Synthesis of the carbon‐14 labeled isotopomers of (R)‐N‐methyl‐3‐[2‐methylphenoxyl]‐benzenepropanamine hydrochloride (atomoxetine hydrochloride,LY139603), and two of its metabolites

Carbon‐14 labeled Straterra^TM (Atomoxetine HCl, LY139603, (‐)‐N‐methyl‐3‐(2‐methylphenoxy)‐benzenepropanamine hydrochloride), a potent inhibitor of the presynaptic norepinephrine transporter, and two of its major metabolites were synthesized. The key component, S‐(+)‐3‐chloro‐l‐phenyl‐l‐propanol‐[1‐¹⁴C] was synthesized by Stille coupling of benzoyl chloride‐[carbonyl‐¹⁴C] with vinyl tri‐n‐butylstannane, followed by HCl addition to the vinyl ketone, and asymmetric reduction of the ketone by Corey's CBS reagent. Mitsunobu reaction of this S‐(+)‐3‐chloro‐l‐phenyl‐l‐propanol‐[1‐¹⁴C] with various phenol derivatives, followed by converting the chloride to amines, gave desired products. 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.     

Facile synthesis of stable isotope‐labeled antibacterial agent RWJ‐416457 and its metabolite

Synthesis of multiple stable isotope‐labeled antibacterial agent RWJ‐416457, (N‐{3‐[3‐fluoro‐4‐(2‐methyl‐2,6‐dihydro‐4H‐pyrrolo[3,4‐c]pyrazol‐5‐yl)‐phenyl]‐2‐oxo‐oxazolidin‐5‐ylmethyl}‐acetamide), and its major metabolite, N‐{3‐[4‐(2,6‐dihydro‐4H‐pyrrolo[3,4‐c]pyrazol‐5‐yl)‐3‐fluoro‐phenyl]‐2‐oxo‐oxazolidin‐5‐ylmethyl}‐acetamide, is described. The stable isotope‐labeled [¹³CD₃]RWJ‐416457 was prepared readily by acetylation of the precursor amine, 5‐aminomethyl‐3‐[3‐fluoro‐4‐(2‐methyl‐2,6‐dihydro‐4H‐pyrrolo[3,4‐c]pyrazol‐5‐yl)‐phenyl]‐oxazolidin‐2‐one with CD₃¹³COCl in pyridine. Synthesis of the stable isotope‐labeled metabolite involved a construction of multiple isotope‐labeled pyrazole ring. N,N‐dimethyl(formyl‐¹³C,D)amide dimethyl acetal was first prepared by treating N,N‐dimethyl(formyl‐¹³C,D)amide with dimethyl sulfate, followed by sodium methoxide. Then, N‐{3‐[3‐fluoro‐4‐(3‐oxo‐pyrrolidin‐1‐yl)‐phenyl]‐2‐oxo‐oxazolidin‐5‐ylmethyl}‐acetamide was condensed with N,N‐dimethyl(formyl‐¹³C,D)amide dimethyl acetal, and the resultant β‐ketoenamine intermediate underwent pyrazole ring formation with hydrazine‐¹⁵N₂, to give the [¹³C¹⁵N₂D]‐labeled metabolite. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis of (S)‐cyano(3‐phenoxyphenyl)methyl (1R,3R)‐ 3‐[(1Z)‐2‐chloro‐3,3,3‐trifluoro‐1‐propenyl]‐2,2‐dimethylcyclopropanecarboxylate‐1‐14C

γ‐Cyhalothrin ( 1a ), (S)‐cyano(3‐phenoxyphenyl)methyl (1R,3R)‐3‐[(1Z)‐2‐chloro‐3,3,3‐trifluoro‐1‐propenyl]‐2,2‐dimethylcyclopropanecarboxylate, is a single‐isomer, synthetic pyrethroid insecticide marketed by Pytech Chemicals GmbH, a joint venture between Dow AgroSciences and Cheminova A/S. As a part of the registration process there was a need to incorporate a carbon‐14 label into the cyclopropyl ring of this molecule. A high yielding radiochemical synthesis of γ‐cyhalothrin was developed from readily available carbon‐14 labeled N‐t‐Boc protected glycine. This seven step synthesis, followed by a preparative normal phase HPLC separation of diastereomers, provided 21.8 mCi of γ‐cyhalothrin‐1‐¹⁴C ( 1b ) with >98% radiochemical purity. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis and mycobacterial evaluation of 5‐substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido‐[2,3‐d]pyrimidin‐4(3H)‐one derivatives

