Salts of treprostinil

Patent metadata

Field	Value
Publication number	US-9988334-B2
Application number	US-201715614801-A
Country	US
Kind code	B2
Filing date	Jun 6, 2017
Priority date	Mar 15, 2013
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

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 benzindene triol with an alkylating reagent to form an intermediate selected from a nitrile intermediate and an ester intermediate;
b) hydrolyzing the intermediate with a base or a base salt to form a treprostinil salt; and
c) isolating and crystallizing the treprostinil salt, wherein a solvent in each of steps a), b) and c) is the same.

2. The method of claim 1 , wherein the alkylating agent is

wherein X is Cl, Br or I and R is CN or COOR′, wherein R′ is an alkyl group or a substituted or unsubstituted benzyl group.

3. The method of claim 2 , wherein the intermediate is a nitrile intermediate and R is CN.

4. The method of claim 2 , wherein the intermediate is an ester intermediate having the following formula:

and R is COOR′.

5. The method of claim 4 , wherein R′ is a (C 1 -C 6 )alkyl.

6. The method of claim 4 , wherein R′ is unsubstituted benzyl.

7. The method of claim 4 , 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.

8. 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.

9. The method of claim 8 , wherein said hydrolyzing is performed with a hydroxide of a Group IA or Group IIA metal.

10. The method of claim 9 , wherein said hydrolyzing is performed with a hydroxide of K, Ca, Mg, Ba, Cs, Li or Na.

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

12. The method of claim 11 , wherein the carbonate basic salt is lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate or ammonium carbonate.

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

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

15. The method of claim 1 , wherein the solvent in each of steps a), b) and c) is selected from the group consisting of ethanol, isopropyl alcohol, methanol, acetone, ethyl acetate, hexanes, heptanes, isopropyl acetate and combinations thereof.

Assignees

• United Therapeutics Corp

Inventors

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

Classifications

• C07C59/72

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

• 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

• A61K31/19

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

• A61P9/12 Primary

  Antihypertensives · CPC title