Title of Invention	"PROCESS FOR THE PREPARATION OF 2'-HALO-ß L-ARABINOFURANOSY1 NUCLEOSIDES"
Abstract	The present invention is directed to the process for the preparation of 2"-halo-B-L-arabinofuranosyl nucleossides, and in particular, 2"-deoxy-2"-fluoro-B-L-arabinofuranosyl thymine (L-FMAU), from L-arabinose, which is commercially available and less expensive than L-ribose or L-xylose, in ten steps. All of the regents and starting materials are inexpensive and no special equipment is required to carry out the reactions.

Title of Invention

"PROCESS FOR THE PREPARATION OF 2'-HALO-ß L-ARABINOFURANOSY1 NUCLEOSIDES"

Abstract

The present invention is directed to the process for the preparation of 2"-halo-B-L-arabinofuranosyl nucleossides, and in particular, 2"-deoxy-2"-fluoro-B-L-arabinofuranosyl thymine (L-FMAU), from L-arabinose, which is commercially available and less expensive than L-ribose or L-xylose, in ten steps. All of the regents and starting materials are inexpensive and no special equipment is required to carry out the reactions.

Full Text	PROCESS FOR THE PREPARATION OF 2"-HALO-ß-L-ARABINOFURANOSYL NUCLEOSIDES FIELD OF THE INVENTION This invention is in the area of the synthesis of 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleosides, and is specifically directed to an efficient method of synthesis and manufacturing of l-(2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl)-thymine (L-FMAU) This application claims priority to U.S Provisional Application No 60/280,307, filed on March 30, 2001. BACKGROUND OF THE INVENTION Infection by hepatitis B virus is a problem of enormous dimensions Hepatitis B virus has reached epidemic levels worldwide It is estimated that as many as 350 million people worldwide are persistently infected with HBV, many of whom develop associated pathologies such as chronic hepatic insufficiency, cirrhosis, and hepatocellular carcinoma After a two to three month incubation period in which the host is unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. About 1-2% of these develop fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed, with a mortality rate of 60-70% The Epstein-Barr virus is a member of the genus Lymphocrypiovirus, which belongs to the subfamily gammaherpesvinne It is notably lymphotropic EBV has the classic structure of herpes viruses, viz , its double-stranded DNA genome is contained within an icosapentahedra! nucleocapsid, v.hich, in turn, is surrounded by a lipid envelope studded with viral glycoproteins EBV is now recognized as a cause of B-cell lymphoprohferative diseases, and has been linked to a variety of other severe and chronic illnesses, including a rare progressive mononucleosis-like syndrome and oral hairy leukoplakia in AIDS patients. The suggestion that EBV is a major cause of chronic fatigue has not withstood scrutiny. EBV is primarily transmitted through saliva, although some infections are transmitted by blood transfusion. More than 85% of patients m the acute phase of infectious mononucleosis secrete EBV. It has been discovered that certain L-nucleosides, mirror images of the natural DNA constituents may inhibit DNA synthesis at the triphosphate level probably by tight binding to the viral polymerase in the first stage of viral DNA synthesis. 2"-Deoxy-2"-fluoro-ß-L-arabinofuranosyl nucleosides have the general formula: (Formula Removed) wherein B is a pynmidine, purine, heterocyclic or heteroaromatic base. Reported syntheses of L-FMAU Yung Chi Cheng, Chung K. Chu and others first reported that l-(2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl)-thymine (L-FMAU) exhibits superior activity against hepatitis B virus and Epstein Barr virus in 1994. See U.S. Patent Nos 5,587,362; 5,567,688; 5,565,438 and 5,S08,040 and International Patent Application published as WO 95/20595. (Formula Removed) The Cheng patents describe a synthesis of L-FMAU from the sugar L-xylose (formula A) as well as the sugar L-ribose (formula B). (Formula Removed) These patents describe the synthesis of L-FMAU from L-xylose via conversion to the key intermediate l-O-acetyl-2,3,5-tn-O-benzoyl-ß-L-ribofuranose (see for example the "688 patent, starting at column 4, line 62) The key intermediate was synthesized from L-xylose in a total yield of 20% (see also L. Vargha, Chem Ber., 1954, 87, 1351; Holy, A, et al., Synthetic Procedures in Nucleic Acid Chemistry, VI, 163-67). This synthesis was also reported in Ma. T.; Pai, S. B.; Zhu, Y. L; Lin, T. S, Shanmunganathan. K.; Du, J. E; Wang, C. G.; Kim, H.; Newton, G. M ; Cheng, Y. C , Chu, C. K. J. Med. Chem. 1996, 39, 2S35. The inversion of the hydroxy group of L-xylose was achieved via the formation of the 5-O-benzoyl-l,2-O-isopropylidene-α-L-ribofuranoside, followed by a stereoselective hydride transfer during the reduction of the cycloketone furanoside with NaBH4. The resulting ribofuranoside was then converted to l-O-acetyl-2,3,5-tn-O-benzoyl-ß-L-nbofuranose, the key intermediate in the synthesis of L-FMAU (See Scheme A). (Scheme Removed) A l-O-Acetyl-2,3,5-tri-O-benzoyl-ß-L-ribofuranose can also be synthesized directly from the more expensive starting material L-ribose (see for example the "688 patent, starting at column 6, line 30; and Holy, A., et al., Synthetic Procedures in Nucleic Acid Chemistry, VI, 163-67). This alternative synthesis of l-0-acetyl-2,3,5-tri- (Scheme Removed) B The key intermediate was subsequently fluonnated in a nucleophilic displacement reaction at C2 to obtain 13,5-tri-O-benzoyl-2-deoxy-2-fluoro-L-arbinofuranose, which was condensed with a desired base, such as thymine (5-methyluracil) through the bromosugar to piovide the 2-deoxy-2-fluoro-arabinofuranosyl nucleosides in various yields. Chu et al. later developed a synthesis for the production of L-FMAU from L-arabmose in 14 steps and an overall yield of 8% (Du, J., Choi, Y.; Lee, K ; Chun, B K.; Hong, J. H., Chu, C. K. Nucleosides and Nucleosides 1999, 18, 187). L-Arabinose was converted to L-ribose in 5 steps (Scheme C) L-Ribose was then used in the synthesis 1- O-acetyl-2,3,5-tri-O-benzoyl-ß-L-ribofuranose, which as described above led to the formation of L-FMAU. (Scheme Removed) C The processes mentioned above either start from an expensive sugar (L-ribose or L-xylose) and/or are very long, with low yields. In addition, they involve the use of a nucleophilic form of fluoride such as KHF2 or Et3N-3HF, which is difficult to handle and requires the displacement of an activated hydroxyl group. The instability of DAST prevents its use on large scale. The conversion of l-0-acetyl-2,3,5-tri-O-benzoyl-3-L-ribofuranose (TBAR) to 1,3,5-tri-O-benzoyl-ß-L-ribofuranose generates 2,3,5-tn-O-benzoyl-ß-L-ribofuranose as a side-product, though it can be reconverted to TBAR. Reported syntheses of l-0-methyl-2-deoxy-2-fluoro-arabinofuranoside The synthesis of l-O-methyl-2-deoxy-2-fluoro-a-D-arabinofuranoside, has been reported by Wnght et al. (Wright, J. A.; Taylor. N. R; Fox, J. J. J. Org. Chem 1969, 34, 2632, and references therein). In this report, D-xylose is used as the starting material, which after a conversion to the corresponding furanose and a series of protection reactions, gave an epoxy furanoside as an intermediate. This compound was further converted to 5-0-benzyl-l-O-methyl-2-deoxy-2-fluoro-α-D-arabinofuranoside, which after removal of the benzyl group afforded l-0-methyl-2-deoxy-2-fluoro-α-D-arabmofuranoside (Scheme D). (Scheme Removed) D The synthesis of the l-O-methyl-2-deoxy-2-fluoro-ß-D-arabmofuranoside (the anomer of the above compound) was reported by Marquez et al. (Wysocki, R. J.; Siddiqui, M. A.; Barchi, J. J.; Dnscoll, J. S.; Marquez, V. E. Synthesis 1991, 1005). D-ribose was converted i several steps to l,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-ß-D-arabinofuranose, the corresponding bromo sugar derivative was produced under HBr/AcOH condition and the reaction of potassium carbonate in methanol gave the desired compound (Scheme E). (Scheme Removed) E Reported synthesis of 2-deoxy-2-fluoro-D-arabinospyranose 2-deo\y-2-fluoro-D-arabinopyranose was previously made from D-arabinose via D-arabinal as it is shown in Scheme F (Albano, E. L et ai. Carbohyd. Res. 1971,19,63). (Scheme Removed) F The same material was made from D-Ribose as shown below in Scheme G (Bols, M.; Lundt, L; Acta Chem. Scand. 1990, 44, 252). (Scheme Removed) G Reported synthesis of 2-deoxy-2-fluoro-3,4-di-0-acetyl-D-arabinospyranose The title compound was previously made as a result of an electrophilic addition of selectfluor on D-arabinal (Albert, M. et al, Tetraliedron 1998,54,4839; Scheme H). (Scheme Removed) H In light of the commercial importance of L-FMAU, and its use m the treatment of patients afflicted with hepatitis B and Epstein Ban virus, it is an object of the invention to provide an improved synthesis of L-FMAU and related nucleosides It is another object of the invention to provide a synthesis of 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleosides from inexpensive starting materials in relatively high yield. SUMMARY OF THE INVENTION The present invention is a process for the preparation of 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleosides, and in particular, 2"-deoxy-2"-fluoro-\|3-L-arabmofuranosyl thymine (L-FMAU). from L-arabmose, which is commercially available and less expensive than L-nbose or L-xylose. The process involves the initial synthesis of a 2-deoxy-2-halo-3,4-di-0-protected-L-arabinospyranose, via an electrophilic halogenatmg agent, and in particular a fluonnatmg reagent. Deprotection and isomerization affords a 2-deoxy-2-halo-L-arabinofuranoside, a key intermediate in this synthesis. The 3- and 5-hydroxyl groups can then be protected, preferably by benzoylation, and the 1-position can be activated, preferably halogenated, and even more preferably brominated. This compound can then be condensed with a protected pyrimidine, purine, heterocyclic or heteroaromatic base to form the desired 2"-deoxy-2"-fluoro-L-arabinofuranosyl-nucleoside. This process for the preparation of 2"-deoxy-2"-fluoro-L-arabinofuranosyl-nucleoside, and in particular, L-FMAU, is the first synthesis of this class of nucleosides from L-arabinose in ten steps. All of the reagents and starting materials are inexpensive and no special equipment is required to carry out the reactions. A key step for the synthesis is the conversion of a pyranoside. 2-deoxy-2-halo-L-arabmopyranose, into a furanoside, 2-deoxy-2-halo-L-arabmofuranoside. In particular, in one embodiment of the present invention, a process for the preparation of a 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside of the formula (I): (Formula Removed) wherein X is a halogen (F, CI, Br or I), though preferably fluorine; and B is a pynmidme. purine, heterocyclic or heteroaromatic base; is provided, comprising (a) obtaining a 2-deoxy-2-halo-L-arabmopyranose of the formula (II): (Formula Removed) wherein each of R1 and R2 is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl; (b) converting the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabmofuranose; (c) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br. CI or I), though preferably a halogen, and even more preferably Br; (d) coupling the arabmofuranose to an optionally protected pyrimidine, purine, heterocyclic or heteroaromatic base, and (e) deprotecting. if necessary, to obtain the 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside. In another embodiment of the invention, a process for the preparation of a 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside of the formula (I): (Formula Removed) wherein X is a halogen (F, CI, Br or I), though preferably fluorine, and B is a pynmidine. purine, heterocyclic or heteroaromatic base; is provided, comprising (a) obtaining an optionally protected L-arabmose of the formula (IV): (Formula Removed) wherein each of R1, R2, R3 and R4 is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl; (b) substituting OR1 with a halogen (F, Br, CI or I), preferably Br, to obtain a compound of the formula (V); (Formula Removed) wherein X1 is a halogen (F, Br, CI or I), preferably Br; (c) reducing the compound of formula (V) to form a compound of formula (III) (Formula Removed) (d) halogenating the compound of formula (HI) and deprotectmg if necessary to form the 2-deoxy-2-halo-L-arabmopyranose of the formula (II). (Formula Removed) wherein X is a halogen (F, Br. CI or I), preferably F; (e) converting the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L~ arabinofuranose; (f) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br, CI or I), though preferably a halogen, and even more preferably Br; (g) coupling the arabmofuranose to an optionally protected pyrimidme, purine, heterocyclic or heteroaromatic base; and (h) deprotecting, if necessary, to obtain the 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside. In one particular embodiment of the present invention, the conversion of the 2-deoxy-2-halo-L-arabmopyranose to a 2-deoxy-2-halo-L-arabmofuranose is accomplished using one equivalent of sulfuric acid In a further embodiment of the present invention, the conversion of the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabino-furanose is accomplished in dry methanol. In a preferred embodiment, the conversion of the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabinofuranose is accomplished using one equivalent of sulfuric acid in dry methanol. In another embodiment of the present invention, a process for the preparation of 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymine (L-FMAU) comprising (a) obtaining a 2-deoxy-2-fluoro-L-arabmopyranose of the formula (II-a)- (Formula Removed) wherein each of R and R" is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl; (b) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabinofuranose; (c) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br. CI or I), though preferably a halogen, and even more preferably Br; (d) coupling the arabinofuranose to an optionally protected thymidine; and (e) deprotectmg, if necessary, to obtain the 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymidine. In yet another embodiment of the invention, a process for the preparation of 2"-deoxy-2"-fluoro-f3-L-arabinofuranosyl thymine (L-FMAU) comprising (a) obtaining an optionally protected L-arabmose of the formula (IV) (Formula Removed) wherein each of R1, R2, R3 and R4 is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl; (b) substituting OR1 with a halogen (F, Br, CI or I), preferably Br to obtain a compound of the formula (V); (Formula Removed) wherein X1 is a halogen (F, Br, CI or I), preferably Br; (c) reducing the compound of formula (V) to form a compound of formula (III) (Formula Removed) (d) fluonnaung the compound of formula (III) and deprotectmg if necessary to form the 2-deoxy-2-fluoro-L-arabinopyranose of the formula (II-a); (Formula Removed) (f) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabmofuranose, (g) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br, CI or I), though preferably a halogen, and even more preferably Br; (h) coupling the arabmofuranose to an optionally protected thymine; and (i) deprotectmg, if necessary, to obtain the 2"-deoxy-2"-fluoro-\|3-L-arabinofuranosyl thymidine. In a particular embodiment of the present invention, the halogenation, and in particular, the fluonnation, of the compound of formula (III) is accomplished in nitromethane:water In an alternate embodiment, the halogenation, and in particular, the fluorination, of the compound of formula (III) is accomplished in acetone:water In one particular embodiment of the present invention, the conversion of the 2-deoxy-2-fluoro-L-arabmopyranose to a 2-deoxy-2-fluoro-L-arabmofuranose is accomplished using one equivalent of sulfuric acid. In a further embodiment of the present invention, the conversion of the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabmo-furanose is accomplished in dry methanol. In a preferred embodiment, the conversion of the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabinofuranose is accomplished using one equivalent of sulfuric acid m dry methanol In one embodiment of the invention the 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside, and in particular the 2."