PROCESS FOR PREPARATION OF 2'-FLUORO-5-METHTh- -L-ARABINO- FURANOSYLURIDINE TECHNICAL FIELD The present invention relates to an improved process for preparing <BR> <BR> <BR> 2' -fluoro-5-methyl- -L- -L-arabinofuranosyluridine(generic name: Levovir, hereinafter referred to as "L-FMAU") represented by formula (1), which shows anti-viral activity, especially potent anti-viral activity against hepatitis B-virus(HBV) and Epstein-Bar virus(EBV): BACKGROUND ART Various nucleoside compounds, including L-FMAU of formula (1) have been disclosed (see, for example, International Publication No. WO 95/20595): in which

R' represents purine or pyrimidine base; and R" represents hydrogen, acyl, alkyl, monophosphate, diphosphate or triphosphate.

Nucleoside compounds of formula (2) exhibit anti-viral activity against HBV and EBV. Among these nucleoside compounds, L-FMAU shows particularly potent anti-viral activity against HBV and EBV with very low cytotoxicity and is, therefore, preferred as an anti-viral agent.

Nucleoside compounds of formula (2), including L-FMAU, are useful in the prevention and treatment of HBV infections and related conditions, such as anti-HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. In addition, they can also be used for the treatment of EBV-associated disorders.

According to the method disclosed in International Publication No.

WO 95/20595, L-FMAU of formula (1) may be prepared using L-xylose of formula (3) as a starting material L-xylose of formula (3) cannot be obtained from natural substances and must therefore be produced by synthetic methods. When L-xylose is used as the starting material, the production cost of L-FMAU is therefore very high.

OBJECT OF INVENTION It has been discovered that L-FMAU can be economically prepared from L-arabinose, which is present in many natural substances and, thus, is an inexpensive starting material, thereby completing the present invention.

SUMMARY OF THE INVENTION An improved process for preparing L-FMAU is provided which used L-arabinose as the starting material.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a schematic diagram of one method for the production of L-FMAU according to the disclosed process.

BRIEF DESCRIPTION OF THE INVENTION The term alkyl, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of C1 to C10 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-dimethylbutyl. The alkyl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., "Protective Groups in Organic Synthesis," John Whiley and Sons, Second Edition, 1991. The term lower alkyl, as used herein, and unless otherwise specified, refers to a C1 to C4 saturated straight or branched alkyl group.

The term aryl, as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphtyl, and preferably phenyl. The aryl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, 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.

The term aralkyl or arylalkyl refers to an aryl group with an alkyl substituent.

The term acyl refers to moiety of the formula -C(O)Rl, wherein Rl is alkyl; alkyoxyalkyl including methoxymethyl; arylalkyl including benzyl; aryloxyalkyl such as phenoxymethyl; aryl including phenyl optionally substituted with halogen, C1 to C4 alkyl or C1 to C4 alkoxy.

According to the present invention, the desired compound, L-FMAU, of formula (1) can be economically prepared from the starting material of formula (4) by a process that utilizes the reaction set out in Figure 1, wherein: a) the starting material, L-arabinose of formula (4), is reacted with a compound of formula (18) to obtain a compound of formula (5); b) the compound of formula (5) is condensed with a compound of formula (19) to obtain the compound of formula (6), which is oxidized to obtain the compound of formula (7), which is then reduced to obtain the compound of formula (8); c) the compound of formula (8) is treated with an acid to obtain the compound of formula (9), which is treated with the compound of formula (18) in the presence of an acid to obtain the compound of formula (10), which is reacted with an acyl-chloride such as benzoyl chloride to obtain the compound of formula (11), which is then reacted with an acid, for example, acetic acid and acetic anhydride in the presence of sulfuric acid to obtain the compound of formula (12); d) the compound of formula (12) is converted into the compound of formula (13); e) the compound of formula (13) is reacted with an agent for introducing a reactive leaving group to obtain the compound of formula (14); f) the compound of formula (14) is fluorinated to obtain the compound of formula (15), which is subjected to halogenation to obtain the compound of formula (16), which is then condensed with a thymine base to obtain the compound of formula (17); and g) the compound of formula (17) is treated with ammonia in methanol to produce the desired L-FMAU of formula (1).

