Synthesis of [guanido‐13C]‐γ‐hydroxyarginine

This report describes an efficient method of synthesizing [guanido‐¹³C]‐γ‐hydroxyarginine HCl salt. Iodolactonization of N‐Boc‐protected allylglycine mainly provided the cis iodo compound 2. This was converted to an amine through azide 4. The amine 5 was reacted with N‐Boc‐protected [¹³C]thiourea to afford N‐Boc‐protected [¹³C]guanidine 6, which underwent base catalyzed ring opening. Removal of the N‐Boc group afforded [guanido‐¹³C]‐γ‐hydroxyarginine HCl salt 7 giving a 30% overall yield of the final product from N‐Boc protected allylglycine 1 in five steps. Copyright © 2008 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 5‐[4,5‐13C2]‐ and 5‐[1,5‐13C2]aminolevulinic acid

5‐[4,5‐¹³C₂]‐ and 5‐[1,5‐¹³C₂]Aminolevulinic acid (ALA) have been synthesized by the Gabriel condensation of potassium phthalimide with ethyl bromo[1,2‐¹³C₂]acetate (derived from [1,2‐¹³C₂]acetic acid) or ethyl bromo[2‐¹³C]‐acetate (derived from sodium [2‐¹³C]acetate), followed by conversion to the chloride, coupling reaction with 2‐ethoxycarbonylethylzinc iodide derived from ethyl 3‐iodopropionate or 2‐methoxy[¹³C]carbonylethylzinc iodide derived from methyl 3‐iodo[1‐¹³C]propionate (generated from potassium [¹³C]cyanide), and hydrolysis. Copyright © 2002 John Wiley & Sons, Ltd.     

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.     

An efficient synthesis of [13C6]‐3,5‐dichloroaniline

3,5‐Dichloroaniline is commonly found in many compounds with pharmacological and other biological activities. [¹³C₆]‐Aniline or its hydrochloride salt was converted in three steps to [¹³C₆]‐3,5‐dichloroaniline, which can be incorporated in compounds of interest and used as internal standards in drug metabolism and pharmacokinetics (DMPK) studies. Copyright © 2008 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 [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 (2‐mercaptoacetyl)‐L‐[2‐14C]tryptophan as a selective metallo‐β‐lactamase inhibitor via [2‐14C]indole based on chiral pool strategy

Metallo‐beta‐lactamase enzymes make bacteria resistant to a broad range of commonly used beta‐lactam antibiotics. Several thiol derivatives of L‐amino acids have been shown their inhibitory effects against the metallo‐β‐lactamase IMP‐1. In this study, (2‐mercaptoacetyl)‐L‐tryptophan as a new inhibitor of metallo‐β‐lactamases labeled with carbon‐14 in the 2‐position of the indole ring was prepared from [2‐¹⁴C]indole as a key synthetic intermediate based on chiral pool strategy. The overall synthesis was performed in 10 steps with the overall radiochemical yield 3.6% on the basis of the barium [¹⁴C]carbonate as a starting material.     

An efficient laboratory‐scale preparative method for [1‐13C]glycocholic acid

A breath test using [1‐¹³C]glycocholic acid as a substrate is a potential diagnostic method for small intestinal bacterial overgrowth syndrome. [1‐¹³C]Glycocholic acid has been thus synthesized in an excellent yield from ethyl [1‐¹³C]glycinate hydrochloride in a one‐pot reaction. This method is suitable for the preparation of the labeled compound on a laboratory scale, which helps to perform extensive clinical studies of the breath test.     

Synthesis and purification of [1,2‐13C2]coniferin

The double labelled lignan precursors [1,2‐¹³C₂]coniferin and the glucoside of [1,2‐¹³C₂]ferulic acid were prepared by classical synthetic methods. Pure double labelled lignan precursors could only be obtained after separation from their contaminating Z‐isomers and dihydro by‐products by high‐performance liquid chromatography. Copyright © 2006 John Wiley & Sons, Ltd.     

Practical [14C]‐synthesis of molecules containing an acetic acid moiety: application to [14C]‐labeled DP1 antagonists

Efficient carbon‐14 labeling of four potent and selective DP1 antagonists is reported. The synthetic sequence began with α‐hydroxylation, reduction of an ester, followed by oxidative diol cleavage and aldehyde reduction. The resulting alcohol 4 was converted to a mesylate then nucleophilic substitution with [¹⁴C]‐sodium cyanide was performed to yield a nitrile, which upon basic hydrolysis provided the carbon‐14 labeled acid 1 . Compound 2 was obtained from the same alcohol intermediate 4 and two diastereomeric compounds 6 and 7 were easily prepared from compound 2 . Carbon‐14 synthesis of compounds 1 , 2 , 6 and 7 were achieved in good yields, high radiochemical purity (>99%) and with high specific activity (45 mCi/mmol). Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of [15N3]melamine and [13C3]cyanuric acid

This report presents an efficient syntheses of two labelled internal standards [¹⁵N₃]melamine and [¹³C₃]cyanuric acid with the common substrates [¹⁵N]NH₄Cl and [¹³C]urea, respectively. Both standards with excellent isotopic and chemical purities were prepared in good yields and could be used as internal standards without further purification. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of [14C]‐ and [13C6]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

