Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children.

BACKGROUND: The World Health Organization (WHO) 2019 antiretroviral treatment guidelines recommend use of optimal treatment regimens in all populations. Dolutegravir-based regimens are the preferred first-line and second-line treatment in infants and children with HIV 4 weeks of age and above. There is an urgent need for optimal pediatric formulations of dolutegravir as single-entity (SE) and fixed-dose combination (FDC) to ensure correct dosing and adherence for swallowing and palatability. This article outlines the chronology of dolutegravir pediatric formulation development as granules and conventional and dispersible tablets in a total of 5 pharmacokinetic studies evaluating the relative bioavailability of dolutegravir SE and FDC formulations in healthy adults. METHODS: The relative bioavailability studies were 2-part, Phase I, open-label, randomized studies in healthy adults. Dolutegravir SE study compared conventional dolutegravir 50 and 25 mg with equivalent conventional 10-mg and dispersible 5-mg tablets, respectively. Subsequently, dolutegravir FDC study compared adult FDC of abacavir/dolutegravir/lamivudine and adult FDC of dolutegravir/lamivudine with their respective pediatric FDC formulations, taken as dispersion immediately or swallowed whole. RESULTS: As observed in previous studies, dolutegravir administered as dispersion (granules/dispersible tablets) showed relatively higher bioavailability compared with conventional tablets. The bioavailability of dolutegravir dispersible tablets (both SE and FDC) was approximately 1.6-fold higher when compared with conventional tablets. In addition, the bioavailability of abacavir/lamivudine was not impacted by dispersible formulation. CONCLUSIONS: These studies demonstrate the successful development of pediatric dolutegravir-containing formulations as SE and FDC that permit pediatric dosing in line with WHO recommendations.

Pharmacokinetics, Safety, and Tolerability of a Single Oral Dose of Abacavir/Dolutegravir/Lamivudine Combination Tablets in Healthy Japanese Study Participants.

Pharmacokinetics, safety, and tolerability of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg were assessed in this phase 1, single-arm, open-label, single-dose study in fasted healthy male (n = 4) and female (n = 8) participants of Japanese heritage. Participants received a single dose of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg after an 8-hour fast, with safety assessments and blood samples for pharmacokinetic parameters collected through 72 hours after dosing. Geometric mean maximum plasma concentrations were 5.22 µg/mL (time to maximum concentration [tmax ], 1.01 hours) for abacavir, 4.13 µg/mL (tmax , 3.50 hours) for dolutegravir, and 3.35 µg/mL (tmax , 2.98 hours) for lamivudine. Geometric mean area under the concentration-time curve values were 18.20, 71.60, and 16.60 µg • h/mL for abacavir, dolutegravir, and lamivudine, respectively. No adverse events were reported, and no clinically significant findings were observed in laboratory values, physical examinations, or 12-lead electrocardiographic parameters. Single-tablet administration of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg was well tolerated in Japanese participants. Exposure to abacavir and lamivudine was comparable with that seen in previous studies. A modest increase in exposure to dolutegravir vs previous clinical studies was observed but is not expected to impact the clinical management of HIV-1 or increase the risk for adverse events.

Effects of Low- and High-Mineral Content Water on the Relative Bioavailability of a Coformulated Abacavir/Dolutegravir/Lamivudine Dispersible Tablet in Healthy Adults.

BACKGROUND: The fixed-dose combination (FDC) tablet formulation of abacavir/dolutegravir/lamivudine is indicated for the treatment of HIV-1 infection in adults and pediatric patients weighing ≥40 kg. Alternative formulations with acceptable palatability and convenient dosing are needed for children who require smaller doses and have difficulty swallowing tablets. SETTING: A phase 1, open-label, randomized study was conducted in healthy adults to evaluate the relative bioavailability of a novel dispersible FDC tablet of abacavir 150 mg/dolutegravir 10 mg/lamivudine 75 mg administered under 4 different dosing conditions compared with dolutegravir plus abacavir/lamivudine nondispersible, film-coated tablets. METHODS: The test treatments were 4 dispersible FDC tablets reconstituted in water with high- or zero-mineral content and administered either immediately or after a 30-minute delay. The reference treatment was 4 nondispersible dolutegravir 10-mg tablets plus 1 nondispersible abacavir 600-mg/lamivudine 300-mg tablet administered with zero-mineral content water. The primary endpoints were area under the concentration-time curve from time 0 extrapolated to infinity and the maximum observed plasma concentration. RESULTS: Following administration of dispersible abacavir/dolutegravir/lamivudine, the relative bioavailability of dolutegravir was approximately 50% higher. Abacavir and lamivudine demonstrated bioequivalence when administered as the dispersible FDC tablet compared with coadministration of dolutegravir plus abacavir/lamivudine nondispersible, film-coated tablets. Neither the mineral content of the water nor dosing times affected the pharmacokinetics of individual components. The dispersible tablet was safe and well tolerated, and the palatability was acceptable. CONCLUSIONS: These pharmacokinetic results support further development of a dispersible FDC tablet of abacavir/dolutegravir/lamivudine for future use in pediatric patients.

