Synthesis of deuterium and 15N‐labelled 2,5‐Bis[5‐amidino‐2‐pyridyl]furan and 2,5‐Bis[5‐(methoxyamidino)‐2‐pyridyl]furan

The acetate salt of 2,5‐bis[5‐amidino‐2‐pyridyl]furan‐d₂/¹⁵N₂ ( 4) was synthesized from 2,5‐bis[5‐cyano‐2‐pyridyl]furan‐d₂ ( 2 ), through the bis‐O‐acetoxyamidoxime followed by hydrogenation. Compound 2 was obtained via a Stille coupling reaction of 6‐chloronicotinonitrile with 2,5‐bis[tri‐n‐butyltin]‐furan‐d₂ ( 1 ). 2,5‐bis[5‐amidino‐2‐pyridyl)furan‐d₆ ( 10) was synthesized from 2,5‐bis[5‐cyano‐2‐pyridyl)furan‐d₆ ( 9 ) via a direct reaction with lithium bis(trimethylsilyl)amide, followed by deprotection with ethanolic HCl. ¹⁵N and/or deuterium‐labelled methoxy‐amidines 5a ‐d₂/¹⁵N₂, 5b ‐d₈, 12 , 14 ‐d₆ were prepared in good yield via direct methylation of their respective diamidoximes with either dimethylsulfate‐d₀ or dimethylsulfate‐d₆ in DMF solution and using LiOH as a base. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of deuterium‐labelled 6‐[5‐(4‐amidinophenyl)furan‐2‐yl]nicotinamidine and N‐alkoxy‐6‐{5‐[4‐(N‐alkoxyamidino)phenyl]‐ furan‐2‐yl}‐nicotinamidines

6‐[5‐(4‐Amidinophenyl)furan‐2‐yl]nicotinamidine‐d₄ ( 5 ) was synthesized from 6‐[5‐(4‐cyanophenyl)furan‐2‐yl]nicotinonitrile‐d₄ ( 3 ), through the bis‐O‐acetoxy‐amidoxime followed by hydrogenation. Compound 3 was prepared from 6‐(furan‐2‐yl)‐nicotinonitrile by a Heck coupling reaction with 4‐bromobenzonitrile‐d₄, a product of selective cyanation reaction of 1,4‐dibromobenzene‐d₄ with Cu(1)CN. Deuterium‐labelled N‐methoxy‐6‐{5‐[4‐(N‐methoxy‐amidinophenyl]‐furan‐2‐yl}‐nicotinamidines were prepared via methylation of their respective amidoximes with dimethyl sulfate‐d₆ in aqueous sodium hydroxide in good yields. Copyright © 2004 John Wiley & Sons, Ltd.     

Syntheses of two isotopically labeled CB1 receptor antagonists

Synthesis of deuterium‐labeled CB₁ receptor antagonist 2‐d₉ was accomplished in three steps by alkylation of 2‐nitrophenylacetonitrile with cyclopentyl‐d₉ bromide, reductive cyclization of the resulting secondary nitrile into the 3‐cyclopentyl indole‐d₉ and its N‐sulfonylation with corresponding p‐amidosulfonyl chloride. Another, structurally related, CB₁ receptor antagonist 1 was radiolabeled with carbon‐14 by oxidative cleavage of 3‐cyclopentyl indole followed by the ring closure of o‐acyl substituted N‐formylaniline with potassium cyanide‐[¹⁴C], in situ reduction‐elimination of the intermediate amino alcohol, and N‐sulfonylation of the resulting 3‐cyclopentyl indole‐2‐[¹⁴C].     

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.     

Synthesis of deuterium‐labeled olmesartan and candesartan

This paper describes the synthesis of deuterium‐labeled olmesartan and candesartan. The two desired compounds both used [²H₄] 2‐cyano‐4′‐methyl‐biphenyl as deuterium‐labeled reagent, which was synthesized beforehand in two steps. [²H₄] olmesartan was synthesized in six steps further with 17% overall yield, and [²H₄] candesartan was synthesized in seven steps further with 13% overall yield. Copyright © 2012 John Wiley & Sons, Ltd.     

Investigations into the regioselective C‐deuteriation of enolates derived from 2‐methyl tetralone using piperidine‐d11

Results are reported on the regioselective C‐deuteriation of 2‐methyl tetralone using piperidine‐d₁₁ as a deuterium source. The results presented further aid the understanding of kinetic deuteriation of amine–enolate complexes. Copyright © 2004 John Wiley & Sons, Ltd.     

