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 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 [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.     

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 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 [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.     

Asymmetric synthesis of L‐[4‐13C]glutamic acid and glutamine

L ‐[4‐^l3C]Glutamic acid ( 1 ) and L ‐[4‐¹³C]glutamine ( 2 ) were synthesized from sodium [2‐¹³C]acetate ( 5 ) and Dellaria's oxazinone 3 as a chiral glycine equivalent. Sodium [2‐¹³C]acetate ( 5 ) was converted to [2‐¹³C]acrylate 4 . Diastereoselective Michael addition of the enolate of 3 to the acrylate 4 proceeded with high diastereoselectivity to give the adduct 12 . Reductive cleavage of the C–S bond, ethanolysis, hydrogenolysis and hydrolysis gave L ‐[4‐¹³C]glutamic acid ( 1 ). L ‐[4‐¹³C]Glutamine ( 2 ) was synthesized from 1 in 4 steps. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis and purification of [2‐13C]‐5‐fluorouracil

[2‐¹³C]‐5‐Fluoropyrimidine‐2,4(1H,3H)‐dione ([2‐¹³C]‐5‐fluorouracil or [2‐¹³C]‐5‐FU) is a potential diagnostic agent for measuring 5‐FU‐induced toxicity in cancer patients. It was prepared and purified with isotopic and chemical purity of>99% on a multigram scale in a two‐step synthesis from [¹³C]‐urea. Preparative separation of [2‐¹³C]‐FU and [2‐¹³C]‐uracil was carried out by automated medium pressure silica gel column chromatography. The method is applicable to a broader range of 5‐FU isotopic analogs derived from labeled uracil. Copyright © 2011 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 [13C5] and [carbonyl‐14C]‐5‐chlorofuran‐2‐carboxylic acid

The inventory of labeled compounds and methods for their preparation are constantly growing, but still more building blocks of biologically relevant compounds need to be developed. Furans are frequently encountered in bioactive molecules, and a good synthesis of labeled furan is found in the literature. We required a relatively uncommon labeled furan, 5‐chloro‐2‐furoic acid, for investigative work labeled with C‐13 and C‐14. Carboxylation of the lithium anion of [¹³C₄]furan with ¹³CO₂ followed by chlorination using benzyltrimethylammonium dichloroiodate provided the target compound in modest yield and high purity. The same procedure was then repeated with unlabeled furan and ¹⁴CO₂ to give [carbonyl‐¹⁴C]‐5‐chlorofuran‐2‐carboxylic acid. Copyright © 2010 John Wiley & Sons, Ltd.     

An asymmetric synthesis of l‐[3‐13C]alanine

l ‐[3‐¹³C]Alanine was synthesized from [¹³C]methyl iodide by using Dellaria's oxazinone, prepared from phenyl[2‐¹³C]bromoacetate and (S)‐2‐phenylglycinol, as a chiral glycine equivalent. Alkylation of the oxazinone with [¹³C]methyl iodide was achieved with high diastereoselectivity. Hydrolysis and removal of the chiral auxiliary of the alkylated oxazinone gave l ‐[3‐¹³C]alanine. Copyright © 2003 John Wiley & Sons, Ltd.     

A method for the preparation of [13C6]‐labelled 2‐substituted naphthalenes

A reliable route is described for the preparation of various 2‐substituted derivatives of [1,2,3,4,4a,8a‐¹³C₆]‐naphthalene via the bromide 10. The approach is used to prepare [naphthalene‐1,2,3,4,4a,8a‐¹³C₆]‐2‐(2‐bromoethyl)naphthalene (1), a key intermediate in the synthesis of labelled SR57746A, Xaliproden (2). Copyright © 2010 John Wiley & Sons, Ltd.     

One‐pot radiosynthesis of [13N]urea and [13N]carbamate using no‐carrier‐added [13N]NH3

The aim of this study was to develop a practical labeling method of [¹³N]ligands using no‐carrier‐added [¹³N]NH₃ with high specific activity. [¹³N]urea analogues [¹³N]1a and [¹³N]2a or [¹³N]carbamate [¹³N]3a were synthesized by reacting isocyanate 5a, carbamoyl chloride 6a or chloroformate 7a with [¹³N]NH₃. The precursors 5a–7a were prepared by treating amines 8a and 9a and alcohol 10a with triphosgene in situ. These reaction mixtures were not purified and were used directly for [¹³N]ammonolysis, respectively. Using the one‐pot method, we synthesized [¹³N]carbamazepine ([¹³N]4), a putative positron emission tomography ligand for brain imaging. Copyright © 2009 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.     

Syntheses of stable‐isotope labeled [M+7] and [M+6] 2‐(methylamino)imidazole

Stable isotope‐labeled 2‐methylaminoimidazole (M+7 and M+6) was required as an intermediate in the synthesis of mass labeled drug candidates. These two isotopomers were synthesized with total yields of 24 and 36%, respectively. Labeled 2‐aminoimidazole (M+4) was prepared from labeled isothiourea (M+3) and 2‐aminoacetaldehyde dimethyl acetal (M+1 and M+2). The (M+1) version of 2‐aminoacetaldehyde dimethyl acetal was obtained in two steps starting with potassium [¹⁵N]phthalimide, while the (M+2) version was prepared from the reduction of diethoxyacetamide with LiAlD₄. Two different approaches for the preparation of 2‐methylaminoimidazole from aminoimidazole were explored. Attempts to prepare protected 2‐aminoimidazole to couple with CH₃I (M+4) to form the desired labeled 2‐methyl‐aminoimidazole failed. However, methylation was achieved by applying N‐formamidation followed by deutero‐reduction. These successful syntheses allowed us to selectively label with nitrogen, carbon or hydrogen isotopes at most of the positions of 2‐methylaminoimidazole. Copyright © 2002 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 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 [13C2]nifedipine

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