Population pharmacokinetics modeling and analysis of foretinib in adult patients with advanced solid tumors.

Foretinib is a multikinase inhibitor that inhibits multiple receptor tyrosine kinases, including MET and VEGFR, with the potential for treatment of solid tumors. Hepatocellular carcinoma (HCC) pathogenesis is associated with overexpression of MET, and physiologic changes in the livers of HCC patients may decrease CYP3A isozyme-mediated metabolism of foretinib. A population pharmacokinetic model of foretinib was developed to explore the effect of tumor type, formulation, and other covariates. Data from 1 HCC study in Asia and 3 non-HCC studies in the United States with varying foretinib regimens and formulations were used for analysis. A 2-compartment model with a linear first-order absorption and elimination and lag time in absorption adequately described foretinib pharmacokinetics in 132 advanced non-HCC and HCC patients and identified an effect of formulations on bioavailability. The bisphosphate salt capsules and freebase tablets had a relative bioavailability 37% and 20% higher, respectively, than the solution formulation. HCC patients had ≈19.6% lower mean clearance (70.14 L/h), ≈16% lower mean volume of distribution (1725.6 L), and higher dose-normalized exposure compared with non-HCC patients. This could be a result of differences in metabolism in HCC patients, body weight, or activity of CYP3A isozymes between Asian and Western cancer patients.

Evaluation of in vitro synergy between vertilmicin and ceftazidime against Pseudomonas aeruginosa using a semi-mechanistic pharmacokinetic/pharmacodynamic model.

The aim of this study was to develop a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model to evaluate the in vitro synergy between vertilmicin and ceftazidime against Pseudomonas aeruginosa. The in vitro antimicrobial activity of vertilmicin alone was initially assessed by static and dynamic time-kill experiments against three bacterial strains, including MSSA, MRSA and P. aeruginosa. The combined killing effect with ceftazidime was then evaluated in a static time-kill study against P. aeruginosa. Vertilmicin displayed a concentration-dependent killing effect against the three bacterial strains, and its short half-life may possibly have a dramatic impact on antimicrobial activities. A two-compartment pharmacodynamic model consisting of drug-susceptible and -resistant compartments was developed to characterise the relationship between drug exposure and bacterial response for the time-kill curves from both monotherapy and combination therapy. Loewe additivity was incorporated into the pharmacodynamic model to describe the drug-drug interactive effect in the combination therapy. For monotherapy, the estimated EC50 of the dynamic time-kill study against each strain was close to its MIC but was higher than that of the static time-kill study. The EC50 of combination therapy was estimated at 2.67 mg/L compared with 4.54 mg/L in monotherapy, indicating an enhanced bactericidal capacity. The drug-drug interactive effect was not significantly synergistic but highly varied at each specific combination. Potential synergistic combinations could be screened using PK/PD modelling and simulation. These results demonstrated that PK/PD modelling provides an innovative approach to assist dose selection of combination vertilmicin and ceftazidime for future clinical study design.

Protein binding of rifapentine and its 25-desacetyl metabolite in patients with pulmonary tuberculosis.

Rifapentine is highly protein bound in blood, but the free, unbound drug is the microbiologically active fraction. In this exploratory study, we characterized the free plasma fraction of rifapentine in 41 patients with tuberculosis. We found a lower total rifapentine concentration but significantly higher free rifapentine levels in African patients of black race compared to non-Africans. These data support larger pharmacokinetic/pharmacodynamic studies to confirm these findings and assess free rifapentine in relation to microbiological and clinical outcomes.

Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma.

