Synthesis and deuterium labelling of the pure selective estrogen receptor modulator (SERM) acolbifene glucuronides

Acolbifene (EM‐652·HCl, SCH 57068·HCl), a highly potent and orally active selective estrogen receptor modulator (SERM), is at late stage clinical development for the treatment of estrogen‐sensitive breast cancer. Acolbifene‐7‐glucuronide 1 (major) and acolbifene‐4′‐glucuronide 2 (minor) were identified as metabolites of acolbifene in the human. The two monoglucuronides and a diglucuronide 3 as well as the corresponding ²H‐labelled derivatives 4 – 6 were synthesised for use as preclinical and clinical standards for LC–MS/MS analysis. All glucuronides were prepared by the Schmidt glycosylation of monoprotected acolbifene with a glucuronyl imidate at ?10°C to prevent epimerisation at the C‐2 position. The two monoglucuronides 1 and 2 of acolbifene were separated by semi‐preparative HPLC. Incorporation of three deuteriums was achieved by alkylation of chromanone 15 with C²H₃MgI followed by dehydration with C²H₃CO₂ ²H/²H₂O. After chemical resolution and salt neutralisation, [²H₃]acolbifene 19 was obtained with 99.4% enantiomeric purity and >98% isotopic purity. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis of 3H, 2H4 and 14C‐SCH 417690 (Vicriviroc)

Vicriviroc or SCH 417690 is a potent and selective antagonist of the CCR5 receptor. CCR5 receptor antagonists have the potential for the treatment of HIV infections. Four distinct isotopically labelled forms of SCH 417690 were synthesized. Low specific activity [³H]SCH 417690 was prepared for a preliminary absorption, distribution, metabolism and excretion evaluation of the compound and [¹⁴C]SCH 417690 for more definitive absorption, distribution, metabolism and excretion work, including an absorption, metabolism and excretion study in man. In addition, high specific activity [³H]SCH 417690 was prepared for CCR5 receptor binding work and [²H₄]SCH 417690 was prepared as an internal standard for a liquid chromatography–mass spectrometry bioanalytical method. The paper discusses the synthesis of four isotopically labelled forms of SCH 417690.     

The synthesis of tritium,carbon‐14 and stable isotope labelled selective estrogen receptor degraders

As part of a Medicinal Chemistry program aimed at developing an orally bioavailable selective estrogen receptor degrader, a number of tritium, carbon‐14, and stable isotope labelled (E)‐3‐[4‐(2,3,4,9‐tetrahydro‐1H‐pyrido[3,4‐b]indol‐1‐yl)phenyl]prop‐2‐enoic acids were required. This paper discusses 5 synthetic approaches to this compound class.     

Synthesis of 3H, 13C,2H3,15N and 14C‐labelled SCH 466036, a histamine 3 receptor antagonist

The synthesis of [³H]SCH 466036, [Me‐³H₃]SCH 466036, [¹³C,²H₃,¹⁵N]SCH 466036 and [¹⁴C]SCH 466036 is described. [³H]SCH 466036 was prepared in two steps via Raney Ni‐catalysed exchange with tritiated water. [Me‐³H₃]SCH 466036 was prepared in a single step from [³H]methyl iodide in 45% yield. [¹³C,²H₃,¹⁵N]SCH 466036 was prepared in two steps from [¹⁵N]hydroxylamine and [¹³C,²H₃]methyl iodide with an overall yield of 16%. [¹⁴C]SCH 466036 was prepared in seven steps from [¹⁴C]potassium cyanide in an overall yield of 13%.     

Synthesis of 3H, 13C2, 2H4 14C‐SCH 430765 and 35S‐SCH 500946, potent and selective inhibitors of the NPY5 receptor

SCH 430765 and SCH 500496 are potent and selective antagonists of the NPY₅ receptor. NPY₅ receptor antagonists have the potential for the treatment of obesity. [³⁵S]SCH 500946 was prepared for a competition binding assay which led to the identification of SCH 430765. Three distinct isotopically labelled forms of SCH 430765 were synthesized. [³H]SCH 430765 was prepared for a preliminary absorption, distribution, metabolism and excretion data evaluation of the compound and [¹⁴C]SCH 430765 for more definitive absorption, distribution, metabolism and excretion data work. In addition, [¹³C₂,²H₄]SCH 430765 was prepared as an internal standard for a LC‐MS bioanalytical method. The paper discusses the synthesis of 3 isotopically labelled forms of SCH 430765 and [³⁵S]SCH 500946.     

