8-fluoropurine compounds

Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives

Reexamination Certificate

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Details

C536S027600, C536S027800, C536S027810, C544S264000

Reexamination Certificate

active

06262254

ABSTRACT:

FIELD OF INVENTION
The present invention relates to synthetic methods for making fluoropurines, particularly 8-fluoropurines, and their derivatives.
BACKGROUND OF INVENTION
During the last four decades, interest in fluorinated purine and pyrimidine derivatives has grown, driven by their potential use as anti-cancer and anti-viral agents and the unique properties displayed by fluorine-substituted bioactive molecules. In terms of size, replacement of hydrogen for fluorine would produce minimum stearic perturbations upon the binding of the analogue molecules to receptors or enzymes. Fluorine has a small van der Waals radius (1.35 Å), which closely resembles that of hydrogen (1.2 Å). However, the strong electron-withdrawing properties of fluorine may substantially, yet in a predictable manner, alter the chemical stability or enzymatic activity of substrate molecules. In addition, the carbon-fluorine bond is energetically more stable than the carbon-hydrogen bond.
Although the fluorine atom has been successfully introduced at the 2- and 6-positions of the purine ring system and the sugar moiety of related nucleosides, access to 8-fluoropurines and derivatives has remained limited. The absence of successful syntheses of 8-fluoropurines using elemental fluorine is quite conspicuous, as other halogens—chlorine, iodine, and particularly bromine—have been successfully used in their elemental form to produce regiospecific substitution of the C(8)-hydrogen of purines. Indeed, in many instances, the use of elemental halogen has been the most convenient procedure for regiospecific C(8)-halogen substitution.
Earlier approaches to 8-fluoropurines have been limited to a few reports, involving nucleophilic displacements, Schiemann reactions, halogen exchange reactions, and electrochemical oxidations. None of the synthetic methods involve the use of elemental fluorine or similar agents (e.g., acetyl hypofluorite) that have been successfully used in the synthesis of substituted and unsubstituted 5-fluorouracil and 5-fluorocytosine. Indeed, an attempted fluorination of an oxopurine with phosphoryl fluoride was unsuccessful.
Because of the burgeoning interest in fluorine-substituted bioactive molecules and the numerous failed attempts of others, a need exists for an effective, straightforward synthetic method for making 8-fluoropurines and related derivatives, such as 8-fluoroguanine and 8-fluoropurinylnucleosides.
SUMMARY OF THE INVENTION
The present invention provides an effective synthetic method for making 8-fluoropurines and related compounds, and essentially comprises the step of introducing elemental fluorine or acetyl hypofluorite into a solution containing a substituted or unsubstituted purine compound. Preferably, the reaction is carried out in a polar solvent, which lowers the activation energy of the transition state intermediate and provides a hydrogen acceptor to the counterion of the electrophile (e.g., fluoride ion with F
2
, and acetate ion for AcOF). Despite the fact that monofluorinations of aromatic substrates with elemental fluorine (or AcOF) are unfavored and frequently require the directing effects of Group IVA metals (Si,Ge,Sn), the fluorination reaction of the present invention unexpectedly proceeds readily and in moderate yield, making it very attractive to produce otherwise inaccessible 8-fluoropurine derivatives.
Elemental fluorine or acetyl hypofluorite is conveniently introduced into the solution as a dilute stream in an inert gas. Isolated yields of 8-fluorinated purine compounds as high as 30% have been realized with the new method.
This reliable and direct synthetic approach now makes accessible a variety of 8-fluoro-substituted purines for determination of their biochemical and pharmacological properties. As an indication of the potential of these derivatives, the ability of an 8-fluoroacycloguanine derivative to act as a substrate for HSV tk has already provided a new approach to monitor gene expression in-vivo.
DETAILED DESCRIPTION OF THE INVENTION
Purine is a nitrogenous base having the following formula and numbering system:
The present invention provides an effective, one-step synthesis of 8-fluoropurines using elemental fluorine. In a preferred embodiment, 8-fluoropurine compounds are prepared by bubbling a dilute stream of fluorine or acetyl hypofluorite gas into a solution containing a substituted or unsubstituted purine compound. The reaction proceeds regioselectively, with the C(8)-fluorinated derivative being the major product isolated, in moderate yields.
Although fluorine and acetyl hypofluorite are highly toxic and reactive gases, they can be handled safely by following known procedures developed specifically for such gases (see e.g.,
Matheson Gas Data Book,
Braker, W., Mossman, A. L., Eds.; Matheson, East Rutherford, N.J., 1971; p.261) and the fluorination reaction can be run using ordinary glassware.
It is preferred to introduce fluorine (or its derivative, acetyl hypofluorite) into the reaction vessel as a dilute mixture with an inert gas. Nonlimiting examples of inert gases suitable for use in the present invention include noble gases like He, Ar, etc., as well as nitrogen (N
2
,), with He and N
2
being preferred. The fluorination reaction proceeds readily even at fluorine concentrations as low as 1% by volume. The flow rate of the F
2
/He mixture is controlled to assure a fine dispersion of the gas mixture in the solvents used. Good results are seen with flow rates of approximately 5-10 &mgr;mol of F
2
/min). Progress of the reaction can be monitored by TLC,
1
H NMR, and
19
F NMR. Typically, disappearance of the C(8)-hydrogen singlet at 7.7 at 8.0 ppm in
1
H NMR and the concomitant appearance of a singlet in the
19
F NMR at, e.g., −102.3 to −108.2 ppm, enables the progress of the reaction to be followed and, incidentally, confirms a reaction at carbon-8 of the purine ring.
It is also preferred to run the reaction in a polar solvent. Although not bound by theory, a key element in the success of the fluorination reaction appears to reside in the modulation of the electrophilic character of fluorine reactivity. The use of polar solvents for the fluorination reactions lowers the activation energy of the transition state intermediate below that of homolytic cleavage of the F—F bond (39 kcal/mol). It also provides a hydrogen acceptor to the counterion of the electrophile (e.g. fluoride ion with F
2
and acetate ion for AcOF).
Although the use of polar solvents for fluorine substitution reactions has been reported for the synthesis of 5-fluorouracil and its nucleosides, and in the controlled fluorination of benzoate esters, similar aromatic substitutions with dilute elemental fluorine (< than 1% F
2
in N
2
) in solvents favoring homolytic F
2
cleavage (e.g., CFCl
3
) produced very low yields (<0.1%) of fluorinated products.
Non-limiting examples of polar solvents suitable for use in the present invention include water, dimethyl sulfoxide, acetonitrile, lower alkyl short chain alcohols (e.g., ethanol), lower alkyl carboxylic acids (e.g., acetic acid) and lower alkyl chlorinated hydrocarbons (e.g., chloroform). As used herein, the term “lower alkyl” means a straight or branched alkyl group having from 1 to 6 carbon atoms. The solubility of the purinyl reactant, or course, can dictate the choice of solvent; unprotected purines such as &bgr;-D-ribofuranosyl-guanine and (2-hydroxyethoxymethyl)guanine, for example, are not particularly soluble in chloroform, but can be fluorinated in ethanol (EtOH) with acceptable results. The addition of base, for example, a tetraalkylammonium hydroxide, such as tetraethylammonium hydroxide, improved their solubility in EtOH.
A large variety of 8-fluoropurines, including 8-fluoro derivatives of adenine, guanine, and their related nucleosides, can be prepared using the method provided by the present invention. Of particular interest are 8-fluoro-9-substituted purine nucleosides, and their precursors. Starting with a substituted or unsubstituted purine of formula 1, reaction with elemen

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