ketone of Formula Ila to form an alcohol of Formula Ilia.

Other preferred embodiments of the present invention are set out in dependent claims.

Other objects and advantages of the present invention will become apparent to those skilled the art in view of the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel process for the preparation of compounds of Formula III, which are intermediate compounds useful for the preparation of ezetimibe.

According to the present invention, the process for the preparation of compounds of Formula III comprises the Asymmetric Transfer Hydrogenation of a compound of Formula II to provide a compound of Formula III,

wherein

X is selected from hydrogen and halogen; and

Y is selected from -OR ¹ , -NR ¹ R ² or a chiral auxiliary group.

Chiral auxiliary groups are represented b the formula R , R and R ^J may be independently selected from Q-C ₆ alkyl, C _! -C ₆ alkoxy, aryl or benzyl groups or may together form a cyclic group, optionally containing a heteroatom such as O; and each Z is independently selected from O and S. In particular, compounds of Formula II include, but are not limited to

The Asymmetric Transfer Hydrogenation (ATH) of aryl-ketones has been extensively studied in the literature. The key reaction features of the ATH are the catalyst, characterized by a chiral ligand and a metal center, the hydrogen donor and the reaction medium.

The current paradigm for the ATH of such substrates endorses the catalysts that incorporate Ru, Rh or Ir as a metal center and a member of the 1 ,2-diphenylethylenediamine (DPEN) family as a chiral ligand. Catalyst loadings of 50:1 to 1000:1 (substrate: catalyst molar ratio) are usually required. The triethylamine:formic acid mixture, commonly in a 5:2 ratio, is being preferred over alternative hydrogen donors and is frequently used as the only reaction medium.

It is remarkable that the Asymmetric Transfer Hydrogenation of the functionalized ketone substrates of Formula II has not been disclosed in the literature, although the enantiomerically enriched alcohols of Formula III are common key starting materials for the synthesis of ezetimibe. It has now been found that chiral alcohols of Formula III may be prepared efficiently and in high yield, purity and stereoselectivity by the Asymmetric Transfer Hydrogenation of compounds of Formula II.

In particular, according to one object of the present invention, a compound of Formula II and an Asymmetric Transfer Hydrogenation catalyst are treated with a hydrogen donor in the presence of an amine base in an organic solvent.

The catalyst used in the process according to the present invention may be selected from suitable ATH catalysts employed in the prior art, usually represented by the formula MX(L1)(L2) in the relevant literature, wherein M is a metal center, X is a halogen atom, LI is a rj ⁵ - or η ⁶ - arene ligand and L2 is a chiral ligand.

M may be selected from Ru, Rh or Ir, and the preferred metal center is X may be selected from CI, Br and I, and the preferred halogen is CI.

LI may be selected from arene ligands such as benzene, p-cymene, mesitylene, 1,3,5- triethylbenzene, hexamethylbenzene, cyclopentadienyl and 1,2,3,4,5- pentamethylcyclopentadienyl, and the preferred arenes are p-cymene and mesitylene.

L2 may be selected from chiral diamine ligands of the structure shown below:

wherein

R ⁴ is selected from C6 to C14 aryl or C5 to C12 heteroaryl rings or CI to C12 alkyl groups, optionally substituted with one or more CI to C12 alkyl, halogen or CI to C 12 alkoxy groups, where the two R ⁴ groups may optionally together form a ring; and

A is selected from C6 to C14 aryl rings, C5 to C12 heteroaryl rings, CI to C12 linear, monocyclic or polycyclic alkyl groups, optionally substituted with one or more CI to C12 alkyl, halogen or CI to C 12 alkoxy groups, and secondary amines, such as pyrrolidine, piperidine and morpholine. Preferably, the R ⁴ group of ligand L2 is a phenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl or 4-methoxyphenyl group. Preferably, the -S0 ₂ -A group of ligand L2 is a p-toluenesulfonyl, methanesulfonyl, benzenesulfonyl, pentafluorophenylsulfonyl, (-)-camphorsulfonyl, (+)-camphorsulfonyl, piperidyl-N-sulfonyl, pyrrolidyl-N-sulfonyl or morpholyl-N-sulfonyl group.

