A Scaleable Synthesis of Fiduxosin
Fiduxosin (1) has been under development at Abbott Laboratories for the treatment of benign prostatic hyperplasia. A convergent strategy required methodologies for preparation of an enantiomerically pure 3,4-cis-disubstituted pyrrolidine and a 2,3,5-trisubstituted thienopyrazine in a regiospecific m...
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| Veröffentlicht in: | Organic process research & development 2004-11, Vol.8 (6), p.897-902 |
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| creator | Haight, Anthony R Bailey, Anne E Baker, William S Cain, Michael H Copp, Richard R DeMattei, John A Ford, Kelley L Henry, Rodger F Hsu, Margaret C Keyes, Robert F King, Steven A McLaughlin, Maureen A Melcher, Laura M Nadler, William R Oliver, Patricia A Parekh, Shyamal I Patel, Hemant H Seif, Louis S Staeger, Mike A Wayne, Gregory S Wittenberger, Steven J Zhang, Weijiang |
| description | Fiduxosin (1) has been under development at Abbott Laboratories for the treatment of benign prostatic hyperplasia. A convergent strategy required methodologies for preparation of an enantiomerically pure 3,4-cis-disubstituted pyrrolidine and a 2,3,5-trisubstituted thienopyrazine in a regiospecific manner. A [3+2] cycloaddition of an enantiopure azomethine ylide followed by a diastereoselective crystallization was employed to prepare the benzopyranopyrrolidine in high diastereomeric and enantiomeric purity. Conditions for reduction of an O-aryl lactone susceptible to epimerization were developed, and cyclization of the alcohol/phenol to the ether was accomplished in high yield. The thienopyrazine was prepared by condensation of methyl thioglycolate and a regiospecifically prepared 2-bromo-3-cyano-5-phenylpyrazine. Conditions for effective halogen substitutive deamination to prepare regiospecific trisubstituted pyrazines will be described. |
| doi_str_mv | 10.1021/op049889k |
| format | Article |
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A convergent strategy required methodologies for preparation of an enantiomerically pure 3,4-cis-disubstituted pyrrolidine and a 2,3,5-trisubstituted thienopyrazine in a regiospecific manner. A [3+2] cycloaddition of an enantiopure azomethine ylide followed by a diastereoselective crystallization was employed to prepare the benzopyranopyrrolidine in high diastereomeric and enantiomeric purity. Conditions for reduction of an O-aryl lactone susceptible to epimerization were developed, and cyclization of the alcohol/phenol to the ether was accomplished in high yield. The thienopyrazine was prepared by condensation of methyl thioglycolate and a regiospecifically prepared 2-bromo-3-cyano-5-phenylpyrazine. Conditions for effective halogen substitutive deamination to prepare regiospecific trisubstituted pyrazines will be described.</description><identifier>ISSN: 1083-6160</identifier><identifier>EISSN: 1520-586X</identifier><identifier>DOI: 10.1021/op049889k</identifier><language>eng</language><publisher>American Chemical Society</publisher><ispartof>Organic process research & development, 2004-11, Vol.8 (6), p.897-902</ispartof><rights>Copyright © 2004 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a259t-ecc031891ede97093301fae0f51bb5c6514afa94979610b0fc6d3b0f4a7ced733</citedby><cites>FETCH-LOGICAL-a259t-ecc031891ede97093301fae0f51bb5c6514afa94979610b0fc6d3b0f4a7ced733</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/op049889k$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/op049889k$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids></links><search><creatorcontrib>Haight, Anthony R</creatorcontrib><creatorcontrib>Bailey, Anne E</creatorcontrib><creatorcontrib>Baker, William S</creatorcontrib><creatorcontrib>Cain, Michael H</creatorcontrib><creatorcontrib>Copp, Richard R</creatorcontrib><creatorcontrib>DeMattei, John A</creatorcontrib><creatorcontrib>Ford, Kelley L</creatorcontrib><creatorcontrib>Henry, Rodger F</creatorcontrib><creatorcontrib>Hsu, Margaret C</creatorcontrib><creatorcontrib>Keyes, Robert F</creatorcontrib><creatorcontrib>King, Steven A</creatorcontrib><creatorcontrib>McLaughlin, Maureen A</creatorcontrib><creatorcontrib>Melcher, Laura M</creatorcontrib><creatorcontrib>Nadler, William R</creatorcontrib><creatorcontrib>Oliver, Patricia A</creatorcontrib><creatorcontrib>Parekh, Shyamal I</creatorcontrib><creatorcontrib>Patel, Hemant H</creatorcontrib><creatorcontrib>Seif, Louis S</creatorcontrib><creatorcontrib>Staeger, Mike A</creatorcontrib><creatorcontrib>Wayne, Gregory S</creatorcontrib><creatorcontrib>Wittenberger, Steven J</creatorcontrib><creatorcontrib>Zhang, Weijiang</creatorcontrib><title>A Scaleable Synthesis of Fiduxosin</title><title>Organic process research & development</title><addtitle>Org. 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Process Res. Dev</addtitle><date>2004-11-01</date><risdate>2004</risdate><volume>8</volume><issue>6</issue><spage>897</spage><epage>902</epage><pages>897-902</pages><issn>1083-6160</issn><eissn>1520-586X</eissn><abstract>Fiduxosin (1) has been under development at Abbott Laboratories for the treatment of benign prostatic hyperplasia. A convergent strategy required methodologies for preparation of an enantiomerically pure 3,4-cis-disubstituted pyrrolidine and a 2,3,5-trisubstituted thienopyrazine in a regiospecific manner. A [3+2] cycloaddition of an enantiopure azomethine ylide followed by a diastereoselective crystallization was employed to prepare the benzopyranopyrrolidine in high diastereomeric and enantiomeric purity. Conditions for reduction of an O-aryl lactone susceptible to epimerization were developed, and cyclization of the alcohol/phenol to the ether was accomplished in high yield. The thienopyrazine was prepared by condensation of methyl thioglycolate and a regiospecifically prepared 2-bromo-3-cyano-5-phenylpyrazine. Conditions for effective halogen substitutive deamination to prepare regiospecific trisubstituted pyrazines will be described.</abstract><pub>American Chemical Society</pub><doi>10.1021/op049889k</doi><tpages>6</tpages></addata></record> |
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| title | A Scaleable Synthesis of Fiduxosin |
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