FIELD OF THE INVENTION:

The present invention provides novel acid addition salts of Emtricitabine namely naphthylates, methyl salicylates, methoxy benzoates, methoxy salicylates, halo benzoates and the like. The present invention further relates to process for the preparation of pure Emtricitabine from the said salts.

BACKGROUND OF THE INVENTION:

Emtricitabine marketed under the trade name Emtriva, is a synthetic nucleoside analog of cytidine with activity against human immunodeficiency virus type-1 (HIV-1) reverse transcriptase. Chemically Emtricitabine [commonly known as cis FTC] is 5-Fluoro-l-(2R,5S)-[2-(hydroxymethyl)-l,3-oxathiolan-5-yl]cytosine and is structurally represented in Formula I. Emtricitabine is the (-) enantiomer of thio analogs differing from other cytosine analogs viz. Lamivudine in that it has a fluorine in the 5-position.

Formula I

EP 0 526 253 Al discloses process for preparing Emtricitabine, wherein L-menthyl cis-l,3-oxathiolan-5S-acetoxy-2R-carboxylate is condensed with 5-fluoro cytosine in the presence of iodotrimethylsilane followed by reduction of the resulting L-menthyl ester group with lithium aluminium hydride to afford Emtricitabine.

The substituents on chiral carbons of purine and pyrimidine rings of 1, 3-oxathiolane nucleosides can be either in cis or trans forms. Both cis and trans racemates consist of pair of optical isomers and further each compound has four individual optical isomers.

Emtricitabine has two chiral centers and therefore four stereo isomers exist namely two cis (2R, 5S and 2S, 5R) and two trans (2R, 5R and 2S, 5S). The two cis enantiomers (2R,5S;2S;5R) together are referred to as racemic mixture of α-enantiomers. Among the four pairs the cis (2R,5S) is found to possess profound therapeutic activity.

WO 92/14743 discloses, enzymatic resolution of racemic mixture of cis isomers, to yield 2R, 5S enantiomer.

US 6541631, discloses various chiral acids for the diastereomeric separation of Emtricitabine and its enantiomers.

In prior art processes the yields of Emtricitabine are low. There is a need in the art for Emtricitabine process which gives good yields and pure compound

OBJECT OF THE INVENTION:

Principle object of the present invention is to provide novel acid addition salts of Emtricitabine.

Another object of the present invention is to provide further conversion of said acid addition salts to Emtricitabine.

Another object of the present invention is to provide processes for the preparation of novel acid addition salts of Emtricitabine and further conversion of the same to pure Emtricitabine.

SUMMARY OF THE INVENTION:

The main aspect of the present invention is to provide a process for the preparation of Emtricitabine, comprising the steps:

a) reducing (2R,5S)-5-(4-Amino-5-fIuoro-2-oxo-2H-pyrimidin-l-yl)- [1,3]-oxathiolane-2-carboxy-licacid, 2S-isopropyl-5R- methyl-IR-cyclohexyl ester [Menthyl Emtricitabine] using buffer and a base to form Emtricitabine;

b) converting the obtained Emtricitabine crude to acid addition salt;

c) treating the acid addition salt with a base; and

d) isolating Emtricitabine.

In another aspect, the present invention provides novel acid addition salts of Emtricitabine, wherein the acid addition salts of Emtricitabine are selected from 3-Hydroxy2-naphthoicacid, 4-Methyl salicylic acid, 3-Methylsalicylic acid, 2-Methoxy benzoic acid, 3-Methoxy salicylic acid, 4-Methoxy salicylic acid, 4-Fluoro benzoic acid and the like. The present invention provides further conversion of said acid addition salts to Emtricitabine

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides novel acid addition salts of Emtricitabine namely 3-Hydroxy2-naphthoicacid, 4-Methyl salicylic acid, 3-Methylsalicylic acid, 2-Methoxy benzoic acid, 3-Methoxy salicylic acid, 4-Methoxy salicylic acid, 4-Fluoro benzoic acid and the like. Present invention further provides conversion of said acid addition salts to Emtricitabine. The present invention also relates to processes for the preparation of the said salts.

