Synthesis of 2-deoxy-2-fluoro-arabinose derivatives

Details Synthesis of 2-deoxy-2-fluoro-arabinose derivatives Synthesis of 2-deoxy-2-fluoro-arabinose derivatives

2000-07-13

2002-10-08

Riley, Jezia (Department: 1637)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S001110, C536S004100, C536S125000

Reexamination Certificate

active

06462191

ABSTRACT:

CROSS-REFERENCE TO RELATED APPLICATIONS
Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
This invention relates to processes for deoxyfluorinating the pentose sugar of a nucleoside to form the corresponding 2-&bgr;-fluoro-arabinose compounds.
The development of safe, efficient, and simple methods for selective incorporation of fluorine into organic compounds has become a very important area of technology. It is of particular importance with respect to the deoxyfluorination of the pentose sugar component of a nucleoside to form 2-&bgr;-fluoro-arabinose compounds, which have been shown to exhibit potent anti-tumor and anti-viral activity. See, e.g., Wright et al., 13(2) J. Med. Chem. 269-72 (1970); Fanucchi et al., 69(1) Cancer Treat. Res. 55-9 (1985); Fox et al., Medicinal Chemistry Advances, p. 27 (Pergamon Press, NY, 1981); and Fox et al., “Herpes Viruses and Virus Chemotherapy,” Pharmacological and Clinical Approaches, p. 53, (Excerpta Medica, Amsterdam, 1985). For example, 2′-fluoro-5-iodo-ara-cytosine (FIAC), 2′-fluoro-5-methyl-ara-uracil (FMAU), 2′-fluoro-5-methyl-ara uracil (FMAU) and 2′-fluoro-5-ethyl-ara uracil (FEAU) are active against DNA viruses, according to Lopez et al., 17(5) J. Antimicrob. Agents Chemother. 803-6 (1980); and Lin et al., 221 Science 519 (1983). Although certain 2′-fluoropurine derivatives are cytotoxic, others have been shown to possess anti-HIV activity. See, e.g., Chu et al., 37 Chem. Pharm. Bull. 336 (1989); and Marquez et al., 33 J. Med. Chem. 978 (1990). This is due to the fact that fluorine strategically positioned at sites of synthetic drugs and agrochemical products can significantly modify and/or enhance their biological activities. Fluorine mimics hydrogen with respect to steric requirements and contributes to an alteration of the electronic properties of the molecule. Increased lipophilicity and oxidative and thermal stabilities have been observed in such fluorine-containing compounds.
The conversion of the C—O bond to the C—F bond, which is referred to herein as deoxofluorination, represents a viable method to produce selectively fluorinated organic compounds. Deoxofluorination represents one technique which has been widely used for the selective introduction of fluorine into organic compounds. See, e.g., Boswell et al., 21 Org. React. 1 (1974). A list of the deoxofluorination methods generally used to fluorinate organic compounds to date includes: nucleophilic substitution via the fluoride anion; phenylsulfur trifluoride; fluoroalkylamines; sulfur tetrafluoride; SeF
4
; WF
6
; difluorophosphoranes and the dialkylaminosulfur trifluorides (DAST). The most common reagent of this class is diethylaminosulfur trifluoride, Et-DAST or simply DAST.
The DAST compounds have proven to be useful reagents for effecting deoxofluorinations. These reagents are conventionally prepared by reaction of N-silyl derivatives of secondary amines with SF
4
. In contrast to SF
4
, DAST compounds are liquids which can be used at atmospheric pressure and at near ambient to relatively low temperature (room temperature or below) for most applications. Deoxofluorination of alcohols and ketones is particularly facile and reactions can be carried out in a variety of organic solvents (e.g., CHCl
3
, CFCl
3
, glyme, diglyme, CH
2
Cl
2
, hydrocarbons, etc.). Most fluorinations of alcohols are done at a temperature within the range of −78° C. to room temperature. Various functional groups are tolerated, including CN, CONR
2
, COOR (where R is an alkyl group), and successful fluorinations have been accomplished with primary, secondary and tertiary (1°, 2°, 3°) allylic and benzylic alcohols. The carbonyl to gem-difluoride transformation is usually carried out at room temperature or higher. Numerous structurally diverse aldehydes and ketones have been successfully fluorinated with DAST. These include acyclic, cyclic, and aromatic compounds. Elimination does occur to a certain extent when aldehydes and ketones are fluorinated and olefinic byproducts are also observed in these instances.
