Synthesis of <Superscript>14</Superscript>C analogue of 1,2-diaryl-[2-<Superscript>14</Superscript>C]-pyrroles

Three 1,2-diaryl pyrroles selective COX-2 inhibitors, 2-(4-fluorophenyl)-5-methyl-1-(4-methylsulfonyl-phenyl)-1H pyrrole, 2-(4-fluorophenyl)-1-[4-(methylsulfonyl) phenyl]-1H-pyrrole and 4-[2-(4-fluorophenyl)-1H-pyrrol-1-yl]benzenesulfon-amide, all three labeled with ¹⁴C in the 2-position were prepared from para-fluoro-benzaldehyde-[carbonyl-¹⁴C].     

Facile conversion of [1-<Superscript>14</Superscript>C]lauronitrile to [1-<Superscript>14</Superscript>C]lauric acid under microwave irradiation

Summary A highly efficient and an optimized synthesis of [1-¹⁴C]lauric acid with high specific activity (50 mCi/mmol) is described. [1-¹⁴C]lauric acid was prepared from [1-¹⁴C]lauronitrile, in 2 minutes with a mixture of concentrated hydrochloric acid: propionic acid (1: 2 v/v) under microwave irradiation, in quantitative yield.     

A facile synthesis of 4,6-dimethoxy-[2-<Superscript>14</Superscript>C]-2-methylsulphonylpyrimidine

Summary 4,6-dimethoxy-2-methylsulphonylpyrimidine is a key intermediate for the synthesis of pyrithiobac-sodium, a selective herbicide for cotton plant. ¹⁴C labeled pyrithiobac-sodium is required for studying the translocation and metabolism in cotton plants. It was prepared by oxidation of 4,6-dimethoxy-[2-¹⁴C]-2-methylmercaptopyrimidine with H₅IO₆/CrO₃ in ethyl acetate at room temperature to give 4,6-dimethoxy-[2-¹⁴C]-2-methylsulphonylpyrimidine in high yields.     

A facile preparation of ammonium [<Superscript>14</Superscript>C]thiocyanate

Summary An attractive and simple method has been developed for the preparation of ammonium [¹⁴C]thiocyanate from [¹⁴C]thiourea which eliminates the necessity of handling highly hazardous potassium [¹⁴C] cyanide. [¹⁴C]thiourea was isomerized to ammonium [¹⁴C]thiocyanate by heating the aqueous solution of thiourea (12%) in a sealed tube at 160 °C for 24 hours. The product formed was purified by silica-gel column chromatography. A radiochemical yield of 92.7% was obtained based on [¹⁴C]thiourea. The specific activity of the product obtained was 53.3 mCi/mmol (1.97 GBq/mmol) and the radiochemical purity was greater than 99%. This method has not been reported so far for the production of this labeled compound.     

Synthesis of <Emphasis Type="Italic">O</Emphasis>-[2-[<Superscript>18</Superscript>F]fluoro-3-(2-nitro-1<Emphasis Type="Italic">H</Emphasis>-imidazole-1-yl)propyl]tyrosine ([<Superscript>18</Superscript>F]FNT]) as a new class of tracer for imaging hypoxia

For detection of hypoxic tumor tissue, all radiotracers synthesized until now, are based on the concept that cellular uptake is being controlled by diffusion. As a new approach, we chose the concept to have the tracer hypothetically transported into the cells by well known carrier systems like the amino acid transporters. For this purpose, radiosynthesis of O-[2-[¹⁸F]fluoro-3-(2-nitro-1H-imidazole-1yl)propyl]tyrosine ([¹⁸F]FNT]) was carried out from methyl 2-(benzyloxycarbonyl)-3-(4-3-(2-nitro-1H-imidazol-1-yl)-2-(tosyloxy)propoxy) phenyl)propanoate via no-carrier-added nucleophilic aliphatic substitution. After labelling, 81 ± 0.9% of labelled intermediate i.e. methyl 2-(benzyloxycarbonyl)-3-(4-(2-[¹⁸F]fluoro-3-(2-nitro-1H-imidazole-1-yl)propoxy) phenyl)propanoate was obtained at 140 °C. At the end of radiosynthesis, [¹⁸F]FNT was obtained in an overall radiochemical yield of 40 ± 0.9% (not decay corrected) within 90 min in a radiochemical purity of >98% in a formulation ready for application in the clinical studies for PET imaging of hypoxia.     

