Phosphorus pentachloride → 4,6-Dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine

Participants

Reaction Steps

The process of the present invention is especially useful for the preparation of 4-tert.butyl-N-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyrimidine-2-yl)-pyrimidine-4-yl-benzenesulphonamide (bosentan). For the preparation of this compound 2-cyanopyrimidine is prepared as described above and converted into pyrimidin-2-carboxamidine hydrochloride by means of NH3 /NH4Cl in a sodium methanolate/methanol solution. This compound is converted in the presence of sodium methanolate with diethyl (o-methoxy-phenoxy-malonate) into rac-5-(2-methoxy-phenoxy)-2-pyrimidin-2-yl-tetrahydro-pyrimidin-4,6-dione. The obtained product is reacted with N,N-diisopropyl-N-ethylamine and phosphorus pentachloride to give 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine. This substance is then reacted with p-tert.butylbenzenesulphonamide to give 4-tert.butyl-N-6-chloro-5-[2-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]-benzenesulphonamide and further reacted with sodium ethylene glycolate to give 4-tert.butyl-N-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl-benzenesulphonamide (bosentan).

Provenance & Evidence