Process to prepare treprostinil, the active ingredient in remodulin®

• US 9,593,066 B2
• Filed: 09/10/2015
• Issued: 03/14/2017
• Est. Priority Date: 12/17/2007
• Status: Active Grant

• Current Assignee: United Therapeutics Corporation
• Original Assignee: United Therapeutics Corporation
• Inventors: Batra, Hitesh, Tuladhar, Sudersan M., Penmasta, Raju, Walsh, David A.
• Primary Examiner(s): VALENROD, YEVGENY
• Application Number:
  US14/849,981
• Publication Number:
  US 20150376106A1
• Time in Patent Office: 551 Days
• US Class Current: 1/1
• CPC Class Codes: A01N 37/10 Aromatic or araliphatic carboxylic acids, or thio analogues thereof; Derivatives thereof
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 213/08 by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
• CPC Class Codes: C07C 253/00 Preparation of carboxylic acid nitriles of cyanogen or compounds thereof C01C3/00
• CPC Class Codes: C07C 2603/12 only one five-membered ring
• CPC Class Codes: C07C 39/12 polycyclic with no unsaturation outside the aromatic rings
• CPC Class Codes: C07C 39/17 containing other rings in addition to the six-membered aromatic rings , e.g. cyclohexylphenol
• CPC Class Codes: C07C 405/0075 having the side-chains or their analogues or derivatives attached to a condensed ring system
• CPC Class Codes: C07C 51/08 from nitriles
• CPC Class Codes: C07C 51/41 Preparation of salts of carboxylic acids C07C51/093 - C07C51/34 take precedence preparation of soap C11D
• CPC Class Codes: C07C 51/412 by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
• CPC Class Codes: C07C 59/60 the non-carboxylic part of the ether being unsaturated
• CPC Class Codes: C07C 59/72 : containing six-membered aromatic rings and other rings

Abstract

This present invention relates to an improved process to prepare prostacyclin derivatives. One embodiment provides for an improved process to convert benzindene triol to treprostinil via salts of treprostinil and to purify treprostinil.

Claims

1. A pharmaceutical composition comprising treprostinil or a pharmaceutically acceptable salt thereof, said composition prepared by a process comprising providing a starting batch of treprostinil having one or more impurities resulting from prior alkylation and hydrolysis steps, forming a salt of treprostinil by combining the starting batch and a base, isolating the treprostinil salt, and preparing a pharmaceutical composition comprising treprostinil or a pharmaceutically acceptable salt thereof from the isolated treprostinil salt, whereby a level of one or more impurities found in the starting batch of treprostinil is lower in the pharmaceutical composition, and wherein said alkylation is alkylation of benzindene triol.

2. The pharmaceutical composition of claim 1, wherein the salt is isolated in crystalline form.

3. The pharmaceutical composition of claim 1, wherein the base is selected from the group consisting of sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, N-methylglucamine, and choline.

4. The pharmaceutical composition of claim 3, wherein the base is diethanolamine.

5. The pharmaceutical composition of claim 1, wherein the base is combined with treprostinil that has not been previously isolated.

6. The pharmaceutical composition of claim 1, wherein the isolated salt is stored at ambient temperature.

7. The pharmaceutical composition of claim 1, which is a pharmaceutical solution.

8. A process of preparing a pharmaceutical product comprising treprostinil or a pharmaceutically acceptable salt thereof, comprising alkylating a triol intermediate of the formula:

9. A pharmaceutical product prepared by the process of claim 8.

10. The process as claimed in claim 8, wherein forming the salt of treprostinil stable at ambient temperature is performed by adding diethanolamine to treprostinil.