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.     

Asymmetric synthesis of L‐[4‐13C]glutamic acid and glutamine

L ‐[4‐^l3C]Glutamic acid ( 1 ) and L ‐[4‐¹³C]glutamine ( 2 ) were synthesized from sodium [2‐¹³C]acetate ( 5 ) and Dellaria's oxazinone 3 as a chiral glycine equivalent. Sodium [2‐¹³C]acetate ( 5 ) was converted to [2‐¹³C]acrylate 4 . Diastereoselective Michael addition of the enolate of 3 to the acrylate 4 proceeded with high diastereoselectivity to give the adduct 12 . Reductive cleavage of the C–S bond, ethanolysis, hydrogenolysis and hydrolysis gave L ‐[4‐¹³C]glutamic acid ( 1 ). L ‐[4‐¹³C]Glutamine ( 2 ) was synthesized from 1 in 4 steps. Copyright © 2006 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.     

A method for the preparation of [13C6]‐labelled 2‐substituted naphthalenes

A reliable route is described for the preparation of various 2‐substituted derivatives of [1,2,3,4,4a,8a‐¹³C₆]‐naphthalene via the bromide 10. The approach is used to prepare [naphthalene‐1,2,3,4,4a,8a‐¹³C₆]‐2‐(2‐bromoethyl)naphthalene (1), a key intermediate in the synthesis of labelled SR57746A, Xaliproden (2). Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of 13C and 15N labeled 2,4‐dinitroanisole

Syntheses of [¹³C₆]‐2,4‐dinitroanisole (ring‐¹³C₆) from [¹³C₆]‐anisole (ring‐¹³C₆) and [¹⁵N₂]‐2,4‐dinitroanisole from anisole using in situ generated acetyl nitrate and [¹⁵N]‐acetyl nitrate, respectively, are described. Treatment of [¹³C₆]‐anisole (ring‐¹³C₆) with acetyl nitrate generated in 100% HNO₃ gave [¹³C₆]‐2,4‐dinitroanisole (ring‐¹³C₆) in 83% yield. Treatment of anisole with [¹⁵N]‐acetyl nitrate generated in 10 N [¹⁵N]‐HNO₃ gave [¹⁵N₂]‐2,4‐dinitroanisole in 44% yield after two cycles of nitration. Byproducts in the latter reaction included [¹⁵N]‐2‐nitroanisole and [¹⁵N]‐4‐nitroanisole.     

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.     

Asymmetric synthesis of L‐[4‐13C]lysine by alkylation of oxazinone derivative as a chiral glycine equivalent

L ‐[4‐¹³C]Lysine ( 2 ) was synthesized from sodium [2‐¹³C]acetate ( 3 ) and Dellaria's oxazinone 1 as a chiral glycine equivalent. Wittig reaction of the glycinal 7 and ¹³C‐labeled phosphonium ylide 5 , prepared from sodium [2‐¹³C]acetate ( 3 ), gave the α, β ‐ unsaturated ester 8 . The ester 8 was converted to the allylic bromide 10 . Alkylation of the oxazinone 1 with 10 proceeded with high diastereoselectivity. Ethanolysis, hydrogenation of the double bond with diimide, removal of the chiral auxiliary, and hydrolysis gave L ‐[4‐¹³C]lysine ( 2 ). Copyright © 2004 John Wiley & Sons, Ltd.     

Efficient syntheses of benzyl and n‐octyl [1,3‐13C2]acetoacetates,and their application to syntheses of 13C‐labelled pyrrole and 13C‐labelled hymecromone

Benzyl [1‐¹³C]acetate (2a) was prepared via esterification of sodium [1‐¹³C]acetate (1) with benzyl bromide in the presence of 18‐crown‐6‐ether in 97% yield. n‐Octyl [1‐¹³C]acetate (2b) was rapidly obtained by microwave irradiation of 1‐bromooctane and potassium [1‐¹³C]acetate (obtained by salt exchange of 1) absorbed on Al₂O₃ in 82% yield. Solvent‐free Claisen condensation of benzyl or n‐octyl [1‐¹³C]acetate (2a or 2b) in the presence of potassium tert‐butoxide efficiently gave benzyl or n‐octyl [1,3‐¹³C₂]acetoacetate (3a or 3b) in 51 or 68% yield, respectively. Dibenzyl 2,4‐dimethyl[2,4‐¹³C₂]pyrrole‐3,5‐di[¹³C]carboxylate (4) was synthesized from benzyl [1,3‐¹³C₂]acetoacetate (3a) in 54% yield. [2,4‐¹³C₂]Hymecromone (6) (7‐hydroxy‐4‐methyl[2,4‐¹³C₂]coumarin) was obtained from n‐octyl [1,3‐¹³C₂]acetoacetate (3b) and 1,3‐benzenediol (5) in 73% yield. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of benzoxazole‐[phenyl‐13C6] by directed ortho‐metalation chemistry

