FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
&
PATENTS RULES, 2006
COMPLETE SPECIFICATION
(SECTION 10; RULE 13)
"PROCESS FOR THE PREPARATION OF CIS NUCLEOSIDES"
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI- 400013, MAHARASHTRA. INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of cis nucleosides and its pharmaceutical compositions thereof.
BACKGROUND OF THE INVENTION
Nucleosides, and in particular, 1, 3-oxathiolanes and their analogues and derivatives are an important class of therapeutic agents. For example, a number of nucleosides have shown antiviral activity against retroviruses such as human immunodeficiency viruses (HIV), hepatitis B virus (HBV) and human T-lymphotropic virus (HTLV).

Cis nucleosides i.e., Lamivudine, chemically, (2R-cis)-4-Amino-l-[2-(hydroxyrnethyl)-l,3
oxathiolan-5-yl]-2(lH)-pyrimidinone; (-)-2'-deoxy-3'-thiacytidine; (-)-l-[(2R,5S)-2-
(hydroxymethyl)-l,3-oxathiolan-5-yl]cystosine; or 3TC is a reverse transcriptase inhibitor. The therapeutic uses of lamivudine and related compounds and their preparations were disclosed in WO 91/17159. Lamivudine is commercially available as 100 mg, 150 mg and 300 mg tablets; 10 mg/mL in 240 mL oral solution. It is sold under the name EPIVIR. The combination of lamivudine and zidovudine is commercially available as 150 mg and 300 mg tablets. It is sold under the name COMBIVIR. Emtricitabine is known as antiviral drug also known under the trade name Coviracil® or FTC. The compound, as illustrated in compound of formula 1, is the cis enantiomer having the 2R,5S absolute configuration, and its chemical name is 4-amino-5-fluoro-l-[(2R,5S)-2-(hydroxymethyl)-l,3-oxathiolan-5-yl]-2(lH)-pyrimidin-2-one (CAS). The other optical isomers, i.e. the cis 2S, 5R enantiomer (lb) and the trans enantiomers 2S, 5S (Ic) and 2R, 5R (Id), have lower therapeutic activity and are therefore found to be of reduced interest in application

US 5,047,407 discloses the 1, 3-oxathiolane derivatives; their geometric (cis/trans) and optical isomers. This patent describes the preparation of Lamivudine as a mixture of cis and trans isomers. The diastereomers obtained are converted into N-acetyl derivatives before separation by column chromatography using ethylacetate and methanol (99:1); however, this patent remains silent about further resolution of the cis isomer to the desired (-)- [2R, 5SJ-Cis-Lamivudine. Secondly, as the ethoxy group is a poor leaving group, the condensation of cytosine with compound VI gives a poor yield, i.e. 30 - 40%, of compound VII. Thirdly, chromatographic separation that has been achieved only after acetylation requires a further step of de-acetylation of the cis-(±)- isomer. Also, separation of large volumes of a compound by column chromatography makes the process undesirable on a commercial scale.
(+/-) Cis (+/-) Cis Lamivudine efforts have been made in the past to overcome the shortcomings of low yield and enantiomeric enrichment. In general, there have been two approaches to synthesize (—)-[2R, 5S]-Cis-Lamivudine. One approach involves stereoselective synthesis, some examples of which are discussed below.
US 5,248,776 describes an asymmetric process for the synthesis of enantiomerically pure p-L-(-)-1, 3-oxathiolone-nucIeosides starting from optically pure 1, 6-thioanhydro-L-gulose, which in turn can be easily prepared from L- Gulose. The condensation of the 1, 3-oxathiolane derivative with the heterocyclic base is carried out in the presence of a Lewis acid, most preferably SnC14 to give the [2R, 5R] and [2R, 5S] diastereomers that are then separated chromatographically.
US 5,756,706 relates to a process where compound A is esterified and reduced to compound B. The hydroxy group is then converted to a leaving group (like acetyl) and the cis- and trans-2R-tetrahydrofuran derivatives are treated with a pyrimidine base, like N-acetylcytosine, in the presence trimethylsilyl trifiate to give compound C in the diastereomeric ratio 4:1 of cis and trans
isomers.
Scheme 1


