A convenient method for palladium‐catalyzed reductive deuteration of organic substrates using deuterated hypophosphite in D2O

A convenient method for the deuteration of organic substrates using deuterated hypophosphite as the deuterium source was investigated. Transfer deuteration of organic substrates, such as aromatic halides, alkenes, alkynes, epoxides, and O‐benzyl derivatives, in the presence of palladium on carbon in deuterium oxide proceeded efficiently to give the corresponding deuterated products in excellent yields with high deuterium contents.     

Investigations into the C‐deuteriation of silyl enol ethers derived from aryl alkyl ketones

Results are reported on the regioselective C‐deuteriation of a series of silyl enol ethers derived from aryl alkyl ketones using deuterium (D₂) gas as the deuterium source and palladium‐on‐barium sulfate as the mediator. These results highlight the numerous reaction pathways and different product types available from simple deuteriation of substituted enol precursors. Copyright © 2006 John Wiley & Sons, Ltd.     

Real‐time monitoring of tritium gas reactions using Raman spectroscopy

The utility of Raman spectroscopy for noninvasive, real‐time monitoring of a range of tritium gas labeling reactions has been investigated, using deuterium gas as a model in most cases. Reaction types include organoiridium‐catalyzed heteroatom‐directed exchange (HDE), olefin hydrogenation and catalytic aryl dehalogenation. Five examples of HDE reactions with several different substrate types were monitored by observation of Raman vibrational bands sensitive to the isotopic substitutions. Changes in peak intensities and/or frequencies associated with the course of labeling are clearly observable at concentrations and reaction scales typical of tritium gas reactions. Similarly, Raman bands sensitive to the chemical changes that occur during catalytic deuterogenation of an olefin and to catalytic deuterium–bromine exchange of an aryl bromide were successfully monitored. This methodology can provide unprecedented real‐time information, otherwise difficult to obtain, over the course of such reactions. Copyright © 2004 John Wiley & Sons, Ltd.     

Combinatorial synthesis of labelled drugs and PET tracers: synthesis of a focused library of 11C‐carbonyl‐labelled acrylamides as potential biomarkers of EGFR expression

Combinatorial synthesis is extensively used in drug development and lead optimisation. However, this approach has rarely been used for positron emission tomography because of limitations in available technologies. [¹¹C]Carbon monoxide is amenable to combinatorial synthesis in transition‐metal‐catalysed reactions because it can react with a wide variety of electrophiles and nucleophiles, which opens up the possibilities for combinatorial radiochemistry. Herein, we exemplify the combinatorial approach by ¹¹C‐labelling a library of epidermal growth factor receptor inhibitors. The selection of candidates was guided by molecular docking. Epidermal growth factor receptor is overexpressed in a variety of tumours, and it has become an important drug target. The ¹¹C‐labelling reactions were performed using four substituted vinyl iodides and three different 4‐anilino‐6‐aminoquinazolines using a palladium‐mediated reaction with [¹¹C]carbon monoxide using a single set of reaction conditions. In total, 12 labelled acrylamide derivatives were radiolabelled and obtained in 24–61% decay‐corrected radiochemical yield (from [¹¹C]carbon monoxide). Starting from 5.6 GBq [¹¹C]carbon monoxide, 0.85 GBq of formulated N‐[4‐(3‐bromo‐phenylamino)‐quinazolin‐6‐yl]‐acryl[¹¹C]amide [¹¹C]12da was obtained within 47 min from end of bombardment (specific activity of 60 GBq µmol^?1). This strategy is an example of how [¹¹C]carbon monoxide can be utilised in the labelling of libraries of drug candidates and positron emission tomography tracers for in vitro and in vivo testing.     