5‐Substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido[2,3‐d]pyrimidin‐4(3H)‐one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus as well as a human monocyte‐derived macrophage (THP‐1), and murine macrophage (RAW 264.7) cell lines to assess their antibacterial and cytotoxic potential, respectively. The compounds showed activity in the range of 1.95–125 µg/ml against M. tuberculosis but showed no activity against M. aurum, E. coli, and S. aureus, indicating selectivity towards slow‐growing mycobacterial pathogens. The compounds exhibited very low to no cytotoxicity up to 500 µg/ml concentration against eukaryotic cell lines. The most potent molecule, 2l , showed a minimum inhibitory concentration of 1.95 µg/ml against M. tuberculosis H37Rv and a selectivity index of >250 against both the eukaryotic cell lines. Furthermore, 2l showed moderate inhibition of whole‐cell mycobacterial drug‐efflux pumps when compared to verapamil, a known potent inhibitor of efflux pumps. Thus, derivative 2l was identified as an antituberculosis hit molecule, which could be used to yield more potent lead molecules.     

Potent and selective inhibitors of 11β‐hydroxysteroid dehydrogenase type 1 labeled with carbon‐13 and carbon‐14

(S )‐6‐(2‐Hydroxy‐2‐methylpropyl)‐3‐((S )‐1‐(4‐(1‐methyl‐2‐oxo‐1,2‐dihydropyridin‐4‐yl)phenyl)ethyl)‐6‐phenyl‐1,3‐oxazinan‐2‐one (1) and (4aR ,9aS )‐1‐(1H‐benzo[d]midazole‐5‐carbonyl)‐2,3,4,4a,9,9a‐hexahydro‐1‐H‐indeno[2,1‐b]pyridine‐6‐carbonitrile hydrochloride (2) are potent and selective inhibitor of 11β‐hydroxysteroid dehydrogenase type 1 enzyme. These 2 drug candidates developed for the treatment of type‐2 diabetes were prepared labeled with carbon‐13 and carbon‐14 to enable drug metabolism, pharmacokinetics, bioanalytical, and other studies. In the carbon‐13 synthesis, benzoic‐¹³C ₆ acid was converted in 7 steps and in 16% overall yield to [¹³C₆]‐(1). Aniline‐¹³C ₆ was converted in 7 steps to 1H‐benzimidazole‐1‐2,3,4,5,6‐¹³C₆‐5‐carboxylic acid and then coupled to a tricyclic chiral indenopiperidine to afford [¹³C₆]‐(2) in 19% overall yield. The carbon‐14 labeled (1) was prepared efficiently in 2 radioactive steps in 41% overall yield from an advanced intermediate using carbon‐14 labeled methyl magnesium iodide and Suzuki‐Miyaura cross coupling via in situ boronate formation. As for the synthesis of [¹⁴C]‐(2), 1H‐benzimidazole‐5‐carboxylic‐¹⁴C acid was first prepared in 4 steps using potassium cyanide‐¹⁴C , then coupled to the chiral indenopiperidine using amide bond formation conditions in 26% overall yield.     

Synthesis,analgesic, anti‐inflammatory and ulcerogenic index activities of novel 2‐methylthio‐3‐substituted‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐ones

A variety of novel 2‐methylthio‐3‐substituted amino‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐ones were synthesized by reacting 3‐amino‐2‐methylthio‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐one with different aldehydes and ketones. The starting material 3‐amino‐2‐methylthio‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐one was synthesized from 2‐amino‐3‐carbethoxy‐4,5‐dimethyl thiophene. The compounds were investigated for their analgesic activity in albino mice, and for their anti‐inflammatory and ulcerogenic index activities in Wistar rats. The compound 2‐(1‐ethylpropylideneamino)‐2‐methylthio‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐one (AS2) showed the most potent analgesic activity of the series. It also showed more potent anti‐inflammatory activity when compared to the reference standard, diclofenac sodium. The test compounds showed only mild ulcerogenic potential when compared to aspirin. Drug Dev Res 68:134–142, 2007. © 2007 Wiley‐Liss, Inc.     

N‐[9‐(ortho‐Fluorobenzyl)‐2‐Phenyl‐8‐Azapurin‐6‐yl]‐Amides as Potent and Selective Ligands for A1 Adenosine Receptors

A series of N‐[9‐(ortho‐fluorobenzyl)‐2‐phenyl‐8‐azapurin‐6‐yl]‐amides were synthesized and tested for their affinity toward A₁, A_2A, and A₃ adenosine receptor subtypes. Biological results demonstrated that the introduction of a fluorine atom at the ortho position of the 9‐benzyl group generally enhanced affinity toward A₁ subtype and did not significantly affect A_2A and A₃ affinity. Very interesting is the compound bearing a meta‐fluorophenyl substituent on the carbonyl carbon of the amide group, which shows significantly high A₁/A_2A‐A₃ selectivity. Compounds of this new series, together with the previously published analogs without the fluorine atom on the 9‐benzyl group, constituted the starting dataset for the development of QSAR models. The models obtained were able to rationally describe the affinity trends resulting from biological testing and to enable investigation of the role of different substituents on the 8‐azapurine scaffold, as well as the influence of the newly introduced fluorine atom on the benzyl moiety. The said QSAR models can also assist in the design of new compounds selectively active on A₁ adenosine receptors. Furthermore, a molecular docking study was carried out to assess hypothetical binding mode of N‐[9‐(ortho‐fluorobenzyl)‐2‐phenyl‐8‐azapurin‐6‐yl]‐amides to A₁ adenosine receptors.     