-deoxy-2"-fluoro-\|3-L-arabinofuranosyI thymine, can be further functionahzed, such as phosphorylated or acylated to form pharmaceutically acceptable salts or prodrugs. BRIEF DESCRIPTION OF THE FIGURE Figure 1 is a non-lmnting example of a process for the preparation of 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymine, according to the present invention. DETAILED DESCRIPTION OF THE INVENTION The present invention is a process for the preparation of 2"-deoxy-2"-halo-p-L-arabmofuranos>l nucleosides, and m particular, 2:-deoxy-2"-fluoro-ß-L-arabmofuranosyl thymine (L-FMAU), from L-arabinose, which is commercially available and less expensive than L-ribose or L-xylose. The process involves the initial synthesis of a 2-deoxy-2-halo-3,4-di-0-protected-L-arabmospyranose. and m particular 2-deoxy-2-fluoro-3.4-di-O-acetyl-L-arabinospyranose, via an electrophilic halogenatmg agent, and in particular a fluonnatmg reagent. Deprotection and isomenzation affords a 2-deoxy-2-halo-L-arabinofuranoside. and in particular, l-O-methyl-2-deoxy-2-fluoro-L-arabmofuranoside, a key intermediate in this synthesis. The 3- and 5- hydroxy] groups can then be protected, preferably by benzoylation, and the 1-position can be activated, prefeiably halogcnated, and even more preferably brommated to form, for example, 1-bromo-3.5-di-O-benzoyl-2-deoxy-2-fluoro-L-arbmofuranose This compound can then be condensed with a protected pynmidine, purine, heterocyclic or heteroaromatic base to form the desired 2"-deo\y-2"-fluoro-L-arabinofuranosyl-nucleoside. This process for the preparation of 2"-deoxy-2"-fluoro-L-arabinofuranosyl-nucleoside, and in particular, L-FMAU, is the first synthesis of this class of nucleosides from L-arabinose in ten steps. All of the reagents and starting materials are inexpensive and no special equipment is required to carry out the reactions. A key step for the synthesis is the conversion of a pyranoside, 2-deoxy-2-halo-L-arabmopyranose, into a furanoside, 2-deoxy-2-halo-L-arabmofuranoside. The term "L-FMAU analog" or "related nucleoside" as used herein refers to a nucleoside thai is formed from a pyrrolidine or purine base that is coupled to a 2-fluoro-arabmofuranosvl moiety. In particular, in one embodiment of the present invention, a process for the preparation of a 2"-deoxy-2"-halo-\|3-L-arabinofuranosyl nucleoside of the formula (I): (Formula Removed) wherein X is a halogen (F, CI, Br or I), though preferably fluorine; and B is a pyrimidme, purine, heterocyclic orbeteroaromatic base; is provided, comprising (a) obtaining a 2-deoxy-2-halo-L-arabmopyranose of the formula (II): (Formula Removed) wherein each of R and R" is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl; (b) converting the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabinofuranose; (c) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br, CI or I), though preferably a halogen, and even more preferably Br; (d) coupling the arabinofuranose to an optionally protected pyrimidine, purine, heterocyclic or heteroaromatic base; and (e) deprotecting, if necessary, to obtain the 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside. In a particular embodiment of the invention, the 2-deoxy-2-halo-L-arabinopyranose of the formula (II): (Formula Removed) wherein R and R is as defined above, is provided by a process, comprising (a) obtaining an optionally protected L-arabinal of the formula (III) (Formula Removed) wherein each of RJ is independently hydrogen or a suitable oxygen protecting group such as alky], acyl or silyl; (b) halogenatmg the compound of formula (III) and deprotectmg, if necessary, to form the 2-deoxy-2-halo-L-arabmopyranose of the formula (II). In an even more particular embodiment of the invention, the 2-deoxy-2-halo-L-arabmopyranose of the formula (II). (Formula Removed) wherein R and R" is as defined above, is provided by a process, comprising (a) obtaining an optionally protected L-arabmose of the formula (IV): (Formula Removed) wherein each of RJ and R is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl; (b) substituting OR1 with a halogen (F, Br, CI or I), preferably Br, to obtain a compound of the formula (V); (Formula Removed) wherein X1 is a halogen (F, Br, CI or I), preferably Br; (c) reducing the compound of formula (V) to form a compound of formula (III) (Formula Removed) (d) halogenating the compound of formula (in) and deprotecting if necessary to form the 2-deoxy-2-halo-L-arabmopyranose of the formula (II). In one embodiment of the invention, a process for the preparation of a 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside of the formula (I): (Formula Removed) wherein X is a halogen (F, CI, Br or I), though preferably fluorine; and B is a pyrimidine. purine, heterocyclic or heteroaromatic base; is provided, comprising (a) obtaining an optionally protected L-arabinose of the formula (IV): (Formula Removed) wherein each of R1, R2, R3 and R4 is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl; (b) substituting OR1 with a halogen (F, Br, CI or I), preferably Br, to obtain a compound of the formula (V); (Formula Removed) wherein X1 is a halogen (F, Br, CI or I), preferably Br; (c) reducing the compound of formula (V) to form a compound of formula (III) (Formula Removed) (d) halogenating the compound of formula (III) and deprotecting if necessary to form the 2-dcoxy-2-halo-L-arabmopyranose of the formula (II): (Formula Removed) wherein X is a halogen (F, Br, CI or I), preferably F; (e) converting the 2-deoxy-2-halo-L-arabmopyranose to a 2-deoxy-2-halo-L-arabmofuranose;. (f) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br, CI or I), though preferably a halogen, and even more preferably Br; (g) coupling the arabinofuranose to an optionally protected pynmidine, purine, heterocyclic or heteroaromatic base; and (h) deprotectmg, if necessary, to obtain the 2"-deoxy-2"-halo-j3-L-arabmofuranosyl nucleoside. In one particular embodiment of the present invention, the conversion of the 2-deoxy-2-halo-L-arabmopyranose to a 2-deoxy-2-halo-L-arabmofuranose is accomplished using one equivalent of sulfuric acid. In a further embodiment of the present invention, the conversion of the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabmo-furanose is accomplished m dry methanol. In a preferred embodiment, the conversion of the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabinofuranose is accomplished using one equivalent of sulfuric acid in dry methanol. In another embodiment of the present invention, a process for the preparation of 2"-deoxy-2"-fluoro-p-L-arabinofuranosyl thymine (L-FMAU) comprising (a) obtaining a 2-deoxy-2-fluoro-L-arabmopyranose of the formula (II-a). (Formula Removed) wherein each of R1 and R2 is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl; (b) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabmofuranose; (c) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br, CI or I), though preferably a halogen, and even more preferably Br; (d) coupling the arabinofuranose to an optionally protected thymidine; and (e) deprotectmg, if necessary, to obtain the 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymidine In a particular embodiment of the invention, the 2-deoxy-2-fluoro-L-arabmopyranose of the formula (H-a): (Formula Removed) wherein R and R is as defined above, is provided by a process, composing (a) obtaining an optionally protected L-arabmal of the formula (III) (Formula Removed) wherein each of RJ is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl; (b) fluonnatmg the compound of formula (III) and deprotecting. if necessary, to form the 2-deoxy-2-fluoro-L-arabmopyranose of the formula (II-a) In an even more particular embodiment of the invention, the 2-deoxy-2-halo-L-arabmopyranose of the formula (II-a): (Formula Removed) wherein R and R" is as defined above, is provided by a process, comprising (a) obtaining an optionally protected L-arabmose of the formula (IV): (Formula Removed) wherein each of RJ and R is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl; (b) substituting OR1 with a halogen (F, Br, CI or I), preferably Br, to obtain a compound of the formula (V); (Formula Removed) wherein X1 is a halogen (F, Br, CI or I), preferably Br; (c) reducing the compound of formula (V) to form a compound of formula (III) (Formula Removed) 3 (d) fluonnating the compound of formula (III) and deprotectmg if necessary to form the 2-deoxy-2-fluoro-L-arabmopyranose of the formula (Il-a). In one embodiment of the invention, a process for the preparation of 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymine (L-FMAU) comprising (a) obtaining an optionally protected L-arabinose of the formula (IV): (Formula Removed) wherein each of R1, R , R3 and R4 is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl; (b) substituting OR1 with a halogen (F, Br, CI or I), preferably Br, to obtain a compound of the formula (V); (Formula Removed) wherein X1 is a halogen (F, Br, CI or I), preferably Br; (c) reducing the compound of formula (V) to form a compound of formula (III) (Formula Removed) (d) fluonnating the compound of formula (III) and deprotecting if necessary to form the 2-deoxy-2-fluoro-L-arabmopyranose of the formula (Il-a); (Formula Removed) (f) converting the 2-deoxy-2-fluoro-L-arabmopyranose to a 2-deoxy-2-fluoro-L-arabmofuranose; (g) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br, CI or I), though preferably a halogen, and even more preferably Br; (h) coupling the arabinofuranose to an optionally protected thymine; and (i) deprotecting, if necessary, to obtain the 2"-deoxy-2"-fluoro-ß-L-arabmofuranosyl thymidine. In a particular embodiment of the present invention, the halogenation, and in particular, the fluorination, of the compound of formula (III) is accomplished in nitromethane"water. In an alternate embodiment, the halogenation, and in particular, the fluorination, of the compound of formula (III) is accomplished m acetone:water. In one particular embodiment of the present invention, the conversion of the 2-deox\-2-fluoro-L-arabinop\xanose to a 2-deoxy-2-fluoro-L-arabmofuranose is accomplished using one equivalent of sulfuric acid. In a further embodiment of the present invention, the conversion of the 2-deoxy-2-fluoro-L-arabmopyranose to a 2-deoxy-2-fluoro-L-arabinofuranose is accomplished m dry methanol. In a preferred embodiment, the conversion of the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabmofuranose is accomplished using one equivalent of sulfuric acid m dry methanol Non limiting examples of fluorinatmg agents that can be used m the electrophilic addition of fluorine to L-arabmal include tnfluoromethyl hypofluonte (CF3OF), acetyl hypoflunte (CH3COOF), xenon difluonde (XeF2). elemental fluonne (F2). In a preferred embodiment the fluonnatmg agent is selectfluor (F-TEDA-BF4). I. Nucleosides Which Can Be Synthesized According to the Present Invention The invention as disclosed herein can be used to produce compounds of formula (C). (Formula Removed) wherein each R and R" is independently hydrogen, alkyl, acyl, aryl, monophosphate, diphosphate, triphosphate, amino acid, or an oxygen protecting group; X is a halogen (F, CI, Br or I), and preferably fluonne, and B is a pyrimidine, purine, heterocyclic or heteroaromatic base. These compounds either possess antiviral (i.e.. anti-hepatitis B virus or anti-Epstein-Barr virus) activity, are metabolized to a compound that exhibits such activity, or can be used in a manufacturing process to prepare compounds having such activity. II. Definitions As used herein, the term "substantially free of or "substantially in the absence of refers to a nucleoside composition that includes at least 95% to 98%, or more preferably, 99% to 100%, of the designated enantiomer of that nucleoside. In a preferred embodiment, the compound is prepared substantially free of its corresponding B-D isomer. The term "enantiomerically enriched"" is used throughout the specification to describe a nucleoside which includes at least about 95%, preferably at least 96%, more preferably at least 97%, even more preferably, at least 98%. and even more preferably at least about 99% or more of a single enantiomer of that nucleoside. When a nucleoside of a particular configuration (D or L) is referred to in this specification, it is presumed that the nucleoside is an enantiomerically enriched nucleoside, unless otherwise stated. The term alkyl, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon, typically of Q to Cis, includes lower alkyl, and specifically includes methyl, ethyl, propyl, isopropyL butyl, isobutyl, t-butyl, pentyl. cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl. cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethyl-butyl. The alkyl group can be optionally substituted with functional groups as desired, as known to those skilled in the art, for example, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference. The term lower alkyl, as used herein, and unless otherwise specified, refers to a C\ to C4 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including both substituted and unsubstituted forms. The term "protected" as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled m the art or organic synthesis. Suitable protecting groups are described, for example, in Greene, et al. "Protective Groups in Organic Synthesis," John Wiley and Sons, Second Edition. 1991, hereby incorporated by reference. The term aryl, as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphthyl, and preferably phenyl. The aryl group can be optionally substituted as known to those skilled m the art, for example, as taught m Greene, et al, "Protective Groups in Organic Synthesis,"" John Wiley and Sons, Second Edition, 1991. The term acyl refers to moiety of the formula -C(O)R", wherein R" is alkyl, aryl, alkaryl. aralkyl, heteroaromatic, heterocyclic, alkoxyalkyl including methoxymethyl, arylalkyl including benzyl; aryloxyalkyl. such as phenoxymethyl; aryl including phenyl optionally substituted with halo groups C1 to C4 alkyl or C1 to C4 alkoxy or the residue of an amino acid The term silyl refers to moiety of the formula -SiR"3, wherein each R" is independent]y alkyl or aryl group as defined herein. The alkyl or aryl group can be optionally substituted as known to those skilled in the art. for example, as taught in Greene, el al, "Protective Groups m Organic Synthesis," John Wiley and Sons, Second Edition. 1991 The term "halogen," as used herein, includes fluorine, chlorine, bromine and iodine. The term purine or pynmidme base includes, but is not limited to, adenine, 6-alkylpunnes, 6-acylpunnes (wherein acyl is C(0)(alkyl, aryl, alkylaryl, or arylalkyl), 6-benzylpunne, 6-halopunne, N6-acyl purine, 6-hydroxyalkyl purine, 6-thioaIkyI purine, N"-alkylpurines, N"-alkyl-6-thiopunnes, thymine, cytosine, 5-fluorocytosine, 5-methyl-cytosine, 6-azapynmidme, including 6-azacytosine, 2- and/or 4-mercaptopyrmidme, uracil, 5-halouracil, including 5-fluorouracil, C5-alkylpynmidmes, C5-benzyl-pyrimidines, C5-halopyri mi dines, C5 -vinylpyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrirmdine, C5-hydroxyalkyl pynmidine, C5-amidopynmidme, C5-cyanopynmidine, C5-nitro-pynmidme, C5-arrunopynmidme, 5-azacytidinyl, 5-azauracilyl. tnazolopyridmyl, lmidazolopyndinyl, pyrrolopyrimidmyl and pyrazolopyrimidmyl. Purine bases include, but are not limited to. guanine, adenine, hypoxanthine, 2,6-diammopunne, and 6-chloro-punne Functional oxygen and nitrogen groups on the base can be protected as necessary or desired Suitable protecting groups are well known to those stalled in the art, and include tnmethylsilyl, dimethylhexylsilyl, r-butyldimethylsilyl and /-butyldiphenylsilyl, tntyl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p- toluenesulfonyl. The heteroaromatic group can be optionally substituted as described above for aryl. The term heteroaryl or heteroaromatic, as used herein, refers to an aromatic that includes at least one sulfur, oxygen, nitrogen or phosphorus m the aromatic ring The term heterocyclic refers to a nonaromatic cyclic group wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen or phosphorus m the ring. Nonlimitmg examples of heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pynmidyl, thienyl. isothiazolyl, limdazolyl, tetrazolyl, pyrazmyl, benzofuranyl, benzothiophenyl, qumolyl. isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl. benzimidazolyl. purinyl, carbazolyl. oxazolyl, thiazolyl, iso-thiazolyl, 1,2,4-thiadiazolyl, isooxazoty}, pyrrolyl, quinazolmyl, cinnolmy], phthalazmyl, xanthmyl. hypoxanthmyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole, 1,2,3-tnazole, 1,2,4-tnazole, oxazole, isoxazole, thiazole, isothiazole, pynrmdine or pyndazme, and ptendmyl, aziridines, thiazole, isothiazole, 1,2,3-oxadiazole, thiazine, pyridine, pyrazine, piperazine, pyrrolidine, oxaziranes, phenazine, phenothiazme, morpholmyl, pyrazolyl, pyridazinyl, pyrazmyl, quinoxalinyl, xanthmyl, hypoxanthmyl, ptendinyl, 5-azacytidinyl, 5-azauracilyl. triazolopyndinyl, imidazolopyndinyl, pyrrolopyrimidinyl, pyrazolo-pyrimidinyl, adenine, N6-alkylpurines, N6-benzylpunne, N6-halopurine,N6-vmypurine, N6-acetylenic purine, N6-acyl purine,N6-hydroxyalkyl purine. N6-thioalkyl purine, thymine, cytosine, 6-azapyrimidine, 2-mercaptopyrmidme, uracil, N -alkylpyrimidines, N5-benzylpyrimidines, N5-halopyrimidines, N6-vmylpyrimidine, N5-acetylenic pynmidine, N5-acyl pyrimidine, N5-hydroxyalkyl punne, and N6-thioalkyl punne, and isoxazolyl. The heteroaromatic group can be optionally substituted as described above for aryl. The heterocyclic or heteroaromatic group can be optionally substituted with one or more substituent selected from halogen, haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amido, amino, alkylamino, dialkylammo. The heteroaromatic can be partially or totally hydrogenated as desired. As a nonlimitmg example, dihydropyndme can be used in place of pyridine. Functional oxygen and nitrogen groups on the heterocyclic or heteroaryl group can be protected as necessary or desired Suitable protecting groups are well known to those skilled in the ait, and include mmethylsilyl, dimethylhexylsilyl, r-butyldimethylsilyl, and r-butyl-diphenylsilyl, tntyl or substituted tntyl, alkyl groups, acyl groups such as acety] and propionyl, methanesulfonyl, and p-toluenylsulfonyl. These purine or pyrimidine bases, heteroaromatics and heterocycles can be substituted with alky] groups or aromatic rings, bonded through single or double bonds or fused to the heterocycle ring system. The purine base, pyrimidine base, heteroaromatic or heterocycle may be bound to the sugar moiety through any available atom, including the ring nitrogen and ring carbon (producing a C-nucleoside). III. Detailed Description of the Process Steps Preparation of Stalling Material - 2-deoxy-2-halo-L-arabinopyranose (II) The key starting material for this process is an appropriately substituted 2-deoxy-2-halo-L-arabmopyranose (II). The 2-deoxy-2-halo-L-arabmopyranose (II) can be purchased or can be prepared by any known means including standard reduction and electrophilic addition techniques. In one embodiment, the 2-deoxy-2-halo-L-arabmopyranose (II) is prepared from L-arabmal followed by halogenation. The L-arabmal can be purchased or can be prepared by any known means including standard reduction techniques. For example, the L-arabmal can be prepared from an appropriately protected L-arabmose, preferably protected with an acyl group such as with an acetyl group, according to the following protocol (Formula Removed) L-Arabmose (1) can be protected by methods well known to those skilled in the art, as taught in Greene, el al, Protective Groups m Organic Synthesis, John Wiley and Sons, Second Edition, 1991, to form an appropriately protected L-arabmose (2), wherein each P is independently hydrogen or an appropriate oxygen protecting group such as an alkyl, acyl or silyl group, though preferably an acyl group such as an acetyl group The protection can be earned out in any appropriate solvent that facilitates the desired result. In one embodiment the reaction is carried out m a mild base, such as pyridine. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is from 0°C to room temperature. The appropriately substituted L-arabmose (2) can then be halogenated. preferably brommated, using an appropriate halide under any suitable conditions, though preferably acidic conditions, to obtain a l-a-halo-2,3,4-tri-ß-protected-L-arabinopyranose (3). such as l-a-bromo-2,334-tri-0-acetyl-L-arabmopyranose The halogenation can be earned out m any appropriate solvent that facilitates the desired result In one non-limiting example, compound (2) can be halogenated with H-X. wherein X is F, CI, Br or I, though preferably Br, optionally with a suitable acid, preferably an acyl acid such as acetic acid, optionally with an acyl anhydnde such as acetic anhydride. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is from room temperature to refluxing conditions. The l-α-halo-2,3,4-tri-0-protected-L-arabinopyranose (3) can then be reduced using any suitable reducing agent to obtain the L-arabmal (4). Possible reducing agents are reagents that promote reduction, including but not limited to, zinc dust m the presence of CuSO4pentahydrate and sodium acetate in ACOH/H2O. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferced temperature is from below -5°C to room temperature. The L-arabinal can be prepared in any solvent that is suitable for the temperature and the solubility of the reagents. Solvents can consist of any protic solvent including, but not limiting to, alcohol, such as methanol, ethanol, isopropanol, butanol, pentanol or hexanol, acyl acid such as acetic acid, water or any combination thereof, though preferably the solvent is acetic acid and water. (Formula Removed) The L-arabinal (4) can then be halogenated, preferably fluorinated, using an appropriate electrophilic halogenating reagent to afford compound (5). Possible electrophilic halogenating agents are reagents that promote regiospecific halogenation. In one particular embodiment, an electrophilic fluormating agent is used. Non-limitmg examples of fluonnating agents that can be used m the electrophilic addition of fluorine to L-arabinal include, but not limited to. tnfluoromethyl hypofluonte (CF3OF), acetyl hypofiunte (CH3COOF), xenon difluonde (XeF2), elemental fluorine (F2). In an alternate embodiment the fluonnating agent is selectfluor™. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is from room temperature to refluxmg conditions The halogenation can be prepared m any solvent that is suitable for the temperature and the solubility of the reagents. Solvents can consist of any polar protic or aprotic solvent including, but not limiting to, alcohol, such as methanol, ethanol, isopropanol, butanol, pentanol or hexanol, acetone, ethyl acetate, dithianes, TFfF, dioxane, acetonitrile, nitromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, water, or any combination thereof, though preferably the solvent is water/nitromethane and water/acetone: (1/2) The optionally protected 2-deoxy-2-halo-L-arabinopyranose (5) can then be deprotected, if necessary, by methods well known to those skilled in the art, as taught in Greene, el ai. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, to obtain the 2-deoxy-2-halo-L-arabinopyranose (II). The deprotection can be earned out in any appropnate solvent that facilitates the desired result. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. For example, acyl protecting groups, and in particular an acetyl group, can be deprotected with sodium methoxide in methanol at room temperature. In one preferred embodiment of the invention, this procedure, can be tailored to produce the cntical intermediate compounds for the synthesis of L-FMAU or L-FMAU analogs. Preparation of 2~deoxy-2-halo-L-arabinofuranose (Formula Removed) The 2-deoxy-2-halo-L-arabinopyranose (II) is reacted with any suitable acid (in gas or liquid form), such as, but not limited to sulfuric or hydrochloric acid m either catalytic amounts or in excess to form a 2-deoxy-2-halo-L-arabmofuranose (7). In a one embodiment of the present invention, 1 molar equivalent of sulfuric acid is used for this reaction. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is from room temperature to refluxing conditions. This reaction can be earned out in any solvent that is suitable for the temperature and the solubility of the reagents. Solvents can consist of any polar protic or aprotic solvent including, but not limiting to, an alcohol, such as methanol, ethanol. isopropanol, butanol, pentanol or hexanol, acetone, ethyl acetate, dithianes, THF, dioxane. acetomtnle, nitromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethyl-acetamide, water, or any combination thereof, though preferably the solvent is methanol. The 2-deoxy-2-halo-L-arabinofuranose (7) can be optionally protected by methods well known to those skilled in the art, as taught m Greene, el al, Protective Groups m Organic Synthesis, John Wiley and Sons, Second Edition, 1991, to form an appropnately protected 2-deoxy-2-halo-L-arabmofuranose (8), wherein each P is independently hydrogen or an appropriate oxygen protecting group such as an alkyl, acyl or silyl group, though preferably an acyl group such as a benzoyl group. The protection can be earned out in any appropriate solvent that facilitates the desired result. In one embodiment the reaction is earned out in a mild base, such as pyndme. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products The preferred temperature is from 0°C to room temperature Preparation of 2"-deoxy-2"-Iialo-ß-L-arabinofuranosyl nucleoside (Formula Removed) The appropriately protected 2-deoxy-2-halo-L-arabmofuranose (8) is optionally activated to form an activated 2-deoxy-2-halo-L-arabmofuranose (9), wherein LG is a suitable leaving group, such as O-Acyl (including OAc) or a halogen (¥, Br. CI or I), though preferably a halogen, and even more preferably Br In one non-limiting example, compound (8) is halogenated with halogenated with H-X, wherein X is F, CI. Br or I, though preferably Br, optionally with a suitable acid, preferably an acyl acid such as acetic acid, to afford compound (9). This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is room temperature. This reaction can be carried out in any solvent that is suitable for the temperature and the solubility of the reagents. Solvents can consist of any polar protic or aprotic solvent including, but not limiting to, an alcohol, such as methanol, ethanol, isopropanol, butanol, pentanol or hexanol, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitnle, nitromethane, dichloromethane, dichloroethane, diethyl ether, dimethylformarrude (DMF), dimethylsulfoxide (DMSO), dimethyl-acetamide, water, or any combination thereof, though preferably the solvent is dichloromethane (Formula Removed) The activated 2-deoxy-2-halo-L-arabmofuranose (9) can then be coupled with an optional!}" protected pynmidrne, purine, heterocyclic or heteroaromatic base to afford the optionally protected 2,-deoxy-2,-halo-L-arabmonucleoside (11). Solubihzing substituents can be added to the purine base, pynrmdine base, heteroaromatic or heterocycle to promote solubility in the desired solvent system It should also be understood that certain functional groups of the purine base, pynrmdine base, heteroaromatic or heterocycle might need to be protected to prevent unnecessary side reactions. The reactive moieties can be protected using conventional means and appropriate protecting groups well known to those skilled in the art, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. For example, the free amine on cytosme may be protected by reaction with benzoyl chloride or any other suitable acyl compound to prevent unnecessary coupling at the N4 position, to activate the cytosme base, and/or to assist in solubilizing the compound in the organic solvent. Alternatively, the free amine and/or free hydroxyl on the punnc base, pynmidine base, heteroaromatic or heterocycle, such as thymine, may be protected with a silyl group, such as trimethylsilyl chloride to prevent unnecessary side products, to activate the purine base, pynmidine base, heteroaromatic or heterocycle. such as tin mine, and/or to assist in solubilizing the compound in the organic solvent Any compound containing a nitrogen that is capable of reaction with a center of electron deficiency can be used in the condensation reaction. In one embodiment an O-protected thymine base, for example a silylated thymine such as trimethylsilyl-thymine, is coupled with compound (9). In a preferred embodiment, the pynmidine or purine base is silylated with a suitable silylating agent to form a silylated base. Possible silylating agents are reagents that promote silylation, including but not limited to, 1,1,1,3,3.3-hexamethyldisilazane, optionally with a catalytic amount of ammonium sulfate. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is refluxing conditions. The coupling reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is room temperature. The reaction can take place in any solvent that provides the appropnate temperature and the solubility of the reagents. Examples of solvents include any aprotic solvent such as an alkyl solvent such as hexane and cyclohexane, toluene, acetone, ethyl acetate, dithianes, THF, dioxane, acetomtnle, chloroform, dichloromethane, dichloroethane, diethyl ether, pyridine, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, 1,1,1,3,3.3-hexamethyldisilazane or any combination thereof, preferably dichloromethane, dichloroethane or a combination of chloroform and 1,1,1,3,3,3-hexamethyldisilazane. The optionally protected 2"-deoxy-2"-halo-L-arabmonucleoside (11) can then be deprotected, if necessary, by methods well known to those skilled m the art. as taught m Greene, et al, Protective Groups m Organic Synthesis. John Wiley and Sons. Second Edition, 1991, to obtain the 2"-deoxy-2"-halo-L-arabinonucleoside (I). The deprotection can be earned out in any appropriate solvent that facilitates the desired result. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products For example, acyl protecting groups, and in particular a benzoyl group, can be deprotected with n-butylamme in methanol at reflux In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, pharmaceutically acceptable salts may be synthesized. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known m the pharmaceutical art. In particular, examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, mefhanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate. ascorbate, a-ketoglutarate, and a-glycerophosphate. Suitable inorganic salts may also be formed, including, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. Any of the nucleosides described herein can be denvatized to its nucleoside or nucleotide prodrug. A number of nucleotide prodrug hgands are known. In general, alkylation, acylation or other lipophilic modification of the mono, di or triphosphate of the nucleoside is well known m the art. Examples of substituent groups that can replace one or more hydrogens on the phosphate moiety aie alkyl, aryl, steroids, carbohydrates, including sugars, l,2-diac\lglycerol and alcohols Many are described m R. Jones and N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can be used to functionalize the disclosed nucleosides to achieve a desired prodrug. The active nucleoside can also be provided as a 5"-phosphoether lipid or a 5"-ether lipid, as disclosed in the following references, which are incorporated by reference herein: Kucera, L.S.. N. Iyer, E. Leake, A. Raben. Modest E.K., D.LW., and C. Piantadosi. 1990. "Novel membrane-interactive ether lipid analogs that inhibit infectious HTV-1 production and induce defective virus formation." AIDS Res. Hum. Retro Viruses. 6-491-501: Piantadosi, C, J. Marasco C.J., S.L. Morns-Natschke. KL. Meyer. F. Gumus, J.R. Surles, K.S. Ishaq, L.S. Kucera, N. Iyer, CA Wallen, S. Piantadosi, and E.J Modest. 1991. ""Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HTV activity." J. Med Chem. 34:1408.1414; Hosteller. K.Y., D.D. Richman. D.A. Carson, L.M. Stuhmiller, G.M. T. van Wijk, and H. van den Bosch. 1992. "Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3"-deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of 3,-deoxythymidme." Anthmcrob. Agents Chemother. 36:2025 2029; Hosetler, K.Y., L.M. Stuhmiller, H.B. Lenting. H. van den Bosch, and D.D. Richman, 1990. "Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides." J. Biol. Chem. 265:61127. Nonlimiting examples of U.S. patents that disclose suitable lipophilic substituents that can be covalently incorporated into the nucleoside, preferably at the 5*-OH position of the nucleoside or lipophilic preparations, include U.S. Patent Nos. 5,149.794 (Sep. 22. 1992, Yatvin et al.)\ 5,194,654 (Mar. 16, 1993, Hostetler et al, 5,223,263 (June 29, 1993, Hostetler et al); 5,256,641 (Oct. 26, 1993, Yatvin et al); 5,411,947 (May 2,1995. Hostetler et al): 5,463,092 (Oct. 31, 1995, Hostetler et al); 5,543,389 (Aug. 6, 1996, Yatvin et al); 5.543,390 (Aug. 6, 1996, Yatvin et al.); 5,543,391 (Aug. 6. 1996, Yatvin et al); and 5,554,728 (Sep. 10, 1996; Basava et al), all of which are incorporated herein by reference. Foreign patent applications that disclose lipophilic substituents that can be attached to the nucleosides of the present invention, or lipophilic preparauons, include WO 89/02733, WO 90/00555, W0 91/16920, W0 91/18914, W0 93/00910, W0 94/26273, W0 96/15132. EP 0 350 287, EP 93917054.4, and W0 91/19721. Preparation of 2 "-deoxy-2 "-fluoro-ß-L-arabinofuranosyl thymidine (L-FMA U) The peracetylated bromosugar of L-arabinose (15, Figure 1) can be obtained according to hterature-procedure as a solid, in 57% yield after crystallization from ether (Balog, A.; Yu, M. S., Curran, D. P. Synthetic Comm. 1996, 26, 935). The material is very unstable at room temperature and had to be used immediately or stored in a freezer. An optionally protected L-arabmal can also be obtained according to a literature procedure m 60% yield after column chromatography (Smiatacz, Z ; Myszka. H. Carbohydr. Res 1988.172. 171). The optionally protected L-arabmal can then be fluonnated via addition of selectfluor™ by a modification of a hterature procedure to afford an optionally protected 2-deoxy-2-fluoro-L-arabinopyranose as a syrup m 42% yield (Albert, M.; Dax. K, Ortner, J. Tetrahedron 199S. 54, 4839). Traces of what could possibly be the L-nbo isomer were detected by 19F-NMR (ratio L-arabino:L-nbo 30:1). The D-isomer of 2-deoxy-2-fluoro-L-arabinopyranose was made by a similar procedure (Albert. M.; Dax. K.; Ortner, J. Tetrahedron 1998, 54, 4839). In the reference, nitromethane:water was used as a solvent, which may account for better yields (68% D-arabmo and 7% of the D-nbo isomer). Alternatively, acetone water can be used, which may account for better selectivity. Optionally protected 2-deoxy-2-fluoro-L-arabmopyranose can then be deprotected if necessary. For example, deacetylation of 3,4-di-0-acetyl-2-deoxy-2-fluoro-L-arabinopyranose was (17, Figure 1) can be achieved with NaOMe m methanol in one hour at room temperature. The desired unprotected 2-deoxy-2-fluoro-L-arabmopyranose (18) was obtained as an oil in a 100% yield. ^-NMR and 13C-NMR are coincident with the ones described m the literature for the D-isomer (Bols. M.; Lundt, I. Acta Chem. Scand. 1990, 44, 252) The D-isomer of IS was previously made by three different groups but m a less efficient way. Treatment of unprotected 2-deoxy-2-fluoro-L-arabmopyranose with one equivalent of either sulfuric or hydrochloric acid at room temperature failed to give the desired furanoside Only unreacted starting material was detected. Using nine equivalents of hydrochloric acid gave the desired product 2-deo\y-2-fluoro-L-arabinofuranose, which was contaminated with starting material (2:1 ratio). The best result, so far, was achieved by refluxing 2-deoxy-2-fluoro-L-arabinopyranose with 1 equivalent of sulfuric acid in dry methanol. After 6 hours all of the starting material had disappeared affording 2-deoxy-2-fluoro-L-arabinofuranose as an oil in 80% yield. ]H-, 13C- and 19F-NMR indicated a 3:1 a:{3 mixture of anomers, with some minor impurities L-ribo- and L-arabmopyranoside as well as L-ribofuranoside are the possible side products. The D-isomer of 2-deoxy-2-fluoro-L-arabinofuranose was previously made by two different groups, but in less efficient ways (Wright, J. A.; Taylor, N. F.; Fox, J. J. J Org Chem 1969, 34, 2632. and Wysocki, R. J.; Siddiqui, M. A.; Barchi, J. J., Dnscoll, J. S.; Marquez, V. E Synthesis 1991, 1005). 2-Deoxy-2-fluoro-L-arabmofuranose can then be optionally protected. For example, benzoylation of crude 2-deoxy-2-fluoro-L-arabinofuranose gave a mixture that was resolved by flash column chromatography to afford the a furanoside form of 1-0-methyl-2-deoxy-2-fluoro-3,5-di-O-benzoyl-L-arabinofumaoside (20) as an oil m 44% yield. Other fractions were isolated and have been characterized and the corresponding ß-L-arabmofuranoside derivative was detected as the major impurity. The same reaction is described for the D-isomer (7. Med. Chem. 1970,13, 269). They partially describe the D-isomer of 20 optical rotation and CHN, but no spectroscopic data was provided. The absolute value for the optical rotation was similar to the one described for the D-isomer: [α]D20=-98 (c 1.0 EtOH) (lit value: [α]D20= + 108 (c 1.8 EtOH for the D-isomer). Optionally protected 2-deoxy-2-fluoro-L-arabmofuranose can then be activated, preferably via brommation, and coupled to an optionally protected thymine, such as trimethylsilylthymme, to obtain optionally protected 2"-deoxy-2"-fluoro-L-arabino-furanosyl-thymine. For example, the methyl glycoside (20) can be converted to the intermediate bromosugar (21) under FfBr/AcOH condition, which m turn was coupled with silylated thymine (22) under standard conditions affording the known di-0-benzo\l-L-FMAU (23) in 42% crude yield (30% after crystallization from EtOH) The 1H-NMR was identical to the ones described in the literature for the L- and D-isomers (Du, J : Choi, Y., Lee, K.; Chun. B. K.; Hong. J. H.; Chu, C. K. Nucleosides and Nucleotides 1999, 75, 1S7), and to a reference sample (Ma, T.; Pai, S. B.; Zhu, Y. L.. Lin, T. S.; Shanmunganathan, K.; Du, J. F.; Wang, C.-G.; Kim, H.; Newton. G.M., Cheng, Y.-C; Chu, C. K J. Med. Chem. 1996, 39, 2S35.; and Du. J.; Choi, Y.; Lee, K.; Chun, B. K.; Hong, J. H.; Chu, C. K Nucleosides and Nucleotides 1999, 18, 187, and Tan, C. H.; Brodfuehrer, P.R.; Brundidge, S. P.; Sapmo, C; Howell, H. G. J. Org. Chem. 1985, 50, 3647). However, the melting point (160°C) was identical to the reference sample but differs with the values published in the literature: 120-122°C for the D-isomer and 118-120°C for the L-isomer (Tan, C. H.; Brodfuehrer, P.R.; Brundidge, S. P.; Sapmo, C; Howell, H. G. J. Org. Chem. 1985,50, 3647.; and Du, J.; Choi, Y.; Lee, K.; Chun, B. K.; Hong, J. H, Chu, C. K. Nucleosides and Nucleotides 1999,18. 187) The optionally protected 2"-deoxy-2"-fluoro-L-arabino-furanosyl-thymine can then be deprotected, if necessary. For examples, di-O-benzoyl-L-FMAU (23) can be debenzoylated with n-butylamme in refluxmg methanol reducing the reaction time to 3 hours, from the 24 or 48 hours required when ammonia was used at room temperature (Ma, T.; Pai. S. B.; Zhu, Y. L.; Lin, T S.: Shanmunganathan, K.; Du, J. F.; Wang, C.-G.; Kim, H.; Newton, G.M.; Cheng, Y.-C; Chu, C. K J. Med Chem. 1996, 39, 2835, and Du, J.; Choi. Y.; Lee, K: Chun, B. K: Hong, J. H.; Chu, C. K. Nucleosides and Nucleotides 1999, IS, 187). Yield of L-FMAU (24) was 77%. Melting point: 1S8°C (lit. mp 185-187° C, 1S4-185°C, 187-188°C) for the D-isomer; [α]D20 = -93 (c 0.25 MeOH) (lit value: [α]D20 = -111 (c 0.23 MeOH), [α]D20 = -112 (c 0.23 MeOH)); !H-NMR was identical to the ones described in the literature and to a reference sample (Ma, T.; Pai, S. B.; Zhu, Y. L.; Lin, T. S.; Shanmunganathan, K.; Du, J. F.; Wang, C.