Synthesis of deuterium‐labeled 3‐O‐methyldopa and 4‐O‐methyldopa

Concise methods for the synthesis of 4‐hydroxy‐3‐[²H₃]‐methoxyphenylalanine (3‐O‐[²H₃]‐methydopa) and 3‐hydroxy‐4‐[²H₃]‐methoxyphenylalanine (4‐O‐[²H₃]‐methydopa) are described. The 3‐O‐[²H₃]‐methydopa is a valuable internal standard for the tandem MS quantification of 3‐O‐methyldopa, a metabolite of value in the diagnosis of aromatic l‐amino acid decarboxylase (AADC) deficiency. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of [phenyl‐13C6]lachnanthocarpone and other 13C‐labelled phenylphenalenones

[phenyl‐¹³C₆]Lachnanthocarpone ([phenyl‐¹³C₆]2,6‐dihydroxy‐9‐phenylphenalen‐1‐one), a hypothetical intermediate in the biosynthesis of various natural phenylphenalenones, was prepared in four steps using [U‐¹³C]bromobenzene to introduce the label. Based on related methodologies further native phenylphenalenones such as [phenyl‐¹³C₆]anigorufone, [1‐¹³C]anigorufone and [4′‐O¹³CH₃]4′‐methoxyanigorufone were synthesized in labelled form. Copyright © 2004 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.     

The synthesis and structures of deuterium‐labeled 5‐substituted 1H‐tetrazoles

The synthesis and crystal structures of deuterium‐labeled 5‐substituted 1H‐tetrazoles, 5‐[²H₅]phenyl‐1H‐tetrazole (I), 5‐[²H₇]tolyl‐1H‐tetrazole (II), and 5‐[²H₇]benzyl‐1H‐tetrazole (III) are reported. All syntheses were carried out using simple, facile steps and the products were obtained in high yields. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of herbicidal ZJ0273 labeled with tritium and carbon‐14

ZJ0273, propyl 4‐(2‐(4,6‐dimethoxypyrimidin‐2‐yloxy)benzylamino)benzoate, is a broad‐spectrum herbicidal ingredient used for weed control in oilseed rape in China. Two mono‐labeled ZJ0273, propyl 4‐(2‐(4,6‐dimethoxypyrimidin‐2‐yloxy)[phenyl‐3,4,5,6‐³H₄]benzylamino)benzoate (7) and propyl 4‐(2‐(4,6‐dimethoxy[4,6‐¹⁴C₂]pyrimidin‐2‐yloxy)benzylamino)benzoate (12), were synthesized separately from [2,3,4,5,6‐³H₅]phenol in a four‐step yield of 27% and from 4,6‐dichloro‐2‐(methylthio)[4,6‐¹⁴C₂]pyrimidine in a three‐step yield of 54%. In addition, two dual‐labeled analogues of ZJ0273 were prepared by homogeneously mixing tritium‐labeled ZJ0273 (7) in the benzyl ring separately with two carbon‐14‐labeled ZJ0273 (2, 12) in the benzoate ring and the pyrimidine ring. These labeled ZJ0273 could be used as radiotracers in the studies on the metabolism, mode of action, environmental behavior, and fate of ZJ0273. Copyright © 2008 John Wiley & Sons, Ltd.     

The synthesis of [phenyl‐2H5]gluconasturtiin and its metabolites for metabolic studies

The synthesis of a deuterium labelled glucosinolate, [²H₅]gluconasturtiin, is described starting from [²H₅]bromobenzene. The potential metabolites of the glucosinolate, namely the [phenyl‐²H₅]phenethyl isothiocyanate, nitrile, thiocyanate, amine and the mercapturic acid conjugate of phenethyl isothiocyanate are also described. This series of compounds has been prepared for use in feeding studies to examine the mammalian metabolism of gluconasturtiin and search for new biomarkers of exposure. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of deuterium labeled standards of 5‐methoxy‐N,N‐dimethyltryptamine (5‐Meo‐DMT)

The Batcho‐Leimgruber strategy was employed to synthesize 5‐[²H₃]‐methoxy‐1 H‐indole 4 from commercially available 5‐hydroxy‐2‐nitrotoluene 1 and CD₃I. Compound 4 was treated with oxalyl chloride, dimethylamine and lithium aluminum hydride to yield 5‐[²H₃]‐methoxy‐N,N‐dimethyltryptamine 6 . Copyright © 2006 John Wiley & Sons, Ltd.     