Autoradiolysis of the 2-deoxy-2-[<Superscript>18</Superscript>F]fluoro-D-glucose radiopharmaceutical

Summary To control virtually the toxic compounds and to improve quality control of the solution of 2-deoxy-2-[¹⁸F]fluoro-d-glucose (2-[¹⁸F]FDG), the products of its autoradiolysis were analyzed by high-performance liquid chromatography with electrospray mass spectrometric and radiometric detectors (HPLC/MS/RAD), thin layer chromatography on TLC silica plate and HPTLC on amino modified silica plate. Except Kryptofix^™ 2.2.2, glucose and fluoride anion, no by-products and impurities were observed by LC/MS analysis of fresh 2-[¹⁸F]FDG samples. The analysis performed in the time interval of 6 to 48 hours after the end of 2-[¹⁸F]FDG synthesis indicated that the activity of the autoradiolysis products separated by HPLC did not exceed 1.3%. As the main autoradiolysis products of 3.3 ^. 10^-5 to 4.4 ^. 10^-5M 2-[¹⁸F]FDG solution of original specific activity 0.5-1.5 GBq ^. cm^-3 were established: arabinose - 2.8 μM (G= 0.07/100 eV), gluconic and glucuronic acids 1.8-0.5 μM (G =0.01-0.05/100 eV), arabinose and araburonic acids occurred under 0.5 μM concentration at residual glucose contents about 0.14 mM. Radiation chemical yields of active products were calculated from molar activity of 2-[¹⁸F]FDG and the percentage of their activity: 0.5% radiochemical yield of 2-[¹⁸F]fluoroglucuronic acid corresponds to the G = 0.004/100 eV and 0.3% yield of 2-[¹⁸F]fluorogluconic acid issues G = 0.003/100 eV.     

An improved method for the preparation of [<Superscript>14</Superscript>C]thiourea of high radiochemical purity

Summary An improved method for the preparation of [¹⁴C]thiourea of high radiochemical purity is described. [¹⁴C]thiourea is prepared by the barium cyanamide route and is purified by vacuum-sublimation. The labeled product showed ammonium [¹⁴C]thiocyanate as a radiochemical impurity in the range of 2-4%. This was further purified by silica-gel column chromatography to get the product having more than 99% radiochemical purity.     

Nucleophilic aromatic substitution by [<Superscript>18</Superscript>F]fluoride at substituted 2-nitropyridines

For the radiofluorination of benzenes and benzene derivatives, the electrophilic reaction with [¹⁸F]F₂ is a very common route. Yet, aromatic nucleophilic substitution (S_NAr) by n.c.a [¹⁸F]fluoride, which can be produced efficiently in high amounts, has been considered to be very desirable. However, to facilitate ¹⁸F-labelling via S_NAr at an electron rich aromatic system, an appropriate leaving group must be present together with an auxiliary group in ortho or para position to the leaving group. An interesting alternative for the auxiliary group is the heteroatom of a heteroaromatic system, for which pyridine is a leading example. Dolci et al. (J Label Compd Radiopharm 42:975–985, 1999) have evaluated the scope of the nucleophilic aromatic fluorination of 2-substituted pyridine rings using the activated K [¹⁸F]F-K₂₂₂ complex. As methyl and methoxy groups are known to enhance the electron density of an aromatic system by the +I and the +M effect, respectively, S_NAr is unlikely to occur. Until now, the effect of these substituents has not been studied towards the ¹⁸F-radiofluorination of substituted 2-nitropyridines by use of [¹⁸F]fluoride. Therefore, we have investigated the effect of methoxy and methyl groups in 2-nitropyridines. The results showed that 3-methoxy-2-nitropyridine and 3-methyl-2-nitropyridine can efficiently be substituted by [¹⁸F]fluoride with high RCY’s (70–89%) in short reaction times (1–30 min) at a reaction temperature of 140 °C. Moreover, 3-methoxy-6-methyl-2-[¹⁸F]fluoropyridine was obtained from the corresponding nitro-precursor in a high yield of 81 ± 1% after 30 min at 140 °C. In case of 2-nitropyridines data indicates the effect of methyl and methoxy groups on S_NAr to be of minor importance.     

