Synthesis of [F]xenon difluoride as a radiolabeling reagent from [F]fluoride ion in a micro-reactor and at production scale

[¹⁸F]Xenon difluoride ([¹⁸F]XeF₂), was produced by treating xenon difluoride with cyclotron-produced [¹⁸F]fluoride ion to provide a potentially useful agent for labeling novel radiotracers with fluorine-18 (t_1/2 = 109.7 min) for imaging applications with positron emission tomography. Firstly, the effects of various reaction parameters, for example, vessel material, solvent, cation and base on this process were studied at room temperature. Glass vials facilitated the reaction more readily than polypropylene vials. The reaction was less efficient in acetonitrile than in dichloromethane. Cs⁺ or K⁺ with or without the cryptand, K 2.2.2, was acceptable as counter cation. The production of [¹⁸F]XeF₂ was retarded by K₂CO₃, suggesting that generation of hydrogen fluoride in the reaction milieu promoted the incorporation of fluorine-18 into xenon difluoride. Secondly, the effect of temperature was studied using a microfluidic platform in which [¹⁸F]XeF₂ was produced in acetonitrile at elevated temperature (≥85 °C) over 94 s. These results enabled us to develop a method for obtaining [¹⁸F]XeF₂ on a production scale (up to 25 mCi) through reaction of [¹⁸F]fluoride ion with xenon difluoride in acetonitrile at 90 °C for 10 min. [¹⁸F]XeF₂ was separated from the reaction mixture by distillation at 110 °C. Furthermore, [¹⁸F]XeF₂ was shown to be reactive towards substrates, such as 1-((trimethylsilyl)oxy)cyclohexene and fluorene.     

A practical synthesis of [C4] N-benzylpiperazine from [C2] glycine

A high yielding gram-scale synthesis of [¹³C₄] N-benzylpiperazine for use as a convenient and versatile building block in isotope labeling studies of clinical drug candidates is reported.     

The dimerization and photochemical rearrangement of pentacyclo-[5.4.0.0.0.0]undecane-8-thione

Pentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecan-8-one 1 is readily sulfurated into pentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane-8-thione 2 with Lawesson’s reagent in dry THF. Upon standing at ambient temperature the thione 2 formed the corresponding thio-dimer 3 within 10 days. When the thio-dimer 3 was exposed to oxygen and ultraviolet light an unexpected photochemical oxidation and rearrangement took place to form the stable disulfenate 5.     

Novel fluoro-substituted benzo- and benzothieno fused pyrano[2,3-c]pyrazol-4(1H)-ones

A straightforward, two-step synthesis of fluoro substituted chromeno[2,3-c]pyrazol- and [1]benzothieno[2′,3′:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of 1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with fluoro substituted 2-fluorobenzoyl chlorides or 3-chloro-6-fluoro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were cyclized into the fused ring systems. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one was obtained upon treatment of the 1-(4-methoxybenzyl) protected congener with trifluoroacetic acid. Treatment of 5-fluorochromeno[2,3-c]pyrazol-4(1H)-ones with methylhydrazine afforded novel tetracyclic ring systems such as 2-methyl-7-phenyl-2,7-dihydropyrazolo[4′,3′:5,6]pyrano[4,3,2-cd]indazole. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N, ¹⁹F) with the obtained compounds were undertaken.     

Convenient Synthesis of Pyrazolo[4′,3′:5,6]pyrano[4,3-c][1,2]oxazoles via Intramolecular Nitrile Oxide Cycloaddition

A simple and efficient synthetic route to the novel 3a,4-dihydro-3H,7H- and 4H,7H-pyrazolo[4′,3′:5,6]pyrano[4,3-c][1,2]oxazole ring systems from 3-(prop-2-en-1-yloxy)- or 3-(prop-2-yn-1-yloxy)-1H-pyrazole-4-carbaldehyde oximes has been developed by employing the intramolecular nitrile oxide cycloaddition (INOC) reaction as the key step. The configuration of intermediate aldoximes was unambiguously determined using NOESY experimental data and comparison of the magnitudes of ¹J_CH coupling constants of the iminyl moiety, which were greater by approximately 13 Hz for the predominant syn isomer. The structures of the obtained heterocyclic products were confirmed by detailed ¹H, ¹³C and ¹⁵N NMR spectroscopic experiments and HRMS measurements.     

