HK1038921B - Method of manufacture of 1,3-oxathiolane nucleosides - Google Patents

Description

Process for producing 1, 3-oxathiolane nucleosides

This application relates to the field of processes for producing 1, 3-oxathiolane nucleosides and claims priority from U.S. provisional application 60/096,214 filed on 12/8/1998 and U.S. provisional application 60/122,841 filed on 3/1999.

Background

The late eighties of the twentieth century succeeded in the synthesis of a number of nucleosides, such as AZT, D4T, DDI and DDC, which inhibit HIV replication in living organisms and in vitro, thereby prompting researchers to design and test nucleosides in which a heteroatom is substituted for a carbon atom at the 3' -position. Norbeck et al disclose that (. + -.) -1-cis- (2, 4) -2-hydroxymethyl-4- (dioxolanyl) thymine (designated as (. + -.) -thymine-T) has HIV resistance (20. mu.M EC in ATH8 cells)₅₀) And is not toxic to uninfected control cells at 200. mu.M,Tetradron Letters30(46),6246, (1989). Racemic 2-substituted-4-substituted-1, 3-dioxolane is disclosed as having antiviral activity in European patent application No.337,713 and U.S. Pat. No.3, 5,041,449 to Biochem Pharma, Inc. Published PCT US91/09124 and PCTUS93/08044 disclose separate beta-D-1, 3-dioxolanyl nucleosides for the treatment of HIV infection. WO 94/09793 discloses the use of beta-D-1, 3-dioxolanyl nucleosides for the treatment of HBV infection.

Published PCT US95/11464 discloses that (-) -1- (2S, 4S) -1- (2-hydroxymethyl-1, 3-dioxolan-4-yl) cytosine is effective in the treatment of tumors and other abnormal cell proliferation.

U.S. Pat. No. 5,047,407 and European patent application publication No. 0382526 to BioChem Pharma, Inc. disclose that some racemic 2-substituted-5-substituted-1, 3-oxathiolane nucleosides have antiviral activity, and in particular, racemic mixtures of 2-hydroxymethyl-5- (1-cytosinyl) -1, 3-oxathiolane (hereinafter referred to as BCH-189) are reported to have almost the same anti-HIV activity as AZT, and to be less toxic. The (-) -enantiomer of BCH-189 (U.S. Pat. No. 5,539,116 to Liotta et al), referred to as 3TC, is now marketed in the United states for the treatment of human HIV. See EP 513200B 1.

Cis-2-hydroxymethyl-5- [1- (5-fluorocytosine)]-1, 3-oxathiolane ("FTC") is effective against HIV activity. See Schinazi et al, published 11 months 1992,antibacterial Agents and chemotherapy2423 page 2431, "selective HIV inhibition with racemates and enantiomers of cis-5-fluoro-1- (2-hydroxymethyl-1, 3-oxathiolan-5-yl) -cytosine". See also U.S. Pat. nos. 5,814,639; 5,914,331; 5,210,085, respectively; U.S. Pat. Nos. 5,204,466, WO 91/11186 and WO 92/14743.

Because of the commercial value of 1, 3-oxathiolane nucleosides, there is a large body of patent and scientific literature describing the production of many of these products. Three key aspects of synthesis must be considered in the design of these methods. First, the reaction scheme must provide an efficient synthetic route to the ring structure of the 1, 3-oxathiolane, preferably with substituents in place available for subsequent reactions. Secondly, the reaction scheme must provide an efficient means of condensing the 1, 3-oxathiolane with the appropriate protective base, which is cytosine in the case of 3TC and 5-fluorocytosine in the case of FTC. Third, the reaction must be stereoselective, that is, must be capable of providing the enantiomers selectively. The substituent for the chiral carbon (a particular purine or pyrimidine base (referring to the C5 substituent)) and the hydroxymethyl group of the 1, 3-oxathiolane nucleoside (referring to the C2 substituent) may be either cis (on the same side) or trans (in the opposite direction) relative to the ring system of the 1, 3-oxathiolane nucleoside. Both the cis and trans racemates include a pair of optical isomers. Thus, each compound has four separate optical isomers. These four optical isomers have the following configuration (when the oxathiolane moiety is in the horizontal plane, -S-CH₂-partly behind): (1) cis (also referred to as β), both groups are up, the natural L-cis configuration; (2) cis, both groups down, unnatural β -cis configuration (3) trans (also referred to as α -configuration), C2 substituent up and C5 substituent down; (4) trans, the C2 substituent is down and the C5 substituent is up. Two cis enantiomers together refer to the racemic mixture of the β -enantiomer, and two trans enantiomers together refer to the racemic mixture of the α -enantiomer. Separation of a pair of cis racemic optical isomers from a pair of trans racemic optical isomers is generally very simple, and the separation or obtaining of the individual enantiomers in the cis-configurationIs a significant challenge. For 3TC and FTC, the desired stereochemical configuration is the β -L-isomer. Route to 1, 3-oxathiolane ring

The numbering of the 1, 3-oxathiolane ring is as follows:

kraus et al ("Synthesis of 2, 5-disubstituted novel 1, 3-oxathiolane Compounds, intermediates in nucleoside chemistry", Synthesis, pp 1046-1048, 1991) describe the problem of reacting glyoxal aldehydes or glycolic acid with thioglycolic acid in the presence of p-toluenesulfonic acid in toluene. Kraus states that a requirement for the reaction to proceed smoothly is that glycolic acid in the form of a hydrate must be freed of aldehyde by azeotropic removal of water with the addition of toluene prior to ring condensation. Therefore, in order to carry out the reduction of the lactone and carboxylic acid functions, different catalytic reduction reagents must be used. The use of sodium borohydride is not satisfactory and borane-methyl sulfide complex (BMS) only reduces the carboxylic acid function. When the temperature is increased, or an excessive amount of BMS is used, ring-opening polymerization may be caused. The product obtained by reducing 2-carboxy-1, 3-oxathiolan-5-one with sodium bis (2-methoxyethoxy) alaninate in toluene is a mixture. Tributyltin hydride cannot be used for the reduction. Finally, when the protected lactone is subjected to reduction, it is not possible to isolate the desired compound regardless of the conditions of the catalytic reduction.

Because of these difficulties, Kraus et al suggested that anhydrous glyoxylic acid esters and 2-mercaptoacetaldehyde diethyl acetal undergo a cyclocondensation reaction in toluene at reflux to form 5-ethoxy-1, 3-oxathiolane derivatives which can be reduced with BMS to give the corresponding 2-hydroxymethyl-1, 3-oxathiolanes in a yield of 50%, after which benzoylation gives the cis-and trans-2-benzoyloxymethyl-5-ethoxy-1, 3-oxathiolanes. U.S. Pat. No. 5,047,407 describes this process.

U.S. Pat. No.4, 5,248,776 discloses a process for producing pure enantiomers of β -L-1, 3-oxathiolane nucleosides from 1, 6-thioglycidyl-L-gulose.

U.S. Pat. No. 5,204,466 discloses a route for the preparation of 1, 3-oxathiolanes by reaction of thioglycolic acid (mercaptoacetic acid) and glycolaldehyde to give 2- (R-oxy) -methyl-5-oxo-1, 3-oxathiolanes.

U.S. Pat. No. 5,466,806 describes the reaction of dimers with compounds having R via mercaptoacetaldehyde_wOCH₂Method for synthesizing 2-hydroxymethyl-5-hydroxy-1, 3-oxathiolane by reacting compound of CHO general formula under neutral or alkaline condition, wherein R_wIs a hydroxyl protecting group. See McIntosh et al Can.J.chem., 61, 1872-1875, 1983 for "dimer of 2-mercaptoacetaldehyde and 2, 5-dihydrothiophene to 1, 2-oxathiolan-5-one".

Be1leau et al disclose a method for the synthesis of 1, 3-dioxolane nucleosides by oxidative degradation of L-ascorbic acid. Belleau et al, Tetrahedron Letters, Vol.33, No.46, 6949-.

U.S. Pat. No. 5,204,466 discloses the treatment of cancer by having CH₂＝CHCH₂Ozonolysis of allyl ethers OR esters of formula OR to form OHCCH₂Glycolaldehyde of the general formula OR, wherein R is a protective group, is added with thioglycolic acid to form lactone with the structural formula of 2- (R-oxygen) -methyl-5-oxo-1, 3-oxathiolane, thereby synthesizing the 1, 3-oxathiolane. Route for condensation of 1, 3-oxathiolanes with protected bases

U.S. Pat. No. 5,204,466 discloses a process for condensing 1, 3-oxathiolanes with a protected pyrimidine base using tin chloride as a Lewis acid, which process provides almost complete beta-selectivity. See Choi et al J.Am.chem.Soc.1991, 213,9377-9379 for "stereochemistry of N-glycosylation reactions guided by in situ complexation in the synthesis of dioxolane nucleoside analogues". The use of tin chloride produces undesirable residues and by-products in the reaction and is difficult to separate.

A number of U.S. patents disclose the synthesis of 1, 3-oxathiolane nucleosides by condensation of a 1, 3-oxathiolane intermediate having a chiral ester at the 2-position on the ring with a protective base in the presence of a silicon-based lewis acid. The ester at the 2-position must be reduced to the corresponding hydroxymethyl group to give the final product. See U.S. patent USP5,663,320; 5,864,164, respectively; 5,693,787, respectively; 5,696,254, respectively; 5,744,596, respectively; and 5,756,706.

