Facile One-Pot Process for Large-Scale Production of Highly Pure Bosentan Monohydrate, an Endothelin Receptor Antagonist

Described is an efficient, economic, and one-pot process for the production of highly pure bosentan (1), an endothelin receptor antagonist. The synthesis comprises the reaction of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine (2) with 4-tert-butylbenzenesulfonamide (3) and ethylene glycol (4)...

Full description

Saved in:
Bibliographic Details
Published in:Organic process research & development 2011-11, Vol.15 (6), p.1382-1387
Main Authors: Niphade, Navnath C., Jagtap, Kunal M., Gaikawad, Chandrashekhar T., Jachak, Madhukar N., Mathad, Vijayavitthal T.
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-a259t-b0b689911ce777092b672c167d7f6d940c924ee204605f4d77b985379904c8a13
cites cdi_FETCH-LOGICAL-a259t-b0b689911ce777092b672c167d7f6d940c924ee204605f4d77b985379904c8a13
container_end_page 1387
container_issue 6
container_start_page 1382
container_title Organic process research & development
container_volume 15
creator Niphade, Navnath C.
Jagtap, Kunal M.
Gaikawad, Chandrashekhar T.
Jachak, Madhukar N.
Mathad, Vijayavitthal T.
description Described is an efficient, economic, and one-pot process for the production of highly pure bosentan (1), an endothelin receptor antagonist. The synthesis comprises the reaction of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine (2) with 4-tert-butylbenzenesulfonamide (3) and ethylene glycol (4) in acetonitrile in the presence of potassium carbonate to yield bosentan (1) in the same pot. The present work also describes a novel purification method for the removal of critical dimer impurity (7) and 6-hydroxy impurity (8) in 1 by preparation of bosentan ammonium salt (6) using inexpensive ammonium hydroxide. Upon purification, bosentan monohydrate (1) with an overall yield of 68% and HPLC purity of 99.90% was achieved.
doi_str_mv 10.1021/op200197z
format article
fullrecord <record><control><sourceid>acs_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1021_op200197z</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>a533536874</sourcerecordid><originalsourceid>FETCH-LOGICAL-a259t-b0b689911ce777092b672c167d7f6d940c924ee204605f4d77b985379904c8a13</originalsourceid><addsrcrecordid>eNptkE9LAzEQxYMoWKsHv0EuHgRXJ-lusjnW0lqh0uIf8Lak2dl2y5qUJAXrpzdS8eRp3sz8eDweIZcMbhlwdue2HIAp-XVEeqzgkBWleD9OGspBJpiAU3IWwgYACsF4j3xOtGk7pHOL2cJFuvDOYAi0cZ7OtF9h9mJ0-qd7vTOxdZa6hk7b1brb08XOI713AW3Ulj4569b72uuINzTtY1u7uMautfQZDW5jshwmcuVsG-I5OWl0F_Did_bJ22T8Oppms_nD42g4yzQvVMyWsBSlUowZlFKC4kshuWFC1rIRtcrBKJ4jcsgFFE1eS7lUZTGQSkFuSs0GfXJ98DXeheCxqba-_dB-XzGofiqr_ipL7NWB1SZUG7fzNiX7h_sGe2Rq4g</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Facile One-Pot Process for Large-Scale Production of Highly Pure Bosentan Monohydrate, an Endothelin Receptor Antagonist</title><source>American Chemical Society:Jisc Collections:American Chemical Society Read &amp; Publish Agreement 2022-2024 (Reading list)</source><creator>Niphade, Navnath C. ; Jagtap, Kunal M. ; Gaikawad, Chandrashekhar T. ; Jachak, Madhukar N. ; Mathad, Vijayavitthal T.</creator><creatorcontrib>Niphade, Navnath C. ; Jagtap, Kunal M. ; Gaikawad, Chandrashekhar T. ; Jachak, Madhukar N. ; Mathad, Vijayavitthal T.</creatorcontrib><description>Described is an efficient, economic, and one-pot process for the production of highly pure bosentan (1), an endothelin receptor antagonist. The synthesis comprises the reaction of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine (2) with 4-tert-butylbenzenesulfonamide (3) and ethylene glycol (4) in acetonitrile in the presence of potassium carbonate to yield bosentan (1) in the same pot. The present work also describes a novel purification method for the removal of critical dimer impurity (7) and 6-hydroxy impurity (8) in 1 by preparation of bosentan ammonium salt (6) using inexpensive ammonium hydroxide. Upon purification, bosentan monohydrate (1) with an overall yield of 68% and HPLC purity of 99.90% was achieved.</description><identifier>ISSN: 1083-6160</identifier><identifier>EISSN: 1520-586X</identifier><identifier>DOI: 10.1021/op200197z</identifier><language>eng</language><publisher>American Chemical Society</publisher><ispartof>Organic process research &amp; development, 2011-11, Vol.15 (6), p.1382-1387</ispartof><rights>Copyright © 2011 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a259t-b0b689911ce777092b672c167d7f6d940c924ee204605f4d77b985379904c8a13</citedby><cites>FETCH-LOGICAL-a259t-b0b689911ce777092b672c167d7f6d940c924ee204605f4d77b985379904c8a13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids></links><search><creatorcontrib>Niphade, Navnath C.</creatorcontrib><creatorcontrib>Jagtap, Kunal M.</creatorcontrib><creatorcontrib>Gaikawad, Chandrashekhar T.</creatorcontrib><creatorcontrib>Jachak, Madhukar N.</creatorcontrib><creatorcontrib>Mathad, Vijayavitthal T.