Synthesis of labeled acrylamide and N‐methylolacrylamide (NMA): 15N‐acrylamide, 13C‐NMA, 15N‐NMA,and 13C,15N‐NMA

Labeled derivatives of N‐methylolacrylamide (NMA) including ¹⁵N‐NMA, ¹³C‐NMA, and ¹³C,¹⁵N‐NMA were synthesized and purified. A required chemical precursor, ¹⁵N‐acrylamide, was also prepared. Reported methods for synthesizing unlabeled analogs are noted, and modifications to these methods for achieving the labeled materials are specified. Monomers were examined via ¹H, ¹³C, and ¹⁵N nuclear magnetic resonance (NMR) spectroscopy. Peak assignments and coupling constants are reported for each compound. To our knowledge, this is the first reported publication on the preparation and characterization of ¹³C‐NMA, ¹⁵N‐NMA, ¹³C,¹⁵N‐NMA, and ¹⁵N‐acrylamide. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of [N‐methyl‐13C]clarithromycin

We describe a simple synthesis of [N‐methyl‐¹³C]clarithromycin ( 3 ) via the N‐desmethylation of clarithromycin. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of N‐[1‐13C]caproyl‐N′‐phenylthiourea

An optimal synthesis of N‐[1‐¹³C]caproyl‐N′‐phenylthiourea with isotopic enrichment 82% is described, starting from barium [¹³C]carbonate, using five synthetic steps. Yields were 95% relative to caproyl chloride and 46% relative to barium carbonate. Oxidation of the title compound with manganese dioxide yields the corresponding ureide. Structural similarities with anticonvulsants such as phenacemide make N‐caproyl‐N′‐phenylthiourea an interesting model compound. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of [2‐13C, 4‐13C]‐(2R,3S)‐catechin and [2‐13C, 4‐13C]‐(2R,3R)‐epicatechin

The first synthesis of doubly labeled, [2‐¹³C, 4‐¹³C]‐(2R,3S)‐catechin 15 and [2‐¹³C, 4‐¹³C]‐(2R,3R)‐epicatechin 18 starting from labeled 2‐hydroxy‐4, 6‐bis(benzyloxy)acetophenone 3 and labeled 3, 4‐bis(benzyloxy)‐benzaldehyde 7 are described. 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.     

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.     

Synthesis of 13C and 15N multilabeled 5‐aminolevulinic acid

5‐[4‐¹³C,¹⁵N]‐ and 5‐[5‐¹³C,¹⁵N]Aminolevulinic acid (ALA) were simply synthesized in four steps by the condensation of [1‐¹³C,¹⁵N]‐ or [2‐¹³C,¹⁵N]glycine, respectively, with phthalic anhydride, followed by conversion to the chloride, coupling reaction with a three‐carbon unit and hydrolysis. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of 13C and 15N labeled 2,4‐dinitroanisole

Syntheses of [¹³C₆]‐2,4‐dinitroanisole (ring‐¹³C₆) from [¹³C₆]‐anisole (ring‐¹³C₆) and [¹⁵N₂]‐2,4‐dinitroanisole from anisole using in situ generated acetyl nitrate and [¹⁵N]‐acetyl nitrate, respectively, are described. Treatment of [¹³C₆]‐anisole (ring‐¹³C₆) with acetyl nitrate generated in 100% HNO₃ gave [¹³C₆]‐2,4‐dinitroanisole (ring‐¹³C₆) in 83% yield. Treatment of anisole with [¹⁵N]‐acetyl nitrate generated in 10 N [¹⁵N]‐HNO₃ gave [¹⁵N₂]‐2,4‐dinitroanisole in 44% yield after two cycles of nitration. Byproducts in the latter reaction included [¹⁵N]‐2‐nitroanisole and [¹⁵N]‐4‐nitroanisole.     

Synthesis of 4‐thia[5‐13C]lysine

This report describes the synthesis of 4‐thia[5‐¹³C]lysine, an isotopomer of 4‐thialysine that is an analog of lysine. It was synthesized from 2‐amino[1‐¹³C]ethanol hydrochloride (1) in two steps. In the first step, 1 was converted to 2‐bromo[2‐¹³C]ethylamine hydrobromide (2). The reaction of cysteine with 2 in basic condition followed by acidification afforded 4‐thia[5‐¹³C]lysine hydrochloride (3).     

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 selectively 15N‐ or 13C‐labelled malachite green

Two complimentary syntheses of selectively ¹⁵N‐ or ¹³C‐labelled malachite green hydrochloride were developed in order to provide labelled ligands for structural studies of RNA aptamer/ligand complexes. The ¹⁵N‐ and ¹³C‐labelled versions of the dye have been used in NMR studies to probe the changes in the electronic charge distribution and dynamics of the dye upon binding to RNA. Copyright © 2002 John Wiley & Sons, Ltd.     

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.     

