Pyrimidin-4-ones halogenation

Investigations of the chiroptical properties of 9-halogen derivatives of 6-methyltetrahydro-4//-pyrido[ 1,2-a]pyrimidin-4-ones 28 (X and X1 = Cl, Br) established that the sign of the most characteristic CD bands is determined by the axial halogen atom in position 9 to the inherently achiral pyrimidinone chromophore (87JHC393). 

Conformational analysis of some 9-chloro- and 9-bromo-6,7,8,9-tetrahy-dro-4//-pyrido[ 1,2-a]pyrimidin-4-ones 31 and their 9,9-dichloro and 9,9-dibromo derivatives was also carried out by I3C NMR spectroscopy (83JHC619). The halogen atoms in the 9-chloro and 9-bromo derivatives 31 (R = H) in the predominantly half-chair conformation occupy the pseudoaxial position. This conformer is probably stabilized by a favorable orbital interaction, while the other one, with a presudoequatorial halogen atom, is destabilized by the unfavorable dipole-dipole interaction between the 9-halogen and C(9a)=N(l) bonds. The methyl group in the 6-methyl derivatives in predominantly half-chair conformations is in the pseudoaxial position (83JHC619). 

The halogen atom at position 2 of 4-oxo-4//-pyrido[ 1,2-a]pyrimidin-4-ones 370 easily reacts with N- and O-nucleophiles to yield 2-amino- and 2-alkoxy-4H-pyrido[l,2-tf]pyrimidin-4-ones (82FES747 86JHC1295 ... 

Chloropyrido[l,2-a]pyrimidin-4-ones 399 (R = Me, Cl R1 = 6-Me X = Cl) were prepared in excellent yields when 3-unsubstituted derivatives reacted with phosphorus pentachloride in phosphoryl chloride at 105-110°C for 1.5 hours (85JHC481). Other 3-bromo- and 3-chloro-2-(chloromethyl)-4//-pyrido[l,2-a]pyrimidin-4-ones were also prepared from 3-unsaturated derivatives with halogenation agents (e.g., with N-chlorosuccinimide (NCS) in a mixture of carbon tetrachloride and ethyl acetate) (83EUP81945). 

Methyl groups at the 2-, 4-, or 6-positions of pyrimidine are also reactive. In addition to typical reactions such as condensation with benzaldehyde, selenium dioxide oxidation, and halogenation, they can be converted into oximino groups by nitrous acid and undergo Claisen condensation with (C02Et)2. In the reaction of 2,5-dimethylpyrimidine with benzaldehyde, only the 2-methyl group reacts to yield the 2-styryl derivative 669. In quinazolines partial doublebond fixation makes a methyl group at the 4-position more reactive than one at the 2-position. 

The first class of radiation sensitizer alluded to above, namely the halogenated pyrimidines, includes such materials as 5-bromodeoxyuridine (BUdR) [122], 5-iododeoxyuridine (ludr), and 5-fluorouracil (5-FU). These compounds have shown a certain degree of efficacy due, presumably, to the fact that they are incorporated into DNA [113,114,123]. Indeed, a new drag application (NDA) for one member of this class, BUdr (also known as Broxine ), has recently been filed by Neopharm with the FDA [124]. 

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