SK278200B6 - 9-£5-o-(4-fluorsulfonylbenzoyl)-beta-d -arabinofuranozyl| adenine, its 2-fluorderivative and method of their preparation - Google Patents

Abstract

9-£5-O-(4-fluorsulfonylbenzoyl)-beta-D-arabinofuranozyl| adenine and 9-£5-O-(4-fluorsulfonylbenzoyl)-beta-D- -arabinofuranozyl|-2-fluoradenine of general formula I, where X=H, F is prepared so, that on 9-beta-D-arabinofuranozyladenine or 9-beta-D-arabinofuranozyl-2-fluoradenine of general formula II, where X=H, F in hexamethylenphosphotriamide solvent acts the 4-fluorsulfonylbenzoylchloride by temperature 75 to 90 degrees of Celsius during 1 to 3 hours, then the reactive mixture is extracted by petroleum ether, precipitated by acetone and it is finally cleaned. This solution can be used in medicine and oncological research.

Description

Technical field

The invention relates to 9- [5-O- (4-fluorosulfonylbenzoyl) -β-D-arabinofuranosyl] adenine, its 2-fluoro derivative and a process for their preparation.

BACKGROUND OF THE INVENTION

Fluorosulfonylbenzoyl derivatives of D-ribosyl nucleosides, i.e. nucleosides, which contain D-ribose as a saccharide component have been described in the literature. 5-Fluorosulfonylbenzoyladenosine [PK Pal, WJ Wechter, RF Colman, J. Biol. Chem. 250, 8140 (1975)], 5-fluorosulfonyl-1, N ⁶ -ethenadenosine [J. Likos, RF Colman: Biochemistry 20, 491 (1981)] and 5-fluorosulfonylbenzoylguanine [PK Pal, WJ Wechter, RF Colman: J. Biol. . Chem. 253, 6644 (1978)]. Since these syntheses were carried out at temperatures up to 20 ° C, there were problems with the preparation of these compounds, ie low yields, further high contamination of the products and even the impossibility to prepare some derivatives. Fluorosulfonylbenzoyl derivatives of naturally occurring nucleosides and their synthetic analogs are of interest for their ability to react under certain conditions with enzymes that may cause their biochemical transformation [RF Colman, PK Pal, JL Wyat: Methods in Enzymology XLVI, Afinity Labeling, Eds .: WV Jakoby, M. Wilchek, Academic Press, New York-San Francisco-London 440 (1977)]. The great importance of these cancerostatics from the group of antimetabolites of nucleic acid components is that they are frequently used in clinical oncology, although their metabolic transformations are not always well studied.

9- [5-O- (4-Fluorosulfonylbenzoyl) -β-D-arabinofuranosyl] adenine and its 2-fluoro derivative have not been prepared.

SUMMARY OF THE INVENTION

The present invention provides 9- [5-O- (4-fluorosulfonylbenzoyl) -PD-arabinofuranosyl] adenine and 9- [5-O- (4-fluorosulfonyibenzoyl) -β-D-arabinofuranosyl] -2-fluoroadenine of formula I wherein X is H, F.

The present invention further provides a process for the preparation of compounds of formula (I) which comprises treating 9-PD-arabinofuranosyladenine or 9-PD-arabinofuranosyl-2-fluoroadenine in a hexamethylene phosphotriamide solvent with 4-fluorosulfonylbenzoyl chloride at 75 to 90 ° C. 1-3 hours, then extracted with petroleum ether, precipitated with acetone and purified.