Efficient tritiation of the translocator protein (18 kDa) selective ligand DPA‐714

DPA‐714 (N,N‐diethyl‐2‐(2‐(4‐(2‐fluoroethoxy)phenyl)‐5,7‐dimethylpyrazolo[1,5‐a]pyrimidin‐3‐yl)acetamide) is a recently discovered fluorinated ligand of the translocator protein 18 kDa (TSPO). Labelled with the short‐lived positron emitter fluorine‐18, this structure is today the radioligand of reference for in vivo imaging of microglia activation and neuroinflammatory processes with positron emission tomography. In the present work, an isotopically tritium‐labelled version was developed ([³H]DPA‐714), in order to access high resolution in vitro and ex vivo microscopic autoradiography studies, repeated and long‐lasting receptor binding studies and in vivo pharmacokinetic determination at late time points. Briefly, DPA‐714 as reference, and its 3,5‐dibrominated derivative as precursor for labelling, were both prepared from DPA‐713 in nonoptimized 32% (two steps) and 10% (three steps) yields, respectively. Reductive debromination using deuterium gas and Pd/C as catalyst in methanol, performed at the micromolar scale, confirmed the regioselective introduction of two deuterium atoms at the meta positions of the phenyl ring. Tritiodebromination was analogously performed using no‐carrier tritium gas. HPLC purification provided >96% radiochemically pure [³H]DPA‐714 (7 GBq) with a 2.1 TBq/mmol specific radioactivity. Interestingly, additional hydrogen‐for‐tritium exchanges were also observed at the 5‐methyl and 7‐methyl positions of the pyrazolo[1,5‐a]pyrimidine, opening novel perspectives in the labelling of compounds featuring this heterocyclic core.     

Investigations into the C‐deuteriation of enol acetates derived from aryl alkyl ketones

Results are reported on the regioselective C‐deuteriation of a series of enol acetates (derived from the aryl alkyl ketones) using molecular deuterium as the D‐source and palladium‐on‐barium sulphate as the mediator. The results presented highlight potential problems associated with the deuteriation of enol acetates. Copyright © 2005 John Wiley & Sons, Ltd.     

Practical approaches to labelling terminal alkynes with deuterium

Base catalysed exchange with sodium hydroxide, calcium oxide or N,N,N,N-tetramethylguanidine in deuterium oxide is a viable procedure for the preparation of terminally deuterated alkynes for those alkynes stable to strong base. The use of silver perchlorate as a catalyst is an alternative practical option when labelling alkynes which are sensitive to base or contain functionalities which would lead to labelling elsewhere in the molecule. Labelling with this catalyst takes place smoothly at ambient temperature in a mixture of N,N-dimethylformamide and deuterium oxide.     

Tritium labelling of PACAP‐38 using a synthetic diiodinated precursor peptide

In the interest of developing efficient methods for tritium labelling peptides, we here demonstrate the successful labelling of PACAP‐38 (pituitary adenylate cyclase‐activating polypeptide), a 38‐mer peptide, using a synthetic diiodinated PACAP‐38 precursor. In this example, we employ standard hydrogenation chemistry with the use of a heterogeneous palladium catalyst and carrier‐free tritium gas on a tritium manifold system. Copyright © 2011 John Wiley & Sons, Ltd.     

Radiobromination of closo‐carboranes using palladium‐catalyzed halogen exchange

closo‐Carborane derivatives are often proposed as boron carriers for use in boron neutron capture therapy (BNCT) of cancer. A positron emitting radiolabel on a boron atom in such carborane compounds might facilitate pharmacokinetic studies in patients. In this paper the four iodo‐closo‐carboranes, namely 3‐iodo‐ortho‐carborane, 9‐iodo‐ortho‐carborane, 9‐iodo‐meta‐carborane and 2‐iodo‐para‐carborane were chosen as model compounds in a study of [⁷⁶Br]bromine labelling of carboranes using palladium‐catalyzed halogen exchange. It was found that within a reaction time of 40 min, the four compounds were all radio‐brominated in good to excellent yield, using Herrmann's catalyst (HC) in toluene. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of four racemic nicotine isotopomers doubly labelled with stable isotope

Four racemic nicotine isotopomers, doubly labelled with stable isotope, were prepared for use in studies of plant metabolism. First, starting from halogeno nicotinates, one deuterium was introduced into the pyridine moiety by reductive dehalogenation with zinc, and choosing deuterated acetic acid as the acidic medium. Pyridine ²H‐labelled nornicotine derivatives were then formed in two reaction steps, a condensation reaction with N‐vinylpyrrolidinone followed by catalytic hydrogenation. The deuteromethylation of these monodeuterated nornicotines was achieved by reduction of the corresponding ethyl carbamates with deuterated lithium aluminium hydride. The four regioisotopomers obtained were at the least 90% labelled on each site, sufficient for the metabolic studies envisaged. Copyright © 2009 John Wiley & Sons, Ltd.     

