The invention deals with a novel process and intermediates for making the

pharmaceutically useful product etoricoxib.

OVERVIEW OF THE PRIOR ART

Etoricoxib, i.e. 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyrid ine of formula (1),

is a COX-2-inhibitor which is currently approved, in the free base form, for the treatment of various inflammatory diseases, e.g. rheumatoid arthritis. It is marketed in the form of a film- coated tablet, e.g., under the brand name Arcoxia.

Etoricoxib was first disclosed in WO9803484. Etoricoxib may exist, in the solid state, in various polymorphic forms, which are disclosed, e.g. in WO0137833 and WO0192230.

WO9803484 discloses a process for making etoricoxib which comprises bromination of 2-amino pyridine derivatives, the coupling of the resulting bromide derivative with 4- (methylthio)phenyl-boronic acid in the presence of a suitable base, and the oxidation of the product to give the corresponding sulfone. Then the amino group of the sulfone is converted to the corresponding halide. A palladium-catalyzed coupling of the sulfone halide derivative with an appropriately substituted metal-containing aromatic group gives etoricoxib of formula (1). This method has several disadvantages as the costly catalyst palladium used for the coupling or the difficulties to purify the resulting product.

W09847871 discloses a method for the preparation of etoricoxib (see Scheme 1 below) which comprises reacting a compound of formula (2) with a ketosulfone of formula (3), which after heating in the presence of ammonium acetate yields etoricoxib of formula (1).

Although avoiding the use of palladium catalyst this method has other disadvantages as the formation of the two impurities:

Impurity I; Impurity II.

JOC, VOL.65, No25, 2000 reports in page 8418, second column, that these impurities are obtained in 15% assay yield in the case of impurity I and 5% assay yield in the case of impurity II.

In order to obtain a more efficient process WO9955830 prepares etoricoxib by reacting a ketosulfone derivative with a special vinamidmium hexafiuoro hosphate salt (see Scheme 2 below). The synthesis includes three steps, which has been optimized to a one-pot process.

Scheme 2

When repeating the one-pot synthesis of WO9955830, etoricoxib was only obtained in a yield considerably lower than reported.

Hence, there is a need for an alternative process for preparing the pharmaceutically useful product etoricoxib of formula (1) that is more cost effective.

BRIEF DESCRIPTION OF THE PRESENT INVENTION

The subject of the present invention is a novel synthetic route to intermediates involved in the synthesis of etoricoxib of formula (1). The approach is based on a novel use of a reagent of formula (4) in a synthetic route leading to etoricoxib,

wherein L is a suitable leaving group.

In a first aspect, the invention provides a process for making the compound of formula

(5), or a salt thereof,

said process comprising:

a) reacting the compound of formula (3) with a compound of formula (4)

presence of a base,

wherein L is a suitable leaving group, to form the compound of formula (6),

b) reacting the compound of formula (6) with a nitrogen donor to form the

compound of formula (5),

In a particular aspect, the above process leading to the compound of formula (5) further comprises reducing the compound of formula (5) to etoricoxib with a reducing agent, either by direct reduction of the OH group or by first converting the compound of formula (5) into a compound of formula (7),

(7),

wherein L is a suitable leaving group, and then reducing the compound of formula (7) to etoricoxib with a reducing agent. The leaving group (L) from compound (7) can be the same or different than the leaving group (L) from compound (4).

The compounds of formulas (4) to (6), the above processes of making them, and the use thereof as a starting material for making etoricoxib of formula (1) form next particular aspects of the present invention.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention provides an alternative route for making etoricoxib of formula (1) based on employing a new reagent namely the compound of formula (8). In an important advantageous aspect, this reagent is stable enough to be stored and therefore be used on an industrial scale.

The process of the present invention is primarily drawn to make a compound of formula (5) or a salt thereof. The process according to various aspects of the present invention is shown in the Scheme 3 below.

Etoricoxib (1)

Scheme 3

The starting material of the present invention is l-(6-methylpyridin-3-yl)-2-(4- (methylsulfonyl)phenyl)ethanone or ketosulphone (3). This compound is known. It may be produced by a suitable process, e.g. the one described in WO9955830. The second starting material is the reagent of general formula (4). L is a suitable leaving group, for example a sulfonate group such as mesylate, tosylate, and besylate.

