DESC:NOVEL INTERMEDIATES AND THEIR USE IN PREPARATION OF
CLOFARABINE

This application claims the benefit of priority of our Indian patent application numbers 201821006679 filed on 21th February 2018 and 201821033395 filed on 05th September 2018 which is incorporated herein by reference.

FIELD OF THE INVENTION
The present invention relates to the novel intermediates and their use in preparation of Clofarabine of formula (I).

BACKGROUND OF THE INVENTION
Clofarabine is chemically described as 2-chloro-9-(2-deoxy-2-fluoro-ß-D-arabinofuranosyl)-9H-purin-6-amine having the structural Formula (I).

Clofarabine is a purine nucleoside metabolic inhibitor. The drug has been approved both in US and Europe for the treatment of relapsed or refractory acute lymphoblastic leukaemia.
US5034518 patent first discloses Clofarabine and process for its preparation. The disclosed process involves the reaction of 2, 6-dichloro-9-(3-O-acetyl-5-O-benzyl-2-deoxy-2-fluoro-ß-D-arabinofuranosyl)-9Hpurine with anhydrous ammonia in ethanol at room temperature as shown below in the scheme.

However the above reaction step provides very low yields of 42% only. Also the starting material was prepared by the process disclosed in Journal of Medicinal Chemistry, 1986, Vol. 29, No. 11, page: 2389-2392. The disclosed process involve the reaction of 3-acetyl-5-benzoyl-2-deoxy-2-fluoroarabinofuranosylbromide with 2,6-dichloropurine in dichloroethane in presence of molecular sieves at 100°C for 16 hours provides 2,6-Dichloro-9-(3-O-acetyl-5-O-benzyl-2-deoxy-2-fluoro-ß-D-arabinofuranosyl)-9H-purine. The obtained compound was purified by flash column chromatography to give the required product in an overall yield of 32%. The above disclosed route of synthesis has so many disadvantages. It involves column chromatography technique for purification of the reaction intermediate which is not suggestible. Further the above process provides the required product in very low yields.
US 6,949,640 ?2 discloses the preparation of Clofarabine by the reaction of 2-deoxy-2-fluoro-3,5-di-O-benzoyl-a-D-arabinofuranosyl bromide with 2,6-dichloropurine in presence of sodium hydride at room temperature. The reaction takes place over night and the obtained compound contains mixture of a and ß isomers, which are separated by chromatography. The obtained ß-anomer was further treated with sodium methoxide in methanol followed by chromatography purification to provide 2-Chloro-9-(2-deoxy-2-fluoro-ß-D-arabinofuranosyl)-6-methoxy-9H-purine. Finally the obtained methoxy compound was treated with anhydrous ammonia in ethanol at 80°C for 16-20 hours to provide Clofarabine. However the process involves longer reaction times and requires column chromatography technique at various stages for purification of the reaction products, which makes the process tedious and uneconomic.
US 6,680,382 discloses a process for the preparation of Clofarabine by the reaction of 2-deoxy-2-fluoro-3,5-di-O-benzoyl-[alpha]-D-arabinofuranosyl bromide with chloroadenine in presence of potassium tert-butoxide in various solvents provides mixture of a, ß-anomers of 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-ß-D-arabinofuranosyl)adenine. Further the obtained compound was purified from different solvents and provides pure ß-anomer which was further converted into Clofarabine by treating it with sodium methoxide. This process also involves longer reaction times and provides the product with less purity.
WO 2015/118558 (F: IN 518/CHE/2014) discloses a process for the preparation of Clofarabine by reacting 2,6-dichloro-9-(3,5-di-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl)-9H-purine with ammonia in dimethoxyethane and further debenzoylation step to provide Clofarabine.
All the prior-reported processes for the preparation of Clofarabine by reaction of 3-acetyl-5-benzoyl-2-deoxy-2-fluoroarabinofuranosylbromide/2-deoxy-2-fluoro-3,5-di-O-benzoyl-a-D-arabinofuranosyl bromide with 2,6-dichloropurine / chloroadenine requires longer reaction times, higher temperatures and leads to the formation of corresponding a, ß-anomer mixture. Further the yields and quality of the product obtained is also very low.
Therefore, it is desirable to provide an alternate process using novel intermediates which can be carried out advantageously on an industrial scale and which supports an active compound in high yield and high purity in pharmaceutically acceptable quality.

