Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin
A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxa-bicyclo[3.2.1]octane motif is prepared from commercially availabl...
Gespeichert in:
| Veröffentlicht in: | Organic process research & development 2014-01, Vol.18 (1), p.66-81 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 81 |
|---|---|
| container_issue | 1 |
| container_start_page | 66 |
| container_title | Organic process research & development |
| container_volume | 18 |
| creator | Bowles, Paul Brenek, Steven J Caron, Stéphane Do, Nga M Drexler, Michele T Duan, Shengquan Dubé, Pascal Hansen, Eric C Jones, Brian P Jones, Kris N Ljubicic, Tomislav A Makowski, Teresa W Mustakis, Jason Nelson, Jade D Olivier, Mark Peng, Zhihui Perfect, Hahdi H Place, David W Ragan, John A Salisbury, John J Stanchina, Corey L Vanderplas, Brian C Webster, Mark E Weekly, R. Matt |
| description | A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxa-bicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-d-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with l-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality. |
| doi_str_mv | 10.1021/op4002802 |
| format | Article |
| fullrecord | <record><control><sourceid>acs_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1021_op4002802</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>a073316171</sourcerecordid><originalsourceid>FETCH-LOGICAL-a325t-3a50f2755def82baa4d5dea53842111c200f6211f2d2b124b1a381656624683a3</originalsourceid><addsrcrecordid>eNptkMFKAzEQhoMoWKsH3yAXDx5WJ7ObmKustQoFobbgbZndTWzK7qYkW0Gf3kjFk6f5Br5_GH7GLgXcCEBx63cFAGrAIzYREiGTWr0dJwadZ0ooOGVnMW4BQCqBE7Yufd-b0Djq-NLvR8OXJhoKzYbT0PIH82E6v-vNMHLrA3-dL1bIn4eNq92Y9jJJrqUUm4Vx_9452_kvN5yzE0tdNBe_c8rWj7NV-ZQtXubP5f0ioxzlmOUkweKdlK2xGmuiok1IMtcFCiEaBLAqkcUWa4FFLSjXQkmlsFA6p3zKrg93m-BjDMZWu-B6Cp-VgOqnj-qvj-ReHVxqYrX1-zCkz_7xvgFzRF2c</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin</title><source>American Chemical Society Journals</source><creator>Bowles, Paul ; Brenek, Steven J ; Caron, Stéphane ; Do, Nga M ; Drexler, Michele T ; Duan, Shengquan ; Dubé, Pascal ; Hansen, Eric C ; Jones, Brian P ; Jones, Kris N ; Ljubicic, Tomislav A ; Makowski, Teresa W ; Mustakis, Jason ; Nelson, Jade D ; Olivier, Mark ; Peng, Zhihui ; Perfect, Hahdi H ; Place, David W ; Ragan, John A ; Salisbury, John J ; Stanchina, Corey L ; Vanderplas, Brian C ; Webster, Mark E ; Weekly, R. Matt</creator><creatorcontrib>Bowles, Paul ; Brenek, Steven J ; Caron, Stéphane ; Do, Nga M ; Drexler, Michele T ; Duan, Shengquan ; Dubé, Pascal ; Hansen, Eric C ; Jones, Brian P ; Jones, Kris N ; Ljubicic, Tomislav A ; Makowski, Teresa W ; Mustakis, Jason ; Nelson, Jade D ; Olivier, Mark ; Peng, Zhihui ; Perfect, Hahdi H ; Place, David W ; Ragan, John A ; Salisbury, John J ; Stanchina, Corey L ; Vanderplas, Brian C ; Webster, Mark E ; Weekly, R. Matt</creatorcontrib><description>A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxa-bicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-d-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with l-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.