In one aspect, the present invention provides a process for the preparation of Emtricitabine schematically represented in scheme I, comprising the steps:

a) reducing (2R,5S)-5-(4-Amino-5-fluoro-2-oxo-2H-pyrimidin-l-yl)- [1,3]-oxathiolane-2-carboxy-licacid, 2S-isopropyl-5R- methyl-IR-cyclohexyl ester [Menthyl Emtricitabine] using buffer and a base to form Emtricitabine;

b) converting the obtained Emtricitabine crude to acid addition salt;

c) treating the acid addition salt with a base; and

d) isolating Emtricitabine.

X=3 –Hydroxy2-naphthoicacid
2-Methoxy benzoic acid
4-Methyl salicylic acid
3-Methylsalicylic acid
4-Methoxy salicylic acid
3-Methoxy salicylic acid
4-Fluoro benzoic acid

In one embodiment, reducing agent employed for reduction of (2R,5S)-5-(4-Amino-5-fluoro-2-oxo-2H-pyrimidin-l-yl)- [l,3]-oxathiolane-2-carboxylicacid, 2S-isopropyl-5R- methyl-1R-cyclohexyl ester (Menthyl Emtricitabine) can be selected from metal hydrides such as sodium borohydride, sodium hydride, lithium aluminum hydride, Diisobutyl aluminum hydride preferably sodium borohydride and sodium hydroxide.

In another embodiment, crude Emtricitabine is extracted into aqueous layer and treated with different organic acids to obtain acid addition salts, wherein the organic acids employed for the salt preparation can be selected from 3-Hydroxy-2-naphthoicacid, 4-Methyl salicylic acid, 3-Methylsalicylic acid, 2-Methoxy benzoic acid, 3-Methoxy salicylic acid, 4-Methoxy salicylic acid, 4-Fluoro benzoic acid and the like.

In one another embodiment, the said acid addition salts are prepared in-situ.

In another embodiment, the acid addition salt of Emtricitabine is treated with a base, wherein the base is selected from organic or inorganic base. Organic base is selected from ammonia, triethylamine, diethylamine, N-N-diisopropylethylamine preferably triethylamine.

Solvent used for desaltification can be selected from alcohol solvents such as ethanol, methanol, isopropanol preferably isopropanol; ester solvent such as ethyl acetate, isopropyl acetate; ketone solvent such as acetone, methylisobutylketone; polar solvents such as N,N-dimethylformamide, tetrahydrofuran, dimethyl sulphoxide; preferably ethylacetate and the like to obtain pure Emtricitabine.

As per the present invention, Emtricitabine is prepared by reduction of L-menthyl Emtricitabine using buffer and metal hydride followed by the conversion of the obtained Emtricitabine crude to Emtricitabine acid addition salts using organic acids like 3-Hydroxy-2-naphthoicacid, 4-Methyl salicylic acid, 3-Methylsalicylic acid, 2-Methoxy benzoic acid, 3-Methoxy salicylic acid, 4-Methoxy salicylic acid, 4-Fluoro benzoic acid and finally treating the obtained acid addition salts of Emtricitabine with a base such as triethylamine in solvent such as ethylacetate to yield pure Emtricitabine.

As per the present invention, the obtained Emtricitabine is in high yields and enantiomerically more pure.

In another aspect, the present invention provides a process for the preparation of Emtricitabine comprising the steps of:

a) treating the acid addition salt of Emtricitabine with a base; and

b) isolating Emtricitabine.

wherein, the acid addition salts of Emtricitabine is selected from 3-Hydroxy-2-naphthoicacid, 4-Methyl salicylic acid, 3-Methylsalicylic acid, 2-Methoxy benzoic acid, 3-Methoxy salicylic acid, 4-Methoxy salicylic acid, 4-Fluoro benzoic acid.