-G.; Kim, H; Newton, G. M.; Cheng, Y.-C; Chu, C. K. J. Med. Chem. 1996, 39. 2835; and Du, J.; Choi, Y.; Lee, K.; Chun, B. K.; Hong, J H; Chu, C. K. Nucleosides and Nucleotides 1999,18, 187; and Tan, C. H; Brodfuehrer, P. R.; Brundidge, S. P.; Sapino, C; Howell, H. G. J. Org. Chem. 1985,50, 3647). EXAMPLES Melting points were determined in open capillary tubes on a Gallenkamp MFB-595-010 M apparatus and are uncorrected The UV absorption spectra were recorded on an Uvikon 931 (KONTRON) spectrophotometer m ethanol. "H-NMR spectra were run at room temperature in DMSO-d6 with a Bruker AC 250 or 400 spectrometer. Chemical shifts are given m ppm, DMSO-Jj being set at 2.49 ppm as reference. Deuterium exchange, decoupling experiments or 2D-COSY were performed in order to confirm proton assignments. Signal multiplicities are represented by s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quadruplet), br (broad), m (multiplet). All J-values are in Hz FAB mass spectra were recorded in the positive- (FAB>0) or negative-(FAB Example 1 1,2,3,4-tetra-O-acetyl-L-arabinopyranose (14) To a well stirred suspension of L-arabmose (13) (lOOg, 0.67 mol) m dry pyridine (270 mL) at 0°C, was slowly added acetic anhydride (360 mL, 3SSg, 3.8 mol.) The suspension was then stirred at room temperature for 4 hours, after which it became a light brown colored solution. Excess pyridine and acetic anhydride were removed by azeotropic evaporation with toluene. Crude (14) was obtained as a clear oil, and was used in the next step without any further purification. Example 2 l-a-Bromo-2,3,4-tri-O-acetyl-L-arabmopyranose (15) Crude tetra-O-acetyl-L-arabmopyranose (14) was dissolved in a mixture of 30% wt HBr m AcOH (400 mL, 2.0 mol) and acetic anhydride (8.0 mL). The solution was stirred at room temperature for 36 hours. The reactrem mixtures was diluted with methylene chloride (400 mL), and successively washed with- water (3 x 600 mL). saturated NaHC03 (2 x 500 mL) and water (3 x 600 mL), dried, filtered and evaporated to a syrup that was crystallized from ethyl ether to afford (14) (129 g, 0.3S0 mol, 57% from 13), as a white solid" 1H-NMR (CDC13) δ 6.67 (1H, d, J = 3.8, H-l), 5 37 (2H, m) and 5.06 (1H, m) (H-2, H-3 and H-4), 4.18 (1H, d, J = 13.3, H-5), 3.91 (1H, dd, J = 13 3 and J = 1.7, H-5"), 2.13 (3H, s, CH3COO), 2.09 (3H, s, CH3COO), 2.01 (3H, s. CH3COO). Example 3 3,4-di-O-acetyl-L-arabinal (16) To a well stirred solution of NaOAc (35 g, 0.43 mol) and AcOH (115 mL) in water (200 mL) at -5°C, was slowly added a solution of CuSO4-5H2O (7 g, 28 mmol) in water (23 mL), and then Zn dust (70 g, 0.11 mol) in portions, maintaining the temperature at or below -5°C. To this suspension was added the bromo sugar 15 (34 g. 0.10 mol) in portions and the mixture stirred vigorously for 3 hours at -5°C and then overnight at room temperature. The mixture was filtered and washed with water (250 mL) and methylene chloride (250 mL). The phases were separated, and the aqueous layer washed with methylene chloride (2 x 125 mL). The combined organic layers were successively washed with: water (2 x 250 mL), saturated NaHCO3 (2 x 1250 mL) and water (2 x 250 mL), dried, filtered, and evaporated to a colorless syrup (-20 g). The syrup was purified by flash column chromatography (300 g silica gel, hexane:EtOAc 4:1) to afford 16 (12.0 g, 60 mmol, 60%) as a colorless syrup: 1H-NMR (CDCI3) 56 48 (lH,d, J = 6.0 H-l), 5.44 (1H, m, H-3), 5.19 (1H, dt J = 4, J = 4, J - 4, J = 9, H-4), 4.83 (1H, dd, J = 5, J = 6, H-4), 4.00 (2H, m, H-5 and H-5"), 2.08 (3H, s, CH3COO), 2.07 (3H, s CH3COO). Example 4 3,4-di-0-acetyl-2-deoxy-2-fluoro-L-arabinopyranose (17) To a well stirred solution of glycal (16) (12.0 g, 60 mmol) m acetone water (4:2 v:v, 120 mL) was added selectfluor " (26 g, 73 mmol). The solution was stirred overnight at room temperature. The solution was then heated at reflux for 1 hour to complete the reaction. After cooling to room temperature, the acetone was removed in vacuo. Water (150 mL) was added and extracted with EtOAc (3 x 150 mL). The combined organic fractions were successively washed with: IN HC1 (2 x 200 mL), and water (2 x 200 mL) dried, filtered, and evaporated to afford 17 (6 0 g, 25 mmol, 42%) as a syrup: I3C-NMR (CDCI3 5 170.35 (CH3COO), 170.27 (CH3COO), 95.01 (C-lα, d, Jc. I.F= 24.5), 90 81 (C-lß, d, JC-1,F = 21.5), 89.10 (C-2α, d, JC-2,F = 184.3), 85.85 (C-2{3d, Jc. 2.F= 188.0), 70.61 (C-3as d, JC-3,F= 19.5), 69.57 (C-4p, d, JC-4,F= 7.7), 68.66 (C-4a, d, Jc. 4,F= 8.3), 67.53 (C-3P, d, JC-3,F= 17.8), 63.90 (C-5a), 60.26 (C-5P), 20.73 (CH3COO), 20.67 (CH3COO). 20 62 (CHC3COO), 20.56 (CH3COO). Anal. Calcd. for C9H13O6F: C, 45.77; H, 5.55. Found: C, 45.64; H. 5.51. Example 5 2-deoxy-2-fluoro-L-arabinopyranose (18) A solution of 17 (5.7 g, 24.1 mmol) in dry methanol (220 mL) was treated with 0.1 N NaOMe in methanol (114 mL, 114 mmol) and stirred for 1 hour at room temperature. The solution was then neutralized with DOWEX 50W X8-100, filtered and evaporated to afford 18 (3.7 g, 24 mmol, 100%) as a yellow syrup: 13C-NMR (D2O) 5 94 19 (C-la, d, JC-I-F = 23.0), 92.24 (C-2a, d, JC-2.F= 179.6). 90.10 (C-lp, d, JC-I,F = 20.3), S8 60 (C-2p, d, JC-2,F= 1S2.3), 70 77 (C-3α, d, JC-3.F= 18 2). 69.03 (C-4p, d, JC.4F= 8.0), 68.90 (C-4a, d, JC-4,F= 10.2), 66.85 (C-3ß, d, JC-3,F = 18.2), 66.32 (C-5α), 62.21 (C-5ß). Example 6 l-0-meihyl-2-deoxy-2-fluoro-L-arabviofuranoside (19) A solution of is (790 mg, 5 2 mmol) and H2SO4 (60 1 µL, 1 1 mmol) in dry methanol (12.2 niL) was treated at reflux for 6 hours The reaction was cooled to room temperature, neutralized with DOWEX SBR. filtered and evaporated, to afford 19 (700 mg, 4.21 mmol, 80%) as a syrup: 13C-NMR (CD3OD) δ 107 48 (C-la, d, Jc.i,F= 35.6). 103.20 (C-2α, d, JC-2,F = 178.8), 101 98 (C-lß d, JC-I,F= 16.8), 96 80 (C-2ß, d, JC-2,F = 199.3). 85.15 (C-4a. d, JC-3,F = 5 0), 83.69 (C-4(3, d, JC-4,F= 10.7), 76.70 (C-3α, d, JC.4,F = 27.0), 74 54 (C-3p. d, JC-3,F= 21.5), 65.00 (C-5p), 62.52 (C-5α). 55.58 (OCH3ß), 54.94 (OCH3α) Example 7 l-O-methyl-2-deoxy-2-fluoro-3,5-di-O-benzoyl-L-arabinofnranoside(20) To a well stirred solution of 19 (664 mg, 4 mmol) in dry pyridine (10 mL) at 0°C, was slowly added benzoyl chloride (2.5 mL. 3.0 g, 21.5 mmol). After stirring for 30 minutes at 0°C, it was left at room temperature for 3 hours. The reaction was quenched with water (10 mL) and saturated NaHCO3 (30 mL) and stirred for 30 minutes. It was then diluted with methylene chloride (50 mL) and more saturated NaHCO3 (30 mL). The organic layer was separated and successively washed with: saturated NaHC03 (50 mL), water (2 x 50 mL), IN HC1 (2 x 50 mL), water (50 mL), saturated NaHCO3 (50 mL) and water (2 x 50 mL), dried, filtered and evaporated to a brown syrup (1.9 g), that was purified by flash column chromatography (50 g silica gel, hexane:EtOAc 95:5). A major faction was isolated as a syrup and characterized as 20 (a anomer, 670 mg, 1.79 mmol, 44%): [α]D20 = -9S (c 1.0 EtOH) (lit. value: [α]D20= + 108 (c 1.8 EtOH) for the D- isomer); 1H-NMR (CDC13) δ 8.20 - 7.40 (15 H, m, ArH), 5.48 (1H, dd, J = 23.1, H-3), 5.21 (1H, d, J = 10.6, H-l), 5.11 (1H, d, J = 49.2, H-2), 4.76 (lH,dd, J = 3.6 and J = 12.0, H-5), 4.63 (1H, dd, J = 4.4 and J = 12.0, H-5"), 3.45 (3H, s, OCH3); I3C-NMR (DC13) δ 166 20 (C = O), 165.67 (C = O), 133 57 (Ar), 133 07 (Ar), 129.87 (Ax), 129.76 (Ar), 128.49 (Ar), 128.31 (Ar). 106.22(C-l,dJc-3.F= 35.1). 98.20 (C-2, d, JC.2,F = 182.7), SO 85 (C-4), 77 58 (C-3,dJC-3,F= 30 44), 63.62 (C-5), 54.86 (OCH3). Anal. Calcd. For C2OH19O6F: C, 64.17, H, 5 12 Found: C, 64.14; H, 5.08 Example 8 l-(3,5-di-0-benzoyl-2-deoxy-2-fluoro-ß-L-arabinofuranosyl) thymine (23) To a well stirred solution of 20 (289 mg, 0.75 mmol) in dry methylene chlonde (0.56 mL) at 0°C, was slowly added 30% \vt HBr in AcOH (0.8 mL, 1.0S g, 0.32 g of HBr, 4.0 mmol) The solution was then stared at room temperature overnight. The brown-red solution was evaporated under vacuum at or below 40°C. It was then coevaporated with dry benzene (3x3 mL) and then once with dry chloroform (3 mL). Bromosugar 21, a syrup, was redissolved in dry chloroform (2 mL): solution A. At the same time a mixture of thymine (25, 208 mg, 1 65 mmol), ammonium sulfate (19 mg), and 1,1,1,3,3,3-hexamethyldisilazane (798 mg, 1.04 mL, 4.95 mmol) in dry chloroform (7.12 mL) was heated at reflux overnight The resulting clear solution, (an indication that all the thymine was silylated to form compound 22) was cooled to room temperature: solution B. Solution A was added to solution B and heated at reflux for 4 hours. Water (10 mL) was added, and the mixture stirred for 20 minutes. Chloroform (10 mL) was added, the organic phase separated, washed with water (2 x 10 mL), dried, filtered and evaporated to a syrup that was purified by flash column chromatography (hexane: EtOAc 1:1). Crude 23 (150 mg, 0.32 mmol, 42%) was obtained as a solid. It was crystallized from EtOH to afford pure 23 (100 mg, 0.22 mmol, 30%) as a white solid: mp 160°C was identical to an original sample of 23 (lit. value: mp 120-122°C for the D-isomer and 11S-120°C for the L-isomer); 1H-NMR (CDC13) δ 8.52 (1H. bs, N-H). 8.13-7.43 (10H, m, ArH), 7.36 (1H, q, J = 1), C-H thymine, 6.35 (1H, dd, J = 3.0 and J = 22.2, H-l), 5.64 (1H, dd, J = 3.0 and J = IS 0, H-3), 5.32 (1H, dd, J = 3.0 and J = 50 0, H-2), 4.86-4.77 (2H, m, H-5 and H-5"), 4.49 (1H, q, H-4), 1.76 (3H, d, J = 1.0, Thymine CH3). Example 9 l-(2-deoxy-2-fluoro-ß-L-arabinofuranosyl)lhymine (24) A solution of 23 (47 mg, 0 1 mmol) and n-butylamme (0.74 g, 1.0 mL. 10 mmol) in methanol (2 mL) was heated at reflux for 3 hours. The solution was evaporated to dryness and triturated with ethyl ether to afford a solid that was filtered, washed with ether and dried to afford 24 (20 mg, 0.077 mmol, 77% as a white solid: mp 188°C (lit. value: mp 185-187°C. 184-1S5°C, 187-188°C for the D-isomer); [α]D20 = -93 (c 0 25 MeOH); (lit. value: [α]D20 = -111 (c 0.23 MeOH), [α]D20 = -122 (c.023 MeOH)), ]H-NMR (DMSO-dfi) 8 11.0 (1H, bs, N-H, 7.58 (1H, s, C-H thymine), 6.09 (1H. dd, J = 4.2 and J = 15.6, H-l), 5.85 (1H, bs, OH), 5.10 (1H, bs, OH), 5.02 (1H, dt, J - 4.0, J - 3.8 and J - 52.8, H-2), 4.22 (1H, dt, J - 3.8, J- 4.0 and J = 20.3, H-3), 3.76 (1H, q, J = 4.0 and J -9.5, H-4), 3.69-3.57 (2H, m, H-5 and H-5"), 1.77 (3H, s, Thymine CH3). Many modifications and other embodiments of the invention will be apparent to one skilled in the art to which this invention pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the invention is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. WE CLAIM: 1. A process for the preparation of a 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside of the formula (I): (Formula Removed) wherein X is a halogen (F, CI, Br or I); and B is a pyrimidine, purine, heterocyclic or heteroaromatic base; by preparing a 2-deoxy-2-halo-L-arabinofuranose comprising the steps of: (a) obtaining a 2-deoxy-2-halo-L-arabinopyranose of the formula (II): (Formula Removed) wherein each of R1 and R2 is independently hydrogen, alkyl, acyl or silyl; and (b) converting the 2-deoxy-2-halo-L-arabinopyranose to the 2-deoxy-2-halo- L-arabinofuranose. 2. The process of claim 1, wherein the process further comprises the steps of: (a) optionally substituting OR1 of the 2-deoxy-2-halo-L-arabinofuranose with O-acyl or a halogen (F, Br, CI or I); (b) coupling the arabinofuranose to an optionally protected pyrimidine, purine, heterocyclic or heteroaromatic base; and (c) deprotecting, if necessary, to obtain the 2"-deoxy-2"-halo-J3-L-arabinofuranosyl nucleoside. 3. The process of claim 1, wherein the process further comprises the process for the preparation of the 2-deoxy-2-halo-L-arabinopyranose of the formula (II) comprising the steps of: (a) obtaining an optionally protected L-arabinal of the formula (III) (Formula Removed) wherein each of R3 is independently hydrogen, alkyl, acyl or silyl; (b) halogenating the compound of formula (III) and deprotecting, if necessary, to form the 2-deoxy-2-halo-L-arabinopyranose of the formula (II). 4. The process of claim 1, wherein the process further comprises the process for the preparation of the 2-deoxy-2-halo-L-arabinopyranose of the formula (II) comprising the steps of: (a) obtaining an optionally protected L-arabinose of the formula (IV): (Formula Removed) wherein each of R3 and R is independently hydrogen, alkyl, acyl or silyl; (b) substituting OR1 with a halogen (F, Br, CI or I), to obtain a compound of the formula (V); (Formula Removed) wherein X1 is a halogen (F, Br, CI or I); (c) reducing the compound of formula (V) to form a compound of formula (III) (Formula Removed) (d) halogenating the compound of formula (III) and deprotecting if necessary to form the 2-deoxy-2-halo-L-arabinopyranose of the formula (II). 5. A process for the preparation of a 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside of the formula (I): (Formula Removed) wherein X is a halogen (F, CI, Br or I); and B is a pyrimidine, purine, heterocyclic or heteroaromatic base; comprising the steps of: (a) obtaining an optionally protected L-arabinose of the formula (IV): (Formula Removed) wherein each of R1, R2, R3 and R4 is independently hydrogen, alkyl, acyl or silyl; (b) substituting OR1 with a halogen (F, Br, CI or I), to obtain a compound of the formula (V); (Formula Removed) wherein X1 is a halogen (F, Br, CI or I); (c) reducing the compound of formula (V) to form a compound of formula an) (Formula Removed) (d) halogenating the compound of formula (III) and deprotecting if necessary to form the 2-deoxy-2-halo-L-arabinopyranose of the formula (II): (Formula Removed) wherein X is a halogen (F, Br, CI or I); (e) converting the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabinofuranose; (f) optionally substituting OR1 with O-Acyl or a halogen (F, Br, CI or I); (g) coupling the arabinofuranose to an optionally protected pyrimidine, purine, heterocyclic or heteroaromatic base; and (h) deprotecting, if necessary, to obtain the 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside. 6. A process for the preparation of 2"-deoxy-2"-fluoro-(3-L-arabinofuranosyl thymine (L-FMAU) by preparing a 2-deoxy-2-halo-L-arabinofuranose comprising the steps of: (a) obtaining a 2-deoxy-2-fluoro-L-arabinopyranose of the formula (H-a): (Formula Removed) wherein each of R1 and R2 is independently hydrogen, alkyl, acyl or silyl; and (b) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2- fluoro-L-arabinofuranose. 7. The process of claim 6, wherein the process further comprises the steps of: (a) optionally substituting OR1 with O-acyl or a halogen (F, Br, CI or I); (b) coupling the arabinofuranose to an optionally protected thymidine; and (c) deprotecting, if necessary, to obtain the 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymidine. 8. The process of claim 6, wherein the process further comprises the process for the preparation of the 2-deoxy-2-fIuoro-L-arabinopyranose of the formula (II-a) comprising the steps of: (a) obtaining an optionally protected L-arabinal of the formula (III) (Formula Removed) wherein each of R is independently hydrogen, alkyl, acyl or silyl; (b) fluorinating the compound of formula (III) and deprotecting, if necessary, to form the 2-deoxy-2-fluoro-L-arabinopyranose of the formula (Il-a). 9. The process of claim 6, wherein the process further comprises the process for the preparation of the 2-deoxy-2-fluoro-L-arabinopyranose of the formula (II-a) comprising the steps of: (a) obtaining an optionally protected L-arabinose of the formula (IV): (Formula Removed) ■a A wherein each of R and R is independently hydrogen, alkyl, acyl or silyl; (b) substituting OR1 with a halogen (F, Br, CI or I), to obtain a compound of the formula (V); (Formula Removed) wherein X1 is a halogen (R Br, CI or I); (c) reducing the compound of formula (V) to form a compound of formula an) (Formula Removed) (d) fluorinating the compound of formula (III) and deprotecting if necessary to form the 2-deoxy-2-fluoro-L-arabinopyranose of the formula (II-a). 10. A process for the preparation of 2"-deoxy-2"-fluoro-\|3-L-arabinofuranosyl thymine (L-FMAU) comprising (a) obtaining an optionally protected L-arabinose of the formula (IV): (Formula Removed) wherein each of R1, R2, R~ and R4 is independently hydrogen, alkyl, acyl or silyl; (b) substituting OR1 with a halogen (F5 Br, CI or I), to obtain a compound of the formula (V); (Formula Removed) wherein X1 is a halogen (F, Br, CI or I); (c) reducing the compound of formula (V) to form a compound of formula (HI) (Formula Removed) (d) fluorinating the compound of formula (III) and deprotecting if necessary to form the 2-deoxy-2-fluoro-L-arabinopyranose of the formula (II-a); (Formula Removed) (e) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabinofuranose; (f) optionally substituting OR1 with O-Acyl or a halogen (F, Br, CI or I); (g) coupling the arabinofuranose to an optionally protected thymine; and (h) deprotecting, if necessary, to obtain the 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymidine. 11. The process of any one of claims 1-10, wherein the halogenation of the compound of formula (III) is accomplished in nitromethanerwater. 12. The process of any one of claims 1-10, wherein the halogenation of the compound of formula (III) is accomplished in acetonerwater. 13. The process of any one of claims 1-10, wherein the conversion of the L-arabinopyranose to the L-arabinofuranose is accomplished using one equivalent of sulfuric acid. 14. The process of any one of claims 1-10, wherein the conversion of the L-arabinopyranose to the L-arabinofuranose is accomplished in dry methanol. 15. The process of any one of claims 6-10, wherein the fluorination of the compound of formula (III) is accomplished using selectfluor™ (F-TEDA-BF4). 16. A process for the preparation of a 2"-deoxy-2"-halo-ß-L- arabinofuranosyl nucleoside of the formula (I) substantially as herein described with reference to the foregoing description and the accompanying examples and drawing. 17. A process for the preparation of 2"-deoxy-2"-fluoro-ß-L- arabinofuranosyl thymine (L-FMAU) by preparing a 2-deoxy-2-halo- L- arabinofuranose comprising the steps of substantially as herein described with reference to the foregoing description and the accompanying examples and drawing. 18. A process for the preparation of 2"-deoxy-2"-fluoro-ß-L- arabinofuranosyl thymine (L-FMAU) comprising substantially as herein described with reference to the foregoing description and the accompanying examples and drawings.

