PRIORITY

This application claims the benefit under Indian Provisional Application No. 1876/CHE/2013, filed on April 26, 2013 entitled "An improved process for the preparation of Emtricitabine", the contents of which is incorporated by reference herein.

FIELD OF THE INVENTION The present invention generally relates to an improved process for preparation of Emtricitabine in high yield and purity. More particularly, the invention relates to a process for isolating emtricitabine in a high purity without involving emtricitabine organic or inorganic acid salts as an intermediate. BACKGROUND OF THE INVENTION

Emtricitabine, also known as 4-amino-5-fluoro-l-[(2R,5S)-2-(hydroxymethyl)-l,3- oxatMolan-5-yl]-2-(lH)-pyrimidinone, is represented by the structural Formula I:

Formula I

Emtricitabine (FTC) is a nucleoside reverse transcriptase inhibitor (NRTI) for the treatment of HrV in adults and children, which, works by inhibiting reverse transcriptase, the enzyme that copies HIV RNA into new viral DNA. Emtricitabine is the cis-enantiomer having 2R,5S absolute configuration. Emtricitabine is available in the market under the trade name Emtriva® and a fixed dose in combination with tenofovir as trade name Truvada®.

The synthetic approach adopted for emtricitabine involves introduction of the pyrimidine base in the 1,3-oxathiolane ring. There are various processes used in the prior art for the preparation of emtricitabine using different, synthetic approaches. Generally the process involves enaymatic or stereoselective chemical synthesis for the preparation of chiral emtricitabine. The stereoselective chemical synthesis particularly comprises two kinds of processes. First one is the reduction of L- menthyl emtncitabine with reducing agent in the presence of a solvent to obtain a salt of emtncitabine and subsequent conversion of the salt of emtncitabine to obtain emtricitabine free base, involving tedious and lengthy methods of separation and the second process involves the preparation of emtricitabine free base directly without forming the salts of emtricitabine by reduction of L-menthyl emtricitabine with reducing agent in presence of buffer solution and solvent.

U.S. Patent No. 5,696,254 ("the '254 Patent") discloses a stereo selective chemical synthesis for the preparation of emtricitabine of formula I. The process comprises steps of: (i) reaction of L-menthyl emtricitabine with lithium, aluminum hydride (LAH) as a reducing agent in the presence of tetrahydrofuran (THF) as a solvent and the obtained reaction mixture was subjected to column chromatography to yield gummy solid, which was dried azeotropically with toluene to obtain emtricitabine in 80 % yield. Even though the process disclosed in the US '254 Patent provides emtricitabine with 80% yield, the process involves use of hazardous reagents and tedious process for the isolation of emtricitabine. The process involves use of LAH as a reducing agent, which is highly corrosive in nature. Moreover, the product emtricitabine isolated from the reaction mixture using column chromatography and is obtained as a gummy solid; thereby making the process is tedious, hazardous and industrially disadvantageous.

U.S. Patent No. 6,051,709 ("the '709 Patent") discloses a process for preparing cis nucleoside analogues in which L-menthyl cis- l,3-oxathiolan-5-yl-2R-carboxylate derivative is condensed with 5-fluorocytosine in the absence of Lewis acid to afford L-menthyl l,3-oxathiolan-5S-(5-fluorocytosin-l-yl)-2R-carboxylate. It further provides a process for isolation of such nucleoside analogues in the form of salts. It specifically exemplifies the isolation of lamivudine, a defluoro analogue of emtricitabine as its salicylate salt. This patent necessitates isolation of salt of cis- nucleoside analogues and then conversion of such salt compounds to free base, thereby making the process lengthy and tedious and hence, not viable for commercial manufacturing.

U.S. Patent No. 8,350,030 ("the '030 Patent") discloses a process for the preparation of emtricitabine of formula I comprising the steps of: (i) reducing the L- menthyl emtricitabine with reducing agent in the presence of organic solvents to obtain reaction mixture containing emtricitabine, (ii) followed by insitu salification of emtricitabine using an organic acid or a mineral acid in the presence of an organic solvent to yield organic or mineral acid salt of emtricitabine, such as hydrochloride, hydrobromide or methane sulfonate salt of emtricitabine, (iii) neutralizing the product obtained in step (ii) using an organic amine bases in the presence of organic solvent to yield emtricitabine. The process disclosed in the Ό30 patent involves additional step of isolation of emtricitabine salts as an intermediate step, which further conversion in to emtricitabine free base, thereby making the process lengthy and not viable for commercial operations.