In one more aspect, the present invention provides novel acid addition salts of Emtricitabine, wherein acid is selected from 3-Hydroxy-2-naphthoicacid, 4-Methyl salicylic acid, 3-Methylsalicylic acid, 2-Methoxy benzoic acid, 3-Methoxy salicylic acid, 4-Methoxy salicylic acid and 4-Fluoro benzoic acid and the like.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

EXAMPLE-1:

Preparation of 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yl) IH- pyriniidin-2-one mono naphthylate (Emtricitabine naphthylate)

A solution of dipotassium hydrogen phosphate (137 g) in water (330 ml) was stirred for 10 min. Ethanol (900 ml) was added and the reaction mass was cooled to 18 °C. (2R,5S)-5-(4-Amino-5-fluoro-2-oxo-2H-pyrimidin-l-yl)-[l,3]oxathiolane-2-carboxylicacid-2S-Isopropyl-5R- ethyl-lR-cyclohexyl ester, (100 gm) was added at 15-20 °C. The suspension was stirred for 1 hr at 18-20 °C. A solution of sodium borohydride [20gms in Sodium hydroxide solution (95 ml)] was added drop wise maintaining the temperature at 18-20°C. The mixture was stirred at 18-22 °C for 4 hrs. On completion of the reaction as confirmed by TLC, pH of the reaction mass was adjusted to 6-6.5 with dil. Hydrochloric acid followed by to 8.0 to 8.5 with 2N Sodium hydroxide. Reaction mass was transferred and ethanol was distilled off completely under reduced pressure. To the remaining mass, water was added and given washings with toluene. To the aqueous layer, 3-Hydroxy-2-naphthoicacid (47.17) was charged and acetone (100 ml) was added. Reaction contents were heated to 60-65 °C to obtain clear solution. Mass was gradually cooled to 25-30°C over 60 min and allowed to crystallize the material. Obtained solid was filtered and washed with water and acetone to isolate Emtricitabine naphthylate (60 gm).

EXAMPLE-2:

Preparation of 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothioIane-5S-yI) lH-pyrimidin-2-one 4-Methyl salicylate (Emtricitabine 4-Methylsalicylate)

To the aqueous layer (350 ml) of Example.1, 4-Methyl salicylic acid (38.15 gms,) was added and heated to 80-85 °C. Contents were stirred for 30 min. Reaction mass was gradually cooled to 25-30 °C in 60 min and allowed to crystallize the material. The obtained solid was filtered using methanol to isolate Emtricitabine 4-methylsalicylate (75 gm).

EXAMPLE-3:

Preparation of 4-Ainino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yl) lH-pyrimidin-2-one 3-MethyI salicylate (Emtricitabine 3-Methylsalicylate)

To the aqueous layer (350 ml) of Example.1, 3-Methyl salicylic acid (38.15 gm) was charged and heated to 80-85°C. Contents were stirred for 30 min. Mass was gradually cooled to 25-30 °C in 60 min and allowed to crystallize the material. The obtained solid was filtered using methanol to isolate Emtricitabine 3-methylsalicylate (70 gm).

EXAMPLE-4: Preparation of Preparation of 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yl) lH-pyrimidin-2-one 2-Methoxy benzoic acid salt To the aqueous layer (350 ml) of Example.1, 2-Methoxy benzoic acid (38.15 gm) was charged and heated to 60-65 °C. Contents were stirred for 30 min and gradually cooled to 25-30 °C in 60 min to allow for crystallization of the material. The obtained solid was filtered using methanol to isolate Emtricitabine methoxy benzoate (60 gm).

EXAMPLE-5:

Preparation of 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yl) lH-pyriniidin-2-one (Emtricitabine)

Emtricitabine naphthylate (60gr) was taken into an RB flask and charged with ethyl acetate (300 ml). Triethylamine (27.9gm) was added at 25-30 °C and contents were heated to 40-45 °C, stirred for 30 min. Mass was gradually cooled to 25-30 °C in 60 min and was allowed to crystallize. The obtained solid was filtered using ethyl acetate to isolate Emtricitabine (27 gm).

EXAMPLE-6:

Preparation of 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yl) lH-pyrimidin-2-one (Emtricitabine)

Emtricitabine 4-Methyl salicylate (60gm) was taken into an RB flask and charged with ethyl acetate (300 ml). Triethylamine (30.4 gm) was added at 25-30 °C and contents were heated to 40-45 °C, stirred for 30 min. Mass was gradually cooled to 25-30 °C in 60 min and was allowed to crystallize. The obtained solid was filtered using ethyl acetate to isolate Emtricitabine (30 gm).