U.S. patent No. USP5,763,606 discloses a method for the synthesis of cis-2-carboxylic or thiocarboxylic 1, 3-oxathiolane nucleosides which comprises coupling a desired pre-silylated purine or pyrimidine base with a bicyclic intermediate in the presence of a lewis acid.

U.S. Pat. No.4, 5,272,151 describes a process for the synthesis of 1, 3-dioxolane nucleosides which comprises reacting 2-protected oxo-5-acylated oxo-1, 3-dioxolane with a protected oxo-or nitrogen-containing purine pyrimidine base in the presence of a titanium catalyst.

The "stereochemistry of N-glycosylation reactions guided by in situ complexation in the synthesis of oxathiolane and dioxolane nucleoside analogues" in J.Am.chem.Soc.199l, 213,9377-9379 by Choi et al reported that 1, 3-oxathiolane did not couple with a protected pyrimidine base in mercuric chloride, diethylaluminum chloride, or diisopropoxytitanium dichloride (see footnote 2). Choi et al also reported that reacting an anomer of the acetate of 1, 3-oxathiolane with a silylated cytosine and almost all Lewis acids except tin chloride gave an inseparable mixture of N-glycosylated anomers.

U.S. patent 5,922,867 discloses a method of synthesizing dioxolane nucleosides which comprises glycosylating a purine or pyrimidine base with a 2-protected oxymethyl-4-halo-1, 3-dioxolane. Route to 1, 3-oxathiolanes with desired spatial configuration

U.S. Pat. No. 5,728,575 discloses an enzymatic resolution of 5' -acyl protected racemic nucleosides to 3TC and FTC using porcine liver esterase, porcine pancreatic lipase, or subtilisin lysozyme. U.S. Pat. No.3, 5,539,116 claims 3TC and patent 5,728,575 resolves the resulting product.

Liotta in us patent 5,827,727 applied a stereoselective deamination using cytidine deaminase to give 3TC and FTC.

Liotta et al in us patent 5,892,025 applied a method of resolving a mixture of cis-FTC enantiomers by passing the cis-FTC through an acetylated beta-cyclodextrin chiral column.

U.S. patent 5,663,320 claims a process for producing chiral 1, 3-oxathiolane intermediates which involves resolution of racemic intermediates using a chiral auxiliary.

Due to the importance of 1, 3-oxathiolane nucleosides for the treatment of AIDS and hepatitis B, it is an object of the present invention to provide a method for synthesizing 1, 3-oxathiolane nucleosides that is amenable to scale-up production.

Brief introduction to the invention

Methods for synthesizing 1, 3-oxathiolane nucleosides are provided, including efficient methods for synthesizing 1, 3-oxathiolanes, followed by condensation of the 1, 3-oxathiolanes with a pyrimidine or purine base. The individual enantiomeric compounds can be obtained using the methods described herein.

It has been found that compounds having (R) in an organic solvent such as acetonitrile in the presence of a Lewis or protonic acid in an anhydrous organic solvent (with a minimum of water)¹O)₂Direct reaction of acetals of the general formula CHR with mercaptoacetic acid permits the synthesis of 2- [ R ] in high yields¹C(O)OCH₂]-1, 3-oxathiolan-5-one, wherein R is- (CH)₂-O-C(O)R¹)，R¹Is alkyl, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle or arylalkyl. Or alternatively, a precursor (OH) of an aldehyde may be used₂CHR or (R)¹O) (OH) CHR. Acetals may also be used as hemiacetals, acetal monomers or corresponding highly condensed acetalsAnd (3) synthesizing a mixture of products. By reacting thioglycolic acid directly with acetal, by-products are reduced and the purity of the product and the yield of starting material can be improved. For example, the reaction of a diether alcohol with n-butyryl chloride readily affords the acetal.

(R) can be synthesized by an appropriate route¹O)₂CHR, e.g. either by (i) having the general formula HO-CH₂-C＝C-CH₂Reaction of the-OH compound with RC (O) Cl to form RC (O) OCH₂C (h) ═ c (h) oc (o) R, which yields the desired product by ozonation or other means of cleavage; or (ii) (R)¹O)₂Reduction of CHC (O) H to (R)¹O)₂CHCH₂OH, and then reacting with ClC (O) R to generate a target product.

In an alternative route, HC (O) CH₂OC(O)R¹Reaction with thioglycolic acid produces the desired 1, 3-oxathiolane ring. HC (O) CH₂OC(O)R¹May be synthesized by any suitable method, for example, by methods a and B described in fig. 2.

The 5-protected oxo-2-protected hydroxymethyl-1, 3-oxathiolane or its 5-acyloxy derivative can be condensed with a silylated pyrimidine or purine base including cytosine or 5-fluorocytosine using a Lewis acid catalyst, including stannic chloride, titanium trichloride isopropoxide, trimethylsilyl triflate, trimethylsilyl iodide, or other known Lewis acids, including those described in U.S. Pat. No. 5,5,663,320; 5,864,164, respectively; 5,693,787, respectively; 5,696,254, respectively; 5,744,596 and 5,756,706, which have high beta-selectivity for the corresponding nucleoside. Given that it has been reported that 1, 3-oxathiolane does not couple to a protected pyrimidine base in the presence of mercuric chloride, diethylaluminum chloride, or diisopropoxytitanium dichloride, titanium isopropoxide trichloride has surprisingly been found to catalyze the condensation of 1, 3-oxathiolane with a protected base very well.

In another embodiment, glycolic acid replaces thioglycolic acid in the presence of a lewis acid to form the corresponding 1, 3-dioxolane, which can be condensed with a purine or pyrimidine base to form a 1, 3-dioxolane nucleoside. Preferably, the cyclic condensation of glycolic acid with an acetal (or aldehyde) is carried out in the presence of a lewis acid such as boron trifluoride etherate, rather than in the presence of a protic acid such as p-benzenesulfonic acid.

Wherein the Lewis acid is boron trifluoride ethyl ether. Said R¹Is an alkyl group, preferably an isopropyl group.

Or, use (R)¹O) (OH) CHR instead of (R)¹O)₂CHR。

In the present invention, the acetal is used as a mixture of hemiacetal, acetal monomer or highly condensed product thereof.

The method further comprises the preparation of (R)¹O)₂CHR, i.e. by converting the general formula HO-CH₂-CH＝CH-CH₂Compounds of the formula-OH with ClC (O) R¹Reaction to form R¹C(O)OCH₂CH＝CH-CH₂OC(O)R¹Which can form the target compound by ozonolysis or other dissociation means.

The method further comprises the preparation of (R)¹O)₂CHR, i.e. reduction (R)¹O)₂CHC (O) H to (R)¹O)₂CHCH₂OH with ClC (O) R¹The reaction forms the target compound.

The process further comprises reacting the 2- [ R ] in the presence of a Lewis acid¹C(O)OCH₂]-1, 3-dioxolan-5-one is condensed with a purine or pyrimidine base to form a 1, 3-dioxolan nucleoside.

The method further comprises (I) reacting the 2- [ R ] with¹C(O)OCH₂]-1, 3-dioxolan-5-one is converted into its 5-acetoxy derivative, and (II) 2- [ R in the presence of a lewis acid¹C(O)OCH₂]-1, 3-dioxolan-5-one condensed with a purine or pyrimidine base.

The reaction produces a mixture of alpha and beta anomers.

The mixture of alpha and beta anomers or derivatives thereof, is separated by crystallization or by chromatography. The chromatography is achiral or chiral.

The present invention includes a process for producing a 1, 3-oxathiolane nucleoside comprising: (i) preparing a 5-halo-2-protected oxymethyl-1, 3-oxathiolane; and (ii) coupling the 5-halo-2-protected oxymethyl-1, 3-oxathiolane with the protected purine or pyrimidine base in the absence of a Lewis acid. The coupling reaction is carried out at a temperature of less than 25 degrees celsius, preferably less than 10 degrees celsius.

The 5-halogen substituent is 5-chloro or 5-bromo. The reaction produces a mixture of alpha and beta anomers. A mixture of said alpha and beta anomers or derivatives thereof, separated by crystallization or separated by chromatography. The chromatography is achiral or chiral.

Wherein the 5-halo-2-protected oxymethyl-1, 3-oxathiolane is prepared by halogenation of a chiral 5-oxo-acylated-2-protected oxymethyl-1, 3-oxathiolane. Alternatively, the 5-halo-2-protected oxymethyl-1, 3-oxathiolane is prepared by halogenation of a racemic mixture of a 5-oxo-acylated-2-protected oxymethyl-1, 3-oxathiolane. The 5-halo-2-protected oxymethyl-1, 3-oxathiolane contains a 5-oxo-acyl moiety selected from the group consisting of acetate, propionate, butyrate, benzoate, p-methoxybenzoate and p-tert-butylbenzoate.

A compound having the formula:

wherein R is¹Is alkyl, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle or arylalkyl. The 1, 3-dioxolane is in the form of isolated enantiomers. The R is¹Is a lower alkyl group, preferably a propyl group, more preferably an isopropyl group.

A compound having the formula:

wherein R is¹Is alkyl, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle or arylalkyl.

A compound having the formula:

wherein R is¹Is alkyl, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle or arylalkyl; r¹¹Is a purine or pyrimidine base. The 1, 3-dioxolane nucleosides are in isolated enantiomeric form. Said R¹¹Is 6-aminopurine, 6-chloropurine or 2, 6-dichloropurine, preferably 2, 6-diaminopurine.

