Synthesis of sequentially deuterated 1‐n‐Butyl‐3‐methylimidazolium ionic liquids

Deuterium isotopologues of the ionic liquid (IL) 1–n‐butyl‐3‐methylimidazolium chloride ([C₄mim]Cl) sequentially labeled on the C‐1″, C‐1′, C‐2′, C‐3′, and C‐4′ positions of the N‐alkyl groups were prepared following a strategy that minimizes the number of distinct reactions through the use of analogous synthetic routes. In several cases, good yields after the initial deuterium incorporation reaction were achieved by combining well‐established chemical transformations into efficient single‐step processes. Copyright © 2011 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.     

Synthesis of deuterium‐labelled (−)‐galanthamine

The synthesis of deuterium‐labelled galanthamine is reported. 6‐[²H₃]methoxy‐N‐[²H₃]methyl‐(?)‐galanthamine was obtained in seven steps from galanthamine. The synthesis was carried out by selective O‐ and N‐demethylations. The [²H₃]‐N‐methyl and [²H₃]‐O‐methyl‐groups were introduced by selective aminoreduction and O‐methylation. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of deuterium labeled standards of 5‐methoxy‐N,N‐dimethyltryptamine (5‐Meo‐DMT)

The Batcho‐Leimgruber strategy was employed to synthesize 5‐[²H₃]‐methoxy‐1 H‐indole 4 from commercially available 5‐hydroxy‐2‐nitrotoluene 1 and CD₃I. Compound 4 was treated with oxalyl chloride, dimethylamine and lithium aluminum hydride to yield 5‐[²H₃]‐methoxy‐N,N‐dimethyltryptamine 6 . Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of 15N‐labelled 3,5‐dimethylpyridine

¹⁵N‐labelled pyridines are liquid‐ and solid‐state nuclear magnetic resonance (NMR) probes for chemical and biological environments because their ¹⁵N chemical shifts are sensitive to hydrogen‐bond and protonation states. By variation of the type and number of substituents, different target pyridines can be synthesized exhibiting different pK_a values and molecular volumes. Various synthetic routes have been described in the literature, starting from different precursors or modification of other ¹⁵N‐labelled pyridines. In this work, we have explored the synthesis of ¹⁵N ¹⁵N‐labelled pyridines using a two‐step process via the synthesis of alkoxy‐3,4‐dihydro‐2H‐pyran as precursor exhibiting already the desired pyridine substitution pattern. As an example, we have synthesized 3,5‐dimethylpyridine‐¹⁵N (lutidine‐¹⁵N) as demonstrated by ¹⁵N‐NMR spectroscopy. That synthesis starts from methacrolein, propenyl ether, and ¹⁵N‐labelled NH₄Cl as nitrogen source.     

A simple method for α‐position deuterated carbonyl compounds with pyrrolidine as catalyst

A simple, cost‐effective method for deuteration of carbonyl compounds employing pyrrolidine as catalyst and D₂O as deuterium source was described. High degree of deuterium incorporation (up to 99%) and extensive functional group tolerance were achieved. It is the first time that secondary amines are used as catalysts for H/D exchange of carbonyl compounds, which also allow the deuteration of complex pharmaceutically interesting substrates. A possible catalytic mechanism, based on the hydrolysis of 1‐pyrrolidino‐1‐cyclohexene, for this pyrrolidine‐catalyzed H/D exchange reaction has been proposed.     

Synthesis of 2‐(5Z,8Z,11Z,14Z)‐Icosa‐5,8,11,14‐tetraenamidoethyl‐d4 dihydrogen phosphate,tetra‐deuterated pAEA

A labile intermediate phospho‐anandamide (2‐(5Z,8Z,11Z,14Z)‐icosa‐5,8,11,14‐tetraenamidoethyl dihydrogen phosphate, pAEA) has been identified in mouse brain and macrophages, but its precise quantitation was difficult because of its low concentration and chemical instability. We report the synthesis of tetra‐deuterated pAEA from 2‐aminoethyl dihydrogen phosphate‐1,1,2,2‐d⁴ and (5Z,8Z,11Z,14Z)‐2,5‐dioxopyrrolidin‐1‐yl icosa‐5,8,11,14‐tetraenoate. The compound will be used to quantitate the pAEA necessary for a novel biosynthetic pathway. Published in 2008 by John Wiley & Sons, Ltd.     