OBJECT OF THE INVENTION
In one aspect, the present invention relates to novel intermediates and their use in preparation of Clofarabine of Formula (I).

In another aspect, the present invention relates to novel intermediates of general formula (VI) as shown below:

In further aspect, the present invention encompasses process for the preparation of Clofarabine of Formula (I) which comprises the steps of:
a) reacting compound of Formula (II) with brominating reagent in presence of solvent(s) to obtain compound of formula (IIIa);

b) reacting compound of Formula (IV) with compound of formula (X) in the presence of solvent(s) to obtain compound of formula (Va);

c) reacting compound of Formula (IIIa) with compound of Formula (Va) in the presence of base and solvent(s) to obtain compound of formula (VIa);

d) aminating Formula (VIa) in the presence of source of ammonia and solvent(s) to obtain compound of formula (VIIa);

e) reacting compound of Formula (VIIa) in the presence of base and solvent(s) to obtain Clofarabine of formula (I); and

f) optionally purifying in the presence of solvent(s) to obtain substantially pure Clofarabine of formula (I).

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustration of a PXRD pattern of crystalline form of Clofarabine.
Figure 2 is an illustration of a PXRD pattern of crystalline form of Clofarabine.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention encompasses novel intermediates and their use in preparation of Clofarabine of Formula (I).

In another embodiment, the present invention encompasses novel intermediates of Formula (VI) as shown below:

wherein R’, R”, R’” represents substitution on either one or all carbons on imidazole ring and independently selected from H; (C1-C6)alkyl which may optionally be substituted; aryl which may optionally be substituted; acyl; sulfonyl; nitro; halogens selected from Cl, Br, F or I and like.
R” and R’” together represents a phenyl ring which is optionally substituted with (C1-C6)alkyl; aryl which may optionally be substituted; acyl; sulfonyl; nitro; halogens selected from Cl, Br, F or I and like.
In another embodiment, the present invention encompasses novel intermediates of Formula as shown below:
wherein R’, R’’ and R’’’ are as defined in aforesaid embodiment.
In another embodiment, the present invention novel intermediates may be in either a-alpha or ß-beta isomer or other isomeric form.
In another embodiment, the present invention encompasses novel intermediate 6-(1H-Imidazole-1-yl)-2-chloro-9-(2’-deoxy-2’-fluoro-3’,5’-di-O-benzoyl-ß-D-arabinofuranosyl)-9H-purine or 6-(1H-benzimidazole-1-yl)-2-chloro-9-(2’-deoxy-2’-fluoro-3’,5’-di-O-benzoyl-ß-D-arabinofuranosyl)-9H-purine as shown below:

In another embodiment, the present invention provides process for the preparation of Clofarabine of Formula (I) using novel intermediates as shown in below schemes:

In another embodiment, the present invention encompasses process for the preparation of Clofarabine of Formula (I) which comprises the steps of:
a) reacting compound of Formula (II) with brominating reagent in presence of solvent(s) to obtain compound of formula (IIIa);

b) reacting compound of Formula (IV) with compound of formula (X) in the presence of solvent(s) to obtain compound of formula (Va);

c) reacting compound of Formula (IIIa) with compound of Formula (Va) in the presence of base and solvent(s) to obtain novel compound of formula (VIa);

d) aminating Formula (VIa) in the presence of source of ammonia and solvent(s) to obtain compound of formula (VIIa);

e) reacting compound of Formula (VIIa) in the presence of base and solvent(s) to obtain Clofarabine of formula (I); and

