[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 [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.     

Microwave‐assisted synthesis of (RS) methyl‐2‐([2′‐14C]4,6‐dimethoxypyrimidin‐2′‐yloxy)‐2‐phenyl [1‐14C]ethanoate

We report here a facile synthesis of (RS) methyl‐2‐([2′‐¹⁴C]4,6‐dimethoxypyrimidin‐2′‐yloxy)‐2‐phenyl [1‐¹⁴C]ethanoate under microwave irradiation. Copyright © 2006 John Wiley & Sons, Ltd.     

A rapid microwave assisted synthesis of [U‐14C]isosorbide and dimethyl[U‐14C]isosorbide from D‐[U‐14C]glucose

[U‐¹⁴C]Isosorbide and [U‐¹⁴C]dimethyl isosorbide with a specific activity of 462 MBq/mmol was prepared from D ‐[U‐¹⁴C]glucose, in an overall yield of 79%, under microwave heating conditions. Copyright © 2006 John Wiley & Sons, Ltd.     

A convenient method to produce [14C]carbon monoxide and its application to the radiosynthesis of [carboxyl‐14C]celivarone, [carboxyl‐14C]SSR149744

[carboxyl‐¹⁴C]Celivarone was synthesised from barium [¹⁴C]carbonate with overall radiochemical yields in the range 49–53%. The synthetic route involves [¹⁴C]carbonylation methodology, which both decreased the number of synthetic steps and increased the yields obtained from previous synthetic routes.     

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‐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 [quinoline‐3‐14C]‐SSR97193 (ferroquine) from [2‐14C]‐malonic acid

The antimalarial [quinoline‐3‐¹⁴C]‐SSR97193 (ferroquine) ( 8 ), an analogue of chloroquine (CQ) ( 1 ), was synthesized from [2‐¹⁴C]‐malonic acid with an overall radiochemical yield of 15%. The synthetic route via [¹⁴C]‐Meldrum's acid ( 9 ) was designed to minimize the intermediacy of radiolabelled volatiles. This synthesis involves a four‐step route to labelled 4,7‐dichloroquinoline, which is the key intermediate for the synthesis of many analogues of CQ. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of [2H4]oxymetazoline and [14C]oxymetazoline

An efficient synthesis of [²H₄] and [¹⁴C]oxymetazoline has been developed. Both compounds follow the same synthetic route with the introduction of the label occurring at different synthetic steps. The synthesis of [²H₄]oxymetazoline from [²H₄]ethylene diamine was achieved in one step with a 40% yield. The synthesis of [¹⁴C]oxymetazoline from potassium [¹⁴C]cyanide was achieved in two steps with an overall radiochemical yield of 67%. Copyright © 2010 John Wiley & Sons, Ltd.     

Simple single‐step single‐enzyme synthesis of [14C]‐GSH

The tri‐peptide [¹⁴C]‐glutathione ([¹⁴C]‐GSH) was synthesized in a single step by GSH synthetase catalyzed reaction of L ‐γ‐glutamyl‐L ‐cysteine and [¹⁴C]‐glycine. Preparative reverse phase HPLC afforded [¹⁴C]‐GSH in 30% yield and 98% purity. Preparation of GSH synthetase from E. coli via recombinant DNA and the interconversion of [¹⁴C]‐GSH to the disulfide [¹⁴C]‐GSSG for storage are discussed. Copyright © 2010 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.     

A facile synthesis of high specific activity sodium [1‐14C] lauryl sulphate under microwave irradiation

A highly efficient and optimized synthesis of sodium[1‐¹⁴C] lauryl sulphate having high specific activity (50 mCi/mmol) is described. Lauric acid was converted to undecyl bromide using a modified Hunsdiecker reaction. This was treated with potassium ¹⁴C cyanide (specific activity 50 mCi/mmol) using phase transfer catalysis to yield [1‐¹⁴C]lauronitrile, which was subsequently hydrolysed with a mixture of concentrated hydrochloric acid:propionic acid (1:2 v/v) under microwave irradiation for 2 min to obtain [1‐¹⁴C] lauric acid in quantitative yield. The latter on reaction with chlorosulphonic acid and subsequent neutralization with sodium bicarbonate yielded the title compound. Copyright © 2005 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.     