Convenient methods for the synthesis of d4, d2 and d6 isotopomers of 4‐(4‐fluorobenzyl)piperidine

Pure 4‐(4‐fluoro‐[2,3,5,6‐²H₄]benzyl)piperidine was prepared via the Grignard reaction of 4‐fluoro‐[2,3,5,6‐²H₄]bromobenzene and pyridine‐4‐aldehyde followed by consecutive deoxygenation and heteroatomic ring saturation in the presence of palladium on carbon catalyst. An improved method for the catalytic H/D exchange in benzylic positions of 4‐(4‐fluorobenzyl)piperidine and its d₄ derivative has also been described. Copyright © 2005 John Wiley & Sons, Ltd.     

The effect of adding Crabtree's catalyst to rhodium black in direct hydrogen isotope exchange reactions

A new catalytic system based on rhodium black using Crabtree's catalyst as an additive for direct hydrogen isotope exchange in aromatic compounds has been investigated. The level of deuterium incorporation can be improved from for example 16 to 93%. The new catalyst mixture tolerates a variety of solvents. Copyright © 2009 John Wiley & Sons, Ltd.     

Labelling of anilines,benzylamines and some N‐heterocyclics using cycloocta‐1,5‐dienyliridium(I)‐1,1,1,5,5,5‐hexafluoro‐pentan‐2,4‐dionate and isotopic hydrogen gas in DMF or DMA

A wide range of anilines, benzylamines and some N‐heterocyclics can be ortho‐deuterated at room temperature using deuterium gas and cycloocta‐1,5‐dienyliridium(I)‐1,1,1,5,5,5‐hexafluoropentan‐2,4‐dionate in DMF or DMA. The method is applicable to labelling with tritium. Copyright © 2004 John Wiley & Sons, Ltd.     

Non-mast cell histamine kinetics. V. 3 H-histamine formation in vivo and effects of precursor pool perturbations

The analysis of homovanillic acid (HVA) in serum of humans and goats is described for the first time. The method uses gas chromatographic separation and mass spectrometric detection with the deuterated methyl ester of HVA as an internal standard. Simultaneous measurement of the protium and deuterium forms was performed with a multiple ion detector focused at the molecular ions of the methyl ester heptaflurobutyryl derivatives. The method has high specificity, a precision of ±10% (S.E.) and a sensitivity which determines normal levels (100 pmole/ml) at 10 times above the background. The serum level in man was increased several fold following physical exercise. In goats probenecid elevated the level of HVA, whereas nialamide had the opposite effect.     

Synthesis of carbon‐14 and stable isotope labelled NN414: a potent potassium channel opener

Currently, NN414, a potent β‐cell selective potassium channel opener, is undergoing clinical trials for the treatment of type 2 diabetes. Here, we report the synthesis of carbon‐14 and stable isotope labelled NN414 for use in metabolic studies and as an internal standard in pharmacokinetic assays, respectively. The carbon‐14 labelling was performed in two steps starting from an advanced intermediate. This provided [¹⁴C]NN414 in 60% overall radiochemical yield with a specific activity of 58mCi/mmol. The stable isotope labelling was accomplished from benzyl tert‐butyl malonate in eight steps using [¹³C,²H₃]iodomethane and [²H₂]dibromomethane as the source of carbon‐13/deuterium. The synthetic sequence, which included a Mannich reaction followed by deamination, a Simmons–Smith‐type cyclopropanation and a modified Curtius reaction, provided [¹³C,²H₅]NN414 in 8.6% overall yield. Copyright © 2004 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.     

