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.     

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.     

Highly efficient preparation of carbon‐14 labeled,auxin herbicide 4‐amino‐3,5,6‐trichloropicolinic acid

A highly efficient, seven‐step route has been developed for the preparation of 2,6‐[¹⁴C₂]‐4‐amino‐3,5,6‐trichloropicolinic acid ([¹⁴C₂]‐ 1 , 2,6‐[¹⁴C₂]‐picloram) from 2,6‐[¹⁴C₂]‐pentachloropyridine. The method involves the stepwise, highly selective and high yield introduction of amino and carboxylic acid groups to the 4‐ and 2‐positions, respectively, of pentachloropyridine affording [¹⁴C₂]‐ 1 in an overall radiochemical yield of >70% with the use of only one formal purification step. Copyright © 2006 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.     

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 C‐14 and C‐13, H‐2‐labeled IKK inhibitor: [14C] and [13C4,D3]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido[3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide

[¹⁴C]‐N‐(6‐Chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5B ), an IKK inhibitor, was synthesized from [¹⁴C]‐barium carbonate in two steps in an overall radiochemical yield of 41%. The intermediate, [carboxyl‐¹⁴C]‐2‐methylnicotinic acid, was prepared by the lithiation and carbonation of 3‐bromo‐2‐methylpyridine. [¹³C₄,D₃]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5C ) was synthesized from [1,2,3,4‐¹³C₄]‐ethyl acetoacetate and [D₄]‐methanol in six steps in an overall yield of 2%. [¹³C₄]‐2‐methylnicotic acid, was prepared by condensation of [¹³C₄]‐ethyl 3‐aminocrotonate and acrolein, followed by hydrolysis with lithium hydroxide. Copyright © 2006 John Wiley & Sons, Ltd.     

Practical [14C]‐synthesis of molecules containing an acetic acid moiety: application to [14C]‐labeled DP1 antagonists

Efficient carbon‐14 labeling of four potent and selective DP1 antagonists is reported. The synthetic sequence began with α‐hydroxylation, reduction of an ester, followed by oxidative diol cleavage and aldehyde reduction. The resulting alcohol 4 was converted to a mesylate then nucleophilic substitution with [¹⁴C]‐sodium cyanide was performed to yield a nitrile, which upon basic hydrolysis provided the carbon‐14 labeled acid 1 . Compound 2 was obtained from the same alcohol intermediate 4 and two diastereomeric compounds 6 and 7 were easily prepared from compound 2 . Carbon‐14 synthesis of compounds 1 , 2 , 6 and 7 were achieved in good yields, high radiochemical purity (>99%) and with high specific activity (45 mCi/mmol). Copyright © 2006 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 three isotopically labeled versions and a metabolite of Aurora A kinase inhibitor

Sodium ring‐[¹⁴C]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoate (1A, MLN8054), an Aurora A kinase inhibitor, was synthesized from [¹⁴C]‐cyanamide in two steps in an overall radiochemical yield of 7%. The intermediate, [¹⁴C]‐4‐guanidinobenzoic acid, was prepared by coupling [¹⁴C]‐cyanamide with 4‐aminobenzoic acid. Sodium carboxyl‐[¹⁴C]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoate (1B) was synthesized from carboxyl‐[¹⁴C]‐4‐guanidinobenzoic acid in one step in a radiochemical yield of 35%. [D₄,¹⁵N]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid (1C) was synthesized from [¹⁵N₂]‐cyanamide and [D₄]‐4‐aminobenzoic acid in two steps in an overall yield of 37%. The major metabolite, β‐acyl glucuronide of 4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid (14), was synthesized from D‐glucuronic acid in three steps in an overall yield of 1%. The key intermediate for synthesis of glucuronide was prepared by HATU catalyzed coupling of 4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid with allyl glucuronate. Copyright © 2009 John Wiley & Sons, Ltd.     

A novel no‐carrier‐added submicromolar scale radiosynthesis of [S‐methyl‐14C]‐florfenicol

In this paper is reported a novel reaction scheme for the no‐carrier‐added submicromolar scale radiosynthesis of [S‐methyl‐¹⁴C]‐florfenicol that has been newly designed, developed and employed by us successfully. The [¹⁴C]‐product was obtained in an overall radiochemical yield of 30% based on [¹⁴C]‐methyl iodide taken for the reaction with a radiochemical purity of more than 96%. The specific activity of the product was ~50 mCi (1.85 GBq)/mmol. Chlorosulfonation of compound I was followed by sodium salt formation in situ and it was succeeded by the introduction of [¹⁴C]‐methyl group by coupling with [¹⁴C]‐CH₃I. Subsequently, the oxazolidin‐2‐one protecting group was opened up by a reaction with sulfuric acid in dioxane and later, the amino group was dichloroacetylated with methyl‐2,2‐dichloroacetate in triethylamine to obtain [S‐methyl‐¹⁴C]‐florfenicol.     