The advantage of the process for the preparation of 9- [5-O- (4-fluorosulfonylbenzoyl) -β-D-arabinofuranosyl] adenine and its 2-fluoro cosidide analogues is that new biologically active compounds can be prepared in this manner at temperatures up to 30 ° C. cannot arise. Another advantage is the relatively good yield and ease of preparation.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

134 mg of 9-PD-arabinofuranozyladenine are dissolved in 1 ml of hexamethylene phosphotriamide at 70 ° C. 133 mg of 4-fluorosulfonylbenzoyl chloride are then added and reacted at 90 ° C for 1 hour. The reaction mixture is extracted with 3 ml of petroleum ether, then precipitated with 3 ml of acetone. The white precipitate was purified by preparative thin layer chromatography with ethyl acetate, ethanol, acetone and water in a ratio of 18: 3: 1: 1 9- [5-O- (4-Fluórsulfonylbenzoyl) -PD-arabinofuranozyljadenín a retention factor _Rf = 0 = M.p. 188 DEG-189 DEG C. was extracted with methanol and precipitated with ether (35 mg, 15% yield). In the ultraviolet spectrum using methanol as solvent, these wavelengths were measured to be λ _ro „= 231.5 nm and /. _m , λ = 221 nm. In the proton spectrum using hexadeuterium dimethylsulfoxide as solvent, the following determining peaks are: 3.798; 4,183; 4,284; 4,671; 6,338; 7,461; 8,167; 8,329; 8.331 and after heavy water exchange peaks: 4.142; 4,280; 4,610; 4,692; 6,308; 8,132; 8,256; 8,371.

Elemental analysis for CpHH ^Cl ^F SF.HjO, MW 471.4, calculated: 43.31 wt. % carbon; 3.85 wt. % hydrogen; 14.85 wt. N;

found: 42.91 wt. % carbon; 4.19 wt. % hydrogen, 15.15 wt. % Of nitrogen.

Example 2

The procedure was as in Example 1 except that 143 mg of 9-PD-arabinofuranosyl-2-fluoroadenine was used and reacted at 75 ° C for 3 hours. 9- [5-0- (4-Fluórsulfonylbenzoyl) -PD-arabinofuranosyl] -2-fluoroadenine with a retention factor _Rf = 0.87 and a melting point of 122 to 124 ° C was extracted with MeOH and precipitated with ether in an amount of 45 mg of ( 18% yield). In the ultraviolet spectrum using methanol as solvent, these wavelengths were measured to _raax = 231.5 nm and λ _mln = 217 nm. In the proton spectrum using hexadeuterium dimethylsulfoxide as solvent, the following determining peaks are: 3,752; 4,178; 4,257; 4,659; 6,191; 7,783 ,; 8,118; 8.288 and after heavy water exchange peaks: 3.808; 3,884; 4,207; 4,261; 4,661; 6,172; 8,087; 8,267.

H, C H _{ls t7} O7N _the SF2.3H2O, MW 525.4, calc: 38.86 wt. % carbon; 4.02 wt. % hydrogen; 13.33 wt. N; 7.23 wt. % fluorine; 6.10 wt. % sulfur;

found: 39.10 wt. % carbon; 3.69 wt. % hydrogen; 12.99 wt. % nitrogen; 7.63 wt. % fluorine; 5.84 wt. % sulfur.

Industrial usability

9- [5-O- (4-Fluorosulfonylbenzoyl) -β-D-arabinofuranosyl] adenine and its 2-fluoro derivative have utility in medicine as a virostatic, cancerostatic and in the study

In comparison with the hitherto known method of preparation of nuenzymatic activities in processes occurring in tumor and normal cells.

Claims (2)

PATENT CLAIMS 1. 9- [5-O- (4-Fluorosulfonylbenzoyl) -β-D-arabinofuranosyl] adenine and 9- [5-O- (4-fluorosulfonylbenzoyl) -PD-arabinofuranosyl] -2-fluoroadenine of the general formula I: 9-PD-arabinoor 9-PD-arabinofuranosyl-2-fluoro- (D wherein X is H, F. A process for the preparation of compounds according to claim 1, characterized in that furanozyladenine adenine of the formula II wherein X is H and F, in a solvent of hexamethylene phosphotriamide, is treated with 4-fluorosulfonylbenzoyl chloride at 75 to 90 ° C for 1 to 3 hours. extracted with petroleum ether, precipitated with acetone and purified.