It has been discovered that 1, 3-oxathiolane nucleosides can be synthesized by (i) preparing a 5-halo-2-protected oxymethyl-1, 3-oxathiolane; and (ii) reacting the 5-halo-2-protected oxymethyl-1, 3-oxathiolane with the protected purine or pyrimidine base at low temperature, preferably less than 25 degrees celsius, more preferably less than 10 degrees celsius. It has surprisingly been found that the condensation reaction can be carried out efficiently without the aid of lewis acids. In a preferred embodiment, the halogen in the 5-position of the oxathiolane is a chlorine substitution. The reaction usually produces a mixture of beta and alpha anomers, which must be separated. The beta anomer is typically in excess relative to the alpha anomer. The separation of the beta and alpha anomers can be performed by any known method, including fractional crystallization, chromatography (achiral or chiral), or synthesis and separation of diastereomeric derivatives. In one embodiment, racemic 5-acylated-2-protected oxymethyl-1, 3-oxathiolane is chlorinated at low temperature (e.g., 0 degrees Celsius) and subsequently condensed with a protecting base such as 5-fluorocytosine or cytosine to form a diastereomeric mixture (usually with a substantial excess of the β compound). In another embodiment, a chiral 5-acylated-2-protected oxymethyl-1, 3-oxathiolane is chlorinated and reacted with a protecting base. Any 5-acylated-2-protected oxymethyl-1, 3-oxathiolane may be used to obtain the desired product. Non-limiting examples of suitable acyl moieties include, but are not limited to, acetate, propionate, butyrate, benzoate, p-methoxybenzoate, and p-tert-butoxybenzoate. The halogenation reaction can be carried out in any useful organic solvent, including toluene, chloroform, acetic acid, tetrahydrofuran, ethers, benzene, and the like. The ratio of the alpha and beta anomers in the condensation reaction is influenced by the solvent selected for the reaction. And selecting the solvent which generates the optimal yield of the target product by evaluating the various organic solvents.

Brief description of the drawings

FIG. 1 illustrates a method for synthesizing 1, 3-oxathiolane nucleosides according to the invention, comprising a compound of the formula (R)¹O)₂Preparation of 2- [ R ] by reaction of acetals of CHR with mercaptoacetic acid¹C(O)OCH₂]-1, 3-oxathiolan-5-one, wherein R is- (CH)₂-O-C(O)R¹)。

FIG. 2 illustrates four different methods (A-D) for the synthesis of 1, 3-oxathiolanes according to the invention.

FIG. 3 illustrates the synthesis of 1, 3-oxathiolane nucleoside enantiomers using a process of pre-and post-coupling resolution.

Detailed description of the invention

A method is provided for synthesizing 1, 3-oxathiolane nucleosides, comprising an efficient method of synthesizing a 1, 3-oxathiolane ring, followed by condensation of the 1, 3-oxathiolane ring with a protected pyrimidine or purine base.

It has been found that by reacting a compound of the formula (alkoxy) in the presence of a Lewis acid in an organic solvent containing a minimum of water₂Direct reaction of CHR acetal with mercaptoacetic acid allows the preparation of 2- [ R ] in high yield¹C(O)OCH₂O]-1, 3-oxathiolan-5-one, wherein R is- (CH)₂-O-C(O)R¹)，R¹Is alkyl, aryl, heteroaryl, alkaryl, alkheteroaryl, or aralkyl.The acetal may be a mixture of hemiacetals, acetal monomers or highly condensed products thereof. By reacting thioglycolic acid directly with acetal, by-products are reduced and the purity of the product and the yield of starting material can be improved.

The 5-oxo protecting group-2-protected hydroxymethyl-1, 3-oxathiolane or its 5-acyloxy derivative can be condensed with a protected silylated pyrimidine or purine base including cytosine or 5-fluorocytosine using a Lewis acid catalyzed by a Lewis acid including stannic chloride, titanium isopropoxide trichloride, trisilyl triflate, trisilyl iodide, or other known Lewis acids, including those described in U.S. Pat. No. 5,5,663,320; 5,864,164, respectively; 5,693,787, respectively; 5,96, 254; 5,744,596 and 5,756,706, which have high beta-selectivity for the corresponding nucleoside. Given that it has been reported that 1, 3-oxathiolane does not couple to a protected pyrimidine base in the presence of mercuric chloride, diethylaluminum chloride, or diisopropoxytitanium dichloride, titanium isopropoxide trichloride has surprisingly been found to catalyze the condensation of 1, 3-oxathiolane with a protected base very well.

In another embodiment, glycolic acid replaces thioglycolic acid in the presence of a lewis acid to form the corresponding 1, 3-dioxolane, which can be condensed with a purine or pyrimidine base to form a 1, 3-dioxolane nucleoside. Preferably, the cyclic condensation of glycolic acid with an acetal (or aldehyde) is carried out in the presence of a lewis acid such as boron trifluoride etherate, rather than in the presence of a protic acid such as p-benzenesulfonic acid.

It has been discovered that 1, 3-oxathiolane nucleosides can be synthesized by (i) preparing a 5-acylated-2-protected oxymethyl-1, 3-oxathiolane; and (ii) reacting the 5-halo-2-protected oxymethyl-1, 3-oxathiolane with the protected purine or pyrimidine base at low temperature, preferably less than 25 degrees celsius, more preferably less than 10 degrees celsius. It has surprisingly been found that the condensation reaction can be carried out efficiently without the aid of lewis acids. In a preferred embodiment, the halogen in the 5-position of the oxathiolane is a chlorine substitution. The reaction usually produces a mixture of beta and alpha anomers, which must be separated. The beta anomer is typically in excess relative to the alpha anomer. The separation of the beta and alpha anomers can be carried out by any known method, including fractional crystallization, chromatography (achiral or chiral), or synthesis and separation of diastereomers. In one embodiment, racemic 5-acylated-2-protected oxymethyl-1, 3-oxathiolane is chlorinated at low temperature (e.g., 0 degrees Celsius) and subsequently condensed with a protecting base such as 5-fluorocytosine or cytosine to form a diastereomeric mixture (usually with a substantial excess of the β compound). In another embodiment, a chiral 5-acylated-2-protected oxymethyl-1, 3-oxathiolane is chlorinated and reacted with a protecting base. Any 5-acylated-2-protected oxymethyl-1, 3-oxathiolane may be used to obtain the desired product. Non-limiting examples of suitable acyl moieties include, but are not limited to, acetate, propionate, butyrate, benzoate, p-methoxybenzoate, and p-tert-butoxybenzoate. The halogenation reaction can be carried out in any useful organic solvent, including toluene, chloroform, acetic acid, tetrahydrofuran, ethers, benzene, and the like. The ratio of the alpha and beta anomers in the condensation reaction is influenced by the solvent selected for the reaction. And selecting the solvent which generates the optimal yield of the target product by evaluating the various organic solvents.

The selected 5-acylated-2-protected oxymethyl-1, 3-oxathiolanes can be halogenated, for example, using known methods to form 5-chloro, 5-bromo, 5-iodo derivatives.

A number of documents describe chiral stationary phases in chiral chromatography, including, for example, Strari et al Perkin Elmer in 1992, for analysis using enantiomeric separations, polysaccharides and their derivatives used as chiral stationary phases.

Any other leaving group capable of being displaced and substituted by halogen, preferably chlorine, may be used instead of the 5-acyl group. Examples of leaving groups are alkoxy, alkoxycarbonyl, amido, azido, and isocyano. I. Definition of

The term "individual enantiomers" as used herein refers to a nucleoside component comprising at least approximately 95-100%, or more preferably greater than 97%, of a single enantiomer of a nucleoside.

The terms purine or pyrimidineThe pyridines include, but are not limited to, 6-alkylpurines and N⁶-alkylpurine, N⁶-acyl purine, N⁶-benzylpurine, 6-halopurine, N⁶-alkynylpurine, N⁶-acyl purine, N⁶-hydroxyalkyl purine, 6-thioalkyl purine, N²-alkylpurine, N⁴Alkyl pyrimidines, N⁴Acyl pyrimidines, 4-halogenopyrimidines, N⁴Alkynylpyrimidines, 4-amino and N⁴Acylpyrimidines, 4-hydroxyalkylpyrimidines, 4-thioalkylpyrimidines, thymines, cytosines, 6-azapyrimidines, including 6-azacytosines, 2-and/or 4-mercaptopyrimidines, uracils, C⁵Alkyl pyrimidines, C⁵-benzylpyrimidine, C⁵-halogenopyrimidines, C⁵-vinyl pyrimidine, C⁵Alkynyl pyrimidines, C⁵Acyl pyrimidines, C⁵-hydroxyalkyl purine, C⁵Acylaminopyrimidine, C⁵-cyanopyrimidine, C⁵-nitropyrimidine, C⁵-aminopyrimidine, N²-alkylpurine, N²-alkyl-6-thiapurine, 5-azacytidine, 5-azauridine, triazolopyridine, imidazopyridine, pyrrolopyrimidine, and pyrazolopyrimidinyl. The oxygen and nitrogen containing functional groups on the base may be protected as needed or desired. Suitable protecting groups are well known to those skilled in the art and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl, acyl such as acetyl, propionyl, methanesulfonyl, and p-toluenesulfonyl. Preferred bases include cytosine, 5-fluorocytosine, uracil, thymine, adenine, guanine, xanthine, 2, 6-diaminopurine, 6-aminopurine, 6-chloropurine and 2, 6-dichloropurine.

The term alkyl, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic primary, secondary, or tertiary hydrocarbon group, typically C₁To C₁₈In particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl,2, 2-dimethylbutyl, and 2, 3-dimethylbutyl. The alkyl group may optionally be substituted with one or more groups selected from the group consisting of hydroxy, carboxylic acid or ester, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, which groups may be optionally unprotected or protected using known techniques, such as the "protective groups in organic synthesis" described by Green et al, John Wiley and Sons, second edition 1991, which is incorporated herein by reference.

