Lawrence Jones

Palladium-catalyzed aryl cyanations with [14C]KCN: Synthesis of 14C-labelled fadrozole, a potent aromatase inhibitor

The potent aromatase inhibitor [14C]Fadrozole (1), was prepared in a single radiosynthetic step via a palladium(0)-catalyzed cyanation of the imidazole-containing aryl iodide 2b with [14C]KCN. Attempted preparation of 2b by metal-halogen interchange of the corresponding aryl bromide 2a with tert-butyl lithium followed by quenching with iodine afforded only the imidazole iodide 5 via disproportionation of the intermediate anion. The desired precursor was finally synthesized through a three-step sequence beginning with the alkylation of known imidazole derivative 8 with 4-iodobenzylbromide. This alkylation product was treated with thionyl chloride to convert a side chain hydroxyl to its corresponding primary chloride 10. Cyclization of chloride 10 using LDA/TMEDA gave the desired aryl iodide 2b. While initial attempts at the palladium(0)-catalyzed cyanation of 2b with unlabelled KCN in THF at reflux gave modest yields of Fadrozole, the reaction with [14C]KCN afforded only trace amounts of [14C]Fadrozole. By including Copper(I) iodide as a co-catalyst and using deoxygenated THF, the palladium(0)-catalyzed cyanation of 2b gave [14C]Fadrozole in 39% radiochemical yield with >99% radiochemical purity. Copyright

Synthesis of tritium, deuterium, and carbon-14 labeled (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]carbamic acid, phenyl ester, (L)-2,3-dihydroxybutanedioic acid salt (SDZ ENA 713 hta), an investigational drug for the treatment of Alzheimer's Disease

(S)-(-)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]carbamic acid, phenyl-2-3H-ester, (L)-2,3-dihydroxybutanedioic acid salt was synthesized via directed ortho-metallation methodology. (S)-(-)-N-Ethyl-N-methyl-3-[1-(di-(2H3)-methylamino)ethyl]carbamic acid, phenyl ester, (L)-2,3-dihydroxybutanedioic acid salt was synthesized from 3-hydroxyacetophenone. The molecule was resolved by classical diastereomeric salt formation and fractional crystallization. The carbon-14 analog,(S)-(-)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl-1-(14C)]carbamic acid, phenyl ester, (L)-2,3-dihydroxybutanedioic acid salt was constructed starting from 3-iodoanisole and featured the enantioselective reduction of a methoxylamine intermediate.

Synthesis of carbon–14 labeled fluvastatin (Lescol®)

[R*, S*]–(±)–7–[3–(4–Fluorophenyl)–1–(1–methylethyl)–1H–indol–2–yl–3–114C]–3, 5– dihydrox –6–heptenoic acid, sodium salt (fluvastin, 4) was prepared from [14C] bromoacetyl chloride in a six step synthesis with an overall radiochemical yield of 13.2%. This synthetic route was chosen because it puts the label in the metabolically stable 3– position of the indole ring.

Synthesis of a 11C‐labelled nitrated 1,4‐dihydroquinoxaline‐2,3‐dione, the NMDA glycine receptor antagonist ACEA 1021 (Licostinel)

ACEA 1021 (6,7-dichloro-5-nitro-1,4-dihydroquinoxaline-2,3-dione, Licostinel) is a potent antagonist for the glycine site of the NMDA receptor. With the purpose of evaluating the drugs biodistribution in vivo as well as its potential as a PET tracer for the glycine binding sites, ACEA 1021 was labelled in the heterocyclic ring with carbon-11 in a five-step synthesis. The radiolabelling precursor, derived from [11C]cyanide, was diethyl [1-11C]oxalate. Yields of its cyclization with the deactivated nitrated diamine, 4,5-dichloro-3-nitro-1,2-phenylenediamine, were too low to be reliable for the planned in vivo studies. Instead, diethyl [1-11C]oxalate was reacted with 4,5-dichloro-1,2- phenylenediamine to give [2-11C]6,7-dichloro-1,4-dihydroquinoxaline-2,3-dione (DCQX). Interference from the excess diamine during the subsequent nitration reaction was reduced by two methods. After formation of [2-11C]DCQX, unlabelled diethyl oxalate was added and allowed to cyclize before adding the nitrating agent, giving a carrier-added product suitable for use in pharmacokinetic studies. For the non-carrier-added tracer studies, the diamine was condensed with acetic acid before adding fuming HNO3/concentrated H2SO4. Both procedures gave high conversions of [2-11C]DCQX to [11C]ACEA 1021, which was subsequently isolated by semi-preparative liquid chromatography. The total synthesis time was 70–80 min. The conversions according to radio-analytical LC were 25–30% and isolated yields for the five-step synthesis were≈5–10% (decay-corrected, based on [11C]CN− at end of trapping). The specific activity of the no-carrier-added product was 15–20 GBq/μmol at end-of-synthesis.

Proton exchange reactions in isotope chemistry (II) synthesis of stable isotope‐labeled LCQ908

The proton exchange reaction was applied to the preparation of stable isotope-labeled LCQ908. For this synthesis, a suitable intermediate with protons alpha to a carbonyl group was first subjected to the H-D exchange reaction; subsequent coupling of a carbonyl group with [(13)C2 ]triethyl phosphonoacetate, followed by hydrogenation and hydrolysis, led to the stable labeled compound. Incorporation of two carbon-13 atoms in the molecule eliminated the presence of undesired M+0.