In the above reaction scheme, R represents a hydroxy-protecting group such as alkyl, aryl, halogenoalkyl, aralkyl, etc., R1 and R2 independently of one another represent hydrogen, alkyl or aryl, L represents a reactive leaving group such as imidazolylsulfonyl, toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, etc., and Hal

represents a halogen atom such as chloro or bromo.

The process of the present invention is explained in more detail below.

As illustrated in Figure 1, by reacting the starting material, L-arabinose of formula (4), with an alcohol of formula (18), for example, benzyl alcohol, in the presence of hydrogen chloride gas, the 1-hydroxy group of L-arabinose is protected to produce the compound of formula (5).

In reaction b), the compound of formula (5) prepared in the reaction a) is condensed with a propane derivative of formula (19), for example, 2,2-dimethoxypropane, to produce the compound of formula (6).

The compound of formula (6) is oxidized to produce the compound of formula (7), which is subsequently reduced to produce the compound of formula (8). In this reaction, oxidizing agents which can preferably be used include aqueous chromic acid (CrOs), sodium dichromate (Na2CrO7), pyridinium chlorochromate (POC), pyridinium dichromate (PDC), potassium permanganate (KMnO4), lead tetraacetate/pyridine, oxygen over platinum/ carbon catalyst, Ru04, RuO4/NaIO4, dimethylsulfoxide/dicyclohexylcarbo- diimide (DMSO/DCC) and a proton donor, silver carbonate, triphenyl bismuth carbonate, Oppenauer oxidation (aluminum alkoxides in acetone), chlorine dioxide (C102), dimethylsulfoxide/oxalyl chloride (DMSO/( COCl )2), dimethylsulfoxide/sulfuryl chloride (DMSO/SO2C12), dimethylsulfoxide/ thionyl chloride (DMSO/SOC12), dimethylsulfoxide/toluenesulfonyl chloride (DMSO/TsCl), dimethylsulfoxide/trifluoroacetic anhydride (DMSO/ (CF3CO )20), dimethylsulfoxide/acetic anhydride (DMSO/Ac20), etc.

Among them, pyridinium dichromate in the presence of a solvent such as dichloromethane is particularly preferred. Reducing agents which can preferably be used include sodium borohydride (NaBH4), diisobutyl- aluminum hydride (DIBAL-H), lithium borohydride (LiBH4), sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), lithium aluminum hydride (LiAlH4), potassium borohydride (KBH4), Raney nickel, rhodium/ hydrogen (H2), palladium/hydrogen, platinum/hydrogen, rubidium/hydrogen,

rubidium-silica/hydrogen, etc. Among them, sodium borohydride (NaBH4) is particularly preferred.

In reaction c), the compound of formula (8) is treated with an acid such as trifluoroacetic acid to remove the hydroxy-protecting group of the compound(8) and thereby produce the compound of formula (9), which is then treated with the compound of formula (18) in the presence of an acid, for example, methanol in the presence of hydrochloric acid to produce the compound of formula (10), which has a ribofuranose structure. The compound of formula (10) is then reacted with an acylchloride such as benzoyl chloride in the presence of a base to protect all the hydroxy groups of the compound of formula (10) with benzoyl groups, thereby producing the compound of formula (11). The compound of formula (11) is then treated with an acid such as acetic acid and anhydrous acetic acid in the presence of sulfuric acid to produce the compound of formula (12). The series of reaction steps for preparing the compound of formula (12) from the compound of formula (8) can preferably be practiced consecutively, without isolation of any intermediate.

In reaction d), the compound of formula (12) produced in reaction c) is treated with hydrogen chloride in a solvent such as dichloromethane, cyclohexane, chloroform, etc., and then treated with water in a solvent such as acetonitrile to produce the compound of formula (13). In this reaction, the reaction by-product 1-hydroxy-isomer must be removed by treating with an ether such as dibutyl ether, diethyl ether, etc.