The term "protected" as used herein, unless otherwise specified, refers to a group added to an oxygen, nitrogen, or phosphorus atom for the purpose of preventing further reaction or for other purposes. Many oxygen and nitrogen protecting groups are well known in the art of organic synthesis. It is contemplated that suitable protecting groups, such as those described by Green et al in John Wiley and Sons, second edition in 1991, "protecting groups in organic Synthesis", are incorporated herein by reference.

The term aryl as used herein, unless otherwise specified, refers to phenyl, biphenyl or naphthyl, preferably phenyl. The aryl group may optionally be substituted with one or more groups selected from the group consisting of hydroxy, carboxylic acid or ester, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, which groups may be unprotected if desired or protected using known techniques, such as the "protecting groups in organic synthesis" described by Green et al, John Wiley and Sons, second edition 1991, which is incorporated herein by reference.

The term alkaryl or alkylaryl refers to an alkyl group with an aryl substituent.

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

The term halogen as used herein refers to chlorine, bromine, iodine and fluorine.

The term acyl refers to a moiety having the general formula-c (o) R ', wherein R' is alkyl, aryl, alkaryl, aralkyl, heteroaryl, heterocycle, alkoxyalkyl including methoxymethyl, arylalkyl including benzyl, aryloxyalkyl such as phenoxymethyl; aryl groups including phenyl optionally substituted with halogen, C1-C4 alkyl or C1-C4 alkoxy, or residues of amino acids.

As used herein, a leaving group refers to a functional group that is attached to a molecule in a suitable location and can be dissociated from the molecule.

The term heteroaryl or heterocyclic as used herein refers to a cyclic moiety containing at least one sulfur, oxygen, or nitrogen in the ring. Non-limiting examples are furyl, pyridyl, pyrimidinyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazolyl, benzofuryl, benzothienyl, quinolinyl, isoquinolinyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1, 2, 4-thiadiazolyl, isoxazolyl, pyrrolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthyl, hypoxanthine, and pteridinyl. The oxygen and nitrogen functional groups on the heterocyclic ring may be protected as needed and desired. Suitable protecting groups are well known to those skilled in the art and include trimethylsilyl, dimethylhexylsilyl. The alkyl group may optionally be substituted with one or more groups selected from the group consisting of hydroxy, carboxylic acid or ester, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, which groups may be unprotected if desired or protected using known techniques, such as described by Green et al, John Wiley and sons, second edition of 1991, "protecting groups in organic Synthesis", which is incorporated herein by reference.

The term alkylheteroaryl refers to an alkyl group substituted with a heteroaryl substituent. II.1, 3-Dioxolane lactone Ring preparation

FIG. 1 illustrates an apparatus for practicing the disclosed methodsA route of the method. The 2-butene-1, 4-diol is reacted with an acid chloride of a carboxylic acid or other ester precursor to give the diester of 2-butene-1, 4-diol. The choice of acid chloride or other ester precursor of the carboxylic acid depends on the desired group at the 2-position on the resulting 1, 3-dioxolane ring. For example, if butyryl chloride is reacted with 2-butene-1, 4-diol, 2- [ R ] is formed as a result¹C(O)OCH₂O]-1, 3-oxathiolan-5-one, R¹Is propyl. In another embodiment, the acid chlorides or other ester precursors of different carboxylic acids are selected such that R is¹Is alkyl, aryl, heteroaryl, alkaryl, alkheteroaryl or aralkyl.

In the second step of the reaction, the 2-butene-1, 4-diester is dissociated, preferably by ozonolysis, to give a compound of the formula (alkoxy)₂Acetals of CHR wherein R is- (CH)₂-O-C(O)R¹) And R¹Is alkyl, aryl, heteroaryl, alkaryl, alkheteroaryl, or aralkyl. The ozonolysis reaction is usually carried out at very low temperatures, typically-70 ℃ or lower. The reaction is carried out at relatively high temperatures, perhaps-10 ℃, and no special low temperature reactor is required. The reaction to form the acetal may be carried out in a variety of alcoholic solvents with or without co-solvents such as methylene chloride. The preferred alcoholic solvent is methanol. The ozonolysis reaction is generally stopped using dimethyl sulfide, but it has been found that the purity of the target product can be made higher using thiourea.

Furthermore, (alkoxy)₂CHCH₂Acylation of OH with an appropriate acid chloride or anhydride in the presence of a base such as triethylamine can be used to prepare compounds having the general formula (alkoxy)₂Acetals of CHR wherein R is- (CH)₂-O-C (O) R '), and R' is alkyl, aryl, heteroaryl, alkaryl, alkheteroaryl, or aralkyl.

The key step of this process is the direct reaction of an acetal with thioglycolic acid in the presence of a lewis or protonic acid in an organic solvent containing a minimum of water. The acetal may be a hemiacetal, an acetal monomer or a mixture of products thereof having a higher degree of condensation. Any protic or lewis acid that provides the desired results is suitable for this process. It was found that the cyclic condensation of acetals with mercaptoacetic acid can be carried out efficiently to give 1, 3-oxathiolanes. In contrast, the cyclocondensation of aldehydes with mercaptoacetic acid often presents several fold problems, resulting in low yields of 1, 3-oxathiolanes, and incorporating unreacted aldehydes and aldehyde by-products.

In the next step, the 2-protected hydroxymethyl-5-oxo-1, 3-oxathiolane is resolved using a variety of existing methods which may be practiced. The 2-position substituent is selected according to the principle of easy resolution in this step. For example, groups known to be stereoselectively cleavable by the enzyme may be selected. Liotta et al in U.S. Pat. No. 5,204,466 describe a process for the enzymatic stereoselective hydrolysis of oxathiolanes using porcine pancreatic lipase, subtilisin or porcine liver esterase. U.S. patent 5,663,320 claims a method of synthesizing chiral 1, 3-oxathiolane intermediates comprising resolving racemic intermediates with a chiral auxiliary. WO91/17159 discloses a process for separating 1, 3-oxathiolane nucleoside enantiomers using a cellulose triacetate or beta-cyclodextrin chiral column.

As in 3TC and FTC, where it is desired to obtain the individual (2R) -enantiomer of a 2-protected hydroxymethyl-5-oxo-1, 3-oxathiolane, providing the β -L-enantiomer, reduction may be carried out using a reducing agent, preferably lithium tri-tert-butoxide hydride, to give the corresponding 5-protected oxy-compound, for example the 5-acetate.

FIG. 2 illustrates four other embodiments (methods A-D) for the preparation of 1, 3-oxathiolanes. In the non-limiting illustrative example of method A of FIG. 2, 2- (5-oxo-1, 3-oxathiolanyl) methylbutyrate is synthesized in four steps and without purification of the intermediate. In the first step, 4- (2, 2-dimethyl-1, 3-oxathiolanyl) methylbutyrate is synthesized from acetonide (Solketal) and n-butylchloride in tert-butyl methyl ether, DMAP and triethylamine. Subsequently, 4- (2, 2-dimethyl-1, 3-oxathiolanyl) methylbutyrate was placed under conditions of Dowex 50W X8-100H⁺The 2, 3-dihydroxypropyl butyrate is obtained from the methanol solution of the resin. The resulting diol is reacted with sodium periodate in distilled water to produce 2-oxoethyl butyrate. When p-toluenesulfonic acid monohydrate (p-TsOH. H)₂O) reacting 2-oxoethyl butyrate with mercaptoacetic acid in acetonitrile to synthesize (5-oxo-1, 3-oxathiolan-2-yl) methyl butyrate. (5-oxo-1, 3-oxathiolan-2-yl) methyl butyrate is converted to its 5-acyloxy derivative by reaction with lithium tri-tert-butoxide hydride in THF.

FIG. 2, a non-limiting illustration of method B, uses 1, 2-dihydroxyethane reacted with n-butyryl chloride in triethylamine to form (5-oxo-1, 3-oxathiolan-2-yl) methyl butyrate or its 5-acyloxy derivatives. The reaction produced 2-hydroxyethyl butyrate, which was further reacted with phosphorus pentoxide in anhydrous DCM followed by 2-oxoethyl butyrate with DMSO and triethylamine. The 2-oxoethyl butyrate can be converted to the 5-acyloxy derivative of (5-oxo-1, 3-oxathiolan-2-yl) methyl butyrate by the methods described above, or with thioglycolic acid and CSA in anhydrous DCM to (5-oxo-1, 3-oxathiolan-2-yl) methyl butyrate.

In a non-limiting illustrative example of method C of FIG. 2, a method of synthesizing butyric acid (5-oxo-1, 3-oxathiolan-2-yl) methyl ester or its 5-acyloxy derivative comprises reacting butyric acid 2, 2-diethoxyethyl ester in DCM and treating with TFA and water. The reaction produces 2-oxoethyl butyrate, which can be reacted with mercaptoacetic acid in CAS and DCM to produce the desired (5-oxo-1, 3-oxathiolan-2-yl) methyl butyrate, or its 5-acyloxy derivative in THF with 1, 4-dithiane-2, 5-diol.

Method D in fig. 2 is similar to the method described in fig. 1.

These steps can be better understood by the following examples, which are not intended to limit the scope of the present invention.

