Salts of treprostinil

Patent metadata

Field	Value
Publication number	US-9701611-B2
Application number	US-201615359941-A
Country	US
Kind code	B2
Filing date	Nov 23, 2016
Priority date	Mar 15, 2013
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

Abstract

Provided are novel treprostinil salts as well as methods for making treprostinil salts.

First claim

What is claimed is:

1. A method of synthesizing a treprostinil salt comprising:
a) alkylating a compound of formula (1)

with an alkylating agent having the following formula:

to form a compound of formula (2)

wherein X is Cl, Br or I, R is COOR′ and R′ is an alkyl group or substituted or unsubstituted benzyl; and
b) hydrolyzing the compound of formula (2) with a hydroxide or a basic salt to form a treprostinil salt, wherein R 1 and R 2 are each H.

2. The method of claim 1 , wherein R′ is a (C1-C6)alkyl.

3. The method of claim 1 , wherein R′ is unsubstituted benzyl.

4. The method of claim 1 , wherein R′ is benzyl substituted at one or more meta, ortho or para positions with one or more substituents selected from the group consisting of —NO 2 , —CN, halogen, (C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkoxy and halo(C1-C3)alkoxy.

5. The method of claim 1 , wherein said hydrolyzing is performed with a hydroxide selected from the group consisting of ammonia hydroxide and a metal hydroxide.

6. The method of claim 5 , wherein said hydrolyzing is performed with a hydroxide of a Group IA or Group IIA metal.

7. The method of claim 5 , wherein said hydrolyzing is performed with a hydroxide of K, Ca, Mg, Ba, Cs, Li or Na.

8. The method of claim 1 , wherein said hydrolyzing is performed with a carbonate basic salt.

9. The method of claim 8 , wherein the carbonate basic salt is lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate or ammonium carbonate.

10. The method of claim 1 , wherein said alkylating is performed in a polar aprotic solvent.

11. The method of claim 1 , wherein said alkylating is performed in the presence of a base or a base salt.

12. The method of claim 1 , wherein said alkylating is performed in the presence of an alkylating catalyst.

13. The method of claim 12 , wherein the alkylating catalyst is tetrabutyl ammonium bromide, potassium iodide or sodium iodide.

14. The method of claim 1 , further comprising isolating and/or crystallizing the treprostinil salt.

15. The method of claim 14 , wherein a solvent for said isolating and/or crystallizing is the same as a solvent for said hydrolyzing.

16. A method of synthesizing a salt of treprostinil comprising:
a) alkylating a compound of formula (1)

with an alkylating agent having the following formula:

to form a compound of formula (2)

wherein X is Cl, Br or I, R is COOR′ and R′ is substituted or unsubstituted benzyl; and
b) hydrogenalizing the compound of formula (2) to form treprostinil; and
c) reacting the treprostinil with a base or a base salt to form a treprostinil salt, wherein each of R 1 and R 2 is H.

17. The method of claim 16 , wherein R′ is unsubstituted benzyl.

18. The method of claim 16 , wherein R′ is benzyl substituted at one or more meta, ortho or para positions with one or more substituents selected from the group consisting of —NO 2 , —CN, halogen, (C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkoxy and halo(C1-C3)alkoxy.

19. The method of claim 16 , wherein said reacting comprises reacting the treprostinil with ammonia hydroxide or a metal hydroxide.

20. The method of claim 19 , wherein said reacting comprises reacting the treprostinil with a hydroxide of Group IA or Group IIA metal.

21. The method of claim 19 , wherein said reacting comprises reacting the treprostinil with a hydroxide of K, Ca, Mg, Ba, Cs, Li or Na.

22. The method of claim 16 , wherein said reacting comprises reacting the treprostinil with a carbonate.

23. The method of claim 22 , wherein the carbonate is lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate or ammonium carbonate.

24. The method of claim 16 , wherein said alkylating is performed in a polar aprotic solvent.

25. The method of claim 16 , wherein said alkylating is performed in the presence of a base or a base salt.

26. The method of claim 16 , wherein said alkylating is performed in the presence of an alkylating catalyst.

27. The method of claim 26 , wherein the alkylating catalyst is tetrabutyl ammonium bromide, potassium iodide or sodium iodide.

28. The method of claim 16 , wherein said hydrogenalizing comprises forming a raw mixture comprising the treprostinil and wherein said reacting comprises treating the raw mixture with the base or the base salt.

29. The method of claim 16 , further comprising isolating the treprostinil formed in said hydrogenalizing before said reacting.

30. The method of claim 29 , wherein said isolating comprises forming solid treprostinil by filtering and evaporating a raw mixture formed in said hydrogenalizing.

31. The method of claim 16 , further comprising isolating and/or crystallizing the treprostinil salt.

32. The method of claim 31 , wherein a solvent for said isolating and/or crystallizing is the same as a solvent for said hydrolyzing.

33. The method of claim 32 , wherein the solvent for said isolating and/or crystallizing comprises an organic solvent selected from ethanol, isopropyl alcohol, methanol, acetone, ethyl acetate, hexanes, heptanes, isopropyl acetate, and mixtures thereof.

34. The method of claim 33 , wherein the solvent for said isolating and/or crystallizing comprises ethanol.

35. The method of claim 16 , further comprising converting the treprostinil salt to treprostinil as free acid.

36. The method of claim 35 , further comprising converting the treprostinil as free acid formed from the treprostinil salt into a treprostinil salt.

37. The method of claim 1 , further comprising converting the treprostinil salt to treprostinil as free acid.

38. The method of claim 37 , further comprising converting the treprostinil as free acid formed from the treprostinil salt into a treprostinil salt.

Assignees

• United Therapeutics Corp

Inventors

• Batra Hitesh
• Sharma Vijay
• Yang Sanmin
• Zhang Yi

Classifications

• C07C51/41 Primary

  Preparation of salts of carboxylic acids ({C07C51/093 - C07C51/34 take precedence} preparation of soap C11D) · CPC title

• C07C51/412

  by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part · CPC title

• C07C59/72

  containing six-membered aromatic rings and other rings · CPC title

• A61K31/19

  Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60) · CPC title

• A61P9/12 Primary

  Antihypertensives · CPC title