ChemInform Abstract: Asymmetric Synthesis and Biological Evaluation of β‐L‐(2R,5S)‐ and α‐L‐(2R,5R)‐1,3‐Oxathiolane‐Pyrimidine and ‐Purine Nucleosides as Potential Anti‐HIV Agents.

Jeong, Lak Shin; Schinazi, Raymond F.; Beach, Joseph Warren; Kim, H. O.; Nampalli, Satyanarayana; Shanmuganathan, K.; Alves, A. J.; McMillan, A; Chu, C. K.; Mathis, R

doi:10.1002/chin.199408291

Cited by 2 publications

(3 citation statements)

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“…N-(1-(2-(((tert-Butyldiphenylsilyl)oxy)methyl)-1,3-oxathiolan-5yl)-2-oxo-1,2-dihydropyrimidin-4-yl)acetamide (14). 11 In a 2-dram vial, N,O-bis(trimethylsilyl)acetamide (34 μL, 0.14 mmol) was added to a suspension of 19 (14 mg, 0.088 mmol) in CH 2 Cl 2 (2 mL). The mixture was warmed to 40 °C in a heat block until a clear solution was observed (5c).…”

Section: -((Tert-butyldiphenylsilyl)oxy)acetaldehyde (22)mentioning

confidence: 99%

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Synthesis of (±)-Emtricitabine and (±)-Lamivudine by Chlorotrimethylsilane–Sodium Iodide-Promoted Vorbrüggen Glycosylation

et al. 2022

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By simply adding water and sodium iodide (NaI) to chlorotrimethylsilane (TMSCl), promotion of a Vorbrüggen glycosylation en route to essential HIV drugs emtricitabine (FTC) and lamivudine (3TC) is achieved. TMSCl-NaI in wet solvent (0.1 M water) activates a 1,3-oxathiolanyl acetate donor for N-glycosylation of silylated cytosine derivatives, leading to cis oxathiolane products with up to 95% yield and >20:1 dr. This telescoped sequence is followed by recrystallization and borohydride reduction, resulting in rapid synthesis of ()-FTC/3TC from an achiral tartrate ester. Table 2. Screening of recrystallization conditions for glycosylation product 17. Solvent* soluble at rt? soluble with heating? crystallization observed? MeCN/hex 1:1 Yes Yes No IPA/hex 1:1 No Yes No IPA/hex 2:1 No Yes No IPA/hex 1:2 No Yes at -20˚C EA/hex 1:1 No Yes at -20˚C EA/hex 1:2 No Yes at rt* MeCN = acetonitrile, IPA = isopropanol, EA = ethyl acetate, hex = hexanes. 17 (10 mg, 0.03 mmol) was added to a vial and solvent (1 mL) was added. The resulting mixture was heated with a heat gun until dissolution was observed and monitored for 24 h at room temperature, then moved to -20 ˚C for 24 h.

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Section: -((Tert-butyldiphenylsilyl)oxy)acetaldehyde (22)mentioning

confidence: 99%

“…(4-Acetamido-2-oxopyrimidin-1(2H)-yl)-1,3-oxathiolane-2-carboxylate(11). Iodine (457 mg, 1.8 mmol) was suspended in CH 2 Cl 2 (20 mL), and triethylsilane (575 μL, 3.6 mmol) was added.…”

mentioning

confidence: 99%

Synthesis of (±)-Emtricitabine and (±)-Lamivudine by Chlorotrimethylsilane–Sodium Iodide-Promoted Vorbrüggen Glycosylation

et al. 2022

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“…Structure-activity relationships (SAR) disclosed that fluorine substitution at C5-of the cytosine moiety is essential for the anti-HIV activity (13, anti-HIV-1 in PBM cells, EC50 = 1.3 nM). More than 2 x 10 3 fold lower activity was found when the fluorine atom was replaced by chlorine at C5 (13A, EC50 = 31.8 μM) [114]. The process for the preparation of emtricitabine ( 13) is presented in Scheme 30 [115], and An enzymatic kinetic resolution process has also been developed for the preparation of emtricitabine (13).…”

Section: Emtricitabinementioning

confidence: 99%

Next generation organofluorine containing blockbuster drugs

Han

Remete

Dobson

et al. 2020

Journal of Fluorine Chemistry

227

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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].

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ChemInform Abstract: Asymmetric Synthesis and Biological Evaluation of β‐L‐(2R,5S)‐ and α‐L‐(2R,5R)‐1,3‐Oxathiolane‐Pyrimidine and ‐Purine Nucleosides as Potential Anti‐HIV Agents.

Cited by 2 publications

References 1 publication

Synthesis of (±)-Emtricitabine and (±)-Lamivudine by Chlorotrimethylsilane–Sodium Iodide-Promoted Vorbrüggen Glycosylation

Synthesis of (±)-Emtricitabine and (±)-Lamivudine by Chlorotrimethylsilane–Sodium Iodide-Promoted Vorbrüggen Glycosylation

Next generation organofluorine containing blockbuster drugs

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