[F]Fluoromethyl iodide ([F]FCH2I): preparation and reactions with phenol, thiophenol, amide and amine functional groups

In this study, we report the synthesis and reactivity of [¹⁸F]fluoromethyl iodide ([¹⁸F]FCH₂I) with various nucleophilic substrates and the stabilities of [¹⁸F]fluoromethylated compounds. [¹⁸F]FCH₂I was prepared by reacting diiodomethane (CH₂I₂) with [¹⁸F]KF, and purified by distillation in radiochemical yields of 14-31% (n = 25). [¹⁸F]FCH₂I was stable in organic solvents commonly used for labeling and aqueous solution with pH 1-7, but was unstable in basic solutions. [¹⁸F]FCH₂I displayed a high reactivity with various nucleophilic substrates such as phenol, thiophenol, amide and amine. The [¹⁸F]fluoromethylated compounds synthesized by the reactions of phenol, thiophenol and tertiary amine with [¹⁸F]FCH₂I were stable for purification, formulation and storage. In contrast, the [¹⁸F]fluoromethylated compounds synthesized by the reactions of primary or secondary amines, and amide with [¹⁸F]FCH₂I were too unstable to be detected or purified from the reaction mixtures. Defluorination of these [¹⁸F]fluoromethyl compounds was a main decomposition route.     

Efficient alkali iodide promoted F-fluoroethylations with 2-[F]fluoroethyl tosylate and 1-bromo-2-[F]fluoroethane

Radiochemical ¹⁸F-fluorination yields of several compounds using the secondary labelling precursors 2-[¹⁸F]fluoroethyl tosylate ([¹⁸F]FETos) and 1-bromo-2-[¹⁸F]fluoroethane ([¹⁸F]BFE) could be considerably enhanced by the addition of an alkali iodide. The radiochemical yield of [¹⁸F]fluoroethyl choline for example could be doubled with [¹⁸F]BFE and increased from 13% to ≈80% with [¹⁸F]FETos. By addition of alkali iodide to the precursor, the ¹⁸F-fluoroethylation yields of established radiopharmaceuticals, especially in the case of automated syntheses, could be significantly increased without major changes of the reaction conditions.     

An unexpected synthesis of 7-azidofurazano[3,4-b]tetrazolopyrazine

In the course of our program focused on the preparation of high-nitrogen content heterocyclic compounds, we wish to report an original synthesis of the tricyclic 7-azidofurazano[3,4-b]tetrazolopyrazine via an unprecedented reaction between 2,6-dimethoxy-3,5-dinitropyrazine and hydrazine hydrate. This compound was identified by an X-ray diffraction analysis. Further studies of its structure by ¹⁵N and ¹³C NMR spectroscopy were carried out in different solvents. This allowed us to observe a noteworthy equilibrium involving three forms resulting from the reversible opening of a tetrazole ring.     

Low-temperature heat capacity and thermodynamic properties of endo-Tricyclo[5.2.1.0]decane

Endo-Tricyclo[5.2.1.0^2,6]decane (CAS 6004-38-2) is an important intermediate compound for synthesizing diamantane. The lack of data on the thermodynamic properties of the compound limits its development and application. In this study, endo-Tricyclo[5.2.1.0^2,6]decane was synthesized and the low temperature heat capacities were measured with a high-precision adiabatic calorimeter in the temperature range from (80 to 360) K. Two phase transitions were observed: the solid-solid phase transition in the temperature range from (198.79 to 210.27) K, with peak temperature 204.33 K; the solid-liquid phase transition in the temperature range from 333.76 K to 350.97 K, with peak temperature 345.28 K. The molar enthalpy increments, ΔH_m, and entropy increments, ΔS_m, of these phase transitions are ΔH_m=2.57 kJ · mol⁻¹ and ΔS_m=12.57 J · K⁻¹ · mol⁻¹ for the solid-solid phase transition at 204.33 K, and, Δ_fusH_m=3.07 kJ · mol⁻¹ and Δ_fusS_m=8.89 J · K⁻¹ · mol⁻¹ for the solid-liquid phase transition at 345.28 K. The thermal stability of the compound was investigated by thermogravimetric analysis. TG result shows that endo-Tricyclo[5.2.1.0^2,6]decane starts to sublime at 300 K and completely changes into vapor when the temperature reaches 423 K, reaching the maximal rate of weight loss at 408 K.     

