Research and Development of a Second-Generation Process for Bosentan, an Endothelin Receptor Antagonist

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• 作者：Peter J. Harrington ; Hiralal N. Khatri ; Brad S. DeHoff ; Martin R. Guinn ; Mark A. Boehler ; and Karl A. Glaser
• 刊名：Organic Process Research & Development
• 出版年：2002
• 出版时间：March 2002
• 年：2002
• 卷：6
• 期：2
• 页码：120 - 124
• 全文大小：59K
• 年卷期：v.6,no.2(March 2002)
• ISSN：1520-586X

文摘

A second-generation manufacturing process from 5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4,6-(1H,5H)-dione to bosentanis based on the synthesis and deprotection of the tert-butyl etherof bosentan using available and inexpensive ethylene glycolmono-tert-butyl ether. This new strategy triggered a cascadeof process improvements. Isolations are reduced from six tothree, and drying operations, from five to two. Process solventsare reduced from six to two. The isolations of two sensitizersare eliminated. Toluene is used in place of methylene chloride.Two aqueous waste streams are eliminated by replacing DMFand ethylene glycol by toluene. Two methanol-isopropyl acetaterecrystallizations of bosentan are replaced by the decantationof a suspension of bosentan formate monoethanolate in ethanol-toluene. Finally, the overall yield is increased from 67 to84% and the final product purity improved from 99.3 to 99.7%.