An improved synthesis of [2‐14C]2, 5‐dichloropyrimidine

A previously described, five‐step synthesis of [2‐¹⁴C]2, 5‐dichloropyrimidine was based on condensation of [¹⁴C]urea with an acetal, followed by bromination, chlorination, boronic acid formation, and finally chlorination. This improved synthesis also started from readily available [¹⁴C]urea, which was condensed with 2‐chloromalonaldehyde, followed by chlorination with POCl₃ yielding [2‐¹⁴C]2, 5‐dichloropyrimidine with a radiochemical purity of 99% in an overall radiochemical yield of 72%. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis of a series of carbon‐14 labeled tetrahydropyrido[4,3‐d]pyrimidin‐4(3H)‐ones

A series of tetrahydropyrido[4,3‐d]pyrimidin‐4(3H)‐ones labeled with carbon‐14 in the 2‐position of pyrimidinone moiety were prepared as part of a 3‐step sequence from benz[amidino‐¹⁴C]amidine hydrochloride as a key synthetic intermediate. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis of multi‐labeled [14C]Aripiprazole

Development of Aripiprazole as an oral treatment of schizophrenia required the synthesis of a suitably labeled drug product for use in human metabolism and pharmacokinetic studies. Due to the potential metabolic degradation of the molecule, a multi‐labeled approach utilizing ¹⁴C was adopted. The synthesis of [¹⁴C]Aripiprazole was accomplished in separate syntheses from 2,3‐dichloro[U‐¹⁴C]aniline and [3‐¹⁴C]‐cinnamic acid, respectively. Labeled versions were combined on the basis of molar radioactivity giving a final product with a radiochemical purity of 99.9% and a specific activity of 15.5 µCi/mg. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of [14C]‐ and [13C6]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

5,11‐Dihydro‐11‐ethyl‐5‐methyl‐8‐{2‐{(1‐oxido‐4‐quinolinyl)oxy}ethyl}‐6H‐dipyrido[3,2‐b:2′,3′‐e][1,4]diazepin‐6‐one, (1), labeled with carbon‐14 in the quinoline–benzene ring, in one of the pyridine rings of the dipyridodiazepinone tricyclic moiety, and in the side chain, was prepared in three different syntheses with specific activities ranging from 44 to 47 mCi/mmol (1.63–1.75 GBq/mmol). In the first synthesis, 5,11‐dihydro‐11‐ethyl‐8‐(2‐hydroxyethyl)‐5‐methyl‐6H‐dipyrido[3,2‐b:2′,3′‐e][1,4]diazepin‐6‐one (2) was coupled to 4‐hydroxyquinoline, [benzene‐¹⁴C(U)]‐, using Mitsunobu's reaction conditions, followed by the oxidation of the quinoline nitrogen with 3‐chloroperoxybenzoic acid to give ([¹⁴C]‐(1a)) in 43% radiochemical yield. Second, 3‐amino‐2‐chloropyridine, [2,6‐¹⁴C]‐, was used to prepare 8‐bromo‐5,11‐dihydro‐11‐ethyl‐5‐methyl‐6H‐dipyrido[3,2‐b:2′,3′‐e][1,4]diazepin‐6‐one (8), and then Stille coupled to allyl(tributyl)tin followed by ozonolysis of the terminal double bond and in situ reduction of the resulting aldehyde to alcohol (10). Mitsunobu etherification and oxidation as seen before gave ([¹⁴C]‐(1b)) in eight steps and in 11% radiochemical yield. Finally, carbon‐14 potassium cyanide was used to prepare isopropyl cyanoacetate (12), which was used to transform bromide (8) to labeled aryl acetic acid (13) under palladium catalysis. Trihydroborane reduction of the acid gave alcohol (14) labeled in the side chain, which was used as described above to prepare ([¹⁴C]‐(1c)) in 4.3% radiochemical yield. The radiochemical purities of these compounds were determined by radio‐HPLC and radio‐TLC to be more than 98%. To prepare [¹³C₆]‐(1), [¹³C₆]‐4‐hydroxyquinoline was prepared from [¹³C₆]‐aniline and then coupled to (2) and oxidized as seen before. Copyright © 2008 John Wiley & Sons, Ltd.     