U.S. Patent No 7,534,885 ("the '885 Patent") discloses a process for the preparation of emtricitabine by reduction of L-menthyl Emtricitabine with a solution of sodium borohydride and 30% sodium hydroxide in water in presence of a mixture of tetrahydrofuran, methanol and water as solvent, potassium carbonate and dipotassium hydrogen phosphate, then crystallizing the thus obtained emtricitabine in a solvent mixture of methanol and isopropyl acetate to obtain emtricitabine having about 0.16 w/w (25.5%) yield.

PCT Publication No. WO 2007/077505 ("the '505 publication") discloses a process for the preparation of emtricitabine comprising the steps of: (i) reaction of L- menthyl emtricitabine with a solution of sodium borohydride in the presence of dipotassium hydrogen phosphate and 8.5 volmes of ethanol solvent, (ii) adding an aqueous acid to the mixture to adjust pH of the reaction mixture to 7.2, (iii) the resulted mixture was stirred and concentrated under vacuum to obtain an oily residue, (iv) treating the residue with absolute ethanol and concentrating under vaccum to obtain a foamy residue, (v) the residue further treated with ethanol, heated to reflux (vi) cooled the reaction mixture and isolated the emtricitabine having yield of about 57%. PCT Publication No. WO 2011/120927 ("the '927 publication") discloses a process for the preparation of emtricitabine by reduction of L-menthyl emtricitabine with sodium borohydride in presence of methanol solvent at about -7°C, then separating the boron species followed by isolating the emtricitabme in a mixture of isopropanol and water. The '927 publication discloses the reduction step is carried out at lower temperatures, resulting in a process that is expensive, particularly on a commercial scale.

PCT Publication No. WO 2012/131541 ("the '541 publication") discloses the preparation of emtricitabine by reduction of L-menthyl emtricitabine with sodium borohydride in aqueosu sodium hydroxide in presence of buffer solution and isopropanol, later isolating in ethanol or isopropanol to obtain emtricitabine having yields in the range of about 50-60%.

PCT Publication No. WO 2013/021290 (the 290 publication) discloses a process the preparation of emtricitabine by reduction of L-menthyl emtricitabine with sodium borohydride in presence of buffer solution and ethanol, later emtricitabine is isolated in methanol with yield of about 80%, however the product contains about 2% of enantiomer content.

The processes for preparation of emtricitabine described in the above literature have certain drawbacks as it involves: a) use of hazardous reagents and tedious process for the isolation b) preparation of emtricitabine via formation of emtricitabine salts, which makes the process lengthy and expensive.

The process for the isolation of emtricitabine disclosed in the cited prior art references mostly suggest saltification of emtricitabine as intermediate stage, which is subsequent neutralization to yield emtricitabine free base. The reported process for the preparation emtricitabine necessitates isolation of emtricitabine from the reaction mixture as a salt of emtricitabine for the reason being emtricitabine is highly soluble in water and other polar solvents, thereby making isolation of emtricitabine from the reaction mixture difficult. Further isolation of emtricitabine salts as an intermediate stage removes emtricitabine acid impurity, which is formed · during the course of reduction using sodium borohydride in aqueous sodium hydroxide. Preparation of emtricitabine via formation of emtricitabine salts makes the process lengthy and expensive.

Hence there remains a need to develop a single step process for the preparation of emtricitabine from L-menthyl emtricitabine, avoiding preparation of any salt of emtricitabine as an intermediate, which is simple, cost-effective and industrially applicable.

The present invention provides a single step process for the preparation of emtricitabine in good yield and high purity from L-menthyl emtricitabine through an improved process, which involves addition of solid sodium borohydride as a reducing agent in a lot wise manner, which process minimizes the formation of unwanted acid impurity, thereby avoiding the step of saltification of emtricitabine as an intermediate and further use of ketone and/or alcohol solvents to crystallize the emtricitabine: Thus, the present invention provides a simple, cost-effective, industrially applicable process for the isolation of emtricitabine.

OBJECT OF THE INVENTION

The main object of the present invention is to provide a single step process for the preparation of emtricitabine in high yield, which is simple and cost effective, and avoids isolation of salts of emtricitabine as an intermediate, which is suitable for large scale production. Yet another object of the invention is to provide a single step process for the preparation of emtricitabine without isolating any organic or inorganic acid salts which affords the product in commercially acceptable yields and purity. Yet another object of the invention is to provide a process for the preparation of emtricitabine by reduction of L-menthyl emtricitabine with sodium borohydride in a lot wise addition in the presence of phosphate buffer and a polar solvent, followed by isolation in polar solvent resulting in emtricitabine having high yield of about 70%.

