[14C]Dimethyltitanocene and [14C]Methyl(methyltrimethylsilyl) titanocene–Reagents for the [14C]olefination of carbonyl compounds: synthesis of [14C]Aprepitant

A neurokinin (NK‐1) receptor antagonist, [¹⁴C]Aprepitant, was synthesized using two labeled olefination reagents: [¹⁴C]dimethyltitanocene 1 and [¹⁴C]methyl (methyltrimethylsilyl)titanocene 7. Both reagents can be readily prepared from [¹⁴C]methyllithium and have been shown to convert a variety of carbonyls to [¹⁴C]methylenes in good radiochemical yields. Copyright © 2009 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.     

A synthesis of [14C]formamidine acetate

The one-step synthesis of [¹⁴C]formamidine acetate from [¹⁴C]barium cyanamide is described with product characterization by TLC and proton NMR.     

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.     

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.     

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 [14C] Sarin

Synthetic routes for the synthesis of [¹⁴C] sarin and related nerve agents are described. Triethyl phosphite and [¹⁴C] methyl iodide are reacted in the Michaelis–Arbusov reaction to produce diethyl methyl phosphonate which is converted to methylphosphonic acid by hydrolysis. After chlorination and subsequent fluorination the final product is formed by reaction with the appropriate alcohol. Copyright © 2003 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.     

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.     

Carbon‐14 labeling of hydrochlorothiazide via [14C]formaldehyde production from [14C]carbon dioxide at ambient temperature

[¹⁴C]Formaldehyde was synthesized by reducing ¹⁴CO₂ at ambient temperature with Schwartz's reagent. The [¹⁴C]formaldehyde was then used in the radiosynthesis of high specific activity (2.1 GBq/mmol) [¹⁴C]hydrochlorothiazide via cyclization of 4‐amino‐5‐chloro‐1,3‐benzenedisulfonamide.     

Synthesis of [14C]omarigliptin

An efficient synthesis for [¹⁴C]Omarigliptin (MK‐3102) is described. The initial synthesis of a key ¹⁴C‐pyrazole moiety did not work due to the lack of stability of ¹⁴C‐DMF‐DMA reagent. Thus, a new radiolabeled synthon, ¹⁴C‐biphenylmethylformate, was synthesized from ¹⁴C‐sodium formate in one step in 92% yield and successfully used in construction of the key ¹⁴C‐pyrazole moiety. Regioselective N‐sulfonation of the pyrazole moiety was achieved through a dehydration‐sulfonation‐isomerization sequence. [¹⁴C]MK 3102 was synthesized in five steps from ¹⁴C‐biphenylmethylformate with 25% overall yield.     

[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.     

〔~(14)C〕氨三肼(AT-1902)在小鼠体内的动态观察

氨三肼(AT-1902)由中国科学院上海药物研究所合成室合成。经我室实验证明,对多种动物移植性肿瘤有很强的抗肿瘤作用。本文采用整体放射自显影术,研究[~(14)C]AT-1902在动物体内的分布情况,进一步阐明分布与疗效及毒性之间的关系,为临床合理用药提供依据。     

Synthesis of triple [14C]‐labeled moxonidine

The synthesis of radiolabeled antihypertensive compound [2,4,6‐¹⁴C₃]‐4‐chloro‐5‐(imidazolidin‐2‐ylidenimino)‐6‐methoxy‐2‐methylpyrimidine ([¹⁴C₃]moxonidine) was accomplished based on condensation of [1‐¹⁴C]acetamidine with diethyl [1,3‐¹⁴C₂]malonate to form [2,4,6‐¹⁴C₃]‐4,6‐dihydroxy‐2‐methylpyrimidine. Subsequent nitration, chlorination, and hydrogenation gave [2,4,6‐¹⁴C₃]‐4,6‐dichloro‐2‐methyl‐5‐aminopyrimidine. The final product was obtained after the coupling of the above aminopyrimidine with 1‐acetylimidazolidin‐2‐one, followed by hydrolysis using sodium methoxide. Copyright © 2004 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.     

The disposition of [2,3-14C]-methyl and [2,3-14C]-2-ethylhexyl acrylate in male wistar albino rats

The disposition of methyl [2,3-¹⁴C]-acrylate (MA) and 2-ethylhexyl [2,3-¹⁴C]-acrylate (EHA) following intraperitoneal and oral administration to rats has been studied. The¹⁴C found in the tissues was mainly associated with liver, kidneys and lungs. Loss of¹⁴C from these tissues occurred fairly rapidly, excluding the rats given EHA intraperitoneally. Most of the administered acrylates underwent rapid metabolism and excretion with expired air (more than 50% of the dose and urine (10–50% of the dose). Significant differences in the rates of¹⁴C loss from tissues and excretion occurred after intrapritoneal administration of MA and EHA. A possible cumulation of EHA in the organism was suggested.     

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.     

Distribution of [14C]-Labelled Aflatoxin B1 in Mice

Abstract The distribution of [¹⁴C]-labelled aflatoxin B₁ has been studied in mice with the aid of whole-body autoradiography. In addition to the localisation of labelled aflatoxin B₁ and/or its metabolites in the liver, bile, kidney, lung and urine an uptake of ¹⁴C in the pigment of the Harderian gland and the eye was observed. Uptake of radioactivity was also found in the eyes of the foetuses although their livers did not accumulate radioactivity.     

A facile synthesis of [14C]pyrithiobac‐sodium

Condensation of thiourea 1 with diethyl malonate 2 in the presence of sodium methoxide furnished 4,6‐dihydroxy‐2‐mercaptopyrimidine 3 . Compound 3 on methylation with diazomethane followed by oxidation with H₅IO₆/CrO₃ in ethyl acetate gave 4,6‐dimethoxy‐2‐methylsulphonylpyrimidine 5 . Compound 5 on condensation with 2‐mercapto‐6‐chlorobenzoic acid in the presence of a phase transfer catalyst, tetrabutylammonium bromide and sodium carbonate gave the title compound – pyrithiobac‐sodium 6 with an overall yield of > 35% starting from thiourea. Following the above standardized procedure, using [¹⁴C]‐thiourea in lieu of thiourea, ¹⁴C labelled product 6 , was synthesized with an overall radiochemical yield > 30% (with respect to [¹⁴C]‐thiourea) for further evaluations of environmental fate of 6 , in soils and plants. Copyright © 2006 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.