Synthesis of 3H‐, 14C‐, and stable‐isotope‐labelled galantamine

Reminyl^® is a newly approved drug, used in the treatment of mild to moderate Alzheimer disease. The active compound, galantamine, was initially isolated from the bulbs of certain Narcissus species, but is at the moment also produced synthetically. In the process leading to the final approval, the synthesis of tritium‐, carbon‐14‐ and stable‐isotope‐labelled galantamine for pharmacokinetic studies was required. Racemic (±)‐1‐bromonarwedine, a compound available as intermediate from the commercial synthesis, was transformed to racemic 1‐bromo‐galantamine. Catalytic bromo‐tritium exchange, followed by HPLC purification and resolution afforded tritium‐labelled galantamine. The [¹⁴C]‐label was introduced on the nitrogen as well as on the oxygen‐methyl position. This was achieved by N‐ and O‐demethylation of galantamine and reaction of the thoroughly purified intermediate with [¹⁴C]‐methyl iodide. Stable‐isotope‐labelled galantamine was obtained likewise by ¹³CD₃OD‐methylation of O‐demethylated galantamine under Mitsunobu conditions. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of 14C‐labeled piperidines and application to synthesis of [14C]SCH 351125, a CCR5 receptor antagonist

1‐Benzyl‐4‐hydroxy[2‐¹⁴C]piperidine, a useful intermediate in labeled compound synthesis, was prepared from [¹⁴C]formaldehyde in high yield. The distribution pattern of ¹⁴C in the product is consistent with a mechanism involving reversible iminium ion formation and rapid equilibration of the iminium ion through a cationic aza‐Cope rearrangement. These steps precede the rate‐determining intramolecular cyclization step. SCH 351125 is a potent, selective CCR5 receptor antagonist with potential as a treatment for HIV infection. [¹⁴C]SCH 351125, required for metabolism studies, was prepared from 1‐benzyl‐4‐hydroxy[2‐¹⁴C]piperidine in six steps. [¹⁴C]SCH 351125 is a mixture of four atropisomers. Preparation of [¹⁴C]SCH 351125 besylate salt of the desired atropisomer pair is also described. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis of 3H, 2H4, and 14C‐MK 3814 (preladenant)

MK 3814 is a potent and selective antagonist of the A_2a receptor. A_2a receptor antagonists have the potential for the treatment of Parkinson disease. Three distinct isotopically labelled forms of MK 3814 were synthesized. [³H]MK 3814 was prepared for a preliminary absorption, distribution, metabolism, and excretion data (ADME) evaluation of the compound and [¹⁴C]MK 3814 for more definitive ADME work, including an absorption, metabolism, and excretion study in man. In addition, [²H₄]MK 3814 was prepared as an internal standard for a liquid chromatography mass spectrometry bioanalytical method. This paper discusses the synthesis of 3 isotopically labelled forms of MK 3814.     

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 [14C]‐labelled repinotan hydrochloride and its major metabolite M‐6

For studies of pharmacokinetics and drug metabolism of the new 5‐HT_1A agonist repinotan, the ¹⁴C‐labelled version was synthesized. Starting from [U‐¹⁴C]phenol, a 10‐step synthesis led to 457 mg (1.58 GBq) of [U‐¹⁴C]repinotan hydrochloride, labelled uniformly in the aromatic ring of the chromane moiety. For a study in man, a mono‐carbon‐14 labelled substance was required. Therefore a 7‐step synthesis was performed starting from [carbonyl‐¹⁴C]2‐hydroxy‐acetophenone. The yield was 106 mg (0.396 GBq) of [4‐chromane‐¹⁴C]repinotan hydrochloride. The carbon‐14 labelled major metabolite, hydroxylated in the 6‐position of the chromane moiety, was synthesised as reference compound. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of a series of carbon‐14 labelled 4‐aminoquinazolines and quinazolin‐4 (3H)‐ones

