Regioselective syntheses of [13C]4‐labelled sodium 1‐carboxy‐2‐(2‐ethylhexyloxycarbonyl)ethanesulfonate and sodium 2‐carboxy‐1‐(2‐ethylhexyloxycarbonyl)ethanesulfonate from [13C]4‐maleic anhydride

The entitled monohydrolysis products, also known as α‐ethylhexyl and β‐ethylhexyl sulfosuccinate (EHSS), of the surfactant diisooctyl sulfosuccinate (DOSS) were synthesized in stable isotope‐labelled form from [¹³C]₄‐maleic anhydride. Sodium [¹³C]₄‐1‐carboxy‐2‐(2‐ethylhexyloxycarbonyl)ethanesulfonate (α‐EHSS) was prepared by the method of Larpent by reaction of 2‐ethylhexan‐1‐ol with [¹³C]₄‐maleic anhydride followed by regioselective conjugate addition of sodium bisulfite to the resulting monoester (38% overall yield). The regiochemical outcome of bisulfite addition was confirmed by a combination of ¹³C/¹³C (incredible natural abundance double quantum transfer) and ¹H/¹³C (heteronuclear multiple‐bond correlation (HMBC)) NMR spectral correlation experiments. Sodium [¹³C]₄‐2‐carboxy‐1‐(2‐ethylhexyloxycarbonyl)ethanesulfonate (β‐EHSS) was prepared in four steps by reaction of 4‐methoxybenzyl alcohol with [¹³C]₄‐maleic anhydride, regioselective sodium bisulfite addition, N,N′‐dicyclohexylcarbodiimide‐mediated esterification with 2‐ethylhexan‐1‐ol, and p‐methoxybenzyl ester deprotection with trifluoroacetic acid (13% overall yield). The regiochemical outcome of the second synthesis was confirmed by a combination of ¹J_CC scalar coupling constant analysis and ¹H/¹³C (HMBC) NMR spectral correlation. The materials prepared are required as internal standards for the liquid chromatography–mass spectrometry (LC‐MS)/MS trace analysis of the degradation products of DOSS, the anionic surfactant found in Corexit, the oil dispersant used during emergency response efforts connected to the Deepwater Horizon oil spill of April 2010. Copyright © 2014 John Wiley & Sons, Ltd.     

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 [3‐13C]‐, [4‐13C]‐ and [11‐13C]‐porphobilinogen

[4‐¹³C]‐porphobilinogen 1a, [3‐¹³C]‐porphobilinogen 1b and [11‐¹³C]‐porphobilinogen 1c are prepared from [1‐¹³C]‐3‐(tetrahydropyran‐2′‐yloxy)‐propionaldehyde 2a, methyl [4‐¹³C]‐4‐nitrobutyrate 3b and [1‐¹³C]‐isocyanoacetonitrile 5c, respectively. The building blocks 2, 3 and 5 can be prepared efficiently in any isotopomeric form. Via base‐catalyzed condensation of these building blocks porphobilinogen can be enriched with ¹³C and ¹⁵N stable isotopes at any position and combination of positions. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of [14C]‐, [13C4]‐, and [13C4, 15N2]‐ 5‐amino‐4‐iodopyrimidine

5‐Amino‐4‐iodopyrimidine labeled with either carbon‐14 or with the stable isotopes carbon‐13 and nitrogen‐15 was prepared starting from commercially available labeled diethylmalonate and formamide. This compound is a useful intermediate for carbon–nitrogen and carbon–carbon bond formations. Copyright © 2008 John Wiley & Sons, Ltd     

Synthesis of [13C2, 15N]‐1,3‐2H‐1‐benzyl‐(Z)‐3‐(benzylidene)indolin‐2‐one

Parkinson disease (PD) is a neurodegenerative disorder characterized by the accumulation of α‐synuclein into Lewy bodies. 3‐Benzylidine‐indolin‐2‐one represents a class of compounds, which are known to inhibit the accumulation of α‐synuclein. In this paper, we report the synthesis of [¹³C] and [¹⁵N] labelled 1‐benzyl‐(Z)‐3‐(benzylidene)indolin‐2‐one from commercially available [¹³C₂]‐chloroacetic acid and [¹⁵N]‐aniline in five steps. The product will be used to study its metabolites in human liver microsomes by liquid chromatography‐tandem mass spectrometry.     

