Construction of CF2 moieties in FDA-approved drugs (2016-2025): industrial routes, mechanisms, and scale-up considerations.

The incorporation of CF2 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 CF2-containing drugs from 2016 to 2025, categorizing them according to the chemical environment of the CF2 group (alkyl-CF2, heteroaryl-CF2, and ArO-CF2). For each drug, the industrial routes for CF2 construction and the reasons for eliminating alternative routes are analyzed. Methods for CF2 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 - nucleophilic fluorination, electrophilic fluorination, radical pathways, and carbene insertion - and evaluates their applicability in industrial production. The analysis shows that for alkyl-CF2 groups, the industry strongly favors preformed CF2 building blocks or indirect fluorination strategies to avoid hazardous reagents and harsh conditions. Continuous flow technology using SF4 has emerged as an important complement to traditional fluorination methods. For heteroaryl-CF2 groups, metal-catalyzed direct introduction of the CF2 unit still faces challenges for industrial application, whereas the difluorocarbene route for ArO-CF2 has been validated. This review provides a reference for process development of new CF2-containing drugs, from strategic design to scale-up evaluation.