Claims:1. An improved process for the preparation of Cladribine of formula (I)

comprising the steps of:
a. condensing 2-chloro adenine of formula (II) or its pharmaceutically acceptable salt

with 5-chloro-2-(((4-chlorobenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-chloro benzoate of formula (III)

in presence of base and solvent to produce 5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((4-chlorobenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-chlorobenzoate of formula (IV);

b. deprotecting compound of formula (IV), to obtain Cladribine of formula (I); and
c. optionally purifying the obtained compound of formula (I) with an alcohol or water or mixture thereof to obtain highly pure cladribine.

2. An improved process for the preparation of Cladribine as claimed in claim 1, wherein the base is used in step-a) is selected from organic base such as methylamine, triethylamine, diisopropylethylamine, t-butylamine, N,N-dimethylamine, dimethylformamide, pyridine, DBU, DBN, N-methyl piperazine or inorganic base is such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide; more preferably potassium carbonate.

3. An improved process for the preparation of Cladribine as claimed in claim 1, wherein the solvent is selected from alcohol selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; ketone solvent selected from acetone, butanone, 2- pentanone, 3-pentanone, methyl butyl ketone, and methyl isobutyl ketone; ester solvent selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; and the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; polar aprotic solvent selected from dimethylformamide, acetonitrile, dichloromethane, dimethyl sulfoxide, and N-methyl- pyrrolidone; water or mixtures thereof.

4. An improved process for the preparation of Cladribine as claimed in claim 1, wherein the deprotection is carried out in presence of methanolic ammonia or methanolic sodium methoxide.

5. An improved process for the preparation of Cladribine as claimed in claim 1, wherein 2-chloro adenine or its pharmaceutically acceptable salt selected from sodium, potassium and lithium salt.

6. A cladribine intermediate of formula (IV)

7. An improved process for the preparation of Cladribine intermediate of formula (IV)

comprising condensing 2-chloro adenine of formula (II) or its pharmaceutically acceptable salt

with 5-chloro-2-(((4-chlorobenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-chloro benzoate of formula (III)

in presence of base and solvent to produce 5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((4-chlorobenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-chlorobenzoate of formula (IV).

8. An improved process for the preparation of Cladribine intermediate as claimed in claim 7, wherein the base is used in step-a) is selected from organic base such as methylamine, triethylamine, diisopropylethylamine, t-butylamine, N,N-dimethylamine, dimethylformamide, pyridine, DBU, DBN, N-methyl piperazine or inorganic base is such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide; more preferably potassium carbonate.

9. An improved process for the preparation of Cladribine intermediate as claimed in claim 7, wherein the solvent is selected from alcohol selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; ketone solvent selected from acetone, butanone, 2- pentanone, 3-pentanone, methyl butyl ketone, and methyl isobutyl ketone; ester solvent selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; and the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; polar aprotic solvent selected from dimethylformamide, acetonitrile, dichloromethane, dimethyl sulfoxide, and N-methyl- pyrrolidone; water or mixtures thereof.

10. An improved process for the preparation of Cladribine intermediate as claimed in claim 7, wherein the deprotection carried out in presence of methanolic ammonia or methanolic sodium methoxide.
, Description:FIELD OF THE INVENTION
The present invention provides an improved process for the preparation of Cladribine of formula I.

Cladribine is an active pharmaceutical ingredient useful as an anti-leukemic agent, i.e., in treatment of leukemia, such as hairy cell leukemia

BACKGROUND OF THE INVENTION
Cladribine is chemical known as 2-chloro-6-amino-9-(2-deoxy-ß-D-erythropentofuranosyl) purine and the structure represented as below:

Cladribine approved by USFDA as Leustatin™ and is useful as an anti-leukemic agent, i.e., in treatment of leukemia, such as hairy cell leukemia. 2-CdA is also known to have immunosuppressive activity. Many processes for preparing 2-CdA and similar compounds are known which involve the direct condensation or coupling of a heterocycle (e.g., purine, pyrimidine, imidazole) with an activated, conveniently protected sugar at C-1.
Brigham et al in US 4760137 provides the first disclosure of the process for the preparation of Cladribine, which comprises 2, 6-dichloropurine is condensed with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-a-D-erythro-pentofuranose in presence of sodium hydride and acetonitrile to produce 2,6-Dichloro-9-(2-deoxy-3,5-di-O-p-toluoyl-6-D-erythro-pentofuranosyl)-purine is reacted with alcohol solvent and ammonia to obtain 2-Chloro-6-amino-9-(2-deoxy-3-D-erythropento furanosyl)purine (2-Chloro-2'-deoxyadenosine) (Cladribine).
The process of cladribine is represented as below:

The U.S. patent application Ser. No. 5,208,327 describes a synthesis method of the cladribine starting from guanosine in 7 chemical synthesis steps with the use of numerous reagents.