Synthesis of uniformly deuterated n‐dodecyl‐β‐d‐maltoside (d39‐DDM) for solubilization of membrane proteins in TROSY NMR experiments

This work reports the first synthesis of uniformly deuterated n‐dodecyl‐β‐d ‐maltoside (d₃₉‐DDM). DDM is a mild non‐ionic detergent often used in the extraction and purification of membrane proteins and for solubilizing them in experimental studies of their structure, dynamics and binding of ligands. We required d₃₉‐DDM for solubilizing large α‐helical membrane proteins in samples for [¹⁵N–¹H]TROSY (transverse relaxation‐optimized spectroscopy) NMR experiments to achieve the highest sensitivity and best resolved spectra possible. Our synthesis of d₃₉‐DDM used d₇‐d ‐glucose and d₂₅‐n‐dodecanol to introduce deuterium labelling into both the maltoside and dodecyl moieties, respectively. Two glucose molecules, one converted to a glycosyl acceptor with a free C4 hydroxyl group and one converted to a glycosyl donor substituted at C1 with a bromine in the α‐configuration, were coupled together with an α(1 → 4) glycosidic bond to give maltose, which was then coupled with n‐dodecanol by its substitution of a C1 bromine in the α‐configuration to give DDM. ¹H NMR spectra were used to confirm a high level of deuteration in the synthesized d₃₉‐DDM and to demonstrate its use in eliminating interfering signals from TROSY NMR spectra of a 52‐kDa sugar transport protein solubilized in DDM.     

Synthesis of stable isotopically labelled 3‐methylfuran‐2(5H)‐one and the corresponding strigolactones

Conventional synthetic procedures of strigolactones (SLs) involve the independent synthesis of ring ABC and ring D, followed by a coupling of the two fragments. Here we prepared three kinds of stable, isotopically labelled D‐ring analogues productively using a facile protocol. Then, a coupling of the D‐rings to ring ABC produced three isotope‐labelled SL derivatives. Moreover, (+)‐D₃‐2′‐epi‐ 1A and (?)‐ent‐D₃‐2′‐epi‐ 1A with high enantiomeric purity were obtained via chiral resolution.     

Synthesis of 3,7,8‐15N3‐N1‐(β‐D‐erythro‐pentofuranosyl)‐5‐guanidinohydantoin

3,7,8‐¹⁵N₃‐N¹‐(β‐D‐erythro‐pentofuranosyl)‐5‐guanidinohydantoin was synthesized from the oxidation of 1,7,NH₂‐¹⁵N₃‐8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine with 2 equivalents of Ir(IV) in pH 4.5 potassium phosphate buffer. The synthesis of 1,7,NH₂‐¹⁵N₃‐8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine started with bromination of 1,7,NH₂‐¹⁵N₃‐2′‐deoxyguanosine. The resulting 1,7,NH₂‐¹⁵N₃‐8‐bromo‐7,8‐dihydro‐2′‐deoxyguanosine reacted with sodium benzyloxide to afford 1,7,NH₂‐¹⁵N₃‐8‐benzyloxy‐7,8‐dihydro‐2′‐deoxyguanosine. Subsequent catalytic transfer hydrogenation of 1,7,NH₂‐¹⁵N₃‐8‐benzyloxy‐7,8‐dihydro‐2′‐deoxyguanosine with cyclohexene and 10% Pd/C yielded 1,7,NH₂‐¹⁵N₃‐8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine. Purification of 3,7,8‐¹⁵N₃‐N¹‐(β‐D‐erythro‐pentofuranosyl)‐5‐guanidinohydantoin was first carried out on a C18 column and the product was further purified on a graphite column. ESI‐MS was used to confirm the identity and to determine the isotopic purity of all the labeled compounds. The isotopic purity of 3,7,8‐¹⁵N₃‐N¹‐(β‐D‐erythro‐pentofuranosyl)‐5‐guanidinohydantoin was 99.4 atom% based on LC‐MS measurements. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of 2‐d‐acrylamide

2‐d‐Acrylamide was synthesized via the 2‐step procedure starting from acrylonitrile and deuterium oxide. This procedure affords 2‐d‐acrylamide in 99.9% chemical purity and 98.4% isotopic enrichment.     