</creatorcontrib><title>Facile One-Pot Process for Large-Scale Production of Highly Pure Bosentan Monohydrate, an Endothelin Receptor Antagonist</title><title>Organic process research &amp; development</title><addtitle>Org. Process Res. Dev</addtitle><description>Described is an efficient, economic, and one-pot process for the production of highly pure bosentan (1), an endothelin receptor antagonist. The synthesis comprises the reaction of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine (2) with 4-tert-butylbenzenesulfonamide (3) and ethylene glycol (4) in acetonitrile in the presence of potassium carbonate to yield bosentan (1) in the same pot. The present work also describes a novel purification method for the removal of critical dimer impurity (7) and 6-hydroxy impurity (8) in 1 by preparation of bosentan ammonium salt (6) using inexpensive ammonium hydroxide. Upon purification, bosentan monohydrate (1) with an overall yield of 68% and HPLC purity of 99.90% was achieved.</description><issn>1083-6160</issn><issn>1520-586X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNptkE9LAzEQxYMoWKsHv0EuHgRXJ-lusjnW0lqh0uIf8Lak2dl2y5qUJAXrpzdS8eRp3sz8eDweIZcMbhlwdue2HIAp-XVEeqzgkBWleD9OGspBJpiAU3IWwgYACsF4j3xOtGk7pHOL2cJFuvDOYAi0cZ7OtF9h9mJ0-qd7vTOxdZa6hk7b1brb08XOI713AW3Ulj4569b72uuINzTtY1u7uMautfQZDW5jshwmcuVsG-I5OWl0F_Did_bJ22T8Oppms_nD42g4yzQvVMyWsBSlUowZlFKC4kshuWFC1rIRtcrBKJ4jcsgFFE1eS7lUZTGQSkFuSs0GfXJ98DXeheCxqba-_dB-XzGofiqr_ipL7NWB1SZUG7fzNiX7h_sGe2Rq4g</recordid><startdate>20111118</startdate><enddate>20111118</enddate><creator>Niphade, Navnath C.</creator><creator>Jagtap, Kunal M.</creator><creator>Gaikawad, Chandrashekhar T.</creator><creator>Jachak, Madhukar N.</creator><creator>Mathad, Vijayavitthal T.</creator><general>American Chemical Society</general><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20111118</creationdate><title>Facile One-Pot Process for Large-Scale Production of Highly Pure Bosentan Monohydrate, an Endothelin Receptor Antagonist</title><author>Niphade, Navnath C. ; Jagtap, Kunal M. ; Gaikawad, Chandrashekhar T. ; Jachak, Madhukar N. ; Mathad, Vijayavitthal T.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a259t-b0b689911ce777092b672c167d7f6d940c924ee204605f4d77b985379904c8a13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Niphade, Navnath C.</creatorcontrib><creatorcontrib>Jagtap, Kunal M.</creatorcontrib><creatorcontrib>Gaikawad, Chandrashekhar T.</creatorcontrib><creatorcontrib>Jachak, Madhukar N.</creatorcontrib><creatorcontrib>Mathad, Vijayavitthal T.</creatorcontrib><collection>CrossRef</collection><jtitle>Organic process research &amp; development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Niphade, Navnath C.</au><au>Jagtap, Kunal M.</au><au>Gaikawad, Chandrashekhar T.</au><au>Jachak, Madhukar N.</au><au>Mathad, Vijayavitthal T.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Facile One-Pot Process for Large-Scale Production of Highly Pure Bosentan Monohydrate, an Endothelin Receptor Antagonist</atitle><jtitle>Organic process research &amp; development</jtitle><addtitle>Org. Process Res. Dev</addtitle><date>2011-11-18</date><risdate>2011</risdate><volume>15</volume><issue>6</issue><spage>1382</spage><epage>1387</epage><pages>1382-1387</pages><issn>1083-6160</issn><eissn>1520-586X</eissn><abstract>Described is an efficient, economic, and one-pot process for the production of highly pure bosentan (1), an endothelin receptor antagonist. The synthesis comprises the reaction of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine (2) with 4-tert-butylbenzenesulfonamide (3) and ethylene glycol (4) in acetonitrile in the presence of potassium carbonate to yield bosentan (1) in the same pot. The present work also describes a novel purification method for the removal of critical dimer impurity (7) and 6-hydroxy impurity (8) in 1 by preparation of bosentan ammonium salt (6) using inexpensive ammonium hydroxide. Upon purification, bosentan monohydrate (1) with an overall yield of 68% and HPLC purity of 99.90% was achieved.</abstract><pub>American Chemical Society</pub><doi>10.1021/op200197z</doi><tpages>6</tpages></addata></record>
fulltext fulltext
identifier ISSN: 1083-6160
ispartof Organic process research & development, 2011-11, Vol.15 (6), p.1382-1387
issn 1083-6160
1520-586X
language eng
recordid cdi_crossref_primary_10_1021_op200197z
source American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list)
title Facile One-Pot Process for Large-Scale Production of Highly Pure Bosentan Monohydrate, an Endothelin Receptor Antagonist
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T13%3A06%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-acs_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Facile%20One-Pot%20Process%20for%20Large-Scale%20Production%20of%20Highly%20Pure%20Bosentan%20Monohydrate,%20an%20Endothelin%20Receptor%20Antagonist&rft.jtitle=Organic%20process%20research%20&%20development&rft.au=Niphade,%20Navnath%20C.&rft.date=2011-11-18&rft.volume=15&rft.issue=6&rft.spage=1382&rft.epage=1387&rft.pages=1382-1387&rft.issn=1083-6160&rft.eissn=1520-586X&rft_id=info:doi/10.1021/op200197z&rft_dat=%3Cacs_cross%3Ea533536874%3C/acs_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-a259t-b0b689911ce777092b672c167d7f6d940c924ee204605f4d77b985379904c8a13%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_id=info:pmid/&rfr_iscdi=true