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.     

Synthesis of N,N‐diethyl‐4‐[phenyl‐(piperidin‐4‐ylidene)methyl]‐[carboxy‐14C]benzamide,a potent δ opioid receptor agonist

The synthesis of carbon‐14 labelled N,N‐diethyl‐4‐[phenyl‐(piperidin‐4‐ylidene)methyl]‐benzamide is described. The radioisotope is introduced via an aryllithium reaction with ¹⁴CO₂ to form the labelled acid, which is subsequently transformed into the amide. Copyright © 2002 John Wiley & Sons, Ltd.     

Genotoxicity evaluation of two kinds of smoke‐water and 3,7‐dimethyl‐2H‐furo[2,3‐c]pyran‐2‐one

Smoke, smoke‐water and aerosols have a stimulatory effect on seed germination and growth vigour of many seedlings, making them potentially useful for different purposes, provided they do not pose a health risk. Therefore, the genotoxicity of two kinds of smoke‐water and 3,7‐dimethyl‐2H‐furo[2,3‐c]pyran‐2‐one, a variant of the most active smoke compound (3‐methyl‐2H‐furo[2,3‐c]pyran‐2‐one) was evaluated using the Vitotox? assay. Smoke‐water extracts were obtained from burning leaves: Themeda triandra (smoke‐water Tt) and a mix of Themeda triandra and Passerina vulgaris (smoke‐water Kb). No genotoxic effect was observed for any of the three samples. However, the three samples are toxic at the highest concentrations (3,7‐dimethyl‐2H‐furo[2,3‐c]pyran‐2‐one, 2 ppm; smoke‐water Tt, dilutions 1 : 1, 1 : 2, 1 : 4; smoke‐water Kb, dilution 1 : 1) without addition of S9 mix. Both the butenolide 3,7‐dimethyl‐2H‐furo[2,3‐c]pyran‐2‐one and smoke‐water Tt are also toxic at high doses in the presence of S9 (2 ppm and dilutions 1 : 1 and 1 : 2, respectively), but not smoke‐water Kb. Thus, from these results, no genotoxicity of these three samples can be assumed, which is accordance with the previous tests performed with 3‐methyl‐2H‐furo[2,3‐c]pyran‐2‐one and a smoke‐water. Copyright © 2010 John Wiley & Sons, Ltd.     

Potent Opioid Peptide Agonists Containing 4′‐[N‐((4′‐phenyl)‐phenethyl)carboxamido]phenylalanine (Bcp) in Place of Tyr

Analogues of the opioid peptides H‐Tyr‐c[d ‐Cys‐Gly‐Phe(pNO₂)‐d ‐Cys]NH₂ (non‐selective), H‐Tyr‐d ‐Arg‐Phe‐Lys‐NH₂ (μ‐selective) and dynorphin A(1‐11)‐NH₂ (κ‐selective) containing 4′‐[N‐((4′‐phenyl)‐phenethyl)carboxamido]phenylanine (Bcp) in place of Tyr¹ were synthesized. All three Bcp¹‐opioid peptides retained high μ opioid receptor binding affinity, but showed very significant differences in the opioid receptor selectivity profiles as compared with the corresponding Tyr¹‐containing parent peptides. The cyclic peptide H‐Bcp‐c[d ‐Cys‐Gly‐Phe(pNO₂)‐d ‐Cys]NH₂ turned out to be an extraordinarily potent, μ‐selective opioid agonist, whereas the Bcp¹‐analogue of dynorphin A(1‐11)‐NH₂ displayed partial agonism at the μ receptor. The obtained results suggest that the large biphenylethyl substituent contained in these compounds may engage in a hydrophobic interaction with a receptor subsite and thereby may play a role in the ligand’s ability to induce a specific receptor conformation or to bind to a distinct receptor conformation in a situation of conformational receptor heterogeneity.     

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.     

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.     

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.     

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.     

