The acid-catalyzed synthesis of substituted 3,4-dihydro-2(l//)-pyrimidinones from a variety of precursors was studied. The major products of the condensation of 3-methoxyacrylate with urea and monomethylurea are 5-carbomethoxy-4-carboxymethyl-3,4-dihydro-2(l//)-pyrimidinone and its N-l methyl derivative. The decarboxylated derivatives, 5-carbomethoxy-4-methyl-3,4-dihydro-2(l//)-pyrimidinone and 5-carbomethoxy-l ,4dimethyl-3,4-dihydro-2( 1 //j-pyrimidinone, are minor products of the same reaction. syw-Dimethylurea produces 5-carbomethoxy-3,4-dihydro-l,3,4-trimethyl-2(l//)-pyrimidinone and 1,3-dimethyluracil, both in small yield. An integrated mechanism for these reactions is proposed involving a preliminary acid-catalyzed aldol condensation and subsequent reactions of a carbonium ion formed from the aldol intermediate. An interaction, probably through hydrogen bonding, is shown to occur between the carboxylic group on the substituent at C-4 and the N-3 group in 5-carbomethoxy-4-carboxymethyl-3,4-dihydro-2(l//)-pyrimidinone. Its effect upon the hydrolysis of an ester of the same carboxylic group has been demonstrated. The reaction of methyl 2-dimethoxymethyl-3-methoxypropionate with ureas also produces 5-carbomethoxy-3,4-dihydro-2(l//)-pyrimidinones. Factors influencing the orientation of these condensations are considered. It is concluded that the more nucleophilic of the two nitrogens in a substituted urea reacts first by displacing the protonated alkoxy group, which is activated through an enol-allyl system derived from the aldehyde function. Cyclization to the 3,4-dihydro-2(l//)-pyrimidinone is completed by reaction of the free ureide nitrogen with the aldehyde group. The results of the condensations of 2-dimethoxymethyl-3-methoxy-l-propanol and 2-hydroxymethyl-1,1,3,3-tetramethoxypropane with ureas are consistent with the proposed enhanced reactivity of an allylic center as compared to an aldehyde function and with the corollary carbonium ion mechanism. This mechanism also applies to the Biginelli pyrimidine synthesis in which the limiting step is now considered to be an in situ aldol condensation required to produce the reactive unit which condenses with a urea to give the corresponding 3,4-dihydro-2(l//)-pyrimidinone. The mechanism proposed here for the Biginelli synthesis explains the course of reactions which had previously been considered "anomalous."

Copper-64 shows promise as both a suitable PET imaging and therapeutic radionuclide due to its nuclear characteristics. Stable attachment of radioactive (64)Cu(2+) to targeted imaging probes requires the use of a bifunctional chelator. Sarcophagine (Sar) ligands coordinate the metal ion (64)Cu(2+) within the multiple macrocyclic rings comprising the cage structure, yielding extraordinarily stable complexes that are inert to dissociation of the metal ion in vivo. Several (64)Cu labelled RGD derivatives have been applied in imaging of the alpha(nu)beta(3) integrin receptor expression during tumour angiogenesis. In order to design and develop novel molecular imaging probes containing RGD and Sar ligands, we designed a novel versatile Sar cage-like bifunctional chelator named AmBaSar, synthesized using a conventional synthetic strategy. Conjugation with the cyclic peptide RGD, and subsequent labelling with (64)Cu, provided a new PET probe (64)Cu-AmBaSar-RGD for imaging the alpha(nu)beta(3) integrin receptor.

SummarySynthesis of 2 0 -deoxy-2 0 -[ 1-bromo-derivative 3 and coupled with protected thymine 4. The crude product mixture (5a and 5b) was hydrolyzed in base and purified by HPLC to obtain the radiolabeled FMAU 6a. The radiochemical yield of 6a was 20-30% decay corrected (d.c.) in four steps with an average of 25% in four runs. Radiochemical purity was >99% and average specific activity was 2300 mCi/mmol at the end of synthesis (EOS). The synthesis time was 3.5-4.0 h from the end of bombardment (EOB).

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