The preparation of [pentane‐5,5,5‐3H3]‐abnormal‐cannabidiol

A bromoalkane precursor was synthesized in six steps, and its copper catalysed coupling with methylmagnesium chloride to provide unlabelled abnormal‐cannabidiol (1a) was optimized. The methodology was used for an analogous coupling using [³H₃]‐methylmagnesium iodide to provide [pentane‐²H₃]‐abnormal‐cannabidiol (1b). Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of benzoxazole‐[phenyl‐13C6] by directed ortho‐metalation chemistry

A new method for the preparation of benzoxazole‐[phenyl‐¹³C₆] ( 1 ) starting from aniline‐[¹³C₆] ( 4 ) has been developed involving directed ortho‐metalation (DoM) chemistry. The synthesis comprises four steps and an overall yield of 39% was obtained. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of deuterium and C‐13‐labelled ethyl glycolate and their subsequent use in the synthesis of labelled analogues of the DNA adduct O6‐carboxymethyl‐2′‐deoxyguanosine

The adduct O⁶‐carboxymethyl‐2′‐deoxyguanosine (O⁶CMdG) is of importance as it has been previously linked to high red meat diet in humans, and as yet, a liquid chromatography‐mass spectrometry (LC‐MS) method has not been developed due to lack of appropriate standards. The synthesis of the deuterated and C‐13 analogues required the use of [²H₂]‐ and [¹³C₂]ethyl glycolate to label the carboxymethyl moiety of O⁶CMdG. [²H₂]Ethyl glycolate was synthesised via acid hydrolysis of ethyl diazoacetate using deuterated solvents (59% yield), whilst [¹³C₂]ethyl glycolate was synthesised from [¹³C₂]glycine in a three‐step procedure (35% yield). The labelled ethyl glycolates were then used to synthesise [²H₂]‐ and [¹³C₂]O⁶CMdG for future use as internal standards in the LC‐MS analysis of biological samples. Copyright © 2011 John Wiley & Sons, Ltd.     

Ring‐chain tautomerism in 2,2‐bis(2‐thienyl)tetrahydrofurans: preparation of [butene‐2H5]‐tiagabine

A concise preparation of [butene‐²H₅]‐tiagabine hydrochloride starting from [²H₆]‐γ‐butyrolactone is described. It was necessary to ring‐open the labeled γ‐butyrolactone precursor before the addition of 2‐thienyllithium to avoid cyclisation of the intermediate to a 2,2‐bis(2‐thienyl)tetrahydrofuran. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of N‐(2‐chloro‐5‐methylthiophenyl)‐ N′‐(3‐methyl‐thiophenyl)‐ N′‐[3H3]methylguanidine, {[3H3]CNS‐5161}

The preparation of the title compound, [³H₃]CNS‐5161, was accomplished in three steps starting with the production of [³H₃]iodomethane (CT₃I). The intermediate N‐[³H₃]methyl‐3‐(thiomethylphenyl)cyanamide was prepared in 77% yield by the addition of CT₃I to 3‐(thiomethylphenyl)cyanamide, previously treated with sodium hydride. Reaction of this tritiated intermediate with 2‐chloro‐5‐thiomethylaniline hydrochloride formed the guanidine compound [³H₃]CNS‐5161. Purification by HPLC gave the desired labeled product in an overall yield of 9% with >96% radiochemical purity and a final specific activity of 66 Ci mmol^?1. Copyright © 2002 John Wiley & Sons, Ltd.     

Isotope labeled ‘HEA Moiety’ in the synthesis of labeled HIV‐protease inhibitors – Part 1

[(S)‐1′‐((N‐tert‐Butyloxycarbonyl)amino)‐2S‐[²H₅]phenyl‐ethyl]oxirane 11 , made from [²H₅]‐bromobenzene, was transformed into the HIV‐protease inhibitors [²H₅]‐DPH 153893 and [²H₅]‐DPH 140662. Both compounds are members of the hydroxyethylamine class of protease inhibitors (HIV‐PIs). The method of synthesis is applicable to members of this class and the HEE group of HIV‐PIs. Copyright © 2004 John Wiley & Sons, Ltd.     

Isotope labeled ‘HEA/HEE’ moiety in the synthesis of labeled HIV‐protease inhibitors—Part II

[²H₅]‐Amprenavir and [²H ₅]‐saquinavir have been prepared from a common labeled precursor (1S, 2S)‐(1‐oxiranyl‐2‐[²H₅]phenylethyl)‐carbamic acid tert‐butyl ester, 1 . Both of these compounds are in the ‘HEA’ class of HIV protease inhibitors. [²H₅]‐Indinavir, a representative of the ‘HEE’ group of protease inhibitors, has also been synthesized. In the case of indinavir, 1S‐(2,2‐dimethyl‐8, 8a‐dihydro‐3aH‐indeno‐[1,2‐d]‐oxazol‐3R‐yl)‐2‐oxiranylmethyl‐3‐[²H₅]phenylpropan‐1‐one, 11 , provided the [phenyl‐²H₅]‐HEE core structure for synthesis of the desired labeled compound. Copyright © 2005 John Wiley & Sons, Ltd.     

