Process for the preparation of dapagliflozin

1. A Dapagliflozin solvate of general Formula (III),

wherein X is 1,2-butanediol, 1,2-pentanediol, 1,2-hexanediol, 1,2-heptanediol, (S)-1,2-butanediol, (R)-1,2-butanediol, (S)-1,2-pentanediol, (R)-1,2-pentanediol, (S)-1,2-hexanediol, (R)-1,2-hexanediol, (S)-1,2-heptanediol or (R)-1,2-heptanediol, or a hydrate, or a mixture or a hydrate thereof.

2. A process for the preparation of the dapagliflozin solvate of Formula (III) according to claim 1 ,

wherein X is 1,2-butanediol, 1,2-pentanediol, 1,2-hexanediol, 1,2-heptanediol, (S)-1,2-butanediol, (R)-1,2-butanediol, (S)-1,2-pentanediol, (R)-1,2-pentanediol, (S)-1,2-hexanediol, (R)-1,2-hexanediol, (S)-1,2-heptanediol or (R)-1,2-heptanediol or a mixture or hydrates thereof, the process comprising:

(a) preparing a solution of dapagliflozin in one or more solvents;

(b) adding a diol and one or more second solvents to obtain a reaction mixture;

(c) stirring the reaction mixture at 0-5° C.; and

(d) obtaining the dapagliflozin solvate.

3. The process according to claim 2 , wherein the solvents in the steps (a) and (b) comprises one or more of di-isopropyl ether, methyl-t-butyl ether, diethyl ether, isopropyl acetate, ethyl acetate, hexane, heptane, 1,4-dioxane, tetrahydrofuran, and tetrahydropyran, or a mixture thereof.

4. The process according to claim 2 , wherein the diol in the step (b) a comprises one or more of 1,2-butanediol, 1,2-pentanediol, 1,2-hexanediol, 1,2-heptanediol, (S)-1,2-butanediol, (R)-1,2-butanediol, (S)-1,2-pentanediol, (R)-1,2-pentanediol, (S)-1,2-hexanediol, (R)-1,2-hexanediol, (S)-1,2-heptanediol or (R)-1,2-heptanediol.

5. A dapagliflozin 1,2-butanediol monohydrate of Formula (II),

6. The compound according to claim 5 is crystalline dapagliflozin 1,2-butanediol monohydrate characterized by a powder X-ray diffraction pattern having characteristic peaks as expressed at about 3.9°, 15.2°, 15.7°, 17.1°, 18.7°, 19.0°, 19.9°, 20.2°, 21.4°, 23.9°, 24.3° and 25.2°±0.2° 2θ.

7. The crystalline dapagliflozin 1,2-butanediol monohydrate according to claim 6 , characterized by differential scanning calorimetry (DSC) thermogram having endothermic event at about 63.4° C.

8. A process for the preparation of the compound dapagliflozin 1,2-butanediol monohydrate of Formula (II) according to claim 5 ,

the process comprising:

(a) preparing a solution of dapagliflozin in one or more solvents;

(b) adding 1,2-butane diol and one or more second solvents to obtain a reaction mixture;

(c) stirring the reaction mixture at 0-5° C.; and

(d) obtaining the dapagliflozin 1,2-butanediol monohydrate.

9. The process according to claim 8 , wherein the solvents in the steps (a) and (b) comprises one or more of di-isopropyl ether, methyl-t-butyl ether, diethyl ether, isopropyl acetate, ethyl acetate, hexane, heptane, 1,4-dioxane, tetrahydrofuran, and tetrahydropyran, or mixture thereof.

10. A stable amorphous dapagliflozin that does not convert to any other solid form when stored at a temperature of up to about 40° C. and at a relative humidity of about 25% to about 75% for about three months or more.

11. A process for the preparation of the stable amorphous dapagliflozin according to claim 10 , the process comprising:

(a) treating dapagliflozin or its solvates with water to obtain a reaction mixture;

(b) stirring the reaction mixture at 80° C. to 90° C.;

(c) cooling the reaction mixture at 70° C. to 75° C. and adding isopropyl alcohol;

(d) stirring the reaction mixture at 5° C. to 10° C. for 16-18 hours;

(e) filtering the product;

(f) drying the product under vacuum for 20 to 24 hours below 25° C.;

(g) drying the product under vacuum for 20 to 24 hours at 25° C. to 30° C.;

(h) drying the product under vacuum for 18 to 20 hours at 35° C. to 40° C. till water content is less than 3.0% as measured by KF; and

(i) optionally drying the product under vacuum for 18 to 21 hours at 40° C. to 45° C. to obtain the stable amorphous dapagliflozin.

12. The process according to claim 11 , wherein the solvates in steps (a) is selected from 1,2-butanediol, 1,2-pentanediol, 1,2-hexanediol, 1,2-heptanediol, (S)-1,2-butanediol, (R)-1,2-butanediol, (S)-1,2-pentanediol, (R)-1,2-pentanediol, (S)-1,2-hexanediol, (R)-1,2-hexanediol, (S)-1,2-heptane diol, (R)-1,2-heptanediol or a mixture or a hydrate thereof.

13. The process for the preparation of the stable amorphous dapagliflozin according to claim 11 , the process comprising:

(a) treating dapagliflozin 1,2-butanediol monohydrate with water to obtain a reaction mixture;

(b) stirring the reaction mixture at 80° C. to 90° C.;

(c) cooling the reaction mixture at 70° C. to 75° C. and adding isopropyl alcohol;

(d) stirring the reaction mixture at 5° C. to 10° C. for 16-18 hours;

(e) filtering the product;

(f) drying the product under vacuum for 20 to 24 hours below 25° C.;

(g) drying the product under vacuum for 20 to 24 hours at 25° C. to 30° C.;

(h) drying the product under vacuum for 18 to 20 hours at 35° C. to 40° C. till water content is less than 3.0% as measured by KF; and

(i) optionally drying the product under vacuum for 18 to 21 hours at 40° C. to 45° C. to obtain the stable amorphous dapagliflozin.

14. A pharmaceutical composition comprising a therapeutically effective amount of stable amorphous dapagliflozin according to claim 10 and one or more pharmaceutically acceptable carriers, excipients or diluents for the treatment of diabetes.

15. A method for treating diabetes comprising administering a pharmaceutical composition comprising a therapeutically effective amount of stable amorphous dapagliflozin according to claim 10 and one or more pharmaceutically acceptable carriers, excipients or diluents to a subject in need thereof.