METHOD FOR THE PRODUCTION OF OXAZOLES BY CONDENSING AROMATIC ALDEHYDES WITH a-KETOXIMES TO N-OXIDES AND THEN REACTING THE SAME WITH ACTIVATED ACID DERIVATIVES

• US 20090286988A1
• Filed: 07/27/2009
• Published: 11/19/2009
• Est. Priority Date: 12/15/2004
• Status: Active Grant

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Inventors: SCHEFFER, Robert J. H., HOLLA, Wolfgang, HOERLEIN, Rolf-Ludwig, LAUX, Wolfgang, KULITZSCHER, Berndt, STUEDEMANN, Thomas, TAPPERTZHOFEN, Christoph
• Granted Patent: US 7,825,144 B2
• Time in Patent Office: Days
• US Class Current: 548/225
• 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 invention is related to a process for preparing compounds of the formula IV by means of conversion of aromatic aldehydes of the formula I using α-ketoximes of the formula II via N-oxides of the formula III to halomethyloxazoles of the formula IV,

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X¹, X², X³, o, n1 and n2 are as defined herein.

Claims

1. A compound of formula III,

wherein:

R¹, R² and R³ are each independently 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, wherein the aryl is unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, I, (C1-C4)-alkyl, O—

(C1-C4)-alkyl or CF₃;

R⁹ is H, (C1-C8)-alkyl, Li, Na, K, ½

Mg, ½

Ca, or an ammonium ion which is un-substituted or mono-, di- or trisubstituted by (C1-C4)-alkyl;

R¹⁰ and R¹¹ are each independently H, (C1-C5)-alkyl, phenyl or CH₂-phenyl, 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, wherein one CH₂ group may be replaced by O, S, NH, N—

CH₃ or N-benzyl;

W is CH, or N when o is 1;

W is O, S, or NR12 when o is 0;

o is 0 or 1;

R12 is H, (C1-C6)-alkyl, (C1-C6)-alkylenephenyl, or phenyl;

R⁴ is H, COOR⁹, CONR(10)R(11), (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C3)-alkylene-(C3-C8)-cycloalkyl, phenyl, (C1-C3)-alkylenephenyl, (C5-C6)-heteroaryl, (C1-C3)-alkylene-(C5-C6)-heteroaryl, or (C1-C3)-alkyl, wherein the (C1-C3)-alkyl is fully or partly substituted by F;

R⁵ and R⁶ are each independently H, (C1-C8)-alkyl, F, Cl, Br, I, O—

(C0-C8)-alkylene-H, O—

(C6-C10)-aryl, O—

(C1-C4)-alkylene-(C6-C10)-aryl, COOR⁹, CONR¹⁰R¹¹, SH or NR¹⁰R¹¹, or

R⁵ and R⁶ together are (C4-C5)-alkylene, wherein one CH₂ group may be replaced by O, S, NH, N—

CH₃ or N-benzyl;

R⁷ is H;

n1 is 0, 1, ½

or ⅓

; and

HX¹ is HCl, HBr, H₂SO₄, H₃PO₄, HOOCCF3, HOOCCCl₃, HO₃SCF₃, HO₃SCH₃, HO₃SC₆H₅, HO₃S—

C₆H₄-p-CH₃, or HOOCH.

2. The compound according to claim 1, wherein:

W is CH; and

o is 1.

3. The compound according to claim 1, wherein:

R1 is H.

4. The compound according to claim 1 wherein:

R² is H.

5. The compound according to claim 1, wherein:

R¹, R² and R³ are each independently H, (C1-C6)-alkyl, F, Cl, Br, I, O—

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

(C6-C10)-aryl, O—

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

(C1-C4)-alkyl or CF₃.

6. The compound according to claim 1, wherein:

W is CH;

o is 1;

R¹ is H;

R² is H, CH₃, OCH₃, Br or Cl;

R³ is H, CH₃, OCH₃, Br or Cl;

R⁴ is CH₃, CH₂CH₃ or CH(CH₃)₂;

R⁵ is H, CH₃, CH₂CH₃ or CH(CH₃)₂;

R⁶ is H, CH₃, CH₂CH₃ or CH(CH₃)₂;

HX¹ is HCl, HO₃SCH₃ or HO₃S—

C₆H₄-p-CH₃; and

n1 is 0 or 1.

7. The compound according to claim 1, of formula XI

8. The compound according to claim 1, of formula XIV

9. The compound according to claim 1, of formula XVII