Chemo-, regio-, and stereoselectivity in acid-catalyzed hydromethoxylation of tricyclo[4.1.0.0<Superscript>2,7</Superscript>]hept-1-yl and 7-methyltricyclo[4.1.0.0<Superscript>2,7</Superscript>]hept-1-yl phenyl sulfones

Hydromethoxylation of tricyclo[4.1.0.0^2,7]hept-1-yl and 7-methyltricyclo[4.1.0.0^2,7]hept-1-yl phenyl sulfones with methanol at 20°C in the presence of a catalytic amount of perchloric acid is initiated by the endo attack of proton at the C¹ atom, and the subsequent cleavage of the side C¹–C² bond leads to formation of mixtures of diastereoisomeric exo-7-phenylsulfonyl-2-methoxybicyclo[4.1.0]heptanes, the endo-2 isomer prevailing. Probable factors responsible for the observed chemo-, regio-, and stereoselectivity of the addition are discussed.     

Synthesis of a <Superscript>14</Superscript>C analogue of N-(3,5-dichlorobenzyl)-4-(fluoromethoxy) benzene carboximidamide-[carboxy-<Superscript>14</Superscript>C] as NR2B-selective NMDA receptor antagonist

N-(3,5-Dichlorobenzyl)-4-(fluoromethoxy) benzenecarboximidamide labeled with carbon-14 was prepared from 4-hydroxy-benzonitrile-[cyano-¹⁴C].     

Synthesis of 2-dichloromethyl-2-methyl [2-14C]-1,3-dioxolane

The labelled compound was prepared by chlorination of [2-¹⁴C]acetone obtained from the barium salt of [1-¹⁴C]acetic acid by pyrolysis. The reaction product 1,1-dichloro [2-¹⁴C]acetone was converted to 2-dichloromethyl-2-methyl [2-¹⁴C]-1,3-dioxolane by condensation with ethylene glycol in the presence of thionyl chloride. Radiochemical yield: 62% based on [1-¹⁴C]acetic acid.     

Glycosylation of Bovine Serum Albumin with D-[<Superscript>14</Superscript>C]-Glucose

Certain parameters of the Maillard reaction between bovine serum albumin (BSA) and D-[¹⁴C]-glucose were investigated.__________Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 275–277, May–June, 2005.     

Synthesis of 24-Methylidene[24-14C]- and 24-Methylidene[7-3H]cholesterol

The syntheses of 24-methylidene[24-¹⁴C]cholesterol ( 7a ) and of 24-methylidene[7-³H]cholesterol ( 7b ) from commercially available (20S)-3-oxopregn-4-ene-20-carbaldehyde ( 1 ) are described. The method also provides simple preparations of 3β-acetoxy[24-¹⁴C]chol-5-en-24-oic acid ( 4 ) and 24-oxocholest-5-en-3β-yl acetate ( 6b ).     