f) optionally purifying in the presence of solvent(s) to obtain substantially pure Clofarabine of formula (I).
In another embodiment, the present invention encompasses the purification of intermediates and Clofarabine by recrystallization, distillation and other methods as well known to those skilled in the art.
In another embodiment, the present invention process reduces formation of a-anomer and obtains desired ß-anomer of Clofarabine in high yields and purity.
2-Deoxy-1-a-bromo-2-ß-fluoro-3,5-di-O-benzoyl-d-ribofuranose can be prepared from 2-Deoxy-2-fluoro-l,2,5-tri-O-benzoyl-D-ribofuranose using process known in prior art.
In another embodiment, the present invention reaction steps can be carried out within the temperature range of 0oC to 200oC, more preferable within the temperature range of 0oC to 100oC and like.
“Ammonia source” include but not limited to ammonia gas and liquor ammonia.
“Brominating reagent” include but not limited to hydrogen bromide; PBr3; Br2 (bromine); NBS (N-bromo succinimide); HBr in glacial acetic acid; 1, 3-Dibromo-5, 5-dimethylhydantoin and like.
Base or reagents of the present invention includes but not limited to an inorganic base or organic base selected from the group comprising of carbonates, bicarbonates, hydroxides, hydrides, phosphates and alkoxides of alkali or alkaline earth metals such as sodium methoxide and sodium ethoxide; ammonia and the like, hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, lithium hydroxide; carbonates such as sodium carbonate, potassium carbonate, ammonium carbonate, cesium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate; phosphates such as dipotassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, diammonium monohydrogen phosphate, ammonium dihydrogen phosphate and triammonium phosphate; acetates such as potassium acetate, sodium acetate and ammonium acetate; formates such as potassium formate and sodium formate; n-butyl lithium, n-hexyllithium, sodium hydride and lithium diisopropylamide. These inorganic bases may be used singly, or in combination of two or more kinds thereof. The organic base is selected from the group comprising of lutidine, diisopropylethylamine, dimethylaminopyridine, triethylamine, tri-n-propylamine, tri-n-butylamine, piperidine, pyridine, 2-picoline, 3-picoline, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine, N,N-diethylaniline, N-ethyl-N-methylaniline, diisopropylethylamine, 3-methylimidazole, 1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane and 4-dimethylaminopyridine; and metal alcoholates such as sodium methoxide, potassium tert-butoxide and sodium ethoxide. Other bases are known to the person skilled in the art.
The solvent(s) in any of the step of the present invention may be protic or aprotic polar or non-polar solvents selected from the group comprising of water, alcohols, esters, ketones, acids, amides, ethers, nitriles, halogenated hydrocarbons, hydrocarbons or mixtures thereof.
Alcohol solvents include methanol, ethanol, n-propanol, 2-propanol, ethylene glycol, PEG, butanol, n-butanol and like; ester solvents include ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and like; ketone solvents include acetone, methyl ethyl ketone; ether solvents include tetrahydrofuran, dioxane, methyl ether, ethyl ether, methyl ethyl ether, isopropyl ether, di isopropyl ether and like; polar aprotic solvent includes N, N-dimethylformamide, ?, ?-dimethylacetamide, dimethyl sulphoxide, acetonitrile, acetic acid, 1,4-dioxane and N-methyl pyrrolidone; halogenated hydrocarbons include dichloromethane, chloroform; 1,2-dichloroethane and hydrocarbons include hexane, heptane, benzene, toluene and like.
Advantages of the invention
1. The invention provides novel intermediates of Clofarabine and their use in process for the preparation of Clofarabine.
2. The invention provides process for preparation of a highly pure Clofarabine with high yields and also helps to minimizes tautomeric as well as anomeric impurities.
3. The process for the preparation of Clofarabine is simple, commercially viable and economical.
In the foregoing section, embodiments are described by way of an example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.
Examples

