{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:55:35Z","timestamp":1790765735359,"version":"4.1.0"},"reference-count":30,"publisher":"Wiley","issue":"4-6","license":[{"start":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T00:00:00Z","timestamp":1682294400000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Labelled Comp Radiopharmac"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:p>(<jats:italic>R<\/jats:italic>)\u20104\u2010((<jats:italic>R<\/jats:italic>)\u20101\u2010((6\u2010(1\u2010[<jats:italic>tert\u2010<\/jats:italic>butyl]\u20101<jats:italic>H<\/jats:italic>\u2010pyrazol\u20104\u2010yl)\u20102\u2010methyl\u20102<jats:italic>H<\/jats:italic>\u2010pyrazolo[3,4\u2010d]pyridin\u20104\u2010yl)oxy)ethyl)pyrrolidin\u20102\u2010one (<jats:bold>BI 894416<\/jats:bold>, <jats:bold>1<\/jats:bold>) and (<jats:italic>R<\/jats:italic>)\u20104\u2010((<jats:italic>R<\/jats:italic>)\u20101\u2010((6\u2010(1\u2010[<jats:italic>tert<\/jats:italic>\u2010butyl]\u20101<jats:italic>H<\/jats:italic>\u2010pyrazol\u20104\u2010yl)\u20102,3\u2010dimethyl\u20102<jats:italic>H<\/jats:italic>\u2010indazol\u20104\u2010yl)oxy)ethyl)pyrrolidin\u20102\u2010one (<jats:bold>BI 1342561<\/jats:bold>, <jats:bold>2<\/jats:bold>) are two new potent and selective spleen tyrosine kinase inhibitors developed to treat severe asthma. Both compounds have similar structures and they differ only in the bicyclic moiety 2\u2010methyl\u20102<jats:italic>H<\/jats:italic>\u2010pyrazolo[4,3\u2010c]pyridine in <jats:bold>1<\/jats:bold> versus 2,3\u2010dimethyl\u20102<jats:italic>H<\/jats:italic>\u2010indazole in <jats:bold>2<\/jats:bold>. In the carbon 14 synthesis, 1\u2010(1\u2010[<jats:italic>tert<\/jats:italic>\u2010butyl]\u20101<jats:italic>H<\/jats:italic>\u2010pyrazol\u20104\u2010yl)ethan\u20101\u2010one\u20101\u2010<jats:sup>14<\/jats:sup><jats:italic>C<\/jats:italic> (<jats:bold>[<\/jats:bold><jats:sup><jats:bold>14<\/jats:bold><\/jats:sup><jats:bold>C]\u20108<\/jats:bold>) was prepared from the cyanation of 4\u2010bromopyrazole using zinc [<jats:sup>14<\/jats:sup>C]cyanide followed by methyl lithium addition on the nitrile group. The enolate of <jats:bold>[<\/jats:bold><jats:sup><jats:bold>14<\/jats:bold><\/jats:sup><jats:bold>C]\u20108<\/jats:bold> was then used to access these two bicyclic moieties via pyrano\u2010pyrazoles <jats:bold>[<\/jats:bold><jats:sup><jats:bold>14<\/jats:bold><\/jats:sup><jats:bold>C]\u201011<\/jats:bold> and <jats:bold>[<\/jats:bold><jats:sup><jats:bold>14<\/jats:bold><\/jats:sup><jats:bold>C]\u201012<\/jats:bold>, which were further transformed in few more steps to <jats:bold>[<\/jats:bold><jats:sup><jats:bold>14<\/jats:bold><\/jats:sup><jats:bold>C]\u2010(1)<\/jats:bold> and <jats:bold>[<\/jats:bold><jats:sup><jats:bold>14<\/jats:bold><\/jats:sup><jats:bold>C]\u20102<\/jats:bold>. Both inhibitors contain a <jats:italic>tert\u2010<\/jats:italic>butyl group. Introducing <jats:italic>tert\u2010<\/jats:italic>butyl\u2010<jats:italic>d<\/jats:italic><jats:sub>9<\/jats:sub> will not only provide internal standards for bioanalytical studies, but it is also expected to slow down the metabolism of these two compounds. Most of the metabolites of compound <jats:bold>1<\/jats:bold>, for example, are the result of <jats:italic>tert<\/jats:italic>\u2010butyl oxidation, like alcohol <jats:bold>3<\/jats:bold>, acid <jats:bold>4<\/jats:bold>, and the further <jats:italic>N<\/jats:italic>\u2010demethylation of <jats:bold>4<\/jats:bold> to <jats:bold>5<\/jats:bold>. The detailed preparation of these deuterium\u2010labeled metabolites is also described.<\/jats:p>","DOI":"10.1002\/jlcr.4024","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T06:04:26Z","timestamp":1681452266000},"page":"155-168","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Synthesis of BI 894416 and BI 1342561, two potent and selective spleen tyrosine kinase inhibitors, labeled with carbon 14 and with deuterium"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0024-9792","authenticated-orcid":false,"given":"Bachir","family":"Latli","sequence":"first","affiliation":[{"name":"The Radiosynthesis Laboratory, Chemical Development Boehringer Ingelheim Pharmaceuticals, Inc  Ridgefield Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt J.","family":"Hrapchak","sequence":"additional","affiliation":[{"name":"The Radiosynthesis Laboratory, Chemical Development Boehringer Ingelheim Pharmaceuticals, Inc  Ridgefield Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lalith P.","family":"Samankumara","sequence":"additional","affiliation":[{"name":"The Radiosynthesis Laboratory, Chemical Development Boehringer Ingelheim Pharmaceuticals, Inc  Ridgefield Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R.","family":"Fandrick","sequence":"additional","affiliation":[{"name":"The Radiosynthesis Laboratory, Chemical Development Boehringer Ingelheim Pharmaceuticals, Inc  Ridgefield Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Pennino","sequence":"additional","affiliation":[{"name":"The Radiosynthesis Laboratory, Chemical Development Boehringer Ingelheim Pharmaceuticals, Inc  Ridgefield Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heewon","family":"Lee","sequence":"additional","affiliation":[{"name":"The Radiosynthesis Laboratory, Chemical Development Boehringer Ingelheim Pharmaceuticals, Inc  Ridgefield Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua J.","family":"Song","sequence":"additional","affiliation":[{"name":"The Radiosynthesis Laboratory, Chemical Development Boehringer Ingelheim Pharmaceuticals, Inc  Ridgefield Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,4,24]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432\u20101033.1990.tb15433.x"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5788"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2018.05.019"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2765"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.13.7.743"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.14.126"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2019.12.014"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2014.05.007"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2010.05.001"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2018.1459562"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010017\u20100512\u20101"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543770903207039"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm201271b"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1159\/000446879"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2015.08.037"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.27545"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2018.96"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.109058"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.116.233155"},{"key":"e_1_2_7_21_1","unstructured":"(a)DahmannG HoffmanM KlicicJ.et al.Heteroaryl SYK inhibitors. 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