SUMMARY OF THE INVENTION

The present invention encompasses an improved process for the preparation of emtricitabine of Formula I in high yield, by reduction of L-menthyl emtricitabine with sodium borohydride in the presence of phosphate buffer and a solvent, then isolating the emtricitabine from polar solvents to obtain emtricitabine having high yield, which avoids isolation of salts of emtricitabine, which reduces the number of steps, makes the process simple, cost effective and suitable for large scale production.

In accordance with one embodiment, the present invention provides an improved process for the preparation of emtricitabine of Formula I, comprising the steps of:

Formula I

a) reacting L-menthyl emtricitabine of Formula II with sodium borohydride in presence of a buffer and a polar solvent, at a temperature of about 5°C to 15°C to obtain a reaction mixture;

Formula II

wherein the reaction is carried out by adding sodium borohydride in a lot wise manner;

b) isolating the emtricitabine; and

c) purifying the obtained emtricitabine from alcoholic solvent to obtain pure emtricitabine.

In accordance with a second embodiment, wherein isolating the emtricitabine of step b) further comprising the steps of:

i) separating the polar solvent from the reaction mixture obtained from step a), ii) adding an aqueous acid to the polar solvent mixture of step (i) to adjust the pH of the reaction mixture to about 5.0-6.5;

iii) filtering off the inorganic salts obtain in step ii),

iv) adding an aqueous base to the filtrate obtain in step iii) to adjust the pH of the reaction mixture to about 8.0-8.5 and distilling out the polar solvent to obtain aqueous solution,

v) extracting the aqueous solution with a non polar solvent and distilling out the aqueous solution to obtain semi solid product,

vi) diluting the semi solid product with alcoholic solvent and distilling out the solvent to remove the traces of water,

vii) diluting the mixture of step (vi) with alcoholic solvent and refluxing the reaction mixture,

viii) filtering off the inorganic salts obtain in step vii) and distilling out the filtrate to obtain residue, and

ix) crystallizing the residue of step viii) with a ketone and/or alcohol solvents to obtain emtricitabine.

In accordance with a third embodiment, the present invention provides a process for purification of emtricitabine, comprising:

a) providing a solution or suspension of emtricitabine in a polar solvent selected from a ketone solvent or an alcohol solvent,

b) cooling the reaction mass,

c) stirring for about 2 hours and filtering the crude emtricitabine,

d) treating the crude emtricitabine with an alcohol solvent, ·

e) heating the reaction mass at a temperature of about 30°C to about reflux temperature, and

f) cooling the reaction mass to less than 10°C and ^filtering the pure emtricitabine having purity greater than about 99.8%. DETAILED DESCRIPTION OF THE INVENTION The present invention encompasses an improved single step process for the preparation of emtricitabine of Formula I in high yield, by reduction of L-menthyl emtricitabine with sodium borohydnde in the presence of phosphate buffer and a solvent, then isolating the emtricitabine with an improved conditions and crystallizing from a ketone and/or alcohol solvents to obtain emtricitabine with improved yields and high purity, which avoids isolation of salts of emtricitabine, which reduces the number of steps, makes the process simple, cost effective and is suitable for large scale production.

In one embodiment, the present invention provides an improved process for the preparation of emtricitabine of Formula I, comprising the steps of:

Formula I

a) reacting L-menthyl emtricitabine of Formula II with sodium borohydnde in presence of a buffer and a polar solvent, at a temperature of about 5°C to 15°C to obtain a reaction mixture;

Formula II

wherein the reaction is carried out by adding sodium borohydride in a lot wise manner;

b) isolating the emtricitabine; and

c) purifying the obtained emtricitabine from alcoholic solvent to obtain pure emtricitabine. In accordance with a second embodiment, wherein isolating the emtricitabine of step b) further comprising the steps of: i) separating the polar solvent from the reaction mixture obtained from step a), ii) adding an aqueous acid to the polar solvent mixture of step (i) to adjust the pH of the reaction mixture to about 5.0-6.5;

iii) filtering off the inorganic salts obtain in step ii),

iv) adding an aqueous base to the filtrate obtain in step iii) to adjust the pH of the reaction mixture to about 8.0-8.5 and distilling out the polar solvent to obtain aqueous solution,

v) extracting the aqueous solution with a non polar solvent and distilling out the aqueous solution to obtain semi solid product,

vi) diluting the semi solid product with alcoholic solvent and distilling out the solvent to remove the traces of water,

vii) diluting the mixture of step (vi) with alcoholic solvent and refluxing the reaction mixture,

viii) filtering off the inorganic salts obtain in step vii) and distilling out the filtrate to obtain residue, and

ix) crystallizing the residue of step viii) with a ketone and/or alcohol solvents to obtain emtricitabine.

