{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:34:23Z","timestamp":1760661263218,"version":"build-2065373602"},"reference-count":18,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T00:00:00Z","timestamp":1695168000000},"content-version":"vor","delay-in-days":0,"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":[[2023,11]]},"abstract":"<jats:p>Stable isotope labeled <jats:bold>Iclepertin (BI 425809, 1)<\/jats:bold> and its major metabolites are needed as internal standards in bioanalytical studies. <jats:bold>BI 425809<\/jats:bold> consists of two main building blocks, 5\u2010methylsulfonyl\u20102\u2010[(1<jats:italic>R<\/jats:italic>)\u20102,2,2\u2010trifluoro\u20101\u2010methyl\u2010ethoxy]benzoic acid (<jats:bold>2<\/jats:bold>) and 3\u2010[(1<jats:italic>R<\/jats:italic>,5<jats:italic>R<\/jats:italic>)\u20103\u2010azabicyclo[3.1.0]hexan\u20105\u2010yl]\u20105\u2010(trifluoromethyl)isoxazole (<jats:bold>3<\/jats:bold>) linked to each other via an amide bond. We used fluoro[<jats:sup>13<\/jats:sup>C<jats:sub>6<\/jats:sub>]benzene as the starting material in the preparation of <jats:bold>[<\/jats:bold><jats:sup><jats:bold>13<\/jats:bold><\/jats:sup><jats:bold>C<\/jats:bold><jats:sub><jats:bold>6<\/jats:bold><\/jats:sub><jats:bold>]\u20102<\/jats:bold>. This intermediate was then employed to access carbon 13 labeled <jats:bold>Iclepertin<\/jats:bold> (<jats:bold>[<\/jats:bold><jats:sup><jats:bold>13<\/jats:bold><\/jats:sup><jats:bold>C<\/jats:bold><jats:sub><jats:bold>6<\/jats:bold><\/jats:sub><jats:bold>]\u20101<\/jats:bold>) and other metabolites. The major metabolite <jats:bold>BI 761036<\/jats:bold> (<jats:bold>6<\/jats:bold>), which resulted from cytochrome P450 oxidation and amide hydrolysis of <jats:bold>BI 425809<\/jats:bold>, was prepared labeled with carbon 13 and nitrogen 15 via two synthetic routes. In the first route, diethyl [<jats:sup>13<\/jats:sup>C<jats:sub>3<\/jats:sub>]malonate, [<jats:sup>13<\/jats:sup>C]methyl iodide, and hydroxyl[<jats:sup>15<\/jats:sup>N]amine were used to provide <jats:bold>[<\/jats:bold><jats:sup><jats:bold>13<\/jats:bold><\/jats:sup><jats:bold>C<\/jats:bold><jats:sub><jats:bold>4<\/jats:bold><\/jats:sub>,<jats:sup><jats:bold>15<\/jats:bold><\/jats:sup><jats:bold>N]\u2010BI 761036 ([<\/jats:bold><jats:sup><jats:bold>13<\/jats:bold><\/jats:sup><jats:bold>C<\/jats:bold><jats:sub><jats:bold>4<\/jats:bold><\/jats:sub>,<jats:sup><jats:bold>15<\/jats:bold><\/jats:sup><jats:bold>N]\u20106a)<\/jats:bold> in 13 steps in 6% overall yield, whereas in the second route, [<jats:sup>13<\/jats:sup>C<jats:sub>3<\/jats:sub>]propargyl alcohol, potassium [<jats:sup>13<\/jats:sup>C]cyanide, and [<jats:sup>15<\/jats:sup>N]ammonia were used to furnish <jats:bold>[<\/jats:bold><jats:sup><jats:bold>13<\/jats:bold><\/jats:sup><jats:bold>C<\/jats:bold><jats:sub><jats:bold>4<\/jats:bold><\/jats:sub>,<jats:sup><jats:bold>15<\/jats:bold><\/jats:sup><jats:bold>N]\u2010BI 761036 ([<\/jats:bold><jats:sup><jats:bold>13<\/jats:bold><\/jats:sup><jats:bold>C<\/jats:bold><jats:sub><jats:bold>4<\/jats:bold><\/jats:sub>,<jats:sup><jats:bold>15<\/jats:bold><\/jats:sup><jats:bold>N]\u20106b)<\/jats:bold> in 11 steps in 1% overall yield. The detailed stable isotope synthesis of <jats:bold>1<\/jats:bold> and its major metabolites is described.<\/jats:p>","DOI":"10.1002\/jlcr.4063","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T04:03:41Z","timestamp":1695182621000},"page":"414-427","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Stable isotope synthesis of glycine transporter 1 inhibitor Iclepertin (BI 425809) and its major metabolites"],"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":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matt J.","family":"Hrapchak","sequence":"additional","affiliation":[{"name":"The Radiosynthesis Laboratory, Chemical Development Boehringer Ingelheim Pharmaceuticals, Inc.  Ridgefield Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maxim","family":"Chevliakov","sequence":"additional","affiliation":[{"name":"The Radiosynthesis Laboratory, Chemical Development Boehringer Ingelheim Pharmaceuticals, Inc.  Ridgefield Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lalith P.","family":"Samankumara","sequence":"additional","affiliation":[{"name":"The Radiosynthesis Laboratory, Chemical Development Boehringer Ingelheim Pharmaceuticals, Inc.  Ridgefield Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rogelio P.","family":"Frutos","sequence":"additional","affiliation":[{"name":"The Radiosynthesis Laboratory, Chemical Development Boehringer Ingelheim Pharmaceuticals, Inc.  Ridgefield Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heewon","family":"Lee","sequence":"additional","affiliation":[{"name":"The Radiosynthesis Laboratory, Chemical Development Boehringer Ingelheim Pharmaceuticals, Inc.  Ridgefield Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,9,20]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2215\u20100366(20)30513\u20107"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095\u2010023\u201003530\u2010z"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jlcr.4051"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040\u20104039(00)60805\u20105"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jlcr.1183"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm100210p"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.7b03022"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.2c03053"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.9b02258"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00044\u2010018\u20102152\u20106"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.oprd.2c00373"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo0709605"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm9705869"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-1997-1376"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022\u20101139(95)03252\u20109"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol061650w"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo0302206"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2004.05.063"}],"container-title":["Journal of Labelled Compounds and Radiopharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jlcr.4063","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T18:12:00Z","timestamp":1760638320000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/jlcr.4063"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,20]]},"references-count":18,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.1002\/jlcr.4063"],"URL":"https:\/\/doi.org\/10.1002\/jlcr.4063","archive":["Portico"],"relation":{},"ISSN":["0362-4803","1099-1344"],"issn-type":[{"type":"print","value":"0362-4803"},{"type":"electronic","value":"1099-1344"}],"subject":[],"published":{"date-parts":[[2023,9,20]]},"assertion":[{"value":"2023-07-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}