Radiosynthesis of 13N‐labeled thalidomide using no‐carrier‐added [13N]NH3

Recent studies revealed that thalidomide (1) has unique and broad pharmacological effects on multi‐targets although the application of 1 in therapy is still controversial. In this study, we synthesized nitrogen‐13‐labeled thalidomide ([¹³N]1) as a potential positron emission tomography (PET) probe using no‐carrier‐added [¹³N]NH₃ as a labeling agent. By use of an automated system, [¹³N]1 was prepared by reacting N‐phthaloylglutamic anhydride (2) with [¹³N]NH₃, following by cyclization with carbonyldiimidazole in a radiochemical yield of 56±12% (based on [¹¹N]NH₃, corrected for decay) and specific activity of 49±24 GBq/µmol at the end of synthesis (EOS). At EOS, 570–780 MBq (n=7) of [¹³N]1 was obtained at a beam current of 15 µA after 15 min proton bombardment with a synthesis time of 14 min from the end of bombardment. Using a small animal PET scanner, preliminary biodistribution of [¹³N]1 in mice was examined. 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.     

Novel synthesis of [13C4,15N]1H‐pyrrole‐2,3,5‐tricarboxylic acid: an important biomarker for melatonin metabolism

1H‐pyrrole‐2,3,5‐tricarboxylic acid is a breakdown product of melatonin. A labeled version of this compound would serve as a key biomarker for drug candidates which track this substance to monitor their effectiveness (e.g. hyperpigmentation drugs). A Hantzsch synthesis using readily available starting materials was used to generate [¹³C₄,¹⁵N]1H‐pyrrole‐2,3,5‐tricarboxylic acid in six steps (12% overall yield). Copyright © 2009 John Wiley & Sons, Ltd.     

Large‐scale preparation of 13C‐labeled 2‐(phenylthio)acetic acid and the corresponding labeled sulfoxides and sulfones

We have developed large‐scale efficient procedures for the conversion of commercially available [¹³C]‐ or [²H₃,¹³C]methanol and ¹³CO₂ or ¹³C‐labeled bromoacetic acid to 2‐(phenylthio)[1,2‐¹³C₂]‐, [1‐¹³C]‐, and [2‐¹³C]acetic acid. The resulting derivatives are versatile, chemically stable, and nonvolatile two‐carbon labeling precursors. We have used the ¹³C‐isotopomers of 2‐(phenylthio)acetic acid in the synthesis of ¹³C‐labeled acrylic acid, methacrylic acid, and trans‐crotonic acid.     

Synthesis of stable isotopes of auxinic herbicides 4‐amino‐3,5,6‐trichloropicolinic acid and 4‐amino‐3,6‐dichloropicolinic acid

Pentachloropyridine serves as a key intermediate in the synthesis of 4‐amino‐3,5,6‐trichloropicolinic acid (picloram) and 4‐amino‐3,6‐dichloropicolinic acid (aminopyralid). An M+3 stable isotope of pentachloropyridine (1, pentachloropyridine‐1‐¹⁵N‐2,6‐¹³C₂) was prepared from K¹³C¹⁵N. Isotopically labeled pentachloropyridine was then carried through a seven‐step synthesis to give an M+3 stable isotope of 4‐amino‐3,5,6‐trichloropicolinic acid (2, picloram‐1‐¹⁵N‐2,6‐¹³C₂) in an overall yield of 42%. The chlorine atom in the 5‐position of 2 was selectively removed via electrochemical reduction. Carrying out the electrochemical reduction in water provided an M+3 stable isotope of 4‐amino‐3,6‐dichloropicolinic acid (3, aminopyralid‐1‐¹⁵N‐2,6‐¹³C₂), whereas conducting the reduction in deuterium oxide produced an M+4 stable isotope (4, aminopyralid‐1‐¹⁵N‐2,6‐¹³C₂‐5‐²H). Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of [13C2]nifedipine

[¹³C₂]Nifedipine (3 ) was synthesized from [¹³C]methanol (&1macr;) in two steps. Copyright © 2003 John Wiley & Sons, Ltd.     

Biosynthesis of glucose‐d‐13C6 from Hansenula polymorpha and methanol‐13C

A simple and effective method for synthesis of glucose‐d ‐¹³C₆ by fermentation using the methylotrophic yeast Hansenula polymorpha with 99% abundance methanol‐¹³C is described. Using methanol‐¹³C as a sole source of carbon, H. polymorpha can accumulate large amounts of α,α‐trehalose‐¹³C₁₂ under unfavourable growth conditions; the trehalose can then be hydrolysed to give glucose‐d ‐¹³C₆ with 98.5% abundance ¹³C. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of carbon‐14 labeled ZJ0712, a novel strobilurin fungicide

ZJ0712, a broad‐spectrum fungicidal ingredient of strobilurin, exhibits a high protective and curative activity against plant pathogenic fungi. To support the study on its metabolism, residue, environmental behavior, and fate for safety evaluation, two versions of carbon‐14 labeled ZJ0712, methyl (E)‐2‐(2‐((2,5‐dimethylphenoxy)methyl)phenyl)‐3‐methoxy[2‐¹⁴C]acrylate ( 2 ) and methyl (E)‐2‐(2‐((2,5‐dimethyl[phenyl‐U‐¹⁴C₆]phenoxy)methyl)phenyl)‐3‐methoxyacrylate ( 3 ), were synthesized from barium [¹⁴C]carbonate in 6‐step yield of 47% and from 2,5‐dimethyl[phenyl‐U‐¹⁴C₆]phenol in the yield of 91%, respectively.