5-Fluoro-2 -pyrimidinones

Cech et al. (105) described a simple synthesis of 5-fluoro-2-pyrimidinone and its -substituted derivatives on silica with several solvent systems including isopropanol-H20 (7 3). 

Cech D, Beerbaum H, Holy A (1977) Simple synthesis of 5-fluoro-2-pyrimidinone and its N1-substituted derivatives. Collect Czech Chem Commun 42 2694-27(X)... 

All the prodrugs of Fluorouracil discussed above contained the fragment of 1 in their structure their transformation to 1 included hydrolysis reaction as the key step. On the contrary, 5-fluoro-2-pyrimidinone (5-FP, 38) which has been studied in Phase I clinical trials [45] is activated through oxidative process. In particular, pyrimidine 38 is transformed to 1 by aldehyde oxidase, which is present in high concentrations in the human livers but not in the gastrointestinal tract [46]. 

Guo X, Lemer-Tung M, Chen HX, Chang CN, Zhu JL, Chang CP, Pizzomo G, Lin TS, Cheng YC (1995) 5-fluoro-2-pyrimidinone, a liver aldehyde oxidase-activated prodrug of 5-lluorouracil. Biochem Pharmacol 49 1111-1116... 

US patent 6,723,728, Polymorphic and other crystalline forms cis-FTC [106], The present invention relates to polymorphic and other crystalline forms of (—)-and ( )-cA-(4-amino-5-fluoro-l-(2-(hydroxymethyl)-l,3-oxathiolan-5-yl)-2(lH)-pyrimidinone, or FTC) [106]. Solid phases of (—)-cz>FTC that were designated as amorphous (—)-FTC, and Forms II and III were found to be distinguishable from Form I by X-ray powder diffraction, thermal analysis properties, and their methods of manufacture. A hydrated crystalline form of ( )-cA-FTC and a dehydrated form of the hydrate, were also disclosed, and can similarly be distinguished from other forms of FTC by X-ray powder diffraction, thermal properties, and their methods of manufacture. These FTC forms can be used in the manufacture of other forms of FTC, or as active ingredients in pharmaceutical compositions. Particularly preferred uses of these forms are in the treatment of HIV or hepatitis B. 

Direct 5-fluorination can be effected on activated pyrimidines for example, F2 in HOAc or anhydrous HF have been used for the preparation of 5-fluoro-2(lH)-pyrimidinones (77CCC2694), and for 5,5-difluorination of 6-O-cyclouridines (83TL1055). Uracil and cytosine are 5-fluorinated by the same procedure (80TL4605,82CPB887). 

Figure 4 Catalytic activation of cytosine for C5-methylation by nucleophilic addition of a thiolate at the C6 position, (a) The chemical mechanism of enzymatic DNA cytosine-S methylation. Mechanism-based inhibition of DMA MTases by cytidine analogs 5-fluoro-2 -deoxycytidine (b), 5-aza-2 -deoxy-cytidine (c), and 2-pyrimidinone-l-p-D-(2 -deoxyriboside) (d).

Flucytosine, USP. 5-Fluonx ytosine. 5-FC. 4-amino-3-lluoro-2( l//)-pyrimidinone. 2-hydroxy-4-amiiio-5-fluoro-pyriiniditie (Ancobon). S-Fluorocytosine is an orally active mlifungal agent with a very narrow spectrum of activity. It is indicated only for the treatment of seriou.s systemic infections caused by susceptible strains of Caiutida and Cryp-Uicomis. spp. 

Fluoro and 2,4-difluoropyrimidines have also been prepared in good yields directly from pyrimidinones by the use of anhydrous potassium fluoride in tetraglyme-18-crown-6 at elevated temperature <85JHC145>. Synthesis of fluorinated pyrimidines via diazonium salts appears to be inferior to other methods <85JHC145>. 

Compound (VIII.98), a folic acid analogue with a y-fluoro substituent in the side-chain was described first by Alekseeva e/ al. [281] and several years later by Bergmann and Chun-Hsu [282]. The synthesis of (VIII.98), as mixture of threo and erythro isomers, was achieved via the Waller method from V-(4-ami-nobenzoyl)-y-fluoroglutamic acid, 2,4,5-triamino-6(lif)-pyrimidinone, and 2,3-dibromopropionaldehyde, but the yield was low (5.6%). y-Fluoroglutamic acid, as a mixture of D- and L-enantiomers, was prepared from diethyl 2-fluoromalonate by condensation with ethyl 2-acetamidoacrylate followed by hydrolysis and decarboxylation in refluxing 12 M HCl, or from ethyl 3-chloro-2-hydroxypropanoate by a sequence consisting of (i) 0-t-butylation with CH2 = C(CH3)2, (ii) condensation with diethyl 2-acetamidomalonate, (hi)... 

Amino-l-(2,3-dideoxy-2-fluoro- -D-ety-thio-pentofuranosyl)-2(lH) -pyrimidinone, 9CI. l-(2,3-Dideoxy-2-fluoro-P-D-etythto-pentofuranosyl) cytosine... 

InouyeY, Yokozawa T, Ishikawa N (1985) 2-Hydryl-2-(F-methyl)-F-propanoyl fluoride as a useful building block for the synthesis of trifluoromethylated heterocyclic compounds. Synthesis of l,3-dimethyl-2,3-dihydro-5-(F-methyl)-6-fluoro-2-thioxo-4(lH)-pyrimidinone and l,3-dimethyl-5-(F-methyl)-6-fluoro-2,4(lH, 3H)-pyrimidinedione. J Fluor Chem 27 379-384... 

Inouye Y, Tezuka K, Takeda N (1987) Synthetic utilization of methyl 2-(F-methyl)-2-hydryl-F-propyl ether. Part 111 [1]. A simple one-pot preparation and derivatization of 2-alkylthio-5-(F-methyl)-6-fluoro-3,4-dihydro-4(3H)-pyrimidinones. J Fluor Chem 35 275-285... 

Sokolov VB, Aksinenko AY (2005) Synthesis of fluoro-containing pyrimidinones from hexa fluoroacetone(ethoxycarbonylimine). Russ Chem Bull 54 1518-1522... 

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