The US 6252061 describes a synthesis which foresees a direct halogenation of 2, 6-diaminopurine deoxyribose in a mixture of protic and aprotic solvents, in the presence of a lewis acid and an organic nitrite. The synthesis foresees a column purification of the final product.

Christensen et al. in Journal of Medicinal chemistry 1972, 15(7), 735-739, discloses a process for the preparation of Cladribine which comprises fusion coupling of 2,6-dichloropurine with 1,3,5-tri-O-acetyl-2-deoxy-D-erythropentofuranose resulting in an anomeric mixture of the acetyl-protected deoxynucleosides. When the resulting mixture of this coupling was treated with liquid ammonia, the clean ammonolysis of the chlorine atom at C-6 and deacetylation took place and 2-chloro-2’-deoxy-9-a-adenosine and 2-chloro-9-ß-adenosine were obtained. This mixture was then reacylated with p-toluoyl chloride and the new blocked mixture was finally resolved by chromatography. Removal of the p-toluoyl groups with sodium methoxide at room temperature resulted in a mixture of 2-chloro-2’-deoxyadenosine and its a-anomer with a total yield of 16% and 9%, respectively. Fusion of 2,6-dichloropurine with methyl 3,5-di-O-p-toluoyl-2-deoxy-D-erythropentofuranoside gave a mixture of blocked deoxyribonucleosides which was separated by silica gel chromatography. Treatment of each anomer with liquid ammonia was used as an alternative route and deprotection of the toluoyl groups and simultaneous substitution at C-6 took place resulting in 2-chloro-2’-deoxyadenosine with a total yield of 8%, while the yield for the a-anomer was 13%.

The synthesis of biologically active 9-3-purine-2-deoxyribonucleosides commonly involves direct glycosylation of the heterocycle with an activated 2-deoxyribose derivative. Glycosylation procedures introducing the 2-deoxy-3-D-ribofuranosyl moiety into an aglycon invariably provide anomeric mixtures as well as positional isomers. Not only is the yield of the desired product low in such reactions, but purification is often difficult due to the Similar mobility of isomeric products during chromatographic Separation. Such a process is both time consuming and costly.

Cladribine production by means of chemical synthesis processes has significant limitations, since such processes often consist of multiple-stage reaction, which comprise protection and deprotection reactions starting from compounds which are costly and/or hard to find on the market, and sometimes involve non-stereospecific reactions (i.e. which lead to the production of the final product in both a and (3 conformations). Such processes are therefore long and costly, and the yields are rarely satisfying. These process types, therefore, by their nature, do not lend themselves to be employed on an industrial scale.

Though the review of the above-mentioned literature discloses diverse processes for preparation of Cladribine, but due to reasons most of them are not particularly convenient and amenable to industrial scale-up. Thus, there is an apparent need of new improved processes for preparation of Cladribine, which may be efficient, cost-effective, and industrially amenable and may overcome the drawbacks of various prior disclosed processes, e.g., multiple solvent combinations as well as multiple steps.

Therefore, inventors of the present application provide an improved process for preparation of Cladribine, which is amenable to scale up at industrial level and may solve purity/ compliance related issues of the end product.

SUMMARY OF INVENTION
Particular aspects of the present specification relate to an improved process for preparation of Cladribine.
In another aspect of the present invention provides, an improved process for the preparation of Cladribine of formula (I)

comprising the steps of:
a. condensing 2-chloro adenine of formula (II) or its pharmaceutically acceptable salt

with 5-chloro-2-(((4-chlorobenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-chloro benzoate of formula (III)

in presence of base and solvent to produce 5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((4-chlorobenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-chlorobenzoate of formula (IV);

b. deprotecting compound of formula (IV), to obtain Cladribine of formula (I); and
c. optionally purifying the obtained compound of formula (I) with an alcohol or water or
mixture thereof to obtain highly pure cladribine.

In another aspect, the present invention further relates to a cladribine intermediate of formula (IV)

One more aspect of the present invention relates an improved process for the preparation of Cladribine intermediate of formula (IV)

comprising condensing 2-chloro adenine of formula (II) or its pharmaceutically acceptable salt

with 5-chloro-2-(((4-chlorobenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-chloro benzoate of formula (III)

in presence of base and solvent to produce 5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((4-chlorobenzoyl) oxy)methyl)tetrahydrofuran-3-yl 4-chlorobenzoate of formula (IV).