Dissolving compound C in a mixture of 3:7 ethyl acetate-hexane separates the cis isomer. The product containing predominantly the cis-2R,5S isomer and some trans-2R,5R compound is reduced with NaBH4 and subjected to column chromatography (30% MeOH-EtOAc) to yield the below compound.
US 6,175,008 describes the preparation of Lamivudine by reacting mercaptoacetaldehyde dimer with glyoxalate and further with silylated pyrimidine base to give mainly the cis-isomer by using an appropriate Lewis acid, like TMS-1 TMS-Tf, TiC14 et cetera. However the stereoselectivity is not absolute and although the cis isomer is obtained in excess, this process still requires its separation from the trans isomer. The separation of the diastereomers is done by acetylation and chromatographic separation followed by deacetylation. Further separation of the enantiomers of the cis-isomer is not mentioned.
US 6,939,965 discloses the glycosylation of 5-fluoro-cytosine with compound F (configuration: 2R and 2S). The glycosylation is carried out in the presence of TiCB(OiPr) which is stereoselective and the cis-2R,5S-isomer is obtained in excess over the trans- 2S,5S-isomer. These diastereomers are then separated by fractional crystallization.
US 6,600,044 relates a method for converting the undesired trans-l,3-oxathiolane nucleoside to the desired cis isomer by a method of anomerization or transglycosylation and the separation of the hydroxy-protected form of cis-, trans- {-)-nucleosides by fractional crystallization of their hydrochloride, hydrobromide, methanesulfonate salts. However, these cis-trans isomers already bear the [R] configuration at C2 and only differ in their configuration at C5; i.e. the isomers are [2R, 5R] and [2R,5S]. Hence diastereomeric separation directly yields the desired [2R, 5S] enantiomer of Lamivudine
US 6,329,522 describes the invention relates to a diastereoselective process for the preparation of compounds of formula (1), wherein W is S, S=0, S02 or O; X is S, S-O, S02 or O; Rl is hydrogen or acyl, and R 2is a purine or pyrimidine base or an analogue or derivative thereof.

The cis-nucleoside analogue obtained from the reaction of the compound of formula (I) with the purine or pyrimidine base or analogue thereof may then be reduced to give a specific stereoisomer of formula (I). Appropriate reducing agents included, for example, hydride reducing agents such as lithium aluminium hydride, lithium borohydride or sodium borohydride. The stereointegrity was maintained using sodium borohydride in the presence of a phosphate or borate buffer, for example dipotassium hydrogen phosphate, as the reducing agent.
The phoT art processes described above, discloses cis-nucleoside analogue, which have been prepared by the various process.
In the process of the present invention, the cis-nucleoside analogue formula (I) is obtained by the reduction of the compound of formula (II)

which is a purine or pyrimidine base or substituted pyrimidine or analogue. We have surprisingly found that stereointegrity of cis-nucleoside derivatives is maintained using sodium borohydride as the reducing agent in the presence of alkali carbonate or bicarbonate base by treatment with organic or mineral acids to give formula (1) without isolating its corresponding salt.
It is preferred that the compound of formula (U) used in the process of the present invention is compound of formula (Ila)


wherein, R is hydrogen or fluoro.
The compound of formula (Ha) may be reduced to give a specific stereoisomer such as
Lamivudine or emtricitabine.
Despite various processes disclosed in the prior art for the preparation of cis-nucleoside analogue thereof, there is still a need for improved process for producing cis-nucleoside analogue such as for example lamivudine or emtricitabine, As mentioned before, prior art generally used 4-amino-2-oxo-pyrimidinyl-oxathiolane-2-carboxylicacid-isopropyl-methyl-cyc]ohexyl ester or ]' R, 2'S, 5'R-Menthyl-5(S)-cvtosin-ry'-lJ3-oxathiolane-2(R)-carboxylate (CME) as reactant for the preparation of cis-nucleoside analogue thereof and sodium borohydride as the reducing agent in the presence of borate or phosphate buffer. In this prior art process salicylic acid salt is obtained which has to be converted to the free base. This makes the process tedious and time consuming. Hence there is a need for a process for synthesizing cis nucleoside analogues that minimizes the total number of synthetic transformations, simplifies the steps involved and reduces the operation time.
SUMMARY OF THE INVENTION
According to first aspect of the present invention is to provide an improved process for producing cis nucleosides of formula I and its pharmaceutical^ acceptable salts.
According to another aspect of the present invention, there is provided an improved process for producing cis nucleosides of formula I, comprising the step of combining compound of formula II in the presence of hydride reducing agents, alkali carbonate/b(carbonate base dissolved in suitable solvent by treatment with organic or mineral acids to give formula (I) without isolating its corresponding salt.

