Development of a Scalable Alkylation via a Protection/Deprotection Sequence for BMT-773752: Key Intermediate in the Synthetic Route to Repotrectinib

The development of a practical and scalable synthetic route to BMT-773752-02, a key starting material for repotrectinib, is described. The original sequence exhibited various limitations such as use of pyrophoric organolithium reagents, low yield, poor diastereoselectivity, and lengthy workup/purifi...

Full description

Saved in:
Bibliographic Details
Published in:Organic process research & development 2024-07, Vol.28 (7), p.2659-2666
Main Authors: Zhang, Han, Li, Binfeng, Yang, Jin, Xu, Changchun, Carmona, Rafaela, Zhu, Jason, Hoblos, Bilal, Wisniewski, Steven
Format: Article
Language:English
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by
cites cdi_FETCH-LOGICAL-a233t-6685a5a599486423646856b1b2d3107b68bdf1e1ada447b55ff02b8a85c176a73
container_end_page 2666
container_issue 7
container_start_page 2659
container_title Organic process research & development
container_volume 28
creator Zhang, Han
Li, Binfeng
Yang, Jin
Xu, Changchun
Carmona, Rafaela
Zhu, Jason
Hoblos, Bilal
Wisniewski, Steven
description The development of a practical and scalable synthetic route to BMT-773752-02, a key starting material for repotrectinib, is described. The original sequence exhibited various limitations such as use of pyrophoric organolithium reagents, low yield, poor diastereoselectivity, and lengthy workup/purification procedures, which were overcome by development of a new route. A salt screening was conducted to improve the physical properties of the title compound. The scalability of the newly designed synthetic strategy has been demonstrated on multihundred-kilogram scale production to afford greater than a metric ton of this intermediate.
doi_str_mv 10.1021/acs.oprd.4c00061
format article
fullrecord <record><control><sourceid>acs_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1021_acs_oprd_4c00061</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>c175149808</sourcerecordid><originalsourceid>FETCH-LOGICAL-a233t-6685a5a599486423646856b1b2d3107b68bdf1e1ada447b55ff02b8a85c176a73</originalsourceid><addsrcrecordid>eNp1UEtOwzAQtRBIlMKepQ9AWtuJnZRdaflUFIHaIrGLbGciUlI7OG6l3oMD46gVOzSLmXmf0eghdE3JgBJGh1K3A9u4YpBoQoigJ6hHOSMRz8THaZhJFkeCCnKOLtp2HSRcUNZDP1PYQW2bDRiPbYklXmpZS1UDHtdf-1r6yhq8q2Rg3pz1oDtgOIXmb8FL-N6C0YBL6_DdyypK0zjl7BY_wx7PjAe3gaKSHnBlsP8EvNyb0Hyl8cJuA-wtXkBjvesOmkpdorNS1i1cHXsfvT_cryZP0fz1cTYZzyPJ4thHQmRchhqNkkwkLBZJAISiihUxJakSmSpKClQWMklSxXlZEqYymXFNUyHTuI_I4a52tm0dlHnjqo10-5ySvEs1D6nmXar5MdVguTlYOmZtt86EB_-X_wKhvnyS</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Development of a Scalable Alkylation via a Protection/Deprotection Sequence for BMT-773752: Key Intermediate in the Synthetic Route to Repotrectinib</title><source>American Chemical Society:Jisc Collections:American Chemical Society Read &amp; Publish Agreement 2022-2024 (Reading list)</source><creator>Zhang, Han ; Li, Binfeng ; Yang, Jin ; Xu, Changchun ; Carmona, Rafaela ; Zhu, Jason ; Hoblos, Bilal ; Wisniewski, Steven</creator><creatorcontrib>Zhang, Han ; Li, Binfeng ; Yang, Jin ; Xu, Changchun ; Carmona, Rafaela ; Zhu, Jason ; Hoblos, Bilal ; Wisniewski, Steven</creatorcontrib><description>The development of a practical and scalable synthetic route to BMT-773752-02, a key starting material for repotrectinib, is described. The original sequence exhibited various limitations such as use of pyrophoric organolithium reagents, low yield, poor diastereoselectivity, and lengthy workup/purification procedures, which were overcome by development of a new route. A salt screening was conducted to improve the physical properties of the title compound. The scalability of the newly designed synthetic strategy has been demonstrated on multihundred-kilogram scale production to afford greater than a metric ton of this intermediate.