In reaction e), the compound of formula (13) is reacted with an agent for introducing a suitable reactive leaving group, for example, sulfuryl chloride and imidazole, to produce the compound of formula (14).

This reaction can be carried out in the presence of a solvent such as dimethylformamide, dichloromethane, etc.

In reaction f), the compound of formula (14) produced in reaction e) is fluorinated in the presence of a solvent such as ethyl acetate,

thereby substituting the reactive leaving group with fluorine to produce the compound of formula (15). In this reaction, the preferred fluori- nating agent includes potassium hydrogen fluoride (KHF2)/hydrofluoric acid/pyridine or hydrofluoric acid/amine such as triethylamine. The resulting compound of formula (15) is then halogenated, for example, with hydrobromic acid or hydrochloric acid, in the presence of acetic acid to produce the compound of formula (16). The compound of formula (16) is then reacted with thymine base in the presence of hexamethyl- disilazane and ammonium sulfate to produce the compound of formula (17). This reaction can preferably be carried out in the presence of a solvent, for example, chloroform, dichloromethane, 1,2-dichloroethane, acetonitrile, etc.

In reaction g), the compound of formula (17) produced in reaction f) is treated with ammonia in the presence of a solvent to remove the benzoyl group, the hydroxy-protecting group, from rhe compound of formula (17), thereby producing the desired compound L-FMAU.

Although various aspects of the present invention are illustrated by the following examples, the present invention is not in any manner limited by these examples. Other reactants can be used as known to those of ordinary skill, which perform substantially the same function.

In the examples, the number of the compound in parentheses corresponds to the number in the reaction scheme A.

Example 1 : Prenaration of 1-O-benzvl- B -L-arabinoside (5) Benzyl alcohol 1000nrQ was saturated with hydrogen chloride for 40 minutes at 0°C, 200g(1.33 mole) of L-arabinose was added and the resulting mixture was stirred at room temperature for 10 hours, during which a quantity of the compound (5) precipitated. To induce additional precipitation, 1.5 f of ethyl acetate was slowly added while the mixture was stirred. The resulting solid product was filtered, washed with ethyl acetate and then dried in air to obtain 300g (Yield : 94%) of the title compound (5) in the form of a white solid.

m.p. : 170-171°C H NMR 8 (ppm) : 3.46(q, 1H, J=2.87, 11.8), 3.63-3.73(m, 4H), 4.45(d, 1H, J=12.8), 4.76(d, 1H, J=12.32), 7.29-7.38 (m, 5H) Example 2 : Prenaration of l-O-benzvl-3.4-O-isoDroDvlidene- -L-riboside (8) A mixture of 200g(0.83 mole) of 1-O-benzyl- P -L-arabinoside (5), 240my(1.95 mole) of 2,2-dimethoxypropane and 4g(0.02 mole) of p-TsOH 1120 in 2000me of acetone was stirred at room temperature for 2 hours.

The reaction mixture thereby obtained was neutralized with triethylamine and evaporated under reduced pressure to obtain the compound (6) in the form of a yellowish syrup, which was used for the next reaction without further purification.

To a mixture of the compound (6) and 240g(0.63 mole) of pyridinium dichromate in 2000mQ of dichloromethane was added 240my(2.54 mole) of acetic anhydride at 0°C and the mixture thereby obtained was then refluxed until the starting material disappeared (ca. 4 hours). At this time, the system was vented. The solvent was removed under reduced pressure until the mixture occupied one-third of its initial volume and the residue was poured into 1500mQ of ethyl acetate with vigorous stirring accomplished using a mechanical stirrer. The mixture thus obtained was filtered through a celite pad and the filter cake was thoroughly washed with ethyl acetate. The blackish combined filtrate was filtered through a silica gel (2-20 micron) column (20cm height, 10cm diameter). The silica gel was washed with ethyl acetate until the compound (7) was no longer detected by TLC. The clear combined filtrate thereby obtained was evaporated to yield the compound (7) in the form of a syrup, which was coevaporated twice with toluene.