Example 1

To a 200 gallon reactor equipped with a high efficiency cooling system were charged methyl tert-butyl ether (MtBE, 278 liters), DMAP (391 g, 3.2 moles), triethylamine (102.3 liters, 74.4 kg, 736.2 moles) and 2-butene-1, 4-diol (26.4 liters, 28.2 kg, 320 moles). Stirring was started and the temperature of the reaction mixture was cooled to approximately 4 ℃. Butyryl chloride (69.6 l, 71.5 kg, 672 mol) was added to the reaction mixture at a rate that maintained the reaction temperature below 20 ℃. During the addition triethylamine hydrochloride precipitated out and the reaction mixture thickened but still was a flowable slurry. The reaction mixture was analyzed by thin layer chromatography (silica gel plate; Analtech No.02521, developed with 9: 1 hexane/ethyl acetate and developed with PMA colorant) and was stirred for an additional 1 hour to complete the reaction after the addition was complete. Water (120 l) was added to the reactor and the reaction mixture was stirred until all the solids dissolved. The phases were separated and the lower aqueous layer was analyzed by thin layer chromatography to find no product (if any, the aqueous layer was retained for further recovery of product). The upper organic layer was washed with water (72 l), saturated aqueous potassium bicarbonate (72 l), checked to ensure that the aqueous layer removed was basic, and distilled under reduced pressure to give 69.4 kg of the 2-butene-1, 4-dibutyrate product as a pale golden yellow oil (95% yield). The NMR spectrum of the obtained product was in agreement with the standard spectrum. Example 2 ozonolysis of 2-oxoethyl butyrate methanol hemiacetal

A12 liter three necked round bottom flask was equipped with mechanical stirring, immersion thermometer, oil sealed gas escape diffuser and ozone inlet tube, to which was added 2-butene-1, 4-dibutyrate (1005.0 g, 4.4 moles) and methanol (5 liters). Ozonia CFS-2 ozone generator, 1200 Watts, 1 atmosphere oxygen, flow rate 1 cubic meter/hour, start stirring, the mixture is cooled to-20 ℃ in an ice/methanol bath. Ozone is bubbled into the solution. The temperature of the mixture increased to-10 ℃ during the addition of ozone. After 2 hours the reaction mixture was analyzed by thin layer chromatography (silica gel plate; Analtech No.02521, developed with 9: 1 hexane/ethyl acetate and developed with PMA colorant) and the starting material was found to have disappeared completely. The reaction mixture was stirred, purged with nitrogen for 15 minutes and cooled back to-20 ℃. Thiourea (170 g, 2.23 mol, johnson mattey 10B16) was added at a rate of 17 g every 1.5 hours. The temperature of the mixture was raised to 0 ℃. After 1 hour of thiourea addition, thin layer chromatography and¹h NMR analysis revealed complete disappearance of the ozonide. The mixture was cooled back to-20 ℃ and filtered. The filtrate was evaporated to give 1.5 kg of 2-oxoethyl butyrate methanol hemiacetal as a pale golden yellow oil (yield 9)7%). The NMR spectrum of the obtained product was in agreement with the standard spectrum. Example 32-Butyloxymethyl-1, 3-oxathiolan-5-one

A72 liter round bottom flask was equipped with mechanical stirring, immersion thermometer, nitrogen inlet, pressure equalizing addition funnel and distillation head. Toluene (31L, Fisher) and 2-oxoethyl butyrate methanol hemiacetal (10 kg, 9.3 kg actual removed residual methanol) were added. The starting material is in fact a mixture of acetals, hemiacetals, dimers, and trimers. Stirring was started and thioglycolic acid (4.5 l, 64.7 mol) was added dropwise over 2 hours via a pressure equalizing addition funnel. The temperature of the reaction mixture rose to 28 ℃ during the addition. The reaction mixture was subjected to thin layer chromatography (silica gel plate; Analtech No.02521, developed with 7: 3 hexane/ethyl acetate and developed with PMA colorant) to find that the starting material was consumed after the completion of the addition. The mixture was heated to 85 ℃ (internal temperature). The distillate (5 liters of a mixture of toluene and aqueous methanol) was collected at 75 c (head temperature). The reaction mixture was subjected to thin layer chromatography (silica gel plate; Analtech No.02521, developed with 7: 3 hexane/ethyl acetate and developed with PMA colorant) to find that the reaction was completed after heating for 8 hours. After the reaction mixture was cooled to room temperature, it was slowly pumped into a 100 liter reactor containing 16 liters of an agitated saturated aqueous solution of potassium bicarbonate. The mixture was stirred for 20 minutes and the phases were separated. The organic layer was washed with 6 l of saturated sodium chloride solution and evaporated to dryness. The crude product was passed through a 2 inch Pope Scientific rotary membrane distiller (column temperature 90 ℃ C., vacuum 0.5 mm Hg, speed about 0.5 kg/hr). Low boiling impurities were in the distillate flask and product was collected in the bottom flask, yield 5.8 kg (53.8%). The product was analyzed by gas chromatography (HP-1 methylsilane column, nitrogen gas at a flow rate of 50 ml/min as carrier gas, flame ionization detector temperature 280 ℃, column temperature 65 ℃ constant for 1 min, 12.5 ℃/min ramp to 250 ℃ and then constant for 1 min, sample volume of 1-2. mu.l ethyl acetate solution) with a purity of 92%. The NMR spectrum of the obtained product was in agreement with the standard spectrum. Example Synthesis of 45-acetoxy-2-butyryloxymethyl-1, 3-oxathiolane

A50 liter four-necked round bottom flask equipped with overhead mechanical stirring, two nitrogen diffusers, a stopper and a thermocouple/thermometer cannula was charged with anhydrous tetrahydrofuran THF (4.1 liters, Aldrich). Lithium aluminum hydride particles (334 g; 8.8 mol, Aldrich #04414KR) were then added slowly in 100 g portions. The slurry was diluted with another portion of tetrahydrofuran THF (4.1L) and stirred for an additional 15 hours. The initial temperature of the addition was raised to 38 ℃ and then gradually cooled to 22 ℃. The resulting grey mixture was cooled to-5 ℃ with an ice/methanol bath. The stopper was replaced with a 5 l pressure equalizing addition funnel and a mixture of t-butanol (2.0 kg, 2.6 l, 27.6 mol) and THF (600 ml) was added. This mixture was added to the reaction mixture over 2.5 hours. The reaction temperature rose to 15.9 ℃ during the addition. The cooling bath was removed and the hot water bath was replaced and the reaction temperature was raised to 33 ℃ which was maintained for 1.5 hours or until gas evolution ceased. The reaction mixture was cooled to-6 ℃ with an ice/methanol bath. A mixture of 2-butyryloxymethyl-1, 3-oxathiolan-5-one [1410.6 g, 6.9 mol and THF (350 ml) ] was added to the pressure-equalizing addition funnel. This mixture was slowly added to the reaction mixture, maintaining the internal temperature below 5 ℃. The reaction was stirred for 1.5 hours and an aliquot (5 drops of the reaction mixture) was quenched with acetic anhydride/4-dimethylaminopyridine and diluted with ethyl acetate (ca. 1 ml). An aliquot of the mixture was analyzed by gas chromatography (HP-1 methylsilane column with nitrogen as carrier gas at a flow rate of 50 ml/min, flame ionization detector temperature of 280 ℃ C., column temperature of 65 ℃ C. constant for 1 min, increasing to 250 ℃ C. at a rate of 12.5 ℃/min, constant for 1 min, and loading of 1 microliter of the discontinued reaction mixture) showing no initial lactone (retention time of 7.4 min). The cooling bath was replenished with a fresh ice/methanol mixture and the reaction cooled to-9.0 ℃. To the resulting green reaction mixture was added 4-dimethylaminopyridine (42 g, 0.35 mol) in one portion. Acetic anhydride (7065.6 g, 6.5 l, 69.0 moles) was added in portions to the addition funnel. Acetic anhydride was added to the reaction mixture over 1.5 hours, maintaining the temperature below 0 ℃. The resulting green reaction mixture was stirred for 13 hours and the temperature was gradually increased to 19 ℃. Gas chromatography (HP-1 methylsilane column with nitrogen as carrier gas at a flow rate of 50 ml/min, flame ionization detector temperature of 280 ℃ C., column temperature of 65 ℃ C. constant for 1 min, then increasing to 250 ℃ C. at a rate of 12.5 ℃/min, then constant for 1 min, sample volume of 1-2. mu.l of reaction mixture) showed that the reaction was complete (two new peaks formed, retention times of 8.4 and 8.6 min, respectively).

The brown-orange reaction mixture was diluted with ethyl acetate (13 l). Half of the reaction mixture was filtered through a layer of celite (7.5 cm thick, 18 inch upper funnel) and the filtration was very slow. Diatomaceous earth (1.5 kg) was added to the other half of the reaction mixture, and after stirring for 4 hours, it was passed through a layer of diatomaceous earth in the same manner as above. The filtration is smooth. The filtrates were combined and transferred to a 72 liter dropper bottle equipped with overhead mechanical stirring. To this was added a saturated sodium bicarbonate solution (20 l), the resulting biphasic mixture was stirred for 1h and separated, and the organic layer was washed with another saturated sodium bicarbonate solution (10 l) and then with a saturated sodium chloride solution (20 l). After separation the organic layer was dried over anhydrous magnesium sulfate (3.0 kg) and the suspension was stirred very quickly. The magnesium sulfate was removed by vacuum filtration and the filtrate was evaporated in vacuo (35 ℃ water bath) to give a red liquid. After further concentration for 1.5 hours on a high vacuum pump (23 mm Hg, 40 ℃ C.), a crude 5-acetoxy-2-butyryloxymethyl-1, 3-oxathiolane was obtained as a red oil (1483.0 g, 87% yield).