According to another aspect of the present invention is provided a process for producing cis nucleosides of formula I, wherein the solvent is selected from the group comprising alcohols, hydrocarbons, esters, ethers and chlorinated solvents, or mixtures thereof-According to another aspect of the present invention is provided a process for producing cis nucleosides of formula I, wherein the hydride reducing Agents is selected from the group comprising lithium aluminum hydride, lithium borohydride or sodium borohydride and the like or mixtures thereof.
According to another aspect of the present invention is provided a process for producing cis nucleosides of formula I, wherein the alkali carbonate/bicarbonate base is selected from the group comprising sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate and the like or mixtures thereof.
Yet another aspect of the present invention is provided a process for producing cis nucleosides of JhrmuJa 1, wherein the organic or mineral acids used for the isolation of compound of formuJa (J) is selected from the group comprising fumaric acid, maleic acid, lactic acid, salicylic acid, succinic acid, glycolic acid, tartaric acid, acetic acid, citric acid, formic acid, benzoic acid, malonic acid, oxalic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, perchloric acid, phosphoric acid, phthallic acid p-toluenesulphonic acid, methanesulphonic acid. 2-naphthalenesulphonic acid, benzenesulphonic acid and 4-ch.IorobenzenesuIphonic acid and the like or mixtures thereof.

Wherein
W is S, S=0, S02s or O; X is S, S=Or S02 or 0; Ri is hydrogen or acyl; and
The invention may be summarized as given below: A. Process for producing cis nucleosides of formula (I)

R2 is a purine or pyrimidine base or substituted pyrimidine or an analogue or a derivative thereof which comprises reacting the intermediate compound of formula II,

(Ha) wherein, R is hydrogen or fluoro;
dissolved in a suitable solvent and alkali carbonate or bicarbonate base with a reducing agent, followed by treatment with organic or mineral acids to give cis nucleoside of formula (I) without isolating its salt.
B. Process as in step A above, wherein the solvent is selected from the group comprising substituted,
unsubstituted, cyclic, bicyclic, saturated, or unsaturated, straight or branched hydrocarbon but not
limited to aliphatic or aromatic hydrocarbon, having Cg-Cio atoms, alcohols, esters, ethers and
chlorinated solvents, and the like or mixtures thereof.
C. Process as in step B above, wherein the solvent is selected from the group comprising toluene;
ester such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate;
alcohols, such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran, and Dioxanc
and chlorinated solvents such as methylene chloride, and the like or mixtures thereof.
D. Process as in step C above, wherein the solvent is selected from the group comprising alcohols
Such as methanol, isopropanol, and esters such as ethyl acetate.
E. Process as in step A above, wherein the reducing agents is selected from the group comprising
lithium aluminum hydride, lithium borohydride or sodium borohydride and the like or mixtures
thereof.
F. Process as in step A above, wherein in the alkali carbonate/bicarbonate base is selected from the
group comprising sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium
bicarbonate and the like or mixtures thereof.
G. Process as in step F above, wherein the alkali carbonate or bicarbonate base is sodium
bicarbonate.
H. Process as in step A above, wherein the said organic or mineral acid is selected from the group comprising fumaric acid, maleic acid, lactic acid, salicylic acid, succinic acid, glycol ic acid, tartaric acid, acetic acid, citric acid, formic acid, benzoic acid, malonic acid, oxalic acid,

hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, perchloric acid, phosphoric acid,
p-toluenesulphonic acid, methanesulphonic acid, 2-naphthalenesulphonic acid, benzenesulphonic
acid and 4-chlorobenzenesulphonic acid and the like or mixtures thereof. I, Process as in step H above, wherein the said acid is selected from oxalic acid, succinic acid,
maleic acid, methanesulphonic acid, 4-chlorobenzenesulphonic acid, hydrochloric acid, acetic
acid and the like or mixtures thereof. J. The process as in step A above, wherein cis nucleosides of formula (I) is lamivudine or
emtricitabine and derivatives thereof. K. Use of cis nucleosides of formula (I) according as in step A above in the manufacture of a
medicament for treating HIV infections in animals and humans.
BRIEF DESCRIPTION OF DRAWING FIGURES
Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein
Scheme 1 is a schematic representation of a prior art process where compound A is esterified and reduced to compound B. The hydroxy group is then converted to a leaving group and the cis- and trans-2R-tetrahydrofuran derivatives are treated with a pyrimidine base, like N-acetylcytosine, in the presence trimethylsilyl triflate to give compound C in the diastereomeric ratio 4:1 of cis and trans isomers.
Scheme 2 is a schematic representation of an embodiment of the present invention for a process for producing cis nucleosides of formula I, comprising the step of reacting compound of formula II in the presence of hydride reducing agents, alkali carbonate or bicarbonate base dissolved in suitable solvent by treatment with organic or mineral acids to give formula (1) without isolating corresponding salt.
DETAILED DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing

particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. Al! publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed,
In accordance with the present invention, there is provided an improved process for producing a cis nucleosides of formula I and its pharmaceutically acceptable salts.

In accordance with the present invention, there is provided a process for producing the cis-nucleoside analogue obtained from the reaction of the compound of formula (II) with the purine or pyrimidine base or analogue thereof may then be reduced to give a specific stereoisomer such as lamivudine or emtricitabine or derivatives thereof. Appropriate reducing agents will be readily apparent to those skilled in the art and include, for example, hydride reducing agents is selected from the group comprising lithium aluminium hydride, lithium borohydride or sodium borohydride in the presence of alkali carbonate or bicarbonate base, for example sodium carbonate, sodium bicarbonate, potassium bicarbonate and the like or mixtures thereof for maintaining stereointegrity of cis-nucleoside analogue and after it by treatment with organic or mineral acids to give cis nucleosides of formula (I) without isolating its corresponding salt. Scheme 2:

W is S, S=0, S02, or O;
X is S, S=0, S02 or O;
R is hydrogen or fluoro;
R, is hydrogen or acyl; and
R2 is a purine or pyrimidine base or an analogue or a derivative thereof.
In accordance with the present inventio, there is provided the process for producing cis nucleosides of formula I, wherein the solvent is selected from the group comprising alcohols, hydrocarbons, esters, ethers and chlorinated solvents, or mixtures thereof. The solvent used in the present invention is selected from the group consisting of substituted, unsubstituted, cyclic, bicyclic, saturated, or unsaturated, straight or branched hydrocarbon but not limited to aliphatic or aromatic hydrocarbon, having C6-Cio atoms, Suitable solvents are generally alcohols, such as methanol, ethanol, isopropanol, hydrocarbon such as toluene, ester, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and ethers such as tetrahydrofuran, and dioxane, chlorinated solvents such as methylene chloride, or mixtures of these solvents preferably alcohols, esters or ethers or mixtures thereof, even more preferably methanol, isopropanol and ethyl acetate, or mixtures thereof.

In accordance with the present inventio, there is provided a process for producing cis nucleosides of formula I, wherein the hydride reducing agents is selected from the group comprising lithium aluminum hydride, lithium borohydride or sodium borohydride and the like or mixtures thereof.
In accordance with the present inventio, there is provided a process for producing cis nucleosides of formula I, wherein the alkali carbonate base is selected from the group comprising sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate and the like or mixtures thereof.
In accordance with the present inventio, there is provided a process for producing cis nucleosides of formula I, wherein the organic or mineral acids used for the isolation of compound of formula (I) is selected from the group comprising fiimarie acid, maleic acid, lactic acid, salicylic acid, succinic acid, glycolic acid, tartaric acid, acetic acid, citric acid, formic acid, benzoic acid. malonic acid, oxalic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, perchloric acid, phosphoric acid, phthallic acid p-toluenesulphonic acid, methanesulphonic acid, 2-naphthalenesulphonic acid, benzenesulphonic acid and 4-chlorobenzenesulphonic acid and the like or mixtures thereof.
Acids that may be used are generally organic acids, for instance mono-or polycarboxylic acids or sulphonic acids, and mineral acids provided that they are capable of forming the corresponding salts in the reaction, for instance fumaric acid, maleic acid, lactic acid, salicylic acid, succinic acid, glycolic acid, tartaric acid, acetic acid, citric acid, formic acid, benzoic acid, malonic acid, oxalic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, perchloric acid, phosphoric acid, phthallic acid, p-toluenesulphonic acid, methanesulphonic acid, 2-naphthalenesulphonic acid, benzenesulphonic acid and 4-chlorobenzenesulphonic acid, preferably oxalic acid, succinic acid, maleic acid, methanesulphonic acid, 4-chlorobenzenesulphonic acid and hydrochloric acid, and even more preferably acetic acid. The amount of acid used is at least equal to the stoichiometric or excess amount. The by-product menthol has been removed by extracting the acidic aqueous mass by using water insoluble or partly soluble solvents. Suitable solvents are generally selected from the group comprising alcohols, hydrocarbons, esters, ketone ether or cyclic ether, acetonitrile and chlorinated solvents, or mixtures of these group solvents.
The obtained acidic aqueous solution of formula I is basified by using an organic or inorganic base like mono, di, or triethyl amine, pyridine, diisopropyl ethyl amine, 4-N,N-dimethyl amine pyridine, alkali hydroxides, carbonates and bicarbonates or mixtures thereof.

