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.     

Synthesis of the carbon‐14 labeled isotopomers of (R)‐N‐methyl‐3‐[2‐methylphenoxyl]‐benzenepropanamine hydrochloride (atomoxetine hydrochloride,LY139603), and two of its metabolites

Carbon‐14 labeled Straterra^TM (Atomoxetine HCl, LY139603, (‐)‐N‐methyl‐3‐(2‐methylphenoxy)‐benzenepropanamine hydrochloride), a potent inhibitor of the presynaptic norepinephrine transporter, and two of its major metabolites were synthesized. The key component, S‐(+)‐3‐chloro‐l‐phenyl‐l‐propanol‐[1‐¹⁴C] was synthesized by Stille coupling of benzoyl chloride‐[carbonyl‐¹⁴C] with vinyl tri‐n‐butylstannane, followed by HCl addition to the vinyl ketone, and asymmetric reduction of the ketone by Corey's CBS reagent. Mitsunobu reaction of this S‐(+)‐3‐chloro‐l‐phenyl‐l‐propanol‐[1‐¹⁴C] with various phenol derivatives, followed by converting the chloride to amines, gave desired products. 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.     

Carbon‐14‐and carbon‐13‐labeled phosphoric acid [2‐4‐(4‐cyanophenyl)‐thiazol‐2‐yl]‐(2,4‐difluorophenyl)‐1‐[1,2,4]triazol‐4‐yl‐methylpropoxymethyl] monoester dilysine salt,a prodrug of ravuconazole

4‐Bromobenzoic acid [carboxyl‐¹⁴C] and 4‐(2‐bromoacetyl) [Ar‐¹³C₆]benzonitrile were transformed into the title compounds containing [ring¹⁴C‐thiazol‐4‐yl] and [Ar‐¹³C₆‐benzonitrile]. ¹⁴C‐Ravuconazole was prepared in 37% yield and Purity >99%. ¹³C₆‐Ravuconazole was made in 56% overall yield and Purity of >98%. Each labeled compound was converted by additional reaction steps to the corresponding labeled prodrug. Copyright © 2011 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.     

The synthesis of [1‐14C]2‐(1H‐tetrazol‐5‐yl)acetic acid

Tetrazoles are a common heterocyclic functionality in many biologically active molecules. [1‐¹⁴C]2‐(1H‐Tetrazol‐5‐yl)acetic acid was required as an intermediate in the synthesis of a development candidate as part of a discovery phase program to complete metabolic profiling studies. [1‐¹⁴C]2‐(1H‐Tetrazol‐5‐yl)acetic acid was prepared in 4 steps overall and in 3 radiochemical steps from K¹⁴CN in an overall 32% radiochemical yield.     

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 [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 3H and 14C labeled (S)‐3‐(5‐chloro‐2‐methoxyphenyl)‐1,3‐dihydro‐3‐fluoro‐6‐(trifluoromethyl)‐2H‐indol‐2‐one,maxipost™. An agent for post‐stroke neuroprotection

The syntheses of tritium labeled (S)‐3‐(5‐chloro‐2‐[OC³H₃]methoxyphenyl‐1,3‐dihydro‐3‐fluoro‐6‐(trifluoromethyl)‐1H‐indol‐2‐one, and carbon‐14 (S)‐3‐(5‐chloro‐2‐methoxyphenyl)‐1,3‐dihydro‐3‐fluoro‐6‐(trifluoromethyl)‐2H‐[2,3‐¹⁴C₂] indol‐2‐one are reported. The ³H‐labeled compound was prepared in a two‐step synthesis from C³H₃I. The final product was purified via chiral HPLC to yield the desired enantiomer in a 4% radiochemical yield and a specific activity of 60 Ci/mmol. The ¹⁴C‐labeled compound was prepared in a four‐step synthesis from diethyl [carboxylate‐¹⁴C₁,₂] oxalate. The final product was purified via chiral HPLC to yield the desired enantiomer in a 20% radiochemical yield and a specific activity of 28.4 μCi/mg. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of a carbon‐14 labeled 1‐(indole‐6‐carbonyl‐D‐phenylglycinyl)‐4‐(1‐methylpiperidin‐4‐YL)piperazine‐[carbonyl‐14C], LY517717‐[14C], a factor Xa inhibitor

Human Factor Xa is a trypsin‐like serine protease, which serves a critical role in blood coagulation events. LY517717 is currently under clinical investigation as a Factor Xa inhibitor. To support the ADME studies, LY517717 was synthesized using D ‐phenylglycine with a carbon‐14 labeled carboxyl moiety. This key component, D ‐phenylglycine‐[carboxyl‐¹⁴C], was synthesized by a Strecker synthesis on benzaldehyde with potassium [¹⁴C]cyanide, followed by a resolution of DL ‐phenyl‐glycine methyl ester‐[carbonyl‐¹⁴C] with (+)‐tartaric acid in the presence of benzaldehyde. Copyright © 2004 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 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.     