A new method for the preparation of benzoxazole‐[phenyl‐¹³C₆] ( 1 ) starting from aniline‐[¹³C₆] ( 4 ) has been developed involving directed ortho‐metalation (DoM) chemistry. The synthesis comprises four steps and an overall yield of 39% was obtained. Copyright © 2003 John Wiley & Sons, Ltd.     

An asymmetric synthesis of l‐[3‐13C]alanine

l ‐[3‐¹³C]Alanine was synthesized from [¹³C]methyl iodide by using Dellaria's oxazinone, prepared from phenyl[2‐¹³C]bromoacetate and (S)‐2‐phenylglycinol, as a chiral glycine equivalent. Alkylation of the oxazinone with [¹³C]methyl iodide was achieved with high diastereoselectivity. Hydrolysis and removal of the chiral auxiliary of the alkylated oxazinone gave l ‐[3‐¹³C]alanine. Copyright © 2003 John Wiley & Sons, Ltd.     

Biosynthesis of glucose‐d‐13C6 from Hansenula polymorpha and methanol‐13C

A simple and effective method for synthesis of glucose‐d ‐¹³C₆ by fermentation using the methylotrophic yeast Hansenula polymorpha with 99% abundance methanol‐¹³C is described. Using methanol‐¹³C as a sole source of carbon, H. polymorpha can accumulate large amounts of α,α‐trehalose‐¹³C₁₂ under unfavourable growth conditions; the trehalose can then be hydrolysed to give glucose‐d ‐¹³C₆ with 98.5% abundance ¹³C. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of isotopically labelled glycyl‐L‐prolyl‐L‐glutamic acid (Glypromate®) and derivatives

The related tripeptides glycyl‐L ‐prolyl‐L ‐glutamic acid (GPE) and glycyl‐L ‐2‐methylprolyl‐L ‐glutamic acid (G‐2‐MePE) were labelled with commercially available [1,2,3,4,5‐¹³C₅, 2‐¹⁵N₁]‐L ‐glutamic acid in 3 steps in excellent overall yield with high isotope incorporation. A related cyclic dipeptide was labelled with [2,2‐²H₂, 2‐¹⁵N₁]glycine giving a mixture of compounds resulting from deuterium scrambling. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of [13C4,15N2]pyrrolo[2,1‐f][1,2,4]triazinone

[¹³C₄,¹⁵N₂]Pyrrolotriazinone, 1 , was synthesized in six steps from ethyl (1,2,3,4‐¹³C₄)acetoacetate and (¹⁵N)ammonium hydroxide. A total of 1.3 g [¹³C₄,¹⁵N₂]pyrrolotriazinone was obtained in an overall yield of 17% based on isotopic ethyl acetoacetate. Chemical purity was determined by HPLC to be 99.5%. The percent [¹³C,¹⁵N]‐isotopic abundance in [¹³C₄,¹⁵N₂]pyrrolotriazinone was determined by mass spectral analysis to be 98.0%. The fully assigned ¹H and ¹³C NMR spectra of [¹³C₄,¹⁵N₂]pyrrolotriazinone were consistent with the desired structure. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of [13C6]‐labelled phenethylamine derivatives for drug quantification in biological samples

