Next generation organofluorine containing blockbuster drugs

Abstract

The role of organo-fluorine compounds in modern health, food and energy related 2 industries is widely-appreciated. The unique properties that fluorine imparts to organic molecules, stemming from its high electronegativity and stability when bound to carbon, finds it increasing being used in the development of new bioactivities. Around 25% of the current blockbuster drugs contain fluorine and this number is increasing to well above 30% for recent FDA approvals. In this Review we highlight a selection of the most successful organo-fluorine drugs, that have achieved blockbuster status, namely, sitagliptin (diabetes), sofosbuvir (hepatitis C), emtricitabine (HIV), glecaprevir/pibrentasvir (hepatitis C), elvitegravir (HIV), dolutegravir (HIV), bictegravir (HIV), efavirenz (HIV), enzalutamide (prostate cancer), aubagio (immunomodulatory) and paliperidone palmitate (schizophrenia). For each compound we discuss their discovery, their relevant disease state and how they are made, emphasizing the source of fluorine-containing moieties, and where known, their mode of action. Scheme 7. Synthesis of intermediate 23 for the preparation of sitagliptin (4). The synthesis of β-amino acid 28 was shown in Scheme 8. An asymmetric Ru-catalyzed reduction of the carbonyl group on β-ketoester 24 is another illustration of the contribution of Noyori's asymmetric methodology to the development of pharmaceutical processes. This asymmetric reduction is followed by ester hydrolysis to generate intermediate 25. A coupling reaction between carboxylic acid 25 and BnONH2 in the presence of EDC-HCl afforded hydroxamate 26, which was subjected to an intramolecular cyclization reaction to generate lactam 27. The treatment of lactam 27 with HCl and then a hydrolysis under basic conditions, provided the key intermediate 28. Triazole 23 was then coupled to amino acid 28 in the presence of EDC-HCl and N-methylmorpholine (NMM) to afforded intermediate 29, which was finally converted into sitagliptin ( 4) via a Pd-catalyzed hydrogenation. It should be noted that Soloshonok and co-workers applied their chiral Ni-complex approach to the synthesis of sitagliptin (4) [33].

Synthesis and Conformational Analysis of Fluorinated Uridine Analogues Provide Insight into a Neighbouring-Group Participation Mechanism

“…Furthermore, the widely used antidepressant fluoxetine (Prozac), the antibacterial ciprofloxacin (Ciprobay) and the anti-inflammatory fluticasone are fluorine-containing drugs. A selection of the most successful organofluorine-containing blockbuster drugs, including sitagliptin (for the treatment of diabetes); sofosbuvir (hepatitis C); dolutegravir, bictegravir and efavirenz (HIV); and enzalutamide (prostate cancer), highlight the significance of fluorinated bioactive compounds [ 6 , 7 ]. Fluorinated nucleoside analogues nucleocidin 1 , 5-fluorouracil 2 , gemcitabine 3 , LY2334737 4 , sofosbuvir 5 , NUC-1031 6 and RX3117 7 are shown in Scheme 1 [ 8 , 9 ].…”

Transition‐Metal Free Catalytic Synthesis of Trifluoromethyl Indolines by [4+1] Cycloaddition of Trifluoromethyl Benzoxazinones with Sulfur Ylides

“…Organofluorine compounds are promising candidates for pharmaceuticals and agrochemicals due to the unique effects of fluorine on chemical and physicochemical properties [1–4] . Nearly half of the FDA‐approved small‐molecule drugs in 2018 and 2019 are fluoro‐organic compounds [2,5–7] . In particular, trifluoromethylated heterocycles are recognized as being one of the most attractive groups of pharmacophores, as exemplified by efavirenz (an anti‐HIV drug) and sitagliptin (an anti‐diabetic drug) [2,3] .…”

“…[1][2][3][4] Nearly half of the FDAapproved small-molecule drugs in 2018 and 2019 are fluoro-organic compounds. [2,[5][6][7] In particular, trifluoromethylated heterocycles are recognized as being one of the most attractive groups of pharmacophores, as exemplified by efavirenz (an anti-HIV drug) and sitagliptin (an anti-diabetic drug). [2,3] Therefore, the development of facile and efficient synthetic methods for trifluoromethylated heterocycles are required for drug discovery.…”

Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic dienes

“…The incorporation of fluorine into molecules can significantly influence their pharmacokinetic and physicochemical properties and enhance their metabolic and chemical stability [1][2][3][4][5]. For instance, nearly a quarter of the currently manufactured agrochemical and pharmaceutical products contains at least one fluorine atom [6][7][8]. Fluorinated functional materials have also found wide application as durable ion exchange membranes, e.g., in fuel cells [9][10][11], as thermoplastic polymers [12][13][14], in electronic and optoelectronic technologies [15], and in liquid crystal display applications [16][17][18][19][20][21], etc [22].…”