Abstract: The invention relates to a process for manufacturing the compound of formula I wherein R is H, (C1-C6)alkyl or benzyl, or a salt thereof, said process comprising the reaction of the compound of formula I-1 wherein X is Br, Cl or F, or a salt thereof, with the compound of formula I-2 wherein R is H, (C1-C6)alkyl or benzyl, or a salt thereof, in the presence of a base, and, when X is Br or Cl, in the presence of tetra-n-butyl ammonium fluoride hydrate or cesium fluoride. The invention further relates to the compound of formula I-1 and uses thereof.

Abstract: The present invention relates to a new synthetic intermediate, namely the compound of formula I-2 or a salt thereof. Said compound of formula I-2 or its salt can be used to prepare the compound of formula I-3 which is an important synthetic intermediate used in the preparation of macitentan.

Abstract: The invention relates to a process for preparing a pyrimidine intermediate, namely the compound of formula I-2 or a salt thereof, which involves the use of a liquid-liquid extraction using methyl iso-butyl ketone. Said compound of formula I-2 or its salt can be used to prepare macitentan.

Abstract: The invention relates to a process for manufacturing the compound of formula I wherein R is H, (C1-C6)alkyl or benzyl, or a salt thereof, said process comprising the reaction of the compound of formula I-1 wherein X is Br, Cl or F, or a salt thereof, with the compound of formula I-2 wherein R is H, (C1-C6)alkyl or benzyl, or a salt thereof, in the presence of a base, and, when X is Br or Cl, in the presence of tetra-n-butyl ammonium fluoride hydrate or cesium fluoride. The invention further relates to the compound of formula I-1 and uses thereof.

Abstract: The present invention relates to a new synthetic intermediate, namely the compound of formula I-2 or a salt thereof. Said compound of formula I-2 or its salt can be used to prepare the compound of formula I-3 which is an important synthetic intermediate used in the preparation of macitentan.

Abstract: The present invention relates to a new synthetic intermediate, namely the compound of formula I-2 or a salt thereof. Said compound of formula I-2 or its salt can be used to prepare the compound of formula I-3 which is an important synthetic intermediate used in the preparation of macitentan.

Abstract: The present invention relates to a process for preparing a pyrimidine intermediate, namely the compound of formula I-2 or a salt thereof. Said compound of formula I-2 or its salt can be used to prepare macitentan. Macitentan (chemical names: N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N?-propylsulfamide or N-[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]-N?-propylsulfuric diamide) is an endothelin receptor antagonist that has notably been approved by the US Food and Drug Administration and the European Commission for the treatment of pulmonary arterial hypertension. It has been first disclosed in WO 02/053557. The last step of one of the potential preparation routes described in WO 02/053557, called “Possibility A” and “Possibility B”, can be summarised as shown in Scheme A1 hereafter.

Abstract: The present invention relates to a new process for the preparation of 6-hydroxy-5-arylbicyclo[2.2.2]octan-2-one compounds of the formula (II); which may subsequently be further transformed to compounds of the formula (I): The present invention further relates to novel compounds as such, which compounds are useful intermediates in the above process.

Abstract: The present invention relates to a new synthetic intermediate, namely the compound of formula I-2 I or a salt thereof. Said compound of formula I-2 or its salt can be used to prepare the compound of formula I-3 I which is an important synthetic intermediate used in the preparation of macitentan.

Abstract: The present invention relates to a new process for the diastereoselective preparation of (1R*,4R*,5S*,6S*)-6-hydroxy-5-arylbicyclo[2.2.2]octan-2-one compounds, the compounds of the formula (II), which may subsequently be further transformed to 5-aryl-bicyclo[2.2.2]oct-5-en-2-one compounds of the formula (I): The present invention further relates to novel (1R*,2S*,3S*,4R*)-6-oxo-3-arylbicyclo[2.2.2]octan-2-yl methanesulfonate compounds as such, which compounds are useful intermediates in the preparation of 5-aryl-bicyclo[2.2.2]oct-5-en-2-one compounds of the formula (I).

Abstract: The present invention relates to a new process for the diastereoselective preparation of (1R*,4R*,5S*,6S*)-6-hydroxy-5-arylbicyclo[2.2.2]octan-2-one compounds, the compounds of the formula (II), which may subsequently be further transformed to 5-aryl-bicyclo[2.2.2]oct-5-en-2-one compounds of the formula (I): The present invention further relates to novel (1R*,2S*,3S*,4R*)-6-oxo-3-arylbicyclo[2.2.2]octan-2-yl methanesulfonate compounds as such, which compounds are useful intermediates in the preparation of 5-aryl-bicyclo[2.2.2]oct-5-en-2-one compounds of the formula (I).

Abstract: The present invention relates to a new process for the preparation of 6-hydroxy-5-arylbicyclo[2.2.2]octan-2-one compounds of the formula (II); which may subsequently be further transformed to compounds of the formula (I): The present invention further relates to novel compounds as such, which compounds are useful intermediates in the above process.

Abstract: The invention relates to crystalline salts of isobutyric acid (1R*,2R*,4R*)-2-(2-{[3-(4,7 -dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester, processes for the preparation thereof, pharmaceutical compositions containing said crystalline salts, and their use as medicaments, especially as calcium channel blockers.

Abstract: The invention relates to crystalline salts of isobutyric acid (1R*,2R*,4R*)-2-(2-{[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester, processes for the preparation thereof, pharmaceutical compositions containing said crystalline salts, and their use as medicaments, especially as calcium channel blockers.