# US 10,478,410 B2 · Process to prepare treprostinil, the active ingredient in Remodulin®

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- Number: US 10,478,410 B2
- Document ID: US10478410B2
- Status: Granted
- Kind: B2
- Application number: 15/423,011
- Filed: 2017-02-02
- Published: 2017-05-25
- Granted: 2019-11-19
- Earliest claimed: 2007-12-17
- Assignees: United Therapeutics Corporation
- Applicants: United Therapeutics Corporation
- Inventors: Hitesh Batra; Sudersan M. Tuladhar; Raju Penmasta; David A. Walsh
- Web page: https://patentgrep.com/patent/US10478410B2

## CPC

- C07C 405/00: Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins {; Analogues or derivatives thereof}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 35/00: Antineoplastic agents
- C07C 51/08: from nitriles
- C07C 51/41: Preparation of salts of carboxylic acids ({C07C51/093 - C07C51/34 take precedence} preparation of soap C11D)
- C07C 51/412: {by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part}
- C07C 59/72: containing six-membered aromatic rings and other rings
- C07C 213/08: by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
- C07C 253/00: Preparation of carboxylic acid nitriles (of cyanogen or compounds thereof C01C3/00)
- C07C 405/0075: {having the side-chains or their analogues or derivatives attached to a condensed ring system}
- A01N 37/10: Aromatic or araliphatic carboxylic acids, or thio analogues thereof; Derivatives thereof
- C07C 39/12: polycyclic with no unsaturation outside the aromatic rings
- C07C 39/17: containing other rings in addition to the six-membered aromatic rings {, e.g. cyclohexylphenol}
- C07C 59/60: the non-carboxylic part of the ether being unsaturated
- C07C 2603/12: only one five-membered ring
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS

## 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

### Claim 1

A method of preparing a pharmaceutical batch of a salt of treprostinil that can be stored as a stable compound at ambient temperature, said pharmaceutical batch being at least 2.9 grams, the method comprising (a) alkylating a benzindene triol, (b) hydrolyzing the product of step (a) to form a solution comprising treprostinil, (c) contacting the solution comprising treprostinil from step (b) with a base to form a salt of treprostinil, wherein forming the salt of step (c) reduces the amount of one or more impurities resulting from steps (a) and/or (b) in the pharmaceutical batch.

### Claim 2 (depends on 1)

A method as claimed in claim 1, wherein the salt of treprostinil is a diethanolamine salt.

### Claim 3 (depends on 1)

A method as claimed in claim 1, wherein no purification by column chromatography is performed between steps (a) and (b).