Microwave assisted reactions of 2-[3-(Trifluoromethyl)phenyl]-4-R<Superscript>1</Superscript>-furo[3,2-<Emphasis Type="Italic">b</Emphasis>] pyrrole-5-carboxhydrazides

The effect of microwave irradiation on the reactions of 2-[3-(trifluoromethyl)phenyl]-4-R¹-furo[3,2-b]pyrrole-5-carboxhydrazides 1 with 5-arylfuran-2-carboxaldehydes 2, thiophene-2-carboxaldehyde (3) and methyl 2-formylfuro[3,2-b]pyrrole-5-carboxylates 4 has been studied. Reactions of 1 with formic and acetic acid, respectively, led to acylhydrazides 9a–c. Reaction of 1a with 4-substituted 1,3-oxazol-5(4H)-one 10 led to imidazole derivative 13. 1,2,4-Triazole-3-thiones 15a,b were synthesized by two-step reaction of 1a with potassium isothiocyanate and phenyl isothiocyanate, respectively, and subsequent base-catalyzed cyclization of thiosemicarbazides 14a,b. Pyrazole 16 was prepared by reaction of 1a with pentane-2,4-dione.      

Synthesis of 1-(4-methylsulfone-phenyl)-5-(4-fluoro-phenyl)-5-[14C]-1,2,3-triazole and 1-(4-sulfonamide-phenyl)-5-(4-fluoro-phenyl)-5-[14C]-1,2,3-triazole as novel carbon-14 anticonvulsant

Summary Two 1,2,3-triazole anticonvulsants, 1-(4-methylsulfone-phenyl)-5-(4-fluoro-phenyl)-5-[¹⁴C]-1,2,3-triazole and 1-(4-sulfonamide-phenyl)-5-(4-fluoro-phenyl)-5-[¹⁴C]-1,2,3-triazole, both labeled with carbon-14 in the 5-position were prepared from para-fluoro-benzonitrile-[cyano-¹⁴C].     

Products and mechanism of some halogenation reactions of 1-sulfonyl-substituted tricyclo[4.1.0.0<Superscript>2,7</Superscript>]heptanes

Reactions of 1-methylsulfonyl- and 1-phenylsulfonyltricyclo[4.1.0.0^2,7]heptanes with iodine, dioxane dibromide, and dichloro-λ³-iodanylbenzene (under irradiation) gave products of stereoselective syn addition of halogen at the C¹–C⁷ central bicyclobutane bond. 7-Methyl-1-phenylsulfonyltricyclo[4.1.0.0^2,7]-heptane reacted with dioxane dibromide in carbon tetrachloride to produce a mixture of 2-bromo- and 2,3-dibromo-1-methyl-exo-7-phenylsulfonylnorcaranes at a ratio of 1: 4 as a result of cleavage of the C¹–C² bicyclobutane bond. 7-Bromo- and 7-methoxycarbonyl-1-phenylsulfonyltricyclo[4.1.0.0^2,7]heptanes take up bromine exclusively at the C¹–C⁷ central bond with strict syn stereoselectively. The regio- and stereoselectivity of the addition and their relations with the halogen nature were interpreted with account taken of structural specificities of intermediate 6-sulfonyl-substituted 6-norpinanyl radicals determined by ab initio quantumchemical calculations using 6-31G basis set.     

DNA intercalating studies of [Ru(bpy)<Subscript>2</Subscript>HPIP]<Superscript>2+</Superscript> with intramolecular hydrogen bond ligand based on introduction of copper ion

The effects of copper ion on the interaction of [Ru(bpy)₂HPIP]²⁺(bpy = 2,2′-bipyridine, HPIP = 2-(2-hydroxyphenyl) imidazo [4,5-f] [1, 10] phenanthroline) with DNA have been investigated by electronic absorption spectroscopy and fluorescence spectroscopy. HPIP ligand of the complex with an intramolecular hydrogen bond can bind Cu²⁺ in the absence of DNA, as revealed by the absorbance and fluorescence decrease for [Ru(bpy)₂HPIP]²⁺. The resultant heterometallic complex binds to DNA via intercalation of HPIP into the DNA base pairs and its DNA-binding ability is stronger than [Ru(bpy)₂HPIP]²⁺ itself. The DNA bound [Ru(bpy)₂HPIP]²⁺ cannot bind Cu²⁺ at low Cu²⁺ concentration and the intramolecular hydrogen bond in HPIP is located inside the DNA helix. While the Cu²⁺ concentration is relative high, Cu²⁺ can quench the fluorescence of DNA bound [Ru(bpy)₂HPIP]²⁺. The quenching reason is proposed.     