Further particular aspects of the invention are detailed in the description of invention, wherever appropriate.

DETAILED DESCRIPTION
The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Cladribine and its pharmaceutically acceptable salts thereof.

In another aspect of the present invention provides, an improved process for the preparation of Cladribine of formula (I)

comprising the steps of:
a. condensing 2-chloro adenine of formula (II) or its pharmaceutically acceptable salt

with 5-chloro-2-(((4-chlorobenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-chloro benzoate of formula (III)

in presence of base and solvent to produce 5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((4-chlorobenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-chlorobenzoate of formula (IV);

b. deprotecting compound of formula (IV), to obtain Cladribine of formula (I); and
c. optionally purifying the obtained compound of formula (I) with an alcohol or water or
mixture thereof to obtain highly pure cladribine.

In one embodiment of, the present invention also relates to an improved process for the preparation of Cladribine comprising the, condensation of 2-chloro adenine of formula (II) or its salts selected from sodium, potassium, and lithium and the like thereof with 5-chloro-2-(((4-chlorobenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-chloro benzoate of formula (III) in presence of base selected from organic base such as methylamine, triethylamine, diisopropylethylamine, t-butylamine, N,N-dimethylamine, dimethylformamide, pyridine, DBU, DBN, N-methylpiperazine or inorganic base is such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide; more preferably potassium carbonate; a solvent is selected from alcohol selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; ketone solvent selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone, more preferably acetone; ester solvent selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; and the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; polar aprotic solvent selected from dimethylformamide, acetonitrile, dichloromethane, dimethylsulfoxide, and N-methyl- pyrrolidone; water or mixtures thereof; at a temperature 0-5° C for a period of 4 hours to 8 hours to obtain crude 5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((4-chlorobenzoyl) oxy)methyl)tetrahydrofuran-3-yl 4-chlorobenzoate of formula (IV). The crude compound was dissolved in any of the solvents selected from dichloromethane, Methanol, ethanol, IPA, Hexane or mixture thereof and stirred for 2 hours to 4hours at 25-35° C. The reaction mixture was allowed to cool and the obtained solid was filtered. The obtained product dried under vacuum to obtained pure 5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((4-chloro benzoyl) oxy) methyl) tetrahydrofuran-3-yl 4-chlorobenzoate.

The coupling reaction preferably takes place in anhydrous acetone at room temperature under a nitrogen atmosphere

The present invention is industrially scalable, allow the desired compounds to be obtained with high yields, and involve cheaper reagents which are industrial feasible.

On the other hand, the prior art process does not suggest the particular process for the preparation of Cladribine, further, the prior art processes involve the use of excess solvents and reagents, further involves distillation of solvent and purifications, which leads in the decomposition of product and lowering the quantity of yield.

The present invention involves the use of 4-chloro-benzoyl chloride as a protecting group, which is different from the teaching of the prior art. The particular use of this protecting groups has advantages over the prior art as follows:
a) the 4-chloro-benzoyl chloride protected compound (III) is stable, even after the reaction mass is purged with HCl gas for long time compare to the use of 4-Toluyl chloride protected compound of Formula (A) as used in prior art.
b) compound of Formula (III) can dry at 35-40°C for 10 hours under vacuum, it doesn’t affect in the stability even it is stored for stability for a period of 6 months.
c) Prior disclosed p-toluyl compound of Formula (A) undergoes degradation immediately after 1 hour, whereas the present invention process involves the use of compound of Formula (III)
d) the isolation of solid material of compound of Formula (III) is industrially feasible even in large scale production.

On the other hand, the prior art disclosed intermediate of compound of Formula A has undergoes degradation even at the time of isolation, which is not yet all feasible for industrial production. Further, the degradation of this compound yields in highly impure cladribine, which requires further additional purification steps to obtain highly pure cladribine.

To overcome the above disadvantage the inventors of the present invention developed a process, which is industrially liable, viable and environmentally friendly.

The above obtained pure 5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((4-chloro benzoyl) oxy) methyl) tetrahydrofuran-3-yl 4-chlorobenzoate of compound of formula (IV) is converted to is converted to Cladribine or its pharmaceutically acceptable salts using any of the prior art processes / process, which are feasible for a person skilled in the art.