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.     

Nitroaldol reaction of nitro[11C]methane to form 2‐(hydroxymethyl)‐2‐nitro[2‐11C]propane‐1,3‐diol and [11C]Tris

The nitroaldol reaction of nitro[¹¹C]methane and formaldehyde, which yields 2‐(hydroxymethyl)‐2‐nitro[2‐¹¹C]propane‐1,3‐diol, is explored. The fluoride‐ion‐assisted nitroaldol reaction using (C₄H₉)₄NF was rapid and provided the desired nitrotriol in more than 97% radiochemical conversion (decay‐corrected) in 3 min at room temperature. Neither 2‐nitro[2‐¹¹C]ethanol nor 2‐nitro[2‐¹¹C]propane‐1,3‐diol was observed under the reaction conditions. The preparation of 2‐amino‐2‐(hydroxymethyl)‐[2‐¹¹C]propane‐1,3‐diol ([¹¹C]Tris) was described, which was followed by the nitro‐group reduction using NiCl₂ and NaBH₄ in aqueous MeOH. The decay‐corrected radiochemical conversion to [¹¹C]Tris was 68.0±6.5% in two steps. Copyright © 2010 John Wiley & Sons, Ltd.     

Radiosynthesis and validation of [5‐cyano‐N‐(4‐(4‐[11C]methylpiperazin‐1‐yl)‐2‐(piperidin‐1‐yl)phenyl) furan‐2‐carboxamide] ([11C]CPPC), a PET radiotracer for imaging CSF1R,a microglia‐specific marker

In this practitioner protocol, the radiochemical synthesis of [¹¹C]CPPC is described in detail, and a quality control summary of three validation productions is presented. The results indicate that the radiotracer product can be produced in good radiochemical yield (> 60 mCi (2.22 GBq) at end‐of‐synthesis (EOS)), at high specific activity (molar activity > 11,435 mCi/μmole (423 GBq/μmole) at EOS) and high chemical and radiochemical purity. The entire production conforms to current Good Manufacturing Practice (cGMP) requirements. The final product is formulated as a sterile, pyrogen‐free solution suitable for human injection.     

Synthesis of [13C4]‐labeled 2′‐deoxymugineic acid

The phytosiderophore 2′‐deoxymugineic acid (DMA) is exuded via the root system by all grasses (including important crop plants like rice, wheat and barley) to mobilize Fe(III) from soil and improve plant Fe nutrition, crucial for high crop yields. Elucidation of the biogeochemistry of 2′‐deoxymugineic acid in the rhizosphere requires its quantification in minute amounts. To this end, ¹³C₄‐DMA was synthesized for the first time, from cheap isotopically labeled starting materials. The synthetic route utilizes l ‐allyl(¹³C₂)glycine and l ‐(2‐¹³C)azetidine (¹³C)carboxylic acid as versatile labeled building blocks. The title compound was recently used as an internal standard for analysis of soil and plant samples allowing the first accurate quantification of DMA in these matrices by means of LC‐MS/MS. It is furthermore used in tracer experiments investigating biodegradation of DMA in soil.     

The synthesis of [1‐14C]2‐(1H‐tetrazol‐5‐yl)acetic acid

Tetrazoles are a common heterocyclic functionality in many biologically active molecules. [1‐¹⁴C]2‐(1H‐Tetrazol‐5‐yl)acetic acid was required as an intermediate in the synthesis of a development candidate as part of a discovery phase program to complete metabolic profiling studies. [1‐¹⁴C]2‐(1H‐Tetrazol‐5‐yl)acetic acid was prepared in 4 steps overall and in 3 radiochemical steps from K¹⁴CN in an overall 32% radiochemical yield.     

