Process for production of glycopyrronium tosylate

1. A method of producing glycopyrronium tosylate comprising:

(a) contacting glycopyrrolate base with methyl tosylate to produce glycopyrronium tosylate:

and

(b) purifying the glycopyrronium tosylate obtained in step (a) by one or more crystallizations in an aqueous solvent to obtain a purified glycopyrronium tosylate; wherein the aqueous solvent consists essentially of water.

2. The method of claim 1 , wherein the glycopyrrolate base contacted with methyl tosylate is contacted with an organic solvent.

3. The method of claim 2 , wherein the organic solvent is acetone or ethyl acetate.

4. The method of claim 1 , wherein the aqueous solvent consists of water.

5. The method of claim 4 , wherein the purified glycopyrronium tosylate is in the form of glycopyrronium tosylate monohydrate.

6. The method of claim 1 , wherein in the purified glycopyrronium tosylate of step (b) the threo-glycopyrronium tosylate is at least 99.5% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 0.5% of the total glycopyrronium tosylate in the mixture.

7. The method of claim 1 , wherein in the purified glycopyrronium tosylate of step (b) the threo-glycopyrronium tosylate is at least 99.6% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 0.4% of the total glycopyrronium tosylate in the mixture.

8. The method of claim 1 , wherein the glycopyrrolate base is produced by contacting a glycopyrrolate base, 5-nitroisophthalate salt with an inorganic base to form the glycopyrrolate base:

9. The method of claim 8 , wherein the glycopyrrolate base, 5-nitroisophthalate salt and inorganic base are contacted with an organic solvent.

10. The method of claim 9 , wherein the organic solvent is toluene.

11. The method of claim 8 , wherein the inorganic base is aqueous sodium hydroxide.

12. The method of claim 8 , wherein the glycopyrrolate base is produced as a mixture of threo-glycopyrrolate base and erythro-glycopyrrolate base, and the threo-glycopyrrolate base is at least 95% of the total glycopyrrolate base produced and the erythro-glycopyrrolate base is less than 5% of the total glycopyrrolate base produced.

13. The method of claim 12 , wherein the threo-glycopyrrolate base is at least 96% of the total glycopyrrolate base produced and the erythro-glycopyrrolate base is less than 4% of the total glycopyrrolate base produced.

14. The method of claim 12 , wherein the threo-glycopyrrolate base is at least 97% of the total glycopyrrolate base produced and the erythro-glycopyrrolate base is less than 3% of the total glycopyrrolate base produced.

15. The method of claim 8 , wherein the glycopyrrolate base, 5-nitroisophthalate salt is produced by contacting a glycopyrrolate base with 5-nitroisophthalic acid to form the glycopyrrolate base, 5-nitroisophthalate salt:

16. The method of claim 15 , wherein the glycopyrrolate base and 5-nitroisophthalic acid are contacted with methanol.

17. The method of claim 2 , wherein the organic solvent is ethyl acetate.

18. The method of claim 1 , wherein the level of total impurity is not more than 0.15%.

19. A method of producing glycopyrronium tosylate comprising:

(i) contacting cyclopentylmandelic acid with 1-methylpyrrolidin-3-ol to form glycopyrrolate base:

(ii) contacting the glycopyrrolate base with 5-nitroisophthalic acid to form glycopyrrolate base, 5-nitroisophthalate salt:

(iii) contacting the glycopyrrolate base, 5-nitroisophthalate salt with an inorganic base to form glycopyrrolate base:

(iv) contacting the glycopyrrolate base with methyl tosylate to produce glycopyrronium tosylate:

and

(v) purifying the glycopyrronium tosylate obtained in step (iv) by one or more crystallizations in an aqueous solvent to obtain a purified glycopyrronium tosylate; wherein the aqueous solvent consists essentially of water.

20. The method of claim 19 , wherein the aqueous solvent in step (v) consists of water.

21. The method of claim 1 , wherein the step (b) is purifying the glycopyrronium tosylate obtained in step (a) by at least two crystallizations in the aqueous solvent to obtain a purified glycopyrronium tosylate;

wherein the purified glycopyrronium tosylate is a mixture of threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate, and the threo-glycopyrronium tosylate is at least 99.6% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 0.4% of the total glycopyrronium tosylate in the mixture.

22. The method of claim 1 , wherein the step (b) is purifying the glycopyrronium tosylate obtained in step (a) by at least two crystallizations in the aqueous solvent to obtain a purified glycopyrronium tosylate; wherein the aqueous solvent consists of water;

wherein the purified glycopyrronium tosylate is a mixture of threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate, and the threo-glycopyrronium tosylate is at least 99.6% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 0.4% of the total glycopyrronium tosylate in the mixture.

23. The method of claim 19 , wherein the step (v) is purifying the glycopyrronium tosylate obtained in step (iv) by at least two crystallizations in the aqueous solvent to obtain a purified glycopyrronium tosylate;

wherein the purified glycopyrronium tosylate is a mixture of threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate, and the threo-glycopyrronium tosylate is at least 99.6% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 0.4% of the total glycopyrronium tosylate in the mixture.

24. The method of claim 19 , wherein the step (v) is purifying the glycopyrronium tosylate obtained in step (iv) by at least two crystallizations in the aqueous solvent to obtain a purified glycopyrronium tosylate; wherein the aqueous solvent consists of water;

wherein the purified glycopyrronium tosylate is a mixture of threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate, and the threo-glycopyrronium tosylate is at least 99.6% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 0.4% of the total glycopyrronium tosylate in the mixture.

25. A method of producing glycopyrronium tosylate comprising:

(i) contacting glycopyrrolate base with 5-nitroisophthalic acid to form a glycopyrrolate base, 5-nitroisophthalate salt:

(ii) contacting the glycopyrrolate base, 5-nitroisophthalate salt with an inorganic base to form glycopyrrolate base:

wherein the glycopyrrolate base is a mixture of threo-glycopyrrolate base and erythro-glycopyrrolate base, and the threo-glycopyrrolate base is 95% to 97% of the total glycopyrrolate base produced and the erythro-glycopyrrolate base is 5% to 3% of the total glycopyrrolate base produced;

(iii) contacting the glycopyrrolate base with methyl tosylate to produce glycopyrronium tosylate:

wherein the glycopyrronium tosylate is a mixture of threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate, wherein the threo-glycopyrronium tosylate is 95% to 97% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is 5% to 3% of the total glycopyrronium tosylate in the mixture; and

(iv) purifying the glycopyrronium tosylate in step (iii) by one or more crystallizations in an aqueous solvent to obtain a purified glycopyrronium tosylate;

wherein the purified glycopyrronium tosylate is a mixture of threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate, wherein the threo-glycopyrronium tosylate is at least 99% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 1% of the total glycopyrronium tosylate in the mixture.

26. The method of claim 25 , wherein in the purified glycopyrronium tosylate of step (iv) the threo-glycopyrronium tosylate is at least 99.5% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 0.5% of the total glycopyrronium tosylate in the mixture.

27. The method of claim 25 , wherein in the purified glycopyrronium tosylate of step (iv) the threo-glycopyrronium tosylate is at least 99.6% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 0.4% of the total glycopyrronium tosylate in the mixture.

28. The method of claim 1 , wherein in the purified glycopyrronium tosylate of step (b) the threo-glycopyrronium tosylate is at least 99% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 1% of the total glycopyrronium tosylate in the mixture.

29. The method of claim 19 , wherein in the purified glycopyrronium tosylate of step (v) the threo-glycopyrronium tosylate is at least 99% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 1% of the total glycopyrronium tosylate in the mixture.