In particular, for instance when L is tosylate, it may be obtained by reaction of methyl 2-chloro-2-hydroxyacetate with tosyl chloride, advantageously using triethylamine as a base.

The first step of the process of the present invention includes providing the compound of formula (6). This compound can be obtained by reaction of ketosulphone (3) with a compound of formula (4), wherein L is a suitable leaving group, in the presence of a base. A suitable base is, without limitations, a strong base such as Lithium diisopropylamide (LDA), sodium hydride (NaH), or potassium tert butoxide (t-BuOK). A suitable solvent for the condensation of compound (3) with compound (4) is an organic solvent and optionally preferably an aprotic solvent is used. A more preferable solvent is an ether solvent, and a still more preferable solvent is THF. After the condensation, a mixture of water/organic solvent needs to be added in order to close the ring to form compound 6. A suitable solvent could be, without limitations, water/ dichloromethane. In particular, compound (6) may be obtained by reaction of the compound of formula (3) with methyl 2-chloro-3-(tosyloxy)acrylate (8) in the presence of t-BuOK in THF, isolation of the unstable open ring intermediate, followed by rapid addition of water/dichloromethane. If desired or advantageous, the compound of formula (6) may be isolated from the reaction mixture as such or in the form of a salt, and optionally purified.

In the next step of the process of the invention, the compound of formula (6) is converted to the compound of formula (5) by reaction with a nitrogen donor. A suitable nitrogen donor is, without limitations, an ammonia-containing reagent, such as ammonium hydroxide, ammonium formate or ammonium acetate, or a mixture thereof. A suitable solvent can optionally be added, preferred solvents are C1-C4 aliphatic alcohol such as 2-propanol. If desired or advantageous, the compound of formula (5) may be isolated from the reaction mixture as such as a mixture of two isomers or in a single enolate form or in the form of a salt, and optionally may be purified.

In a specific aspect of the present invention, the compound of formula (6) is not purified after reaction of (3) with (4), and the nitrogen donor advantageously is added to the reaction mixture to give compound (5).

In accordance with the process of the present invention, the OH group of the compound of formula (5) is converted into a leaving group in the presence of a base to form a compound of formula (7). Suitable examples of leaving group include a sulfonate such as mesylate, tosylate, besylate, and imidazole sulfonate.

A useful leaving group is, without limitation, a sulfonate, preferably a tosylate. The compound of formula (7) further is reduced to form etoricoxib. A preferred reducing agent contains a metal such as palladium, nickel or zinc. Preferably, a homogenous palladium (Pd) catalyst, Ra/ Ni, or Zn/acid, more preferably zinc/formic acid or acetic acid is used.

Optionally acetic anhydride can be used in order to avoid the presence of water in the reaction mixture.

If desired or advantageous, the compound of formula (5) can be directly reduced to etoricoxib.

If desired or advantageous, the etoricoxib obtained can optionally be further recrystallized.

In a specific aspect of the present invention, the present application provides a novel compound of formula (4) useful as an intermediate for making the compound of formula (5) and, subsequently, for preparing etoricoxib of formula (1). The leaving group (L) in compound (7) can be the same or different than the leaving group (L) in compound (4).

Suitable examples of leaving group include halogens such as chlorine, bromine, or iodine, sulfonates such as mesylate, tosylate, besylate, and imidazole sulfonate. In a more specific aspect, the leaving group L in the compound of formula (4) is a tosylate. The tosylate of formula (8) is stable enough to be stored and therefore can be used on an industrial scale.

In a specific aspect of the invention, the present application provides a novel compound of formula (5) useful for preparing etoricoxib of formula (1). The present invention also includes the use of the compound of formula (5) for making etoricoxib of formula (1).

In a specific aspect of the invention, the present application also provides the novel compound of formula (6) useful as an intermediate in making the compound of formula (5) and, subsequently, for preparing etoricoxib of formula (1).

Etoricoxib, produced according to any one of the processes in accordance with the present invention or otherwise obtainable by the use of any of the compounds of formula (4), (5), (6), or (7) as starting material in a process for making etoricoxib, may be advantageously provided in an isolated, typically solid and crystalline form, details of which procedures are known in the art. Accordingly, the obtained etoricoxib may be used in pharmaceutical compositions, e.g. for the treatment of inflammatory diseases.

