A second-generation manufacturing process from 5-(2-methoxyphenoxy)-[2,2‘-bipyrimidine]-4,6-(1H,5H)-dione to bosentan
is based on the synthesis and deprotection of the tert-butyl ether
of bosentan using available and inexpensive ethylene glycol
mono-tert-butyl ether. This new strategy triggered a cascade
of process improvements. Isolations are reduced from six to
three, and drying operations, from five to two. Process solvents
are reduced from six to two. The isolations of two sensitizers
are eliminated. Toluene is used in place of methylene chloride.
Two aqueous waste streams are eliminated by replacing DMF
and ethylene glycol by toluene. Two methanol−isopropyl acetate
recrystallizations of bosentan are replaced by the decantation
of a suspension of bosentan formate monoethanolate in ethanol−toluene. Finally, the overall yield is increased from 67 to
84% and the final product purity improved from 99.3 to 99.7%.
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