{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:48:35Z","timestamp":1785836915431,"version":"3.56.0"},"reference-count":65,"publisher":"Beilstein Institut","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Beilstein J. Org. Chem."],"accepted":{"date-parts":[[2026,7,13]]},"abstract":"<jats:p>\n                    The incorporation of CF\n                    <jats:sub>2<\/jats:sub>\n                    moieties into drug molecules offers unique advantages in improving metabolic stability and target affinity, making their efficient construction a major focus in pharmaceutical process chemistry. This review systematically examines the synthetic processes of 12 FDA-approved CF\n                    <jats:sub>2<\/jats:sub>\n                    -containing drugs from 2016 to 2025, categorizing them according to the chemical environment of the CF\n                    <jats:sub>2<\/jats:sub>\n                    group (alkyl-CF\n                    <jats:sub>2<\/jats:sub>\n                    , heteroaryl-CF\n                    <jats:sub>2<\/jats:sub>\n                    , and ArO-CF\n                    <jats:sub>2<\/jats:sub>\n                    ). For each drug, the industrial routes for CF\n                    <jats:sub>2<\/jats:sub>\n                    construction and the reasons for eliminating alternative routes are analyzed. Methods for CF\n                    <jats:sub>2<\/jats:sub>\n                    formation are classified into two major strategies: fluorinating reagent-based approaches and building block-based approaches. Key process steps and scale-up data are summarized in Table 1. The article systematically discusses four types of reaction mechanisms \u2013 nucleophilic fluorination, electrophilic fluorination, radical pathways, and carbene insertion \u2013 and evaluates their applicability in industrial production. The analysis shows that for alkyl-CF\n                    <jats:sub>2<\/jats:sub>\n                    groups, the industry strongly favors preformed CF\n                    <jats:sub>2<\/jats:sub>\n                    building blocks or indirect fluorination strategies to avoid hazardous reagents and harsh conditions. Continuous flow technology using SF\n                    <jats:sub>4<\/jats:sub>\n                    has emerged as an important complement to traditional fluorination methods. For heteroaryl-CF\n                    <jats:sub>2<\/jats:sub>\n                    groups, metal-catalyzed direct introduction of the CF\n                    <jats:sub>2<\/jats:sub>\n                    unit still faces challenges for industrial application, whereas the difluorocarbene route for ArO-CF\n                    <jats:sub>2<\/jats:sub>\n                    has been validated. This review provides a reference for process development of new CF\n                    <jats:sub>2<\/jats:sub>\n                    -containing drugs, from strategic design to scale-up evaluation.\n                  <\/jats:p>","DOI":"10.3762\/bjoc.22.91","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:39:56Z","timestamp":1785836396000},"page":"1122-1150","source":"Crossref","is-referenced-by-count":0,"title":["Construction of CF\n                    <sub>2<\/sub>\n                    moieties in FDA-approved drugs (2016\u20132025): industrial routes, mechanisms, and scale-up 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