A10 g portion of the crude 5-acetoxy-2-butyryloxymethyl-1, 3-oxathiolane was dissolved in hexane (100 ml, 10 volumes) and stirred vigorously until only a small amount of red oil was present at the bottom of the flask. Silica gel (2 g) was added to the stirred mixture and the mixture was stirred for an additional 10 minutes. The resulting slurry was filtered through a layer of celite to give a pale yellow filtrate. The solvent was removed by evaporation in vacuo to give 5-acetoxy-2-butyryloxymethyl-1, 3-oxathiolane (7.7 g, 77% recovery) as a pale yellow oil. The impurities at the baseline in the thin layer chromatography were removed and the gas chromatography results were unchanged. Example 55-acetoxy-2-butyryloxymethyl-1, 3-oxathiolane and 5-fluorocytosine condensation Using trimethylsilyl iodide as Lewis acid

A3-liter three-necked round bottom flask was equipped with overhead mechanical stirring, stopper and water-cooled reflux condenser equipped with a nitrogen diffuser, and 5-fluorocytosine (51.6 g, 0.40 mol), hexamethyldisilazane (665 ml, 3.10 mol) and ammonium sulfate (2.0 g) were added. The resulting slurry was heated under reflux for 2.5 hours, and formation of a white solid was observed on the inner wall of the condenser tube. The resulting yellow solution was cooled to room temperature, and a white precipitate precipitated from the reaction solution. Excess hexamethyldisilazane was removed under reduced pressure under an inert atmosphere. Dichloromethane (890 ml) was added to the white solid to give a yellow clear solution. The reaction vessel was equipped with a thermocouple/thermometer thimble and the claisen head was fitted with a pressure equalizing addition funnel and nitrogen diffuser. The reaction solution was cooled to-5 ℃ in an ice-methanol bath, whereupon a solution of oxathiolane acetate (175.6 g, 65% GC assay purity, 0.41 mol) in dichloromethane (300 ml) was added portionwise to the addition funnel and subsequently added dropwise to the reaction mixture over 45 minutes. The temperature of the reaction solution was maintained between-5 ℃ and 0 ℃ and after the addition was complete, the addition funnel was rinsed with 100 ml of dichloromethane and added to the reaction mixture. A solution of trimethylsilyl iodide (89.0 ml, 0.62 mol) in dichloromethane (150 ml) was added to the addition funnel, followed by addition to the reaction mixture over 45 minutes, maintaining the internal temperature of the mixture between-5 ℃ and 0 ℃. It was noted that white smoke formed at the beginning of the charge and disappeared very quickly with the end of the charge. The resulting reaction mixture was maintained at room temperature and stirred overnight. The reaction mixture was carefully quenched with saturated aqueous sodium bicarbonate and the phases were separated. The organic layer was washed with brine and concentrated under reduced pressure to give 228 g of a yellowish brown semisolid. HPLC analysis by high pressure liquid chromatography found a mixture containing approximately 1: 1 of the alpha and beta anomers. A portion of this material was recrystallized from toluene to give completely separated alpha and beta anomers. Example 6 cleavage of butyrate protecting group

A sample of 8.0 g (25 mmol) butyrate ester (sa.494.89.1) was dissolved in 160 ml methanol, stirred vigorously and the solution immersed in an ice/water bath. After 10 minutes the solution was treated with 6.4 g of DOWEXSBR strong base anion exchange resin (Sigma cat # I-9880, P.1803). After stirring for 3 hours the ice/water bath was removed and stirring was continued until complete consumption of the starting material by thin layer chromatography was observed. The mixture was diluted with 100 ml of methanol and filtered. The resin was washed with 100 ml of methanol, the solutions combined and concentrated to give a pale yellow solid. The resulting solid was triturated with cold ethyl acetate to give, after drying, 5.0 g of an off-white solid 9/152-15 (81%).

Care was taken that the resin was washed thoroughly with methanol and dried before use. The developing solution for this well-reacted thin layer chromatography system was 15% methanol/85% chloroform.

In addition, the butyrate can also be removed by treating with primary amine and secondary amine in an alcohol solvent. Preferred amines are ammonia and butylamine, and the preferred solvent is methanol. EXAMPLE 7 Synthesis of butyric acid (5-oxo-1, 3-oxathiolan-2-yl) methyl ester (25) and butyric acid (5-acetoxy-1, 3-oxathiolan-2-yl) methyl ester (26) from (2, 2-dimethyl-1, 3-oxathiolan-4-yl) methanol (2, 2-dimethyl-1, 3-oxathiolan-4-yl) methyl ester (22)

To a well stirred solution of acetone glycidol (Solketal, 21, 62.6 ml, 500 mmol), triethylamine (83.6 ml, 600 mmol) and DMAP (5 g, 40.9 mmol) in methyl tert-butyl ether (1L) was added n-butyryl chloride (52.4 ml, 500 mmol) dropwise over 75 minutes at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour and at room temperature for 5 hours. The mixture was diluted with ethyl acetate (1 l), washed with water (1 l), dried over magnesium sulfate, filtered and evaporated to give 22 as an oil (104.6 g, 500 mmol, 100%). This material was used in the next step without further purification. Synthesis of 2, 3-dihydroxypropyl butyrate (23)

22(50.6 g, 250 mmol), and Dowex 50W X8-100H⁺The resin (76.5 g) was heated to 50 ℃ in methanol (500 ml) for 2 hours, cooled to room temperature, filtered, and the resin washed with methanol (1 × 200 ml). The methanol fractions were combined and concentrated in vacuo. The crude product was passed through a silica gel layer using ethyl acetate: hexane (1: 1) as eluent. The product containing fractions were combined and concentrated in vacuo to afford 23 as an oil (32.8 g, 200 mmol, 81%). This material was used in the next step without further purification. Synthesis of 2-oxoethyl butyrate (24)

A mixture of sodium periodate (89.4 g, 418 mmol) and distilled water (450 ml) was heated at 45 ℃ for approximately 20 minutes to give a sodium periodate solution. This solution was added dropwise over 60 minutes to a solution of diol 23(30.8 g, 190 mmol) in acetone (225 ml). After the addition was complete, the mixture was stirred for a further 2 hours at room temperature. Acetone was removed using a rotary evaporator (heated bath temperature not exceeding 35 ℃). The reaction mixture was diluted with water (250 ml) and the aqueous layer was extracted with ethyl acetate (3 × 250 ml). The organic fractions were combined, washed with water (250 ml), dried over magnesium sulphate, filtered and evaporated (bath temperature not exceeding 35 ℃) to give 24(20.5 g, 157 mmol, 83%) as an oil. This material was used in the next step without further purification. Synthesis of butyric acid (5-oxo-1, 3-oxathiolan-2-yl) methyl ester (25)

A solution of 24(3.90 g, 0.030 mol), thioglycolic acid (3.32 g, 0.036 mol) and p-toluenesulphonic acid hydrate (p-tsoh. h2o, 0.28 g, 1.5 mmol) in acetonitrile (600 ml) was heated at reflux for 3.5 h. During reflux, four 25 ml portions of the solution were passed through a Dean-Stark trap (water-acetonitrile azeotrope was removed). Thin layer chromatography analysis (6: 1 hexane: ethyl acetate) of the reaction solution showed a predominantly new composition and no unreacted aldehyde (color development with PMA and 2, 4-DNP colorant). The reaction solution was stirred at room temperature for 16 hours and evaporated to dryness. The residue was partitioned with concentrated sodium bicarbonate (50 ml) and ethyl acetate (75 ml); the aqueous portion was extracted with additional ethyl acetate (2 × 75 ml). The combined organic fractions were dried over magnesium sulfate and concentrated in vacuo. The crude product (6 g) was purified by flash chromatography (125 g silica gel with 20% ethyl acetate in hexanes). Compound 25 was obtained as an oil (3.27 g, 16 mmol, 53%). Thin layer chromatography analysis (3: 1 hexane: ethyl acetate) found that the spot contained Rf 0.41,¹H-NMR(CDCl₃) The results are consistent with the structure; mass to charge ratio M/z of mass spectrum (FAB) 205.1(M + 1). Synthesis of butyric acid (5-acetoxy-1, 3-oxathiolan-2-yl) methylEster (26)

To a solution of 25(0.50 g, 2.5 mmol) in anhydrous tetrahydrofuran (15 ml) was added a 1.0M solution of lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran (2.7 ml) at-5 deg.C to-10 deg.C for 2 hours using a sample pump, and the temperature was maintained between-5 deg.C and-10 deg.C. After the addition was complete, the solution was allowed to stand at 3 ℃ for 18 hours and then warmed to room temperature. DMAP (1.7 mmol, 0.20 g) and acetic anhydride (25.0 mmol, 2.4 g) were added and the resulting orange solution stirred at ambient temperature for 3 hours at which time concentrated sodium bicarbonate (25 ml) was added. After stirring for 1 hour, the phases were separated and the aqueous phase was extracted with two more portions of ethyl acetate. The organic fractions were combined, dried over magnesium sulfate, filtered and evaporated to give the crude product (0.77 g). After separation by flash chromatography (20 g silica gel and 20% ethyl acetate in hexanes) gave compound 26 as an oil (0.50 g, 2.0 mmol, 80%); thin layer chromatography (25% ethyl acetate: hexane) found to contain R_fA point of 0.51 is set as,¹H-NMR(CDCl₃) The result is consistent with the structure. EXAMPLE 8 Synthesis of butyric acid (5-oxo-1, 3-oxathiolan-2-yl) methyl ester (25) from 2, 2-diethoxyethanol (27) in acid 2, 2-diethoxyethyl ester (28)