Standard treatment of transplant-eligible patients with relapsed diffuse large B-cell lymphoma (DLBCL) consists of rituximab and platinum-based chemotherapy, either ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, cytarabine, and cisplatin (DHAP), with autologous transplant consolidation for those with chemosensitive disease. Nonetheless, outcomes are suboptimal for patients failing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We performed a multi-center phase II trial investigating the safety and efficacy of ofatumumab, a monoclonal antibody against CD20, combined with ICE or DHAP second-line therapy in patients with relapsed or refractory DLBCL, grade 3b follicular lymphoma, or transformed follicular lymphoma. Sixty-one patients were treated with either ofatumumab-ICE (35) or ofatumumab-DHAP (26). The overall response rate (ORR) was 61%, and the complete response (CR) rate was 37%. In patients with 2 or 3 adverse risk factors according to the second-line, age-adjusted, international prognostic index, the ORR was 59% and CR 31%, and in patients with early-relapsing or primary refractory disease, the ORR was 55% and CR 30%. Toxicity was largely hematologic, and stem cell mobilization was successful in 43 of 45 patients. Substitution of ofatumumab for rituximab in standard second-line regimens following failure of R-CHOP is a promising approach. This trial was registered at www.clinicaltrials.gov as NCT00823719.

Influence of CYP3A5 6986A > G and ABCB1 3435C > T Polymorphisms on Adverse Events Associated With Tacrolimus in Jordanian Pediatric Renal Transplant Patients.

The aim of the study is to investigate the influence of ABCB1(3435) and CYP3A5(6986) polymorphisms, tacrolimus troughs and clinical factors on the time of adverse events associated with tacrolimus in pediatric kidney transplant patients. Clinical data, adverse events, tacrolimus troughs, corresponding doses, ABCB1 3435C > T and CYP3A5 6986A > G genotypes were collected from 38 pediatric kidney transplant patients in a retrospective study for over 2 years post-transplant. We used a marginal Cox proportional hazard model to evaluate the influence of clinical factors and single nucleotide polymorphisms (SNPs) on tacrolimus-associated adverse events. CYP3A5 genotype, the Bayesian predicted tacrolimus concentrations, hematocrit and mean corpuscular volume are significant risk factors of adverse events over a 2-year-period. CYP3A5*1 genotype was associated with 36% relative risk of CYP3A5*3/*3 genotype. In the 9-month period, the additional factor, ABCB1 3435TT genotype, was shown to be associated with 38% relative risk of the CC and CT genotypes. For graft loss, acute and chronic rejection, only tacrolimus concentration and hematocrit, but not CYP3A5 or ABCB1 polymorphisms, are important factors influencing their occurrences.

Dermal pharmacokinetics of Terpinen-4-ol following topical administration of Zingiber cassumunar (plai) oil.

The purpose of this study was to investigate dermal pharmacokinetics of terpinen-4-ol in rats following topical administration of plai oil derived from the rhizomes of Zingiber cassumunar Roxb. Unbound terpinen-4-ol concentrations in dermal tissue were measured by microdialysis. The dermal pharmacokinetic study of terpinen-4-ol was performed under non-occlusive conditions. The oil was topically applied at a dose of 2, 4, and 8 mg/cm2 plai oil corresponding to the amount of 1.0, 1.9, and 3.8 mg/cm2 terpinen-4-ol, respectively. Following topical application of the oil, terpinen-4-ol rapidly distributed into the dermis and demonstrated linear pharmacokinetics with no changes in the dose-normalized area under the concentration-time curves across the investigated dosage range. The mean percentages of free terpinen-4-ol distributed in the dermis per amount of administered were 0.39 ± 0.06 %, 0.41 ± 0.08 %, and 0.30 ± 0.03 % for 2, 4, and 8 mg/cm2 doses, respectively. The dermal pharmacokinetics of terpinen-4-ol could provide information for its further formulation development and therapy schedules.

The concentration-dependent binding of linagliptin (BI 1356) and its implication on efficacy and safety.

OBJECTIVES: Linagliptin (BI 1356) is a dipeptidyl peptidase-4 (DPP-4) inhibitor for treatment of Type 2 diabetes which recently gained approval in the US, Europe, and Japan. Linagliptin showed nonlinear pharmacokinetics after intravenous and oral administration, which is due to a concentration-dependent protein binding of linagliptin to its target enzyme DPP-4. The aim of this analysis was to investigate this target-mediated binding of linagliptin and its implication on efficacy and safety. METHODS: Pharmacokinetic modeling and simulations were performed using a two-compartment model with concentration-dependent binding in the central and in one peripheral compartment. The optimum therapeutic dose with minimal off-target side effects was simulated assuming that an antidiabetic effect of linagliptin was due to the linagliptin concentration bound to DPP-4 and that off-target side effects were related to free linagliptin. RESULTS: The difference between steady state AUCs of specifically bound and free linagliptin was maximized at oral doses of 2 - 5 mg. Since plasma DPP-4 inhibition increased slightly from 2.5 to 10 mg, pharmacokinetic simulations and the pharmacodynamic measurements taken together suggest that 5 mg linagliptin could be considered an optimum dose. Simulations with missed doses and additional doses at steady state showed the effect on DPP-4 bound linagliptin and change in DPP-4 inhibition was minimal after missing one 5 mg oral dose of linagliptin while two doses of 5 mg linagliptin resulted in a less than proportional increase of steady state AUC of free linagliptin. CONCLUSIONS: Results from modeling and simulation support a stable antidiabetic effect of linagliptin over 24 h at steady state and further indicate a low risk for off-target side effects.

