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  • The reference standards methyl difluoro

    2020-01-13

    The reference standards methyl 3-((2,2-difluoro-5-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-]imidazol-6-yl)carbamoyl)benzoate () and -(2,2-difluoro-5-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-]imidazol-6-yl)-3-methoxybenzamide (), and their corresponding desmethylated precursors 3-((2,2-difluoro-5-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-]imidazol-6-yl)carbamoyl)benzoic a common staple food () and -(2,2-difluoro-5-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-]imidazol-6-yl)-3-hydroxybenzamide (), were synthesized as shown in , according to the literature method with modifications. The commercially available starting material 5-amino-2,2-difluoro-1,3-benzodioxole was treated with acetic anhydride in toluene to obtain acetamide in 92% yield. Compound was then converted to the intermediate through a concurrent nitration and deprotection with nitronium tetrafluoroborate (NOBF) in 69% yield. In comparison with the reported method, the use of the nitration reagent NOBF simplified the reaction steps, combining nitration reaction and deprotecting reaction into one step, and improved the reaction yield. The nitro compound was reduced through hydrogenation using H and Pd/C as catalyst instead of Raney Nickel reported in the literature to give the intermediate containing two amino groups, which was subsequently reacted with cyanogen bromide to provide the key intermediate amino in 82% yield. The catalyst change in hydrogenation also improved the yield. Then the amino was reacted with several 3-substituted benzoic acids under the catalysis of -tetramethyl-(1-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) and ,-diisopropylethylamine (DIPEA) to afford the standard compounds and in 63% and 21% yield, respectively. A protected benzamide was also synthesized in 18% yield. Compound was hydrolyzed in methanol solution of KOH to yield its acid precursor in 93% yield. Compound was converted to desmethylated precursor for compound through the deprotecting reaction of benzyl group employing boron trifluoride diethyl etherate (BF·EtO) and dimethyl sulfide (MeS) in 65% yield. This deprotective reagent system was found to be better than other deprotective reagent system like H and Pd/C, which is easy to result in byproduct formation and lower yield. Synthesis of the target tracers [C] and [C] is indicated in . Desmethylated precursor or underwent -[C]methylation, using the reactive [C]methylating agent [C]methyl triflate ([C]CHOTf), in acetonitrile at 80 °C under basic conditions (2N NaOH). The product was isolated by semi-preparative reverse-phase (RP) high performance liquid chromatography (HPLC) with a C-18 column, and then concentrated by solid-phase extraction (SPE), with a disposable C-18 Light Sep-Pak cartridge to produce the corresponding pure radiolabeled compound [C] or [C] in 40–45% radiochemical yield, decay corrected to end of bombardment (EOB), based on [C]CO. The radiosynthesis was performed in a home-built automated multi-purpose [C]-radiosynthesis module., , Our radiosynthesis module facilitated the overall design of the reaction, purification and reformulation capabilities in a fashion suitable for adaptation to preparation of human doses. The radiosynthesis includes three stages: 1) labeling reaction; 2) purification; and 3) formulation. More reactive [C]CHOTf, instead of commonly used [C]methyl iodide ([C]CHI), was used in -[C]methylation to improve radiochemical yield of [C] and [C]. The Eckert & Ziegler Modular Lab C-11 Methyl Iodide/Triflate module in our facility can produce [C]methylating agent either [C]CHOTf or [C]CHI ([C]CHBr passed through a NaI column). The direct comparison between [C]CHOTf and [C]CHI confirmed the result that the labeling yield was improved from 30 to 35% to 40–45%. The labeling reaction was conducted using a V-vial method. Addition of aqueous NaHCO to quench the radiolabeling reaction and to dilute the radiolabeling mixture prior to the injection onto the semi-preparative HPLC column for purification gave better separation of [C] or [C] from its desmethylated precursor or . Both Sep-Pak trap/release and rotatory evaporation are available for formulation in our multi-purpose [C]-radiosynthesis module, and we used Sep-Pak method instead of rotatory evaporation for formulation to improve the chemical purity of radiolabeled product [C] or [C]. The direct comparison between Sep-Pak method and rotatory evaporation confirmed the result that the chemical purity of radiolabeled product was improved from <90% to >90%. In addition, a C18 Light Sep-Pak to replace a C18 Plus Sep-Pak allowed final product formulation with ≤5% ethanol. Overall, it took ∼40 min for synthesis, purification and dose formulation.