The purified syrup (7) thus obtained was dissolved in 2000mQ of methanol and cooled to -20°C. 40g(1.06 mole) of NaBH4 pellets were very slowly added to the resulting solution over 3 hours at -20°C. After

completion of the reaction, the solution was neutralized with acetic acid, evaporated under reduced pressure to obtain a white solid residue. The residue was partitioned between 1000mQ of ethyl acetate and 200mQ of water. The aqueous layer was extracted with 100me of ethyl acetate.

The combined organic layer was washed with 200mQ of brine, dried over MgSO4 and then evaporated to yield a white solid, which was recrystallized from 700mQ of hot hexane to yield 123g (Yield : 53% from the compound (5)) of the compound (8) in the form of a white crystal.

m.p. : 79-80"C []25D = +143° (c 0.7, ethanol) H NMR 8 (ppm) : 1.37(s, 3H), 1.55(s, 3H), 2.37(d, 1H, J=6.45), 3.71-3.76 (m, 2H), 3.86(q, 1H, J=3.44 and 12.89), 4.27-4.30(m, 1H), 4.49-4.52(m, 1H), 4.56(d, 1H, J=11.8), 4.83(d, 1H, J=11.8), 4.86(d, 1H, J=5.40), 7.26-7.36(m, 5H) Example 3 : Prenaration of 1-0-acetvl-2.3.5-tri-O-benzovl- ribofuranose (12) 201g(0.717 mole) of the compound (8) dissolved in 1000me of 4% trifluoroacetic acid(CF3COOH) was refluxed until the starting material (ca.

1 hour) and the intermediate (1-O-benzyl derivative) had disappeared (ca.

4-8 hours). The reaction mixture was cooled to room temperature and washed with dichloromethane (4X500mQ) to remove benzyl alcohol. The aqueous layer thereby obtained was evaporated in vacuo and coevaporated with toluene (2 x 200mQ) to yield the compound (9) in the form of a yellowish syrup, which was completely dried under high vacuum to remove a trace amount of water.

The compound (9) was dissolved in 2000mQ of methanol and 15.8g(0.43 mole) of HCl (gas) was bubbled into the mixture at room temperature. The mixture thereby obtained was stirred at room temperature for 2 hours, neutralized with 183me of pyridine and concentrated in vacuo at 30-35C to give a yellowish syrup, which was in turn coevaporated with pyridine to yield the compound (10) in the form

of a yellowish syrup. The compound (10) was dissolved in 800mQ of pyridine and 212me of benzoyl chloride was added dropwise to the mixture at 0°C. The mixture was stirred at room temperature for 8 hours.

After the reaction had gone almost to completion, the mixture was heated at 45"C for 1.5 hour. The mixture was cooled to room temperature and ice was added to remove the remaining benzoyl chloride. Pyridine was evaporated from the mixture at 35-40C until the mixture occupied half of its initial volume. The residue was dissolved in 1500mQ of ethyl acetate, which was washed in succession with 500me of cold water, 576mQ of cold 3N H2SO4, 500mQ of aqueous sodium bicarbonate (x2), and 500mQ of brine, in that order. The organic layer was dried over MgSO4 and activated carbon, filtered through a silica gel (2-20 p) pad and evaporated to obtain the compound (11) in the form of a yellowish syrup.

To a mixture of the compound (11) dissolved in 144ml(2.52 mole) of acetic acid and 334ml(3.54 mole) of acetic anhydride, 48me(0.9 mole) of c-H2SO4 was slowly added dropwise at 0°C, during which crystallization occurred. The mixture was brought to room temperature and kept in a refrigerator overnight. The mixture was poured into 700me of an ice-water mixture, filtered and the filter cake was washed twice with cold water. The solid was dissolved in 2000mQ of ethyl acetate, which was washed in succession with 500mQ of water, 500mQ of saturated sodium bicarbonate and 500me of brine. The organic layer was dried over MgSO4 and activated carbon and the resulting mixtrue was filtered through a silica gel (2-20 p ) pad. The solvent was removed and the residue was recrystallized from methanol to obtain 144.7g (Yield : 40% from the compound (8)) of the compound (12) in the form of a white solid.