Heptacoordinated diphenyllead; hexa- and pentacoordinated triphenyllead and tin compounds derived from 5H-benzimidazo[1,2-c]quinazoline-6-thione

Heptacoordinated diphenyllead; hexa- and pentacoordinated triphenyllead and tin compounds derived from 5H-benzimidazo[1,2-c]quinazoline-6-thione are reported. The same molecular structures were found in solution by ¹¹⁹Sn and ²⁰⁷Pb NMR and in the solid state by X-ray diffraction analysis. The ligand was bound through S and N giving a four-membered ring. Due to the tension of the chelate ring in the penta- and hexacoordinated compounds, the nitrogen approaches the metal atom from an oblique direction giving a weak coordination. Hexacoordinated metal atoms were obtained by Lewis bases coordination to the polycyclic tin and lead compounds, which was possible because the M-phenyl groups form a cavity that allows the bases to approach from the opposite direction to the sulfur atom. In some crystals, two molecules formed a cavity where a solvent molecule was included. A heptacoordinated diphenyllead bound to two ligands and having the less common pentagonal bipyramidal geometry and cis-mer configuration with two sulfur atoms lying very close together was obtained.     

Structural investigations on diorgano- and triorganotin(IV) derivatives of [meso-tetra(4-sulfonatophenyl)porphine] metal chlorides

Several new complexes of organotin(IV) moieties with MCl_n[meso-tetra(4-sulfonatophenyl)porphine], (R₂Sn)₂MCl_n[meso-tetra(4-sulfonatophenyl)-porphinate]s and (R₃Sn)₄MCl_n [meso-tetra(4-sulfonatophenyl)porphinate]s, [M = Fe(III), Mn(III): n = 1, R = Me, n-Bu; Ph; M = Sn(IV): n = 2, R = Me, n-Bu] have been synthesized and their solid state configuration investigated by infrared (IR) and Mössbauer spectroscopy, and by ¹H and ¹³C NMR in D₂O.The electron density on the metal ion coordinated inside the porphyrin ring is not influenced by the organotin(IV) moieties bonded to the oxygen atoms of the side chain sulfonatophenyl groups, as it has been inferred on the basis of Mössbauer spectroscopy and, in particular, from the invariance of the isomer shift of the Fe(III) and Sn(IV) atoms coordinated into the porphyrin square plane of the newly synthesized complexes, with respect to the same atoms in the free ligand.As far as the coordination polyhedra around the peripheral tin atoms are concerned, infrared spectra and experimental Mössbauer data would suggest octahedral and trigonal bipyramidal environments around tin, in polymeric configurations obtained, respectively, in the diorganotin derivatives through chelating or bridging sulfonate groups coordinating in the square plane, and in triorganotin(IV) complexes through bridging sulfonate oxygen atoms in axial positions.The structures of the (Me₃Sn)₄Sn(IV)Cl₂[meso-tetra(4-sulfonatophenyl)porphinate] and of the two model systems, Me₃Sn(PS)(HPS) and Me₂Sn(PS)₂ [HPS = phenylsulfonic acid], have been studied by a two layer ONIOM method, using the hybrid DFT B3LYP functional for the higher layer, including the significant tin environment. This approach allowed us to support the structural hypotheses inferred by the IR and Mössbauer spectroscopy analysis and to obtain detailed geometrical information of the tin environment in the compounds investigated.¹H and ¹³C NMR data suggested retention of the geometry around the tin(IV) atom in D₂O solution.     

[1,3]Dioxolo[5,6][1]benzothieno[2,3-c]-quinolin-6(5H)-ones

Summary The reaction of 3,4-methylenedioxycinnamic acid (1) with thionyl chloride resulted in the formation of 7-chlorothieno[2,3-f]-1,3-benzodioxole-6-carbonyl chloride (2) and cinnamoyl chloride (3). Subsequent reaction of the former withp-substituted anilines led to the formation of 7-chloro-N-(p-substituted phenyl)-thieno[2,3-f]-1,3-benzodioxole-6-carboxamides (4a–c) which on photocyclization afforded 2-substituted [1,3]dioxolo[5,6][1]benzothieno[2,3-c]quinolin-6(5H)-ones (5a–c) in fairly good yields and high purity. The structures have been confirmed by IR,¹H NMR, and analytical methods.Accepted for presentation at the Hong Kong International Symposium on Heterocyclic Chemistry (August 13–16, 1995)     

Highly regioselective synthesis of trifluoromethyl derivatives of pyrazolo[1,5-a]pyrimidines bearing fused cycloalkane rings using (2-ethoxycycloalkenyl)-2,2,2-trifluoroethanones

8-Trifluoromethyl-6,7-dihydro-5H-1,4,8a-triaza-s-indacene and 9-trifluoromethyl-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolines were efficiently generated by condensation of 5(3)-aminopyrazoles with (2-ethoxycycloalkenyl)-2,2,2-trifluoroethanones and isolated in excellent yields. The regiochemistry of the prepared compounds was established by ¹H, ¹³C and ¹⁹F NMR spectroscopy and X-ray diffraction analysis.     

