Synthesis of carbon‐14 labelled (5Z)‐4‐bromo‐5‐(bromomethylene)‐2(5H)‐furanone: a potent quorum sensing inhibitor

The potent quorum sensing inhibitor (5Z)‐4‐bromo‐5‐(bromomethylene)‐2(5H)‐[2‐¹⁴C]furanone has been prepared in five steps in 7.7% overall yield starting from bromo[1‐¹⁴C]acetic acid. Condensation of ethyl bromo[1‐¹⁴C]acetate with ethyl acetoacetate followed by decarboxylation was accelerated by microwave heating to afford [1‐¹⁴C]levulinic acid. Subsequently, bromination and oxidation gave the targeted furan‐2‐one with a radiochemical purity of > 97% and a specific activity of 57 mCi/mmol. Copyright © 2004 John Wiley & Sons, Ltd.     

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.     

Synthesis of C‐14‐labeled novel IKK inhibitor: 2‐[14C]‐N‐(6‐chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide

2‐[¹⁴C]‐N‐(6‐Chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide (9A , also referred to as [¹⁴C]‐PS‐1145) was synthesized from [¹⁴C]‐paraformaldehyde in five steps in an overall radiochemical yield of 15%. The key intermediate 1‐[¹⁴C]‐6‐chloro‐1,2,3,4‐tetrahydro‐β‐carboline was obtained by Pictet–Spengler cyclization of chlorotryptamine with [¹⁴C]‐paraformaldehyde. Similar reactions were conducted with tryptamine to address the generality of the methodology. Copyright © 2005 John Wiley & Sons, Ltd.     

A novel five‐lipoxygenase activity protein inhibitor labeled with carbon‐14 and deuterium

2‐[4‐(3‐{(1R)‐1‐[4‐(2‐Aminopyrimidin‐5‐yl)phenyl]‐1‐cyclopropylethyl}‐1,2,4‐oxadiazol‐5‐yl)‐1H‐pyrazol‐1‐yl]‐N,N‐dimethylacetamide (1), is a novel and selective five‐lipoxygenase activity protein (FLAP) inhibitor with excellent pharmacokinetics properties. The availability of a key chiral intermediate allowed the synthesis of [¹⁴C]‐(1) in six radiochemical steps and in 47% overall radiochemical yield with a specific activity of 51 mCi/mmol using carbon‐14 zinc cyanide. 2‐Chloro‐N,N‐dimethyl‐²H₆‐acetamide was prepared and condensed with a penultimate intermediate to give [²H₆]‐(1) in very high yield and in more than 99% isotopic enrichment.     

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 of carbon‐14 labeled 4‐[4‐[2‐[2‐[bis(4‐chlorophenyl) methoxy]ethyl sulfonyl][1‐14C]ethoxy]phenyl]‐1,1,1‐trifluoro‐2‐butanone

Carbon‐14 labeled 4‐[4‐[2‐[2‐[bis(4‐chlorophenyl)methoxyethylsulfonyl] [1‐¹⁴C]ethoxy]phenyl]‐1,1,1‐trifluoro‐2‐butanone was prepared in a six step radioactive synthesis from 2‐bromo[1‐¹⁴C]acetic acid. The overall radiochemical yield was 2.2%. The specific activity of the final product was found to be 42μCi/mg with a radiochemical purity of >98%. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of three isotopically labeled versions and a metabolite of Aurora A kinase inhibitor

Sodium ring‐[¹⁴C]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoate (1A, MLN8054), an Aurora A kinase inhibitor, was synthesized from [¹⁴C]‐cyanamide in two steps in an overall radiochemical yield of 7%. The intermediate, [¹⁴C]‐4‐guanidinobenzoic acid, was prepared by coupling [¹⁴C]‐cyanamide with 4‐aminobenzoic acid. Sodium carboxyl‐[¹⁴C]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoate (1B) was synthesized from carboxyl‐[¹⁴C]‐4‐guanidinobenzoic acid in one step in a radiochemical yield of 35%. [D₄,¹⁵N]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid (1C) was synthesized from [¹⁵N₂]‐cyanamide and [D₄]‐4‐aminobenzoic acid in two steps in an overall yield of 37%. The major metabolite, β‐acyl glucuronide of 4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid (14), was synthesized from D‐glucuronic acid in three steps in an overall yield of 1%. The key intermediate for synthesis of glucuronide was prepared by HATU catalyzed coupling of 4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid with allyl glucuronate. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of isotope‐labeled HSP90 inhibitor: [13CD3] and [14C]‐TAK‐459

[¹³CD₃]‐TAK‐459 (1A), an HSP90 inhibitor, was synthesized from [¹³CD₃]‐sodium methoxide in three steps in an overall yield of 29%. The key intermediate [¹³CD₃]‐2‐methoxy‐6‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)pyridine was synthesized in two steps from 2,6‐dibromopyridine and stable isotope‐labeled sodium methoxide. [¹⁴C]‐TAK‐459 (1B) was synthesized from [¹⁴C(U)]‐guanidine hydrochloride in five steps in an overall radiochemical yield of 5.4%. The key intermediate, [¹⁴C]‐(R)‐2‐amino‐7‐(2‐bromo‐4‐fluorophenyl)‐4‐methyl‐7,8‐dihydropyrido[4,3‐d]pyrimidin‐5(6H)‐one, was prepared by microwave‐assisted condensation.     

