Synthesis 2015; 47(09): 1291-1302
DOI: 10.1055/s-0034-1380345
paper
© Georg Thieme Verlag Stuttgart · New York

Efficient Synthesis of N-[4-(4-Chlorophenyl)butyl]-S-(3-piperidinopropyl)isothiourea (OUP-186) and Its Analogues Using 2-Nitrophenylacetyl Isothiocyanate: Application to Novel Histamine H3R Antagonists

Hiroki Yoneyama
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan   Email: yoneyama@gly.oups.ac.jp
,
Takuji Magata
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan   Email: yoneyama@gly.oups.ac.jp
,
Kenji Uemura
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan   Email: yoneyama@gly.oups.ac.jp
,
Yoshihide Usami
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan   Email: yoneyama@gly.oups.ac.jp
,
Satoshi Tanaka
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan   Email: yoneyama@gly.oups.ac.jp
,
Masanori Takaoka
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan   Email: yoneyama@gly.oups.ac.jp
,
Shinya Harusawa*
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan   Email: yoneyama@gly.oups.ac.jp
› Author Affiliations
Further Information

Publication History

Received: 27 January 2015

Accepted after revision: 14 February 2015

Publication Date:
19 March 2015 (online)


Abstract

A potent histamine H3 receptor antagonist OUP-186 with an S-alkyl-N-alkylisothiourea structure was synthesized using 3-phenylpropanoyl isothiocyanate (PPI) as an SCN source. The synthetic route was significantly improved by replacing 3-phenylpropanoyl isothiocyanate with 2-nitrophenylacetyl isothiocyanate (NPAI), giving a 74% overall yield in three steps from 4-(4-chlorophenyl)butylamine. In addition, the 2-nitrophenylacetyl isothiocyanate method successfully yielded two fluorine-containing analogues, and a shorter, C2 homologue of OUP-186.

Supporting Information

 
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