The precipitated salt of the compound of formula I is generally recovered by filtration, centrifugation or decantation, preferably by filtration, although other conventional methods known to those skilled in the art may also be used. The filtration is formed using standard filtration means such as press filters, static filters, centrifuges and other standard industrial filtration techniques.
The method according to the invention may result in the preparation of cis-nucleoside analogue or salts having the moisture content and particle size in the suitable range for the preparation of pharmaceutical formulation.
The cis-nucleoside analogue produced by said process comprises lamivudine and emtricitabine and other cis-nucleoside analogue and their pharmaceutically acceptable salts.
The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of present invention in any way.
EXAMPLE 1 Preparation of Lamivudine Technical:
Aqueous sodium bicarbonate (66.0 g, 0.786 mol in 250.0 ml water), ethanol (500.0 ml) and CME (100.0 g, 0.260 mol) were combined and cooled to 10°C, Sodium borohydride (25.0 g, 0.660 mol in 50.0 ml 1% w/v sodium hydroxide solution) was added and the reaction mixture was allowed to warm to 20°C. The reaction mixture was stirred for four hours. After completion of the reaction, the solid mass and filtered and washed with WO.O ml of ethanol. The wet solid was refluxed using 300.0 ml of ethanol and the clear solution was filtered through hyflow super cell. The filtrate was acidified using acetic acid (17.0 ml) to get pH=5.0-6.0. Charcoal (5.0 g) was added to the acidic mass and filtered followed by stirring. The bed was washed with 100.0 ml of ethanol. The filtrate was concentrated under reduced pressure to give residue. Water (200.0 ml) and toluene (200.0 ml) were added to the residue and the aq layer extracted by 200.0 ml of toluene. Charcoal (5.0 g) was added to the aq. layer and filtered followed by stirring at 45°C. The bed washed with 50.0 ml of water. The aq. layer was concentrated under reduced pressure. Methanol (125.0 ml) was added and basified using triethylamine (16.0 g) to get pH= 9.0-10.5. The reaction mass was refluxed followed by adding charcoal (5.0 g). It was filtered, followed by

washing with hot methanol (50.0 ml). Adjusted the water content 9-11% (w/v) and refluxed for 3 hours. The mixture was cooled to 10°C and filtered after one hour stirring. The solid was washed with 50.0 ml of methanol. The solid was again washed with 100.0 ml of acetone. The wet solid was dried at 50°C to get 33.5 g of Lamivudine Technical. HPLC purity: 99.89 %, Isomer: Not
detected.
Procedure of Lamivudine:
Methanol (1300.0 ml) and lamivudine technical (100.0 g) were combined and refluxed up to clear solution. Charcoal (8.0 g) was added at 60-65°C and maintained for one hour. The mixture was filtered through hyflo super cell and the bed washed with 100.0 ml hot methanol. The hot filtrate was chilled to 5°C and filtered. The wet solid was dried under reduced pressure at 50°C to get 73.9 g of Lamivudine. HPLC purity. 99.96 %.
EXAMPLE 2
Preparation of Emtricitabine:
Aqueous sodium bicarbonate (63.0 g, 0.750 moles in 250,0 ml water), ethanol (500,0 ml) and FCME (100.0 g, 0.250 mol) were combined and cooled to 10°C. Sodium borohydride solution (18.94 g, 0.50 moles in 1% w/v sodium hydroxide solution) was added and then reaction mixture was allowed to warm to 20°C. The reaction mixture was stirred for four hours. After completion of the reaction, the solid mass was filtered and washed with 100.0 ml of ethanol. The wet solid was refluxed using 300.0 ml of ethanol and the solid was filtered and washed with 100ml ethanol. The filtrate was acidified using acetic acid (15.0 ml) to get pH=5.0-6.0. Charcoal (5.0 g) was added to the acidic mass and filtered followed by stirring. The bed was washed with 100.0 ml of ethanol and the filtrate was concentrated under reduced pressure to give residue. 200.0 ml water and 200.0 ml toluene were added to the residue and the aqueous layer extracted by 200.0 ml of toluene. 5.0 g Charcoal was added to the aqueous layer and filtered followed by stirring at 45°C and bed was washed with 50.0 ml of water. The aqueous layer was concentrated under reduced pressure. Methanol was added and basified using 14.0 g triethylamine to get pH= 9.0-10.5. The reaction mass was refluxed followed by adding charcoal (5.0 g). It was filtered, followed by

