Bosentan is first oral dual endothelin A and B receptor (ETA/ETB) antagonist. The drug is indicated for the treatment of pulmonary arterial hypertension (PAH). In patients with systemic sclerosis and ongoing digital ulcer disease it is used for the reduction of new digital ulcers.

The synthesis of bosentan was carried out according to the scheme shown below, described in the patent EP 0526708. The main problem in this synthesis was obtaining pharmaceutical grade bosentan, due to the presence of three impurities in the final product. All these impurities were very difficult to remove. Improved methods of bosentan synthesis or purification of bosentan are described in many patent applications however, the problem of the obtaining pharmaceutical grade bosentan with a good yield had to be reconsidered.

We have investigated all steps of this process, and we have developed the best conditions in the last key step of the synthesis. The synthesis of bosentan was optimized, all chemical and degradation impurities were isolated or synthesized and characterized by NMR, MS and HPLC techniques. Moreover, the efficient method of bosentan purification was developed. We obtained bosentan with a proper polymorphic form and particle size favorable for a pharmaceutical formulation. Furthermore, X-ray single-crystal investigation of bosentan unambiguously proved its structure.

These allowed us to develop the large scale efficient synthesis of pharmaceutical grade bosentan containing < 0,1 % of known impurities and <  0,5 % of total impurities.

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