The starting material of the process, (lR,2S,5R)-menthyl-(2S,5R)-5-(4-amino-5- fluoro-2-oxo-l(2H)-pyrimidinyl)-l,3 -oxathiolane-2-carboxylate (L-menthyl emtricitabine of Formula II) is a known compound and can be prepared by any process disclosed i the literature. For example, the compound of Formula II may be prepared by following the process disclosed in the US Patent No. 5,696,254, which is incorporated herein by reference.

According to step a) of the foregoing process involves the reaction of L-menthyl emtricitabine with sodium borohydride as reducing agent in the presence of a buffer and a polar solvent to obtain a reaction mixture.

The buffer used herein is selected from the group consisting of dipotassium hydrogen phosphate, potassium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen orthophosphate or mixtures thereof, preferably dipotassium hydrogen phosphate.

The reduction is conducted in the presence of a polar solvent. The polar solvent is selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, isobutanol; ether solvents such as tetrahydrofuran, 1,4-dioxane, diethyl ether or dimethyl ether and the like; preferably methanol, ethanol, isopropanol, n- propanol, n-butanol or isobutanol; more preferably ethanol or isopropanol.

The reduction process of L-menthyl emtricitabine in to emtricitabine is schematically represented as follows:

It has been observed that during the reduction of L-menthyl emtricitabine with sodium borohydride by conventional methods such as fast addition of sodium borohydride either alone or in combination with aqueous sodium hydroxide generates high amounts of acid compound of Formula III as impurity along with emtricitabine. The high amounts of acid impurity may be formed due to availability of the sodium borohydride at large in the reaction medium.

Formula III

The inventors of the present invention have surprisingly found that addition of sodium borohydride in a controlled manner such as lot wise addition for about 3 to about 8 hours, at a temperature of about 5°C to 15°C are considerably favorable to minimize the formation of the acid impurity.

The process of step (a) involves: charging of buffer such as dipotassium hydrogen phosphate and water in a reaction vessel. To this mixture L-menthyl emtricitabine in polar solvent charged, followed by addition of sodium borohydride in a lot wise over about 3 hours to about 8 hours in equal lots, preferably about 5 hours at a temperature of about 5°C to about 15°C, preferably at about 8°C to about 12°C.

After compete addition of the sodium borohydride, the reaction may be stirred for about 2 to 8 hours at a temperature of about 5°C to about 15°C for complete formation of emtricitabine; preferably for about 4 hours at a temperature of about 8°C to about 12°C. After completion of the reaction, according to step (i) of the foregoing process, the aqueous and organic layers formed in the reaction mixture of step a) are separated. The organic layer containing polar solvent is used as such for next step.

Step (ii) of the foregoing process, the polar solvent of step (i) is adjusted to pH about 5.0 to 6.5 using an aqueous acid.

The aqueous acid used for pH adjustment is a mineral acid and is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid or a weak organic acid selected from the group consisting of formic acid, acetic acid or oxalic acid or a mixture thereof, preferably aqueous sulphuric acid.

The pH adjustment may be carried out at a temperature of about 5°C to 15°C, preferably at about 8°C to 12°C. After pH adjustment, the reaction temperature may be raised to about 40°C, preferably about 25°C to about 35°C for about 30 minutes. At this stage, the product, emtricitabine gets extracted in to the polar solvent and the undissolved inorganic salts precipitated out from the reaction mixture, which are separated by filtration.

In step (iv) of the foregoing process, the filtrate obtained from step iii) can be adjusted pH to about 8.0 to 8.5 with aqueous base, preferably aqueous sodium hydroxide or aqueous ammonia and the reaction mixture obtained is distilling out polar solvent to obtain aqueous solution. The distillation may be carried out at a temperature of less than 85 ° C .