washing with hot methanol (50.0 ml) and distilled out Methanol completely. Add 200 ml ethanol, reflux for 15 minutes, cool to room temperature and maintained for 3 hours. The solid was filtered off and washed with 50.0 ml of chilled ethanol. The wet solid was dried at 50°C to get 33.0 g of Emtricitabine. Recrystallized in ethanol to get pure Emtricitabine. SOR - 139.2° (std --135 to -145°), Melting point - 150°C (std-149.2°C).

Claims:
1, Process for producing cis nucleosides of formula (I)

Wherein
W is S, S=0, S02, or 0;
X is S, S=0, S02 or O;
Rt is hydrogen or acyl; and
R2 is a purine or pyrimidine base or substituted pyrimidine or an analogue or a derivative thereof
which comprises reacting the intermediate compound of formula II,

wherein, R is hydrogen or fluoro;
dissolved in a suitable solvent and alkali carbonate or bicarbonate base with a reducing agent, followed by treatment with organic or mineral acids to give cis nucleoside of formula (I) without isolating its salt.
2. The process according to Claim 1, wherein the solvent is selected from the group comprising substituted, unsubstituted, cyclic, bicyclic, saturated, or unsaturated, straight or branched hydrocarbon but not limited to aliphatic or aromatic hydrocarbon, having C6-C 10 atoms, alcohols, esters, ethers and chlorinated solvents, and the like or mixtures thereof.
3. The process according to Claim 2, wherein the solvent is selected from the group comprising toluene; ester such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate; alcohols, such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran, and dioxane and chlorinated solvents such as methylene chloride, and the like or mixtures thereof.

4. The process according to Claim 3, wherein the solvent is selected from the group comprising alcohols such as methanol, isopropanol, and esters such as ethyl acetate.
5. The process according to Claim 1, wherein the reducing agents is selected from the group comprising lithium aluminum hydride, lithium borohydride or sodium borohydride and the like or mixtures thereof.
6. The process according to Claim 1, wherein the alkali carbonate/bicarbonate base is selected from the group comprising sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate and the like or mixtures thereof.
7. The process according to Claim 6, wherein the alkali carbonate or bicarbonate base is sodium bicarbonate.
8. The process according to Claim 1, wherein the said organic or mineral acid is selected from the group comprising fumaric acid, maleic acid, lactic acid, salicylic acid, succinic acid, glycolic acid, tartaric acid, acetic acid, citric acid, formic acid, benzoic acid, malonic acid, oxalic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, perchloric acid, phosphoric acid, p-toluenesulphonic acid, methanesulphonic acid, 2-naphthaIenesulphonic acid, benzenesulphonic acid and 4-chlorobenzenesulphonic acid and the like or mixtures thereof.
9. The process according to Claim 8, wherein the said acid is selected from oxalic acid, succinic acid, maleic acid, methanesulphonic acid, 4-chlorobenzenesulphonic acid, hydrochloric acid, acetic acid and the like or mixtures thereof.
10. The process according to Claim 1, wherein the cis nucleosides of formula (I) is lamivudine or emtricitabine and derivatives thereof.
11. Use of cis nucleosides of formula (I) according to claim 1 above in the manufacture of a medicament for treating HIV infections in animals and humans.