The above obtained pure 5-(6-amino-2-chloro-9H-purin-9-yl)-2-(((4-chloro benzoyl) oxy) methyl) tetrahydrofuran-3-yl 4-chlorobenzoate is deprotecting with methanolic ammonia or methanolic sodium methoxide at temperature 40-45° C and stir for 8-10 hours. After completion of reaction the reaction mixture was treated with activated carbon and maintained for 1 hour at same temperature. Filtered the reaction mass through celite bed and washed with methanol. The solvent from the reaction mixture was distilled out under reduced pressure below 50° C to get pale yellow crude. Methanol was added to the crude compound and stirred for 2-3 hours at room temperature. The wet solid was filtered and dried under vacuum to obtain 2-chloro-2'-deoxyadenosine.

Hydrolysis of both p-chlorobenzoyl groups may be conducted at room temperature, either by the treatment with methanolic ammonia or methanolic sodium methoxide. In the event methanolic ammonia is used, the work up consists of solvent removal by evaporation and then treatment of the resulting residue with methanol to remove the p-chlorobenzoyl by-products. When methanolic sodium methoxide is employed, the solution must be neutralized, preferably with an ion exchange resin (cationic form), and then treated with n-hexane.

The above obtained crude cladribine undergoes purification with an alcohol, dichloromethane or water or mixture thereof. The reaction mixture was heated to 80-85° C, and stir for 30-45 minutes clear solution was observed. The clear solution was treated with activated carbon and maintained for 1 hour at 80-85° C temperature. Filtered the reaction mass under heating condition and washed with methanol and water mixture and stir for 20-25 hours at 20-25° C to get the solid. The wet solid was filtered and dried under vacuum to obtain pure 2-chloro-2'-deoxyadenosine.

Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 50-65°C for a time ranging from 12 to 16 hours depending upon the physical attributes of the end product obtained.

The process related impurities that appear in the impurity profile of the Cladribine may be substantially removed by the process of the present invention resulting in the formation of highly pure material. The process of the present invention is as summarized below:

The process related impurities that appear in the impurity profile of the Cladribine (I) or its pharmaceutically acceptable salts may be substantially removed by the process of the present invention resulting in the formation of Cladribine (I) or its pharmaceutically acceptable salts of high purity.

The merit of the process according to the present invention resides in that product isolated after drying is directly obtained as pure Cladribine or its pharmaceutically acceptable salts (I). Said material is found devoid of any other crystal lattice and is adequately stable to handle and store for longer time (at least up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics. Cladribine or its pharmaceutically acceptable salts (I) obtained according to the process of the present invention results in the final API purity by HPLC of more than 99.5 % w/w, and found to be stable at different ICH conditions.

In another embodiment, the Cladribine or its pharmaceutically acceptable salts (I) obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising Cladribine or its pharmaceutically acceptable salts (I) obtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions derived from Cladribine or its pharmaceutically acceptable salts (I) of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

Example-1
Preparation of 1-O-Methyl-2-Deoxy-D-Ribose:
100 gm of 2-deoxy-D-Ribose was dissolved in 500ml of methanol and stirred the reaction mass for 30 minutes. Sulfuric acid (0.5 ml) was added slowly to the above reaction mass at ambient temperature. After completion of addition, maintain the reaction mixture under stirring for 3-5 hours. The reaction mass was neutralized with sodium bicarbonate and stirred for 30 min. Filtered the reaction mass through celite-bed and distilled off the solvent under vacuum at below 45°C. The obtained residue was co-distilled with 100ml of toluene to get pale brown residue.
Yield- 108 gm

Example-2
Preparation of 1-O-Methyl-3,5-Di-O-(P-Chlorobenzoyl)-2-Deoxy-D-Ribofuranose:
1-O-Methyl-2-Deoxy-D-Ribose (108 gm) was charged in to a reaction flask containing toluene (1080 ml) under nitrogen atmosphere at 25-35°C. TEA (305 ml) and DMAP (18.9gm) were added to the solution. To the obtained reaction mass slowly add 4-chloro benzoyl chloride (215 ml) at 0-10° C, after completion of addition reaction temperature was raised to 25-35°C and maintained for 4 hours to 5 hours. Filtered the reaction mass and washed the filtrate with 10% Sodium carbonate solution. Finally washed the organic layer with water. The organic layer was distilled out completely under reduced pressure to get the residue. The wet residue was dried for 2 hours at below 50° C to yield pale yellow brown residue.
Yield -309gm