Production of 6-l-[18F]Fluoro-m-tyrosine in an Automated Synthesis Module for 11C-Labeling

6-l-[¹⁸F]Fluoro-m-tyrosine (6-l-[¹⁸F]FMT) represents a valuable alternative to 6-l-[¹⁸F]FDOPA which is conventionally used for the diagnosis and staging of Parkinson’s disease. However, clinical applications of 6-l-[¹⁸F]FMT have been limited by the paucity of practical production methods for its automated production. Herein we describe the practical preparation of 6-l-[¹⁸F]FMT using alcohol-enhanced Cu-mediated radiofluorination of Bpin-substituted chiral Ni(II) complex in the presence of non-basic Bu₄ONTf using a volatile iPrOH/MeCN mixture as reaction solvent. A simple and fast radiolabeling procedure afforded the tracer in 20.0 ± 3.0% activity yield within 70 min. The developed method was directly implemented onto a modified TracerLab FX C Pro platform originally designed for ¹¹C-labeling. This method enables an uncomplicated switch between ¹¹C- and ¹⁸F-labeling. The simplicity of the developed procedure enables its easy adaptation to other commercially available remote-controlled synthesis units and paves the way for a widespread application of 6-l-[¹⁸F]FMT in the clinic.     

Unusual ring-chain tautomerism in bicyclo[4.2.0]octane derivatives

A new type of ring-chain tautomerism, which consists of the reversible conversion of bicyclo[4.2.0]octane derivatives into trisubstituted enamines was found and studied by ¹H NMR spectroscopy. The starting materials were prepared by the stereoselective reaction of (E)-3,3,3-trichloro-1-nitropropene with cyclohexanone enamines.     

Synthesis and characterization of some novel cadmium(II) complexes with 3-hydroxypicolinic acid (3-OHpicH): Crystal and molecular structures of [CdI(3-OHpic)(3-OHpicH)(H2O)]2, [Cd(3-OHpic)2(H2O)2] and [Cd(3-OHpic)2]n

Cadmium(II) complexes of 3-hydroxypicolinic acid, namely [CdI(3-OHpic)(3-OHpicH)(H₂O)]₂ (1), [Cd(3-OHpic)₂(H₂O)₂] (2) and [Cd(3-OHpic)₂]_n (3) were prepared and characterized by spectroscopic methods (IR, NMR) and their molecular and crystal structures were determined by X-ray crystal structure analysis. Complexes 1 and 2 were prepared in similar reaction conditions using different cadmium(II) salts: cadmium(II) iodide and cadmium(II) acetate dihydrate, respectively, while 3 was prepared by recrystallization of 2 from N,N-dimethylformamide solution. Various coordination modes of 3-OHpicH in 1–3 were established in the solid state: bidentate N,O-chelated mode in 1 and 2, monodentate mode through the carboxylate O atom from zwitterionic ligand in 1 and bidentate N,O-chelated and bridging mode in 3. In the DMF solution of all prepared complexes, only monodentate mode of 3-OHpicH binding to cadmium(II) through the carboxylate O atom was established by ¹H, ¹³C, ¹⁵N and ¹¹³Cd NMR spectroscopy.     

The association constants of Na(+) with dibenzo[3n]crown-n in THF/water using ISE

The Na⁺ association constants, K₁₁ and β₁₂, of 1/1 and 1/2 stoichiometry of macrocycles of (1,2)dibenzo[15]crown-5, (1,3)dibenzo[18]crown-6, (1,4)dibenzo[21]crown-7, (2,3)dibenzo[21]crown-7, (2,4)dibenzo[24]-crown-8 and dicyclohexano[24]crown-8 were determined in THF/water, (50/50), mixtures. We used a Methrom Na⁺ ISE for the potentiometric measurements and applied the 1/(β_nm[A_o⁺])^n+m−1=(1−nP_c)(1−mP_c)/P_c equation where the P_c=P/[1+(m−1)P] and P is the mole fraction of the complexed cation, [A_n⁺L_m] for association constants with linear best fit. Results were in well agreement with the macrocyclic size and cation radii relationships. Measurements showed the role of aromatic groups of macrocyclics in THF/water (50/50) which allowed the macrocyclic molecules more selectively bind Na⁺ compared to the associations those obtained in water.     