Fully automated radiosynthesis of [<Superscript>18</Superscript>F]Fluoromisonidazole with single neutral alumina column purification: optimization of reaction parameters

1-H-1-(3-[¹⁸F]fluoro-2-hydroxypropyl)-2-nitroimidazole ([¹⁸F]FMISO), is the most used hypoxia-imaging agent in oncology and we have recently reported a fully automated procedure for its synthesis using the Nuclear Interface FDG module and a single neutral alumina column for purification. Using 1-(2′-nitro-1′-imidazolyl)-2-O-tetra-hydropyranyl-3-O-toluenesulfonylpropanediol (NITTP) as the precursor, we have investigated the yield of [¹⁸F]FMISO using different reaction times, temperatures, and the amount of precursor. The overall yield was 48.4 ± 1.2% (n = 3), (without decay correction) obtained using 10 mg NITTP with the radio-fluorination carried out at 145 °C for 3 min followed by acid hydrolysis for 3 min at 125 °C in a total synthesis time of 32 ± 1 min. Increasing the precursor amount to 25 mg did not improve the overall yield under identical reaction conditions, with the decay uncorrected yield being 46.8 ± 1.6% (n = 3), but rather made the production less economical. It was also observed that the yield increased linearly with the amount of NITTP used, from 2.5 to 10 mg and plateaued from 10 to 25 mg. Radio-fluorination efficiency at four different conditions was also compared. It was also observed by radio thin layer chromatography (radio-TLC) that the duration of radio-fluorination of NITTP, not the radio-fluorination temperature favoured the formation of labeled thermally degraded product, but the single neutral alumina column purification was sufficient enough to obtain [¹⁸F]FMISO devoid of any radiochemical as well as cold impurities.     

Stereochemistry of conjugate halogenation of 1-phenyltricyclo[4.1.0.0<Superscript>2,7</Superscript>]heptane

1-Phenyltricyclo[4.1.0.0^2,7]heptane reacts with N-bromo- and N-chlorosuccinimides in the presence of external nucleophiles providing products of a conjugate (electrophilic with respect to halogen) addition across the central bond C¹-C⁷ of the bicyclo[3.1. 1]heptane structure with a pronounces endo, anti-stereoselectivity. In similar reactions with N-iodosuccinimide the products obtained originated mainly from endo, syn-addition across the C¹-C⁷ bond. The reasons for differences in the selectivity of the conjugate halogenation are discussed applying the data of the quantum-chemical calculation in the basis MP2/STO 3G of the electronic and spatial structure of the reaction intermediates, norpinanyl cations of benzyl type.Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 11, 2004, pp. 1647–1655.Original Russian Text Copyright © 2004 by Vasin, Semenov, Razin.     

Functionalization of one or two methyl groups in the [Cp*<Subscript>2</Subscript>RuBr]<Superscript>+</Superscript>Br<Superscript>−</Superscript> complex in the reaction with bromine

The reaction of [Cp*₂RuBr]⁺Br⁻ with bromine in CH₂Cl₂ (CD₂Cl₂) in an inert atmosphere at room temperature produces the complexes [Cp*Ru(Br)C₅Me₄CH₂Br]⁺Br₃ ⁻ (syn conformer), [Cp*Ru(Br)C₅Me₃(CH₂Br)₂]⁺ (syn and anti conformers), and [Ru(Br)(C₅Me₄CH₂Br)₂]⁺ (syn conformer). All complexes were characterized by ¹H and ¹³C NMR spectroscopy; the former complex, by elemental analysis. These complexes were also prepared by the reaction of [Cp*RuC₅Me₄CH₂]⁺BF₄ ⁻ with bromine in CH₂Cl₂. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2712–2718, December, 2005.