Collect. Czech. Chem. Commun. 1989, 54, 2470-2501

Synthesis of (3-hydroxy-2-phosphonylmethoxypropyl) derivatives of heterocyclic bases

Antonín Holý, Ivan Rosenberg and Hana Dvořáková

Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences, 166 10 Prague 6


Analogs of the antiviral 9-(S)-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA, I), containing modified heterocyclic base, were prepared from racemic or (S)-N-(2,3-dihydroxypropyl) derivatives II. Compounds II are heated with chloromethylphosphonyl dichloride (XVII), the formed chloromethylphosphonylester chlorides of compounds II react with water to give a mixture of 2'- and 3'-chloromethylphosphonyl derivatives XVIII and XIX, respectively, which on isomerization by boiling with water in the arising acidic medium affords predominantly the 3'-isomer XIX. Treatment of this isomeric mixture with aqueous sodium hydroxide yields a mixture of 2'-O-phosphonylmethyl ethers (predominating, XXI) and 3'-O-phosphonylmethyl ethers of compounds II (XX). This approach has been applied to the synthesis of isomeric mixtures in the racemic as well as in the (S)-series derived from C-2, C-8 and N-6 substituted derivatives of adenine, from hypoxanthine and additional 6-substituted derivatives of purine, from guanine, 3-deazaadenine and other modified purine bases, from uracil, cytosine, their 5-methyl derivatives and 5-fluorouracil. Regioselective synthesis of compounds XXI was performed for biologically active derivatives (derivative of 2-aminoadenine (XXIe), guanine (XXIn), 3-deazaadenine (XXIp) and cytosine (XXIt)) as well as some other compounds (derivative of hypoxanthine (XXIj), uracil (XXIr), thymine (XXIs) and 5-methylcytosine (XXIu)): the former were obtained either from 3'-O-chloromethylphosphonyl derivatives XIX, isolated from the above-mentioned mixtures by ion-exchanger chromatography or HPLC, or by regioselective substitution, whereas the latter compounds were prepared by deamination (compound XXIj from adenine derivative I or the uracil and thymine derivatives XXIr and XXIu from the cytosine derivatives XXIt and XXIu). N-(S)-(3-Hydroxy-2-benzoyloxypropyl) derivative of N4-benzoylcytosine (XXIX) and N2-benzoylguanine (XXIV), obtained from compounds IIn and IIt by successive N-benzoylation, reaction with dimethoxytrityl chloride, benzoylation and mild acid treatment, were subjected to reaction with the chloride XVII and subsequent neutral and alkaline hydrolysis (compound XXIV), or to reaction with sodium methoxide followed by treatment with bromotrimethylsilane (compound XXIX), being thus converted into 1-(S)-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (XXIt, HPMPC) and 9-(S)-(3-hydroxy-2-phosphonylmethoxypropyl)guanine (XXIn, HPMPG), respectively. The starting compounds (S)-II were synthesized from sodium salt of the corresponding heterocyclic base by reaction with 1-O-p-toluenesulfonyl-2,3-O-isopropylidene-(R)-glycerol (IIIa) (the (RS)-derivatives by reaction with 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (IIIb)), followed by acid hydrolysis.