Specific examples of the most preferred catalysts are:

(RuCl[(S,S)-Ts-DPEN](mesitylene)), (RuCl[(S,S)-Ts-DPEN](p-cymene)),

(RuCl[(S,S)-Ms-DPEN](mesitylene)), (RuCl[(S,S)-Ms-DPEN](p-cymene)),

(RuCl[(S,S)-PhS0 ₂ -DPEN](mesitylene)), (RuCl[(S,S)-PhS0 ₂ -DPEN](p-cymene)),

(RuCl[(S,S)-Fs-DPEN](mesitylene)), (RuCl[(S,S)-Fs-DPEN](p-cymene)),

(RuCl[(S,S,S)-Cs-DPEN](mesitylene)), (RuCl[(S,S,S)-Cs-DPEN](p-cymene)),

(RuCl[(R,S,S)-Cs-DPEN](mesitylene)), (RuCl[(R,S,S)-Cs-DPEN](p-cymene)),

(RuCl[(S,S)-(piperidyl-N-sulfonyl)-DPEN](mesitylene)), (RuCl[(S,S)-(piperidyl-N-sulfonyl)- DPEN](p-cymene)),

(RuCl[(S,S)-(pyrrolidyl-N-sulfonyl)-DPEN](mesitylene)), (RuCl[(S,S)-(pyrrolidyl-N-sulfonyl)- DPEN](p-cymene)),

(RuCl[(S,S)-(moφholyl-N-sulfonyl)-DPEN](mesitylene)), (RuCl[(S,S)-(morpholyl-N-sulfonyl)- DPEN](p-cymene)).

Alternatively a tethered catalyst of the following structure may be used,

wherein n is an integer selected from 0, 1, 2 or 3;

Y is selected from CH ₂ or O;

R is selected from H or a CI to C3 alkyl group; and

M, R ⁴ , A and X are defined as previously. Suitable catalysts may be prepared using published methods or are available commercially. The catalyst complex may be prepared previously and optionally isolated, or may be generated as a part of the Asymmetric Transfer Hydrogenation reaction, optionally in the same container {one-pot reactions). The catalyst loading is usually expressed by the substrate-to-catalyst molar ratio (S:C or S/C), which is calculated as the ratio of the molar quantities of the substrate and the catalyst employed during the attempted Asymmetric Transfer Hydrogenation reaction.

S:C ratio = (moles of substrate used) / (moles of catalyst used)

The main components of the chiral catalyst, the metal center and the chiral ligand, are significantly more expensive than the rest of the raw materials used in the Asymmetric Transfer Hydrogenation transformation. As a result, the catalyst loading is unequivocally the major cost- driving factor of this kind of reactions. Additionally, lower catalyst loadings reduce the potential for carry-over of residual heavy metals to the next steps of the synthesis, thereby contributing to the quality of the final product and to the overall efficiency of the process by suppressing avoidable analytical strain.

The hydrogen donor of the Asymmetric Transfer Hydrogenation may be selected from hydrogen donors known in the literature as suitable for transfer hydrogenations, such as formic acid or a salt or derivative of formic acid, cyclohexene or I-methylcyclohexane. The preferred hydrogen donor is formic acid or a salt thereof.

The amine base used in the reaction is a tertiary amine and the preferred amine base is triethylamine.

The organic solvent used in the reaction is selected from ethers, such as diethylether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, t-butylmethylether (TBME), diisopropylether, cyclopentylmethylether, glymes, such as monoglyme and diglyme, dioxane, saturated or unsaturated hydrocarbons, such as hexanes, heptanes, benzene, toluene, chlorinated hydrocarbons, such as dichloromethane, dichloroethanes and chloroform, acetate esters such as ethylacetate, propylacetates, polar aprotic solvents, such as DMSO, DMF, DMAC. The preferred solvents are ethers and glymes, and even more preferred are THF and TBME. The reaction temperature may range between 0 °C and the boiling point of the solvent or solvent mixture, preferably between about 30°C and the boiling point of the solvent or solvent mixture.

When TLC analysis shows complete consumption of the starting ketone, standard workup procedures, such as filtration, extraction and solvent evaporation, provide the crude product of Formula III, which may be used without further purification. Optionally, isolated product of Formula III may be obtained through chromatography or crystallization from suitable solvents according to the relevant prior art methods. The impact of the experimental ATH parameters on the efficiency or even the feasibility of a given transformation has been repeatedly found to be decisive (J. Mol. Cat. A, 2012, 357, 133; Chem. Eur. J 2008, 14, 7699). In order to further improve the efficiency of the Asymmetric Transfer Hydrogenation of compounds of Formula II, we further explored the design space defined by these parameters. Moreover, the findings on ATH in aqueous media, first reported in Angew. Chem. Int. Ed. 2005, 44, 3407, prompted us to query this industrially and environmentally important possibility for the intermediates of ezetimibe, whose yearly production amounts to several metric tons worldwide.

Owing to the continuous systematic research on the ATH technology, the pH and the composition of the reaction medium have emerged as the key reaction parameters of the transformation, since they have been found to critically interfere with catalyst performance, and, therefore, catalyst loading, which is the major cost-driving factor of the ATH {Platinum Metals Rev. 2010, 54, 3). Furthermore, in the case of non-simple ketone substrates such as the intermediates of ezetimibe, which contain additional functionalities and structural features, the composition and the pH of the reaction medium greatly affect the solubility, the reactivity but also the stability of both substrate and product of the reaction. It has now been found that the Asymmetric Transfer Hydrogenation of compounds of Formula II may be advantageously performed in aqueous media and in the presence of an organic ion pair additive, to provide compounds of Formula III in high yield, purity and enantiomeric purity.