5,11‐Dihydro‐11‐ethyl‐5‐methyl‐8‐{2‐{(1‐oxido‐4‐quinolinyl)oxy}ethyl}‐6H‐dipyrido[3,2‐b:2′,3′‐e][1,4]diazepin‐6‐one, (1), labeled with carbon‐14 in the quinoline–benzene ring, in one of the pyridine rings of the dipyridodiazepinone tricyclic moiety, and in the side chain, was prepared in three different syntheses with specific activities ranging from 44 to 47 mCi/mmol (1.63–1.75 GBq/mmol). In the first synthesis, 5,11‐dihydro‐11‐ethyl‐8‐(2‐hydroxyethyl)‐5‐methyl‐6H‐dipyrido[3,2‐b:2′,3′‐e][1,4]diazepin‐6‐one (2) was coupled to 4‐hydroxyquinoline, [benzene‐¹⁴C(U)]‐, using Mitsunobu's reaction conditions, followed by the oxidation of the quinoline nitrogen with 3‐chloroperoxybenzoic acid to give ([¹⁴C]‐(1a)) in 43% radiochemical yield. Second, 3‐amino‐2‐chloropyridine, [2,6‐¹⁴C]‐, was used to prepare 8‐bromo‐5,11‐dihydro‐11‐ethyl‐5‐methyl‐6H‐dipyrido[3,2‐b:2′,3′‐e][1,4]diazepin‐6‐one (8), and then Stille coupled to allyl(tributyl)tin followed by ozonolysis of the terminal double bond and in situ reduction of the resulting aldehyde to alcohol (10). Mitsunobu etherification and oxidation as seen before gave ([¹⁴C]‐(1b)) in eight steps and in 11% radiochemical yield. Finally, carbon‐14 potassium cyanide was used to prepare isopropyl cyanoacetate (12), which was used to transform bromide (8) to labeled aryl acetic acid (13) under palladium catalysis. Trihydroborane reduction of the acid gave alcohol (14) labeled in the side chain, which was used as described above to prepare ([¹⁴C]‐(1c)) in 4.3% radiochemical yield. The radiochemical purities of these compounds were determined by radio‐HPLC and radio‐TLC to be more than 98%. To prepare [¹³C₆]‐(1), [¹³C₆]‐4‐hydroxyquinoline was prepared from [¹³C₆]‐aniline and then coupled to (2) and oxidized as seen before. Copyright © 2008 John Wiley & Sons, Ltd.     

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).     

Synthesis of [14C]‐l‐tryptophan and [14C]‐5′‐hydroxy‐l‐tryptophan labeled in the carboxyl group

The synthesis of selectively ¹⁴C‐labeled l ‐tryptophan and its derivative 5‐hydroxy‐l ‐tryptophan using chemical and multienzymatic methods is reported. The mixture containing [1‐¹⁴C[‐dl ‐alanine, indole or 5‐hydroxyindole has been converted to [1‐¹⁴C]‐l ‐tryptophan or 5′‐hydroxy‐[1‐¹⁴C]‐l ‐tryptophan, respectively, in a one‐pot multienzymatic reaction using four enzymes: d ‐amino acid oxidase, catalase, glutamic‐pyruvic transaminase and tryptophanase. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and purification of [2‐13C]‐5‐fluorouracil

[2‐¹³C]‐5‐Fluoropyrimidine‐2,4(1H,3H)‐dione ([2‐¹³C]‐5‐fluorouracil or [2‐¹³C]‐5‐FU) is a potential diagnostic agent for measuring 5‐FU‐induced toxicity in cancer patients. It was prepared and purified with isotopic and chemical purity of>99% on a multigram scale in a two‐step synthesis from [¹³C]‐urea. Preparative separation of [2‐¹³C]‐FU and [2‐¹³C]‐uracil was carried out by automated medium pressure silica gel column chromatography. The method is applicable to a broader range of 5‐FU isotopic analogs derived from labeled uracil. Copyright © 2011 John Wiley & Sons, Ltd.     

Chemical synthesis of allyl‐[13C6]‐glucuronate

The synthesis of allyl‐[¹³C₆]‐glucuronate from α‐D‐[¹³C₆]‐glucose in five steps is described. Selective protection of the primary alcohol in the glucose with the bulky trityl group followed by acetylation in the same pot gave the fully protected sugar. Removal of the trityl group followed by oxidation of the primary alcohol to the acid and removal of the acetate groups using catalytic amounts of sodium methoxide gave the glucuronic acid. Reaction with allyl bromide using resin‐bound fluoride gave the title compound. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of 3H‐, 13C3‐, and 14C‐labeled Sch 727965

The preparation of [³H]Sch 727965 from unlabeled compound and tritiated water was base catalyzed. Diethyl [¹³C₃]malonate was used to prepare [¹³C₃]Sch 727965 in five steps in 21.8% overall yield. In a similar manner, [¹⁴C]Sch 727965 was prepared in five steps from diethyl [2‐¹⁴C]malonate in 11.1% radiochemical yield. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of [3H], [13C215N] and [14C]Sch 66336 (Sarasar™)

[³H]Sch 66336 was prepared at a specific activity of 1.35 Ci/mmol by Ru(Ph₃P)₃Cl₂ catalysed exchange with tritiated water. [¹³CN]Sch 66336 was synthesized from potassium [¹³C]cyanide and [¹³C¹⁵N₂]urea in 29% overall yield from potassium [¹³C]cyanide. [¹⁴C]Sch 66336 was synthesized from potassium [¹⁴C]cyanide in 31% yield. A second synthesis, from N‐Boc‐4‐hydroxy[¹⁴C]piperidine, gave [¹⁴C]Sch 66336 labelled in a different site in 19% overall yield. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of 13C3‐hydroxyacetone

¹³C₃‐Hydroxyacetone is prepared in three steps from ¹³C₂‐2‐bromoacetic acid. Bromide displacement by sodium p‐methoxybenzyl alkoxide followed by treatment of the carboxylic acid with ¹³C‐methyl lithium furnishes PMB‐protected hydroxyacetone. Deprotection using DDQ delivers the title compound. Copyright © 2003 John Wiley & Sons, Ltd.