An efficient synthesis of carbon‐14‐labeled 6‐[2‐(dimethylamino)ethyl]‐14‐(1‐ethylpropyl)‐5,6,7,8‐tetrahydroindolo [2,1‐α] [2,5]benzodiazocine‐11‐carboxylic acid using Curtius rearrangement reaction as a key step

Here we report an efficient synthesis of ¹⁴C‐labeled 6‐[2‐(dimethylamino)ethyl]‐14‐(1‐ethylpropyl)‐5,6,7,8‐tetrahydroindolo‐[2,1‐α][2,5]benzodiazocine‐11‐carboxylic acid (1) using the Curtius rearrangement as a key step. The synthesis was initiated by converting the unlabeled aryl carboxylic acid to an aryl amine via Curtius rearrangement reaction. The resulting aryl amine was then converted to an aryl iodide which was coupled with zinc [¹⁴C]cyanide to form an aryl [¹⁴C]nitrile. Subsequent hydrolysis yielded the ¹⁴C‐labeled carboxylic acid [¹⁴C]‐1. This overall process represents a mild and potentially general approach for conversion of unlabeled carboxylic acids to isotopically labeled carboxylic acids. Copyright © 2010 John Wiley & Sons, Ltd.     

13C‐ and 14C‐labelling of N‐[1‐(4‐chlorophenyl)‐1H‐pyrrol‐2‐yl‐methyleneamino] guanidinium acetate

N‐[1‐(4‐chlorophenyl)‐1H‐pyrrol‐2‐yl‐¹³C₄‐methyleneamino]guanidinium acetate has been synthesized by a four‐step procedure. This involved reduction of the Weinreb amide N,N′‐dimethyl‐N,N′‐dimethyloxybutane‐1,4‐diamide‐1,2,3,4‐¹³C₄ by Dibal‐H to give the corresponding unstable dialdehyde which is reacted in situ with 4‐chloroaniline to form 1‐(4‐chlorophenyl)‐1H‐pyrrole‐¹³C₄. This pyrrole analogue underwent a Vilsmeyer acylation with POCl₃/DMF followed by final reaction with aminoguanidine bicarbonate to produce the desired labelled compound with 99% atom ¹³C. By using DMF [α‐¹⁴C] a radio‐labelled analogue was synthesized with a specific activity of 60 mCi/mmol. Copyright © 2005 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 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.     

[125I], [127I]‐and [14C]‐Labelling of the GLP‐1‐(7‐37) derivative NN2211

Arg³⁴Lys²⁶(N^ε‐(γ‐L ‐glutamyl(N^α‐palmitoyl)))‐GLP‐1(7‐37) (NN2211) is currently in development as a diabetes type 2 drug. The fatty acid attached to the GLP‐1(7‐37) ensures a long and controlled duration of action. The synthesis of [¹²⁵I]NN2211, [¹²⁷I]NN2211 and [¹⁴C]NN2211 used for preclinical ADME studies are described. NN2211 was iodinated using the lactoperoxidase/hydrogen peroxide method, and [¹⁴C]NN2211 was synthesized in 4 steps by two routes both starting from an α‐protected [U‐¹⁴C]glutamic acid. Copyright © 2003 John Wiley & Sons, Ltd.     

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 2‐(methylsulfonyl)‐5‐(4‐(methylsulfonyl) phenyl)‐4‐phenyl‐1H‐[5‐14C]imidazole,a selective COX‐2 inhibitor,via asymmetrical benzoins

4,5‐Diarylimidazoles labeled with carbon‐14 in the 5‐position of the imidazole ring were prepared as a part of three‐step sequence from 2‐hydroxy‐1‐(4‐(methylthio)phenyl)‐2‐phenyl[1‐¹⁴C]ethanone as a key synthetic intermediate which has been synthesized from potassium [¹⁴C]cyanide.     

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.