New energetic polynitro cyclic esters: ammonium, hydrazinium, and hydroxylammonim salts of polynitramines.

Reaction of 2,2-dinitro-1,3-propanediol (1) with oxalyl dichloride or malonyl dichloride in refluxing ether led to the formation of cyclic dinitro-containing esters (2, 3) in very good yields. Compounds 2 and 3 were also isolated in similar yields by the treatment of 1 with oxalic acid or malonic acid in trifluoroacetic anhydride at room temperature. Nitration of 3 with fuming nitric acid resulted in the corresponding trinitro cyclic ester 4 in 70% isolated yield. Treatment of 1 with a large excess of methanolic ammonia gave impure 2,2-dinitro-1,3-diaminopropane (5). Polynitraamines, 7 and 11, were treated with aqueous ammonia, hydrazine monohydrate or hydroxylamine in methanol at room temperature to obtain their corresponding salts 8-10 and 12-14, respectively, in excellent isolated yields. All new compounds were characterized by IR, NMR spectroscopy ((1)H, (13)C, (15)N), DSC, and elemental analysis. Their energetic properties, such as impact sensitivity, detonation velocity, and detonation pressure were also determined and compared with existing energetic compounds, such as PETN (pentaerythritol tetranitrate), RDX (1,3,5-trinitro-1,3,5-triazacyclohexane), and TNT (trinitrotoluene).

Repeated pre-exposure to tobacco smoke potentiates subsequent locomotor responses to nicotine and tobacco smoke but not amphetamine in adult rats.

These studies investigated if pre-exposure to tobacco smoke affects the locomotor response to tobacco smoke, nicotine, and amphetamine in adult rats. The rats were habituated to an open field for 3-4 days and then exposed to tobacco smoke for 2h/day for 13-14 days. The effect of exposure to tobacco smoke on locomotor activity was investigated after 1, 7, and 14 days of smoke exposure and after one 2-hour exposure session that followed a 3-week off period. The effects of tobacco smoke on the locomotor responses to nicotine (0.04 and 0.4 mg/kg, base) and amphetamine (0.1 and 0.5mg/kg) were investigated on day 14, one day after the last smoke exposure session. The locomotor response to tobacco smoke was increased after 7 and 14 days of smoke exposure and after one exposure session after the 3-week off-period. The acute administration of the high dose of nicotine (0.4 mg/kg) led to a brief period of hypoactivity that was followed by a period of hyperactivity. Pre-exposure to tobacco smoke attenuated the nicotine-induced hypoactivity and potentiated the nicotine-induced hyperactivity. The low dose of nicotine (0.04 mg/kg) did not affect locomotor activity in the control rats but increased the total distance traveled in the tobacco smoke exposed rats. Exposure to tobacco smoke did not affect the locomotor response to amphetamine. These findings indicate that exposure to tobacco smoke leads to tolerance to the depressant effects of nicotine and potentiates the stimulant effects of nicotine and tobacco smoke.

4-Fluoropyrrolidine-2-carbonyl fluorides: useful synthons and their facile preparation with 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride.

4-Fluoropyrrolidine derivatives are useful in medicinal chemistry applications such as dipeptidyl peptidase IV inhibitors. As attractive synthons for these, N-protected (2S,4S)-4-fluoropyrrolidine-2-carbonyl fluorides were synthesized in high yield by double fluorination of N-protected (2S,4R)-4-hydroxyproline with 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead). The 4-fluoropyrrolidine-2-carbonyl fluorides were converted to useful intermediates such as 4-fluoropyrrolidine-2-carboxamides, -N-methoxy-N-methylcarboxamide (Weinreb amide), -carboxylate methyl esters, and -carbonitriles in excellent yields. The crystalline N-Fmoc-cis-4-fluoropyrrolidine-2-carbonyl fluoride 2a is a particularly useful synthon due to its high yield of preparation and easy isolation as an enantiomerically pure compound by crystallization. Thus, the methodology using the synthons prepared by the stereospecific double fluorination has enabled a significant decrease in the synthetic steps needed for the preparation of the 4-fluoropyrrolidine derivatives useful for medicinal applications.