Example 1: Preparation of 2-Chloro-6-(1H-imidazol-1-yl)-9H-purine

Process-I: To a stirred solution of 2, 6-Dichloropurine (5.0 g, 0.026 moles) in N, N-Dimethylformamide (25 mL) was added a solution of Imidazole (7.19 g, 0.106 moles) in N, N-Dimethylformamide. The reaction mixture was heated to 60-65°C and stirred till completion of reaction and then cooled. After cooling the reaction mixture to 25-30°C, the reaction mixture was stirred. The obtained solid was filtered, washed with water and dried to get 5.20 g of the title compound.
1H NMR 300 MHz (DMSO), d: 9.13 (s, 1H), 8.39 (s, 1H), 8.24 (s, 1H), 7.22 (s, 1H), 2.55 (s, 1H); Mass (m/z): 222.75 (M+H)
Process-II: To a stirred solution of 2, 6-Dichloropurine (10.0 g, 0.053 moles) in N, N-Dimethylformamide (70 mL) was charged Imidazole (3.59 g, 0.053 moles). The reaction mixture was heated to 60-65°C along with stirring. Solvents distilled out under vacuum and water (100 mL) was charged into the reaction mass. After cooling the reaction mixture to 25-30°C, the pH of the reaction mixture was adjusted to 11-12 by using aq. Sodium hydroxide solution. The reaction mixture was stirred for 30 minutes. The pH of the reaction mixture was adjusted to 6.5-7.0 by using 10 % aqueous citric acid solution and stirred for one hour. The obtained solid was filtered, washed with water and dried to get 8.86 g of the title compound.
Process-III: To a stirred solution of 2, 6-Dichloropurine (50.0 g, 0.264 moles) in N, N-Dimethylformamide (350 mL) was charged Imidazole (19.0 g, 0.279 moles). The reaction mixture was heated to 70-75°C and stirred for about 3 hours. Further Imidazole (3.60 g, 0.053 moles) was charged into the reaction mixture. Solvents distilled out under vacuum and water (100 mL) was charged into the reaction mass. After cooling the reaction mixture to 25-30°C, the pH of the reaction mixture was adjusted to 11-12 by using aq. Sodium hydroxide solution. The reaction mixture was stirred for 30 minutes. The pH of the reaction mixture was adjusted to 6.5-7.0 by using 10 % aqueous citric acid solution and stirred for one hour. The obtained solid was filtered, washed with water and dried to get 8.86 g of the title compound. (Purity 99.0%)
Example 2: Preparation of 6-(1H-Imidazole-1-yl)-2-chloro-9-(2’-deoxy-2’-fluoro-3’,5’-di-O-benzoyl-ß-D-arabinofuranosyl)-9H-purine

To a stirred solution of 2-Chloro-6-(1H-imidazol-1-yl)-9H-purine (5.0 g, 0.023 moles) in acetonitrile (50 mL) was charged cesium carbonate (4.04 g, 0.012 moles) at 25-30°C. The reaction mixture was stirred for about 2.0 hours at 25-30°C. A solution of 2-Deoxy-1-a-bromo-2-ß-fluoro-3,5-di-O-benzoyl-d-ribofuranose in N, N-Dimethylformamide was added into the reaction mixture at 25-30°C. The reaction mixture was stirred for at 25-30°C till completion of reaction. Solvents were distilled out under vacuum. Water was charged in residue and product was extracted in MDC (100 mL). The solvent was distillation out and residue was triturated in hot isopropanol and obtained solid was filtered and dried to get 3.30 g of the title compound. (Purity 98.3%)
1H NMR 300 MHz (DMSO), d: 9.00 (s,1H), 8.84-8.83 (d,1H, J=3), 8.33-8.32 (t, 1H, J=3), 8.13-8.10 (dd,2H,J=6), 8.00-7.97 (dd, 2H, J=6), 7.77-7.62 (m,4H,J=3),7.53-7.48(t,2H,J=6), 7.28 (q, 1H), 6.83-6.76 (dd, 1H, J=15), 5.98-5.76 (m, 2H), 4.82-4.74 (m, 3H, J= 3); Mass (m/z): 562.80 (M+H)
Example 3: Preparation of 6-amino-2-chloro-9-(2’-deoxy-2’-fluoro-3’,5’-di-O-benzoyl-ß-D-arabinofuranosyl)-9H-purine

6-(1H-Imidazole-1-yl)-2-chloro-9-(2’-deoxy-2’-fluoro-3’,5’-di-O-benzoyl-ß-D-arabinofuranosyl)-9H-purine (1.50 g, 0.003 moles) was agitated in isopropanol with ammonia in autoclave at 25-30°C. After completion of reaction, solvents were distilled under vacuum. The residue obtained was stirred in water (10 mL) for one hour. The obtained solid was filtered, washed with water and dried to get 1.05 g of the title compound. (Purity 98.1%)
Example 4: Preparation of Clofarabine (2-chloro-9-(2-deoxy-2-fluoro-ß-D-arabinofuranosyl)-9H-purin-6-amine)