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).     

Fully automated synthesis and purification of 4‐(2′‐methoxyphenyl)‐1‐[2′‐(N‐2″‐pyridinyl)‐p‐[18F]fluorobenzamido]ethylpiperazine

We have developed an efficient synthesis method for the rapid and high‐yield automated synthesis of 4‐(2′‐methoxyphenyl)‐1‐[2′‐(N‐2″‐pyridinyl)‐p‐[¹⁸F]fluorobenzamido]ethylpiperazine (p‐[¹⁸F]MPPF). No‐carrier‐added [¹⁸F]F^? was trapped on a small QMA cartridge and eluted with 70% MeCN(aq) (0.4 mL) containing Kryptofix 222 (2.3 mg) and K₂CO₃ (0.7 mg). The nucleophilic [¹⁸F]fluorination was performed with 3 mg of the nitro‐precursor in DMSO (0.4 mL) at 190 °C for 20 min, followed by the preparative HPLC purification (column: COSMOSIL Cholester, Nacalai Tesque, Kyoto, Japan; mobile phase: MeCN/25 mm AcONH₄/AcOH = 200/300/0.15; flow rate: 6.0 mL/min) to afford p‐[¹⁸F]MPPF (retention time = 9.5 min). p‐[¹⁸F]MPPF was obtained automatically with a radiochemical yield of 38.6 ± 5.0% (decay corrected, n = 5), a specific activity of 214.3 ± 21.1 GBq/µmol, and a radiochemical purity of >99% within a total synthesis time of about 55 min. Copyright © 2012 John Wiley & Sons, Ltd.     

Carbon‐14‐and carbon‐13‐labeled phosphoric acid [2‐4‐(4‐cyanophenyl)‐thiazol‐2‐yl]‐(2,4‐difluorophenyl)‐1‐[1,2,4]triazol‐4‐yl‐methylpropoxymethyl] monoester dilysine salt,a prodrug of ravuconazole

4‐Bromobenzoic acid [carboxyl‐¹⁴C] and 4‐(2‐bromoacetyl) [Ar‐¹³C₆]benzonitrile were transformed into the title compounds containing [ring¹⁴C‐thiazol‐4‐yl] and [Ar‐¹³C₆‐benzonitrile]. ¹⁴C‐Ravuconazole was prepared in 37% yield and Purity >99%. ¹³C₆‐Ravuconazole was made in 56% overall yield and Purity of >98%. Each labeled compound was converted by additional reaction steps to the corresponding labeled prodrug. Copyright © 2011 John Wiley & Sons, Ltd     

Synthesis and in vivo evaluation of [O‐methyl‐11C] 2‐(4‐methoxyphenyl)‐N‐(4‐methylbenzyl)‐N‐(1‐methyl‐ piperidin‐4‐yl)acetamide as an imaging probe for 5‐HT2A receptors

2‐(4‐Methoxyphenyl)‐N‐(4‐methylbenzyl)‐N‐(1‐methylpiperidin‐4‐yl)acetamide (AC90179, 4 ), a highly potent and selective competitive 5‐HT_2A antagonist, was labeled by [¹¹C]‐methylation of the corresponding desmethyl analogue 5 with [¹¹C]methyl triflate. The precursor molecule 5 for radiolabeling was synthesized from p‐tolylmethylamine in three steps with 46% overall yield. [¹¹C]AC90179 was synthesized in 30 min (30 ± 5% yield, EOS) with a specific activity of 4500 ± 500 Ci/mmol and >99% chemical and radiochemical purities. Positron emission tomography studies in anesthetized baboon revealed that [¹¹C] 4 Penetrates the blood–brain barrier (BBB) with a rapid influx and efflux of the tracer in all brain regions. Due to lack of tracer retention or specific binding, [¹¹C] 4 cannot be used as PET ligand for imaging 5‐HT_2A receptors. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of 2‐(methylsulfonyl)‐5‐(4‐(methylsulfonyl) phenyl)‐4‐phenyl‐1H‐[5‐14C]imidazole,a selective COX‐2 inhibitor,via asymmetrical benzoins

4,5‐Diarylimidazoles labeled with carbon‐14 in the 5‐position of the imidazole ring were prepared as a part of three‐step sequence from 2‐hydroxy‐1‐(4‐(methylthio)phenyl)‐2‐phenyl[1‐¹⁴C]ethanone as a key synthetic intermediate which has been synthesized from potassium [¹⁴C]cyanide.     