An improved synthesis of [24‐14C]cholic acid,and its application to the synthesis of [14C]SCH 209702 (Syn3). Synthesis of [2H8]SCH 209702

An efficient synthesis of [24‐¹⁴C]cholic acid from potassium [¹⁴C]cyanide has been developed. The key intermediate, 23‐chloro‐3α, 7α, 12α‐triformyloxynorcholane, was synthesized by degradation of triformyl protected cholic acid. Different degradation conditions were explored. The synthesis of [¹⁴C]SCH 209702 from 23‐chloro‐3α, 7α, 12α‐triformyloxynorcholane and potassium [¹⁴C]cyanide is described. The synthesis of [²H₈]SCH 209702 from [²H₄]cholic acid is also presented. Copyright © 2008 John Wiley & Sons, Ltd.     

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 3H, 13C,2H3,15N and 14C‐labelled SCH 466036, a histamine 3 receptor antagonist

The synthesis of [³H]SCH 466036, [Me‐³H₃]SCH 466036, [¹³C,²H₃,¹⁵N]SCH 466036 and [¹⁴C]SCH 466036 is described. [³H]SCH 466036 was prepared in two steps via Raney Ni‐catalysed exchange with tritiated water. [Me‐³H₃]SCH 466036 was prepared in a single step from [³H]methyl iodide in 45% yield. [¹³C,²H₃,¹⁵N]SCH 466036 was prepared in two steps from [¹⁵N]hydroxylamine and [¹³C,²H₃]methyl iodide with an overall yield of 16%. [¹⁴C]SCH 466036 was prepared in seven steps from [¹⁴C]potassium cyanide in an overall yield of 13%.     

Synthesis of 14C‐labeled and 13C‐,15N‐labeled dasatinib and its piperazine N‐dealkyl metabolite

Dasatinib (SPRYCEL^®) is a multiple kinase inhibitor approved for the treatment of chronic myelogenous leukemia and Philadelphia chromosome‐positive acute lymphoblastic leukemia in patients with resistance to prior therapy, including imatinib mesylate (Gleevec^®). Radiolabeled dasatinib and its piperazine N‐dealkyl metabolite were synthesized to investigate absorption, distribution, metabolism, and elimination of the compounds in humans and animals. These compounds were prepared following a three‐step sequence, which included thiazole carboxamide formation via cyclization of labeled thiourea with a brominated oxyacrylamide precursor. In the final step a common intermediate was converted to either [¹⁴C]dasatinib or the radiolabeled piperazine N‐dealkyl metabolite with labeling in the aminothiazole ring. Syntheses of both compounds were achieved with radiochemical purities in excess of 98%. Stable‐labeled dasatinib and the piperazine N‐dealkyl metabolite were also needed for use as mass spectral internal standards in support of bioanalytical assays. By following the same route used for the carbon‐14 synthesis, [¹³C₄, ¹⁵N₂]dasatinib and the [¹³C₄, ¹⁵N₂]metabolite were prepared with labeling in both the dichloropyrimidine and thiazole ring systems. This convergent process introduced stable isotope labeling through (1, 2, 3‐¹³C₃) diethyl malonate and [¹³C,¹⁵N₂]thiourea. Copyright © 2008 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 3H, 13C2, 2H4 14C‐SCH 430765 and 35S‐SCH 500946, potent and selective inhibitors of the NPY5 receptor

SCH 430765 and SCH 500496 are potent and selective antagonists of the NPY₅ receptor. NPY₅ receptor antagonists have the potential for the treatment of obesity. [³⁵S]SCH 500946 was prepared for a competition binding assay which led to the identification of SCH 430765. Three distinct isotopically labelled forms of SCH 430765 were synthesized. [³H]SCH 430765 was prepared for a preliminary absorption, distribution, metabolism and excretion data evaluation of the compound and [¹⁴C]SCH 430765 for more definitive absorption, distribution, metabolism and excretion data work. In addition, [¹³C₂,²H₄]SCH 430765 was prepared as an internal standard for a LC‐MS bioanalytical method. The paper discusses the synthesis of 3 isotopically labelled forms of SCH 430765 and [³⁵S]SCH 500946.     

Synthesis of 3H‐, 13C3‐, and 14C‐labeled Sch 727965

The preparation of [³H]Sch 727965 from unlabeled compound and tritiated water was base catalyzed. Diethyl [¹³C₃]malonate was used to prepare [¹³C₃]Sch 727965 in five steps in 21.8% overall yield. In a similar manner, [¹⁴C]Sch 727965 was prepared in five steps from diethyl [2‐¹⁴C]malonate in 11.1% radiochemical yield. Copyright © 2010 John Wiley & Sons, Ltd.     