The step (v) of the foregoing process, the reaction mixture obtained in step (iv) is extracted with a non-polar solvent.

The non-polar solvent used for the step (v) of the process is selected from hexane, heptane, cyclohexane, toluene, chloroform, xylene or mixture thereof, preferably the non-polar solvent used for the reaction is toluene.

The aqueous solution obtained after the extraction with non-polar solvent such as toluene, the aqueous solution may optionally be treated with charcoal for 30 minutes at a temperature of 25°C to 35°C and the reaction mixture obtained is filtered off. The filtrate obtained is distilled out under vacuum at below 60°C to obtain a semisolid material.

Step (vi) of the foregoing process, the semisolid material obtained in step (v) may be cooled to 40-45°C and diluted with an alcoholic solvent such as isopropanol and stirred for about 15 min at same temperature. The obtained reaction mass was heated to below 60°C and distill out isopropanol at a temperature of about 50°C to about 60° C under vacuum to remove the traces of water to obtain a semisolid material.

Step (vii) of the foregoing process, the semisolid material obtained in step (vi) may be cooled to 25-35°C and is diluted with alcoholic solvent such as isopropanol. The reaction temperature may be raised to about reflux temperature and stirred for about 30 minutes at same temperature.

Step (viii) of the foregoing process, the reaction mixture obtained in step (vii) may be cooled to about 75 °C and undissolved inorganic salts precipitated out from the reaction mixture are separated by filtration. The filtrate obtained is distilled out under vacuum at below 60°C to obtain emtricitabine as semisolid material.

Step (ix) of the foregoing process, the semisolid material obtained from step (viii) can be isolated by crystallization with a ketone and/or alcohol solvent to obtain emtricitabine.

In another embodiment, the present invention provides a process for purification of emtricitabine, comprising:

a) providing a solution or suspension of emtricitabine in a polar solvent selected from a ketone solvent or an alcohol solvent,

b) cooling the reaction mass,

c) stirring for about 2 hours and filtering the crude emtricitabine,

d) treating the crude emtricitabine with an alcohol solvent,

e) heating the reaction mass at a temperature of about 30°C to about reflux temperature, and

f) cooling the reaction mass to less than 10°C and filtering the pure emtricitabine having purity greater than about 99.8%.

The one or more of ketone solvent includes, but are not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; the alcohol solvents include, but are not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like and mixtures thereof; preferably the ketone solvent is acetone and the alcoholic solvent is isopropanol.

The step a) of providing a solution or suspension of emtricitabine in a polar solvent selected from a ketone solvent or an alcohol solvent; preferably either acetone or isopropanol, may include heating the reaction mass to a temperature of about 40°C to about reflux temperature, preferably to a temperature of 50 °C to about 55°C.

Emtricitabine used in the present invention can be obtained by any of the methods known in the art or by the method herein described before or it may be obtained as a solution directly from a reaction mixture containing the said ketone or alcoholic solvent in which emtricitabine is formed and used as such without isolation.

The step b) of cooling the reaction mass may include cooling the reaction mass initially to a temperature of about 30°C or less and later to a temperature of about - 10°C to about 10°C; preferably about 5 to 10°C such that the emtricitabine can be precipitated from the reaction mass. The resulting reaction mass may be stirred for 2 hours such that emtricitabine can be isolated by conventional techniques. The crude emtricitabine can be recovered by any conventional techniques known in the art, for example filtration and the resultant product may optionally be further dried by techniques known in the art, for example tray drying under vacuum.

The step d) of treating the crude emtricitabine with an alcohol solvent may be done at about 25°C.

The alcohol solvent includes, but is not limited to methanol, ethanol, isopropanol and the like; preferably isopropanol.

The reaction mass may be further heated at a temperature of about 30°C to about reflux temperature; preferably at about 75°C to about reflux; The resulting mass may be concentrated prior to isolation in order to minimize product loss in case the product is more soluble in the alcohol solvent. Alternatively, the resulting mass may be decolorized on charcoal and filtered prior to concentration. The step f) of cooling the reaction mass may include cooling the reaction mass initially to a temperature of about 25-35°C and later to a temperature of about - 10°C to about 10°C; preferably about 5 to 10°C such that the emtricitabine can be precipitated from the reaction mass. The resulting reaction mass may be stirred for 4 hours and the pure emtricitabine can be recovered by any conventional techniques known in the art, for example filtration. The resultant product may optionally be further dried by techniques known in the art, for example tray drying under vacuum.