Full Text

PROCESS FOR THE PREPARATION OF 2"-HALO-ß-L-ARABINOFURANOSYL NUCLEOSIDES
FIELD OF THE INVENTION
This invention is in the area of the synthesis of 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleosides, and is specifically directed to an efficient method of synthesis and manufacturing of l-(2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl)-thymine (L-FMAU)
This application claims priority to U.S Provisional Application No 60/280,307, filed on March 30, 2001.
BACKGROUND OF THE INVENTION
Infection by hepatitis B virus is a problem of enormous dimensions Hepatitis B virus has reached epidemic levels worldwide It is estimated that as many as 350 million people worldwide are persistently infected with HBV, many of whom develop associated pathologies such as chronic hepatic insufficiency, cirrhosis, and hepatocellular carcinoma After a two to three month incubation period in which the host is unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. About 1-2% of these develop fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed, with a mortality rate of 60-70%
The Epstein-Barr virus is a member of the genus Lymphocrypiovirus, which belongs to the subfamily gammaherpesvinne It is notably lymphotropic EBV has the classic structure of herpes viruses, viz , its double-stranded DNA genome is contained within an icosapentahedra! nucleocapsid, v.hich, in turn, is surrounded by a lipid envelope studded with viral glycoproteins EBV is now recognized as a cause of B-cell lymphoprohferative diseases, and has been linked to a variety of other severe and chronic
illnesses, including a rare progressive mononucleosis-like syndrome and oral hairy leukoplakia in AIDS patients. The suggestion that EBV is a major cause of chronic fatigue has not withstood scrutiny. EBV is primarily transmitted through saliva, although some infections are transmitted by blood transfusion. More than 85% of patients m the acute phase of infectious mononucleosis secrete EBV.
It has been discovered that certain L-nucleosides, mirror images of the natural DNA constituents may inhibit DNA synthesis at the triphosphate level probably by tight binding to the viral polymerase in the first stage of viral DNA synthesis.
2"-Deoxy-2"-fluoro-ß-L-arabinofuranosyl nucleosides have the general formula:
(Formula Removed)
wherein B is a pynmidine, purine, heterocyclic or heteroaromatic base.
Reported syntheses of L-FMAU
Yung Chi Cheng, Chung K. Chu and others first reported that l-(2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl)-thymine (L-FMAU) exhibits superior activity against hepatitis B virus and Epstein Barr virus in 1994. See U.S. Patent Nos 5,587,362; 5,567,688; 5,565,438 and 5,S08,040 and International Patent Application published as WO 95/20595.
(Formula Removed)
The Cheng patents describe a synthesis of L-FMAU from the sugar L-xylose (formula A) as well as the sugar L-ribose (formula B).
(Formula Removed)
These patents describe the synthesis of L-FMAU from L-xylose via conversion to the key intermediate l-O-acetyl-2,3,5-tn-O-benzoyl-ß-L-ribofuranose (see for example the "688 patent, starting at column 4, line 62) The key intermediate was synthesized from L-xylose in a total yield of 20% (see also L. Vargha, Chem Ber., 1954, 87, 1351; Holy, A, et al., Synthetic Procedures in Nucleic Acid Chemistry, VI, 163-67). This synthesis was also reported in Ma. T.; Pai, S. B.; Zhu, Y. L; Lin, T. S, Shanmunganathan. K.; Du, J. E; Wang, C. G.; Kim, H.; Newton, G. M ; Cheng, Y. C , Chu, C. K. J. Med. Chem. 1996, 39, 2S35. The inversion of the hydroxy group of L-xylose was achieved via the formation of the 5-O-benzoyl-l,2-O-isopropylidene-α-L-ribofuranoside, followed by a stereoselective hydride transfer during the reduction of the cycloketone furanoside with NaBH4. The resulting ribofuranoside was then converted to l-O-acetyl-2,3,5-tn-O-benzoyl-ß-L-nbofuranose, the key intermediate in the synthesis of L-FMAU (See Scheme A).
(Scheme Removed) A
l-O-Acetyl-2,3,5-tri-O-benzoyl-ß-L-ribofuranose can also be synthesized directly from the more expensive starting material L-ribose (see for example the "688 patent, starting at column 6, line 30; and Holy, A., et al., Synthetic Procedures in Nucleic Acid Chemistry, VI, 163-67). This alternative synthesis of l-0-acetyl-2,3,5-tri- (Scheme Removed) B
The key intermediate was subsequently fluonnated in a nucleophilic displacement reaction at C2 to obtain 13,5-tri-O-benzoyl-2-deoxy-2-fluoro-L-arbinofuranose, which was condensed with a desired base, such as thymine (5-methyluracil) through the bromosugar to piovide the 2-deoxy-2-fluoro-arabinofuranosyl nucleosides in various yields.
Chu et al. later developed a synthesis for the production of L-FMAU from L-arabmose in 14 steps and an overall yield of 8% (Du, J., Choi, Y.; Lee, K ; Chun, B K.; Hong, J. H., Chu, C. K. Nucleosides and Nucleosides 1999, 18, 187). L-Arabinose was converted to L-ribose in 5 steps (Scheme C) L-Ribose was then used in the synthesis 1-
O-acetyl-2,3,5-tri-O-benzoyl-ß-L-ribofuranose, which as described above led to the formation of L-FMAU.
(Scheme Removed) C

The processes mentioned above either start from an expensive sugar (L-ribose or L-xylose) and/or are very long, with low yields. In addition, they involve the use of a nucleophilic form of fluoride such as KHF2 or Et3N-3HF, which is difficult to handle and requires the displacement of an activated hydroxyl group. The instability of DAST prevents its use on large scale. The conversion of l-0-acetyl-2,3,5-tri-O-benzoyl-3-L-ribofuranose (TBAR) to 1,3,5-tri-O-benzoyl-ß-L-ribofuranose generates 2,3,5-tn-O-benzoyl-ß-L-ribofuranose as a side-product, though it can be reconverted to TBAR.
Reported syntheses of l-0-methyl-2-deoxy-2-fluoro-arabinofuranoside
The synthesis of l-O-methyl-2-deoxy-2-fluoro-a-D-arabinofuranoside, has been reported by Wnght et al. (Wright, J. A.; Taylor. N. R; Fox, J. J. J. Org. Chem 1969, 34, 2632, and references therein). In this report, D-xylose is used as the starting material, which after a conversion to the corresponding furanose and a series of protection reactions, gave an epoxy furanoside as an intermediate. This compound was further converted to 5-0-benzyl-l-O-methyl-2-deoxy-2-fluoro-α-D-arabinofuranoside, which
after removal of the benzyl group afforded l-0-methyl-2-deoxy-2-fluoro-α-D-arabmofuranoside (Scheme D).
(Scheme Removed) D
The synthesis of the l-O-methyl-2-deoxy-2-fluoro-ß-D-arabmofuranoside (the anomer of the above compound) was reported by Marquez et al. (Wysocki, R. J.; Siddiqui, M. A.; Barchi, J. J.; Dnscoll, J. S.; Marquez, V. E. Synthesis 1991, 1005). D-ribose was converted i several steps to l,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-ß-D-arabinofuranose, the corresponding bromo sugar derivative was produced under HBr/AcOH condition and the reaction of potassium carbonate in methanol gave the desired compound (Scheme E).

(Scheme Removed) E

Reported synthesis of 2-deoxy-2-fluoro-D-arabinospyranose
2-deo\y-2-fluoro-D-arabinopyranose was previously made from D-arabinose via D-arabinal as it is shown in Scheme F (Albano, E. L et ai. Carbohyd. Res. 1971,19,63).
(Scheme Removed) F

The same material was made from D-Ribose as shown below in Scheme G (Bols, M.; Lundt, L; Acta Chem. Scand. 1990, 44, 252).
(Scheme Removed) G
Reported synthesis of 2-deoxy-2-fluoro-3,4-di-0-acetyl-D-arabinospyranose
The title compound was previously made as a result of an electrophilic addition of selectfluor on D-arabinal (Albert, M. et al, Tetraliedron 1998,54,4839; Scheme H).
(Scheme Removed) H
In light of the commercial importance of L-FMAU, and its use m the treatment of patients afflicted with hepatitis B and Epstein Ban virus, it is an object of the invention to provide an improved synthesis of L-FMAU and related nucleosides
It is another object of the invention to provide a synthesis of 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleosides from inexpensive starting materials in relatively high yield.
SUMMARY OF THE INVENTION
The present invention is a process for the preparation of 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleosides, and in particular, 2"-deoxy-2"-fluoro-|3-L-arabmofuranosyl thymine (L-FMAU). from L-arabmose, which is commercially available and less expensive than L-nbose or L-xylose. The process involves the initial synthesis of a 2-deoxy-2-halo-3,4-di-0-protected-L-arabinospyranose, via an electrophilic halogenatmg agent, and in particular a fluonnatmg reagent. Deprotection and isomerization affords a 2-deoxy-2-halo-L-arabinofuranoside, a key intermediate in this synthesis. The 3- and 5-hydroxyl groups can then be protected, preferably by benzoylation, and the 1-position can be activated, preferably halogenated, and even more preferably brominated. This compound can then be condensed with a protected pyrimidine, purine, heterocyclic or heteroaromatic base to form the desired 2"-deoxy-2"-fluoro-L-arabinofuranosyl-nucleoside.
This process for the preparation of 2"-deoxy-2"-fluoro-L-arabinofuranosyl-nucleoside, and in particular, L-FMAU, is the first synthesis of this class of nucleosides from L-arabinose in ten steps. All of the reagents and starting materials are inexpensive and no special equipment is required to carry out the reactions. A key step for the synthesis is the conversion of a pyranoside. 2-deoxy-2-halo-L-arabmopyranose, into a furanoside, 2-deoxy-2-halo-L-arabmofuranoside.
In particular, in one embodiment of the present invention, a process for the preparation of a 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside of the formula (I):
(Formula Removed)
wherein X is a halogen (F, CI, Br or I), though preferably fluorine; and B is a pynmidme. purine, heterocyclic or heteroaromatic base; is provided, comprising
(a) obtaining a 2-deoxy-2-halo-L-arabmopyranose of the formula (II):
(Formula Removed)

wherein each of R1 and R2 is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) converting the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabmofuranose;
(c) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br. CI or I), though preferably a halogen, and even more preferably Br;
(d) coupling the arabmofuranose to an optionally protected pyrimidine, purine, heterocyclic or heteroaromatic base, and
(e) deprotecting. if necessary, to obtain the 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside.
In another embodiment of the invention, a process for the preparation of a 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside of the formula (I):
(Formula Removed)

wherein X is a halogen (F, CI, Br or I), though preferably fluorine, and B is a pynmidine. purine, heterocyclic or heteroaromatic base; is provided, comprising
(a) obtaining an optionally protected L-arabmose of the formula (IV):
(Formula Removed)

wherein each of R1, R2, R3 and R4 is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) substituting OR1 with a halogen (F, Br, CI or I), preferably Br, to obtain a
compound of the formula (V);
(Formula Removed)
wherein X1 is a halogen (F, Br, CI or I), preferably Br;
(c) reducing the compound of formula (V) to form a compound of formula (III)
(Formula Removed)

(d) halogenating the compound of formula (HI) and deprotectmg if necessary to form
the 2-deoxy-2-halo-L-arabmopyranose of the formula (II).
(Formula Removed)

wherein X is a halogen (F, Br. CI or I), preferably F;
(e) converting the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L~ arabinofuranose;
(f) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br, CI or I), though preferably a halogen, and even more preferably Br;
(g) coupling the arabmofuranose to an optionally protected pyrimidme, purine, heterocyclic or heteroaromatic base; and
(h) deprotecting, if necessary, to obtain the 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside.
In one particular embodiment of the present invention, the conversion of the 2-deoxy-2-halo-L-arabmopyranose to a 2-deoxy-2-halo-L-arabmofuranose is accomplished using one equivalent of sulfuric acid In a further embodiment of the present invention, the conversion of the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabino-furanose is accomplished in dry methanol. In a preferred embodiment, the conversion of
the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabinofuranose is accomplished using one equivalent of sulfuric acid in dry methanol.
In another embodiment of the present invention, a process for the preparation of 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymine (L-FMAU) comprising
(a) obtaining a 2-deoxy-2-fluoro-L-arabmopyranose of the formula (II-a)-
(Formula Removed)

wherein each of R and R" is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabinofuranose;
(c) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br. CI or I), though preferably a halogen, and even more preferably Br;
(d) coupling the arabinofuranose to an optionally protected thymidine; and
(e) deprotectmg, if necessary, to obtain the 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymidine.
In yet another embodiment of the invention, a process for the preparation of 2"-deoxy-2"-fluoro-f3-L-arabinofuranosyl thymine (L-FMAU) comprising
(a) obtaining an optionally protected L-arabmose of the formula (IV)
(Formula Removed)
wherein each of R1, R2, R3 and R4 is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) substituting OR1 with a halogen (F, Br, CI or I), preferably Br to obtain a
compound of the formula (V);
(Formula Removed)
wherein X1 is a halogen (F, Br, CI or I), preferably Br;
(c) reducing the compound of formula (V) to form a compound of formula (III)
(Formula Removed)
(d) fluonnaung the compound of formula (III) and deprotectmg if necessary to form
the 2-deoxy-2-fluoro-L-arabinopyranose of the formula (II-a);
(Formula Removed)
(f) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabmofuranose,
(g) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br, CI or I), though preferably a halogen, and even more preferably Br;
(h) coupling the arabmofuranose to an optionally protected thymine; and
(i) deprotectmg, if necessary, to obtain the 2"-deoxy-2"-fluoro-|3-L-arabinofuranosyl thymidine.
In a particular embodiment of the present invention, the halogenation, and in particular, the fluonnation, of the compound of formula (III) is accomplished in nitromethane:water In an alternate embodiment, the halogenation, and in particular, the fluorination, of the compound of formula (III) is accomplished in acetone:water
In one particular embodiment of the present invention, the conversion of the 2-deoxy-2-fluoro-L-arabmopyranose to a 2-deoxy-2-fluoro-L-arabmofuranose is accomplished using one equivalent of sulfuric acid. In a further embodiment of the present invention, the conversion of the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabmo-furanose is accomplished in dry methanol. In a preferred embodiment, the conversion of the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabinofuranose is accomplished using one equivalent of sulfuric acid m dry methanol
In one embodiment of the invention the 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside, and in particular the 2."-deoxy-2"-fluoro-|3-L-arabinofuranosyI thymine, can be further functionahzed, such as phosphorylated or acylated to form pharmaceutically acceptable salts or prodrugs.
BRIEF DESCRIPTION OF THE FIGURE
Figure 1 is a non-lmnting example of a process for the preparation of 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymine, according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is a process for the preparation of 2"-deoxy-2"-halo-p-L-arabmofuranos>l nucleosides, and m particular, 2:-deoxy-2"-fluoro-ß-L-arabmofuranosyl thymine (L-FMAU), from L-arabinose, which is commercially available and less expensive than L-ribose or L-xylose. The process involves the initial synthesis of a 2-deoxy-2-halo-3,4-di-0-protected-L-arabmospyranose. and m particular 2-deoxy-2-fluoro-3.4-di-O-acetyl-L-arabinospyranose, via an electrophilic halogenatmg agent, and in particular a fluonnatmg reagent. Deprotection and isomenzation affords a 2-deoxy-2-halo-L-arabinofuranoside. and in particular, l-O-methyl-2-deoxy-2-fluoro-L-arabmofuranoside, a key intermediate in this synthesis. The 3- and 5- hydroxy] groups can then be protected, preferably by benzoylation, and the 1-position can be activated, prefeiably halogcnated, and even more preferably brommated to form, for example, 1-bromo-3.5-di-O-benzoyl-2-deoxy-2-fluoro-L-arbmofuranose This compound can then be condensed with a protected pynmidine, purine, heterocyclic or heteroaromatic base to form the desired 2"-deo\y-2"-fluoro-L-arabinofuranosyl-nucleoside.
This process for the preparation of 2"-deoxy-2"-fluoro-L-arabinofuranosyl-nucleoside, and in particular, L-FMAU, is the first synthesis of this class of nucleosides from L-arabinose in ten steps. All of the reagents and starting materials are inexpensive and no special equipment is required to carry out the reactions. A key step for the synthesis is the conversion of a pyranoside, 2-deoxy-2-halo-L-arabmopyranose, into a furanoside, 2-deoxy-2-halo-L-arabmofuranoside.
The term "L-FMAU analog" or "related nucleoside" as used herein refers to a nucleoside thai is formed from a pyrrolidine or purine base that is coupled to a 2-fluoro-arabmofuranosvl moiety.
In particular, in one embodiment of the present invention, a process for the preparation of a 2"-deoxy-2"-halo-|3-L-arabinofuranosyl nucleoside of the formula (I):
(Formula Removed)
wherein X is a halogen (F, CI, Br or I), though preferably fluorine; and B is a pyrimidme, purine, heterocyclic orbeteroaromatic base; is provided, comprising
(a) obtaining a 2-deoxy-2-halo-L-arabmopyranose of the formula (II):
(Formula Removed)
wherein each of R and R" is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) converting the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabinofuranose;
(c) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br, CI or I), though preferably a halogen, and even more preferably Br;
(d) coupling the arabinofuranose to an optionally protected pyrimidine, purine, heterocyclic or heteroaromatic base; and
(e) deprotecting, if necessary, to obtain the 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside.
In a particular embodiment of the invention, the 2-deoxy-2-halo-L-arabinopyranose of the formula (II):
(Formula Removed)

wherein R and R is as defined above, is provided by a process, comprising
(a) obtaining an optionally protected L-arabinal of the formula (III)
(Formula Removed)

wherein each of RJ is independently hydrogen or a suitable oxygen protecting group such as alky], acyl or silyl;
(b) halogenatmg the compound of formula (III) and deprotectmg, if necessary, to form
the 2-deoxy-2-halo-L-arabmopyranose of the formula (II).
In an even more particular embodiment of the invention, the 2-deoxy-2-halo-L-arabmopyranose of the formula (II).
(Formula Removed)

wherein R and R" is as defined above, is provided by a process, comprising (a) obtaining an optionally protected L-arabmose of the formula (IV):
(Formula Removed)

wherein each of RJ and R is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) substituting OR1 with a halogen (F, Br, CI or I), preferably Br, to obtain a
compound of the formula (V);
(Formula Removed)

wherein X1 is a halogen (F, Br, CI or I), preferably Br;
(c) reducing the compound of formula (V) to form a compound of formula (III)
(Formula Removed)

(d) halogenating the compound of formula (in) and deprotecting if necessary to form
the 2-deoxy-2-halo-L-arabmopyranose of the formula (II).
In one embodiment of the invention, a process for the preparation of a 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside of the formula (I):
(Formula Removed)

wherein X is a halogen (F, CI, Br or I), though preferably fluorine; and B is a pyrimidine. purine, heterocyclic or heteroaromatic base; is provided, comprising
(a) obtaining an optionally protected L-arabinose of the formula (IV):
(Formula Removed)

wherein each of R1, R2, R3 and R4 is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) substituting OR1 with a halogen (F, Br, CI or I), preferably Br, to obtain a
compound of the formula (V);
(Formula Removed)

wherein X1 is a halogen (F, Br, CI or I), preferably Br;
(c) reducing the compound of formula (V) to form a compound of formula (III)
(Formula Removed)