A potent IκB kinase‐β inhibitor labeled with carbon‐14 and deuterium

3‐Amino‐4‐(1,1‐difluoro‐propyl)‐6‐(4‐methanesulfonyl‐piperidin‐1‐yl)‐thieno[2,3‐b]pyridine‐2‐carboxylic acid amide (1) is a potent IκB Kinase‐β (IKK‐β) inhibitor. The efficient preparations of this compound labeled with carbon‐14 and deuterium are described. The carbon‐14 synthesis was accomplished in six radiochemical steps in 25% overall yield. The key transformations were the modified Guareschi–Thorpe condensation of 2‐cyano‐¹⁴C‐acetamide and a keto‐ester followed by chlorination to 2,6‐dichloropyridine derivative in one pot. The isolated dichloropyridine was then converted in three steps in one pot to [¹⁴C]‐ (1) . The carbon‐14 labeled (1) was isolated with a specific activity of 54.3 mCi/mmol and radiochemical purity of 99.8%. The deuterium labeled (1) was obtained in eight steps and in 57% overall chemical yield using 4‐hydroxypiperidine‐2,2,3,3,4,5,5,6,6‐²H₉. The final three steps of this synthesis were run in one pot.     

Synthesis of 14C‐labelled myosmine, [2′‐14C] ‐3‐(1‐pyrrolin‐2‐yl)pyridine

¹⁴C‐Labelled myosmine ([2′‐¹⁴C]‐3‐(1‐pyrrolin‐2‐yl)pyridine) was synthesized for autoradiography studies starting from [carboxyl‐¹⁴C]‐nicotinic acid by initial esterification of the latter in the presence of 1,1,1‐triethoxyethane. Without any purification the ethyl nicotinate formed was directly reacted with N‐vinyl‐2‐pyrrolidinone in the presence of sodium hydride, yielding ¹⁴C‐labelled myosmine. The product was purified by silica gel column chromatography. The radiochemical yield was 15% and the specific activity 55.2 mCi/mmol. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of empagliflozin,a novel and selective sodium‐glucose co‐transporter‐2 inhibitor,labeled with carbon‐14 and carbon‐13

Empagliflozin, (2S,3R,4R,5S,6R)‐2‐[4‐chloro‐3‐[[4‐[(3S)‐oxolan‐3‐yl]oxyphenyl]methyl]phenyl]‐6‐(hydroxymethyl)oxane‐3,4,5‐triol was recently approved by the FDA for the treatment of chronic type 2 diabetes mellitus. Herein, we report the synthesis of carbon‐13 and carbon‐14 labeled empagliflozin. Carbon‐13 labeled empagliflozin was prepared in five steps and in 34% overall chemical yield starting from the commercially available α‐D‐glucose‐[¹³C₆]. For the radiosynthesis, the carbon‐14 atom was introduced in three different positions of the molecule. In the first synthesis, Carbon‐14 D‐(+)‐gluconic acid δ‐lactone was used to prepare specifically labeled empagliflozin in carbon‐1 of the sugar moiety in four steps and in 19% overall radiochemical yield. Carbon‐14 labeled empagliflozin with the radioactive atom in the benzylic position was obtained in eight steps and in 7% overall radiochemical yield. In the last synthesis carbon‐14 uniformly labeled phenol was used to give [¹⁴C]empagliflozin in eight steps and in 18% overall radiochemical yield. In all these radiosyntheses, the specific activities of the final compounds were higher than 53 mCi/mmol, and the radiochemical purities were above 98.5%.     