The present invention advantageously provides emtricitabine, obtained by the process described herein, having a chemical purity of at least about 98%, as measured by HPLC, preferably at least about 99%, as measured by HPLC, and more preferably at least about 99.7%, as measured by HPLC; and contains less than 0.3%, as measured by HPLC of acid Impurity of Formula III; preferably less, than 0.15%), as measured by HPLC, and more preferably less than 0.1%, as measured by HPLC. The reported literature discloses process for the preparation of emtricitabine, which was involved additional step of isolation of salt of emtricitabine from the reaction mixture as intermediate, which further conversion in to emtricitabine free base, thereby making the process lengthy and not viable for commercial operations. In contrast, the process herein described arrives at a emtricitabine, which may be involved an improved process conditions such as sodium borohydride addition at lot wise manner to miiiimize the formation of acid impurity instead of fast addition and crystallization of emtricitabine with a ketone or alcohol solvents, thereby avoiding the additional step of saltification. Particularly, the process herein described allows that emtricitabine may be prepared substantially lower level of acid impurity.

EXAMPLES The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

EXAMPLE 1

Preparation of emtricitabine

To a 2.0 L round bottom flask equipped with a mechanical stirrer, thermometer pocket, water (330ml) and dipotassium hydrogen phosphate (137gms) was charged and stirred the reaction mixture for 10 minutes. To the reaction mixture, charged L- menthyl emtricitabine (100 gms) and ethanol (800 ml) at 25-35°C, further allowed to cool to 8-12°C and stirred for 1 hour at same temperature. To the reaction mixture, Sodium borohydride (20gms) was added lot wise over 5 hours in 8 equal lots and in equal time intervals at 8-12°C. Stirred for 4 hours at same temperature and monitored the reaction completion by HPLC. After reaction completion, the two layers formed were separated. To the organic layer dilute sulphuric acid (2.5 gms of sulphuric acid diluted with 25 ml of water) was added to adjust the pH to 6.0-6.5 at 8-12°C. The reaction mass was heated to 25-35°C and filtered the undissolved salts. To the filtrate aq ammonia was added to adjust the pH to 8.0-8.5 and the reaction mixture was distilled out and the aqueous solution obtained was extracted with toluene (200ml + 100 ml). The layers formed were separated and the organic layer was washed with water (50 ml). The total, aqueous layer was treated with charcoal (5g) and filtered. The filtrate obtained was distilled out completely at below 60°C to obtain a semisolid material. The semisolid material was diluted with isopropanol (200ml) and distilled out the isopropanol completely. The reaction mixture was again diluted with isopropanol (100 ml) and distilled out. The reaction mixture further diluted with isopropanol (600ml) and refluxed the reaction mixture at a temperature of 75°C-82°C for 30 minutes. The reaction mixture was allowed to cool to 70°C and filtered. The filtrate obtained was then distilled out to obtain residue. The residue obtained was diluted with acetone (100ml) and distilled out. The reaction mixture was again diluted with acetone (300ml) and heated to reflux for 30 minutes and then allowed to cool to 5°C to 10°C. The reaction mixture was stirred for 4 hours and filtered to obtain wet cake. The wet cake was suck dried and the wet product was charged in isopropanol (135 ml) and stirred at 40-45 °C for 30 minutes. The slurry was allowed to cool to 5-10°C and stirred for 4 hours at same temperature. The product was filtered and washed with isopropanol. The wet product was dried at about 50°C to about 55°C under reduced pressure for 8 hours to provide the title compound.