Efficient,scalable and economical preparation of tris(deuterium)‐ and 13C‐labelled N‐methyl‐N‐nitroso‐p‐toluenesulfonamide (Diazald®) and their conversion to labelled diazomethane

A method for the preparation of multi‐gramme quantities of N‐methyl‐d₃‐N‐nitroso‐p‐toluenesulfonamide (Diazald‐d₃) and N‐methyl‐¹³C‐N‐nitroso‐p‐toluenesulfonamide (Diazald‐¹³C) and their conversion to diazomethane‐d₂ and diazomethane‐¹³C, respectively, is presented. This approach uses robust and reliable chemistry, and critically, employs readily commercially available and inexpensive methanol as the label source. Several reactions of labelled diazomethane are also reported, including alkene cyclopropanation, phenol methylation and α‐diazoketone formation, as well as deuterium scrambling in the preparation of diazomethane‐d₂ and subsequent methyl esterification of benzoic acid.     

A facile and efficient synthesis of d6‐labeled PU‐H71, a purine‐scaffold Hsp90 inhibitor

PU‐H71 is a purine‐scaffold Hsp90 inhibitor currently undergoing late stage preclinical evaluation for the treatment of cancer. In this investigation, we present a simple method for the synthesis of d₆‐labeled PU‐H71 for use as an internal standard to accurately quantitate the drug in biological matrices based on an LC‐MS‐MS method. PU‐H71‐d₆ was synthesized in five steps using readily available 1,3‐dibromopropane‐d₆ and is an important compound for the advancement of our clinical program. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of isotopically labelled [14C]ZT‐1 (Debio‐9902), [d3]ZT‐1 and (−)‐[d3]huperzine A,a new generation of acetylcholinesterase inhibitors

A method has been developed for the synthesis of two isotopically labelled forms of a pro‐drug of the acetylcholinesterase inhibitor (?)‐huperzine A. These labelled compounds,[¹⁴C]ZT‐1 (Debio‐9902) and [d₃]ZT‐1, were used in clinical studies to evaluate a potential treatment for Alzheimer's disease. The pro‐drug [¹⁴C]ZT‐1 was isolated with a radiochemical purity of >98% and a gravimetric specific activity of 129 μCi/mg in a seven‐step synthesis starting from [U‐¹⁴C]phenol in 7% yield. Subsequently, the deuterium labelled target (?)‐[d₃]huperzine A was achieved in six steps with an overall yield of 15% and gave an isotopic distribution of d₂ (1.65% huperzine A) and d₃ (97.93% huperzine A) with a chemical purity of 98.5%. Condensation of the substrate (?)‐[d₃]huperzine A with 5‐chloro‐o‐vanillin gave the Schiff base [d₃]ZT‐1 in a chemical yield of 80%. Reduction of the Schiff base gave reduced‐[d₃]ZT‐1, which was converted into the hydrochloride salt with an isotopic distribution of d₂ (1.60%) and d₃ (98.02%). Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of d8‐geranyl diphosphate

Multiply labelled d₈‐geranyl diphosphate (3‐methyl‐7‐²H₃‐methyl‐[1,1,8,8,8]‐²H₅‐2E,6‐octadienyl diphosphate) was synthesised from geraniol in 8 steps. Geraniol was converted to [1,1]‐²H₂‐geraniol by a three step oxidation–reduction sequence in 38% yield. Selective epoxidation of [1,1]‐²H₂‐geranyl acetate gave 6,7‐epoxy‐[1,1]‐²H₂‐geranyl acetate, which, on oxidative cleavage of the epoxide and Wittig elaboration with d₆‐isopropyl triphenylphosphorane, gave d₈‐geraniol (14% yield) which was, in turn, converted to the title compound. Copyright © 2005 John Wiley & Sons, Ltd.     

A facile synthesis of 5,5‐dideutero‐4‐dimethyl(phenyl)silyl‐6‐undecyl‐tetrahydropyran‐2‐one as a deuterium labeled synthon for (−)‐tetrahydrolipstatin and (+)‐δ‐hexadecanolide