Synthesis of potent lymphocyte function‐associated antigen‐1 inhibitors labeled with carbon‐14 and deuterium,part 1

The lymphocyte function‐associated antigen‐1 (LFA‐1) is an essential component in normal immune system function and is a target for drug discovery for its broad therapeutic potential in treating inflammatory diseases. Here, we report the synthesis of three potent antagonists of LFA‐1 labeled with carbon‐14 and deuterium to support drug metabolism and pharmacokinetics studies. Carbon‐14 labeled (R)‐1‐acetyl‐5‐(4‐bromobenzyl)‐3‐(3,5‐dichlorophenyl)‐5‐methyl‐imidazolidine‐2,4‐dione (1) was prepared in 27% radiochemical yield in two steps and with a specific activity of 2.1 GBq/mmol by using [¹⁴C]‐phosgene. Carbon‐14 labeled 5‐bromopyrimidine was used to prepare (R)‐5‐(1‐piperazinylsulfonyl)‐1‐(3,5‐dichlorophenyl)‐3‐[4‐(5‐pyrimidinyl)benzyl]‐3‐methyl‐1‐H‐imidazo[1,2a]imidazol‐2‐one (2) and (R)‐1‐[7‐(3,5‐dichlorophenyl)‐5‐methyl‐6‐oxo‐5‐(4‐pyrimidin‐5‐yl‐benzyl)‐6,7‐dihydro‐5H‐imidazo[1,2‐a]imidazole‐3‐sulfonyl]piperidin‐4‐carboxylic acid amide (3) via a Suzuki reaction with the corresponding boronic acid esters in 42% and 67% radiochemical yield and specific activities of 1.85 GBq/mmol and 1.95 GBq/mmol, respectively. Deuterium labeled piperazine was reacted with the sulfonyl chloride derivative (7), followed by a Suzuki coupling to the pyrimidine boronic ester to give deuterium labeled (2) in 47% yield. Deuterium labeled isonipecotamide was reacted in a similar way with the sulfonyl chloride derivative (14) to furnish deuterium labeled (3) in one step and in 94% yield. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of highly potent lymphocyte function‐associated antigen‐1 antagonists labeled with carbon‐14 and with stable isotopes,part 3

The drug candidates ( 2 ) and ( 3 ) are highly potent LFA‐1 inhibitors. They were efficiently prepared labeled with carbon‐14 using a palladium‐catalyzed carboxylation of an iodo‐precursor ( 5 ) and sodium formate‐¹⁴C to afford acid [¹⁴C]‐( 6 ), which was coupled via an amide bond to chiral amines ( 7 ) and ( 8 ) in 52% and 48% overall yield, respectively, and with specific activities higher than 56 mCi/mmol and radiochemical purities of 99%. For stable isotopes synthesis, the amine [²H₈]‐( 7 ) was synthesized in three steps from 2‐cyanopyridine‐²H₄ using Kulinkovich‐Szymonik aminocyclopropanation, followed by coupling to L ‐alanine‐2,3,3,3‐²H₄‐N‐t‐BOC, and then removal of the BOC‐protecting group. Amide bond formation with acid ( 6 ) gave [²H₈]‐( 2 ) in 36% overall yield. The amine [¹³C₄,¹⁵N]‐( 8 ) was obtained in two steps using L‐threonine‐¹⁴C₄,¹⁵N and then coupled to acid [¹³C]‐( 6 ) to give [¹³C₅,¹⁵N]‐( 3 ) in 56% overall yield.     

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.     

A modified approach to C‐14‐labeled 2‐(3,4‐difluorophenoxy)‐5‐fluoronicotinic acid and other halogen‐substituted analogs

A modified approach to a carbon‐14‐labeled pyridine ring system was developed based on the electrocyclic ring‐closure of 1,4,4‐trisubstituted butadiene. The new method was applied to prepare 2‐(3,4‐difluorophenoxy)‐5‐fluoro‐[2‐¹⁴C] nicotinic acid and other halogen‐substituted analogs. The targeted compound was isolated with a radiochemical purity of >98% and a specific activity of 53 mCi/mmol from four radiochemical steps, starting from ethyl [1‐¹⁴C] cyanoacetate in an overall radiochemical yield of 39%. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis and stability of a carbon‐14‐labeled 3‐hydroxy‐3‐methylglutaryl coenzyme‐A reductase inhibitor

Inhibition of 3‐hydroxy‐3‐methylglutaryl coenzyme‐A reductase (HMGR) is an effective method of lowering plasma low‐density lipoprotein cholesterol levels. Hemi‐calcium (3R,5S,E)‐7‐(4‐(4‐fluorophenyl)‐6‐isopropyl‐2‐(methyl(1‐methyl‐1H‐1,2,4‐triazol‐5‐yl)amino)pyrimidin‐5‐yl)‐3,5‐dihydroxyhept‐6‐enoate (1) is a cholesterol‐lowering statin drug that effectively inhibits HMGR. An important step in the development of this compound was the synthesis of a carbon‐14‐labeled analog for use in preclinical absorption, distribution, metabolism and excretion studies. The synthesis of a carbon‐14‐labeled analog of the cholesterol‐lowering statin drug 1 is described. The carbon‐14‐labeled compound [¹⁴C]‐1 was prepared in 11 steps from [¹⁴C]‐labeled urea. The overall radiochemical yield for the synthesis was 22% and the radiochemical purity of [¹⁴C]‐1 was 99.9% immediately after synthesis. It was found that [¹⁴C]‐1 with a specific activity of 43.2 µCi/mg decomposed at a rate of about 1.9%/month when stored at ?78°C under argon. Three samples of [¹⁴C]‐1 were prepared to study the chemical stability of the molecule. One sample had a specific activity of 3.8 µCi/mg and the other two contained radical inhibitors, L ‐ascorbic acid (1% by weight, specific activity of 10.5 µCi/mg) or BHT (1% by weight, specific activity of 9.8 µCi/mg). For these samples the decomposition rates were decreased to 0.5%/month, 0.2%/month and 0.1%/month, respectively. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of a highly potent leukocyte function‐associated antigen‐1 antagonist and its metabolite labeled with stable isotopes and carbon‐14, part 2