EXAMPLE-7:

Preparation of 4-Ainino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yI) lH-pyriinidin-2-one (Emtricitabine)

Emtricitabine 4-Methyl salicylate (60 gm) was taken into an RB flask and charged with acetone (240 ml). Triethylamine (30.4 gm) was added at 25-30 °C and contents were heated to 40-45 °C, stirred for 30 min. Mass was gradually cooled to 25-30 °C in 60 min and was allowed to crystallize. The obtained solid was filtered using acetone to isolate Emtricitabine (20 gm).

EXAMPLE-8:

Preparation of 4-Amino-5-fIuoro-l-(2R-hydroxy methyl-[l, 3]-oxothioIane-5S-yl) lH-pyrimidin-2-one 3-Methoxy salicylate (Emtricitabine 3-Methoxy salicylate)

To the aqueous layer (350 ml) of Example. 1, 3-Methoxy salicylic acid (44 gm) was charged and heated to 80-85°C. Contents were stirred for 30 min. Mass was gradually cooled to 25-30 °C in 60 min and allowed to crystallize the material. The obtained solid was filtered using methanol to isolate Emtricitabine 3-methoxy salicylate (70 gm).

EXAMPLE-9:

Preparation of 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yl) lH-pyrimidin-2-one 4-Methoxy salicylate (Emtricitabine 4-Methoxy salicylate)

To the aqueous layer (350 ml) of Example. 1, 4-Methoxy salicylic acid (44 gm) was charged and heated to 80-85°C. Contents were stirred for 30 min. Mass was gradually cooled to 25-30 °C in 60 min and allowed to crystallize the material. The obtained solid was filtered using methanol to isolate Emtricitabine 4-methoxy salicylate (70 gm).

EXAMPLE-10:

Preparation of 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yI) lH-pyrimidin-2-one 4-Fluoro benzoate (Emtricitabine 4-Fluoro benzoate)

To the aqueous layer (350 ml) of Example.!, 4-Fluoro benzoic acid (35 gm) was charged and heated to 80-85°C. Contents were stirred for 30 min. Mass was gradually cooled to 25-30 °C in 60 min and allowed to crystallize the material. The obtained solid was filtered using methanol to isolate Emtricitabine 4-Fluoro benzoate (75 gm).

We Claim:

1. A process for the preparation of Emtricitabine comprising the steps of:

a) reducing (2R,5S)-5-(4-Amino-5-fluoro-2-oxo-2H-pyrimidin-l-yl)- [1,3]-oxathiolane-2-carboxy-licacid, 2S-isopropyl-5R- methyl-1 R-cyclohexyl ester [Menthyl Emtricitabine] using buffer and a base to form Emtricitabine;

b) converting the obtained Emtricitabine crude to acid addition salt;

c) treating the acid addition salt with a base; and

d) isolating Emtricitabine.

wherein, the acid addition salts of Emtricitabine is selected from 3-Hydroxy-2-naphthoicacid, 4-Methyl salicylic acid, 3-Methylsalicylic acid, 2-Methoxy benzoic acid, 3-Methoxy salicylic acid, 4-Methoxy salicylic acid, 4-Fluoro benzoic acid and the like.

2. A process for the preparation of Emtricitabine comprising the steps of:

a) treating the acid addition salt of Emtricitabine with a base; and

b) isolating Emtricitabine.

wherein, the acid addition salts of Emtricitabine is selected from 3-Hydroxy-2-naphthoicacid, 4-Methyl salicylic acid, 3-Methylsalicylic acid, 2-Methoxy benzoic acid, 3-Methoxy salicylic acid, 4-Methoxy salicylic acid, 4-Fluoro benzoic acid.

3. The process according to the claim 1 and 2, wherein the base is an organic base.

4. 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yl) IH-pyrimidin-2-one naphthylate.

5. 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yl) IH-pyrimidin-2-one 4-Methyl salicylate.

6. 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yl) IH-pyrimidin-2-one 3-Methyl salicylate

7. 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yl) 1H-pyrimidin-2-one 2-Methoxy benzoate.

8. 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yl) 1H-pyrimidin-2-one 3-Methoxy salicylate.

9. 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yl) 1H-pyrimidin-2-one 4-Methoxy salicylate.

10. 4-Amino-5-fluoro-l-(2R-hydroxy methyl-[l, 3]-oxothiolane-5S-yl) 1H-pyrimidin-2-one 4-Fluoro benzoate.