Synthesis of isotopically labeled 1,3‐dithiane

The 1,3‐dithiane is a protected formaldehyde anion equivalent that could serve as a useful labeled synthon. We report a facile synthesis of 1,3‐[2‐¹³C]‐ and 1,3‐[2‐¹³C, 2‐²H₂]dithiane in two steps from [¹³C]‐ or [¹³C, ²H₃]methyl phenyl sulfoxide. We have previously reported the high yield synthesis of [¹³C]methyl phenyl sulfide from [¹³C]MEOH and the oxidation of [¹³C]methyl phenyl sulfide to [¹³C]methyl phenyl sulfoxide. Here, we describe the facile exchange of deuterium from ²H₂O into [¹³C]methyl phenyl sulfoxide to yield [¹³C, ²H₃]methyl phenyl sulfoxide. Thus, from [¹³C]MEOH and ²H₂O, all possible C2 stable isotopomers of 1,3‐dithiane are available. Our synthetic route is also amenable to preparation of radiolabeled 1,3‐dithianes. Copyright © 2014 John Wiley & Sons, Ltd.     

The synthesis and structures of deuterium‐labeled 5‐substituted 1H‐tetrazoles

The synthesis and crystal structures of deuterium‐labeled 5‐substituted 1H‐tetrazoles, 5‐[²H₅]phenyl‐1H‐tetrazole (I), 5‐[²H₇]tolyl‐1H‐tetrazole (II), and 5‐[²H₇]benzyl‐1H‐tetrazole (III) are reported. All syntheses were carried out using simple, facile steps and the products were obtained in high yields. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of [2H5]‐ebastine fumarate and [2H5]‐hydroxyebastine

This study describes the synthesis of deuterium‐labelled ebastine fumarate and its deuterium‐labelled metabolite hydroxyebastine. The synthesis of the two desired compounds both used [²H₅]‐bromodiphenylmethane as deuterium‐labelled reagent, which was synthesized beforehand in three steps. [²H₅]‐ebastine was synthesized in further three steps with a 27% overall yield and [²H₅]‐hydroxyebastine was synthesized in further seven steps with a 13% overall yield. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of deuterium labelled 2‐bromobenzylamine by directed ortho‐metalation chemistry

Directed ortho‐metalation (DoM) strategy has been applied for the development of a short procedure for the regiospecific synthesis of [phenyl‐²H₄]‐2‐bromo‐benzylamine 6 starting from commercially available [phenyl‐²H₅]‐benzoyl chloride 1 . A strong isotope effect was observed during the ortho‐substitution. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of deuterium and 15N‐labelled 2,5‐Bis[5‐amidino‐2‐pyridyl]furan and 2,5‐Bis[5‐(methoxyamidino)‐2‐pyridyl]furan

The acetate salt of 2,5‐bis[5‐amidino‐2‐pyridyl]furan‐d₂/¹⁵N₂ ( 4) was synthesized from 2,5‐bis[5‐cyano‐2‐pyridyl]furan‐d₂ ( 2 ), through the bis‐O‐acetoxyamidoxime followed by hydrogenation. Compound 2 was obtained via a Stille coupling reaction of 6‐chloronicotinonitrile with 2,5‐bis[tri‐n‐butyltin]‐furan‐d₂ ( 1 ). 2,5‐bis[5‐amidino‐2‐pyridyl)furan‐d₆ ( 10) was synthesized from 2,5‐bis[5‐cyano‐2‐pyridyl)furan‐d₆ ( 9 ) via a direct reaction with lithium bis(trimethylsilyl)amide, followed by deprotection with ethanolic HCl. ¹⁵N and/or deuterium‐labelled methoxy‐amidines 5a ‐d₂/¹⁵N₂, 5b ‐d₈, 12 , 14 ‐d₆ were prepared in good yield via direct methylation of their respective diamidoximes with either dimethylsulfate‐d₀ or dimethylsulfate‐d₆ in DMF solution and using LiOH as a base. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of side chain specifically deuterated (−)‐Δ9‐tetrahydrocannabinols