(S)‐2‐[(R)‐7‐(3,5‐Dichlorophenyl)‐5‐methyl‐6‐oxo‐5‐(4‐trifluoromethoxybenzyl)‐6,7‐dihydro‐5H‐imidazo[1,2‐a]imidazole‐3‐sulfonylamino]‐proprionamide (1), a potent lymphocyte function‐associated antigen‐1 antagonist and its sulfonamide metabolite (2) labeled with stable isotopes and carbon‐14 were prepared for Drug Metabolism and PharmacoKinetics and other studies. A long linear route was used to prepare [¹³C₂, ²H₃]‐(1) using [3,3,3‐²H]‐D‐alanine and [¹³C₂]‐glycine in 15 steps and 2.5% overall yield. With the availability of [¹³C₆]‐3,5‐dichloroaniline, the sulfonamide [¹³C₆]‐(2) was prepared in 12 steps and in 5.6% overall yield. For the carbon‐14 synthesis, a six‐step synthesis gave both compounds [¹⁴C]‐(1) and [¹⁴C]‐(2) from the common sulfonyl chloride intermediate [¹⁴C]‐(15) in 18% and 4% radiochemical yields and specific activities of 44 and 40.5 mCi/mmol, respectively. Copyright © 2011 John Wiley & Sons, Ltd.     

Syntheses of [14C]BAY 59‐7939 and its radiolabeled metabolite M‐4

BAY 59‐7939 is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic diseases. Radiolabeled BAY 59‐7939 was required for drug absorption, distribution, metabolism and excretion (ADME studies). The BAY 59‐7939 was labeled with carbon‐14 in the carboxamide group in one step in an overall radiochemical yield of 85% starting from 4‐{4‐[(5S)‐5‐(aminomethyl)‐2‐oxo‐1,3‐oxazolidin‐3‐yl]phenyl}mor‐pholin‐3‐one and 5‐chlorothiophene‐2‐[¹⁴C]carboxylic acid. The radiolabeled metabolite M‐4 was prepared in 77% yield starting from [1‐¹⁴C]glycine and 5‐chlorothiophene‐5‐carboxylic acid. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of tritium and carbon‐14 labelled NNC 61‐4655: a potent dual‐acting PPARα and PPARγ agonist

The synthesis of the potent dual‐acting PPARα and PPARγ agonist NNC 61‐4655 labelled with tritium and carbon‐14 is reported. Tritium labelled NNC 61‐4655 was obtained in three steps with introduction of tritium through catalytic tritium‐halogen exchange of an aryl bromide precursor. This provided [³H]NNC 61‐4655 in 39% overall radiochemical yield with a specific activity of 49 Ci/mmol. Carbon‐14 labelled NNC 61‐4655 was obtained in five steps starting from bromo[1‐¹⁴C]acetic acid. The synthetic sequence, which included a Horner–Wadsworth–Emmons olefination and a Mitsunobu alkylation, provided [¹⁴C]NNC 61‐4655 in 33% overall radiochemical yield with a specific activity of 57.4 mCi/mmol. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of morphine‐[N‐methyl‐14C]‐6‐β‐D‐glucuronide

Protected morphine‐6‐glucuronide was converted into morphine‐[N‐methyl‐¹⁴C]‐6‐glucuronide by a three‐step procedure. Methyl (3‐pivaloylmorphin‐6‐yl 2,3,4‐tri‐O‐isobutyryl‐β‐D‐glucopyranosid)uronate was N‐demethylated by treatment with 1‐chloroethyl chloroformate to afford protected normorphine‐6‐glucuronide as its hydrochloride salt. The normorphine‐6‐glucuronide derivative was alkylated with iodomethane‐[¹⁴C] in the presence of potassium carbonate to produce C‐14 labelled protected morphine‐6‐glucuronide. Finally, hydrolysis of the protecting groups using 5% sodium hydroxide solution gave morphine‐[N‐methyl‐¹⁴C]‐6‐β‐D‐glucuronide with a specific activity of 41.8 mCi mmol^?1 and radiochemical purity of 99.2% (HPLC). Copyright © 2002 John Wiley & Sons, Ltd.