The synthesis of 14C‐labeled, 13CD2‐labeled saxagliptin,and its 13CD2‐labeled 5‐hydroxy metabolite

¹⁴C‐labeled saxagliptin, ¹³CD₂‐labeled saxagliptin, and its ¹³CD₂‐labeled 5‐hydroxy metabolite were synthesized to further support development of the compound for biological studies. This paper describes new syntheses leading to the desired compounds. A total of 3.0 mCi of ¹⁴C‐labeled saxagliptin was obtained with a specific activity of 53.98 μCi/mg (17.13 mCi/mmol). The radiochemical purity determined by HPLC was 99.29%, and the overall radiochemical yield was 3.0% based upon 100 mCi of [¹⁴C]CH₂I₂ starting material. By following similar synthetic routes, 580.0 mg of ¹³CD₂‐labeled saxagliptin and 153.1 mg of ¹³CD₂‐labeled 5‐hydroxysaxagliptin metabolite were prepared. Copyright © 2014 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     

Potent and selective CC chemokine receptor 1 antagonists labeled with carbon‐13, carbon‐14, and tritium

1‐(4‐Fluorophenyl)‐1H‐pyrazolo[3,4‐c]pyridine‐4‐carboxylic acid (2‐methanesulfonyl‐pyridin‐4‐ylmethyl)‐amide ( 1 ) and its analogs ( 2 ) and ( 3 ) are potent CCR1 antagonists intended for the treatment of rheumatoid arthritis. The detailed syntheses of these 3 compounds labeled with carbon‐13 as well as the preparation of ( 1 ) and ( 2 ) labeled with carbon‐14, and ( 1 ) labeled with tritium, are described.     

An efficient synthesis of trace amine‐associated receptor agonist [1‐14C]tyramine

The 2‐step synthesis of [1‐¹⁴C]tyramine hydrochloride is described with the product being characterized by TLC, HPLC, and UV spectroscopy. Several methods are provided to purify [1‐¹⁴C]tyramine hydrochloride, and its storage and stability are also discussed.     

Synthesis of [7‐14C]bergapten

Bergapten (1) is a furocoumarin natural product and currently employed to treat skin disorders. Since past attempts to radiolabel 1 with ¹⁴C were limited to only its 5‐methoxy group, a synthesis of the required ring [7‐¹⁴C]1 is now described. The literature reported precursor 4‐methoxy‐6‐hydroxybenzofuran‐5‐carboxaldehyde (3) was Wittig reacted with stabilized [carbonyl‐¹⁴C]methoxycarbonylmethylenetriphenylphosphorane (4) to obtain [7‐¹⁴C]1 in 47% radiochemical yield, with the desired product being characterized by thin‐layer chromatography, HPLC, m.p. and proton NMR.     

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 14C‐labeled and tritiated AMPA potentiator LY450108

Asymmetric synthesis of AMPA potentiator LY450108‐[¹⁴C] containing ¹⁴C‐label attached to the chiral center of the molecule, was accomplished based on Evans' chiral oxazolidinone auxiliary method. Diastereoselective methylation of p‐nitrophenylacetic acid derivative was used as a key step. The auxiliary was reductively removed, and the resulting primary alcohol was converted into the corresponding amine. Its sulfonylation, reduction of the aromatic nitro group, and acylation with 3,5‐difluorobenzoyl chloride led to the final product. The synthesis of tritiated LY450108 is also detailed. Copyright © 2005 John Wiley & Sons, Ltd.     

The synthesis of a tritium,carbon‐14, and stable isotope‐labeled cathepsin C inhibitors

As part of a medicinal chemistry program aimed at developing a highly potent and selective cathepsin C inhibitor, tritium, carbon‐14, and stable isotope‐labeled materials were required. The synthesis of tritium‐labeled methanesulfonate 5 was achieved via catalytic tritiolysis of a chloro precursor, albeit at a low radiochemical purity of 67%. Tritium‐labeled AZD5248 was prepared via a 3‐stage synthesis, utilizing amide‐directed hydrogen isotope exchange. Carbon‐14 and stable isotope‐labeled AZD5248 were successfully prepared through modifications of the medicinal chemistry synthetic route, enabling the use of available labeled intermediates.     

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.