To a stirred solution of 6-amino-2-chloro-9-(2’-deoxy-2’-fluoro-3’,5’-di-O-benzoyl-ß-D-arabinofuranosyl)-9H-purine (0.50 g, 0.001 moles) in acetonitrile (5 mL) and water (2 mL) was charged lithium monohydrate ( 0.246 g, 0.006) at 25-30°C. The reaction mixture was stirred for about 2.0 hours at 25-30°C. After completion of reaction, pH of the reaction mixture was adjusted to 6.5-7.0 by using acetic acid. The solvent was distilled under vacuum below 55°C. The residue was stirred in water (5 mL) for one hour at 25-30°C and the obtained solid was filtered and dried to get 100 mg of the title compound. (Purity 99.3%)
Example 5: Preparation of 2-Deoxy-1-a-bromo-2-ß-fluoro-3, 5-di-O-benzoyl-d-ribofuranose

To a stirred solution of 2-deoxy-2-ß-fluoro-1, 3, 5-tri-O-benzoyl-1-a-D-ribofuranose (100.0 g, 0.215 moles) in dichloromethane (500 mL) was charged 33 % HBr in acetic acid (82 mL, 0.333 moles) at 25-30°C. The reaction mixture was stirred for 12 hours at 25-30°C. After completion of reaction, the reaction mixture was quenched into 7 % aqueous sodium bicarbonate solution (1000 mL). The solvents were distilled under vacuum from the organic layer. Di-isopropyl ether (200 mL) was charged into residue and stirred for 2 hours at 25-30°C. N-heptane (1000 mL) was added into the reaction mixture and the reaction mixture and further stirred for 5 hours. The resultant slurry was filtered and the wet cake was washed with n-heptane (100 mL). The wet material was dried under vacuum to get 76.90 g of the title compound.
Example 6: Preparation of 2-Chloro-6-(1H-benzimidazol-1-yl)-9H-purine
To a stirred solution of 2, 6-dichloropurine (100.0 g, 0.529 moles) in N, N-dimethylacetamide (600 mL) was charged benzimidazole (187.52 g, 1.587 moles) at 25-30°C. The reaction mixture was heated to 85-90°C and stirred for 6 hours. The reaction mixture was cooled to 25-30°C and stirred for 12 hours. The resultant slurry was filtered and washed the wet cake with N, N-dimethylacetamide (100 mL). The material was dried under vacuum to get 115 g of the title compound. (Purity 98.0%)
Example 7: Preparation of 2-Chloro-6-(1H-benzimidazol-1-yl)-9H-purine

To a stirred solution of 2, 6-dichloropurine (100.0 g, 0.529 moles) in water (1000 mL) was charged benzimidazole (187.52 g, 1.587 moles) at 25-30°C. The reaction mixture was heated to 95-100°C and stirred for 10 hours. The reaction mixture was cooled to 25-30°C and added isopropyl alcohol (1000 mL) then stirred for 1 hour. The resultant slurry was filtered and washed the wet cake with 50% aqueous isopropyl alcohol solution (200 mL). The material was dried under vacuum to get 131 g of the title compound. (Purity 97.8%)
Example 8: Preparation of 2-Chloro-6-(1H-benzimidazol-1-yl)-9H-purine

To a stirred solution of 2, 6-dichloropurine (100.0 g, 0.529 moles) in water (1000 mL) was charged benzimidazole (187.52 g, 1.587 moles) at 25-30°C. The reaction mixture was heated to 95-100°C and stirred for 10 hours. The reaction mixture was cooled to 25-30°C and stirred for 1 hour. The slurry was filtered and washed with Acetonitrile (200 mL). Wet material dissolved in N, N'-Dimethyl propylene urea (400 mL) at 70-75°C. Acetonitrile (400 mL) was added to reaction mixture and stirred for 1 hour. The reaction mixture was cooled to 25-30°C and filtered. The material was dried under vacuum to get 125 g of the title compound. (Purity 99.2%)
Example 9: Preparation of 6-(1H-benzimidazole-1-yl)-2-chloro-9-(2’-deoxy-2’-fluoro-3’,5’-di-O-benzoyl-ß-D-arabinofuranosyl)-9H-purine