Deuterium‐labeled biologically active compounds are gaining importance because they can be utilized as tracers or surrogate compounds to understand the mechanism of action, absorption, distribution, metabolism, and excretion. Deuterated drug molecules (heavy drugs) become novel as well as popular because of better stability and bioavailability compared with their hydrogen analogs. Labeling of organic molecules with deuterium at specific positions is thus gaining popularity. In this work, we have exploited a highly regioselective and enantioselective direct Michael addition of methyl‐d₃ alkyl ketones to dimethyl(phenyl)silylmethylene malonate that was catalyzed by (S)‐N‐(2‐pyrrolidinylmethyl)pyrrolidine/trifluoroacetic acid/ D₂O combination with high yield and isotopic purity. The 5,5‐dideutero‐4‐dimethyl(phenyl)silyl‐6‐undecyl‐tetrahydropyran‐2‐one was obtained from the adduct of methyl‐d₃ undecanyl ketone and dimethyl(phenyl)silylmethylene malonate by a silicon controlled diastereoselective ketone reduction, lactonization, and deethoxycarbonylation. The dideuterated silylated tetrahydropyran‐2‐one is the precursor for geminal ²H₂‐labeled (+)‐4‐hydroxy‐6‐undecyl‐tetrahydropyran‐2‐one, an advanced intermediate for gem‐dideutero (–)‐tetrahydrolipstatin and (+)‐δ‐hexadecanolide syntheses.     

Synthesis of deuterium‐labeled pregabalin

This paper describes the synthesis of deuterium‐labeled pregabalin. The stable isotopic‐labeled compound was obtained in nine steps starting from the commercially available 4‐[²H₁₁]methylvaleric acid as the stable‐labeled reagent. It is used as an internal standard for analysis and metabolic studies. Pregabalin labeled with ²H was obtained in nine steps using the commercially available 4‐[²H₁₁]methylvaleric acid as the stable‐labeled reagent. The synthesis prevents deuterium from scrambling and offers the labeled compound with over 99% isotopic enrichment. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of N1‐tritylethane‐1,1,2,2‐d4‐1,2‐diamine: a novel mono‐protected C‐deuterated ethylenediamine synthon

A convenient and high‐yield synthesis for N¹‐tritylethane‐1,1,2,2‐d₄‐1,2‐diamine, a novel mono‐protected ethylenediamine‐C‐d₄, is reported. N¹‐tritylethane‐1,1,2,2‐d₄‐1,2‐diamine was prepared in three steps from ethylene oxide‐d₄ in a combined yield in the range 68–76%. Also reported is a synthesis of ethylenediamine‐C‐d₄ in two steps from 1,2‐dibromoethane‐d₄ in a combined yield in the range 61–65%.     

Synthesis of deuterium labelled 2‐bromobenzylamine by directed ortho‐metalation chemistry

Directed ortho‐metalation (DoM) strategy has been applied for the development of a short procedure for the regiospecific synthesis of [phenyl‐²H₄]‐2‐bromo‐benzylamine 6 starting from commercially available [phenyl‐²H₅]‐benzoyl chloride 1 . A strong isotope effect was observed during the ortho‐substitution. Copyright © 2005 John Wiley & Sons, Ltd.     

Gas phase production of [11C]methyl iodide‐d3. Synthesis and biological evaluation of S‐[N‐methyl‐11C]citalopram and deuterated analogues

Three ¹¹C‐labelled tracers for the serotonin reuptake site, S‐[N‐methyl‐¹¹C]citalopram ( [¹¹C]‐4 ), S‐[N‐methyl‐d₃‐¹¹C]citalopram ( [¹¹C]‐12 ), and S‐[N‐methyl‐¹¹C]citalopram‐α,α‐d₂ ( [¹¹C]‐13 ) were synthesized and the distribution of radioactivity after injection of radioligand was examined ex vivo in rats. The deuterated analogue of (S)‐desmethylcitalopram, (S)‐1‐(4‐fluorophenyl)‐1‐(3‐methylamino‐[3‐d₂]‐propyl)‐1,3‐di‐hydro‐isobenzofuran‐5‐carbonitrile ( 11 ), was synthesized in a multi‐step synthesis from escitalopram ( 4 ) and used as precursor in the synthesis of [¹¹C]‐13 . In analogy with the reported gas phase synthesis of [ ¹¹ C]methyl iodide the first gas phase synthesis of [¹¹C]Methyl iodide‐d₃ is reported. The ¹H/²H kinetic isotope effect related to the synthesized compounds were investigated in ex vivo rat studies, where the brain regions of interest to cerebellum ratios of the tracers [¹¹C]‐4 , [¹¹C]‐12 and [¹¹C]‐13 were compared. The ex vivo data indicated no significant differences in binding in any of the investigated brain regions after injection of the three tracers. Copyright © 2004 John Wiley & Sons, Ltd.     