However, while the DAST compounds have shown versatility in effecting deoxofluorinations, there are several well-recognized limitations associated with their use. The compounds can decompose violently and while adequate for laboratory synthesis, they are not practical for large scale industrial use. In some instances, undesirable byproducts are formed during the fluorination process. Olefin elimination byproducts have been observed in the fluorination of some alcohols. Often, acid-catalyzed decomposition products are obtained. Moreover, the two-step synthesis employed with DAST compounds renders these relatively costly compositions only suitable for small scale syntheses.
The inventor and his colleagues have previously disclosed that other aminosulfur trifluorides, such as bis(2-methoxyethyl)aminosulfur trifluoride, are much safer to use than DAST and related aminosulfur trifluorides. See Lal et al., 64(19) J. Org. Chem. 7048 (1999); Lal et al., J. Chem. Soc. Chem. Commun. p. 215 (1999); U.S. Pat. No. 6,080,886 and U.S. patent application Ser. No. 08/939,635 filed Sep. 29, 1997. Compared to DAST compounds, bis(2-methoxyethyl)aminosulfur trifluorides provide more thermally stable fluorine-bearing compounds which have effective fluorinating capability with far less potential of violent decomposition and attendant high gaseous byproduct evolvement, with simpler and more efficient fluorinations. Furthermore, bis(2-methoxyethyl)aminosulfur trifluorides can efficiently effect the transformation of hydroxy and carbonyl functionalities to the corresponding fluoride and gem-difluoride respectively.
It has been observed that the direct replacement of a leaving group at the 2′-position of a pyrimidine nucleoside by the fluoride ion is complicated by neighboring-group participation of the carbonyl group of the base, resulting in the formation of the anhydronucleoside. See Fox, 18 J. Pure Appl. Chem. 223 (1969). In the synthesis of 2′-fluoropurines, attempts to replace a C
2
protecting group (e.g., triflate) with fluoride resulted in base cleavage and formation of olefinic byproducts. See Pankiewicz et al., 64 J. Fl. Chem. 15 (1993). It has also been observed that the direct deoxofluorination of the 2′-hydroxyl of some purine derivatives by diethylaminosulfur trifluoride (DAST) afford only low yields of products even when a large excess of the fluorinating agent is used. See Pankiewicz et al., 57 J. Org. Chem. 553 (1992).
The synthesis of 2′-fluoro-substituted nucleosides is currently carried out by condensation of the appropriate 2-fluoro sugar derivative with the nucleoside base. See Pankiewicz et al., 15 J. Fl. Chem. 64 (1993). However, the fluoro sugar is not easily accessible since its preparation often involves lengthy multi-step and low yielding procedures. See Reichmann et al., 42 J. Cardohydr. Res. 233 (1975). The nucleophilic displacement of a leaving group by fluoride at C-2 of furanosides is often accompanied by elimination reactions resulting in olefinic byproducts. See Tann et al., 50 J. Org. Chem. 3644 (1985). Tann et al. reported on a three-step synthesis of 2-deoxy-2-fluoro-1,3,5-tri-O-benzoyl-&agr;-D-arabinofuranose via a 2-O-imidazolylsulfonate leaving group using KHF
2
as the source of fluoride. Tann et al. found that the direct replacement of the C
2
-hydroxyl of this sugar by F with diethylaminosulfur trifluoride (DAST) failed.
Despite the findings in Tann et al., it has been shown that DAST has been used successfully for the deoxofluorination of hydroxy groups of six-membered ring sugars and the C
3
hydroxyl of five-membered ring sugars (i.e., furanoses). See Welch et al.,
Fluorine in Bioorganic Chemistry,
p. 131 (John Wiley and Sons, 1991). Additionally, the procedure of Tann et al. was improved upon by Chou et al. (37 Tett. Lett. 1 (1996)) where triethylamine poly(hydrogen fluoride) was used as the source of fluoride.
Accordingly, there remai

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