113852-35-0

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InChI:InChI=1/C9H15N6O5P/c10-7-6-8(14-9(11)13-7)15(3-12-6)1-5(2-16)20-4-21(17,18)19/h3,5,16H,1-2,4H2,(H2,17,18,19)(H4,10,11,13,14)

Upstream product

• 141110-74-9 (R)-2--3-ytimethylacetyl-1,2,3-propanetriol 1-p-toluenesulfonate 
• 1904-98-9 2,6-diaminopurine 
• 1374997-60-0 diisopropyl {[(1S)-2-(2,6-diamino-9H-purin-9-yl)-1-(hydroxymethyl)ethyl]oxy}methylphosphonate 
• 148873-49-8 2,6-bis(benzoylamino)-9-(R)-(2,3-dihydroxypropyl)purine 
• 148967-05-9 2,6-diamino-9-(R)-(2,3-dihydroxypropyl)purine 
• 148873-50-1 2,6-bis(benzoylamino)-9-(R)-(2-hydroxy-3-triphenylmethoxypropyl)purine 

Relevant academic research and scientific papers

Microwave-assisted hydrolysis of phosphonate diesters: An efficient protocol for the preparation of phosphonic acids

A new highly efficient method for the hydrolysis of acyclic nucleoside phosphonate diesters (or generally of any organophosphonates) to the corresponding phosphonic acids has been developed. This novel methodology employs inexpensive hydrochloric acid in equimolar amounts to the number of ester groups present in the molecule and thus, avoids using trimethylsilyl halogenides, the standard reagents for these types of transformations. Moreover, simple and easy work-up of the reaction mixture affords very clean products in high yields (usually 77-93%). Another advantage of the described hydrolysis of phosphonate diesters is the fact that the course of the reaction can be instantly monitored through pressure changes in the reaction vessel. This 'green' method has also been successfully used for the preparation of otherwise synthetically difficult to access (phosphonomethoxy)ethyl (PME) derivatives of guanine (PMEG) and hypoxanthine (PMEHx), and furthermore, the method gains access to important novel acyclic nucleoside phosphonates derived from 2-chlorohypoxanthine and from xanthine (e.g. PMEX).

Synthesis of ester prodrugs of 9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl] -2,6-diaminopurine (HPMPDAP) as anti-poxvirus agents

9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) and its cyclic form were selected for further evaluation as potential drug candidates against poxvirus infections. To increase bioavailability of these compounds, synthesis of their structurally diverse ester prodrugs was carried out: alkoxyalkyl (hexadecyloxypropyl, octadecyloxyethyl, hexadecyloxyethyl), pivaloyloxymethyl (POM), 2,2,2-trifluoroethyl, butylsalicylyl, and prodrugs based on peptidomimetics. Most HPMPDAP prodrugs were synthesized in the form of monoesters as well as the corresponding cyclic phosphonate esters. The activity was evaluated not only against vaccinia virus but also against different herpes viruses. The most potent and active prodrugs against vaccinia virus were the alkoxyalkyl ester derivatives of HPMPDAP, with 50% effective concentrations 400-600-fold lower than those of the parent compound. Prodrugs based on peptidomimetics, the 2,2,2-trifluoroethyl, the POM, and the butylsalicylyl derivatives, were able to inhibit vaccinia virus replication at 50% effective concentrations that were equivalent or ～10-fold lower than those observed for the parent compounds.

GENERAL METHOD OF PREPARATION OF N- DERIVATIVES OF HETEROCYCLIC BASES

Reaction of (R)-1-O-p-toluenesulfonyl-1,2,3-propanetriol (IV) with N-trimethylacetylimidazole (II) afforded (R)-1-O-p-toluenesulfonyl-3-O-trimethylacetyl-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-trimethylacetyl-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-trimethylacetyl-1,2,3-propanetriol (IX).Condensation of synthon IX with sodium salts of adenine, 2,6-diaminopurine, or with cytosine, 6-azacytozine 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- 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).

SYNTHESES OF ENANTIOMERIC N-(3-HYDROXY-2-PHOSPHONOMETHOXYPROPYL)DERIVATIVES OF PURINE AND PYRIMIDINE BASES

Methods of preparation of N-(3-hydroxy-2-phosphonomethoxypropyl) (HPMP) derivatives of (2S)- and (2R)-configuration compounds I and XXVII, respectively are described.The general method starts from the corresponding N-(2,3-dihydroxypropyl) derivatives which were converted either into the (R)-enantiomers XIII by reaction of the base with (R)-glycidol butyrate (XII) in the presence of cesium carbonate and subsequent methanolysis, or into the (S)-enantiomers XI by alkylation of the base with (R)-2,2-dimethyl-4-tosyloxymethyl-1,3-dioxolane (V) in the presence of the same reagent.The amino groups on the heterocyclic base in compounds XI and XIII were benzoylated by silylation followed by reaction with benzoyl chloride and the obtained N-benzoates XV and XVII on reaction with trityl chloride afforded the corresponding 3'-O-trityl derivatives XVI and XVIII.These compounds were condensed with bis(2-propyl)-p-toluenesulfonyloxymethanephosphonate (XXIII) in dimethylformamide in the presence of sodium hydride to give the fully protected diesters XXIV and XXVIII.These compounds could be selectively acid-hydrolyzed to remove the trityl group only under formation of compounds XXXV, or methanolyzed and then acid-hydrolyzed to remove the trityl and N-benzoyl groups and lead to compounds XXVI and XXX, or treated with bromotrimethylsilane to remove the trityl and 2-propyl group to give phosphonates of the type XXVI.All the three types of compounds were then converted into free phosphonates of the (S)-series (I) and (R)-series (XXVII).Derivatives of cytosine (Ia, XXVIIa), adenine (Ib, XXVIIb), 2,6-diaminopurine (Ic, XXVIIc) and guanine (Id, XXVIId) were prepared.Condensation of the partially blocked adenine derivative XXXV with the tosyl derivative XXIII and subsequent deprotection afforded 9-(S)-(2,3-diphosphonomethoxypropyl)adenine (XLIII).Reaction of the same compound XXXV or its (R)-enantiomer XXXVIII with diethyl chlorophosphonate, followed by deblocking, afforded 3'-O-phosphoryl derivatives (S)-HPMPA (XXXVII) and (R)-HPMPA (XL).