To a well stirred solution of 27(Lancaster 6282, 13.4 g, 100 mmol), DMAP (61 mg, 0.5 mmol) and triethylamine (16 ml, 11.64 g, 115 mmol) was slowly added n-butyryl chloride (10.90 ml, 11.19 g, 105 mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 1 hour and then diluted with ethyl acetate (50 ml) followed by washing with concentrated sodium bicarbonate (2 × 100 ml) and brine (2 × 100 ml), dried, filtered and evaporated to give a yellow liquid 28(21.5 g, 100 mmol, 100%). This material was used in the next step without further purification. Synthesis of butyric acid (5-oxo-1, 3-oxathiolan-2-yl) methyl ester (25)

Well stirred 28(6.13 g, 30 mmol), thioglycolic acid (4.14 g, 3.13 ml, 45 mmol) and p-toluenesulfonic acid monohydrate (p-tsoh. h)₂O, 60 mg, 31 mmol) in dry toluene was heated to reflux for 2 hours. The solvent was removed sometimes with a Dean-Stark trap and fresh, anhydrous toluene was added. Cooled to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml) and then washed with concentrated sodium bicarbonate (2 × 100 ml) and brine (2 × 100 ml), dried, filtered and evaporated to give yellow liquid 25(5.2 g, 25.5 mmol, 85%). This material was used in the next step without further purification. Example 9 Synthesis of (5-oxo-1, 3-oxathiolan-2-yl) methyl butyrate (25) and (5-acetoxy-1, 3-oxathiolan-2-yl) methyl butyrate (26) from 2, 2-diethoxyethanol (27) from 2, 2-diethoxyethyl butyrate (28) and 2-oxoethyl butyrate (24) to 2-oxoethyl butyrate (24)

A stirred solution of 28(8.16 g, 40 mmol) in DCM dichloromethane (200 ml) was treated at room temperature with TFA (444.4 g, 30 ml, 390 mmol) and water (7.2 g, 7.2 ml, 400 mmol). After stirring at room temperature for 2 hours, the solution was evaporated at 35 ℃. Subsequent co-evaporation with several additions of hexane removed traces of TFA. Colorless liquid 24(5.2 g, 40 mmol, 100%) was obtained. This material was used in the next step without further purification. Synthesis of butyric acid (5-oxo-1, 3-oxathiolan-2-yl) methyl ester (25)

To a well stirred suspension of 24(1.3 g, 10 mmol) and CSA (116 mg, 0.50 mmol) in dry DCM (5 ml) was slowly added a solution of thioglycolic acid (2.76 g, 2.08 ml, 30 mmol) in dry DCM (5 ml). The reaction was carried out at room temperature under stirring for 16 hours. The reaction mixture was diluted with DCM (20 ml), washed with concentrated sodium bicarbonate (3 × 30 ml) and brine (2 × 30 ml), dried, filtered and evaporated to give a colourless slurry 25(0.9 g, 4.4 mmol, 44%). Synthesis of butyric acid (5-acetoxy-1, 3-oxysulfide)Heterocyclopent-2-yl) methyl ester (26)

To a well stirred solution of 24(2.6 g, 20 mmol) and 1, 4-dithian-2, 5-diol (1.68 g, 11 mmol) in anhydrous tetrahydrofuran THF (10 ml) was added boron trifluoride etherate (312 mg, 278 μ l, 2.2 mmol). The mixture was stirred at room temperature for 16 hours. The solid was removed by filtration, and to the remaining solution were added anhydrous pyridine (2.3 g, 2.4 ml, 29 mmol), DMAP (18 mg, 0.15 mmol) and acetic anhydride (30 g, 2.77 ml, 29 mmol). The solution was stirred at room temperature for 16 hours. The reaction was quenched with 8% hydrochloric acid and extracted with ethyl acetate. The organic phase was separated and washed with 8% hydrochloric acid, brine, concentrated sodium bicarbonate and brine, dried, filtered and evaporated to give a pale yellow slurry 26(3.5 g, 14 mmol, 70% purity 60%). EXAMPLE 10 Synthesis of butyric acid (5-oxo-1, 3-oxathiolan-2-yl) methyl ester (25) and butyric acid (5-acetoxy-1, 3-oxathiolan-2-yl) methyl ester (26) from 1, 2-ethanediol (29) Synthesis of butyric acid 2-hydroxyethyl ester (30)

To a well stirred solution of 29(834 g, 750 ml, 13.5 mol) and triethylamine (116 g, 160 ml, 1.15 mol) was slowly added n-butyryl chloride (122 g, 120 ml, 1.15 mol) at 0 ℃. The reaction was stirred at room temperature for 16 hours.

The solution was diluted with brine (1.5 l) and stirred for an additional 1 h. And the diester removed by extraction with heptane (3X 700 ml). The aqueous layer was extracted with ethyl acetate (3 × 600 ml). The combined organic phases were washed with water to remove residual ethylene glycol (29), dried, filtered and evaporated to give compound 30(39.7 g, 0.30 mol, 26%). Synthesis of 2-oxoethyl butyrate (24)

A suspension of phosphorus pentoxide (42.53 g, 150 mmol) in anhydrous DCM (100 ml) was mechanically stirred at 0 ℃, then 30(11.0 g, 83 mmol) was added slowly, followed by dimethyl sulfoxide DMSO (13 g, 11.8 ml, 166 mmol). Stirring was carried out at 0 ℃ for 1 hour, the ice bath was removed and the mixture was stirred at room temperature for a further 1.5 hours. Then cooled to 0 ℃ again and triethylamine (42 g, 58 ml, 416 mmol) was added slowly.

The reaction was stirred at room temperature for a further 6 hours. The reaction was quenched by the addition of 1.0M hydrochloric acid (60 mL) at 0 deg.C and stirring was continued for 30 minutes at 0 deg.C. The organic phase was washed with water (2 × 250 ml), dried, filtered and evaporated to give a yellow liquid 24(6.60 g, 51 mmol, 61%). This material was used in the next step without further purification. Synthesis of butyric acid (5-oxo-1, 3-oxathiolan-2-yl) methyl ester (25)

To a well stirred suspension of 24(1.3 g, 10 mmol) and CSA (116 mg, 0.50 mmol) in dry DCM (10 ml) was slowly added a solution of thioglycolic acid (2.76 g, 2.08 ml, 30 mmol) in dry DCM (5 ml). The reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (20 ml), washed with concentrated sodium bicarbonate (3 × 30 ml) and brine (2 × 30 ml), dried, filtered and evaporated to give a yellow slurry 25(1.4 g, 6.8 mmol, 68%). Synthesis of butyric acid (5-acetoxy-1, 3-oxathiolan-2-yl) methyl ester (26)

To a well stirred solution of 24(2.6 g, 20 mmol) and 1, 4-dithian-2, 5-diol (1.68 g, 11 mmol) in anhydrous tetrahydrofuran THF (10 ml) was added boron trifluoride etherate (312 mg, 278 μ l, 2.2 mmol). The mixture was stirred at room temperature for 16 hours. The solid was removed by filtration, and to the remaining solution were added anhydrous pyridine (2.3 g, 2.4 ml, 29 mmol), DMAP (18 mg, 0.15 mmol) and acetic anhydride (30 g, 2.77 ml, 29 mmol). The solution was stirred at room temperature overnight. The reaction was quenched with 8% hydrochloric acid and extracted with ethyl acetate. The organic phase was separated and washed with 8% hydrochloric acid, brine, concentrated sodium bicarbonate and brine, dried, filtered and evaporated to give a pale yellow slurry 26(4.75 g, 19 mmol, 95% purity 95%). III.1 coupling of 1, 3-Oxothiopentanes with protected bases example 11 coupling of 1, 3-Oxothiopentanes with protected bases Using titanium Isopropoxide trichloride

The protected acetate (150 mg, 0.604 mmol, 1 eq) was dissolved in 1.5 ml of anhydrous dichloromethane under argon. In a separate vessel bis-silylated cytosine (154 mg, 0.604 mmol) was dissolved in 1.5 ml of anhydrous dichloromethane under argon protection and mixed with 1 equivalent of freshly prepared titanium isopropoxide trichloride (0.75 equivalent of titanium tetrachloride from Aldrich in 1M dichloromethane and 0.25 equivalent of titanium tetraisopropoxide). A solution of the complex of base and titanium isopropoxide trichloride was added dropwise to the acetate, and the resulting pale yellow clear solution was stirred at room temperature for an additional 20 minutes, after which 0.6 ml of titanium tetrachloride (1M in methylene chloride from Aldrich) was added slowly. The resulting red solution was stirred at room temperature for 2 hours, after which 1 ml of ammonium hydroxide was added. After 30 minutes the mixture was filtered through silica gel using 4: 1-hexane: ethyl acetate and 9: 1-ethyl acetate: ethanol as eluents to give a white foam which was analysed by nuclear magnetic resonance essentially corresponding to the protected nucleoside analogue, 3 TC. In another embodiment, for example, trimethylsilyl triflate and trimethylsilyl iodide or a mixture of both can be used as the lewis acid in the coupling step. EXAMPLE 12 Synthesis of butyric acid [5- (4-amino-5-fluoro-2-oxo-1 (2H) -pyrimidinyl) - (1, 3-oxathiolan-2-yl)]Methyl ester (2R/2S, B) [31(2R/2S, beta ]]

Chlorination of racemic acetate: hydrogen chloride gas was bubbled into a solution of 26(2R/2S) (49.6 g, 0.2 moles) of chloroform (0.5L) at 0 deg.C over 75 minutes. The homogeneous dark yellow solution was stirred for a further 30 minutes, then toluene (100 ml) was added, the solution was concentrated at 48 ℃ under reduced pressure and the solvent was evaporated. The additional toluene was repeated twice. The resulting crude oil was diluted with chloroform (100 ml) and this solution was used for coupling (see below).

