Synthesis of tertiary 14C‐labelled nonylphenol isomers

The ring‐¹⁴C‐labelled p‐nonylphenol (NP) isomers 4(3′,5′‐dimethyl‐3′‐heptyl)‐phenol (p353NP), 4(3′,6′‐dimethyl‐3′‐heptyl)‐phenol (p363NP) and 4(2′,6′‐dimethyl‐2′‐heptyl)‐phenol (p262NP) were synthesized for application in metabolism and sorption studies. Friedel–Crafts alkylation of ¹⁴C‐labelled phenol and the corresponding tertiary nonylalcohol with BF₃ as catalyst was used. After clean‐up of p262NP and p363NP by preparative thin‐layer chromatography radiochemical yields amounted to 62.8 and 64.6%, specific radioactivities were 332 and 88.2 MBq/mmol, and radiochemical purities 97.6 and 99.0%. For both isomers, a large‐scale synthesis with non‐labelled phenol was additionally developed, which led to pure products (96 and 99%, respectively) without further purification steps. In the case of p353NP, which was formed as a diastereomeric mixture, the crude synthetic product had a radiochemical purity of 96.9% (radiochemical yield: 76.0%; specific activity: 298 MBq/mmol); thus, purification was not necessary. All products were characterized by means of gas chromatography‐mass spectroscopy, ¹H‐ and ¹³C‐NMR, as well as IR. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of [4‐14C]‐pelargonidin chloride and [4‐14C]‐delphinidin chloride

The synthesis of [4‐¹⁴C]‐pelargonidin chloride and [4‐¹⁴C]‐delphinidin chloride via [formyl‐¹⁴C]‐2‐(benzoyloxy)‐4,6‐dihydroxybenzaldehyde, ω,4‐diacetoxyacetophenone and ω,3,4,5‐tetraacetoxyacetophenone is described. The first step comprised labelling of the carbonyl group of 2‐(benzoyloxy)‐4,6‐dihydroxybenzaldehyde, verifying that the coupling with ω,4‐diacetoxyacetophenone or ω,3,4,5‐tetraacetoxyacetophenone under hydrogen chloride atmosphere resulted in the formation of [4‐¹⁴C] labelled anthocyanidins. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of carbon‐14 labelled midazolam

Cytochrome P450 (CYP) enzymes are responsible for much of the phase I oxidative metabolism observed in vivo. Many important pharmaceutical compounds are metabolized by CYP. Co‐administration of a drug with another agent can alter the efficacy or the toxicity, especially in cases where drug clearance depends primarily on the CYP metabolism. Compounds that induce or inhibit the CYP activity are often used in drug–drug interaction studies. Midazolam is one such compound that is routinely used in drug–drug interaction studies because it is a known substrate for CYP3A enzymes. The synthesis of this important tool molecule has been documented, but unfortunately a detailed preparation of carbon‐14‐labelled midazolam has not been reported in the literature. This paper describes a two‐step synthesis leading to [¹⁴C]midazolam. A total of 4.5 mCi of [¹⁴C]midazolam was obtained having a specific activity of 120.1 µCi/mg (39.12 mCi/mmol). The radiochemical purity as determined by HPLC was 99.8% and the overall radiochemical yield was 9%. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of 14C‐labelled myosmine, [2′‐14C] ‐3‐(1‐pyrrolin‐2‐yl)pyridine

¹⁴C‐Labelled myosmine ([2′‐¹⁴C]‐3‐(1‐pyrrolin‐2‐yl)pyridine) was synthesized for autoradiography studies starting from [carboxyl‐¹⁴C]‐nicotinic acid by initial esterification of the latter in the presence of 1,1,1‐triethoxyethane. Without any purification the ethyl nicotinate formed was directly reacted with N‐vinyl‐2‐pyrrolidinone in the presence of sodium hydride, yielding ¹⁴C‐labelled myosmine. The product was purified by silica gel column chromatography. The radiochemical yield was 15% and the specific activity 55.2 mCi/mmol. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of [14C]‐labelled repinotan hydrochloride and its major metabolite M‐6

For studies of pharmacokinetics and drug metabolism of the new 5‐HT_1A agonist repinotan, the ¹⁴C‐labelled version was synthesized. Starting from [U‐¹⁴C]phenol, a 10‐step synthesis led to 457 mg (1.58 GBq) of [U‐¹⁴C]repinotan hydrochloride, labelled uniformly in the aromatic ring of the chromane moiety. For a study in man, a mono‐carbon‐14 labelled substance was required. Therefore a 7‐step synthesis was performed starting from [carbonyl‐¹⁴C]2‐hydroxy‐acetophenone. The yield was 106 mg (0.396 GBq) of [4‐chromane‐¹⁴C]repinotan hydrochloride. The carbon‐14 labelled major metabolite, hydroxylated in the 6‐position of the chromane moiety, was synthesised as reference compound. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of 13C‐ and 14C‐labelled catechol

¹³C‐ and ¹⁴C‐uniformly labelled catechol was synthesized from phenol in three steps. Phenol was derivatized with 2‐chloro‐5‐nitrobenzophenone in THF containing NaH, followed by ortho‐hydroxylation with 35% aqueous H₂O₂ in sulphuric acid/glacial acetic acid solution, and by cleavage with piperidine, giving an overall 80% yield with respect to phenol. Copyright © 2002 John Wiley & Sons, Ltd.     