m.p. : 124-125C [a]25D = -22.1 (c 1, pyridine) H NMR(CDCl3) 8 (ppm) : 8.90-7.32(m, 15H, Ar-H), 6.43(s, 1H, H-1), 5.91(dd, 1H, H-3, J=4), 5.79(d, 1H, H-2, J=8), 4.81-4.76(m, 2H, H-4 and H-5), 4.54- 4.49(m, 1H, H-5), 2.00(s, 3H, CH3COO)

Example 4 : Prenaration of 1,3,5-tri-O-benzovl- a -L-ribofuranose (13) HCl (gas) was bubbled for 1.5 hours into a solution of 50g(99.16 mmole) of the compound (12) dissolved in 460mQ of anhydrous dichloromethane and 7.5mQ of acetyl chloride at 0°C. The resulting solution was kept in a refrigerator for 12 hours and then evaporated in vacuo. The residue was coevaporated with toluene (3 x 150mQ) at 45"C and redissolved in 105me of acetonitrile. To this solution, 13mQ of water was added dropwise at 0°C. A white solid began to precipitate from the mixture after 30 minutes, after which the mixture was kept in a refrigerator for 2 hours to induce additional precipitation. After filtration of the resulting solid, the filter cake was carefully washed with cold diethylether to remove the reaction by-product 1-hydroxy-isomer, which is indistinguishable by TLC from the compound (13). The white solid thereby obtained was dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate to remove the remaining HCl, dried over MgSO4 and filtered. The solvent was removed from the filtrate to obtain 29.2g (Yield : 63.7%) of the compound (13) in the form of a white solid.

m.p. : 137-139C [a]20D = -82.01" (c 1.5, CHCl3) 111 NMR(CDCl3) 8 (ppm) : 7.31, 8.19(m, 15H, Ar-H), 6.69(d, J=4.6Hz, 1H, H-1), 5.59(dd, J=6.7, 1.8Hz, 1H, H-3), 4.64, 4.80(m, 4H, H-2, H-4 and H-5), 2.30(br s, D2O exchangable, OH) Example 5 : Prenaration of 1,3 5-tri-O-benzovl-2-O-imidazolyl- sulfonvl- a -L-ribofuranose (14) 107.0g(0.232 mole) of the compound (13) was dissolved in 1070ml of dichloromethane and 214ml of dimethylformamide, to which 62.5g(37.2 ml, 0.463 mole) of sulfuryl chloride was added dropwise at a low

temperature (-10 to -78°C). The resulting solution was stirred at room temperature for 3 hours and then cooled in an ice-bath. The solution was stirred while 157.8g(2.32 mole) of imidazole was added portionwise at the rate keeping the temperature of reaction mixture under 5"C. The resulting mixture was stirred at room temperature for 20 hours, after which 400mQ of ice-water was added. The aqueous layer was extracted three times with 100me of dichloromethane (3 x 100mQ). The combined organic solution was washed with 200me of brine and dried over MgSO4.

The solvent was removed under reduced pressure and dimethylformamide was removed under high vaccum. The syrupy residue was coevaporated with 100mQ of 2-propanol under reduced pressure to obtain a white solid product (14), which was used for the next reaction without further purification.

Example 6 : Prenaration of 1- (3.5-di-O-benzovl-2-fluoro- arabinofuranosvl )thvmine (17) A mixture of the imidazolate (14) obtained from Example 5, 224.1g(1.39 mole) of triethylamine-3HF and 824mQ of ethyl acetate was <BR> <BR> <BR> <BR> heated at 80°C for 3 hours, 70.3g(92.5mQ, 0.696 mole) of triethylamine was slowly added thereto and the mixture thereby obtained was stirred for one additional hour at the same temperature, after which the mixture was cooled to room temperature. The resulting solution was poured into ice-water containing NaHCO3 to neutralize it to pH 7. The aqueous layer was extracted three times with 100me of ethyl acetate (3 x 100mQ).