</description><identifier>ISSN: 1083-6160</identifier><identifier>EISSN: 1520-586X</identifier><identifier>DOI: 10.1021/acs.oprd.4c00061</identifier><language>eng</language><publisher>American Chemical Society</publisher><ispartof>Organic process research &amp; development, 2024-07, Vol.28 (7), p.2659-2666</ispartof><rights>2024 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-a233t-6685a5a599486423646856b1b2d3107b68bdf1e1ada447b55ff02b8a85c176a73</cites><orcidid>0000-0002-9324-9459 ; 0000-0001-6035-4394</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Zhang, Han</creatorcontrib><creatorcontrib>Li, Binfeng</creatorcontrib><creatorcontrib>Yang, Jin</creatorcontrib><creatorcontrib>Xu, Changchun</creatorcontrib><creatorcontrib>Carmona, Rafaela</creatorcontrib><creatorcontrib>Zhu, Jason</creatorcontrib><creatorcontrib>Hoblos, Bilal</creatorcontrib><creatorcontrib>Wisniewski, Steven</creatorcontrib><title>Development of a Scalable Alkylation via a Protection/Deprotection Sequence for BMT-773752: Key Intermediate in the Synthetic Route to Repotrectinib</title><title>Organic process research &amp; development</title><addtitle>Org. Process Res. Dev</addtitle><description>The development of a practical and scalable synthetic route to BMT-773752-02, a key starting material for repotrectinib, is described. The original sequence exhibited various limitations such as use of pyrophoric organolithium reagents, low yield, poor diastereoselectivity, and lengthy workup/purification procedures, which were overcome by development of a new route. A salt screening was conducted to improve the physical properties of the title compound. The scalability of the newly designed synthetic strategy has been demonstrated on multihundred-kilogram scale production to afford greater than a metric ton of this intermediate.</description><issn>1083-6160</issn><issn>1520-586X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp1UEtOwzAQtRBIlMKepQ9AWtuJnZRdaflUFIHaIrGLbGciUlI7OG6l3oMD46gVOzSLmXmf0eghdE3JgBJGh1K3A9u4YpBoQoigJ6hHOSMRz8THaZhJFkeCCnKOLtp2HSRcUNZDP1PYQW2bDRiPbYklXmpZS1UDHtdf-1r6yhq8q2Rg3pz1oDtgOIXmb8FL-N6C0YBL6_DdyypK0zjl7BY_wx7PjAe3gaKSHnBlsP8EvNyb0Hyl8cJuA-wtXkBjvesOmkpdorNS1i1cHXsfvT_cryZP0fz1cTYZzyPJ4thHQmRchhqNkkwkLBZJAISiihUxJakSmSpKClQWMklSxXlZEqYymXFNUyHTuI_I4a52tm0dlHnjqo10-5ySvEs1D6nmXar5MdVguTlYOmZtt86EB_-X_wKhvnyS</recordid><startdate>20240719</startdate><enddate>20240719</enddate><creator>Zhang, Han</creator><creator>Li, Binfeng</creator><creator>Yang, Jin</creator><creator>Xu, Changchun</creator><creator>Carmona, Rafaela</creator><creator>Zhu, Jason</creator><creator>Hoblos, Bilal</creator><creator>Wisniewski, Steven</creator><general>American Chemical Society</general><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0002-9324-9459</orcidid><orcidid>https://orcid.org/0000-0001-6035-4394</orcidid></search><sort><creationdate>20240719</creationdate><title>Development of a Scalable Alkylation via a Protection/Deprotection Sequence for BMT-773752: Key Intermediate in the Synthetic Route to Repotrectinib</title><author>Zhang, Han ; Li, Binfeng ; Yang, Jin ; Xu, Changchun ; Carmona, Rafaela ; Zhu, Jason ; Hoblos, Bilal ; Wisniewski, Steven</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a233t-6685a5a599486423646856b1b2d3107b68bdf1e1ada447b55ff02b8a85c176a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Han</creatorcontrib><creatorcontrib>Li, Binfeng</creatorcontrib><creatorcontrib>Yang, Jin</creatorcontrib><creatorcontrib>Xu, Changchun</creatorcontrib><creatorcontrib>Carmona, Rafaela</creatorcontrib><creatorcontrib>Zhu, Jason</creatorcontrib><creatorcontrib>Hoblos, Bilal</creatorcontrib><creatorcontrib>Wisniewski, Steven</creatorcontrib><collection>CrossRef</collection><jtitle>Organic process research &amp; development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Han</au><au>Li, Binfeng</au><au>Yang, Jin</au><au>Xu, Changchun</au><au>Carmona, Rafaela</au><au>Zhu, Jason</au><au>Hoblos, Bilal</au><au>Wisniewski, Steven</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of a Scalable Alkylation via a Protection/Deprotection Sequence for BMT-773752: Key Intermediate in the Synthetic Route to Repotrectinib</atitle><jtitle>Organic process research &amp; development</jtitle><addtitle>Org. Process Res. Dev</addtitle><date>2024-07-19</date><risdate>2024</risdate><volume>28</volume><issue>7</issue><spage>2659</spage><epage>2666</epage><pages>2659-2666</pages><issn>1083-6160</issn><eissn>1520-586X</eissn><abstract>The development of a practical and scalable synthetic route to BMT-773752-02, a key starting material for repotrectinib, is described. The original sequence exhibited various limitations such as use of pyrophoric organolithium reagents, low yield, poor diastereoselectivity, and lengthy workup/purification procedures, which were overcome by development of a new route. A salt screening was conducted to improve the physical properties of the title compound. The scalability of the newly designed synthetic strategy has been demonstrated on multihundred-kilogram scale production to afford greater than a metric ton of this intermediate.</abstract><pub>American Chemical Society</pub><doi>10.1021/acs.oprd.4c00061</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-9324-9459</orcidid><orcidid>https://orcid.org/0000-0001-6035-4394</orcidid></addata></record>
fulltext fulltext
identifier ISSN: 1083-6160
ispartof Organic process research & development, 2024-07, Vol.28 (7), p.2659-2666
issn 1083-6160
1520-586X
language eng
recordid cdi_crossref_primary_10_1021_acs_oprd_4c00061
source American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list)
title Development of a Scalable Alkylation via a Protection/Deprotection Sequence for BMT-773752: Key Intermediate in the Synthetic Route to Repotrectinib
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-27T05%3A42%3A46IST&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=Development%20of%20a%20Scalable%20Alkylation%20via%20a%20Protection/Deprotection%20Sequence%20for%20BMT-773752:%20Key%20Intermediate%20in%20the%20Synthetic%20Route%20to%20Repotrectinib&rft.jtitle=Organic%20process%20research%20&%20development&rft.au=Zhang,%20Han&rft.date=2024-07-19&rft.volume=28&rft.issue=7&rft.spage=2659&rft.epage=2666&rft.pages=2659-2666&rft.issn=1083-6160&rft.eissn=1520-586X&rft_id=info:doi/10.1021/acs.oprd.4c00061&rft_dat=%3Cacs_cross%3Ec175149808%3C/acs_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-a233t-6685a5a599486423646856b1b2d3107b68bdf1e1ada447b55ff02b8a85c176a73%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