[5‐14C]‐4‐methyltriazolepyridines via facile preparation of methyl‐[14C]‐isothiocyanate

A fast and convenient microwave assisted one‐pot synthesis of methyl‐[¹⁴C]‐isothiocyanate 4 was shown. The continued one‐pot synthesis with 4 to a highly refined material like [5‐¹⁴C]‐dimethylsulfanyltriazolepyridines 8 and 13 without any intermediate purification, six steps in the same pot from [¹⁴C]KCN. Oxidation of the sulfur provided access to triazole‐ethers upon reaction with alcohols. The triazole‐ethers, 15, were obtained at fair to good yields and specific activities above 2 GBq/mmol. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of [thiazolium‐2,2′‐14C2]‐SAR97276A from [14C]‐thiourea

[thiazolium‐2,2′‐¹⁴C₂]‐SAR97276A, a bis(thiazolium) antimalarial development candidate, was synthesized from [¹⁴C]‐thiourea with an overall radiochemical yield of 15%. The synthetic route involves a modified procedure for the synthesis of [¹⁴C]‐sulfurol, also a key intermediate in thiamine synthesis, which was developed due to unlabelled chemistry proving irreproducible with the radiolabelled substrate. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of [3′‐14C] coenzyme Q10

Radio‐labelled coenzyme Q₁₀, labelled at the 3′‐position with ¹⁴C, was synthesized starting from natural solanesol and ethyl [3‐¹⁴C] acetoacetate. The radiochemical yield was 8.0% from ethyl [3‐¹⁴C] acetoacetate. The specific radioactivity of the product was 44.8 μCi, 1.66 MBq/mg. The specific radioactivity and radiochemical purity are sufficiently high to enable us to use this labelled form of coenzyme Q₁₀ in metabolic studies. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of carbon‐14 labelled gemifloxacin

A new antibacterial agent gemifloxacin was labelled with carbon‐14 for studies of pharmacokinetics and metabolism, the label was located in position 3 of the quinolone ring system. The overall radiochemical yield of the 14‐step synthesis, starting from [2‐¹⁴C]sodium acetate was 16.6%, and the radiochemical purity 97.5%. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of [14C]‐l‐tryptophan and [14C]‐5′‐hydroxy‐l‐tryptophan labeled in the carboxyl group

The synthesis of selectively ¹⁴C‐labeled l ‐tryptophan and its derivative 5‐hydroxy‐l ‐tryptophan using chemical and multienzymatic methods is reported. The mixture containing [1‐¹⁴C[‐dl ‐alanine, indole or 5‐hydroxyindole has been converted to [1‐¹⁴C]‐l ‐tryptophan or 5′‐hydroxy‐[1‐¹⁴C]‐l ‐tryptophan, respectively, in a one‐pot multienzymatic reaction using four enzymes: d ‐amino acid oxidase, catalase, glutamic‐pyruvic transaminase and tryptophanase. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of [2H7]indatraline

Deuterium‐labelled indatraline was synthesized in high efficiency employing a Friedel–Crafts alkylation of [²H₆]benzene with (E)‐3‐(3,4‐dichlorophenyl)acrylic acid as a key step. The desired labelling of the final compound was ascertained in two ways, by incorporation of [²H₆]benzene in the target molecule and additionally by deuterium transfer to the non‐deuterated aryl moiety of the Friedel–Crafts alkylation product from [²H₆]benzene, the latter thus serving as reagent and solvent.     

Synthesis of [14C] labeled 2‐methoxypyrimidine‐5‐carboxylic acid

A versatile method for ¹⁴C labeling of 2‐methoxypyrimidine‐5‐carboxylic acid at the 2‐position has been developed after encountering difficulties with traditional approaches to label the carboxyl function. The method developed can also be used for ¹⁴C labeling other positions of the pyrimidine ring system. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of [14C]‐, [13C4]‐, and [13C4, 15N2]‐ 5‐amino‐4‐iodopyrimidine

5‐Amino‐4‐iodopyrimidine labeled with either carbon‐14 or with the stable isotopes carbon‐13 and nitrogen‐15 was prepared starting from commercially available labeled diethylmalonate and formamide. This compound is a useful intermediate for carbon–nitrogen and carbon–carbon bond formations. Copyright © 2008 John Wiley & Sons, Ltd     

Synthesis of [14C]‐ and [35S]‐labelled PI‐88 for pharmacokinetic and tissue distribution studies

