PROCESS FOR THE PREPARATION OF FESOTERODINE WITH LOW IMPURITIES CONTENT

• US 20110152367A1
• Filed: 12/20/2010
• Published: 06/23/2011
• Est. Priority Date: 12/21/2009
• Status: Active Grant

• Current Assignee: Dipharma Francis SrI (Dipharma SPA)
• Original Assignee: Dipharma Francis SrI (Dipharma SPA)
• Inventors: ARTICO, Marco, ALLEGRI, Pietro, ATTOLINO, Emanuele
• Granted Patent: US 8,455,678 B2
• Time in Patent Office: Days
• US Class Current: 514/546
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: C07C 213/06 from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
• CPC Class Codes: C07C 219/28 having amino groups bound to acyclic carbon atoms of the carbon skeleton

Abstract

Disclosed is a process for the preparation of (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-(hydroxymethyl)-phenol isobutyrate (Fesoterodine) or a pharmaceutically acceptable salt thereof having a low content of impurities such as tolterodine and tolterodine isobutyrate.

Claims

1. A process for the preparation of a compound of formula (I), or a salt thereof,

2. A process according to claim 1, wherein in the treatment of a compound of formula (IIa) with sodium hydroxide or potassium hydroxide an amount of sodium or potassium hydroxide, stoichiometric to the compound of formula (IIa) is used.

3. A process according to claim 1, wherein the treatment of a compound of formula (IIa) with sodium or potassium hydroxide is carried out in a solvent selected from a C₃-C₈ ketone, a cyclic or acyclic ether, an ester and a C₁-C₆ straight or branched alkanol.

4. A process according to claim 1 wherein the reduction of the phenate intermediate of formula (X) is carried out in presence of a cyclic ethereal or acyclic ethereal solvent, preferably tetrahydrofuran.

5. A process according to claim 1, wherein the amount of lithium aluminium hydride is at least stoichiometric to the compound of formula (X), preferably comprised between about 1 and 5 moles compared to the moles of the compound of formula (X).

6. A process according to claim 1 for preparing a compound of formula (I) or a salt thereof, such as fumarate, citrate, hydrochloride, or sulphate, comprising the use of a compound of formula (VIII) and/or (IX), as an analytical standard.

9. A mixture comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1, and a compound of formula (VIII), as defined in claim 1, in an amount equal to or lower than about 0.05% and equal to or higher than about 0.0001% and/or an amount of a compound of formula (IX), as defined in claim 1, lower than or equal to about 0.1% and equal to or higher than about 0.0001%.

10. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1, and a compound of formula (VIII), as defined in claim 1, in an amount equal to or lower than about 0.05% and equal to or higher than 0.0001% and/or an amount of a compound of formula (IX), as defined in claim 1, lower than or equal to about 0.1% and equal to or higher than about 0.0001%;

and a pharmaceutically acceptable excipient and/or carrier.

13. A process for the preparation of the (S) enantiomer of a compound of formula (I), as defined in claim 1, or a salt thereof, containing an amount of the (S) enantiomer of a compound of formula (VIII), as defined in claim 1, equal to or lower than 0.05% and typically equal to or higher than about 0.0001% and/or an amount of the (S) enantiomer of the compound of formula (IX), as defined in claim 1, equal to or lower than about 0.1% and typically equal to or higher than about 0.0001%, comprising the chemoselective reduction of the carboxylate group of a compound of formula (IIb),

7. Use of a compound of formula (VIII)

8. Use of a compound of formula (IX)

11. A process for the preparation of a compound of formula (I)

12. A process for the preparation of a compound of formula (I)