Method for the preparation of oxazoles by condensing aromatic aldehydes with α-ketoximes to form n-oxides and reacting same with activated acid derivatives

• US 7,544,809 B2
• Filed: 05/29/2007
• Issued: 06/09/2009
• Est. Priority Date: 12/15/2004
• Status: Active Grant

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Inventors: Laux, Wolfgang, Hoerlein, Rolf-Ludwig, Scheffer, Robert J. H., Tappertzhofen, Christoph, Holla, Wolfgang, Stuedemann, Thomas, Kulitzscher, Berndt
• Primary Examiner(s): Anderson; Rebecca L
• Assistant Examiner(s): NOLAN, JASON MICHAEL
• Application Number:
  US11/754,477
• Publication Number:
  US 20080058529A1
• Time in Patent Office: 742 Days
• Field of Search: 548/235
• US Class Current: 548/235
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: C07D 263/32 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

The present invention is comprised of improved methods in the preparation of oxazoles which results in higher yields with less impurities and contaminants. Oxazoles constitute valuable intermediates in the synthesis of pharmaceutically active substances such as, for example peroxisome proliferator activated receptor (PPAR) agonists which are pharmaceutical actives which can have a positive influence on both lipid and glucose metabolism.

Claims

1. A process for preparing a compounds of formula IV,

2. The process according to claim 1, wherein:

W=CH and

o=1.

3. The process according to claim 2, wherein:

R¹ is H.

4. The process according to claim 3 wherein:

R² is H.

5. The process according to claim 1, wherein:

W=CH;

o=1;

R¹=H;

R²=H, CH₃, OCH₃, Br or Cl;

R³=H, CH₃, OCH₃, Br or Cl;

R⁴=CH₃, CH₂CH₃ or CH(CH₃)₂;

R⁵=H, CH₃, CH₂CH₃ or CH(CH₃)₂;

R⁶=H, CH₃, CH₂CH₃ or CH(CH₃)₂;

X³=Cl, CH₃SO₃ or p-CH₃—

C₆H₄—

SO₃ and

n2=0 or 1.

6. The process according to claim 1, wherein the compound of formula IV is a compound of formula VIII

7. The process according to claim 6, wherein the reaction temperature for forming the N-oxides of formula III by the reaction of compounds of formulae I and II is between about −

20°

C. and +150°

C.

8. The process according to claim 7, wherein the reaction for forming the N-oxides of formula III is carried out in aprotic, polar, or aprotic nonpolar solvent or a mixture thereof.

9. The process according to claim 6, wherein the reaction temperature for forming the compound of formula IV from the compound of formula III is from about −

20°

C. to +150°

C.

10. The process according to claim 9, wherein the reaction for forming the compound of formula IV is carried out in an aprotic dipolar, aprotic polar or aprotic non-polar solvent or a mixture thereof.

11. The process according to claim 10, wherein the compound of the formula R⁸X² is used in an amount of from about a 1 to 4-fold excess based on the amount of the N-oxide of formula III.