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SYNTHESIS AND CRYSTALLINE FORMS OF BILASTINE

IP.com Disclosure Number: IPCOM000247653D
Publication Date: 2016-Sep-23
Document File: 26 page(s) / 1M

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SYNTHESIS AND CRYSTALLINE FORMS OF BILASTINE

Bilastine ( 2- [4 (2-{4 [1 - (2-ethoxy - ethyl) -1H--benzimidazol-2-yl ] - piperidin-1-yl} ethyl) - phenyl]-2-methyl - propionic acid) is marketed under the trade name Bilaxten by FAES and has been indicated for the treatment of allergic rhinitis and chronic idiopathic urticaria.

It was first described by U.S. Patent No. 5,877,187 but the patent does not mention any crystalline forms of this compound. The procedure described in US patent no. 5,877,187 presumably generates a mixture of polymorphs II and III, as stated in EP 1 505 066 and the synthesis of bilastine is carried out in the following manner:

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WO 2009102155 (Yuhan) discloses the following reaction scheme for the preparation of bilastine:

WO 2014026657 (Zentiva) describes the reaction of the base or salt form of 2-(1-(4- bromophenethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzo[d]imidazole with a suitable alkylation reagent, optionally with the use of auxiliary reagents, producing an ester of bilastine which is them hydrolyzed to bilastine.

Bilastine can also be prepared by any of the following three alternative routes of synthesis shown below:

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1.) Route 1


2.) Route 2


3.) Route 3

3


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EP 1 505 066 disclosesthree different crystalline polymorphic forms of bilastine, form I, II and form III, and is directed to the preparation the new polymorph form I of bilastine, its pharmaceutical formulations and its use for the treatment of allergic reactions and pathological processes mediated by histamine in mammals such as humans. Polymorph I of bilastine was reported to have a melting point at 200.3 °C and was prepared, in high yield, by recrystallization of bilastine as synthetized according to US Patent 5,877,187. According to EP 1 505 066, the procedure described in US patent no. 5,877,187 generates a mixture of polymorphs II and III. While it was found by EP 1 505 066 that polymorphic forms I and II are stable, polymorph III turned out not to be very stable and to be difficult to obtain in the pure form. Both polymorph II and polymorph III eventually converted into polymorph I. Polymorph II of bilastine was reported to have a melting point of 205.2 °C and polymorph III

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a melting point of 197.0 °C. In selected experimental conditions, the mixture of polymorphic forms II and III, obtained according to US patent no. 5,877,187; the pure polymorphic form II as well as the pure polymorphic form III, transformed into polymorph I under the same conditions, e.g. using short chained alcohols, preferably isopropylic alcohol and n-butanol and their mixtures. Crystallisation of bilastine in acetone, dimethylsulphoxide, dimethylformamide, acetonitrile and tetrahydrofurane, or their mixtures, was reported to also lead to the generation of polymorph I, although with lower yields. The calculated X- ray powder diffraction pattern as calculated from the crystalline unit cell data for form I...