An overview of radio or stable isotope‐labeled cis‐neonicotinoid analogs

To support the metabolism and toxicology study of cis‐neonicotinoids, radio or stable isotope was introduced into different sites of the key intermediate 2‐chloro‐5‐((2‐(nitromethylene)imidazolidin‐1‐yl)methyl)pyridine (6‐Cl‐PMNI). [³H₂]‐ and [¹⁴C]‐label were successively prepared from initial materials NaB³H₄ and [¹⁴C]‐nitromethane, respectively. Similarly, [D₂]‐6‐Cl‐PMNI was prepared from NaBD₄ in four steps, with 52.6% overall isotopic yield, and dual‐labeled [D₂, ¹³C]‐target was obtained from NaBD₄ and [¹³C]‐nitromethane, affording overall isotopic yield of 42.5%. Moreover, [¹⁴C₂] was introduced from [U‐¹⁴C]‐ethylenediamine dihydrochloride in three steps, with a 58.3% overall chemical yield. Finally, typical labeled cis‐neonicotinoids paichongding and cycloxaprid were prepared and characterized. The methods were proved to have good generality in the synthesis of other cis‐neonicotinoids, and all results would be useful in metabolism studies of new cis‐neonicotinoids. Copyright © 2012 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.     

Synthesis of a highly potent leukocyte function‐associated antigen‐1 antagonist and its metabolite labeled with stable isotopes and carbon‐14, part 2

(S)‐2‐[(R)‐7‐(3,5‐Dichlorophenyl)‐5‐methyl‐6‐oxo‐5‐(4‐trifluoromethoxybenzyl)‐6,7‐dihydro‐5H‐imidazo[1,2‐a]imidazole‐3‐sulfonylamino]‐proprionamide (1), a potent lymphocyte function‐associated antigen‐1 antagonist and its sulfonamide metabolite (2) labeled with stable isotopes and carbon‐14 were prepared for Drug Metabolism and PharmacoKinetics and other studies. A long linear route was used to prepare [¹³C₂, ²H₃]‐(1) using [3,3,3‐²H]‐D‐alanine and [¹³C₂]‐glycine in 15 steps and 2.5% overall yield. With the availability of [¹³C₆]‐3,5‐dichloroaniline, the sulfonamide [¹³C₆]‐(2) was prepared in 12 steps and in 5.6% overall yield. For the carbon‐14 synthesis, a six‐step synthesis gave both compounds [¹⁴C]‐(1) and [¹⁴C]‐(2) from the common sulfonyl chloride intermediate [¹⁴C]‐(15) in 18% and 4% radiochemical yields and specific activities of 44 and 40.5 mCi/mmol, respectively. Copyright © 2011 John Wiley & Sons, Ltd.     

Preparation of labelled 2‐methoxy‐3‐alkylpyrazines: synthesis and characterization of deuterated 2‐methoxy‐3‐isopropylyrazine and 2‐methoxy‐3‐isobutylpyrazine

Efficient synthetic routes for a number of deuterated analogues of 2‐methoxy‐3‐isopropylpyrazines and 2‐methoxy‐3‐isobutylpyrazines have been developed involving the condensation of glyoxal with an α‐amino acid amide followed by methylation with iodomethane. In this way [²H₃]2‐methoxy‐3‐isopropylpyrazine, 2‐methoxy‐3‐isopropyl‐[²H₂]pyrazine, [²H₃]2‐methoxy‐3‐isopropyl‐[²H₂]pyrazine, [²H₃]2‐methoxy‐3‐isobutylpyrazine; 2‐methoxy‐3‐isobutyl‐[²H₂]pyrazine and [²H₃]2‐methoxy‐3‐isobutyl‐[²H₂]pyrazine were prepared and characterized by NMR and MS. Copyright © 2002 John Wiley & Sons, Ltd.     

An innovative and efficient synthesis of stable isotope labelled 1‐methyl‐5‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H‐pyrazole via [13C42H3] N‐methylpyrazole

In support of a programme to develop a treatment for cancer, a stable isotope labelled version of the drug candidate was required. The key labelled intermediate was [¹³C₄²H₃] N‐methylpyrazole prepared by a novel bisacetal cyclisation. This was prepared from commercially available diethyl [¹³C₃] malonate and [¹³C²H₃] iodomethane. Copyright © 2012 John Wiley & Sons, Ltd.     

A gram‐scale synthesis of [3,4‐13C2,1α,7‐2H2]cortisone

A gram‐scale synthesis of [3,4‐¹³C₂,1α,7‐²H₂]cortisone from prednisone was developed. The deuterium atom at the C‐1 position was introduced through a regioselective and stereoselective deuteration of the 1,2‐double bond of the 1,4‐diene‐3‐one using Wilkinson's catalyst. After the oxidative cleavage of the A‐ring, two carbon‐13 atoms were introduced via acetylation of an A‐ring enol lactone with [1,2‐¹³C₂]acetyl chloride. The steroidal A‐ring was then reconstructed to incorporate the carbon‐13 atoms into the C‐3 and C‐4 positions. The deuterium atom at C‐7 was introduced through a regioselective deuteration of the 6,7‐double bond of a 4,6‐diene‐3‐one intermediate using palladium on strontium carbonate. The M + 4 stable isotope labeled cortisone was thus prepared in ca. 4% overall yield. In addition, [3,4‐¹³C₂,1α,7‐²H₂]‐11‐dehydrocorticosterone, [3,4‐¹³C₂,1α,7‐²H₂]cortisol, and [3,4‐¹³C₂,1α,7‐²H₂]corticosterone were also prepared. Copyright © 2011 John Wiley & Sons, Ltd.