In particular, according to a further object of the present invention, a compound of Formula II and an Asymmetric Transfer Hydrogenation catalyst are treated with a hydrogen donor in the presence of an organic ion pair additive in an aqueous reaction medium containing an organic solvent.

We have observed that the presence of an organic ion pair additive in an aqueous reaction medium enables the accurate monitoring and adjustment of the pH of the reaction medium where the Asymmetric Transfer Hydrogenation is taking place. The acidity of the medium throughout the course of the reaction greatly affects both the reaction parameters, such as the catalyst loading, and the reaction results, such as the yield, purity and enantiomeric purity of the products of Formula III.

Basic organic ion pair reagents have been found suitable as additives during the ATH of compounds of Formula II according to this aspect of the present invention. Adequate additives may be selected from tetra-N-substituted ammonium salts and hydroxides, -, according to the formula R ₄ NX, wherein each R may be independently selected from CI to CI 6 alkyl groups or benzyl groups, and X may be a halogen or a hydroxyl group.

It is also acknowledged that the organic ion pair additives may be used in their pure or hydrate forms, in an aqueous or non-aqueous solution, grafted or attached to a polymeric structure, as in the case of basic ion-exchange polymers.

Examples of suitable organic ion pair additives are tetramethylammonium hydroxide, tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium hydroxide, tetraethylammonium chloride, tetraethylammonium bromide, tetrabutylammonium hydroxide, tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium hydroxide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltriethylammonium hydroxide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, hexadecyltrimethylammonium hydroxide, hexadecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide, silica grafted tetra-alkylammonium hydroxide composites, such as the MCM-41-TMAOH composite, suitable basic ion-exchange polymers from Dow Chemicals, such as amberlite, amberlyst and the like, suitable basic ion-exchange polymers from Sachem, such as Avana, Catana and the like.

The preferred organic ion pair additives are tetra-alkylammonium hydroxides and the basic ion- exchange polymers. Advantageously, and despite the presence of water in the reaction, the catalyst, the hydrogen donor and the organic solvent may be selected as described above. When TLC analysis shows complete consumption of the starting ketone, standard workup procedures, such as filtration, extraction and solvent evaporation, provide the crude product of Formula III, which may be used without further purification. As before, the isolated product of Formula III may be optionally obtained through chromatography or crystallization from suitable solvents, according to the relevant prior art methods.

It is acknowledged that the workup procedures mentioned above may result in the recovery of a layer containing the catalyst. It is also acknowledged that this recovered layer, with or without further treatment, may be further used for one or more additional Asymmetric Transfer Hydrogenation reactions of the same substrate.

The processes described in the present invention will be demonstrated in more details with reference to the following examples, which are provided by way of illustration only and should not be construed as limit to the scope of the reaction in any manner.

EXAMPLES Example 1:

Preparation of compounds of Formula III by Asymmetric Transfer Hydrogenation of compounds of Formula II.

Method A

Dissolve a compound of Formula II in the adequate solvent and heat to 42°C. Add the catalyst at this temperature, then add the adequate HCOOH:Et3N degassed stock solution portionwise until complete conversion by TLC. Upon completion, cool the reaction mixture to 25°C, add DCM and water, then add HC1 IN under stirring. Separate the lower organic layer, dry it over anhydrous Na ₂ S0 ₄ , filter and distill off volatiles until dry, to obtain crude compound of Formula III. Method B

In a round-bottom flask charge a compound of Formula II, the adequate solvent and a portion of HCOOH, then add the catalyst and the additive. Heat the mass to 62°C and maintain the pH at 5- 9 by additions of HCOOH (approximately every hour). After completion, cool the reaction mass to 25-30°C, add DCM and optionally filter to remove insoluble materials. Then add water and HC1 IN under stirring. Separate the layers and dry the lower organic layer over anhydrous Na ₂ S0 ₄ . Filter and distill off volatiles until dry, to obtain crude compound of Formula III. The conversions and diastereomeric ratios are measured by HPLC analysis of the crude reaction mixtures.

The ATH of compound of Formula Ila, using the above described methods, provided the known compound of Formula Ilia, whose analytical data were confirmed using a reference standard. Details and results of indicative reactions may be seen in the following table:

From the examples stated above, it is apparent that the objects described in the present invention lead to an improved, cost-effective, scalable and safe process for the preparation of key intermediates of ezetimibe, which is industrially applicable at a relatively low production cost, compared to the available processes for producing similar products.

The process of the present invention describes the previously undisclosed preparation of key intermediates of ezetimibe through an improved Asymmetric Transfer Hydrogenation protocol. The reaction sequences, the reagents and the isolation procedures of the present process are cost- effective, scalable and of almost no safety concern, therefore suitable for industrial application.

While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the scope thereof, as defined in the appended claims.