CROSS-REFERENCE TO RELATED APPLICATIONS

This application is filed under the provisions of 35 U.S.C. § 371 and claims the priority of International Patent Application No. PCT/EP2019/069772 filed on 23 Jul. 2019 entitled “PROCESS AND INTERMEDIATES FOR THE PREPARATION OF BILASTINE” in the name of Gonzalo HERNANDEZ HERRERO, et al., which claims priority to European Patent Application No. 18382556.1, filed on 24 Jul. 2018, both of which are hereby incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

The invention relates to a process for the preparation of key intermediates in the synthesis of Bilastine and to new intermediates in said process.

BACKGROUND OF THE INVENTION

Bilastine is a second-generation antihistamine medication which is used in the treatment of allergic rhinoconjunctivitis and urticaria.



Several synthesis of Bilastine has been disclosed in the last years using a compound of formula (III) as key intermediate as it provides a straightforward synthetic route for Bilastine, minimizing protecting group chemistry.



For instance, WO 2009/102155 discloses the preparation of this key intermediate by reacting compound 4 and methyltrimethylsilyl dimethylketene acetal (5) in the presence of a Palladium catalyst, t-Bu3P and ZnF2. This key intermediate is then converted into Bilastine by either reaction with 1-(2-ethoxyethyl)-2-piperidin-4-yl-1H-benzoimidazole (3a) followed by hydrolysis of the ester group or by reaction with 2-(4-piperidinyl)-1H-benzoimidazole (7), followed by alkylation of the benzimidazole nitrogen and hydrolysis of the ester group. However, this cross coupling approach lacks industrial interest due to the instability, availability and cost of the ketene acetal and the phosphine used in the key step of the synthesis.



CN 104151160 A refers to the synthesis of compounds similar to key intermediate (III), but which lack a leaving group. The compound is synthesized through the alkylation of the halobenzene compound (2) in the presence of a palladium catalyst and a lithium amide. Then again, this approach uses organometallic reagents and an amide base, which is highly unstable and expensive.



The process for preparing Bilastine disclosed in Synthetic Communications 2011, 41(9), 1394-1402 includes palladium catalyzed vinylation of aryl bromide (3) with vinyl tributylstannane or with vinylboronic anhydride followed by hydroboration of the resulting styrene (11). This alternative cross coupling approach uses in the first step high cost and low available vinyl synthons (and highly toxic in the case of the tin compound). Besides, the anti-Markovnikov hydroxylation step is performed using the well-known and undesirable borane (highly toxic and flammable gas), which also undermines its industrial applicability.



CN 104326909 A and CN 102675101 A refer to a process for the synthesis of key intermediate (III) which comprises acylation of 2-methyl-2-phenyl-propanoic acid or an ester thereof in the presence of a Lewis acid and subsequent reduction of the oxo group. This approach, even if industrially applicable, uses stoichiometric reagents both in the acylation and the reduction step and involves the generation of high amounts of residues.



In general, the methods disclosed in the prior art for the preparation of compounds of formula (III) according to the present invention, require the use of organometallic reagents, toxic reagents, harsh reaction conditions or have a low productivity and, therefore, are not suitable for industrial production.

It is therefore necessary to develop a new process for obtaining compounds of formula (III), which are key intermediates in the synthesis of Bilastine, which overcome all or part of the problems associated with the known processes belonging to the state of the art.

SUMMARY OF THE INVENTION

The invention faces the problem of providing a new process for the preparation of formula (III) and to intermediates thereof.

In contrast to processes of the prior art, the process of the invention meets the needs of industrial production. It allows preparing compounds of formula (III) in the absence of organometallic and toxic reagents, in short reaction times, is a simple and low cost process and gives rise to the desired product with a very high productivity.

The inventors have found that compounds of formula (III) can be obtained in a very straightforward manner by acylation and subsequent oxidative rearrangement of readily available and economical starting materials. As shown in the experimental section, this process not only avoids the use of highly toxic, unstable and/or expensive reagents, but also leads to the compounds of formula (III) in shorter reaction times and with higher productivity than prior art processes. All these features make the process of the invention very cost-efficient and therefore highly suitable for industrial scale production.

The compounds of formula (III) obtained by the process of the invention already include the leaving group required for subsequent reaction with the piperidinyl compound and so does not require additional reaction steps for its use in the preparation of Bilastine.

Thus, in a first aspect the invention is directed to a process for preparing a compound of formula (III)



or a solvate thereof wherein

X is a leaving group; and

R1is C1-C6alkyl;

which comprises oxidative rearrangement of a compound of formula (II) or a solvate thereof



In a second aspect the invention is directed to the use of a compound of formula (II)


or a solvate thereof wherein X is a leaving group as an intermediate in the preparation of Bilastine.

In a third aspect, the invention is directed to a compound of formula (II′)


or a solvate thereof wherein X is selected from Cl, I, OMs, OTs and OTf.