Yield: 43 gms

Purity: 99.74%

Acid impurity: 0.10% EXAMPLE 2

Preparation of emtricitabine

To a 2.0 L round bottom flask equipped with a mechanical stirrer, thermometer pocket, water (330ml) and dipotassium hydrogen phosphate (137gms) was charged and stirred the reaction mixture for 10 minutes. To the reaction mixture, charged L- menthyl emtricitabine (100 gms) and ethanol (800 ml) at 25-35°C, further allowed to cool to 8-12°C and stirred for 1 hour at same temperature. To the reaction mixture, Sodium borohydride (20gms) was added lot wise over 5 hours in 8 equal lots and in equal time intervals at 8-12°C. Stirred for 4 hours at same temperature and monitored the reaction completion by HPLC. After reaction completion, the two layers formed were separated. To the organic layer diluted sulphuric acid (2.5 gms of sulphuric acid diluted with 25 ml of water) was added to adjust the pH to 6.0-6.5 at 8-12°C. The reaction mass was heated to 25-35°C and filtered the undissolved salts. To the filtrate aq ammonia was added to adjust the pH to 8.0-8.5 and the reaction mixture was distilled out and the aqueous solution obtained was extracted with toluene (200ml + 100 ml). The layers formed were separated and the organic layer was washed with water (50 ml). The total aqueous layer was treated with charcoal (5g) and filtered. The filtrate obtained was distilled out completely at below 60°C to obtain a semisolid material. The semisolid material was diluted with isopropanol (200ml) and distilled out the isopropanol completely. The reaction mixture was again diluted with isopropanol (100 ml) and distilled out. The reaction mixture further diluted with isopropanol (600ml) and refluxed the reaction mixture at a temperature of 75°C-82°C for 30 minutes. The reaction mixture was allowed to cool to 70°C and filtered. The filtrate obtained was then distilled out up to 3 volumes remains in the flask. The reaction mixture was then allowed to cool to 5°C to 10°C and stirred for 4 hours. The precipitated solid was filtered to obtain wet cake. The wet cake was suck dried and the wet product was charged in isopropanol (135 ml) and stirred at 40-45°C for 30 minutes. The slurry was allowed to cool to 5- 10°C and stirred for 4 hours at same temperature. The product was filtered and washed with isopropanol. The wet product was dried at about 50°C to about 55°C under reduced pressure for 8 hours to provide the title compound.

Yield: 41 gms

Purity: 99.85%

Acid impurity: 0.10%

EXAMPLE 3

Preparation of emtricitabine

To a 2.0 L round bottom flask equipped with a mechanical stirrer, thermometer pocket, water (330 ml) and dipotassium hydrogen orthophosphate (137 g) was charged. The reaction mixture was allowed to cool to 25-35°C and stirred for 10 min. To the reaction mixture, isopropanol (800 ml) was charged at 25-35°C, cooled to 8-12°C and then charged with L-menthyl emtricitabine (100 g). To the reaction mixture, sodium borohydride (20 g) was added lot wise over 5 hr 15 min in 8 equal lots and in equal time intervals at 8-12°C and stirred the reaction mass for 4 hrs at same temperature. After completion of the reaction by HPLC, the two layers were separated. To the organic layer diluted sulphuric acid (3.5 g of H ₂ S0 ₄ dilute with 35 ml of D.M water) was added to adjust the pH to 5-6 at 8-12°C, and the reaction mass temperature was raised to 25-35°C, stirred for 30 min and filtered the undissolved salts. To the filtrate, aqueous ammonia (4 ml) was added to adjust the pH to 8-8.5 at 25-35°C and the reaction mass was distilled out and the aqueous solution was extracted with toluene (200+100 ml). The two layers formed were separated and the aqueous layer was filtered and the organic layer was washed with water (50 ml). The total aqueous layer was treated with charcoal (lOg) and filtered. The filtrate obtained was distilled out completely under vacuum at below 60°C to get residue. The residue was diluted with isopropanol (200 ml) and distilled out isopropanol completely at below 60°C to obtain semisolid material. The semisolid material was allowed to cool to 25-35°C and further diluted with isopropanol (600 ml) and heated to about 75-82°C and stirred for 30 minutes. The reaction mixture was allowed to cool to 70-75 °C and filtered. The filtrate obtained was distilled out completely at below 60°C to obtain semisolid material. The semisolid material was diluted with acetone (100 ml) at 55°C and distilled out acetone completely to obtain residue. The obtained residue was again diluted with acetone (300 ml) at about 55°C and then cooled to 5-10°C. The reaction mass was stirred for 2 hrs at the same temperature and filtered to obtain wet cake. The obtained wet cake was dried at 50- 55°C to obtain crude Emtricitabine. The crude Emtricitabine was diluted with isopropanol (660 ml) at 25-35°C and the reaction mass was heated to reflux temperature (78-82°C), stirred for 30 min at same temperature followed by allowed to cool to 68-72°C and treated with charcoal (4.4 g) and filtered. The filtrate obtained was partially concentrated at 65-70°C and then cooled to 5-10°C. The reaction mass was maintained 4 hrs at the same temperature and the product was filtered, washed with isopropanol. The wet product was dried at 60-65°C for 12 hrs to provide the title compound.

Yield: 44 gms

Purity: 99.86%

Acid impurity: 0.10%.