Synthesis and radiolabelling of [123I]‐4‐iodo‐N‐(4‐(4‐(2‐methoxyphenyl)‐piperazin‐1‐yl)butyl)‐benzamide,a potential dopamine D3 antagonist for SPECT studies

Schizophrenia is a devastating mental disorder characterized by relapsing psychotic episodes accompanied with emotional, professional and social decline. The classical dopamine hypothesis of schizophrenia postulates that hyperactivity of dopaminergic neurotransmission is responsible for the positive symptoms of the disorder. More exactly hyperactivity of the dopamine D₃ receptor system is thought to be involved in the pathology of schizophrenia. Therefore a new ¹²³I‐labelled compound was developed which may allow in vivo visualization of the D₃ receptor by SPECT. [¹²³I]‐4‐iodo‐N‐(4‐(4‐(2‐methoxyphenyl)‐piperazin‐1‐yl)butyl)‐benzamide was synthesized and labelled by electrophilic aromatic substitution of the tributylstannyl derrivative. The radiochemical yield was 82–85% and the specific activity was >2.96 Ci/µmol. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and radiolabelling of [123I]‐4‐iodo‐N‐(4‐(4‐(2‐methoxyphenyl)‐piperazin‐1‐yl)butyl)‐benzamide,a potential dopamine D3 antagonist for SPECT studies

Schizophrenia is a devastating mental disorder characterized by relapsing psychotic episodes accompanied with emotional, professional and social decline. The classical dopamine hypothesis of schizophrenia postulates that hyperactivity of dopaminergic neurotransmission is responsible for the positive symptoms of the disorder. More exactly hyperactivity of the dopamine D₃ receptor system is thought to be involved in the pathology of schizophrenia. Therefore, a new ¹²³I‐labelled compound was developed which may allow in vivo visualization of the D₃ receptor by SPECT. [¹²³I]‐4‐iodo‐N‐(4‐(4‐(2‐methoxyphenyl)‐piperazin‐1‐yl)butyl)‐benzamide was synthesized and labelled by electrophilic aromatic substitution of the tributylstannyl derrivative. The radiochemical yield was 82–85% and the specific activity was >2.96 Ci/µmol. Copyright © 2003 John Wiley & Sons, Ltd.     

Preparation of [carboxy‐13C]4‐nitrophenylacetic acid

Reaction of sodium [¹³C]cyanide with excess benzyl chloride gave ～75% utilization of the isotope. Subsequent nitration, isomer separation and hydrolysis of the nitrile gave the required carboxy‐labelled 4‐nitrophenylacetic acid. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of N‐(2‐chloro‐3,4‐dimethoxybenzylideneamino)guanidinium acetate [α‐14C]

¹⁴C‐Labelled N‐(2‐chloro‐3,4‐dimethoxybenzylideneamino)guanidinium acetate has been synthesized as a part of a four‐step procedure which involved decarboxylation of 2‐chloro‐3,4‐dimethoxybenzoic acid by Pb(OAc)₄ to give 2‐chloro‐3,4‐dimethoxy‐1‐iodobenzene, followed by a selective lithiation at the iodine position and electrophilic substitution with N,N‐dimethylformamide [α‐¹⁴C] and final reaction with aminoguanidine bicarbonate. The specific activity was 59 mCi/mmol and the overall yield 49%. Copyright © 2002 John Wiley & Sons, Ltd.