(d) halogenating the compound of formula (III) and deprotecting if necessary to form
the 2-dcoxy-2-halo-L-arabmopyranose of the formula (II):
(Formula Removed)
wherein X is a halogen (F, Br, CI or I), preferably F;
(e) converting the 2-deoxy-2-halo-L-arabmopyranose to a 2-deoxy-2-halo-L-arabmofuranose;.
(f) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br, CI or I), though preferably a halogen, and even more preferably Br;
(g) coupling the arabinofuranose to an optionally protected pynmidine, purine, heterocyclic or heteroaromatic base; and
(h) deprotectmg, if necessary, to obtain the 2"-deoxy-2"-halo-j3-L-arabmofuranosyl nucleoside.
In one particular embodiment of the present invention, the conversion of the 2-deoxy-2-halo-L-arabmopyranose to a 2-deoxy-2-halo-L-arabmofuranose is accomplished using one equivalent of sulfuric acid. In a further embodiment of the present invention, the conversion of the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabmo-furanose is accomplished m dry methanol. In a preferred embodiment, the conversion of the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabinofuranose is accomplished using one equivalent of sulfuric acid in dry methanol.
In another embodiment of the present invention, a process for the preparation of 2"-deoxy-2"-fluoro-p-L-arabinofuranosyl thymine (L-FMAU) comprising
(a) obtaining a 2-deoxy-2-fluoro-L-arabmopyranose of the formula (II-a).
(Formula Removed)

wherein each of R1 and R2 is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabmofuranose;
(c) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br, CI or I), though preferably a halogen, and even more preferably Br;
(d) coupling the arabinofuranose to an optionally protected thymidine; and
(e) deprotectmg, if necessary, to obtain the 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymidine
In a particular embodiment of the invention, the 2-deoxy-2-fluoro-L-arabmopyranose of the formula (H-a):
(Formula Removed)

wherein R and R is as defined above, is provided by a process, composing
(a) obtaining an optionally protected L-arabmal of the formula (III)
(Formula Removed)

wherein each of RJ is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) fluonnatmg the compound of formula (III) and deprotecting. if necessary, to form
the 2-deoxy-2-fluoro-L-arabmopyranose of the formula (II-a)

In an even more particular embodiment of the invention, the 2-deoxy-2-halo-L-arabmopyranose of the formula (II-a):
(Formula Removed)
wherein R and R" is as defined above, is provided by a process, comprising
(a) obtaining an optionally protected L-arabmose of the formula (IV):
(Formula Removed)

wherein each of RJ and R is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) substituting OR1 with a halogen (F, Br, CI or I), preferably Br, to obtain a
compound of the formula (V);
(Formula Removed)
wherein X1 is a halogen (F, Br, CI or I), preferably Br;
(c) reducing the compound of formula (V) to form a compound of formula (III)
(Formula Removed)
3
(d) fluonnating the compound of formula (III) and deprotectmg if necessary to form
the 2-deoxy-2-fluoro-L-arabmopyranose of the formula (Il-a).
In one embodiment of the invention, a process for the preparation of 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymine (L-FMAU) comprising
(a) obtaining an optionally protected L-arabinose of the formula (IV):
(Formula Removed)

wherein each of R1, R , R3 and R4 is independently hydrogen or a suitable oxygen protecting group such as alkyl, acyl or silyl;
(b) substituting OR1 with a halogen (F, Br, CI or I), preferably Br, to obtain a
compound of the formula (V);
(Formula Removed)

wherein X1 is a halogen (F, Br, CI or I), preferably Br;
(c) reducing the compound of formula (V) to form a compound of formula (III)
(Formula Removed)
(d) fluonnating the compound of formula (III) and deprotecting if necessary to form
the 2-deoxy-2-fluoro-L-arabmopyranose of the formula (Il-a);
(Formula Removed)

(f) converting the 2-deoxy-2-fluoro-L-arabmopyranose to a 2-deoxy-2-fluoro-L-arabmofuranose;
(g) optionally substituting OR1 with a suitable leaving group, such as O-Acyl (including OAc) or a halogen (F, Br, CI or I), though preferably a halogen, and even more preferably Br;
(h) coupling the arabinofuranose to an optionally protected thymine; and
(i) deprotecting, if necessary, to obtain the 2"-deoxy-2"-fluoro-ß-L-arabmofuranosyl thymidine.
In a particular embodiment of the present invention, the halogenation, and in particular, the fluorination, of the compound of formula (III) is accomplished in nitromethane"water. In an alternate embodiment, the halogenation, and in particular, the fluorination, of the compound of formula (III) is accomplished m acetone:water.
In one particular embodiment of the present invention, the conversion of the 2-deox\-2-fluoro-L-arabinop\xanose to a 2-deoxy-2-fluoro-L-arabmofuranose is accomplished using one equivalent of sulfuric acid. In a further embodiment of the
present invention, the conversion of the 2-deoxy-2-fluoro-L-arabmopyranose to a 2-deoxy-2-fluoro-L-arabinofuranose is accomplished m dry methanol. In a preferred embodiment, the conversion of the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabmofuranose is accomplished using one equivalent of sulfuric acid m dry methanol
Non limiting examples of fluorinatmg agents that can be used m the electrophilic addition of fluorine to L-arabmal include tnfluoromethyl hypofluonte (CF3OF), acetyl hypoflunte (CH3COOF), xenon difluonde (XeF2). elemental fluonne (F2). In a preferred embodiment the fluonnatmg agent is selectfluor (F-TEDA-BF4).
I. Nucleosides Which Can Be Synthesized According to the Present Invention
The invention as disclosed herein can be used to produce compounds of formula (C).
(Formula Removed)
wherein each R and R" is independently hydrogen, alkyl, acyl, aryl, monophosphate, diphosphate, triphosphate, amino acid, or an oxygen protecting group;
X is a halogen (F, CI, Br or I), and preferably fluonne, and
B is a pyrimidine, purine, heterocyclic or heteroaromatic base.
These compounds either possess antiviral (i.e.. anti-hepatitis B virus or anti-Epstein-Barr virus) activity, are metabolized to a compound that exhibits such activity, or can be used in a manufacturing process to prepare compounds having such activity.
II. Definitions
As used herein, the term "substantially free of or "substantially in the absence of refers to a nucleoside composition that includes at least 95% to 98%, or more preferably, 99% to 100%, of the designated enantiomer of that nucleoside. In a preferred embodiment, the compound is prepared substantially free of its corresponding B-D isomer.
The term "enantiomerically enriched"" is used throughout the specification to describe a nucleoside which includes at least about 95%, preferably at least 96%, more preferably at least 97%, even more preferably, at least 98%. and even more preferably at least about 99% or more of a single enantiomer of that nucleoside. When a nucleoside of a particular configuration (D or L) is referred to in this specification, it is presumed that the nucleoside is an enantiomerically enriched nucleoside, unless otherwise stated.
The term alkyl, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon, typically of Q to Cis, includes lower alkyl, and specifically includes methyl, ethyl, propyl, isopropyL butyl, isobutyl, t-butyl, pentyl. cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl. cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethyl-butyl. The alkyl group can be optionally substituted with functional groups as desired, as known to those skilled in the art, for example, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference. The term lower alkyl, as used herein, and unless otherwise specified, refers to a C\ to C4 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including both substituted and unsubstituted forms.
The term "protected" as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled m the art or organic synthesis. Suitable protecting groups are described, for example, in Greene, et al. "Protective Groups in Organic Synthesis," John Wiley and Sons, Second Edition. 1991, hereby incorporated by reference.
The term aryl, as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphthyl, and preferably phenyl. The aryl group can be optionally substituted as known to those skilled m the art, for example, as taught m Greene, et al, "Protective Groups in Organic Synthesis,"" John Wiley and Sons, Second Edition, 1991.
The term acyl refers to moiety of the formula -C(O)R", wherein R" is alkyl, aryl, alkaryl. aralkyl, heteroaromatic, heterocyclic, alkoxyalkyl including methoxymethyl, arylalkyl including benzyl; aryloxyalkyl. such as phenoxymethyl; aryl including phenyl optionally substituted with halo groups C1 to C4 alkyl or C1 to C4 alkoxy or the residue of an amino acid
The term silyl refers to moiety of the formula -SiR"3, wherein each R" is independent]y alkyl or aryl group as defined herein. The alkyl or aryl group can be optionally substituted as known to those skilled in the art. for example, as taught in Greene, el al, "Protective Groups m Organic Synthesis," John Wiley and Sons, Second Edition. 1991
The term "halogen," as used herein, includes fluorine, chlorine, bromine and iodine.
The term purine or pynmidme base includes, but is not limited to, adenine, 6-alkylpunnes, 6-acylpunnes (wherein acyl is C(0)(alkyl, aryl, alkylaryl, or arylalkyl), 6-benzylpunne, 6-halopunne, N6-acyl purine, 6-hydroxyalkyl purine, 6-thioaIkyI purine, N"-alkylpurines, N"-alkyl-6-thiopunnes, thymine, cytosine, 5-fluorocytosine, 5-methyl-cytosine, 6-azapynmidme, including 6-azacytosine, 2- and/or 4-mercaptopyrmidme, uracil, 5-halouracil, including 5-fluorouracil, C5-alkylpynmidmes, C5-benzyl-pyrimidines, C5-halopyri mi dines, C5 -vinylpyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrirmdine, C5-hydroxyalkyl pynmidine, C5-amidopynmidme, C5-cyanopynmidine, C5-nitro-pynmidme, C5-arrunopynmidme, 5-azacytidinyl, 5-azauracilyl. tnazolopyridmyl, lmidazolopyndinyl, pyrrolopyrimidmyl and pyrazolopyrimidmyl. Purine bases include, but are not limited to. guanine, adenine, hypoxanthine, 2,6-diammopunne, and 6-chloro-punne Functional oxygen and nitrogen groups on the base can be protected as necessary or desired Suitable protecting groups are well known to those stalled in the art, and include tnmethylsilyl, dimethylhexylsilyl, r-butyldimethylsilyl and /-butyldiphenylsilyl, tntyl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-
toluenesulfonyl. The heteroaromatic group can be optionally substituted as described above for aryl.
The term heteroaryl or heteroaromatic, as used herein, refers to an aromatic that includes at least one sulfur, oxygen, nitrogen or phosphorus m the aromatic ring The term heterocyclic refers to a nonaromatic cyclic group wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen or phosphorus m the ring. Nonlimitmg examples of heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pynmidyl, thienyl. isothiazolyl, limdazolyl, tetrazolyl, pyrazmyl, benzofuranyl, benzothiophenyl, qumolyl. isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl. benzimidazolyl. purinyl, carbazolyl. oxazolyl, thiazolyl, iso-thiazolyl, 1,2,4-thiadiazolyl, isooxazoty}, pyrrolyl, quinazolmyl, cinnolmy], phthalazmyl, xanthmyl. hypoxanthmyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole, 1,2,3-tnazole, 1,2,4-tnazole, oxazole, isoxazole, thiazole, isothiazole, pynrmdine or pyndazme, and ptendmyl, aziridines, thiazole, isothiazole, 1,2,3-oxadiazole, thiazine, pyridine, pyrazine, piperazine, pyrrolidine, oxaziranes, phenazine, phenothiazme, morpholmyl, pyrazolyl, pyridazinyl, pyrazmyl, quinoxalinyl, xanthmyl, hypoxanthmyl, ptendinyl, 5-azacytidinyl, 5-azauracilyl. triazolopyndinyl, imidazolopyndinyl, pyrrolopyrimidinyl, pyrazolo-pyrimidinyl, adenine, N6-alkylpurines, N6-benzylpunne, N6-halopurine,N6-vmypurine, N6-acetylenic purine, N6-acyl purine,N6-hydroxyalkyl purine. N6-thioalkyl purine, thymine, cytosine, 6-azapyrimidine, 2-mercaptopyrmidme, uracil, N -alkylpyrimidines, N5-benzylpyrimidines, N5-halopyrimidines, N6-vmylpyrimidine, N5-acetylenic pynmidine, N5-acyl pyrimidine, N5-hydroxyalkyl punne, and N6-thioalkyl punne, and isoxazolyl. The heteroaromatic group can be optionally substituted as described above for aryl. The heterocyclic or heteroaromatic group can be optionally substituted with one or more substituent selected from halogen, haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amido, amino, alkylamino, dialkylammo. The heteroaromatic can be partially or totally hydrogenated as desired. As a nonlimitmg example, dihydropyndme can be used in place of pyridine. Functional oxygen and nitrogen groups on the heterocyclic or heteroaryl group can be protected as necessary or desired Suitable protecting groups are well known to those skilled in the ait, and include mmethylsilyl, dimethylhexylsilyl, r-butyldimethylsilyl, and r-butyl-diphenylsilyl, tntyl or substituted
tntyl, alkyl groups, acyl groups such as acety] and propionyl, methanesulfonyl, and p-toluenylsulfonyl.
These purine or pyrimidine bases, heteroaromatics and heterocycles can be substituted with alky] groups or aromatic rings, bonded through single or double bonds or fused to the heterocycle ring system. The purine base, pyrimidine base, heteroaromatic or heterocycle may be bound to the sugar moiety through any available atom, including the ring nitrogen and ring carbon (producing a C-nucleoside).
III. Detailed Description of the Process Steps
Preparation of Stalling Material - 2-deoxy-2-halo-L-arabinopyranose (II)
The key starting material for this process is an appropriately substituted 2-deoxy-2-halo-L-arabmopyranose (II). The 2-deoxy-2-halo-L-arabmopyranose (II) can be purchased or can be prepared by any known means including standard reduction and electrophilic addition techniques. In one embodiment, the 2-deoxy-2-halo-L-arabmopyranose (II) is prepared from L-arabmal followed by halogenation. The L-arabmal can be purchased or can be prepared by any known means including standard reduction techniques. For example, the L-arabmal can be prepared from an appropriately protected L-arabmose, preferably protected with an acyl group such as with an acetyl group, according to the following protocol
(Formula Removed)
L-Arabmose (1) can be protected by methods well known to those skilled in the art, as taught in Greene, el al, Protective Groups m Organic Synthesis, John Wiley and Sons, Second Edition, 1991, to form an appropriately protected L-arabmose (2), wherein each P is independently hydrogen or an appropriate oxygen protecting group such as an alkyl, acyl or silyl group, though preferably an acyl group such as an acetyl group The
protection can be earned out in any appropriate solvent that facilitates the desired result. In one embodiment the reaction is carried out m a mild base, such as pyridine. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is from 0°C to room temperature.
The appropriately substituted L-arabmose (2) can then be halogenated. preferably brommated, using an appropriate halide under any suitable conditions, though preferably acidic conditions, to obtain a l-a-halo-2,3,4-tri-ß-protected-L-arabinopyranose (3). such as l-a-bromo-2,334-tri-0-acetyl-L-arabmopyranose The halogenation can be earned out m any appropriate solvent that facilitates the desired result In one non-limiting example, compound (2) can be halogenated with H-X. wherein X is F, CI, Br or I, though preferably Br, optionally with a suitable acid, preferably an acyl acid such as acetic acid, optionally with an acyl anhydnde such as acetic anhydride. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is from room temperature to refluxing conditions.
The l-α-halo-2,3,4-tri-0-protected-L-arabinopyranose (3) can then be reduced using any suitable reducing agent to obtain the L-arabmal (4). Possible reducing agents are reagents that promote reduction, including but not limited to, zinc dust m the presence of CuSO4pentahydrate and sodium acetate in ACOH/H2O. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferced temperature is from below -5°C to room temperature. The L-arabinal can be prepared in any solvent that is suitable for the temperature and the solubility of the reagents. Solvents can consist of any protic solvent including, but not limiting to, alcohol, such as methanol, ethanol, isopropanol, butanol, pentanol or hexanol, acyl acid such as acetic acid, water or any combination thereof, though preferably the solvent is acetic acid and water.
(Formula Removed)
The L-arabinal (4) can then be halogenated, preferably fluorinated, using an appropriate electrophilic halogenating reagent to afford compound (5). Possible electrophilic halogenating agents are reagents that promote regiospecific halogenation. In one particular embodiment, an electrophilic fluormating agent is used. Non-limitmg examples of fluonnating agents that can be used m the electrophilic addition of fluorine to L-arabinal include, but not limited to. tnfluoromethyl hypofluonte (CF3OF), acetyl hypofiunte (CH3COOF), xenon difluonde (XeF2), elemental fluorine (F2). In an alternate embodiment the fluonnating agent is selectfluor™. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is from room temperature to refluxmg conditions The halogenation can be prepared m any solvent that is suitable for the temperature and the solubility of the reagents. Solvents can consist of any polar protic or aprotic solvent including, but not limiting to, alcohol, such as methanol, ethanol, isopropanol, butanol, pentanol or hexanol, acetone, ethyl acetate, dithianes, TFfF, dioxane, acetonitrile, nitromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, water, or any combination thereof, though preferably the solvent is water/nitromethane and water/acetone: (1/2)
The optionally protected 2-deoxy-2-halo-L-arabinopyranose (5) can then be deprotected, if necessary, by methods well known to those skilled in the art, as taught in Greene, el ai. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, to obtain the 2-deoxy-2-halo-L-arabinopyranose (II). The deprotection can be earned out in any appropnate solvent that facilitates the desired result. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. For example, acyl protecting groups, and in particular an acetyl group, can be deprotected with sodium methoxide in methanol at room temperature.
In one preferred embodiment of the invention, this procedure, can be tailored to produce the cntical intermediate compounds for the synthesis of L-FMAU or L-FMAU analogs.
Preparation of 2~deoxy-2-halo-L-arabinofuranose
(Formula Removed)
The 2-deoxy-2-halo-L-arabinopyranose (II) is reacted with any suitable acid (in gas or liquid form), such as, but not limited to sulfuric or hydrochloric acid m either catalytic amounts or in excess to form a 2-deoxy-2-halo-L-arabmofuranose (7). In a one embodiment of the present invention, 1 molar equivalent of sulfuric acid is used for this reaction. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is from room temperature to refluxing conditions. This reaction can be earned out in any solvent that is suitable for the temperature and the solubility of the reagents. Solvents can consist of any polar protic or aprotic solvent including, but not limiting to, an alcohol, such as methanol, ethanol. isopropanol, butanol, pentanol or hexanol, acetone, ethyl acetate, dithianes, THF, dioxane. acetomtnle, nitromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethyl-acetamide, water, or any combination thereof, though preferably the solvent is methanol.
The 2-deoxy-2-halo-L-arabinofuranose (7) can be optionally protected by methods well known to those skilled in the art, as taught m Greene, el al, Protective Groups m Organic Synthesis, John Wiley and Sons, Second Edition, 1991, to form an appropnately protected 2-deoxy-2-halo-L-arabmofuranose (8), wherein each P is independently hydrogen or an appropriate oxygen protecting group such as an alkyl, acyl or silyl group, though preferably an acyl group such as a benzoyl group. The protection can be earned out in any appropriate solvent that facilitates the desired result. In one embodiment the reaction is earned out in a mild base, such as pyndme. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products The preferred temperature is from 0°C to room temperature
Preparation of 2"-deoxy-2"-Iialo-ß-L-arabinofuranosyl nucleoside
(Formula Removed)

The appropriately protected 2-deoxy-2-halo-L-arabmofuranose (8) is optionally activated to form an activated 2-deoxy-2-halo-L-arabmofuranose (9), wherein LG is a suitable leaving group, such as O-Acyl (including OAc) or a halogen (¥, Br. CI or I), though preferably a halogen, and even more preferably Br In one non-limiting example, compound (8) is halogenated with halogenated with H-X, wherein X is F, CI. Br or I, though preferably Br, optionally with a suitable acid, preferably an acyl acid such as acetic acid, to afford compound (9). This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is room temperature. This reaction can be carried out in any solvent that is suitable for the temperature and the solubility of the reagents. Solvents can consist of any polar protic or aprotic solvent including, but not limiting to, an alcohol, such as methanol, ethanol, isopropanol, butanol, pentanol or hexanol, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitnle, nitromethane, dichloromethane, dichloroethane, diethyl ether, dimethylformarrude (DMF), dimethylsulfoxide (DMSO), dimethyl-acetamide, water, or any combination thereof, though preferably the solvent is dichloromethane
(Formula Removed)