</description><identifier>ISSN: 1083-6160</identifier><identifier>EISSN: 1520-586X</identifier><identifier>DOI: 10.1021/op4002802</identifier><language>eng</language><publisher>American Chemical Society</publisher><ispartof>Organic process research & development, 2014-01, Vol.18 (1), p.66-81</ispartof><rights>Copyright © 2013 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a325t-3a50f2755def82baa4d5dea53842111c200f6211f2d2b124b1a381656624683a3</citedby><cites>FETCH-LOGICAL-a325t-3a50f2755def82baa4d5dea53842111c200f6211f2d2b124b1a381656624683a3</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/op4002802$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/op4002802$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids></links><search><creatorcontrib>Bowles, Paul</creatorcontrib><creatorcontrib>Brenek, Steven J</creatorcontrib><creatorcontrib>Caron, Stéphane</creatorcontrib><creatorcontrib>Do, Nga M</creatorcontrib><creatorcontrib>Drexler, Michele T</creatorcontrib><creatorcontrib>Duan, Shengquan</creatorcontrib><creatorcontrib>Dubé, Pascal</creatorcontrib><creatorcontrib>Hansen, Eric C</creatorcontrib><creatorcontrib>Jones, Brian P</creatorcontrib><creatorcontrib>Jones, Kris N</creatorcontrib><creatorcontrib>Ljubicic, Tomislav A</creatorcontrib><creatorcontrib>Makowski, Teresa W</creatorcontrib><creatorcontrib>Mustakis, Jason</creatorcontrib><creatorcontrib>Nelson, Jade D</creatorcontrib><creatorcontrib>Olivier, Mark</creatorcontrib><creatorcontrib>Peng, Zhihui</creatorcontrib><creatorcontrib>Perfect, Hahdi H</creatorcontrib><creatorcontrib>Place, David W</creatorcontrib><creatorcontrib>Ragan, John A</creatorcontrib><creatorcontrib>Salisbury, John J</creatorcontrib><creatorcontrib>Stanchina, Corey L</creatorcontrib><creatorcontrib>Vanderplas, Brian C</creatorcontrib><creatorcontrib>Webster, Mark E</creatorcontrib><creatorcontrib>Weekly, R. Matt</creatorcontrib><title>Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin</title><title>Organic process research & development</title><addtitle>Org. Process Res. Dev</addtitle><description>A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxa-bicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-d-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with l-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.</description><issn>1083-6160</issn><issn>1520-586X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNptkMFKAzEQhoMoWKsH3yAXDx5WJ7ObmKustQoFobbgbZndTWzK7qYkW0Gf3kjFk6f5Br5_GH7GLgXcCEBx63cFAGrAIzYREiGTWr0dJwadZ0ooOGVnMW4BQCqBE7Yufd-b0Djq-NLvR8OXJhoKzYbT0PIH82E6v-vNMHLrA3-dL1bIn4eNq92Y9jJJrqUUm4Vx_9452_kvN5yzE0tdNBe_c8rWj7NV-ZQtXubP5f0ioxzlmOUkweKdlK2xGmuiok1IMtcFCiEaBLAqkcUWa4FFLSjXQkmlsFA6p3zKrg93m-BjDMZWu-B6Cp-VgOqnj-qvj-ReHVxqYrX1-zCkz_7xvgFzRF2c</recordid><startdate>20140117</startdate><enddate>20140117</enddate><creator>Bowles, Paul</creator><creator>Brenek, Steven J</creator><creator>Caron, Stéphane</creator><creator>Do, Nga M</creator><creator>Drexler, Michele T</creator><creator>Duan, Shengquan</creator><creator>Dubé, Pascal</creator><creator>Hansen, Eric C</creator><creator>Jones, Brian P</creator><creator>Jones, Kris N</creator><creator>Ljubicic, Tomislav A</creator><creator>Makowski, Teresa W</creator><creator>Mustakis, Jason</creator><creator>Nelson, Jade D</creator><creator>Olivier, Mark</creator><creator>Peng, Zhihui</creator><creator>Perfect, Hahdi H</creator><creator>Place, David W</creator><creator>Ragan, John A</creator><creator>Salisbury, John J</creator><creator>Stanchina, Corey L</creator><creator>Vanderplas, Brian C</creator><creator>Webster, Mark E</creator><creator>Weekly, R. Matt</creator><general>American Chemical Society</general><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20140117</creationdate><title>Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin</title><author>Bowles, Paul ; Brenek, Steven J ; Caron, Stéphane ; Do, Nga M ; Drexler, Michele T ; Duan, Shengquan ; Dubé, Pascal ; Hansen, Eric C ; Jones, Brian P ; Jones, Kris N ; Ljubicic, Tomislav A ; Makowski, Teresa W ; Mustakis, Jason ; Nelson, Jade D ; Olivier, Mark ; Peng, Zhihui ; Perfect, Hahdi H ; Place, David W ; Ragan, John A ; Salisbury, John J ; Stanchina, Corey L ; Vanderplas, Brian C ; Webster, Mark E ; Weekly, R. Matt</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a325t-3a50f2755def82baa4d5dea53842111c200f6211f2d2b124b1a381656624683a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bowles, Paul</creatorcontrib><creatorcontrib>Brenek, Steven J</creatorcontrib><creatorcontrib>Caron, Stéphane</creatorcontrib><creatorcontrib>Do, Nga M</creatorcontrib><creatorcontrib>Drexler, Michele T</creatorcontrib><creatorcontrib>Duan, Shengquan</creatorcontrib><creatorcontrib>Dubé, Pascal</creatorcontrib><creatorcontrib>Hansen, Eric C</creatorcontrib><creatorcontrib>Jones, Brian P</creatorcontrib><creatorcontrib>Jones, Kris N</creatorcontrib><creatorcontrib>Ljubicic, Tomislav A</creatorcontrib><creatorcontrib>Makowski, Teresa W</creatorcontrib><creatorcontrib>Mustakis, Jason</creatorcontrib><creatorcontrib>Nelson, Jade D</creatorcontrib><creatorcontrib>Olivier, Mark</creatorcontrib><creatorcontrib>Peng, Zhihui</creatorcontrib><creatorcontrib>Perfect, Hahdi H</creatorcontrib><creatorcontrib>Place, David W</creatorcontrib><creatorcontrib>Ragan, John A</creatorcontrib><creatorcontrib>Salisbury, John J</creatorcontrib><creatorcontrib>Stanchina, Corey L</creatorcontrib><creatorcontrib>Vanderplas, Brian C</creatorcontrib><creatorcontrib>Webster, Mark E</creatorcontrib><creatorcontrib>Weekly, R. Matt</creatorcontrib><collection>CrossRef</collection><jtitle>Organic process research & development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bowles, Paul</au><au>Brenek, Steven J</au><au>Caron, Stéphane</au><au>Do, Nga M</au><au>Drexler, Michele T</au><au>Duan, Shengquan</au><au>Dubé, Pascal</au><au>Hansen, Eric C</au><au>Jones, Brian P</au><au>Jones, Kris N</au><au>Ljubicic, Tomislav A</au><au>Makowski, Teresa W</au><au>Mustakis, Jason</au><au>Nelson, Jade D</au><au>Olivier, Mark</au><au>Peng, Zhihui</au><au>Perfect, Hahdi H</au><au>Place, David W</au><au>Ragan, John A</au><au>Salisbury, John J</au><au>Stanchina, Corey L</au><au>Vanderplas, Brian C</au><au>Webster, Mark E</au><au>Weekly, R. Matt</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin</atitle><jtitle>Organic process research & development</jtitle><addtitle>Org. Process Res. Dev</addtitle><date>2014-01-17</date><risdate>2014</risdate><volume>18</volume><issue>1</issue><spage>66</spage><epage>81</epage><pages>66-81</pages><issn>1083-6160</issn><eissn>1520-586X</eissn><abstract>A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxa-bicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-d-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with l-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.</abstract><pub>American Chemical Society</pub><doi>10.1021/op4002802</doi><tpages>16</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1083-6160 |
| ispartof | Organic process research & development, 2014-01, Vol.18 (1), p.66-81 |
| issn | 1083-6160 1520-586X |
| language | eng |
| recordid | cdi_crossref_primary_10_1021_op4002802 |
| source | American Chemical Society Journals |
| title | Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T19%3A21%3A25IST&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=Commercial%20Route%20Research%20and%20Development%20for%20SGLT2%20Inhibitor%20Candidate%20Ertugliflozin&rft.jtitle=Organic%20process%20research%20&%20development&rft.au=Bowles,%20Paul&rft.date=2014-01-17&rft.volume=18&rft.issue=1&rft.spage=66&rft.epage=81&rft.pages=66-81&rft.issn=1083-6160&rft.eissn=1520-586X&rft_id=info:doi/10.1021/op4002802&rft_dat=%3Cacs_cross%3Ea073316171%3C/acs_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/&rfr_iscdi=true |