Silylation of 5-fluorocytosine: 5-fluorocytosine (30.96 g, 0.24 mol), ammonium sulfate (1 g) and a solution of 1, 1, 1, 3,3, 3-hexamethylsilazane (100 ml, 0.48 mol) in chloroform (0.5 l) were refluxed for 4 hours to give a uniform solution. The solution was cooled to room temperature.

Coupling of silylated 5-fluorocytosine and racemic chloride: the silylated 5-fluorocytosine solution is added to the racemic chloride solution. The resulting solution was heated to reflux for 3 hours and then cooled to room temperature. The solution was diluted with ethyl acetate (300 ml) and concentrated sodium bicarbonate (300 ml) was added. After stirring the mixture at room temperature for a further 1 hour, the phases were separated. The aqueous layer was extracted once with DCM (100 ml), the organic layers were combined and dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The crude product was chromatographed on silica gel to give the desired product 31(2R/2S) (48.8 g, 77%) with a ratio of β: α Anomers (AUC) of 3.5: 1.

Separation of the beta anomers: to a 3: 5: 1 anomer mixture (48.8 g) was added ethyl acetate (290 ml). The suspension was heated under reflux for 10 minutes to obtain a homogeneous solution. The oil bath was removed and the beta anomer (10 mg) was seeded. The mixture was allowed to stand at room temperature for 2 hours. The resulting white crystals were recovered by filtration to give compound 31(2R/2S) (25.4 g, 52% recrystallization recovery) in which the ratio of β: α anomers was 97: 3(AUC) by HPLC.

Instead of the butyrate ester, e.g., benzoate, p-methoxybenzoate and p-tert-butylbenzoate, an oxo acid ester can be coupled with silylated 5-fluorocytosine following the same procedure above to give a corresponding product mixture having a ratio of β: α anomers of 2.2: 1, 2: 1, respectively.

Any suitable organic solvent, including toluene, chloroform, acetic acid, tetrahydrofuran, ethers, benzene, and other common solvents may be used for the chlorination reaction. The solvent has no significant effect on the chlorination reaction or on the stereoselectivity of the final product. However, the stereoselectivity of the coupling reaction of the oxo acid ester with the silylated 5-fluorocytosine is strongly influenced by the solvent. When the above coupling is carried outThe ratio of beta to alpha Anomers (AUC) was 3.0 to 5.0: 1 when the reaction was run in chloroform, and 2.8: 1 in toluene. EXAMPLE 13 Synthesis of butyric acid [5- (4-amino-5-fluoro-2-oxo-1 (2H) -pyrimidinyl) -1, 3-oxathiolan-2-yl]Methyl ester (2R, beta/alpha) [31(2R, beta/alpha)]

Chlorination of chiral acetate: to a solution of chiral acetate 26(2.7 g, 8.0 mmol) [ AUC by gas chromatography 74% ] in 1, 2-dichloroethane (40 ml) was added a solution of hydrogen chloride (16 mmol) in 1, 2-dichloroethane (26 ml) at 0 ℃. After stirring for 30 minutes, a solution of hydrogen chloride (8 mmol) in 1, 2-dichloroethane (13 ml) was added. After the solution was stirred for 1 hour, it was further treated with a solution of hydrogen chloride (16 mmol) in 1, 2-dichloroethane (26 ml), and stirred for 1 hour. When the acetate was consumed, it was degassed with nitrogen for 0.25 h and stored at 0 ℃ under nitrogen until required.

Silylation of 5-fluorocytosine: a suspension of 5-fluorocytosine (1.55 g, 12.0 mmol), ammonium sulfate (155 mg) and 1, 1, 1, 3,3, 3-hexamethylsilazane (7.6 ml, 36 mmol) in 1, 2-dichloroethane (80 ml) was refluxed for 2 hours (the mixture became a uniform pale yellow solution after nearly 1 hour). After completion, the solution was cooled to 0 ℃ and stored under nitrogen until needed.

Coupling of silylated 5-fluorocytosine and chiral chloride: the chiral chloride solution generated above was carefully added to the silylated base under nitrogen protection. The resulting cloudy mixture was heated to reflux for 2 hours. The resulting homogeneous, pale yellow solution was cooled to room temperature and quenched with 1/2 volumes of concentrated sodium bicarbonate. After phase separation the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2.5 g of a viscous brown oil. This oil was purified by passing through silica gel with 5% ethanol: after DCM chromatography development the expected product 31(2R) (1.9 g 76%) was obtained with a beta: alpha anomer ratio of 60: 40 (AUC). The anomers cannot be separated by fractional crystallization. Example 14Synthesis of 4-amino-5-fluoro-1- [ 2-hydroxymethyl-1, 3-oxathiolan-2-yl]-2(1H) -pyrimidinones (2R, β/α) [32(2R, β/α)]

A solution of 31(2R, β/α) (29.61 g, 93.3 mmol), and n-butylamine (30 ml, 304 mmol) was stirred in methanol (400 ml) at room temperature for 16 h. The reaction was concentrated under vacuum. Ethyl acetate (3 × 400 ml) was added and removed under vacuum. Additional methanol (250 ml) was added and removed under vacuum. The crude product was triturated with DCM (250 ml), filtered and washed with more DCM (2 × 100 ml). The tan solid product was dried under vacuum at 45 ℃ for 1 hour to give 32(2R) (18 g, 72 mmol, 77%) with a ratio of β: α anomers of 60: 40 (AUC). This material was used in the next step without further purification. The anomers cannot be separated by fractional crystallization. Synthesis of hydrochloride salt of alpha beta (-) -FTC [32(2R, beta/alpha) ]]

A [32(2R, β/α) ] (60: 40. beta.: α anomer mixture, 3.0 g) mixture of (-) -FTC was dissolved in methanol (30 mL), cooled to 0 deg.C and treated with a 4.0M solution of hydrogen chloride in 1, 4-dioxane (3.3 mL [1.1X ]). The solution was stirred for 20 minutes, then concentrated and evaporated to dryness to give an off-white solid.

Example 15 hydrochloride salt of α:β (-) -FTC [32(2R,. beta./. alpha.) ]]By recrystallization of

Crude (-) -FTC hydrochloride [32(2R, beta/alpha) hydrochloride](60: 40. beta.:. alpha. anomer mixture, 3.0 g) was dissolved in hot ethanol (20 ml). The resulting homogeneous solution was left overnight at room temperature. The resulting crystals were collected. 0.9 g of pure beta material was obtained. The mother liquor was concentrated and the mixture was recrystallized from ethanol to yield 0.5 g of pure α isomer. The combined mother liquors were concentrated again and the material was recrystallized from ethanol to yield 0.5 g of pure β isomer. Co-recovering 1.4 g of beta anomerThe rate was 78% (theoretical yield of the desired β isomer was 1.8 g). Chiral HPLC analysis showed no racemization in the formation of the salt. EXAMPLE 16 Synthesis of Emtricitabine ((-) -FTC or 32(2R, β))

The free base was recovered and the hydrochloride salt (hydrochloride salt of 32(2R, β)) was taken up in 10 volumes of methanol and treated with 3 equivalents of IRA-92 resin. The mixture was stirred for 16 hours and the resin was filtered off. The solvent was removed in vacuo leaving the free base (32(2R, β)) in 90% yield. The ethyl acetate or tetrahydrofuran slurry may be further purified.

The invention has been described with reference to the preferred embodiments. Variations and modifications of the present invention will be obvious to those skilled in the art in view of the foregoing detailed description of the invention. And thus such changes and modifications are intended to be included within the scope of the present invention.

Claims (8)

1. By reacting a compound of the formula (R)¹O)₂Preparation of 2- [ R by direct reaction of acetal of CHR with mercaptoacetic acid¹C(O)OCH₂]A process for preparing (E) -1, 3-oxathiolan-5-one, wherein R is- (CH)₂-O-C(O)R¹)，R¹Is alkyl, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle or arylalkyl.

2. The process according to claim 1, wherein the reaction is carried out in an anhydrous organic solvent.

3. The process of claim 1 further comprising conducting the reaction in the presence of a lewis or protonic acid.

4. The process according to claim 1, wherein (OH) is used₂CHR or (R)¹O) (OH) CHR instead of (R)¹O)₂CHR。

5. The process according to claim 1, wherein (R) is used¹O) (OH) CHR instead of (R)¹O)₂CHR。

6. The process according to claim 1, wherein the acetal is a mixture of hemiacetals, acetal monomers or higher condensation products thereof.

7. The process according to claim 1, which further comprises preparing (R)¹O)₂CHR, i.e. by converting the general formula HO-CH₂-CH＝CH-CH₂Compounds of the formula-OH with C1C (O) R¹Reaction to form R¹C(O)OCH₂CH＝CH-CH₂OC(O)R¹Which can form the target compound by ozonolysis or other dissociation means.

8. The process according to claim 1, which further comprises preparing (R)¹O)₂CHR, i.e. reduction (R)¹O)₂CHC (O) H to (R)¹O)₂CHCH₂OH with ClC (O) R¹The reaction forms the target compound.