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Leman L.,Isotope Chemistry Laboratories | Kitson S.L.,Isotope Chemistry Laboratories | Brown R.T.,Isotope Chemistry Laboratories | Cairns J.,Isotope Chemistry Laboratories | And 4 more authors.
Journal of Labelled Compounds and Radiopharmaceuticals

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 [d 3]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 (-)-[d 3]huperzine A was achieved in six steps with an overall yield of 15% and gave an isotopic distribution of d 2 (1.65% huperzine A) and d 3 (97.93% huperzine A) with a chemical purity of 98.5%. Condensation of the substrate (-)-[d 3]huperzine A with 5-chloro-o-vanillin gave the Schiff base [d 3]ZT-1 in a chemical yield of 80%. Reduction of the Schiff base gave reduced-[d 3]ZT-1, which was converted into the hydrochloride salt with an isotopic distribution of d 2 (1.60%) and d 3 (98.02%). Copyright © 2011 John Wiley & Sons, Ltd. Source

Kitson S.L.,Isotope Chemistry Laboratories | Jones S.,Isotope Chemistry Laboratories | Watters W.,Isotope Chemistry Laboratories | Chan F.,Xention Ltd | Madge D.,Xention Ltd
Journal of Labelled Compounds and Radiopharmaceuticals

A method has been developed for the carbon-14 radiosynthesis of [ 14C]XEN-D0401, a 4-(2-hydroxyphenyl)quinolin-2(1H)-one derivative. The radiosynthetic route involves a series of ortho-lithiations directed by both 2-methoxymethyl (MOM) and pivaloyl protecting groups. This is demonstrated in the first key radiochemical step between the reaction of 5-chloro-2- methoxymethoxy-[carboxyl-14C]benzoic acid methyl ester [ 14C]-3 and the ortho-lithiated intermediate generated from 2,2-dimethyl-N-(4-trifluoromethylphenyl)-propionamide (2) to afford the protected benzophenone [14C]-4. The other key radiochemical step utilizes a variation of the Friedländer quinoline synthesis, which involves a base catalysed, one-pot condensation process between (2-amino-5- trifluoromethyl-phenyl)-(5-chloro-2-methoxymethoxy-phenyl)-[14C] methanone [14C]-5 and c-butyrolactone to give MOM-protected [ 14C]-6. On MOM deprotection, [14C]XEN-D0401 was isolated with a radiochemical purity of >97%, with a specific activity of 55 mCi/mmol from seven radiochemical steps, starting from barium [14C]carbonate in a radiochemical yield of 10.5%. Copyright © 2010 John Wiley & Sons, Ltd. Source

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