Development of a Practical Synthetic Route of a PDE V Inhibitor KF31327

Autor:	and Shin-ichiro Mohri, Hitoshi Takami, Masaji Kasai, Takehiro Ogasa, Kenji Fujino, Toshiyuki Atsumi
Rok vydání:	2001
Předmět:	chemistry.chemical_compound Carbon disulfide Chemistry Phenyl isothiocyanate Yield (chemistry) Organic Chemistry Nitro Substituent Physical and Theoretical Chemistry Selectivity Ring (chemistry) Combinatorial chemistry PDE-V Inhibitor
Zdroj:	Organic Process Research & Development. 5:426-433
ISSN:	1520-586X 1083-6160
DOI:	10.1021/op010025y
Popis:	An efficient route suitable for a large-scale preparation of KF31327 (1), a potent phosphodiesterase V inhibitor, has been developed. We selected 7-chloro-2,4(1H,3H)-quinazolinedione (15) as a starting material, which gave the desired 6-nitro compound with good selectivity. In the chlorination of 7-ethylamino-6-nitro-2,4(1H,3H)-quinazolinedione (17), reaction conditions were optimized to minimize the amount of phosphorus oxychloride, and 2,4-dichloro-7-ethylamino-6-nitroquinazoline (14) was obtained in excellent yield. After the selective substitution at C4 position, the chloro substituent at C2 position was successfully removed by hydrogenation concomitant with the reduction of nitro group. The construction of the imidazothione ring was achieved by using phenyl isothiocyanate as a thiocarbonyl donor instead of extremely flammable carbon disulfide. Multikilograms of drug substance have been successfully prepared by these procedures.
Databáze:	OpenAIRE
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