Process of making cladribine

1. A process of purifying cladribine comprising:

a) dissolving crude solid cladribine in a protic solvent and water in the presence of a base to form a solution, wherein the crude solid cladribine and the solution both comprise protected or partially protected nucleoside impurities;

b) maintaining the solution at an elevated temperature so that the solution is homogeneous until the amount of protected or partially protected nucleoside impurities in the solution is reduced to a pre-determined upper limit;

c) cooling the solution of step b) so that crystals of cladribine are formed and isolated.

2. The process of claim 1 wherein the protic solvent is methanol, and the base is NaOMe.

3. The process of claim 1 wherein the pre-determined upper limit is 0.10% by HPLC analysis.

4. The process of claim 1 wherein prior to step a), the process comprises:

1) treating a mixture comprising a compound of formula IV and at least one undesired isomer with a sulfonic acid based Lewis or Brønsted acid in an organic solvent and in the presence of a silylating agent so that the at least one undesired isomer isomerizes and converts to the compound of formula IV, wherein the compound of formula IV has the following chemical formula:

wherein each of R 1 , R 2 and R 3 is independently alkyl, alkenyl, alkynyl or aryl, x′ is 0, 1 or 2 y′ is 2, 1 or 0, each of R 6 and R 7 is independently a hydroxyl protecting group;

2) isolating the compound of formula IV from the mixture obtained in step 1);

3) converting the compound of formula IV to cladribine to obtain a reaction mixture comprising cladribine; and

4) obtaining the crude solid cladribine by isolating cladribine from the reaction mixture obtained in step 3).

5. The process of claim 4 wherein the organic solvent is MeCN.

6. The process of claim 1 wherein prior to step a), the process comprises:

(a′) coupling a compound of formula II

wherein R 4 is hydrogen or SiR 1 R 2 R 3 , x is 0, 1 or 2, y is 2, 1 or 0, respectively, and

when R 4 is hydrogen, y is 2 or 1; with a protected 2-deoxy-ribofuranose of formula III

wherein R 5 is a leaving group, in an organic solvent and in the presence of a sulfonic acid based Lewis or Brønsted acid to obtain a compound of formula IV:

wherein each of R 6 and R 7 is independently a hydroxyl protecting group, each of R 1 , R 2 and R 3 is independently alkyl, alkenyl, alkynyl or aryl, x′ is 0, 1 or 2, y′ is 2, 1 or 0;

(b′) converting the compound of formula IV to cladribine to obtain a reaction mixture comprising cladribine; and

(c′) obtaining the crude solid cladribine by isolating cladribine from the reaction mixture obtained in step (b′).