The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.

EXAMPLES

Example 1

Preparation of compound 8, a compound of formula (4)

To a solution of methyl 2-chloro-3-hydroxyacrylate (1.365 g) in toluene (20 ml), stirring at ~5°C (ice water bath), p-toluenesulfonyl chloride (2.097 g) was added, followed by addition of triethylamine (1.55 ml). The reaction mixture was stirred for 10 min at 5°C and further at ambient temperature for 30 minutes, then 20 ml of water was added. After stirring for 5 min., the separated toluene layer was washed again with water (10 ml), dried, and concentrated to give a crude product (~2.88g), which solidified overnight at ~5°C.

Example 2

Preparation of compound 6

To a suspension of l-(6-methylpyridin-3-yl)-2-(4-(methylsulfonyl)phenyl)ethanon e (1.74 g) in THF (50 ml), stirring at ~5°C, potassium 2-methylpropan-2-olate (1.2 g) was added. The reaction mixture was stirred at ambient temperature for 30 min. and cooled (ice water) again, before addition of methyl 2-chloro-3-(tosyloxy)acrylate (1.9 g) in portions (in 5 min). The mixture was further stirred at 5 °C for 30 min.

After stirring for another 30 min., 70 ml of ethyl ether was added. The formed suspension was stirred for 20 min. and the solid was filtered off (washed with 20 ml ether). The obtained solid was treated with 50 ml water and 10 ml dichloro methane (DCM) at ambient temperature for 2 hrs. Then, 50 ml of DCM was added and the separated water layer was extracted again with 25 ml of DCM. The combined DCM layers were dried and concentrated to give a crude product (1.65 g). The crude product was purified by

chromatography to give a foam-like solid (1.10 g).

Example 3

Preparation of compound 5

A suspension of 3-chloro-6-(6-methylpyridin-3-yl)-5-(4-(methylsulfonyl)pheny l)-2H- pyran-2-one (40 mg) in 2-propanol (4 ml) was treated with ammonium hydroxide (0.04 ml) at ambient temperature for 2 hrs. Then, 0.04 ml extra ammonia and 50 mg ammonium acetate were added and the reaction mixture was further stirred overnight.

The mixture was concentrated in vacuo to give the desired product in 38% yield. Example 4

Preparation of compound 7

To a solution containing 5-chloro-6'-methyl-3-(4-(methylsulfonyl)phenyl)-2,3'- bipyridin-6-ol (0.96 g) and p-toluenesulfonyl chloride (0.5 g) in DCM (25 ml) at ~5°C, triethylamine (0.40 ml) was added dropwise (in 2 min). The mixture was stirred for 30 min. and further at ambient temperature overnight.

Extra p-toluenesulfonyl chloride (30 mg) and triethylamine (0.1 ml) were added, and further stirred for 4 hrs. 50 ml water was added, and the mixture was stirred for 10 min.

Organic layer was separated, dried and concentrated to give a crude product (1.19 g). Example 5

Preparation of compound 1 (etoricoxib)

To a mixture of 5-chloro-6'-methyl-3-(4-(methylsulfonyl)phenyl)-2,3'-bipyrid in-6-yl 4- methylbenzenesulfonate (250 mg, 0.473 mmol) and acetic anhydride (0.2 ml) in formic acid (10 ml), stirred at 15°C (temperature of water bath), zinc (500 mg) was added. The mixture was stirred at that temperature for 5 min, and further stirred at ~20°C for ~1 hour. Then, 20 ml of ethyl acetate was added. The mixture was stirred for 5 min, and the supernatant was decanted. The residue was washed again with ethyl acetate (20 ml), and the solvent was decanted. The combined organic layers were concentrated in vacuo to give an oil. The oil was dissolved in MeOH (10 ml) and water (1ml), and treated with 100 mg NaOH at 50°C for 30 min. The mixture was concentrated in vacuo.

DCM (15 ml) and water (15 ml) were added to the concentrated product, and the mixture was stirred for 10 min. The separated DCM layer was dried, and concentrated to give the crude product as a solid (70 mg).