Example-3
Preparation Of 1-Chloro-3,5-Di-(4-Chlorobenzoyl)-2-Deoxy-Alpha-D-Ribose:
1-O-Methyl-3,5-Di-O-(P-Chlorobenzoyl)-2-Deoxy-D-Ribofuranose (309gm) was charged into a reaction flask containing acetic acid (927ml) and toluene (927ml). The obtained reaction mass was treated with HCl gas at 0-5° C and stirred the contents for 3-5 hours to precipitate white solid. Filtered the precipitated white solid and washed with Hexane (300 ml). The wet solid was filtered and dried under vacuum at ambient temperature for 10-12 hours to get titled compound as a White solid.
Yield -207 gm
HPLC purity- 95.69%

Example-4
Preparation of 2-Chloroadenine Sodium:
2-Chloroadenine (50 gm) was charged into a reaction flask containing methanol (500 ml). To the solution 25% sodium methoxide (25% sodium methoxide in Methanol) was added (85ml) and stirred for 2 to 3 hours at 25-35° C. The solvent was distilled off under reduced pressure at below 50° C. The obtained mixture was slurred using Acetonitrile (450ml). Filtered the solid material and dried the material at 60-65°C for 10-12hr to comply the moisture content not more than 10%.
Yield -56gm
MC by KF- 9.86%
HPLC purity- 98.13%

Example-5
PREPARATION OF 3,5-Di-O-(4-Chlorobenzoyl)-2'-Deoxy-2-Chloro Adenosine:
Charged 5000 ml of Acetone into reaction flask and 48.18gm of potassium carbonate and cooled to -5 to 0°C. 2-Chloroadenine sodium (46.13 gm) was charged into reaction flask and stirred for 10-15 minutes under nitrogen atmosphere. 1-Chloro-3,5-Di-(4-Chlorobenzoyl)-2-Deoxy-Alpha-D-Ribose (100gm) was added slowly in to the reaction flask over a period of 1hr in lot-wise and maintained the reaction for 6 hours at 0-5°C under nitrogen atmosphere. After completion of reaction, filtered the crude reaction mass and distilled off the acetone solvent below 40°C. This crude compound was slurred in methanol at 60-65°C for 2hr and then allowed to RT for 3hr. Filtered the solid material and dried at 40-45°C for 10hr.
Yield -90 gm
HPLC purity- 93.82%

Example-6
PREPARATION OF 2-CHLORO-2'-DEOXYADENOSINE (CLADRIBINE):
3,5-Di-O-(4-Chlorobenzoyl)-2'-Deoxy-2-Chloro Adenosine (145 gm) was charged into a reaction flask containing Methanolic ammonia (4000 ml). This mixture was maintained under stirring for 12hr at 25-30°C and then heated to 40-45°C and continued stirring for 4hrs. After completion of reaction, the reaction mass was concentrated under reduced pressure at below 50°C to get pale yellow crude. To this crude, methanol (73ml) was added and stirred for 2 to 3 hrs. Filtered the solid material. To the obtained solid material, Methanol (450ml) was added at 60-65°C and stirred for 2hrs. Filtered the solid material on hot condition and dried at below 50°C for 8-10hr under vacuum.
Yield-37gm
HPLC purity- 97.76%

Example-7
Purification of Cladribine
Crude Cladribine (30.5gm) was charged into a reaction flask containing 10 vol mixture of ethanol: water (1:1). This mixture was heated to 70-75°C and stirred for 30 to 45 minutes to get clear solution. To the obtained reaction mass carbon (3gm) was added under stirring at 70-75°C. The obtained mixture was stirred for 60min at 70-75°C. Filtered the mass under hot condition and washed the mass with mixture of hot ethanol: water (1:1) (1vol). Collected filtrate was stirred for 20 to 25 hours at 25-35°C. Filtered the solid material and washed with ethanol: water mixture (1:1) (1vol). Unload the material and dried for 8-10 hrs at below 50°C to yield highly pure cladribine.
Yield -21.5gm
HPLC Purity - 99.16%

Example-8
Purification of Cladribine
Crude Cladribine (21gm) was charged into a reaction flask containing 10vol mixture of ethanol: water (1:1). This mixture was heated to 70-75°C, after 15-30min clear solution was observed. To the obtained reaction mass carbon (2gm) was added under stirring at 70-75°C. The obtained mixture was stirred for 60min at 70-75°C. Filtered the mass under heating and washed with mixture of hot ethanol: water (1:1) (1vol). Collected filtrate was stirred for 20 to 25 hours at 25-35°C. Filtered the solid material and washed with ethanol: water mixture (1:1) (1vol). Unload the material and dried for 8-10 hrs at below 50°C to yield highly pure cladribine.

Yield -16.2gm
HPLC purity (As per EP)- 99.88%

While the foregoing provides a detailed description of the preferred embodiments of the invention, it is to be understood that the descriptions are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.