Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1993-01-13
1994-10-04
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544244, 558 45, 558 44, C07F 902
Patent
active
053527860
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to di(2-propyl) esters of 1-fluoro-2-phosphonomethoxy-3-p-toluenesulfonyloxypropanes, the method of their preparation and utilization in production of antivirals, N-(3-fluoro-2-phosphonomethoxypropyl) derivatives of heterocyclic purine and pyrimidine bases.
BACKGROUND ART
N-(3-Fluoro-2-phosphonomethoxypropyl) derivatives of heterocyclic purine and pyrimidine bases (FPMP-derivatives) occupy a significant place among compounds effective against retro-viruses causing serious illnesses in man and animals. Under in vitro conditions, these compounds exhibit biological parameters (selectivity of action) better than e.g. 9-(2-phosphonomethoxyethyl)adenine (R. Pauwels, J. Balzarini, D. Schols , M. Baba, J. Desmyter, I. Rosenberg, A. Holy, E. De Clercq: Antimicrob. Ag. Chemother. 32, 1025 (1988)). The said derivatives were hitherto accessible from N-(3-fluoro-2-hydroxypropyl) derivatives of purine or pyrimidine bases (prepared e.g. according to CS-patent application PV 2047-90) by reaction with dialkyl p-toluenesulfonyloxymethanesulfonates or methanesulfonyloxymethanephosphonates in the presence of sodium hydride and subsequent removal of the protecting groups by acid or alkaline hydrolysis and finally with bromotrimethylsilane. The drawback of this method (according to CS-patent application PV 2047-90) is that it is necessary first to prepare the optically active N-(3-fluoro-2hydroxypropyl) derivatives and perform their multistage protection. Another possible solution would be condensation of the heterocyclic base (its silyl derivative or alkali metal salt) with a suitable optically active organophosphorus synthon that has a preformed structure of the side chain of FPMP derivatives. Such a reaction of suitably protected derivatives of glycerol with dialkyl esters of p-toluenesulfonyloxymethanephosphonic acid, followed by partial deblocking and introduction of the reactive tosyl or mesyl group has been utilized e.g. in producing analogous N-(3-hydroxy-2-phosphonomethoxypropyl) derivatives (J. J. Bronson, I. Ghazzouli , M. J. M. Hitchcock, R. R. Webb, J. C. Martin: J. Med. Chem. 32, 1457 (1989)). Still another approach made use of introduction of the esterified phosphonomethyl ether functionality on the hydroxyl component via an acetoxymethyl ether by treatment with bromotrimethylsilane and trialkyl phosphite (CS-patent application PV 3871-90).
DISCLOSURE OF INVENTION
The above-mentioned drawbacks in the so far used methods of preparing N-(3-fluoro-2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases are removed by this invention relating to di(2-propyl) esters of 1-fluoro-2-phosphonomethoxy-3-p-toluenesulfonyloxypropanes of the general formula I ##STR1## where the absolute configuration at carbon atom C2 is R, S or RS, and the method of preparing them which is characterized in that 1-fluoro-2,3-propanediols of the general formula II ##STR2## where the absolute configuration at carbon atom C2 is R, S or RS, are reacted with p-toluenesulfonyl chloride in the presence of a tertiary amine, preferably triethylamine or pyridine, in an inert organic aprotic solvent, preferably benzene or dichloromethane, or only in pyridine, the obtained 1-fluoro-3-p-toluenesulfonyloxy-2-propanols of the general formula III ##STR3## where the absolute configuration at carbon atom C2 is R, S or RS, are reacted with dimethoxymethane in the presence of phosphorus pentoxide in an inert organic solvent, preferably dichloromethane, the resulting 1-fluoro-2-methoxymethoxy-3-p-toluenesulfonyloxypropanes of the general formula IV ##STR4## where the absolute configuration at carbon atom C2 is R, S or RS, are treated with acetic anhydride in the presence of a Lewis acid, preferably boron trifluoride etherate, at -5.degree. to +5.degree. C., the obtained 2-acetoxymethoxy-1-fluoro-3-p-toluenesulfonyloxypropanes of the formula V ##STR5## where the absolute configuration at carbon atom C2 is R, S or RS, are heated with bromotrimethylsilane to 100.degree.-120.degree. C. preferably in toluene, t
REFERENCES:
patent: 5130427 (1992-07-01), Alexander et al.
Balzarini et al, "9-[(2RS)-3-Fluoro-2-phosphonylmethoxypropyl] derivatives of purines: A class of highly selective antiretroviral agents in vitro and in vivo", Proc. Natl. Acad. Sci. USA, vol. 88, pp. 4961-4965, (Jun. 1991).
Balzarini et al, "5-Phosphoribosyl 1-Pyrophosphate Synthetase Converts the Acyclic Nucleoside Phosphonates 9-(3-Hydroxy-2-Phosphonylmethoxypropyl)Adenine and 9-(2-Phosphonylmethoxyethyl)-Adenine Directly to their Antivirally Active Diphosphate Derivatives", The Journal of Biological Chemistry, vol. 266, No. 14, pp, 8686-8689, (May 15, 1991).
Bronson et al, "Synthesis and Antiviral Activity of the Nucleotide Analogue (S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl] cystosine", J. Med. Chem., vol. 32, pp. 1457-1463, (1989).
Holy Antonin
Jindrich Jindrich
Dees Jos,e G.
Hensley Max D.
Institute of Organic Chemistry and Biochemistry of the Academy o
Jones Dwayne C.
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