The activated 2-deoxy-2-halo-L-arabmofuranose (9) can then be coupled with an
optional!}" protected pynmidrne, purine, heterocyclic or heteroaromatic base to afford the
optionally protected 2,-deoxy-2,-halo-L-arabmonucleoside (11). Solubihzing
substituents can be added to the purine base, pynrmdine base, heteroaromatic or heterocycle to promote solubility in the desired solvent system It should also be understood that certain functional groups of the purine base, pynrmdine base,
heteroaromatic or heterocycle might need to be protected to prevent unnecessary side reactions. The reactive moieties can be protected using conventional means and appropriate protecting groups well known to those skilled in the art, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. For example, the free amine on cytosme may be protected by reaction with benzoyl chloride or any other suitable acyl compound to prevent unnecessary coupling at the N4 position, to activate the cytosme base, and/or to assist in solubilizing the compound in the organic solvent. Alternatively, the free amine and/or free hydroxyl on the punnc base, pynmidine base, heteroaromatic or heterocycle, such as thymine, may be protected with a silyl group, such as trimethylsilyl chloride to prevent unnecessary side products, to activate the purine base, pynmidine base, heteroaromatic or heterocycle. such as tin mine, and/or to assist in solubilizing the compound in the organic solvent Any compound containing a nitrogen that is capable of reaction with a center of electron deficiency can be used in the condensation reaction. In one embodiment an O-protected thymine base, for example a silylated thymine such as trimethylsilyl-thymine, is coupled with compound (9). In a preferred embodiment, the pynmidine or purine base is silylated with a suitable silylating agent to form a silylated base. Possible silylating agents are reagents that promote silylation, including but not limited to, 1,1,1,3,3.3-hexamethyldisilazane, optionally with a catalytic amount of ammonium sulfate. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is refluxing conditions.
The coupling reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products. The preferred temperature is room temperature. The reaction can take place in any solvent that provides the appropnate temperature and the solubility of the reagents. Examples of solvents include any aprotic solvent such as an alkyl solvent such as hexane and cyclohexane, toluene, acetone, ethyl acetate, dithianes, THF, dioxane, acetomtnle, chloroform, dichloromethane, dichloroethane, diethyl ether, pyridine, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, 1,1,1,3,3.3-hexamethyldisilazane or any combination thereof, preferably dichloromethane, dichloroethane or a combination of chloroform and 1,1,1,3,3,3-hexamethyldisilazane.
The optionally protected 2"-deoxy-2"-halo-L-arabmonucleoside (11) can then be deprotected, if necessary, by methods well known to those skilled m the art. as taught m Greene, et al, Protective Groups m Organic Synthesis. John Wiley and Sons. Second Edition, 1991, to obtain the 2"-deoxy-2"-halo-L-arabinonucleoside (I). The deprotection can be earned out in any appropriate solvent that facilitates the desired result. This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products For example, acyl protecting groups, and in particular a benzoyl group, can be deprotected with n-butylamme in methanol at reflux
In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, pharmaceutically acceptable salts may be synthesized. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known m the pharmaceutical art. In particular, examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, mefhanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate. ascorbate, a-ketoglutarate, and a-glycerophosphate. Suitable inorganic salts may also be formed, including, sulfate, nitrate, bicarbonate, and carbonate salts.
Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
Any of the nucleosides described herein can be denvatized to its nucleoside or nucleotide prodrug. A number of nucleotide prodrug hgands are known. In general, alkylation, acylation or other lipophilic modification of the mono, di or triphosphate of the nucleoside is well known m the art. Examples of substituent groups that can replace one or more hydrogens on the phosphate moiety aie alkyl, aryl, steroids, carbohydrates, including sugars, l,2-diac\lglycerol and alcohols Many are described m R. Jones and
N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can be used to functionalize the disclosed nucleosides to achieve a desired prodrug.
The active nucleoside can also be provided as a 5"-phosphoether lipid or a 5"-ether lipid, as disclosed in the following references, which are incorporated by reference herein: Kucera, L.S.. N. Iyer, E. Leake, A. Raben. Modest E.K., D.LW., and C. Piantadosi. 1990. "Novel membrane-interactive ether lipid analogs that inhibit infectious HTV-1 production and induce defective virus formation." AIDS Res. Hum. Retro Viruses. 6-491-501: Piantadosi, C, J. Marasco C.J., S.L. Morns-Natschke. KL. Meyer. F. Gumus, J.R. Surles, K.S. Ishaq, L.S. Kucera, N. Iyer, CA Wallen, S. Piantadosi, and E.J Modest. 1991. ""Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HTV activity." J. Med Chem. 34:1408.1414; Hosteller. K.Y., D.D. Richman. D.A. Carson, L.M. Stuhmiller, G.M. T. van Wijk, and H. van den Bosch. 1992. "Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3"-deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of 3,-deoxythymidme." Anthmcrob. Agents Chemother. 36:2025 2029; Hosetler, K.Y., L.M. Stuhmiller, H.B. Lenting. H. van den Bosch, and D.D. Richman, 1990. "Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides." J. Biol. Chem. 265:61127.
Nonlimiting examples of U.S. patents that disclose suitable lipophilic substituents that can be covalently incorporated into the nucleoside, preferably at the 5*-OH position of the nucleoside or lipophilic preparations, include U.S. Patent Nos. 5,149.794 (Sep. 22.
1992, Yatvin et al.)\ 5,194,654 (Mar. 16, 1993, Hostetler et al, 5,223,263 (June 29,
1993, Hostetler et al); 5,256,641 (Oct. 26, 1993, Yatvin et al); 5,411,947 (May 2,1995. Hostetler et al): 5,463,092 (Oct. 31, 1995, Hostetler et al); 5,543,389 (Aug. 6, 1996, Yatvin et al); 5.543,390 (Aug. 6, 1996, Yatvin et al.); 5,543,391 (Aug. 6. 1996, Yatvin et al); and 5,554,728 (Sep. 10, 1996; Basava et al), all of which are incorporated herein by reference. Foreign patent applications that disclose lipophilic substituents that can be attached to the nucleosides of the present invention, or lipophilic preparauons, include WO 89/02733, WO 90/00555, W0 91/16920, W0 91/18914, W0 93/00910, W0 94/26273, W0 96/15132. EP 0 350 287, EP 93917054.4, and W0 91/19721.
Preparation of 2 "-deoxy-2 "-fluoro-ß-L-arabinofuranosyl thymidine (L-FMA U)
The peracetylated bromosugar of L-arabinose (15, Figure 1) can be obtained according to hterature-procedure as a solid, in 57% yield after crystallization from ether (Balog, A.; Yu, M. S., Curran, D. P. Synthetic Comm. 1996, 26, 935). The material is very unstable at room temperature and had to be used immediately or stored in a freezer.
An optionally protected L-arabmal can also be obtained according to a literature procedure m 60% yield after column chromatography (Smiatacz, Z ; Myszka. H. Carbohydr. Res 1988.172. 171).
The optionally protected L-arabmal can then be fluonnated via addition of selectfluor™ by a modification of a hterature procedure to afford an optionally protected 2-deoxy-2-fluoro-L-arabinopyranose as a syrup m 42% yield (Albert, M.; Dax. K, Ortner, J. Tetrahedron 199S. 54, 4839). Traces of what could possibly be the L-nbo isomer were detected by 19F-NMR (ratio L-arabino:L-nbo 30:1). The D-isomer of 2-deoxy-2-fluoro-L-arabinopyranose was made by a similar procedure (Albert. M.; Dax. K.; Ortner, J. Tetrahedron 1998, 54, 4839). In the reference, nitromethane:water was used as a solvent, which may account for better yields (68% D-arabmo and 7% of the D-nbo isomer). Alternatively, acetone water can be used, which may account for better selectivity.
Optionally protected 2-deoxy-2-fluoro-L-arabmopyranose can then be deprotected if necessary. For example, deacetylation of 3,4-di-0-acetyl-2-deoxy-2-fluoro-L-arabinopyranose was (17, Figure 1) can be achieved with NaOMe m methanol in one hour at room temperature. The desired unprotected 2-deoxy-2-fluoro-L-arabmopyranose (18) was obtained as an oil in a 100% yield. ^-NMR and 13C-NMR are coincident with the ones described m the literature for the D-isomer (Bols. M.; Lundt, I. Acta Chem. Scand. 1990, 44, 252) The D-isomer of IS was previously made by three different groups but m a less efficient way.
Treatment of unprotected 2-deoxy-2-fluoro-L-arabmopyranose with one equivalent of either sulfuric or hydrochloric acid at room temperature failed to give the desired furanoside Only unreacted starting material was detected. Using nine equivalents of hydrochloric acid gave the desired product 2-deo\y-2-fluoro-L-arabinofuranose, which was contaminated with starting material (2:1 ratio). The best
result, so far, was achieved by refluxing 2-deoxy-2-fluoro-L-arabinopyranose with 1 equivalent of sulfuric acid in dry methanol. After 6 hours all of the starting material had disappeared affording 2-deoxy-2-fluoro-L-arabinofuranose as an oil in 80% yield. ]H-, 13C- and 19F-NMR indicated a 3:1 a:{3 mixture of anomers, with some minor impurities L-ribo- and L-arabmopyranoside as well as L-ribofuranoside are the possible side products. The D-isomer of 2-deoxy-2-fluoro-L-arabinofuranose was previously made by two different groups, but in less efficient ways (Wright, J. A.; Taylor, N. F.; Fox, J. J. J Org Chem 1969, 34, 2632. and Wysocki, R. J.; Siddiqui, M. A.; Barchi, J. J., Dnscoll, J. S.; Marquez, V. E Synthesis 1991, 1005).
2-Deoxy-2-fluoro-L-arabmofuranose can then be optionally protected. For example, benzoylation of crude 2-deoxy-2-fluoro-L-arabinofuranose gave a mixture that was resolved by flash column chromatography to afford the a furanoside form of 1-0-methyl-2-deoxy-2-fluoro-3,5-di-O-benzoyl-L-arabinofumaoside (20) as an oil m 44% yield. Other fractions were isolated and have been characterized and the corresponding ß-L-arabmofuranoside derivative was detected as the major impurity. The same reaction is described for the D-isomer (7. Med. Chem. 1970,13, 269). They partially describe the D-isomer of 20 optical rotation and CHN, but no spectroscopic data was provided. The absolute value for the optical rotation was similar to the one described for the D-isomer: [α]D20=-98 (c 1.0 EtOH) (lit value: [α]D20= + 108 (c 1.8 EtOH for the D-isomer).
Optionally protected 2-deoxy-2-fluoro-L-arabmofuranose can then be activated, preferably via brommation, and coupled to an optionally protected thymine, such as trimethylsilylthymme, to obtain optionally protected 2"-deoxy-2"-fluoro-L-arabino-furanosyl-thymine. For example, the methyl glycoside (20) can be converted to the intermediate bromosugar (21) under FfBr/AcOH condition, which m turn was coupled with silylated thymine (22) under standard conditions affording the known di-0-benzo\l-L-FMAU (23) in 42% crude yield (30% after crystallization from EtOH) The 1H-NMR was identical to the ones described in the literature for the L- and D-isomers (Du, J : Choi, Y., Lee, K.; Chun. B. K.; Hong. J. H.; Chu, C. K. Nucleosides and Nucleotides 1999, 75, 1S7), and to a reference sample (Ma, T.; Pai, S. B.; Zhu, Y. L.. Lin, T. S.; Shanmunganathan, K.; Du, J. F.; Wang, C.-G.; Kim, H.; Newton. G.M., Cheng, Y.-C; Chu, C. K J. Med. Chem. 1996, 39, 2S35.; and Du. J.; Choi, Y.; Lee, K.; Chun, B. K.; Hong, J. H.; Chu, C. K Nucleosides and Nucleotides 1999, 18, 187, and Tan, C. H.;
Brodfuehrer, P.R.; Brundidge, S. P.; Sapmo, C; Howell, H. G. J. Org. Chem. 1985, 50, 3647). However, the melting point (160°C) was identical to the reference sample but differs with the values published in the literature: 120-122°C for the D-isomer and 118-120°C for the L-isomer (Tan, C. H.; Brodfuehrer, P.R.; Brundidge, S. P.; Sapmo, C; Howell, H. G. J. Org. Chem. 1985,50, 3647.; and Du, J.; Choi, Y.; Lee, K.; Chun, B. K.; Hong, J. H, Chu, C. K. Nucleosides and Nucleotides 1999,18. 187)
The optionally protected 2"-deoxy-2"-fluoro-L-arabino-furanosyl-thymine can then be deprotected, if necessary. For examples, di-O-benzoyl-L-FMAU (23) can be debenzoylated with n-butylamme in refluxmg methanol reducing the reaction time to 3 hours, from the 24 or 48 hours required when ammonia was used at room temperature (Ma, T.; Pai. S. B.; Zhu, Y. L.; Lin, T S.: Shanmunganathan, K.; Du, J. F.; Wang, C.-G.; Kim, H.; Newton, G.M.; Cheng, Y.-C; Chu, C. K J. Med Chem. 1996, 39, 2835, and Du, J.; Choi. Y.; Lee, K: Chun, B. K: Hong, J. H.; Chu, C. K. Nucleosides and Nucleotides 1999, IS, 187). Yield of L-FMAU (24) was 77%. Melting point: 1S8°C (lit. mp 185-187° C, 1S4-185°C, 187-188°C) for the D-isomer; [α]D20 = -93 (c 0.25 MeOH) (lit value: [α]D20 = -111 (c 0.23 MeOH), [α]D20 = -112 (c 0.23 MeOH)); !H-NMR was identical to the ones described in the literature and to a reference sample (Ma, T.; Pai, S. B.; Zhu, Y. L.; Lin, T. S.; Shanmunganathan, K.; Du, J. F.; Wang, C.-G.; Kim, H; Newton, G. M.; Cheng, Y.-C; Chu, C. K. J. Med. Chem. 1996, 39. 2835; and Du, J.; Choi, Y.; Lee, K.; Chun, B. K.; Hong, J H; Chu, C. K. Nucleosides and Nucleotides 1999,18, 187; and Tan, C. H; Brodfuehrer, P. R.; Brundidge, S. P.; Sapino, C; Howell, H. G. J. Org. Chem. 1985,50, 3647).
EXAMPLES
Melting points were determined in open capillary tubes on a Gallenkamp MFB-595-010 M apparatus and are uncorrected The UV absorption spectra were recorded on an Uvikon 931 (KONTRON) spectrophotometer m ethanol. "H-NMR spectra were run at room temperature in DMSO-d6 with a Bruker AC 250 or 400 spectrometer. Chemical shifts are given m ppm, DMSO-Jj being set at 2.49 ppm as reference. Deuterium exchange, decoupling experiments or 2D-COSY were performed in order to confirm
proton assignments. Signal multiplicities are represented by s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quadruplet), br (broad), m (multiplet). All J-values are in Hz FAB mass spectra were recorded in the positive- (FAB>0) or negative-(FAB Example 1
1,2,3,4-tetra-O-acetyl-L-arabinopyranose (14)
To a well stirred suspension of L-arabmose (13) (lOOg, 0.67 mol) m dry pyridine (270 mL) at 0°C, was slowly added acetic anhydride (360 mL, 3SSg, 3.8 mol.) The suspension was then stirred at room temperature for 4 hours, after which it became a light brown colored solution. Excess pyridine and acetic anhydride were removed by azeotropic evaporation with toluene. Crude (14) was obtained as a clear oil, and was used in the next step without any further purification.
Example 2
l-a-Bromo-2,3,4-tri-O-acetyl-L-arabmopyranose (15)
Crude tetra-O-acetyl-L-arabmopyranose (14) was dissolved in a mixture of 30% wt HBr m AcOH (400 mL, 2.0 mol) and acetic anhydride (8.0 mL). The solution was stirred at room temperature for 36 hours. The reactrem mixtures was diluted with methylene chloride (400 mL), and successively washed with- water (3 x 600 mL). saturated NaHC03 (2 x 500 mL) and water (3 x 600 mL), dried, filtered and evaporated to a syrup that was crystallized from ethyl ether to afford (14) (129 g, 0.3S0 mol, 57% from 13), as a white solid" 1H-NMR (CDC13) δ 6.67 (1H, d, J = 3.8, H-l), 5 37 (2H, m) and 5.06 (1H, m) (H-2, H-3 and H-4), 4.18 (1H, d, J = 13.3, H-5), 3.91 (1H, dd, J = 13 3 and J = 1.7, H-5"), 2.13 (3H, s, CH3COO), 2.09 (3H, s, CH3COO), 2.01 (3H, s. CH3COO).
Example 3
3,4-di-O-acetyl-L-arabinal (16)
To a well stirred solution of NaOAc (35 g, 0.43 mol) and AcOH (115 mL) in water (200 mL) at -5°C, was slowly added a solution of CuSO4-5H2O (7 g, 28 mmol) in water (23 mL), and then Zn dust (70 g, 0.11 mol) in portions, maintaining the temperature at or below -5°C. To this suspension was added the bromo sugar 15 (34 g. 0.10 mol) in portions and the mixture stirred vigorously for 3 hours at -5°C and then overnight at room temperature. The mixture was filtered and washed with water (250 mL) and methylene chloride (250 mL). The phases were separated, and the aqueous layer washed with methylene chloride (2 x 125 mL). The combined organic layers were successively washed with: water (2 x 250 mL), saturated NaHCO3 (2 x 1250 mL) and water (2 x 250 mL), dried, filtered, and evaporated to a colorless syrup (-20 g). The syrup was purified by flash column chromatography (300 g silica gel, hexane:EtOAc 4:1) to afford 16 (12.0 g, 60 mmol, 60%) as a colorless syrup: 1H-NMR (CDCI3) 56 48 (lH,d, J = 6.0 H-l), 5.44 (1H, m, H-3), 5.19 (1H, dt J = 4, J = 4, J - 4, J
= 9, H-4), 4.83 (1H, dd, J = 5, J = 6, H-4), 4.00 (2H, m, H-5 and H-5"), 2.08 (3H, s, CH3COO), 2.07 (3H, s CH3COO).
Example 4
3,4-di-0-acetyl-2-deoxy-2-fluoro-L-arabinopyranose (17)
To a well stirred solution of glycal (16) (12.0 g, 60 mmol) m acetone water (4:2 v:v, 120 mL) was added selectfluor " (26 g, 73 mmol). The solution was stirred overnight at room temperature. The solution was then heated at reflux for 1 hour to complete the reaction. After cooling to room temperature, the acetone was removed in vacuo. Water (150 mL) was added and extracted with EtOAc (3 x 150 mL). The combined organic fractions were successively washed with: IN HC1 (2 x 200 mL), and water (2 x 200 mL) dried, filtered, and evaporated to afford 17 (6 0 g, 25 mmol, 42%) as a syrup: I3C-NMR (CDCI3 5 170.35 (CH3COO), 170.27 (CH3COO), 95.01 (C-lα, d, Jc. I.F= 24.5), 90 81 (C-lß, d, JC-1,F = 21.5), 89.10 (C-2α, d, JC-2,F = 184.3), 85.85 (C-2{3d, Jc. 2.F= 188.0), 70.61 (C-3as d, JC-3,F= 19.5), 69.57 (C-4p, d, JC-4,F= 7.7), 68.66 (C-4a, d, Jc. 4,F= 8.3), 67.53 (C-3P, d, JC-3,F= 17.8), 63.90 (C-5a), 60.26 (C-5P), 20.73 (CH3COO), 20.67 (CH3COO). 20 62 (CHC3COO), 20.56 (CH3COO).
Anal. Calcd. for C9H13O6F: C, 45.77; H, 5.55. Found: C, 45.64; H. 5.51.
Example 5
2-deoxy-2-fluoro-L-arabinopyranose (18)
A solution of 17 (5.7 g, 24.1 mmol) in dry methanol (220 mL) was treated with 0.1 N NaOMe in methanol (114 mL, 114 mmol) and stirred for 1 hour at room temperature. The solution was then neutralized with DOWEX 50W X8-100, filtered and evaporated to afford 18 (3.7 g, 24 mmol, 100%) as a yellow syrup: 13C-NMR (D2O) 5 94 19 (C-la, d, JC-I-F = 23.0), 92.24 (C-2a, d, JC-2.F= 179.6). 90.10 (C-lp, d, JC-I,F = 20.3), S8 60 (C-2p, d, JC-2,F= 1S2.3), 70 77 (C-3α, d, JC-3.F= 18 2). 69.03 (C-4p, d, JC.4F=
8.0), 68.90 (C-4a, d, JC-4,F= 10.2), 66.85 (C-3ß, d, JC-3,F = 18.2), 66.32 (C-5α), 62.21 (C-5ß).
Example 6
l-0-meihyl-2-deoxy-2-fluoro-L-arabviofuranoside (19)
A solution of is (790 mg, 5 2 mmol) and H2SO4 (60 1 µL, 1 1 mmol) in dry methanol (12.2 niL) was treated at reflux for 6 hours The reaction was cooled to room temperature, neutralized with DOWEX SBR. filtered and evaporated, to afford 19 (700 mg, 4.21 mmol, 80%) as a syrup: 13C-NMR (CD3OD) δ 107 48 (C-la, d, Jc.i,F= 35.6). 103.20 (C-2α, d, JC-2,F = 178.8), 101 98 (C-lß d, JC-I,F= 16.8), 96 80 (C-2ß, d, JC-2,F = 199.3). 85.15 (C-4a. d, JC-3,F = 5 0), 83.69 (C-4(3, d, JC-4,F= 10.7), 76.70 (C-3α, d, JC.4,F = 27.0), 74 54 (C-3p. d, JC-3,F= 21.5), 65.00 (C-5p), 62.52 (C-5α). 55.58 (OCH3ß), 54.94 (OCH3α)
Example 7
l-O-methyl-2-deoxy-2-fluoro-3,5-di-O-benzoyl-L-arabinofnranoside(20)
To a well stirred solution of 19 (664 mg, 4 mmol) in dry pyridine (10 mL) at 0°C, was slowly added benzoyl chloride (2.5 mL. 3.0 g, 21.5 mmol). After stirring for 30 minutes at 0°C, it was left at room temperature for 3 hours. The reaction was quenched with water (10 mL) and saturated NaHCO3 (30 mL) and stirred for 30 minutes. It was then diluted with methylene chloride (50 mL) and more saturated NaHCO3 (30 mL). The organic layer was separated and successively washed with: saturated NaHC03 (50 mL), water (2 x 50 mL), IN HC1 (2 x 50 mL), water (50 mL), saturated NaHCO3 (50 mL) and water (2 x 50 mL), dried, filtered and evaporated to a brown syrup (1.9 g), that was purified by flash column chromatography (50 g silica gel, hexane:EtOAc 95:5). A major faction was isolated as a syrup and characterized as 20 (a anomer, 670 mg, 1.79 mmol, 44%): [α]D20 = -9S (c 1.0 EtOH) (lit. value: [α]D20= + 108 (c 1.8 EtOH) for the D-
isomer); 1H-NMR (CDC13) δ 8.20 - 7.40 (15 H, m, ArH), 5.48 (1H, dd, J = 23.1, H-3), 5.21 (1H, d, J = 10.6, H-l), 5.11 (1H, d, J = 49.2, H-2), 4.76 (lH,dd, J = 3.6 and J = 12.0, H-5), 4.63 (1H, dd, J = 4.4 and J = 12.0, H-5"), 3.45 (3H, s, OCH3); I3C-NMR (DC13) δ 166 20 (C = O), 165.67 (C = O), 133 57 (Ar), 133 07 (Ar), 129.87 (Ax), 129.76 (Ar), 128.49 (Ar), 128.31 (Ar). 106.22(C-l,dJc-3.F= 35.1). 98.20 (C-2, d, JC.2,F = 182.7), SO 85 (C-4), 77 58 (C-3,dJC-3,F= 30 44), 63.62 (C-5), 54.86 (OCH3).
Anal. Calcd. For C2OH19O6F: C, 64.17, H, 5 12 Found: C, 64.14; H, 5.08
Example 8
l-(3,5-di-0-benzoyl-2-deoxy-2-fluoro-ß-L-arabinofuranosyl) thymine (23)
To a well stirred solution of 20 (289 mg, 0.75 mmol) in dry methylene chlonde (0.56 mL) at 0°C, was slowly added 30% \vt HBr in AcOH (0.8 mL, 1.0S g, 0.32 g of HBr, 4.0 mmol) The solution was then stared at room temperature overnight. The brown-red solution was evaporated under vacuum at or below 40°C. It was then coevaporated with dry benzene (3x3 mL) and then once with dry chloroform (3 mL). Bromosugar 21, a syrup, was redissolved in dry chloroform (2 mL): solution A. At the same time a mixture of thymine (25, 208 mg, 1 65 mmol), ammonium sulfate (19 mg), and 1,1,1,3,3,3-hexamethyldisilazane (798 mg, 1.04 mL, 4.95 mmol) in dry chloroform (7.12 mL) was heated at reflux overnight The resulting clear solution, (an indication that all the thymine was silylated to form compound 22) was cooled to room temperature: solution B. Solution A was added to solution B and heated at reflux for 4 hours. Water (10 mL) was added, and the mixture stirred for 20 minutes. Chloroform (10 mL) was added, the organic phase separated, washed with water (2 x 10 mL), dried, filtered and evaporated to a syrup that was purified by flash column chromatography (hexane: EtOAc 1:1). Crude 23 (150 mg, 0.32 mmol, 42%) was obtained as a solid. It was crystallized from EtOH to afford pure 23 (100 mg, 0.22 mmol, 30%) as a white solid: mp 160°C was identical to an original sample of 23 (lit. value: mp 120-122°C for the D-isomer and 11S-120°C for the L-isomer); 1H-NMR (CDC13) δ 8.52 (1H. bs, N-H). 8.13-7.43 (10H, m, ArH), 7.36 (1H, q, J = 1), C-H thymine, 6.35 (1H, dd, J = 3.0 and J = 22.2, H-l), 5.64 (1H, dd, J = 3.0 and J = IS 0, H-3), 5.32 (1H, dd, J = 3.0 and J = 50 0,
H-2), 4.86-4.77 (2H, m, H-5 and H-5"), 4.49 (1H, q, H-4), 1.76 (3H, d, J = 1.0, Thymine CH3).
Example 9
l-(2-deoxy-2-fluoro-ß-L-arabinofuranosyl)lhymine (24)
A solution of 23 (47 mg, 0 1 mmol) and n-butylamme (0.74 g, 1.0 mL. 10 mmol) in methanol (2 mL) was heated at reflux for 3 hours. The solution was evaporated to dryness and triturated with ethyl ether to afford a solid that was filtered, washed with ether and dried to afford 24 (20 mg, 0.077 mmol, 77% as a white solid: mp 188°C (lit. value: mp 185-187°C. 184-1S5°C, 187-188°C for the D-isomer); [α]D20 = -93 (c 0 25 MeOH); (lit. value: [α]D20 = -111 (c 0.23 MeOH), [α]D20 = -122 (c.023 MeOH)), ]H-NMR (DMSO-dfi) 8 11.0 (1H, bs, N-H, 7.58 (1H, s, C-H thymine), 6.09 (1H. dd, J = 4.2 and J = 15.6, H-l), 5.85 (1H, bs, OH), 5.10 (1H, bs, OH), 5.02 (1H, dt, J - 4.0, J - 3.8 and J - 52.8, H-2), 4.22 (1H, dt, J - 3.8, J- 4.0 and J = 20.3, H-3), 3.76 (1H, q, J = 4.0 and J -9.5, H-4), 3.69-3.57 (2H, m, H-5 and H-5"), 1.77 (3H, s, Thymine CH3).
Many modifications and other embodiments of the invention will be apparent to one skilled in the art to which this invention pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the invention is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

