General Method of Preparation of N-[(S)-(3-Hydroxy-2-phosphonomethoxypropyl)] Derivatives of Heterocyclic Bases

Abstract

Reaction of (R)-1-O-p-toluenesulfonyl-1,2,3-propanetriol (IV) with N-trimethylacetylimidazole (II) afforded (R)-1-O-p-toluenesulfonyl-3-O-trimethyacetyl-1,2,3-propanetriol (V) which was reacted with dimethoxymethane in the presence of phosphorus pentoxide to give (R)-2-O-methoxymethyl-1-O-p-toluenesulfonyl-3-O-trimethyacetyl-1,2,3-propanetriol (VI). Compound VI was treated with acetic anhydride and boron trifluoride etherate and the obtained 2-acetoxy derivative VII reacted with bromotrimethylsilane to give the intermediary bromomethyl ether VIII. Compound VIII on reaction with tris(2-propyl) phosphite afforded (R)-2-O-bis(2-propyl)phosphonomethyl-1-O-p-toluenesulfonyl-3-O-trimethyacetyl-1,2,3-propanetriol (IX). Condensation of synthon IX with sodium salts of adenine, 2,6-diaminopurine, or with cytosine, 6-azacytosine or 2-chloroadenine in the presence of cesium carbonate, afforded fully protected diesters X and XIIIb which on methanolysis and reaction with bromotrimethylsilane gave N-[(S)-(3-hydroxy-2-phosphonomethoxypropyl)] derivatives of adenine (XIa), 2- chloroadenine (XIb), 2,6-diaminopurine (XIc), cytosine (XIVa) and 6-azacytosine (XIVb). In an analogous reaction, sodium salt of 4-methoxy-2-pyrimidone reacted with compound IX to give an intermediate XIIIa which on treatment with methanolic ammonia and subsequent deblocking under the same conditions also afforded the cytosine derivative XIVa. Sodium salt of 2-amino-6-chloropurine was in this way converted into the corresponding 2-aminopurine derivative XVIII. Deprotection of this compound gave 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)-2-aminopurine (XIX).

Medicinal Chemistry of Fluorinated Cyclic and Acyclic Nucleoside Phosphonates

“…Another biologically potent ANP is 9‐( S )‐[3‐hydroxy‐2‐(phosphonomethoxy)propyl]‐2,6‐diaminopurine (HPMPDAP, 238 , Fig. ), which was further modified on its phosphonate part in order to improve cellular uptake and toxicity profile. A series of cyclic and acyclic HPMPDAP monoesters 239–246 (Fig.…”

Acyclic Nucleotide Analogs Derived from 8-Azapurines: Synthesis and Antiviral Activity

“…The synthesis of the 8-aza analogue of the antiviral HPMPA ( 23 ) (Scheme ) made use of the cesium carbonate-mediated alkylation of 8-azaadenine ( 11 ) with 2( R )-[(diisopropylphosphono)methoxy]-3-(trimethylacetoxy)propyl p -toluenesulfonate ( 20 ) . This reaction afforded, after methanolysis, an equimolar mixture of the protected isomeric intermediates 21 and 22 .…”

“…The synthesis of the 8-aza analogue of the antiviral HPMPA (23) (Scheme 2) made use of the cesium carbonate-mediated alkylation of 8-azaadenine (11) with 2(R)-[(diisopropylphosphono)methoxy]-3-(trimethylacetoxy)propyl p-toluenesulfonate (20). 31 This reaction afforded, after methanolysis, an equimolar mixture of the protected isomeric intermediates 21 and 22. Their treatment with bromotrimethylsilane followed by hydrolysis gave ultimately (S)-9-(3-hydroxy-2-(phosphonomethoxy)propyl)-8-azaadenine (23) and its 8-isomer (24).…”

Acyclic Nucleotide Analogues and Related Compounds

“…However, its use excludes the alkali-catalyzed introduction of phoshonomethyl ether residue rendering thus the method rather limited in scale. 22 We now report another preparation of both the ( …”