PA-824 exhibits time-dependent activity in a murine model of tuberculosis.

PA-824 is one of two nitroimidazoles in phase II clinical trials to treat tuberculosis. In mice, it has dose-dependent early bactericidal and sterilizing activity. In humans with tuberculosis, PA-824 demonstrated early bactericidal activity (EBA) at doses ranging from 200 to 1,200 mg per day, but no dose-response effect was observed. To better understand the relationship between drug exposure and effect, we performed a dose fractionation study in mice. Dose-ranging pharmacokinetic data were used to simulate drug exposure profiles. Beginning 2 weeks after aerosol infection with Mycobacterium tuberculosis, total PA-824 doses from 144 to 4,608 mg/kg were administered as 3, 4, 8, 12, 24, or 48 divided doses over 24 days. Lung CFU counts after treatment were strongly correlated with the free drug T(>MIC) (R(2) = 0.87) and correlated with the free drug AUC/MIC (R(2) = 0.60), but not with the free drug C(max)/MIC (R(2) = 0.17), where T(>MIC) is the cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions and AUC is the area under the concentration-time curve. When the data set was limited to regimens with dosing intervals of ≤72 h, both the T(>MIC) and the AUC/MIC values fit the data well. Free drug T(>MIC) of 22, 48, and 77% were associated with bacteriostasis, a 1-log kill, and a 1.59-log kill (or 80% of the maximum observed effect), respectively. Human pharmacodynamic simulations based on phase I data predict 200 mg/day produces free drug T(>MIC) values near the target for maximal observed bactericidal effect. The results support the recently demonstrated an EBA of 200 mg/day and the lack of a dose-response between 200 and 1,200 mg/day. T(>MIC), in conjunction with AUC/MIC, is the parameter on which dose optimization of PA-824 should be based.

Discovery of 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride as a deoxofluorinating agent with high thermal stability as well as unusual resistance to aqueous hydrolysis, and its diverse fluorination capabilities including deoxofluoro-arylsulfinylation with high stereoselectivity.

Versatile, safe, shelf-stable, and easy-to-handle fluorinating agents are strongly desired in both academic and industrial arenas, since fluorinated compounds have attracted considerable interest in many areas, such as drug discovery, due to the unique effects of fluorine atoms when incorporated into molecules. This article describes the synthesis, properties, and reactivity of many substituted and thermally stable phenylsulfur trifluorides, in particular, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead, 1k), as a crystalline solid having surprisingly high stability on contact with water and superior utility as a deoxofluorinating agent compared to current reagents, such as DAST and its analogues. The roles of substituents on 1k in thermal and hydrolytic stability, fluorination reactivity, and the high-yield fluorination mechanism it undergoes have been clarified. In addition to fluorinations of alcohols, aldehydes, and enolizable ketones, 1k smoothly converts non-enolizable carbonyls to CF(2) groups, and carboxylic groups to CF(3) groups, in high yields. 1k also converts C(=S) and CH(3)SC(=S)O groups to CF(2) and CF(3)O groups, respectively, in high yields. In addition, 1k effects highly stereoselective deoxofluoro-arylsulfinylation of diols and amino alcohols to give fluoroalkyl arylsulfinates and arylsulfinamides, with complete inversion of configuration at fluorine and the simultaneous, selective formation of one conformational isomer at the sulfoxide sulfur atom. Considering the unique and diverse properties, relative safety, and ease of handling of 1k in addition to its convenient synthesis, it is expected to find considerable use as a novel fluorinating agent in both academic and industrial arenas.

Energetic nitrogen-rich salts and ionic liquids.

Energetic salts offer many advantages over conventional energetic molecular compounds. The use of nitrogen containing anions and cations contributes to high heats of formations and high densities. Their low carbon and hydrogen content gives rise to a good oxygen balance. The decomposition of these compounds is predominantly through the generation of dinitrogen which makes them very promising candidates for highly energetic materials for industrial or military applications.

Low melting inorganic salts of alkyl-, fluoroalkyl-, alkyl ether-, and fluoroalkyl ether-substituted oxazolidine and morpholine.

