NOVEL INTERMEDIATE COMPOUNDS USEFUL IN THE PREPARATION OF OXAZOLES AND PHARMACEUTICAL ACTIVES FOR THE REGULATION OF LIPID AND GLUCOSE METABOLISM

• US 20080114035A1
• Filed: 10/30/2007
• Published: 05/15/2008
• Est. Priority Date: 12/15/2004
• Status: Abandoned Application

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Inventors: SCHEFFER, Robert J. H., HOLLA, Wolfgang, HOERLEIN, Rolf-Ludwig, LAUX, Wolfgang, KULITZSCHER, Berndt, STUEDEMANN, Thomas, TAPPERTZHOFEN, Christoph
• Application Number:
  US11/928,117
• Publication Number:
  US 20080114035A1
• Time in Patent Office: Days
• US Class Current: 514/340
• 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 directed to compounds of Formula III

wherein the R1-R7 groups or substituents are defined herein. The present invention also comprises improved methods in the preparation of oxazoles in which the compounds of Formula III are intermediates and 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. The compounds of formula III,

2. The compounds of formula III as recited in claim 1, wherein:

W=CH and

o=1.

3. The compounds of formula III as recited in claim 2, wherein:

R1 is H;

R² is selected from the group consisting of H, (C1-C6)-alkyl, F, Cl, Br, I, O—

(C1-C8)-alkylene-H, CF₃, OCF₃, SCF₃, SC₂F₅, OCF₂—

CHF₂, (C6-C10)-aryl, O—

(C6-C10)-aryl, O—

(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR⁹, CONR¹⁰R¹¹, SH, or NR¹⁰R¹¹, where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—

(C1-C4)-alkyl or CF₃;

wherein

R⁹ is selected from the group consisting of H, Li, Na, K, ½

Mg, ½

Ca, ammonium ions which are un-substituted or mono-, di- or tri-substituted by (C1-C4)-alkyl, or is (C1-C8)-alkyl,

R¹⁰ and R¹¹ are each independently H, (C1-C5)-alkyl, phenyl or CH₂-phenyl, and wherein the phenyl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—

(C1-C4)-alkyl or CF₃;

or

R¹⁰ and R¹¹ together are (C4-C5)-alkylene, in which one CH₂ group may be replaced by O, S, NH, N—

CH₃ or N-benzyl;

R³ is H, (C1-C6)-alkyl, F, Cl, Br, I, O—

(C0-C8)-alkylene-H, CF₃, OCF₃, SCF₃, SC₂F₅, OCF₂—

CHF2, (C6-C10)-aryl, O—

(C6-C10)-aryl, O—

(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR⁹, CONR¹⁰R¹¹, SH, or NR¹⁰R¹¹, where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—

(C1-C4)-alkyl or CF₃;

wherein R⁹, R¹⁰ and R¹¹ are each as defined above.

4. The compounds of formula III as recited in claim 3 wherein:

R1 is H;

R² is H;

R³ is H, (C1-C6)-alkyl, F, Cl, Br, I, O—

(C0-C8)-alkylene-H, CF3, OCF3, SCF3, SF5, OCF2-CHF2, (C6-C10)-aryl, O—

(C6-C10)-aryl, O—

(C1-C4)-alkylene-(C6-C10)-aryl, NO2, COOR⁹, CONR¹⁰R¹¹, SH, or NR¹⁰R¹¹, where aryl is un-substituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—

(C1-C4)-alkyl or CF3;

wherein

R⁹ is H, Li, Na, K, ½

Mg, ½

Ca, ammonium ions which are un-substituted or mono-, di- or tri-substituted by (C1-C4)-alkyl, or is (C1-C8)-alkyl,

R¹⁰ and R¹¹ are each independently selected from the group consisting of H, (C1-C5)-alkyl, phenyl or CH₂-phenyl,

wherein phenyl is un-substituted or mono-, di- or tri-substituted by F, Cl, Br, I, (C1-C4)-alkyl, O—

(C1-C4)-alkyl or CF3;

or

R¹⁰ and R¹¹ together form a (C4-C5)-alkylene, in which one CH₂ group may be replaced by O, S, NH, N—

CH₃ or N-benzyl.

5. The compounds of formula III as recited in claim 4, 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.

7. A process for the preparation of compounds of formula III as recited in claim 1, wherein the reaction temperature for the formation of the N-oxides as depicted by formula III from the reaction of compounds of formulae I and II is between about −

20°

C. and +150°

C.

8. The process for the preparation of compounds of formula III as recited in claim 7, wherein the reaction for the formation of the N-oxides as depicted by formula III is carried out in protic, polar, aprotic non-polar solvents or mixtures thereof.

9. The process for the preparation of compounds of the formula III as recited in claim 8, wherein the reaction temperature for the formation of the halomethyloxazoles as depicted by formula IV from compounds of the formula III is from about −

20°

C. to +150°

C.

10. The process for the preparation of compounds of formula III as recited in claim 8 wherein one or more of the compounds of formula I and II are used in the preparation thereof.

6. The compounds of formula III

11. The compound of formula XI.

12. The compound of formula XIV

13. The compound of formula XVII