The availability of high‐quality ¹³C‐labelled internal standards will improve accurate quantification of narcotics and drugs in biological samples. Thus, the synthesis of 10 [¹³C₆]‐labelled phenethylamine derivatives, namely amphetamine, methamphetamine, 3,4‐methylenedioxyamphetamine, 3,4‐methylenedioxymethamphetamine, 3,4‐methylenedioxy‐N‐ethylamphetamine, 4‐methoxyamphetamine, 4‐methoxymethamphetamine, 3,5‐dimethoxyphenethylamine 4‐bromo‐2,5‐dimethoxyphenethylamine and 2,5‐dimethoxy‐4‐iodophenethylamine, have been undertaken. [¹³C₆]‐Phenol proved to be an excellent starting material for making ¹³C‐labelled narcotic substances in the phenethylamine class, and a developed Stille‐type coupling enabled an efficient synthesis of the 3,4‐methylenedioxy and 4‐methoxy derivatives. The pros and cons of alternative routes and transformations are also discussed. The [¹³C₆]‐labelled compounds are intended for use as internal standards in forensic analysis, health sciences and metabolomics studies by gas chromatography‐mass spectrometry and liquid chromatography‐tandem mass spectrometry. Copyright © 2014 John Wiley & Sons, Ltd.     

Synthesis of 13C6‐labeled Reyataz™ (BMS‐232632)

An efficient synthesis of ¹³C₆‐labeled Reyataz? (BMS‐232632) is described. ¹³C₆‐labeled Reyataz? was synthesized in eight steps from commercially available [ring‐¹³C₆]‐L ‐phenylalanine. The overall yield of the synthesis was 8% and the purity of the final product was greater than 98%. Copyright © 2005 John Wiley & Sons, Ltd.     

Radiosynthesis and preliminary biodistribution in mice of 6‐deoxy‐6‐[131I]iodo‐L‐ascorbic acid

An ascorbate analog labeled with iodine‐131, 6‐deoxy‐ 6‐[¹³¹I]iodo‐L ‐ascorbic acid was prepared for evaluation as an in vivo tracer of L ‐ascorbic acid. The no‐carrier‐added radiosynthesis was conducted by nucleophilic bromine–iodine exchange between the brominated precursor and sodium [¹³¹I]iodide in 2‐pentanone at 130–140°C. HPLC purification using a reverse‐phase column gave 6‐deoxy‐6‐[¹³¹I]iodo‐L ‐ascorbic acid in radiochemical yield of 36–60% with high radiochemical purity and satisfactory‐specific radioactivity in a total preparation time of 90 min. Biodistribution studies in fibrosarcoma‐bearing mice showed a high uptake in the adrenal glands, accompanied by low activity of tumor accumulation, accumulation properties similar to previous results obtained with ¹⁴C‐labeled ascorbic acid and 6‐deoxy‐6‐[¹⁸F]fluoro‐L ‐ascorbic acid, in spite of high level of deiodination. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of [13C4]Baraclude® (entecavir)

Entecavir, labeled as 1H‐[¹³C₄]purin‐6(9H)‐one, was prepared from commercially available [¹³C]guanidine HCl, 1 and diethyl [1,2,3‐¹³C₃]malonate, 2 . The reagents were condensed together to give 2‐amino‐4,6‐dichloro[2,4,5,6‐¹³C₄]pyrimidine 3 , which in turn was coupled to an optically active amino cyclopentanol derivative, 9 . A further sequence of eight reaction steps completed the constructions of the purine ring system and the exocyclic olefin attachment on the cyclic pentyl portion, 18 . The removal of the methoxide and benzyl protecting groups gave [¹³C₄]entecavir, 20 in an overall yield of 6.8%. The chemical purity of the title compound was determined by HPLC to be 99.23%. The percent isotopic [¹³C₄] abundance was found by mass spectral analysis to be 96.7%. No detectable level of the unlabeled entecavir was found by LC‐MS analysis. Copyright © 2009 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.     

A one-pot synthesis of (±)-(ring 13C6)-mandelic acid

A one-pot synthesis of (±)-(ring ¹³C₆)-mandelic acid is reported. [Ring ¹³C₆]-benzaldehyde was cyanosilylated with trimethylsilyl cyanide (TMSCN)/Znl₂. The resulting cyanosilylated adduct was hydrolyzed with concentrated hydrochloric acid without purification. The workup involves evaporation to dryness and extraction of the (±)-(ring ¹³C₆)-mandelic acid with hot benzene. After one crystallization, the synthesis produced an overall yield of 65% of (±)-(ring ¹³C₆)-mandelic acid that was about 98% pure by HPLC with UV detection.     

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.