To a stirred solution of 2-chloro-6-(1H-benzimidazol-1-yl)-9H-purine (500.0 g, 0.185 moles) in acetonitrile (12.5 L) was charged cesium carbonate (602 g, 1.85 moles) at 25-30°C. The reaction mixture was stirred for 4.0 hours at 25-30°C. The reaction mass was cooled to 0-5°C. A solution of 2-deoxy-1-a-bromo-2-ß-fluoro-3, 5-di-O-benzoyl-d-ribofuranose (938 g, 2.22 moles) in acetonitrile (1.5 L) was added into the reaction mixture at 0-5°C. The reaction mixture temperature was raised to 25-30°C and stirred for 12 hours. After completion of reaction, acetic acid (80 mL) was charged into the reaction mixture at 25-30°C. Water (5 L) was added to reaction mixture at 25-30°C. The reaction mixture was filtered and washed with acetonitrile (1 L). The wet material was dried in vacuum to get 900 g of the title compound. (Purity 98.5%)
Example 10: Preparation of 6-(1H-benzimidazole-1-yl)-2-chloro-9-(2’-deoxy-2’-fluoro-3’,5’-di-O-benzoyl-ß-D-arabinofuranosyl)-9H-purine

To a stirred solution of 2-chloro-6-(1H-benzimidazol-1-yl)-9H-purine (500.0 g, 0.185 moles) in acetonitrile (5 L) was charged cesium carbonate (602 g, 1.85 moles) at 25-30°C. The reaction mixture was stirred for 4.0 hours at 25-30°C. The reaction mass was cooled to 0-5°C. A solution of 2-deoxy-1-a-bromo-2-ß-fluoro-3, 5-di-O-benzoyl-d-ribofuranose (938 g, 2.22 moles) in dichloromethane (5 L) was added into the reaction mixture at 0-5°C. The reaction mixture temperature was raised to 25-30°C and stirred for 12 hours. Acetic acid (80 mL) was charged into the reaction mixture at 25-30°C. Solvents distilled off under vaccum. Acetonitrile (5 L) and water (5 L) was added to reaction mixture at 25-30°C. The reaction mixture was filtered and washed with acetonitrile (1 L). The wet material was dried in vacuum to get 922 g of the title compound. (Purity 98.0%)

Example 11: Preparation of 9-(5-O-benzoyl-2-deoxy-2-fluoro-ß-D-arabinofuranosyl)-2-chloro-9H-purin-6-amine

Process-I: Compound obtained from example-9 / example-10 (1.50 g, 0.003 moles) was agitated in isopropanol with ammonia in autoclave at 25-30°C. After completion of reaction, solvents were distilled under vacuum and the residue obtained was stirred in water. The obtained solid was filtered, washed with water and dried to get 1.05 g of the title compound. (Purity 99.0%)
Process-II: A solution of compound obtained from example-9 / example-10 (10.0 g, 0.016 moles) in THF was charged imidazole (1.11 g, 0.016 moles) at 25-30°C. The resultant solution was charged in an autoclave and agitated with ammonia in autoclave at 25-30°C. After completion of reaction, solvents were distilled under vacuum and the residue obtained was stirred in methanol. The resultant slurry was filtered and washed with methanol. The material was dried in vacuum to get 3.8 g of the title compound. (Purity 98.1%)
Example 12: Preparation of 9-(5-O-benzoyl-2-deoxy-2-fluoro-ß-D-arabinofuranosyl)-2-chloro-9H-purin-6-amine

Compound obtained from example-9 / example-10 (200 g, 0.326 moles) was agitated in 1,4-dioxane (2 L) with ammonia in autoclave at 60-65°C. After completion of reaction, solvents were distilled under vacuum and the residue obtained was stirred in water. The obtained solid was filtered, washed with water and dried to get 131 g of the title compound. (Purity 85.0 %)
Example 13: Preparation of 9-(5-O-benzoyl-2-deoxy-2-fluoro-ß-D-arabinofuranosyl)-2-chloro-9H-purin-6-amine

Compound obtained from example-9 / example-10 (200 g, 0.326 moles) was agitated in 1,4-dioxane (2 L) with ammonia in autoclave at 60-65°C. After completion of reaction, solvents were distilled under vacuum to obtain titled compound (oily residue).
Example 14: Preparation of Clofarabine (2-chloro-9-(2-deoxy-2-fluoro-ß-D-arabinofuranosyl)-9H-purin-6-amine)