(?)‐Δ⁹‐Tetrahydrocannabinols specifically deuterated at the n‐pentyl side chain were prepared using the corresponding resorcinols as key intermediates. To obtain the deuterated resorcinols we developed conditions under which no deuterium scrambling or loss was observed. The methodology allows for the preparative scale synthesis of deuterated resorcinols and corresponding (?)‐Δ⁹‐tetrahydrocannabinols. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of [2H8]‐enterolactone and [2H10]‐enterodiol

Enterolactone and enterodiol are the main mammalian metabolites of dietary butyrolactone type lignans. The study of biological properties and potential health effects of these compounds requires isotopically labelled compounds as standards for quantitative measurements. An expedient deutero‐labelling method for enterolactone is to use the D₃PO₄·BF₃/D₂O complex at room temperature which will exchange all eight aromatic hydrogens, even from inactivated meta positions, to form [2,4,5,6,2′,4′,5′,6′‐²H₈]‐enterolactone in 74% yield and 99% isotopic purity. [2,4,5,6,9,9,2′,4′,5′,6′‐²H₁₀]‐Enterodiol was prepared from [2,4,5,6,2′,4′,5′,6′‐²H₈]‐enterolactone by reduction with LiAlD₄ which introduces two more deuterium atoms into the molecule. Copyright © 2003 John Wiley & Sons, Ltd.     

The synthesis of 14C‐labeled, 13CD2‐labeled saxagliptin,and its 13CD2‐labeled 5‐hydroxy metabolite

¹⁴C‐labeled saxagliptin, ¹³CD₂‐labeled saxagliptin, and its ¹³CD₂‐labeled 5‐hydroxy metabolite were synthesized to further support development of the compound for biological studies. This paper describes new syntheses leading to the desired compounds. A total of 3.0 mCi of ¹⁴C‐labeled saxagliptin was obtained with a specific activity of 53.98 μCi/mg (17.13 mCi/mmol). The radiochemical purity determined by HPLC was 99.29%, and the overall radiochemical yield was 3.0% based upon 100 mCi of [¹⁴C]CH₂I₂ starting material. By following similar synthetic routes, 580.0 mg of ¹³CD₂‐labeled saxagliptin and 153.1 mg of ¹³CD₂‐labeled 5‐hydroxysaxagliptin metabolite were prepared. Copyright © 2014 John Wiley & Sons, Ltd.     

Synthesis and preliminary in vivo evaluation of 4‐[18F]fluoro‐N‐{2‐[4‐(6‐trifluoromethylpyridin‐2‐yl)piperazin‐1‐yl]ethyl}benzamide,a potential PET radioligand for the 5‐HT1A receptor

4‐Fluoro‐N‐{2‐[4‐(6‐trifluoromethylpyridin‐2‐yl)piperazin‐1‐yl]ethyl}benzamide is a full 5‐HT_1A agonist with high affinity (pK_i=9.3), selectivity and a c log P of 3.045. The corresponding PET radioligand 4‐[¹⁸F]fluoro‐N‐{2‐[4‐(6‐trifluoromethylpyridin‐2‐yl)piperazin‐1‐yl]ethyl}benzamide was synthesized by nucleophilic aromatic substitution on the nitro precursor. The fluorinating agent K[¹⁸F]F/Kryptofix 2.2.2 was both dried (9 min, 700 W) and incorporated in the precursor (5 min, 700 W) using a commercially available microwave oven. In a total synthesis time of 60 min, an overall radiochemical yield of 18% (SD=5, n=7, EOS) was obtained. Radiochemical purity was always higher than 99% and specific activity always higher than 81.4 GBq/µmol (2.2 Ci/µmol). Initial brain uptake in mice was 2.19% ID (5.47% ID/g, 2 min) but decreased rapidly (0.17% ID, 0.45% ID/g (60 min)). During the first 20 min p.i., radioactivity concentration of the brain was significantly higher than that of blood demonstrating good brain entry of the tracer. Copyright © 2004 John Wiley & Sons, Ltd.