依西美坦的合成工艺优化

雄甾-4-烯-3,17-二酮(2)、原甲酸三乙酯和对甲基苯磺酸—水合物在四氢呋喃和乙醇中进行烯醇醚化反应,产物不经分离,反应液中直接加入N-甲基苯胺和37％甲醛溶液进行Mannich反应,再在酸性条件下进行消除反应,以71％的收率得到关键中间体6-亚甲基雄甾-4-烯-3,17-二酮(3).3经钯催化的选择性1,2脱氢反...     

Benzylic deuteration of alkylnitroaromatics via amine-base catalysed exchange with deuterium oxide

This paper describes the deuterium-labelling of alkylnitroaromatics by base-catalysed exchange with deuterium oxide. As the alkyl protons alpha to the aromatic ring are the most acidic sites in the molecule, regioselective hydrogen isotope exchange at this benzylic location leads to a regiospecifically deuterated product. The exchange labelling takes place in good yields and with high atom% abundance in the presence of an appropriate nitrogen base. Alkylated 2,4-dinitrobenzenes deuterate at room temperature under catalysis by triethylamine, whilst alkylated 2-nitro- or 4-nitrobenzenes and related mono-nitroaromatics require higher temperatures and catalysis by 1,5-diazobicyclo[4.3.0]non-5-ene (DBN). The labelling reactions require an inert gas atmosphere, but otherwise are simple and high yielding with no obvious byproducts. Those compounds in which the benzylic protons are in an ortho-orientation with respect to the nitro group label somewhat more slowly than the analogues where there is a para relationship. In addition, higher alkyl homologues undergo benzylic deuteration at slower rates than methyl.     

NMR analysis of t‐butyl‐catalyzed deuterium exchange at unactivated arene localities

Regioselective labelling of arene rings via electrophilic exchange is often dictated by the electronic environment caused by substituents present on the aromatic system. Previously, we observed the presence of a t‐butyl group, either covalently bond or added as an external reagent, could impart deuterium exchange to the unactivated, C1‐position of estrone. Here, we provide nuclear magnetic resonance analysis of this exchange in a solvent system composed of 50:50 trifluoroacetic acid and D₂O with either 2‐t‐butylestrone or estrone in the presence of t‐butyl alcohol has shed insights into the mechanism of this t‐butyl‐catalyzed exchange. Fast exchange of the t‐butyl group concurrent with the gradual reduction of the H1 proton signal in both systems suggest a mechanism involving ipso attack of the t‐butyl position by deuterium. The reversible addition/elimination of the t‐butyl group activates the H1 proton towards exchange by a mechanism of t‐butyl incorporation, H1 activation and exchange, followed by eventual t‐butyl elimination. Density functional calculations are consistent with the observation of fast t‐butyl exchange concurrent with slower H1 exchange. The σ‐complex resulting from ipso attack of deuterium at the t‐butyl carbon was 6.6 kcal/mol lower in energy than that of the σ‐complex resulting from deuterium attack at C1. A better understanding of the t‐butyl‐catalyzed exchange could help in the design of labelling recipes for other phenolic metabolites.     

Feasibility of palladium‐catalyzed isotopic exchange between sodium [125I]I and 2‐iodo‐para‐carborane

Many ortho‐/meta‐/para‐closo‐carborane derivatives have been proposed for boron neutron capture therapy. However, it is difficult to follow their pharmacokinetics in patients, which creates a risk of suboptimal treatment. Adding a radioactive label to closo‐carboranes may simplify pharmacokinetic studies. This paper reports on a study of the feasibility of palladium‐catalyzed isotopic exchange of iodinated closo‐carborane with radioisotopes of iodine. 2‐iodo‐para‐carborane was selected as a model compound. It was shown that such isotopic exchange is possible and provides a high yield (83±4.2%) after 40 min of reaction time. The reaction conditions were optimized, and it was demonstrated that the presence of tetra n‐butylammonium hydrogensulfate is important in order to stabilize the catalyst and to give reproducibility of the labeling. Copyright © 2003 John Wiley & Sons, Ltd.