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 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 C‐14‐labeled novel IKK inhibitor: 2‐[14C]‐N‐(6‐chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide

2‐[¹⁴C]‐N‐(6‐Chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide (9A , also referred to as [¹⁴C]‐PS‐1145) was synthesized from [¹⁴C]‐paraformaldehyde in five steps in an overall radiochemical yield of 15%. The key intermediate 1‐[¹⁴C]‐6‐chloro‐1,2,3,4‐tetrahydro‐β‐carboline was obtained by Pictet–Spengler cyclization of chlorotryptamine with [¹⁴C]‐paraformaldehyde. Similar reactions were conducted with tryptamine to address the generality of the methodology. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of 5‐[4,5‐13C2]‐ and 5‐[1,5‐13C2]aminolevulinic acid

5‐[4,5‐¹³C₂]‐ and 5‐[1,5‐¹³C₂]Aminolevulinic acid (ALA) have been synthesized by the Gabriel condensation of potassium phthalimide with ethyl bromo[1,2‐¹³C₂]acetate (derived from [1,2‐¹³C₂]acetic acid) or ethyl bromo[2‐¹³C]‐acetate (derived from sodium [2‐¹³C]acetate), followed by conversion to the chloride, coupling reaction with 2‐ethoxycarbonylethylzinc iodide derived from ethyl 3‐iodopropionate or 2‐methoxy[¹³C]carbonylethylzinc iodide derived from methyl 3‐iodo[1‐¹³C]propionate (generated from potassium [¹³C]cyanide), and hydrolysis. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of deramciclane* labeled with tritium in various positions

[(1R)‐endo]‐(+)‐3‐bromocamphor was dehalogenated with tritium gas to [3‐³H]camphor and via [3‐³H]phenylborneol converted to [3‐³H]deramciclane isolated as the fumarate salt (specific activity 51.8 GBq/mmol). This three step synthesis from [3‐³H]camphor gave an overall yield of 22%. Benzyloxy‐acetic acid methyl ester was reduced with sodium‐borotritide to 2‐benzyloxy‐ethanol‐[1‐³H], and through a four step procedure was converted to 2‐dimethylaminoethyl‐[2‐³H] chloride. The latter was condensed with the sodium derivative of 2‐phenylborneol giving rise to [2‐dimethylamino‐[2‐³H]ethoxy]deramciclane isolated as the fumarate (specific activity 8.177 GBq/mmol). This six step synthesis from [³H]NaBH₄ gave an overall yield of 6%. Copyright © 2005 John Wiley & Sons, Ltd.     

A facile and efficient synthesis of 14C‐labelled sulforaphane

Isothiocyanates have gained considerable attention for their role as potent chemopreventive agents. Sulforaphane, 1a (SFN), a naturally occurring isothiocyanate, was isotopically labelled in five steps starting from 3‐(methylthio)‐1‐propanol ( 2 ) . Reacting 2 with tosyl chloride in the presence of Et₃N yielded the tosylate 3 . Gently refluxing 3 with K¹⁴CN in DMF gave the nitrile 4b . Reduction to the amine 5b was achieved using BH₃‐THF. Oxidation with 30% hydrogen peroxide followed by treatment with thiophosgene yielded (±)[1‐¹⁴C]SFN, 1b . The overall radiochemical yield was 4.4% based on the starting K¹⁴CN. Copyright © 2003 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 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 carbon‐14‐labeled isotopomer of 6‐(4‐methanesulfonylphenyl)‐5‐[4‐(2‐piperidin‐1‐yl‐ethoxy)phenoxy]‐naphthalen‐2‐ol HCL salt (LY2066948‐[14C] HCL salt)

Carbon‐14‐labeled 6‐(4‐methanesulfonylphenyl)‐5‐[4‐(2‐piperidin‐1‐yl‐ethoxy)phenoxy]naphthalen‐2‐ol, a novel selective estrogen receptor modulator (SERM) was synthesized. The key component, 6‐methoxy‐1‐tetralone‐[carbonyl‐¹⁴C], was synthesized from 3‐(3‐methoxyphenyl)‐propionic acid via an intra‐molecular Friedel–Crafts acylation of 4‐(3‐methoxyphenyl)butanoic acid‐[carboxy‐¹⁴C]. A palladium catalyzed alpha‐keto arylation of 6‐methoxy‐1‐tetralone with 4‐methanesulfonyl‐phenyl bromide, followed by a sequence of bromination, DDQ dehydrogenation, aryl Ullmann reaction, and demethylation with BBr₃ gave the desired product LY2066948‐[¹⁴C]. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis of three alpha 7 agonists in labeled form

In support of a program to develop an alpha 7 agonist as a treatment for Alzheimer's disease, three drug candidates, 1, 2, and 3, were prepared in labeled forms. Compound 1 was prepared in C‐14 labeled form by lithiation of [2,6‐¹⁴C₂]2‐chloropyridine and subsequent coupling with spirooxirane‐2,3'‐quinuclidine. When this same coupling was attempted using [3,4,5,6‐²H₄]2‐chloropyridine, alcohol [²H₆]‐6 was the major product indicating that the primary isotope effect for the lithiation step was significant enough to shift the reaction pathway. Therefore, an alternate site of labeling was used to prepare [²H₄]‐1. [¹³C₅]‐2 was prepared in five steps from [¹³C₅]2‐furoic acid, but the C‐14 labeled compound used [¹⁴C₂]‐1 as the starting material instead. [¹⁴C₂]‐3 was prepared in two steps from [carbonyl‐¹⁴C]nicotinic acid.