WE CLAIM:
1. A process for the preparation of a 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside of the formula (I):
(Formula Removed)
wherein X is a halogen (F, CI, Br or I); and B is a pyrimidine, purine, heterocyclic or heteroaromatic base; by preparing a 2-deoxy-2-halo-L-arabinofuranose comprising the steps of:
(a) obtaining a 2-deoxy-2-halo-L-arabinopyranose of the formula (II):
(Formula Removed)
wherein each of R1 and R2 is independently hydrogen, alkyl, acyl or silyl; and
(b) converting the 2-deoxy-2-halo-L-arabinopyranose to the 2-deoxy-2-halo-
L-arabinofuranose.
2. The process of claim 1, wherein the process further comprises the steps of:
(a) optionally substituting OR1 of the 2-deoxy-2-halo-L-arabinofuranose with O-acyl or a halogen (F, Br, CI or I);
(b) coupling the arabinofuranose to an optionally protected pyrimidine, purine, heterocyclic or heteroaromatic base; and
(c) deprotecting, if necessary, to obtain the 2"-deoxy-2"-halo-J3-L-arabinofuranosyl nucleoside.
3. The process of claim 1, wherein the process further comprises the process for the
preparation of the 2-deoxy-2-halo-L-arabinopyranose of the formula (II) comprising the steps of:
(a) obtaining an optionally protected L-arabinal of the formula (III)
(Formula Removed)
wherein each of R3 is independently hydrogen, alkyl, acyl or silyl;
(b) halogenating the compound of formula (III) and deprotecting, if
necessary, to form the 2-deoxy-2-halo-L-arabinopyranose of the formula
(II).
4. The process of claim 1, wherein the process further comprises the process for the preparation of the 2-deoxy-2-halo-L-arabinopyranose of the formula (II) comprising the steps of:
(a) obtaining an optionally protected L-arabinose of the formula (IV):
(Formula Removed)
wherein each of R3 and R is independently hydrogen, alkyl, acyl or silyl;
(b) substituting OR1 with a halogen (F, Br, CI or I), to obtain a compound of
the formula (V);
(Formula Removed)
wherein X1 is a halogen (F, Br, CI or I);
(c) reducing the compound of formula (V) to form a compound of formula
(III)
(Formula Removed)
(d) halogenating the compound of formula (III) and deprotecting if necessary
to form the 2-deoxy-2-halo-L-arabinopyranose of the formula (II).
5. A process for the preparation of a 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside of the formula (I):
(Formula Removed)
wherein X is a halogen (F, CI, Br or I); and B is a pyrimidine, purine, heterocyclic or heteroaromatic base; comprising the steps of:
(a) obtaining an optionally protected L-arabinose of the formula (IV):
(Formula Removed)
wherein each of R1, R2, R3 and R4 is independently hydrogen, alkyl, acyl or silyl;
(b) substituting OR1 with a halogen (F, Br, CI or I), to obtain a compound of
the formula (V);
(Formula Removed)
wherein X1 is a halogen (F, Br, CI or I);
(c) reducing the compound of formula (V) to form a compound of formula
an)
(Formula Removed)
(d) halogenating the compound of formula (III) and deprotecting if necessary
to form the 2-deoxy-2-halo-L-arabinopyranose of the formula (II):
(Formula Removed)

wherein X is a halogen (F, Br, CI or I);
(e) converting the 2-deoxy-2-halo-L-arabinopyranose to a 2-deoxy-2-halo-L-arabinofuranose;
(f) optionally substituting OR1 with O-Acyl or a halogen (F, Br, CI or I);
(g) coupling the arabinofuranose to an optionally protected pyrimidine, purine, heterocyclic or heteroaromatic base; and
(h) deprotecting, if necessary, to obtain the 2"-deoxy-2"-halo-ß-L-arabinofuranosyl nucleoside.
6. A process for the preparation of 2"-deoxy-2"-fluoro-(3-L-arabinofuranosyl
thymine (L-FMAU) by preparing a 2-deoxy-2-halo-L-arabinofuranose
comprising the steps of:
(a) obtaining a 2-deoxy-2-fluoro-L-arabinopyranose of the formula (H-a):
(Formula Removed)
wherein each of R1 and R2 is independently hydrogen, alkyl, acyl or silyl; and
(b) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-
fluoro-L-arabinofuranose.
7. The process of claim 6, wherein the process further comprises the steps of:
(a) optionally substituting OR1 with O-acyl or a halogen (F, Br, CI or I);
(b) coupling the arabinofuranose to an optionally protected thymidine; and
(c) deprotecting, if necessary, to obtain the 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymidine.
8. The process of claim 6, wherein the process further comprises the process for the preparation of the 2-deoxy-2-fIuoro-L-arabinopyranose of the formula (II-a) comprising the steps of:
(a) obtaining an optionally protected L-arabinal of the formula (III)
(Formula Removed)
wherein each of R is independently hydrogen, alkyl, acyl or silyl;
(b) fluorinating the compound of formula (III) and deprotecting, if necessary,
to form the 2-deoxy-2-fluoro-L-arabinopyranose of the formula (Il-a).
9. The process of claim 6, wherein the process further comprises the process for the preparation of the 2-deoxy-2-fluoro-L-arabinopyranose of the formula (II-a) comprising the steps of:
(a) obtaining an optionally protected L-arabinose of the formula (IV):
(Formula Removed)
■a A
wherein each of R and R is independently hydrogen, alkyl, acyl or silyl;
(b) substituting OR1 with a halogen (F, Br, CI or I), to obtain a compound of
the formula (V);
(Formula Removed)
wherein X1 is a halogen (R Br, CI or I);
(c) reducing the compound of formula (V) to form a compound of formula
an)
(Formula Removed)
(d) fluorinating the compound of formula (III) and deprotecting if necessary
to form the 2-deoxy-2-fluoro-L-arabinopyranose of the formula (II-a).
10. A process for the preparation of 2"-deoxy-2"-fluoro-|3-L-arabinofuranosyl thymine (L-FMAU) comprising
(a) obtaining an optionally protected L-arabinose of the formula (IV):
(Formula Removed)
wherein each of R1, R2, R~ and R4 is independently hydrogen, alkyl, acyl or silyl;
(b) substituting OR1 with a halogen (F5 Br, CI or I), to obtain a compound of
the formula (V);
(Formula Removed)
wherein X1 is a halogen (F, Br, CI or I);
(c) reducing the compound of formula (V) to form a compound of formula
(HI)
(Formula Removed)
(d) fluorinating the compound of formula (III) and deprotecting if necessary
to form the 2-deoxy-2-fluoro-L-arabinopyranose of the formula (II-a);
(Formula Removed)
(e) converting the 2-deoxy-2-fluoro-L-arabinopyranose to a 2-deoxy-2-fluoro-L-arabinofuranose;
(f) optionally substituting OR1 with O-Acyl or a halogen (F, Br, CI or I);
(g) coupling the arabinofuranose to an optionally protected thymine; and
(h) deprotecting, if necessary, to obtain the 2"-deoxy-2"-fluoro-ß-L-arabinofuranosyl thymidine.
11. The process of any one of claims 1-10, wherein the halogenation of the compound of formula (III) is accomplished in nitromethanerwater.
12. The process of any one of claims 1-10, wherein the halogenation of the compound of formula (III) is accomplished in acetonerwater.
13. The process of any one of claims 1-10, wherein the conversion of the L-arabinopyranose to the L-arabinofuranose is accomplished using one equivalent of sulfuric acid.
14. The process of any one of claims 1-10, wherein the conversion of the L-arabinopyranose to the L-arabinofuranose is accomplished in dry methanol.
15. The process of any one of claims 6-10, wherein the fluorination of the compound of formula (III) is accomplished using selectfluor™ (F-TEDA-BF4).
16. A process for the preparation of a 2"-deoxy-2"-halo-ß-L-
arabinofuranosyl nucleoside of the formula (I) substantially as
herein described with reference to the foregoing description and
the accompanying examples and drawing.
17. A process for the preparation of 2"-deoxy-2"-fluoro-ß-L-
arabinofuranosyl thymine (L-FMAU) by preparing a 2-deoxy-2-halo-
L- arabinofuranose comprising the steps of substantially as herein
described with reference to the foregoing description and the
accompanying examples and drawing.
18. A process for the preparation of 2"-deoxy-2"-fluoro-ß-L-
arabinofuranosyl thymine (L-FMAU) comprising substantially as
herein described with reference to the foregoing description and
the accompanying examples and drawings.

Documents:

1609-delnp-2003-abstract.pdf

1609-delnp-2003-assignment.pdf

1609-DELNP-2003-Claims (25-09-2009).pdf

1609-delnp-2003-claims.pdf

1609-delnp-2003-complete specification (granted).pdf

1609-delnp-2003-correspondence-others.pdf

1609-delnp-2003-correspondence-po.pdf

1609-delnp-2003-description (complete).pdf

1609-delnp-2003-form-1.pdf

1609-delnp-2003-form-13.pdf

1609-delnp-2003-form-19.pdf

1609-delnp-2003-form-2.pdf

1609-delnp-2003-form-3.pdf

1609-delnp-2003-form-5.pdf

1609-delnp-2003-gpa.pdf

1609-delnp-2003-pct-101.pdf

1609-delnp-2003-pct-210.pdf

1609-delnp-2003-pct-220.pdf

1609-delnp-2003-pct-304.pdf

1609-delnp-2003-pct-306.pdf

1609-delnp-2003-pct-308.pdf

1609-delnp-2003-pct-401.pdf

1609-delnp-2003-pct-409.pdf

1609-delnp-2003-pct-416.pdf

1609-delnp-2003-petition-137.pdf

1609-delnp-2003-petition-138.pdf

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Patent Number

209097

Indian Patent Application Number

01609/DELNP/2003

PG Journal Number

35/2007

Publication Date

31-Aug-2007

Grant Date

20-Aug-2007

Date of Filing

07-Oct-2003

Name of Patentee

TRIANGLE PHARMACEUTICALS, INC

Applicant Address

4 UNIVERSITY PLACE, 4611 UNIVERSITY DRIVE, DURHAM, NC 27707-4674 U.S.A.

Inventors:

#	Inventor's Name	Inventor's Address
1	SZNAIDMAN, MARCOS	5222 GREYFIELD BOULEVARD, DURHAM, NC 27713, USA
2	N. A.	N.A.

PCT International Classification Number

C07H 15/04

PCT International Application Number

PCT/US02/09848

PCT International Filing date

2002-03-29

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/280,307	2001-03-30	U.S.A.