PROCESS FOR MANUFACTURING 3(R)-(2-HYDROXY-2,2-DITHIEN-2-YLACETOXY)-1-(3-PHENOXYPROPYL)-1-AZONIABICYCLO[2.2.2]OCTANE BROMIDE

• US 20090299042A1
• Filed: 07/16/2007
• Published: 12/03/2009
• Est. Priority Date: 07/21/2006
• Status: Active Grant

• Current Assignee: Almirall, S.A. (Grupo Corporativo Landon SL)
• Original Assignee: Almirall, S.A. (Grupo Corporativo Landon SL)
• Inventors: Lorenzo, Francesca Pajuelo, Busquets Baque, Nuria
• Granted Patent: US 8,044,205 B2
• Time in Patent Office: Days
• US Class Current: 534/838
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems

Abstract

This present disclosure relates to a process for manufacturing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide by reacting 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)yl ester and 3-phenoxypropyl bromide, wherein the reaction takes place in a solvent or mixtures of solvents having a boiling point from 50° C. to 210° C. and chosen from ketones and cyclic ethers.

Claims

1. A process for manufacturing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide comprising reacting 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)yl ester and 3-phenoxypropyl bromide, wherein the reaction takes place in a solvent or mixtures of solvents having a boiling point from 50°

C. to 210°

C., and chosen from ketones and cyclic ethers.

2. A process according to claim 1, wherein the equivalent ratio of 3-phenoxypropyl bromide to 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)yl ester is in the range from 1.0 to 3.0.

3. A process according to claim 2 wherein the equivalent ratio is in the range from 1.1 to 1.5.

4. A process according to claim 2, wherein the equivalent ratio is in the range from 1.2 to 1.3.

5. A process according to claim 1, wherein 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)yl ester is suspended or dissolved in a volume of solvent or solvent mixture comprising from 1.7 to 7 liters of solvent(s) per mol of 2-hydroxy-2,2-dithien-2-ylacetic acid 1 -azabicyclo[2.2.2]oct-3(R)yl ester.

6. A process according to claim 5, wherein the volume of solvent comprises from 2 to 4 liters per mol of 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)yl ester.

7. A process according to claim 1, wherein the solvent is chosen from acetone, dioxane and tetrahydrofurane.

8. A process according to claim 7, wherein the solvent is tetrahydrofurane.

9. A process according to claim 1, wherein the mixture is allowed to react for a time period not exceeding 24 hours.

10. A process according to claim 9, wherein the time period is not more than 12 hours.

11. A process according to claim 10, wherein the time period is not more than 9 hours.

12. A process according to claim 11, wherein the time period is not more than 6 hours.