To a stirred solution of compound obtained from example-12 / example-13 (131 g, 0.321 moles) in methanol (2 L) and dichloromethane (2 L) was charged sodium methoxide (5.2 g, 30 mol %) at 0-5°C and reaction mixture was stirred till completion of reaction. After completion of reaction, reaction mass pH adjusted to 6-7 by using acetic acid. The resultant slurry was filtered and washed with methanol. The wet material was dried under vacuum to get 56 g of the title compound. (Purity 98.1%) Clofarabine is characterized by XRD as shown in Figure 1.

Example 15: Purification of Clofarabine (2-chloro-9-(2-deoxy-2-fluoro-ß-D-arabinofuranosyl)-9H-purin-6-amine)

To a stirred solution of compound obtained from example-14 (55 g, 0.182 moles) dissolved in methanol (1 L) at 60-65°C and stirred for 1 hour. Activated carbon added to reaction mass and filtered through hyflow. Wash the hyflow bed with methanol. Cool the filtrate and stir the reaction mixture for 12 hours at 25-30°C. Filter the precipitated product then dried under vacuum to get 33 g of the title compound. (Purity 99.50%) Clofarabine is characterized by XRD as shown in Figure 2.

Dated this 18th day of Feb. 2019

Dr. S. Ganesan
,CLAIMS:We Claim:

1. A process for preparing Clofarabine of Formula (I) comprising the steps of:
a) reacting compound of Formula (IIIa) with compound of Formula (Va) in the presence of base and solvent(s) at a temperature in the range of 0oC to 40oC to obtain compound of formula (VIa)

wherein R’, R”, R’” is independently selected from H and (C1-C6)alkyl;
R” and R’” together represents a phenyl ring, which is optionally substituted with (C1-C6)alkyl;
b) aminating Formula (VIa) in the presence of source of ammonia and solvent(s) at a temperature in the range of 25oC to 65oC to obtain compound of formula (VIIa); and

c) reacting compound of Formula (VIIa) in the presence of base and solvent(s) at a temperature in the range of 0oC to 40oC to obtain Clofarabine of formula (I).

2. The process as claimed in claim 1, wherein compound of formula (Va) is obtained by reacting compound of Formula (IV) with compound of formula (X) in the presence of solvent(s) at a temperature in the range of 60oC to 100oC

wherein R’, R”, R’” is independently selected from H and (C1-C6)alkyl;
R” and R’” together represents phenyl ring which is optionally substituted with (C1-C6)alkyl.

3. The process as claimed in claim 1, wherein the compound of formula (IIIa) is obtained by reacting compound of Formula (II) with brominating reagent in presence of solvent(s) at a temperature in the range of 0oC to 40oC.

4. The process as claimed in claim 3, wherein brominating reagent is selected from hydrogen bromide; PBr3; Br2 (bromine); NBS (N-bromo succinimide); HBr in glacial acetic acid and 1, 3-Dibromo-5, 5-dimethyl hydantoin.

4. The process as claimed in any of the preceding claims wherein base is selected from carbonates like sodium carbonate, potassium carbonate and cesium carbonate; bicarbonates like sodium bicarbonate and potassium bicarbonate; hydroxides like sodium hydroxide, ammonium hydroxide, lithium hydroxide and potassium hydroxide; alkoxides like sodium methoxide and sodium ethoxide; and ammonia.

5. The process as claimed in any of the preceding claims wherein solvent(s) selected from water, methanol, ethanol, isopropanol, n-propanol, methyl acetate, ethyl acetate, propyl acetate, acetone, acetic acid, dimethylformamide, dimethylacetamide, methyl ether, ethyl ether, di isopropyl ether, acetonitrile, dichloromethane, chloroform, hexane, heptane, 1,4-dioxane or mixture thereof.

6. Compounds of formula:

wherein R’, R”, R’” is selected from H and (C1-C6)alkyl;
R” and R’” together represents phenyl ring which is optionally substituted with (C1-C6)alkyl.

7. Compounds of formula:

8. Compounds of formula:

Dated this 18th day of Feb. 2019

Dr. S. Ganesan