4‐Aminoquinazolines and quinazolin‐4 (3H)‐ones, both labelled with carbon‐14 in the 4‐position, were prepared from 2‐aminobenzonitrile‐[cyano‐¹⁴C] and 2‐aminobenzoic acid‐[carboxy ‐¹⁴C] or 2‐amino‐ benzamide‐[carboxy ‐¹⁴C], respectively, using rapid, one‐pot procedures under microwave enhanced conditions. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of C‐14 radiolabeled glucagon receptor antagonist and its use in a human mass balance study

The synthesis of the radiolabeled glucagon receptor antagonist 1‐[ ¹⁴ C ] was accomplished based on decarboxylative iodination of acid 2 followed by “reattachment” of ¹⁴C carboxylic function. The method allowed a significant reduction in the number of steps in preparation of the radiolabeled compound. Iodide 4 , obtained by the halodecarboxylation, was converted to cyanide 5‐[ ¹⁴ C ] , which was hydrolyzed to provide the radiolabeled acid 2‐[ ¹⁴ C ] . Coupling with β‐alanine fragment and hydrolysis of ester 6‐[ ¹⁴ C ] completed the synthesis of the target molecule 1‐[ ¹⁴ C ] . The resulting compound was utilized in a mass balance and metabolism study where hepatic oxidation followed by a trace amount of sulfate conjugation and elimination was the main clearance pathway for 1 in humans.     

Synthesis of [14C]ABT‐770, matrix metalloproteinase inhibitor (MMPI), labelled in the phenoxy ring

The MMPI [¹⁴C]ABT‐770 (1) , N‐[(1S)‐1‐[(4,4‐Dimethyl‐2,5‐dioxo‐1‐imi‐dazolidinyl)methyl]]‐2‐[[4′‐(trifluoromethoxy)[1,1′‐biphenyl]‐4‐yl]oxy]ethyl]‐N‐hydroxyformamide was synthesized in 8 steps using 4‐bromophenol‐UL‐¹⁴C (10) as a starting material. The Carbon‐14 label was introduced in one of the metabolically stable biphenyl rings. The key sequence of the synthesis was a three‐step one‐pot reaction in which the hydantoin moiety was introduced, the imine oxidized and further hydrolyzed to get the penultimate precursor to [¹⁴C]ABT‐770 (1) in 56% yield. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of isotopically labelled [14C]ZT‐1 (Debio‐9902), [d3]ZT‐1 and (−)‐[d3]huperzine A,a new generation of acetylcholinesterase inhibitors

A method has been developed for the synthesis of two isotopically labelled forms of a pro‐drug of the acetylcholinesterase inhibitor (?)‐huperzine A. These labelled compounds,[¹⁴C]ZT‐1 (Debio‐9902) and [d₃]ZT‐1, were used in clinical studies to evaluate a potential treatment for Alzheimer's disease. The pro‐drug [¹⁴C]ZT‐1 was isolated with a radiochemical purity of >98% and a gravimetric specific activity of 129 μCi/mg in a seven‐step synthesis starting from [U‐¹⁴C]phenol in 7% yield. Subsequently, the deuterium labelled target (?)‐[d₃]huperzine A was achieved in six steps with an overall yield of 15% and gave an isotopic distribution of d₂ (1.65% huperzine A) and d₃ (97.93% huperzine A) with a chemical purity of 98.5%. Condensation of the substrate (?)‐[d₃]huperzine A with 5‐chloro‐o‐vanillin gave the Schiff base [d₃]ZT‐1 in a chemical yield of 80%. Reduction of the Schiff base gave reduced‐[d₃]ZT‐1, which was converted into the hydrochloride salt with an isotopic distribution of d₂ (1.60%) and d₃ (98.02%). Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of (S)‐cyano(3‐phenoxyphenyl)methyl (1R,3R)‐ 3‐[(1Z)‐2‐chloro‐3,3,3‐trifluoro‐1‐propenyl]‐2,2‐dimethylcyclopropanecarboxylate‐1‐14C