The Synthesis of Dibenzo[3n]crown-n by Novel Methods and their Cation Binding Studied by Fluorescence Spectroscopy. Part IV

The dibenzo[3n]crown-n were synthesised from1,2-bis(o-hydroxyphenoxy)ethane obtained from 1,2-bis(o-formylphenoxy)ethane via Bayer-Willigeroxidations with H₂O₂/CH₃COOH in good yields. The cyclic condensation of 1,2-bis(o-hydroxyphenoxy)ethanewith dichlorides, and ditosylates of polyethylene glycols in DMF/Me₂CO₃ gave the macrocyclesdibenzo[15]crown-5, dibenzo[18]crown-6, dibenzo[21]crown-7 anddibenzo[24]crown-8. The structures were identified using IR, mass, ¹H and ¹³C NMR spectroscopy. Therecognition of the molecules for the cations, Li⁺, Na⁺, K⁺, Rb⁺ and Zn²⁺were conducted quantitatively with steady state fluorescencespectroscopy. The 1:1 association constants in acetonitrileshowed a good relation of the appropriate size of the macrocyclic ether towards the fitting cationradii. Namely, dibenzo[15]crown-5 was the best for Li⁺ binding and more than 100 times better thanNa⁺ and K⁺. Dibenzo[21]crown-7 was excellent for Rb⁺ binding while K⁺ is 100 timesless preferred. The largest crown ether studied, dibenzo[24]crown-8, exhibited the order of binding power,Rb⁺ > K⁺ > Na⁺. Zn²⁺ displayed, however, a marked binding with only dibenzo[18]crown-6.p>     

[60]Fullerene diol issued from pentaerythritol derivatives

A new [60]fullerene diol is synthesized in good yield, in two steps starting from reaction of C₆₀²⁻ anion with the benzylideneacetal derived from 2,2-bis(iodomethyl)-1,3-propanediol. The corresponding [60]fullerene bis-mesylate is also formed in a similar way starting from bis-iodo bis-mesylate compound in the same series. The scope of this fullerene diol in synthesis is exemplified by its easy esterification with 4-formyl benzoyl chloride.     

Separation of 44Sc from 44Ti in the Context of A Generator System for Radiopharmaceutical Purposes with the Example of [44Sc]Sc-PSMA-617 and [44Sc]Sc-PSMA-I&T Synthesis

Today, ⁴⁴Sc is an attractive radionuclide for molecular imaging with PET. In this work, we evaluated a ⁴⁴Ti/⁴⁴Sc radionuclide generator based on TEVA resin as a source of ⁴⁴Sc. The generator prototype (5 MBq) exhibits high ⁴⁴Ti retention and stable yield of ⁴⁴Sc (91 ± 6 %) in 1 mL of eluate (20 bed volumes, eluent—0.1 M oxalic acid/0.2 M HCl) during one year of monitoring (more than 120 elutions). The breakthrough of ⁴⁴Ti did not exceed 1.5 × 10⁻⁵% (average value was 6.5 × 10⁻⁶%). Post-processing of the eluate for further use in radiopharmaceutical synthesis was proposed. The post-processing procedure using a combination of Presep^® PolyChelate and TK221 resins made it possible to obtain ⁴⁴Sc-radioconjugates with high labeling yield (≥95%) while using small precursor amounts (5 nmol). The proposed method takes no more than 15 min and provides ≥90% yield relative to the ⁴⁴Sc activity eluted from the generator. The labeling efficiency was demonstrated on the example of [⁴⁴Sc]Sc-PSMA-617 and [⁴⁴Sc]Sc-PSMA-I&T synthesis. Some superiority of PSMA-I&T over PSMA-617 in terms of ⁴⁴Sc labeling efficiency was demonstrated (likely due to presence of DOTAGA chelator in the precursor structure). It was also shown that microwave heating of the reaction mixture considerably shortened the reaction time and improved radiolabeling yield and reproducibility of [⁴⁴Sc]Sc-PSMA-617 and [⁴⁴Sc]Sc-PSMA-I&T synthesis.