N-Alkyl- and N-fluoroalkyl-substituted oxazolidinium- and morpholinium-based quaternary salts and ionic liquids have been synthesized and characterized. Reactions of N-methyloxazolidine (1) or N-methylmorpholine (2) with 3-fluoropropyl bromide or iodopropane in THF at 25 degrees C gave the quaternary salts (3a,b, 4a,b). These salts were metathesized with various metal salts to yield the corresponding ionic liquids (5a-h, 6a-i). N-Alkoxyethyl- and N-(fluoroalkoxy)ethyl-substituted morpholines (8-11) were prepared and quaternized with methyl iodide (8a-11a). Their corresponding ionic liquids (12-18) were obtained by anion exchange and characterized. For both series of compounds, nitrate, hexafluorophosphate, perchlorate, triflate, and bis(trifluoromethanesulfonyl)amide were utilized. Most of the final products are liquids at 25 degrees C and are thermally stable with long liquid ranges as determined by thermal gravimetric analyses. For compounds 12, 16, and 18, thermal stabilities of > or =400 degrees C were observed. All the new compounds were characterized by spectroscopic and elemental analyses. Their densities and viscosities were also determined.

Recent highlights in electrophilic fluorination with 1-chloromethyl-4-fluoro- 1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).

Synthetic and structural aspects of organofluorine compounds continue to be the focal points of vigorous research activities, as evidenced by the appearance of a large number of publications. Among the various useful methodologies for the introduction of fluorine into organic molecules, electrophilic fluorination is a promising and exciting area of research. While a variety of electrophilic fluorinating reagents are available, currently 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) provides a remarkably straightforward and effective route. The breadth of applications realizable from this reagent in its role as a key electrophilic fluorinating reagent is highlighted here. This Account covers the literature for electrophilic fluorination reactions that employ Selectfluor during the period January 1999-January 2003.

Bridged tetraquaternary salts from N,N'-polyfluoroalkyl-4,4'-bipyridine.

4,4'-Bipyridine (1) with excess of polyfluoroalkyl bromide or iodides 2a-d at 100-110 degrees C without solvent gave the monoquaternary salts 3a-d in >90% yields. However, 1 with 2.5 equiv of 2a-c in DMF at 110 degrees C resulted in the diquaternary salts 5a-c in >85% yields. In DMF, 5a-c were obtained in comparable yields when a molar excess of 2a-c reacted with 3a-c. 1,4-Dibromobutane with 3a,b in DMF at 100 degrees C led to the tetraquaternary salts 7a,b in approximately 85% yields. In water or acetone/water as a solvent, salts 3a-d and 5a-c were metathesized with LiN(SO(2)CF(3))(2) and KSO(3)CF(3) to produce monoquaternary ionic liquids 4a-h in >88% yields and diquaternary ionic liquids 6a-f in >86% yields, respectively. Tetraquaternary ionic liquids 8a,b were obtained when LiN(SO(2)CF(3))(2) was reacted with salts 7a,b. These compounds were stable to 340 degrees C as determined by DSC. They are the first N-mono-, N,N'-di-, and N,N,N',N'-tetra-4,4'-polyfluoroalkylbipyridinium quaternary salts and ionic liquids.

Quaternary salts containing the pentafluorosulfanyl (SF5) group.

The first quaternary salts of pyridine (2), N-methyl imidazole (3), N-propyl triazole (4), and pyridazine (5) that contain the pentafluorosulfanyl (SF(5)) group were prepared and characterized. Neat reactions of the aromatic nitrogen compounds with SF(5)(CF(2))(n)(CH(2))(m)I (n = 2 or 4, m = 2 or 4) gave quaternary iodides 6a-c, 7a-c, 8a, and 9a,b, which were metathesized with LiN(SO(2)CF(3))(2) to form the bis(trifluoromethylsulfonyl)amides 10a-c, 11a-c, 12a, and 13a,b, in high yields. With the exception of the pyridine bis(trifluoromethylsulfonyl)amide salts, the compounds melted or exhibited a T(g) at <0 degrees C. The methylimidazolium, pyridinium, and pyridazinium salts exhibited densities of approximately 2 g/cm(3). Particularly striking was the density of CF(3)(CF(2))(5)(CH(2))(2)-pyridazinium N(CF(3)SO(2))(2) measured at 2.13 g/cm(3); however, an atypically high density for the 1-CF(3)(CF(2))(5)(CH(2))(2)-3-methyl imidazolium amide (14) was also observed at 1.77 g/cm(3). All quaternary salts were characterized via IR, (19)F, (1)H, and (13)C NMR spectra and elemental analyses.