Design and syntheses of methyl 2‐methyl‐2‐[2‐(4‐benzoyl‐5‐phenyl‐7‐halo‐2‐azabicyclo[4.1.0]hept‐3‐ene)]acetates: novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

A group of methyl 2‐methyl‐2‐[2‐(4‐benzoyl‐5‐phenyl‐7‐halo‐2‐azabicyclo[4.1.0]hept‐3‐ene)]acetates ( 10–15 ), and the related acetamide derivative ( 16 ), that possess a variety of C‐7 substituents (Br, Cl, F, H), were designed for evaluation as analgesic‐antiinflammatory agents. The effect of the C‐7 substituent(s) and the nature of the acetic acid ester (R¹ = Ome) or acetamide (R¹ = NH₂) moiety on analgesic activity was determined using a 4% NaCl‐induced abdominal constriction assay. Compounds 10–16 inhibited writhing by 36–82%, relative to the reference drugs aspirin (58% inhibition) and celecoxib (62% inhibition). The nature of the C‐7 substituents was a determinant of analgesic activity in the 7,7‐dihalo group of compounds where the relative activity profile was 7‐Cl₂ > 7‐Br₂ > 7‐F₂ > 7‐Cl,7‐F, and for 7‐monohalo compounds where the potency order was 7‐Br > 7‐Cl. Elaboration of the 7,7‐dibromo methyl acetate ester ( 10 ) to the corresponding acetamide derivative ( 16 ) enhanced analgesic activity. The nature of the 7‐halo substituent(s) in the 7,7‐dihalo group of compounds was a determinant of antiinflammatory activity, determined using the carrageenan‐induced rat paw edema assay, where the relative potency order was 7‐Br₂ > 7‐Cl₂ > 7‐F₂ > 7‐Cl,7‐F. The most potent 7,7‐dibromo compound ( 10 ) inhibited inflammation by 62%, relative to the reference drug ibuprofen (44%), and 10 inhibited COX‐2 (IC₅₀ = 26.4 μM) and COX‐1 (IC₅₀ = 227 μM) for a COX‐2 selectivity index of 8.6. Docking 10 in the active site of human COX‐2 showed it binds in the center of the COX‐2 binding site with the C‐5 phenyl ring oriented toward the acetylation site (Ser⁵³⁰), and the phenyl group of the C‐4 benzoyl moiety oriented in the vicinity of the COX‐2 secondary binding pocket near Val⁵²³. Drug Dev. Res. 49:75–84, 2000. © 2000 Wiley‐Liss, Inc.     

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.     

Radiosynthesis of 3‐(3‐[18F]fluoropropoxy)‐4‐(benzyloxy)‐N‐[(1‐dimethylaminocyclopentyl)methyl]‐5‐methoxybenzamide,a potential PET radiotracer for the glycine transporter GlyT‐2

The recently described selective and potent GlyT2 antagonist, 4‐benzyloxy‐3,5‐dimethoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide (IC₅₀=16 nM) provided an important additional tool to further characterize GlyT2 pharmacology. In order to identify an effective PET radioligand for in vivo assessment of the GlyT‐2 transporter, 3‐(3‐[¹⁸F]fluoropropoxy)‐4‐(benzyloxy)‐N‐((1‐dimethylaminocyclopentyl) methyl)‐5‐methoxybenzamide ([¹⁸F] 3 ), a novel analog of 4‐benzyloxy‐3,5‐dimethoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide was synthesized using a one‐pot, two‐step method. The NCA radiofluorination of 1,3‐propanediol di‐p‐tosylate in the presence of K₂CO₃ and Kryptofix‐222 in acetonitrile gave 81% 3‐[¹⁸F]fluoropropyl tosylate, which was subsequently coupled with 4‐benzyloxy‐3‐hydroxy‐5‐methoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide in the same reaction vessel. Solvent extraction and HPLC (Eclipse XDB‐C8 column, 80/20/0.1 MeOH/H₂O/Et₃N, 3.0 ml/min) gave [¹⁸F] 3 in 98.5% radiochemical purity. The radiochemical yield was determined to be 14.0–16.2% at EOS, and the specific activity was 1462±342 GBq/µmol. The time of synthesis and purification was 128 min. The final product was prepared as a sterile saline solution suitable for in vivo use. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of [3H]ABT‐518, a matrix metalloproteinase inhibitor (MMPI) labeled in the phenyl rings

A novel matrix metalloproteinase inhibitor, ABT‐518, [S‐(R^*, R^*)]‐N‐[1‐(2, 2‐dimethyl‐1,3‐dioxol‐4‐yl)‐2‐[[4‐[4‐(trifluoromethoxy)‐phenoxy]phenyl]sulfonyl]ethyl]‐N‐hydroxyformamide, was labeled with tritium in two phenyl rings in a seven‐step synthesis. The overall radiochemical yield of [³H]ABT‐518 in seven steps starting from 1‐(methylsulfonyl)‐4‐[4‐(trifluoromethoxy)phenoxy]benzene was 6.2% with the radiochemical purity of 99.4%. Copyright © 2009 John Wiley & Sons, Ltd.