Process for preparing intermediates to 5-HT4 receptor agonist compounds

• US 7,671,198 B2
• Filed: 02/15/2007
• Issued: 03/02/2010
• Est. Priority Date: 02/16/2006
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Genov, Daniel, Liu, Jyanwei, Lee, Junning
• Primary Examiner(s): Wilson; James O
• Assistant Examiner(s): JARRELL, NOBLE E
• Application Number:
  US11/706,732
• Publication Number:
  US 20070191355A1
• Time in Patent Office: 1,111 Days
• Field of Search: None
• US Class Current: 544/56
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 451/04 with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
• CPC Class Codes: C07D 451/06 Oxygen atoms
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides 8-azabicyclo[3.2.1 ]octyl intermediates useful for the preparation of 5-HT₄ receptor agonist compounds. The invention also provides processes for the preparation of such useful intermediates.

Claims

1. A compound of formula (Ib):

2. The compound of claim 1 wherein n is 0 and R¹ is hydrogen.

3. The compound of claim 1 wherein n is 1 and R¹ is —

OH or —

OP¹.

4. The compound of claim 1 wherein A is a covalent bond.

5. The compound of claim 1 wherein W is a moiety of formula (a).

6. The compound of claim 5 wherein Z is selected from NC(O)R⁴, NS(O)₂R⁶, and S(O)₂ and R⁴ and R⁶ are each methyl.

7. The compound of claim 5 wherein Z is NH.

8. The compound of claim 1 wherein W is —

N(R³)C(O)R⁴, or —

N(R⁵)S(O)₂R⁶.

9. A process for preparing a compound of formula (Ib) or a salt thereof:

10. The process of claim 9 wherein the buffering agent is present in an amount sufficient to maintain the pH of the reaction mixture between 4 and 6.

11. A process for preparing a compound of formula (Ia) or a salt thereof:

12. The process of claim 11 wherein the process comprises step (a).

13. The process of claim 12, wherein the product of formula (Ia) has an endo to exo ratio of greater than 99:

1.