The combined organic solution was washed with brine and dried over Na2SO4. The solvent was removed and the residue was redissolved in 300mQ of dichloromethane, filtered through a silica gel pad and washed with dichloromethane. The solvent was removed to obtain 101.0g of crude 2-fluoro-sugar product (15), which was redissolved in 150mQ of dichloromethane. 195.9mQ(88.2g, 1.09 mole) of hydrobromic acid/acetic <BR> <BR> <BR> <BR> acid(45% w/v) was added to the solution at 0 C and then stirred at room temperature for 15 hours. The resulting solution was evaporated to dryness under reduced pressure to give a syrup, which was coevaporated with toluene (3X100mQ) to obtan the sugar bromide (16) in the form of a

semisolid, which was then redissolved in 200mQ of chloroform for the condensation reaction described below.

A mixture of 55.44g(0.44 mole) of thymine, 5g of ammonium sulfate((NH4)2SO4) and 212.5g(278.9mQ, 1.32 mole) of hexamethyldisilazane in 1900mQ of chloroform was refluxed for 24 hours to give a nearly clear solution. A solution of sugar bromide (16) in chloroform was added and the resulting mixture was refluxed for additional 24 hours and then cooled to room temperature. 200mQ of water was added to the reaction mixture, which was stirred at room temperature for 30 minutes and then filtered. The organic layer was separated, dried over Na2SO4, and filtered through a celite pad, which was then washed with ethyl acetate. The combined organic solution was evaporated to give a solid which was recrystallized from 100ml of ethanol to obtain 78.0g (Yield : 69.5% from the alcohol compound (13)) of 3,5-O-dibenzoyl L-FMAU (17) in the form of a crystal.

m.p. : 118-120°C <BR> <BR> <BR> [ a ]20D = +22.40° (c 0.31, CHCl3) <BR> <BR> <BR> <BR> UV (MeOH) max 264.0nm 111 NMR(CDCl3) 8 (ppm) : 8.55(s, NH), 7.37, 8.12(m, Ar), 6.35(dd, JF-H= 22.4Hz, H-1'), 5.64(dd, JF-H=20.4Hz, H-3'), 5.32(dd, JF-H=50.2Hz, H-2'), 4.82(m, H-5), 4.50(m, H-4'), 1.76(s, CH3) Example 7 : Prenaration of 2'-fluoro-5-methvl- -L-arabinofura- nosyluridine (1) NHs gas was bubbled for 2-3 hours into a suspension of 83.0g(0.18 mole) of the compound (17) in 1000mQ of methanol to obtain a clear solution, which was then stirred at room temperature for an additional 48 hours. The solvent was removed under reduced pressure and the residue was triturated with diethyl ether. The resulting solid was collected by filtration, redissolved in 500ml of methanol and twice decolorized with charcoal. Methanol was removed and the resulting solid

was refluxed with 200ml of acetonitrile for 2 hours. The resulting mixture was cooled in refrigerator for 15 hours and then filtered to obtain 35.6g (Yield : 77.35%) of a white solid. The mother liquor was concentrated to dryness and purified by silica gel column chromatography (1-10% methanol in chloroform) to obtain a white solid, which was refluxed with 20mQ of acetonitrile to obtain 4.98g (Yield : 10.8%) of the second crop of the product. Total yield was raised to 88.2% (40.58g).

m.p. : 185-187°C t]20D= -112.06 (c 0.23, methanol) UV (H20) A max 265.0 (E 9695)(pH 2), 265.5 (E 9647)(pH 7), 265.5nm (E 7153)(pH 11) H NMR(DMSO-d6) 8 (ppm) : 11.45(s, NH), 7.59(s, H-6), 6.10(dd, JF-H= 15.4Hz, H-1'), 5.88(d, 3'-OH), 5.12(t, 5'-OH), 5.04(dt, JF-H=52.8Hz, H-2'), 4.22 (dq, JF-H=18.4Hz, H-3'), 3.76(m, H-4'), 3.63(m, H-5'), 1.78(s, CH3) The invention has been described with reference to its preferred embodiments. Variations and modifications of the invention will be obvious to those skilled in the art from the foregoing detailed description of the invention. It is intended that all of these variations and modifications be included within the scope of the appended claims.