PI‐88, uniformly labelled with [¹⁴C] was prepared by incorporating D ‐[¹⁴C]glucose into the fermentation of Pichia (Hansenula) holstii NRRL Y‐2448 under controlled conditions to produce [¹⁴C]‐labelled extracellular phosphomannan. Subsequent acid catalyzed hydrolysis gave the [¹⁴C]‐labelled oligosaccharide phosphate fraction which was sulfonated with excess sulfur trioxide pyridine complex to give [¹⁴C]PI‐88. [³⁵S]‐labelled PI‐88 was similarly prepared by the sulfonation of unlabelled oligosaccharide phosphate fraction with [³⁵S] sulfur trioxide pyridine complex. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of [14C]‐labelled vardenafil hydrochloride and metabolites

For studies of pharmacokinetics and drug metabolism of the new orally active, selective phosphodiesterase type V (PDE V) inhibitor vardenafil (Levitra^®), the ¹⁴C‐labelled version was synthesised. Starting from the cyanation of 2‐iodophenol with K¹⁴CN, an 8‐step synthesis led to two batches with 0.727 g (2.857 GBq) and 2.199 g (5.497 GBq) of [triazinone‐¹⁴C]vardenafil hydrochlo‐ride with different specific radioactivities. The label was located in position 2 of the imidazotriazinone moiety. Several carbon‐14 labelled metabolites were synthesised as reference compounds for metabolism studies. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of [1‐11C]propyl and [1‐11C]butyl iodide from [11C]carbon monoxide and their use in alkylation reactions

A method to prepare [1‐¹¹C]propyl iodide and [1‐¹¹C]butyl iodide from [¹¹C]carbon monoxide via a three step reaction sequence is presented. Palladium mediated formylation of ethene with [¹¹C]carbon monoxide and hydrogen gave [1‐¹¹C]propionaldehyde and [1‐¹¹C]propionic acid. The carbonylation products were reduced and subsequently converted to [1‐¹¹C]propyl iodide. Labelled propyl iodide was obtained in 58±4% decay corrected radiochemical yield and with a specific radioactivity of 270±33 GBq/µmol within 15 min from approximately 12 GBq of [¹¹C]carbon monoxide. The position of the label was confirmed by ¹³C‐labelling and ¹³C‐NMR analysis. [1‐¹¹C]Butyl iodide was obtained correspondingly from propene and approximately 8 GBq of [¹¹C]carbon monoxide, in 34±2% decay corrected radiochemical yield and with a specific radioactivity of 146±20 GBq/µmol. The alkyl iodides were used in model reactions to synthesize [O‐propyl‐1‐¹¹C]propyl and [O‐butyl‐1‐¹¹C]butyl benzoate. Propyl and butyl analogues of etomidate, a β‐11‐hydroxylase inhibitor, were also synthesized. Copyright © 2006 John Wiley & Sons, Ltd.     

A novel synthesis of [2‐14C]2,5‐dichloropyrimidine

[2‐¹⁴ C]2,5‐dichloropyrimidine is a useful reagent for labeling biologically active compounds for use in hepatocyte transport studies, protein covalent binding, and metabolic profiling. This paper describes a novel five‐step synthesis of [2‐¹⁴ C]2,5‐dichloropyrimidine from readily available [¹⁴C]urea by way of a boronic acid intermediate. A total of 4.34 mCi of [2‐¹⁴ C]2,5‐dichloropyrimidine was obtained with a specific activity of 226.0 μCi/mg (33.7 mCi/mmol). The radiochemical purity was 95.8%, and the overall radiochemical yield was 22% based on 20 mCi of [¹⁴C]urea starting material. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of [14C]‐radiolabelled entecavir

Radiolabelled [¹⁴C]entecavir, ( 1 ), was prepared in 12 steps from (1S,2R,3S,5R)‐3‐(benzyloxy)‐2‐(benzyloxymethyl)‐6‐oxa‐bicyclo[3.1.0]hexane 2 . The chemical yield of [¹⁴C]entecavir was 14% from the epoxide 2 . Introduction of [¹⁴C] radiolabel was achieved by elaboration of 4,5‐diaminopyrimidine 8 with triethyl[¹⁴C]orthoformate to purine derivative 9 . The radiochemical yield of [¹⁴C]entecavir from triethyl[¹⁴C]orthoformate was 11.3%. Radiochemical purity of [¹⁴C]entecavir determined by HPLC was 99.8%. The specific activity of [¹⁴C]entecavir was 108 µCi/mg (29.9 mCi/mmol). Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of covalent [14C]‐labeled diarylsulfonylurea (DASU) inhibitors of the processing and release of IL‐1

CP‐452,759 and CP‐470,947, two covalent [¹⁴C]‐labeled diarylsulfonylurea (DASU) inhibitors of the processing and release of IL‐1 from human monocytes, have been synthesized. The radiosyntheses utilize [¹⁴C]‐labeled phosgene to prepare labeled isocyanates which are coupled with an epoxide sulfonamide to give the [¹⁴C]‐DASUs. These tools should allow future studies aimed at purifying and identifying the DASU binding protein involved in the inhibition of the processing and release of IL‐1 from human monocytes. Copyright © 2002 John Wiley & Sons, Ltd.