Synthesis of [1‐11C]ethyl iodide from [11C]carbon monoxide and its application in alkylation reactions

A method is presented for preparing [1‐¹¹C]ethyl iodide from [¹¹C]carbon monoxide. The method utilizes methyl iodide and [¹¹C]carbon monoxide in a palladium‐mediated carbonylation reaction to form a mixture of [1‐¹¹C]acetic acid and [1‐¹¹C]methyl acetate. The acetates are reduced to [1‐¹¹C]ethanol and subsequently converted to [1‐¹¹C]ethyl iodide. The synthesis time was 20 min and the decay‐corrected radiochemical yield of [1‐¹¹C]ethyl iodide was 55 ± 5%. The position of the label was confirmed by ¹³C‐labelling and ¹³C‐NMR analysis. [1‐¹¹C]Ethyl iodide was used in two model reactions, an O‐alkylation and an N‐alkylation. Starting with approximately 2.5 GBq of [¹¹C]carbon monoxide, the isolated decay‐corrected radiochemical yields for the ester and the amine derivatives were 45 ± 0.5% and 25 ± 2%, respectively, based on [¹¹C]carbon monoxide. Starting with 10 GBq of [¹¹C]carbon monoxide, 0.55 GBq of the labelled ester was isolated within 40 min with a specific radioactivity of 36 GBq/µmol. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of isotope‐labeled HSP90 inhibitor: [13CD3] and [14C]‐TAK‐459

[¹³CD₃]‐TAK‐459 (1A), an HSP90 inhibitor, was synthesized from [¹³CD₃]‐sodium methoxide in three steps in an overall yield of 29%. The key intermediate [¹³CD₃]‐2‐methoxy‐6‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)pyridine was synthesized in two steps from 2,6‐dibromopyridine and stable isotope‐labeled sodium methoxide. [¹⁴C]‐TAK‐459 (1B) was synthesized from [¹⁴C(U)]‐guanidine hydrochloride in five steps in an overall radiochemical yield of 5.4%. The key intermediate, [¹⁴C]‐(R)‐2‐amino‐7‐(2‐bromo‐4‐fluorophenyl)‐4‐methyl‐7,8‐dihydropyrido[4,3‐d]pyrimidin‐5(6H)‐one, was prepared by microwave‐assisted condensation.     

Synthesis of [1‐13C]‐para‐xylene and [2‐13C]‐para‐xylene

An efficient synthesis of [1‐¹³C]‐para‐xylene ( 1a ) and [2‐¹³C]‐para‐xylene ( 1b ) is described. The incorporation of the label has been achieved by cyclocondensation of suitable 1,5‐bis(bromomagnesio)alkanes with either ethyl [1‐¹³C]acetate or ethyl [¹³C]formate which gave [ring‐¹³C]‐labelled dimethylcyclohexanols. Dehydration of these alcohols followed by dehydrogenation of the intermediate dimethylcyclohexenes furnished the title compounds in 32 and 40% overall yield, respectively. Copyright © 2001 John Wiley & Sons, Ltd.     

Synthesis of two non‐peptidyl GnRH receptor antagonists via [14C]carbonylation

In support of a program to develop a new gonadotropin releasing hormone (GnRH) receptor antagonist, two ¹⁴C labelled candidate tracers, ¹⁴C‐1 and ¹⁴C‐2 , were synthesized for utilization in metabolism studies. A slight modification of the Medicinal Chemistry route for the synthesis of the antagonists provided iodide 4 . Palladium (0) catalyzed [¹⁴C] carbonylation of 4 proceeded in good chemical yield to afford acid ¹⁴C‐3 which served as a common precursor to ¹⁴C‐1 and ¹⁴C‐2 . Copyright © 2003 John Wiley & Sons, Ltd.     

Syntheses of [14C] and [2H4]PD0205520, an inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor

5‐(4‐Methyl‐piperazin‐1‐yl)‐pent‐2‐ynoic acid [4‐(3‐chloro‐4‐fluoro‐phenylamino)‐pyrido[3,4‐d]pyrimidin‐6‐yl]‐amide, PD0205520, was under investigation as a potential inhibitor of the tyrosine kinase (TK) activity of the epidermal growth factor receptor (EGFR) for cancer treatment. Both radio‐ and stable‐isotope‐labeled compounds were required for drug absorption, distribution, metabolism and excretion (ADME) and quantitative mass spectrometry bio‐analytical studies. PD0205520 ^I4C‐labeled in the pyrimidine ring system was prepared in seven steps in an overall radiochemical yield of 26% from [¹⁴C]thiourea. PD0205520 ²H‐Iabeled in the piperazine ring was synthesized in four steps in a 32% overall yield. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of a delta opioid agonist in [2H6], [2H4], [11C], and [14C] labeled forms

In support of a program to develop a treatment for depression, four labeled forms of a delta opioid agonist were prepared. The [²H₄] labeled form was prepared using a relatively straightforward conversion of [²H₄]bromoethanol to [²H₄]N‐methyl‐2‐hydroxyethylamine. The key step in the synthesis of the [²H₆] labeled form involved the Pd‐catalyzed exchange in D₂O of 8‐quinolin‐8‐ol to give [²H₆] 8‐quinolin‐8‐ol. The C‐14 labeled form was synthesized in one step using [¹⁴C]carbonylation, and the C‐11 labeled form was prepared in two steps from ¹¹CH₃I. Copyright © 2011 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.