Process for the preparation of atazanavir bisulfate

1. A process for preparing crystalline Atazanavir bisulfate Form A, comprising the steps of:

a) providing a solution of Atazanavir free base in one or more organic solvents,

b) adding a first amount of sulfuric acid to the solution, wherein the first amount is about 15% to about 25% by weight of a pre-determined amount of sulfuric acid used in total,

c) optionally seeding the reaction solution with Atazanavir bisulfate Form A seed crystals,

d) adding the remaining pre-determined amount of sulfuric acid, wherein the remaining amount is added at a controlled crystalline-forming continuous rate, and

e) isolating the crystalline Atazanavir bisulfate Form A.

2. The process of claim 1 , wherein the one or more organic solvents are selected from the group consisting of a ketone, a halogenated solvent, a dipolar aprotic solvent, and a mixture thereof.

3. The process of claim 2 , wherein the one or more organic solvents are selected from the group consisting of acetone, methylene chloride, dimethyl formamide, N-methyl pyrrolidone, dimethyl sulfoxide, and a mixture thereof.

4. The process of claim 3 , wherein the one or more organic solvents are a mixture of acetone and dimethyl formamide.

5. The process of claim 3 , wherein the one or more organic solvents are a mixture of acetone and dimethyl sulfoxide.

6. The process of claim 1 , wherein the first amount of sulfuric acid is about 20% by weight of the pre-determined amount of sulfuric acid used in total.

7. The process of claim 1 , wherein the first amount of sulfuric acid is added at a temperature of about 10° C. to about 65° C.

8. The process of claim 7 , wherein the first amount of sulfuric acid is added at a temperature of about 25° C. to about 35° C.

9. The process of claim 1 , wherein the first amount of sulfuric acid is added over a period of about 30 minutes.

10. The process of claim 1 , wherein the seed crystals is about 1% to about 10% of the atazanavir free base in quantity.

11. The process of claim 10 , wherein the seed crystals is about 5% of the atazanavir free base in quantity.

12. The process of claim 1 , wherein the remaining amount of sulfuric acid is continuously added at a temperature of about 35° C. to about 70° C.

13. The process of claim 12 , wherein the remaining amount of sulfuric acid is continuously added at a temperature of about 45° C. to about 50° C.

14. The process of claim 1 , wherein the remaining amount of sulfuric acid is continuously added over a period of about 3 hours to about 7 hours.

15. The process of claim 14 , wherein the remaining amount of sulfuric acid is continuously added over a period of about 5 hours.

16. A process for preparing crystalline Atazanavir bisulfate Form A, comprising the steps of:

a) providing a solution of Atazanavir free base in one or more organic solvents;

b) adding a first amount of sulfuric acid to the solution to form a mixture, wherein the first amount is about 20% by weight of a pre-determined amount of sulfuric acid used in total, and is added at a temperature of about 25° C. to about 35° C. over a period of about 30 minutes;

c) seeding the reaction solution with Atazanavir bisulfate Form A seed crystals over a period of about 30 minutes;

d) adding the remaining pre-determined amount of sulfuric acid, wherein the remaining amount is added at a controlled crystalline-forming continuous rate, and is added at a temperature of about 45° C. to about 50° C. over a period of about 5 hours; and

e) isolating the crystalline Atazanavir bisulfate Form A.