The synthesis of a benzamidine‐containing NR2B‐selective NMDA receptor ligand labelled with tritium or fluorine‐18

A novel tritium or flourine‐18‐labelled benzamidine‐containing NR2B‐selective NMDA receptor ligand has been synthesized. This compound was designed to contain the fluoromethoxy group to allow for the synthesis of a high specific activity, fluorine‐18‐labelled PET tracer for imaging studies of the NR2B receptor. In addition to the fluorine‐18‐labelled compound, this compound was also tritium labelled. The tritiated ligand (11 Ci/mmol) was synthesized by a gas tritiation reaction of an aryl bromide precursor. The fluorine‐18 ligand (2916 Ci/mmol), which was deuterated in the fluoromethoxy group to aid in metabolic stability, was synthesized by alkylating a phenolic precursor with [¹⁸F]fluoromethylbromide‐d₂. Copyright © 2004 John Wiley & Sons, Ltd.     

Benzoxaborole antimalarial agents. Part 3: design and syntheses of (carboxy‐13C‐3,3‐2H2)‐labeled and (3‐14C)‐labeled 7‐(2‐carboxyethyl)‐1,3‐dihydro‐1‐hydroxy‐2,1‐benzoxaboroles

Two new isotopically labeled compounds, (carboxy‐¹³C‐3,3‐²H₂)‐7‐(2‐carboxyethyl)‐1,3‐dihydro‐1‐hydroxy‐2,1‐benzoxaborole (2) and (3‐¹⁴C)‐7‐(2‐carboxyethyl)‐1,3‐dihydro‐1‐hydroxy‐2,1‐benzoxaborole (3), were designed and synthesized to support the preclinical development studies of a potential new antimalarial agent, 7‐(2‐carboxyethyl)‐1,3‐dihydro‐1‐hydroxy‐2,1‐benzoxaborole (1). Copyright © 2012 John Wiley & Sons, Ltd.     

Labeled oxazaphosphorines for applications in mass spectrometry studies. 2. Synthesis of deuterium‐labeled 2‐dechloroethylcyclophosphamides and 2‐ and 3‐dechloroethylifosfamides

The prodrugs cyclophosphamide (CP) and ifosfamide (IF) each metabolize to an active alkylating agent through a cytochrome P450‐mediated oxidation at the C‐4 position. Competing with this activation pathway are enzymatic oxidations at the exocyclic α and α′ carbons, which result in dechloroethylation of CP and IF. The incidence of oxidation at one position relative to another is believed to be at least one factor underlying the high degree of interpatient variability in both CP and IF pharmacokinetics. As standards for the mass spectrometry quantification of dechloroethylation, the following were synthesized: (1) [4,4,5,5‐²H₄]‐2‐dechloroethylcyclophosphamide (equivalent to [4,4,5,5‐²H₄]‐3‐dechloroethylifosfamide); (2) [α,α,4,4,5,5‐²H₆]‐2‐dechloroethylcyclophosphamide (equivalent to [α,α,4,4,5,5‐²H₆]‐3‐dechloroethylifosfamide); and (3) [α,α,4,4,5,5‐²H₆]‐2‐dechloroethylifosfamide. The common precursor to all of the target compounds was [2,2,3,3‐²H₄]‐3‐aminopropanol. A one‐pot reaction of this compound with POCl₃ and unlabeled or labeled 2‐chloroethylamine hydrochloride gave the d₄ and d₆ labeled 2‐dechloroethylcyclophosphamides. The construction of the 2‐dechloroethylifosfamide from the aminopropanol required five discreet steps. Optimization of the synthetic pathways and stability studies are discussed.     

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 β3 adrenergic receptor agonist LY377604 and its metabolite 4‐hydroxycarbazole,labeled with carbon‐14 and deuterium

Synthesis of ¹⁴C‐radiolabeled 4‐hydroxycarbazole was accomplished starting from aniline‐[U‐¹⁴C], based on zinc chloride initiated Fischer cyclization of the phenylhydrazone prepared from phenylhydrazine‐[U‐¹⁴C] and cyclohexane‐1,3‐dione. The resulting tetrahydrooxocarbazole was subjected to dehydrogenation–aromatization using palladium on carbon. The aromatized 4‐hydroxycarbazole‐[4b,5,6,7,8,8a‐¹⁴C] was then used for the synthesis of ¹⁴C‐labeled β₃ adrenergic receptor agonist LY377604. The introduction of four deuteria in the carbazole fragment of LY377604 accomplished by its initial bromination and subsequent catalytic deuteration of the resulting tetrabromide. A similar approach was used for the conversion of 4‐hydroxycarbazole into its tetradeutero‐isotopomer. Copyright © 2005 John Wiley & Sons, Ltd.