Processes for the preparation of 3,5-disubstituted-1,2,4-oxadiazoles

Patent metadata

Field	Value
Publication number	US-9040711-B2
Application number	US-201313933616-A
Country	US
Kind code	B2
Filing date	Jul 2, 2013
Priority date	Jul 2, 2012
Publication date	May 26, 2015
Grant date	May 26, 2015

Abstract

Provided herein are processes for the preparation of 3,5-disubstituted-1,2,4-oxadiazoles and salts thereof comprising reacting a N-hydroxyamidine with an acyl chloride in a reaction mixture comprising a water-immiscible organic solvent and an aqueous base at relatively low reaction temperatures.

First claim

What is claimed is:

1. A process for preparing a 3,5-disubstituted 1,2,4-oxadiazole of Formula (Ia) or (Ib), or a salt thereof,

the process comprising reacting an N-hydroxyamidine of Formula (IIa) or (IIb), respectively, or a tautomeric form thereof,

with an acyl chloride of Formula (IIIa) or (IIIb), respectively,

in a reaction mixture comprising an organic phase and an aqueous phase,
wherein the reaction mixture comprises a water-immiscible organic solvent and an aqueous base,
wherein the temperature of the reaction mixture is no greater than about 85° C.;
and wherein Ar 1 is selected from the group consisting of phenyl, pyridyl, pyrazyl, oxazolyl or isoxazolyl, each of which can be optionally independently substituted with one or more substituents selected from the group consisting of halogen, CF 3 , CH 3 , OCF 3 , OCH 3 , CN and C(H)O; and
Ar 2 is selected from the group consisting of is thienyl, furanyl, oxazolyl or isoxazolyl, each of which can be optionally independently substituted with one or more substituents selected from the group consisting of fluorine, chlorine, CH 3 , and OCF 3 .

2. The process of claim 1 wherein the process comprises reacting an N-hydroxyamidine of Formula (IIa), or a tautomeric form thereof, with an acyl chloride of Formula (IIIa) to form a 3,5-disubstituted 1,2,4-oxadiazole of Formula (Ia), or a salt thereof.

3. The process of claim 1 wherein the process comprises reacting an N-hydroxyamidine of Formula (IIb), or a tautomeric form thereof, with an acyl chloride of Formula (IIb) to form a 3,5-disubstituted 1,2,4-oxadiazole of Formula (Ib), or a salt thereof.

4. The process of claim 1 wherein the reaction mixture further comprises a phase transfer catalyst.

5. The process of claim 4 wherein the phase transfer catalyst is selected from the group consisting of quaternary ammonium salts, phosphonium salts, and crown ethers.

6. The process of claim 4 wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium hydroxide, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylphosphonium bromide, tetrabutylphosphonium chloride, and benzyltrimethylammonium hydroxide.

7. The process of claim 6 wherein the phase transfer catalyst is tetrabutylammonium hydroxide.

8. The process of claim 1 wherein the water-immiscible organic solvent solubilizes the N-hydroxyamidine and the 3,5-disubstituted-1,2,4-oxadiazole.

9. The process claim 1 wherein the water-immiscible organic solvent forms an azeotrope with water.

10. The process of claim 1 wherein the water-immiscible organic solvent is selected from the group consisting of 2-methyltetrahydrofuran and butyl acetate.

11. The process of claim 10 wherein the water-immiscible organic solvent is 2-methyltetrahydrofuran.

12. The process of claim 1 wherein the aqueous base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide.

13. The process of claim 12 wherein the aqueous base is selected from the group consisting of sodium hydroxide and potassium hydroxide.

14. The process of claim 1 wherein the pH of the aqueous phase is greater than about 8.

15. The process of claim 1 wherein the pH of the aqueous phase is greater than about 10.

16. The process of claim 1 wherein the pH of the aqueous phase is increased or maintained by adding additional aqueous base to the reaction mixture.

17. The process of claim 1 wherein the temperature of the reaction mixture is maintained at from about 55° C. to about 75° C.

18. The process of claim 1 wherein the N-hydroxyamidine is dissolved in the water-immiscible organic solvent prior to adding the acyl chloride to form the reaction mixture.

19. The process of claim 1 further comprising recovering the 3,5-disubstituted-1,2,4-oxadiazole from the reaction mixture as a precipitate from an aqueous layer after removal of at least a portion of the water-immiscible organic solvent from the reaction mixture.

20. The process of claim 19 further comprising adding a surfactant to the reaction mixture.

21. The process of claim 20 wherein the surfactant added to the reaction mixture stabilizes droplets of the 3,5-disubstituted-1,2,4-oxadiazole in an aqueous layer and allows the droplets to solidify without coalescing into larger droplets.

22. The process of claim 20 wherein the surfactant is added to the reaction mixture prior to removal of at least a portion of the water-immiscible organic solvent from the reaction mixture.

23. The process of claim 20 wherein the surfactant is added to the reaction mixture after the reaction is substantially complete.

24. The process of claim 20 wherein the surfactant is selected from the group consisting of anionic or nonionic dispersants, anionic or nonionic detergents, anionic or nonionic surfactants, and combinations thereof.

25. The process of claim 1 wherein the reaction of the N-hydroxyamidine and the acyl chloride produces an oxime ester intermediate of Formula (IVa) or (IVb), a salt thereof, or a tautomeric form thereof,

wherein Ar 1 and Ar 2 are defined as in claim 1 .

26. The process of claim 25 wherein the water-immiscible organic solvent solubilizes the N-hydroxyamidine, the oxime ester intermediate, and the 3,5-disubstituted 1,2,4-oxadiazole.

27. The process of claim 25 wherein the oxime ester intermediate is isolated prior to formation of the 3,5-disubstituted 1,2,4-oxadiazole.

28. The process of claim 1 wherein the N-hydroxyamidine is a benzamide oxime formed by reacting a substituted or unsubstituted benzonitrile and hydroxylamine hydrochloride in an alcoholic solvent with sodium hydroxide and the benzamide oxime is separated from the alcohol solvent and subsequently dissolved in a solvent selected from the group consisting of 2-methyltetrahydrofuran and butyl acetate.

29. The process of claim 1 wherein the N-hydroxyamidine is a benzamide oxime formed by reacting a substituted or unsubstituted benzonitrile and hydroxylamine and the formed benzamide oxime is dissolved in a solvent selected from the group consisting of 2-methyltetrahydrofuran and butyl acetate.

30. The process of claim 29 wherein the reaction to form the benzamide oxime is carried out at a temperature of from about 20° C. to about 65° C.

31. The process of claim 1 wherein the N-hydroxyamidine is a benzamide oxime formed by combining and reacting a substituted or unsubstituted benzonitrile and aqueous hydroxylamine.

32. The process of claim 31 wherein the substituted or unsubstituted benzonitrile and aqueous hydroxylamine are combined and reacted in the absence of a water-immiscible organic solvent.

33. The process of claim 31 wherein the substituted or unsubstituted benzonitrile and aqueous hydroxylamine are combined and reacted in a water-immiscible organic so

Assignees

• Monsanto Technology Llc

Inventors

• Miller William Harold
• Graham Charles Richard
• Brown David Louis

Classifications

• C07D413/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D271/06

  1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles · CPC title