γ‐Cyhalothrin ( 1a ), (S)‐cyano(3‐phenoxyphenyl)methyl (1R,3R)‐3‐[(1Z)‐2‐chloro‐3,3,3‐trifluoro‐1‐propenyl]‐2,2‐dimethylcyclopropanecarboxylate, is a single‐isomer, synthetic pyrethroid insecticide marketed by Pytech Chemicals GmbH, a joint venture between Dow AgroSciences and Cheminova A/S. As a part of the registration process there was a need to incorporate a carbon‐14 label into the cyclopropyl ring of this molecule. A high yielding radiochemical synthesis of γ‐cyhalothrin was developed from readily available carbon‐14 labeled N‐t‐Boc protected glycine. This seven step synthesis, followed by a preparative normal phase HPLC separation of diastereomers, provided 21.8 mCi of γ‐cyhalothrin‐1‐¹⁴C ( 1b ) with >98% radiochemical purity. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis of labelled N‐(4‐hydroxy‐[14C(U)]phenyl)‐2‐[2,3‐dihydro‐3‐oxo‐l,2‐benzisothiazol‐2‐yl‐1,1‐dioxide]acetamide

The amidation of 2‐[1,1‐dioxide‐3‐oxo‐1,2‐benzisothiazole‐2(3H)‐yl] acetyl chloride with carbon‐14‐labelled 4‐amino‐[¹⁴C(U)]phenol in NaOAc‐HOAc buffer solution at ?10°C gave N‐(4‐hydroxy‐[¹⁴C(U)]phenyl)‐2‐[2,3‐dihydro‐3‐oxo‐1,2‐benziso‐thiazol‐2‐yl‐1,1‐dioxide]acetamide in 82% yield. Subsequent hydrolysis with aqueous 0.5 N NaOH solution afforded the ring opened product N‐(4‐hydroxy‐[¹⁴C(U)]‐phenyl)‐2‐[2‐carboxy‐phenylsulfonamido]acetamide in 80% yield. Copyright © 2005 John Wiley & Sons, Ltd.     

Preparation of carbon‐14 labeled (3R)‐7‐hydroxy‐N‐(1S)‐1‐{[(3R,4R)‐4‐(3‐hydroxyphenyl)‐3,4‐dimethyl‐1‐piperidinyl]methyl}‐2‐methylpropyl‐1,2,3,4‐tetrahydroisoquinolinecarboxamide (JDTic)

Starting with [¹⁴C]‐D‐tyrosine, carbon‐14 labeled JDTic dihydrochloride with specific activity 15 mCi/mol was prepared in 5% radiochemical yield. Separation of the (3R)‐ and (3S)‐diastereomers was carried out via the 3‐phenyl‐2,3,10,10a‐tetrahydro‐5H‐imidazo[1,5‐b]isoquinolin‐1‐ones formed by reaction with benzaldehyde. Copyright © 2008 John Wiley & Sons, Ltd.     

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.     

An improved synthesis of [24‐14C]cholic acid,and its application to the synthesis of [14C]SCH 209702 (Syn3). Synthesis of [2H8]SCH 209702

An efficient synthesis of [24‐¹⁴C]cholic acid from potassium [¹⁴C]cyanide has been developed. The key intermediate, 23‐chloro‐3α, 7α, 12α‐triformyloxynorcholane, was synthesized by degradation of triformyl protected cholic acid. Different degradation conditions were explored. The synthesis of [¹⁴C]SCH 209702 from 23‐chloro‐3α, 7α, 12α‐triformyloxynorcholane and potassium [¹⁴C]cyanide is described. The synthesis of [²H₈]SCH 209702 from [²H₄]cholic acid is also presented. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of N,N‐diethyl‐4‐[phenyl‐(piperidin‐4‐ylidene)methyl]‐[carboxy‐14C]benzamide,a potent δ opioid receptor agonist

The synthesis of carbon‐14 labelled N,N‐diethyl‐4‐[phenyl‐(piperidin‐4‐ylidene)methyl]‐benzamide is described. The radioisotope is introduced via an aryllithium reaction with ¹⁴CO₂ to form the labelled acid, which is subsequently transformed into the amide. Copyright © 2002 John Wiley & Sons, Ltd.